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ISSN 2364-2351 | A 60711 |

Life Sciences and Industry Magazine Autumn Edition 2018 | Volume 17 | 20 €

Interview Novozymes’s New Business Development Head Sebastian Søderberg on the value of open innovation.

T cell therapies

CARs crash cancer Modern breeding How the ECJ ruling on genome editing thwarts organic farming

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DNA synthesis

Can a new enzyme approach help solve global problems?

Photosynthesis

CROs & CDMOs

Engineers converge on the Holy Grail of energy production

New technologies that trigger pharma outsourcing growth

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Shimadzu_Euro-Bio-Tech_2018:00 09.05.18 10:14 Seite 1

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C2MAP-2000 – Complete LCMS solution

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

INTRO

3

Turning cancer into a “chronic” disease Following last year’s approval by the US FDA, the EU’s EMA has now also approved the first two T-cell-based immunotherapies against certain types of cancer. This marks the ultimate proof-ofconcept for the acceptance of patient-individualised cellular immunotherapies. The regulatory authorities have moved fast, together with the companies and manufacturers, to bring these products to patients as quickly as possible. This is a good start – but what does the future hold?

PROF. DR. DOLORES J SCHENDEL is CEO of Medigene AG. From 1998–2013, Prof. Schendel was Director of the Institute of Molecular Immunology of the German Research Center for Environmental Health at the Helmholtz Center in Munich. Previous to this, she served as a university professor for immunology at the LudwigMaximilian-University, focusing on human cellular immunology and T cell responses within the field of oncology. Prof. Schendel is the author of more than 200 scientific publications.

Initially, prices for such cellular therapies have been set at high levels, mainly due to the individualised nature of the manufacturing processes, but we can anticipate that robotics and automation will play a decisive role in the manufacturing of these products over the next five to ten years. Even more, if production sites are located at nearby hospitals where patients are being treated, this should have a positive effect on reducing the enormous logistic infrastructures that are needed today to deliver these therapies to patients in need. Furthermore, it may become possible to treat patients with fewer but more potent cells, reducing time and costs in cellular manufacturing. Taken together, those improvements have the potential to substantially reduce treatment costs over the years to come.

Beyond manufacturing and delivery costs, possible severe side effects are still a major concern in T cell immunotherapy. We see a lot of research ongoing to find ways to gain better control over T cell activity – for example, by using inducible T cell receptors that can be turned on and off in patients’ T cells as needed. The immunotherapy field shows tremendous growth, and we can anticipate innovation will expand at a rapidly growing pace. Today’s first-generation products will be subject to fast evolution. One important consideration is how long a particular product will remain on the market. Also especially challenging from a researcher’s point of view is how to optimize T cell therapies for solid tumor indications, where one must ensure that T cells can enter the tumor micro-environment, maintain their functions, and tackle the hostile setting that tumors create for the immune system.

Picture: Medigene AG

Generally speaking, big pharma and big biotech recognise more and more that this is an arena they want to play in, and some are probably already looking for means to acquire expertise and know-how, as well as products and technologies from existing companies. Thus, we will also see many collaborations and probably more acquisitions over the next years.

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Most importantly, from a patient and medical point of view, cell therapy is on its way to further revolutionize cancer treatment and become a standard treatment option by  turning cancer more into a “chronic,” if not curable, disease.

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Contents

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Cover Story

Insight Europe 6 European Court of Justice trashes European ambitions in modern crop-breeding methods 11 Innovative Medicines Initiative fosters antibiotics research amidst Big pharma pullbacks; EPO increases assets on cost of quality; European Commission greenlights five genetically modified crops for market

Financial Markets

Development, Incubation & Acquisitions, Novo­zymes

46 Partnering deluxe at BIO-Europe

Regional News 74 Northern Europe 76 Western Europe 78 Central Europe 80 Southern Europe 83 Eastern Europe

21 Analyst commentary

12

CAR-T cell therapy revs up in Europe Ever since reports that blood cancer response rates to T cells carrying chimeric antigen receptors (CARs) exceeded 80%, investors have been betting big on CAR-T cell approaches. In August, the first two therapies hit European markets in a head-to-head race to be the number one next-gen cancer therapy. But will CAR-T cell treatments lead the pack long term? Or will alternatives like TCR-based cell therapy or multi­valent bispecific antibody-T cell engagers leave them in the dust?

22 Euro Biotech Stocks

Science & Technology

24 Sustained optimism – analysis of European biotech companies on the stock market

71 Checkpoint inhibitors trigger metastasis and proliferation in subpopulation

34 Retrospective: Biotech Listings on the Swiss Exchange

88 Targeting asthma more specifically

36 Coming of Age

89 New way to fight lupus; Green plastics; Gaucher gene therapy

38 Interview: Adi Hoess, Chief Executive Officer, Affimed NV

90 POC testings: Closing a gap at ICUs

Economy

Service

40 Interview: Günter Huhle, Johnson & Johnson Innovation, JLABS EMEA, Beerse

91 News from partner associations: ASEBIO report launched; Swiss Biotech Association, Medtec Europe and Europa­Bio

41 Update on clinical trials 44 Interview: Sebastian Søderberg, Vice President of New Business

96 Company index/New products 97 Events 98 Encore

IMPRINT European Biotechnology (ISSN 2364-2351) is published quarterly by: BIOCOM AG, Lützowstr. 33–36, D-10785 Berlin, Germany, Tel.: +49-30-264921-0, Fax: +49-30-264921-11, Email: service@european-biotechnology.com, Internet: www.european-biotechnology.com; Publisher: Andreas Mietzsch; Editorial Team: Thomas Gabrielczyk (Editor in Chief), Derrick Williams (Co-editor), Dr. Martin Laqua, Sandra Wirsching, Helene Märzhäuser; Advertising: Oliver Schnell, +49-30-2649-2145, Christian Böhm, +49-30-2649-2149, Andreas Macht, +49-30-2649-2154; Distribution: Marcus Laschke, +49-30-2649-2148; Graphic Design: Oliver-Sven Reblin; Production editor: Benjamin Röbig; Printed at: Königsdruck, Berlin; European Biotechnology Life Sciences & Industry Magazine is only regularly available through subscription at BIOCOM AG. Annual subscription fees: € 80.00, Students € 40.00 (subject to proof of enrolment). Prices include VAT, postage & packaging. Ordered subscriptions can be cancelled within two weeks directly at BIOCOM AG. The subscription is initially valid for one year. Subscriptions will be renewed automatically for one more year, respectively, unless they are cancelled at least six weeks before the date of expiry. Failures of delivery, which BIOCOM AG is not responsible for, do not entitle the subscriber to delivery or reimbursement of pre-paid fees. Seat of court is Berlin, Germany. As regards contents: individually named articles are published within the sole responsibility of their respective authors. All material published is protected by copyright. No article or part thereof may be reproduced in any way or processed, copied and proliferated by electronic means without the prior written consent of the publisher. Cover Photo: Science RF/fotolia.com; ® BIOCOM is a registered trademark of BIOCOM AG, Berlin, Germany.

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CONTENTS

European Biotechnology | Autumn Edition | Vol. 17 | 2018

DNA SYNTHESIS

BIOECONOMY

EDITORIAL

Counterstroke

Building a genome The methods used to make DNA from scratch have been around for well over 40 years, and have drawbacks. They can be inaccurate, slow and the solvents used are bad for the environment. Now startups are looking to develop new methods for building the code of life that use enzymes rather than chemicals. Will they soon gain a foothold in the market?

84

The cure for CO2

Picture: Thermo Fisher Scientific (left, above), Roche (left below), temmuzcan/istockphoto.com (middle), BIOCOM AG (right)

48

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5

Levels of atmospheric carbon dioxide nearly doubled over the last century. So why not just take a page out of Mother Nature’s book and harness this immense potential energy source with the help of artificial photosynthesis? In the lab, synthetic biology approaches are making decisive progress in the field, and improving on naturally evolved systems.

SPECIAL CROs & CDMOs 57 Vertical integration: Time is key 60 Interview: Michael Scholl, Leukocare 62 Providing future markets with robust technologies 64 Cutting time to market for high quality therapeutics 66 Innovative delivery: dual chamber systems 68 Data managers are worth their weight in gold 70 Managing complexity to bring drugs to clinic faster 72 Fully human antibodies for advanced immunotherapies

For years, cancer immunotherapy has been celebrated as a new treatment paradigm. In September, however, the first hints of possible long-term effects surfaced. A team from the reowned Gustave Roussy cancer centre reported that PD1- or PD-L1 blockers actually cut overall survival in a subgroup of NSCLC patients by pushing proliferation and metastasis (see p. 71). And reports published prior to that analysis indicate the phenomenon of hyperproliferative disease isn’t limited to lung cancer. Another area of successful activation of T cells against cancer has also inspired investor fantasies of hitting the jackpot. In August, two CAR-T cell therapies were okayed by the European Medicines Agency, and are now in the midst of a race to dominate the European blood cancer market. On p. 12 we get you up to speed on the competing technologies, and explain which offer price advantages. After all, payors are now having to shell out swingeing amounts for one-time treatments. In oncology, it’s nearly always two steps forward and one back. But real progress has been reported from the field of artificial photosynthesis (p. 84) and gene synthesis (p. 48). And finally, for all our readers dealing with company performance, this issue for the first time includes a wide-ranging finance and capital market section (p.20). Hope you enjoy it – and give us some feedback!

Thomas Gabrielczyk Editor-in-Chief

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INsIGhT EUROpE

European Biotechnology | Autumn Edition | Vol. 17 | 2018

European Court cements EU agri-biotech deadlock For years, it was clear that most European countries didn’t want to participate in the acreage of GMOs, which peaked at 189.8 million hectares last year. While global growth with GM crops converged to saturation in the past few years, hopes of commercial breeders focused on novel molecular biological methods, including genome editing, which produce crops that are indistinguishable from those made by classical mutagenesis.

According to Ricardo Gent, who chairs the National Association Council of EuropaBio, “There is nothing but the blue sky above the European Court of Justice (ECJ).“ Thus, after years of futile waiting for a political decision on the legal status of crops made by novel recombinant breeding methods, GMO lobbyists and GMO opponents psyched themselves up for a legal interpretation of the EU Directive 2001/18 /EC by the ECJ (see background, p. 9). If deregulated like chemically or physically mutagenised crops, breeds that were mutagenised by oligo-nucleotide-directed mutagenesis (OGM), or non-insertional

genome-editing methods (TALENs, Type I-II CRIspR-Cas9, Zinc Finger Nucleases, Meganucleases) could be marketed without GMO safety assessment or labeling, saving producers some six-digiteuros sums in costs. For sonny perdue, the Us secretary of Agriculture, the case was crystal clear: “There will be no regulation in the Us concerning agriculture produced through new techniques of CRIspR-Cas9 type genome editing,” he said at the end of March. Two months before, Michal Bobek, the ECJ’s General Advocate, supported that perspective in a recommendation to the Court regarding how to in-

AG biotech opponents suggest targeted mutagenesis is something “different.“

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terpret the 17-year-old EU Directive (see European Biotechnology, spring Edition 2018). however, in mid-July, EU lobbyists hardly believed their eyes when reading the ECJ verdict in case C-528/16: First, the Court made clear that all organisms obtained by means of techniques/methods of mutagenesis constitute GMOs (Article 2(2). however, those obtained by in vivo- or in vitro mutagenesis, according to Annex IB, could be exempted due to their long safety record. second, the Court said that crops produced with new breeding technologies do not have been as extensively safety assessed as conventional breeds and thus an exemption under Annex IB rules “would fail to have regard to the intention of the EU legislature to prevent any irreversible harm to humans and the environment” due to deliberation of organisms obtained by techniques that involve DNA hybridisation (Article 3(1), Annex IA, recital 17) or recombinant DNA. After all, EU member states are free to deregulate crops obtained by chemical or physical in-vitro or in-vivo mutagenesis but not crops that have been obtained by new breeding technologies. Though industry associations, including EuropaBio and the EU food trade association Coceral, urged the European Commission and the Member states to establish a science-based legal framework for directed mutagenesis, the ECJ ruling means political paralysis for the development and commercialisation of novel breeding technologies in Europe. The

Pictures: Ernesto del Aguila III, NHGRI

new breeding Methods

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InsIght EuropE

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Breeding technology

Genomic integrity

Cellular integrity

Fertility

Breeding

Nat. crossing barrier

Reproduction

Traceable

› Gene editing, type I+II

+

+

+ (patenting)

not exceeded

+ (patenting)

no

› Gene editing, type III

+

+

+ (patenting)

possible

+ (patenting)

yes

› Oligo nucleotide -directed mutagenesis

+

+

not exceeded

no

› Classical mutagenesis (chemical/radiation)

+

+

not exceeded

no

› Targeting induced local lesions in genomes

+

+

not exceeded

no

› Eco-Tilling

not exceeded

no

› Cisgenesis

+

+

+ (patenting)

not exceeded

+ (patenting)

??

› Transgenesis

+

+

possible

+ (patenting)

exceeded

+ (patenting)

yes

› RNA interference

+

+

+ (patenting)

not exceeded

+ (patenting)

no

› Reverse breeding

+

+

not exceeded

+ (patenting)

no

› Mini chromosomes

+

+

+ (patenting)

exceeded

+ (patenting)

yes

› Protoplast fusion

possible

+

possible (3N)

possible (CMS)

possible

possible

??

› Cytoblast fusion

+

possible (CMS)

possible

possible

no

› Marker-guided selection

not exceeded

no

European parliament and the European Commission are preparing for elections in May and June 2019, respectively, and nobody expects them to contradict the ruling.

Stereotypical comments …. At one end of the spectrum of opinions, Coceral argued that the ECJ ruling would lead to major trade distortions with the us and other trade partners that deregulate genome-edited crops. “such misalignment with key trading partners would constitute yet another trade barrier that will jeopardize essential Eu imports of agricultural commodities needed for the food supply in Europe and will increase food prices,” Coceral stated. At the other end, gMo opponents such as testbio e.V. celebrated that genome-edited crops are now set to become “subject to an obligatory safety assessment before being approved for market.” While most European ag-bio giants and sME ge-

06-11_EB_Autumn_2018_Insight_tg.indd 8

nome-editing specialists – such as Bayer/ Monsanto, BAsF, and Cellectis-spin-out Calyxt – have been moving to Minnesota, us, to develop their business, roughly 5,000 European reseachers signed a petition within one month after the ruling calling for an “immediate review of the ECJ ruling on plant genome editing.”

… and green masterminds however, not everyone expected to paint everything black and white did so. german green party chairman robert habeck, for example, upset his electoral base by stating that one should consider new breeding technologies when it comes to creating crops resistant to climate change or ones that may reduce pesticide usage. plant researchers headed by Michael palmgren from university of Copenhagen suggested in 2015 that new breeding technologies could help rewilding crops in accordance with the values of organic farming

(Trends in PlanT sciences, doi: 10.1016/j. tplants.2015.04.011). Contradicting lobbyist statements that rewilding in such a way that the final crop cannot be distinguished from a crop bred by traditional means would be dangerous, the researchers suggest that speeding up reintroduction of properties from the wild relatives of crops could close the productivity gap in organic farming. Furthermore, they suggest that genome editing with “base editors,” which produce the exact same genetic changes as chemical EMs mutagenesis, could guide a green revolution “that focuses on environmental sustainability, low input, and increased nutritional value.” researchers at the swiss research Institute of organic Agriculture (FiBL) say that the risk of off-target effects from random mutagenesis could be reduced by targeted mutagenesis. the major risks in application of targeted mutagenesis in breeding are that companies may try to file patents on improved crops, subverting the farm-

Picture: FIBL

Implications of diverse breeding technologies on organic breeding criteria: + affected; – not affected

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

ers‘ privilege and breeders‘ exemption, or that farmers may neglect to establish more sustainable farming methods.

Ruling brings EU policymakers into legal limbo There is good reason to criticise ECJ lawyers for not requesting additional scientific advice before their ruling, but rather relying on previous case rulings and legal analyses, which mainly have been published by interest groups. According to FIBL researcher Monika Messmer, tracing crops that have undergone targeted mutagenesis is difficult, as their genome is indistinguishable from a randomly mutagenised genome. “Legally, it’s a problem if you can not clearly identify a GMO because that is the precondition for its market authorisation according to EU rules,” German plant geneticist Jens Boch from Leibniz University Hannover told EuropEan BiotEchnolo gy. “However, it is technically absolutely impossible to distinguish mutations introduced by targeted mutation techniques from naturally occurring point mutations. So, contaminations could not be traced,” he stresses. “The ECJ ruling is an offence to the rational basis of science in general,”

Boch adds. “With the advance of molecular biology in the last decades, we can now detect that the old techniques cause a hundredfold more off-target effects and are accordingly much more unsafe than modern genome-editing techniques. Thus, science clearly contradicts the Court’s argument that conventional use is a measure for safety.” Scientific advice could have also have informed the ECJ about a naturE BiotEch. publication (doi: 10.1038/ Nbt.4192) suggesting that CRISPR-Cas9 genome editing is less precise than previously thought.

Action needed

LABVOLUTION world of labs. Die Fachmesse für innovative Laborausstattung und die Optimierung von Labor-Workflows. 21. – 23. Mai 2019 Hannover ▪ Germany labvolution.de J e tz t nter lden u e anme d ution. labvol

EU member states, such as Germany, Sweden, UK, and Spain, that had adopted preliminary deregulation for Cibus’ rape produced by targeted mutation techniques withdrew their recommendation, pointing to the ECJ ruling. Also Italy, Poland, Finland, and France have expressed their views that products of novel breeding methods should be pushed forward as they do not differ from conventionally mutagenised breeds. They are now waiting for action from Brussels to L fix the problem. t.gabrielczyk@biocom.eu

Background of the case In 2016, nine GMO skeptic associations headed by Confédération Paysanne took action at the Conseil d’Etat in France against the national legislation implementing the EU Directive 2001/18 /EC on the release of genetically modified organisms (GMOs). The GMO critics regarded all kinds of mutagenesis that take place in vitro as GMOs, including EU-approved herbicide-tolerant crops that had been conventionally mutagenised by Monsanto. The Conseil d‘Etat then requested the European Court of Justice provide a legal interpretation of the EU Directive, particularly the so-called mutagenesis exemption, laid out in Annex IB to the Directive. In

06-11_EB_Autumn_2018_Insight_tg.indd 9

addition, the Conseil asked the Court to clarify whether the new molecular biology breeding techniques are finally regulated in EU law or if EU Member States still have their own regulatory latitude. Even before the Court’s Advocate General, Michal Bobek, recommended to include all chemical and physical mutagenesis methods, as well as some novel biological methods for targeted mutagenesis that do not produce transgenic organisms in Annex IB, France, Greece and the EU Commission clearly stated that Annex IB very much reflects the current state of technology as new forms of mutagenesis were already known in 2001 when the Directive was revised. L

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insight EuropE

nEws Master of disaster the number of European patents granted under the eight-year Epo presidency of Benoît Battistelli (2010-2017) have risen by 82%, leading to an 4.5-fold increase in incomes by 2017. in May, the Epo decided (31 yes : 3 no votes) to launch a fund dubbed EpotiF to enhance its current €2.3bn assets. Law firms Grünecker, hoffmann Eitle, Maiwald, and Vossius & partner criticised both: they claim that the time saved for the examination of patents would come at the expense of quality; and the funds would speculate with the money of patent holders. “when it comes to completing the procedure as quickly as possible within certain deadlines, the quality of the search and examination of applications must suffer,” the law firms said in an open letter. “high international search fees and examination fees can only be justified by allowing examiners sufficient time to thoroughly examine each individual application.” high tech and biopharma companies, in particular, previously critised Battistelli’s Early Certainty of Examination initiative, which cuts the current examination time from 22 months to 12 months on average. Like the law firms, companies are concerned that a loss in quality would devaluate Epo patents in patent litigation.

GMOs approved the European Commission approved five gMos for food and feed in August covering new authorisations (maize Mon 87427 x Mon 89034 x nK603, maize 1507 x 59122 x Mon 810 x nK603) and renewals (maize DAs-59122-7, maize gA21, sugar beet h7-1).

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

IMI fosters antibiotics research amidst Big Pharma pullbacks

More than 15% of the 10.8 million people infected with M. tuberculosis die. AMR the innovative Medicines initia-

tive 2 (iMi2) has launched a new Antimicrobial resistance Accelerator programme following on the heels of its outgoing newDrugs4BadBugs pro gramme. the Accelerator is part of the iMi2’s €434m Call 15 for proposals and will consist of three pillars funded with up to €144m:

›› a capability-building network that will manage the projects of the Accelerator and deliver pre-competive academic and sME research enabling future drug discovery and improved infection models; ›› a drug development network for tuberculosis aimed at acclererating discovery of novel combination treatments; ›› company-specific portfolio-building networks that cover preventive and therapeutic approaches to fight AMR. over a period of six years, the new iMi AMr Accelerator is expected to deliver more than ten preclinical drug can-

didates and more than five programmes ready for phase ii testing. the AMr Accelerator “represents a strategic, coordinated response to one of the biggest challenges facing the world today,” said pierre Meulien, iMi Executive Director. the iMi2’s move comes at a time in which Sanofi has licenced its early antimicrobial pipeline to Evotec and in which novartis has abandoned r&D into antimicrobials. Meanwhile, the us government is taking steps to incentivise antimicrobial development. A bipartisan bill plans to offer companies that bring “priority” antimicrobial products to market an award of 12 additional months of market exclusivity. the award can be conveyed to any drug, split, and even sold – an asset potentially worth hundreds of millions. Life science decision-makers, business developers, investors, and legal experts will discuss models to revive the antimicrobial market at the 2019 Berlin Conference on Life sciences (https://amr-conL ference.com/home/).

Picture: American Thoracic Society

10

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Meet us at e d i w d l r o W I h CP in Madrid October 09 – 11

Advancing Austrian life sciences // at the heart of Europe 2018/2019 meet LISA at

BIO-Europe Copenhagen, November 05 – 07 Medica Duesseldorf, November 12 – 15 HIMSS Annual Conference & Exhibition Orlando, February 11 – 15 BIO-Europe Spring Vienna, March 25 – 27 MedtecLIVE Nuernberg, May 21 – 23 BIO International Convention Philadelphia, June 03 – 06 www.lifescienceaustria.at

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16.08.18 21:50 13.09.2018 13:11:01 Uhr


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coVEr story

European Biotechnology | Autumn Edition | Vol. 17 | 2018

13

CARs right on track Since reports that blood cancer response rates to T cells carrying chimeric antigen receptors (CARs) exceed 80%, investors have been laying bets on CAR-T cell approaches. In August, the first two therapies hit European markets in a head-to-head race to be the number one next-gen cancer therapy. So will CAR-T cell treatment really take pole position? Or will alternatives like TCRbased cell therapy or multivalent antibody-T cell engagers leave them in the dust?

oncology

Pictures: cgtoolbox/istockphoto.com (left), Gilead Sciences (right)

t

he story of eight-year-old Kaitlyn from Dallas sounds like a Hollywood screenplay. After being diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) in 2011, she was one of the 15% of patients that relapse from chemotherapy. After two and a half years of chemo, with every recurrence bringing a worsening prognosis and drop in quality of life, she was given a one-time cAr-t cell infusion within a clinical trial. Previously, her own t cells were engineered outside her body to carry a receptor activating them to attack cancerous blasts upon binding the cellline specific CD19 surface marker. When reinjected, they proceeded to wipe out her cancerous and healthy B cells. In september 2017, according to Us broadcaster cNBc, she had been in remission for almost three years. It’s still too early to know whether Kaitlyn is an isolated case. But clinical data from two FDA- and EU-approved cAr-t cell therapies, as well as results from latestage clinical trials, suggest she might not be. According to seeking Alpha analyst Bill Koski, over 80% of the 75 children with chemo-recurrent B-ALL responded to Novartis’ KymriahtM (tisagenleucel) in the pivotal ELIANA trail. 60% of those exhibited a complete response (cr). the therapy was greenlighted by the FDA in August 2017, just five years after Novartis licensed it from carl June at the University of Pennsylvania. Just a year later, the EMA followed suit. the short time-to-market and low patient numbers (well below 100) required for accelerated market authorisation have

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Novartis, adding that ”there haven’t been very many cases where it didn’t work”. According to her, “there are about 300 patients in the relapsed, refractory patient population” in the Us. A further 300 patients per year are in other target markets. In early september, the British National Health service (NHs) agreed to reimburse Kymriah at “well below the European list price of Us$363,000 per B-ALL patient,” a spokesman at the UK’s health technology assessor NIcE told EuropEan BiotEchnology.

Michael elliot VP Medical affairs europe, Gilead Sciences

?

Will hospitals offer both EUapproved cAr-t treatments to treat DBcL?

!

I think maybe the preference would be to work with one company and their system, but it may be that some units want to do their own internal comparison.

A huge and hopeful market

helped trigger a wave of company foundations, multi-billion M&As, licensing deals, and a burgeoning crowd of cAr-t cell candidates. 354 are currently in pipelines, 76% of them in preclinical testing. the pricing for cAr-t cell therapies has contributed to the surge. (For a company/ programme overview, see fig. 1, p.14). Kymriah, which is made individually for every patient, has an outcomebased price tag of $475,000 in the Us. “If we don’t see a complete response by 30 days, they don’t pay for the therapy,” explains Liz Barrett, cEo of oncology at

However, Novartis and other cAr-t cell players – like celgene, bluebird bio or Gilead – are focusing on blood cancer indications with much higher patient numbers, because they translate into better profits. “It’s important to keep in mind where cAr-t is going. you start in the later lines of therapy, because that’s where the highest unmet medical need is,” says Barrett. “But we’re planning clinical studies in earlier lines of therapy where patient populations are much larger. catching patients earlier will hopefully prove better for everyone,” she remarks. And of course the real hope is not only to treat blood cancers – which make up just 10% of all cancers – but solid cancers as well. they’re already being targeted by companies like Eureka therapeutics, celyad NV, Minerva Biotechnologies, Autolus Ltd and others. A range of academic groups and companies in the Us and Europe have begun to seek ways for cAr-ts to overcome the t-cell-paralys-

“We think it’s very important to

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COVER STORY

European Biotechnology | Autumn Edition | Vol. 17 | 2018

ing microenvironment in solid tumours, and an array of clinical trials are underway (see above). Even with no proof their approaches could work, companies are getting IPO valuations in the hundreds of millions, and R&D investment is sky-

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rocketing. “Everyone is trying to jump on the bandwagon,” says Martin Schleef, CEO of Plasmid Factory. “In the last two years, we’ve seen a huge rise in the scale of orders for high quality plasmids needed to make lentiviral and non-viral vectors

used in CAR-T cell engineering. This year we had to expand our production capabilities,” he says (see p. 62). And the cell therapy hype isn’t limited to CARs, but also includes T cell receptors (TCRs) engineered to recognise tumour targets with

Picture: Wells Fargo Securities

Fig. 1: Competitive landscape in adoptive cellular therapies with a focus on CARs and TCRs (as of December 2017).

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

high affinity. Companies like MediGene, Immunocore or Adaptimmune argue that targeting solid tumours with optimised TCRs is the better strategy, because unlike CARs, TCRs can recognise intracellular cancer antigens presented by the cancer cells’ major histocompatibility complex (MHC). It’s the early laps in what promises to be an exciting race. In addition to Novartis, just one other CAR-T specialist has reached the market so far: Kite Pharma/Gilead Sciences.

The Best Antibody Discovery Technology Is Now at Your Fingertips

Barreling down on the market in Europe

Beyond the hype – still a long way to go While the first two CAR-T cell therapies have been approved, a lot of questions remain to be answered. Topping the list:

› The huge prices of autologous therapies, which producers justify with the laborious CAR engineering into T cells, their expansion, and delivery back to the hospital, where the individually produced autologous CAR-T cells are reinfused into the patient.

Trianni Mouse Antibodies are a Match for Humans The Trianni MouseTM platform is the only transgenic antibody discovery platform ever developed that offers the entirety of human antibody variable gene diversity in a single organism. The V-gene segments in The Trianni Mouse are chimeric, but the variable domains of antibodies made by the mouse are entirely human. The result is human antibody leads generated from antibody genes optimized for function in the mouse. Or, in the simplest terms, The Trianni Mouse is a more human mouse. To learn more about this innovative platform and how it can help you leave your mark on therapeutic antibody discovery and development, visit Trianni.com.

Amino Acid frequency

HUMAN

Amino Acid position

TRIANNI Amino Acid frequency

In October 2017, the Kite Pharma arm of Gilead Sciences – two months before it was acquired in a US$11.9bn deal – received FDA approval for its CD19-targeting CAR-T cell therapy YescartaTM (axicaptagene ciloleucel) in chemo-refractory adults with diffuse large B-cell lymphoma (DLBCL). It’s a patient group of approximately 6,700 adults per year – ten times more than B-ALL – and it represents US$5bn in sales, according to Seeking Alpha analyst Koski. In May 2018, Novartis’ Kymriah received its second FDA approval in DLBCL. Koski reports that in this indication, Yescarta – priced at US$373,000 per patient – clearly outperformed Kymriah in its pivotal ZUMA-1 trial, with 82% response in 101 patients, and 58% of them CRs. Among the 81 participants in Novartis’ JULIET trial, the response rate was just 50% (32% CRs). In Europe, however, where both therapies were granted market authorisation at the end of August, Kite/Gilead already lost a head-to-head race against Novartis in the first of its target markets, the UK. The Swiss giant has had a remarkable run of good luck. First, the EMA downgraded Gilead’s fast-track status for Yescarta’s MAA, which Kite Pharma had submitted two months earlier than Kymriah, “to better understand the data”. Then the UK health assessor NICE rejected reimbursement of Yescarta on the day it was approved in the EU, arguing that the drug’s incremental cost-effectiveness ratio more than doubled the threshold of £50,000 per quality-adjusted life year (QALY) vs. standard-of-care. What’s worse for Gilead Sciences, which wanted to roll out Yescarta in Germany, Austria and France in addition to the UK, is that its CAR-T cell therapy did not meet the criteria required for coverage by the UK’s Cancer Drugs Fund, which provides patients access to cancer drugs that would not otherwise be available from the NHS.

Amino Acid position

CDR-H3 residue utilization in antibodies derived from human samples and the Trianni transgenic Ig Mouse. In the naive Trianni Mouse, heavy chain CDR3 (CDR-H3) aa utilization frequency is effectively the same in humans and in The Trianni Mouse.

Exceptional Human Antibody Discovery 12-18_EB_Autumn_2018_Big shot_CARs over Europe_tg.indd 15

13.09.2018 13:12:22 Uhr


16

coVEr story

European Biotechnology | Autumn Edition | Vol. 17 | 2018

CAR-T cell therapy principles

›› safety. cytokine release syndrome (crs) occurs often upon cAr-t reinfusion, and seems correlated with response to therapy. A second life-threatening adverse effect is neurotoxicity. ›› Durability of response, as early cAr-t cell death and therapy resistance often lead to recurrence of the cancer. Currently, T cells are isolated in certified hospitals, then shipped to approved production centres or cDMos. there the T cells are genetically modified to carry a chimeric antibody receptor consisting of a tumour-antigen (i.e. cD19)-binding single chain antibody fused to a signalling domain, which is made up of co stimulatory t cell receptor fragments and the CD3 protein (see figure to left). These trigger t cell activation and proliferation upon binding the tumour antigen.

In the cAr-t cell therapy process, t cells are isolated from patient or donor blood, activated, then genetically engineered to express the cAr construct. After ex vivo expansion of the CAR-T cells, they’re formulated into the final product. Patients today undergo a prior conditional chemotherapy before reinfusion. B t cell receptor (tcr) and four types of chimeric antigen receptors (cArs) are displayed on the surface of a t cell attracted to their antigen (red) on the tumour cell. the single-chain variable fragment (scFv) that zeroes in on tumour surface antigens is shown in light blue, with the VH and VL domains connected via a long flexible linker and transmembrane domain to intracellular signalling domains. Pro-inflammatory cytokines or co-stimulatory ligands expressed by the cAr-t cells are depicted for the 4th generation. C overview of “smart cAr-t cells products”: Pooled cAr-t cell products consist of two or more single-targeting cAr-t cell types with distinct antigen specificities. Multi-CAR-T cells harbour several CAR molecules with different antigen specificities. A tandem CAR-T cell expresses a CAR construct harbouring two ligand-binding domains with different antigen specificities. In a conditional CAR-T cell, activation and co-stimulation are separated on two cAr constructs recognising different target antigens. In the split cAr construct, the ligand-binding or signalling domain is physically separated, allowing controlled cAr-t cell activation. icAr-t cells additionally express a receptor engineered to recognise an antigen expressed on normal tissue to provide an inhibitory signal in turn. In addition, cAr-t cells can be equipped with suicide genes or switches. A

12-18_EB_Autumn_2018_Big shot_CARs over Europe_tg.indd 16

While Novartis, Kite/Gilead and other relevant players claim the expensive manufacturing process is at the root of the huge therapy cost, two blood cancer patients published a different calculation this year, arguing cAr-t cell therapies were “significantly overpriced” (HealtH affairs, doi: 10.1377/hblog20180205.292531). the authors – Pr expert David Mitchell and exLek Pharmaceuticals cEo Paul Kleutghen – estimate that even if Kymriah cost just Us$190,000, Novartis could afford to invest 19% of its earnings in r&D and still generate a profit margin of 65% – more than twice what the company generates on its current product portfolio. While Novartis spokesman Eric Althoff stresses the authors’ assumption of Us$20,000 for cost-of-goods is false, experts in the field have told european Bio ­ tecHnology that their estimate is close when it comes to pure material costs, but that costs for labour, infrastructure, logis-

Pictures:EMBO Mol Med. 2017 Sep; 9(9)- 1183–1197. Published online 2017 Aug 1. doi- 10.15252:emmm.201607485

“If patients like us cannot afford the drug, then the hope it could become a life-saving treatment for our diseases is pointless.”

13.09.2018 13:12:27 Uhr


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13.09.2018 13:12:47 Uhr


18

COVER STORY

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Antibody-based approach to cell surface antigens

SPEAR T cell

The majority of approaches access only extracellular proteins CAR-NK-cells Bispecific Ab

Cancer cell

ADC

TCR-based recognition

The majority of approaches access more options for targeting cancers by enhancing the body’s natural immune system: – T cells scan HLA-peptides with TCRs – Access to entire spectrum of extra- and intra-cellular proteins –TCR is T cell’s native receptor – Ability to address solid tumours

T cell receptor

Cancer cell

CAR-T cell

Cancer cell

T cell

Other approaches TCR mimic Ab NK-cells

TILs

γ∂ T-cells

ImmTAC

HLA-peptide antigen Source: Adaptimmune

mice that genetic or pharmacologic (with Anakinra from SOBI AB) depletion of the proinflammatory cytokine IL-1 helped prevent both neurotoxicity and CRS. Side effects may also drop with more defined cell therapy products. Researchers at the Fraunhofer IZI, a European manufacturing site for Kymriah, told EUROPEAN BIO TECHNOLOGY that only 20% of viable cells carry a CAR construct. Higher proportions of CAR-T cells in the end product might reduce cytokine release by nonCAR-T cells, thus possibly reducing IL-6and IL-1-triggered adverse effects.

Making cures permanent

Technologies that are used to activate T cell responses.

Off-the-peg vs. tailored In April, a company claiming to be able to solve the price problem with autologous CAR-T cell therapy closed a US$300m Series A round. Allogene, which was founded by the managers that sold Kite to Gilead, has taken over pipeline candidates from Cellectis SA’s licensees Pfizer and Servier. They now say genome edited allogenic CAR-T cells with switchable T cell activity are the future. Cellectis CEO André

12-18_EB_Autumn_2018_Big shot_CARs over Europe_tg.indd 18

Choulika believes donor T cells cleared of antigenic determinants by genome editing could be manufactured “off-thepeg”, driving prices for treatments down to US$10,000/patient. But skeptics predict the immune system will always recognise allogeneic CAR-T cells sooner or later, and think that even in a best-case scenario, they would only bridge the gap to stem cell transplantation – but not provide longterm solutions to hematological cancers.

Cutting down on side effects Beyond the issues of manufac turing and delivery costs, severe side effects are still a major concern in T cell immunotherapy. Kymriah (costimulatory 4-IBB domain) triggered severe (grade 3+) cyto kine release syndrome (CRS) in 46% of B-ALL children and 23% of DLBCL patients, but neurotoxicity was low (13% in B-ALL, 18% in DLBCL). Yescarta (costimulatory (CD28) domain) triggered cytokine storms in just 13% of subjects enrolled in ZUMA-1, but led to neurotoxicity in 31% of them. While clinicians can manage CRS with Roche’s IL-6 receptor blocker tocolizumab, research into blockers of CAR-Ttriggered seizures and encephalopathies like brain edemas is still in its infancy. In August, Attilio Bondanza from San Raffaele Hospital (Milan) and Michel Sadelain from Memorial Sloan Kettering Cancer Center (New York) showed in

Given their high price, developers are working on ways to assure long-term efficacy in CAR-T cell therapies. Increasingly, a high relapse rate after CD19-targeting CAR-T cell therapy has emerged as a major problem. “Less than half of patients with DLBCL who receive CART cell therapy are still in remission a year later,” says Jeremy Abramson from Massachusetts General Hospital, adding that single-target therapy may select for and lead to escape variants. One possible workaround is targeting additional B cell antigens CD22/40/75/76 or combining CAR-Ts with other immunomodulators. This might prevent resistance when the tumour no longer exhibits CD19 antigens on its surface. Solid tumours are even more problematic. They can go into stealth mode by erasing all antigenpresenting proteins from their surfaces, a process called antigen-shedding.

Many avenues to progress CNBC didn’t respond to our enquiries about the current state of Kaitlyn’s health. Three years of survival is a great start, but currently no one knows whether other subjects will show similar longterm remission. Or whether in the end, CAR-Ts, TCR-based approaches or followup drugs to Amgen’s fully approved bispecific T-cell engager (BITE)-based ALL therapy blinatumomab, will provide the best  solution for cancer patients. t.gabrielczyk@biocom.eu

Pictures: Adaptimmune

tics, etc. would lead to a total manufacturing price tag of at least US$100,000. For payors, the current cost of cell therapies is burdensome, even in more common orphan blood cancers such as multiple myeloma, an indication with 30,000 US patients per year targeted by antiBCMA CAR T cell therapies such as Celgene’s bb2121 or Poseida’s P-BCMA-101. Because healthcare systems find it difficult to set appropriate pricing models for such expensive one-time-treatments, players like Roche or Amgen haven’t stepped into the field. Instead they’ve stuck with antibody-based methods for activating T cell responses like bispecific T cell engagers (BITEs). These can be produced more cheaply, with up to 80% complete responses as shown by Amgen’s multiple myeloma-BITE AMG 420 in September. Still, improved antibody formats such as IgG1like bispecifics compete with TCR- and CAR-T-based cell therapy approaches.

13.09.2018 13:12:33 Uhr


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07.08.18 19:20 13.09.2018 13:12:59 Uhr


20

ADVERTORIAL

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Setting equity incentives Equity incentives are perhaps the most emotive element of biotech reward. In the current talent market, it is important that biotech long-term incentives (equity incentives) are competitive with respect to peer practices. Determining the right peers, and setting competitive award levels requires careful analysis. Getting this wrong can lead to turnover at senior levels in the company.

HUMAN RESOURCES

In the pre-IPO stage, remuneration is characterised by modest cash with equity geared towards an IPO. The focus here is on managing executive and employee ownership on a percentage of company basis as funding rounds dilute ownership. As a guide, immediately pre-IPO total overhang (equity issued but not yet settled, i.e. unexercised options and unvested shares plus shares available for future awards) can exceed 15% on a fully diluted basis. Caution is required as European biotechs listing on the Nasdaq have higher overhang levels compared to domestic European peers. Once public, equity levels at pre-commercial or early commercial biotechs are managed by a combination of a percent of company and value approach. This varies considerably by company and the table shows the potential range of values. By contrast, more established biotechs tend to have a regular cadence to their equity award policy with an annual expected value set (typically a Black-Scholes value), expressed as a percent of salary and benchmarked relative to peers.

Getting the peer comparisons right In order for public biotechs to manage pay in ation and set competitive

Source: Deloitte Life Science Database

Equity practice evolves over the lifecycle of a biotech

awards, careful peer group selection is required. This should consider stage of development, location, size, and therapeutic area. Comparisons to larger and or only Nasdaq listed biotechs can in ate equity award sizes creating governance concerns. In addition to award levels, the type of equity approach also varies across public biotechs. The chart outlines the range of practices by stage of development.

A word on governance Executive reward is increasingly under the spotlight. Biotechs are subject to the core European themes of pay

Source: Deloitte Life Science Database

Equity vehicle by clinical stage of development

20_EB_Autumn_2018_Advertorial_Deloitte.indd 20

fairness and transparency. This will only increase as the impending Shareholder Rights Directive comes into force for member states, where a robust say on pay regime will be in effect. When Deloitte examined the remuneration propo sals at the 2018 annual general meetings of 50 European biotechs, we found that 70% of companies received a vote against recommendation on their proposals from the proxy adviser ISS, citing concerns around pay for performance, incentive measures disclosure and quantum. Proxy advisers operate guidelines that are inconsistent with biotech pay practices (notably high overhang levels, burn rates, phased vesting and director equity awards). Careful management of proxy advisers and shareholders is essential in this governance environment. Contact Rob Miller, Partner Deloitte LLP robemiller@deloitte.co.uk www.deloitte.co.uk

13.09.2018 13:13:23 Uhr


European Biotechnology | Autumn Edition | Vol. 17 | 2018

FINANCIAL MARKETS

21

Diversifying into oncology if ROI on bugs is too low OLAV ZILIAN Senior Healthcare Analyst, Mirabaud Securities_ Big Pharma’s interest in R&D on

anti-infectives declined when other areas like oncology began offering higher returns. A few biotechs mirror pharma (Basilea, Idorsia and Polyphor), but could stay hidden gems.

As with other economic sectors, cyclicality is also seen in biopharmaceuticals, though over a longer period of time. A prevailing megacycle of today’s healthcare industry is found in the expanding oncology market. Key drivers for its lasting and far-reaching growth are increasingly personalised treatment regimens, triggered by a series of innovations including: 1) diagnostic tests for biomarkers, or direct tumour sequencing; 2) an increasing number of drugs selectively targeting vulnerable points of tumours; 3) novel means to mobilize the immune system against cancer cells like checkpoint inhibitors. At the same time, these novel cancer drugs are more profitable due to a double multiplier, i.e. prolonged survival entails longer treatment multiplied by the lifted price point

that is justified by the drugs’ improved risk-benefit ratio. Novel antibiotics, by contrast, were expected to provide higher returns on R&D, which eventually couldn’t be met because: 1) diagnostics for identifying the causative microbe take too long vs the quick manifestation of the infection thus putting the patient’s life at risk; 2) some infections are caused by more than a single agent; 3) under all these premises, broad spectrum antibiotics continue to prevail over novel narrow spectrum drugs; 4) despite their truly curative benefit, the price of antibiotics remains low. What has been the consequence of the diverging economics of both therapeutic areas? Big Pharma’s original enthusiasm reverted into deprioritizing R&D on antibiotics, e.g. in favour of oncology. By contrast,

only a few biotechs initiated such a reversal, but investors do not necessarily welcome such a move. They could be hidden gems if their valuation is depressed. Swiss Basilea is a prime example: its pipeline has been consistently expanded into oncology, starting ten years ago, yielding BAL101553 (now in Phase II for glioblastoma and ovarian cancer); BAL3833 (in Phase I); and inlicensed derazantinib (in pivotal Phase II for intrahepatic cholangiocarcinoma); while the antibiotic Zevtera (approved in the EU; US Phase III ongoing) and the antifungal Cresemba (approved in the US and EU) are being commercialized by various distributors (e.g. Correvio and Hikma) and partners (e.g. Astellas and Pfizer) in an increasing number of markets. Convincing clinical trial success is needed to see companies like Basilea, Idorsia, and Polyphor properly valued, a breakthrough in oncology could be an occasion. 

News from the floor

Picture: Mirabaud Securities

VEC TUR A GROUP PLC JPMorgan Chase & Co. restated their overweight rating on shares of Vectura Group (LON:VEC) in a report issued in August. They currently have a GBX140 price objective on the stock that traded around GPX90 all summer. OXFORD BIOMEDICA PLC The lenti-

virus vector platform company‘s stock (LON:OXB) had its “buy” rating reiterated by equities research analysts at

21_EB_Autumn_2018_market-sentiment_ml.indd 21

Peel Hunt in a research report issued in late August. After a Parkinson’s Disease deal with Axovant in June, the stock soared to more than GBX1,060 but later normalized to around GPX850.

Celgene (US) and another one with Centogene (Germany) in rare diseases, Evotec’s stock had hit an all-time high of €23.36 in early September. ZEALAND PHARMA A/S Needham &

EVOTEC AG German biopharma play

Evotec (ETR:EVT) has been given a €26.00 price target by Oddo BHF in September. The price target suggests a potential upside of 17.75%. After sealing the third drug discovery deal with

Company LLC set a US$26.00 price objective on Danish peptide drug developer Zealand Pharma (NASDAQ:ZEAL) in a research report released in August. The brokerage currently has a “buy” rating on the stock. 

13.09.2018 13:13:46 Uhr


22

financial markets

COMPANY

QUOTE

4D Pharma plc

european Biotechnology | autumn edition | Vol. 17 | 2018

M-CAP

52 weeks indicator low high

COMPANY

QUOTE

M-CAP

2.10

140,000k

C4X Discovery Holdings plc

1.02

47,000k

Calliditas Therapeutics AB

5.35

190,000k

Cantargia AB

1.98

130,000k

Carbios SAS

8.84

40,000k

Cassiopea SpA

53.26

530,000k 970,000k

4SC AG

3.61

110,000k

A1M Pharma AS

0.44

3,600k

AB Science SA

4.25

170,000k

AB-Biotics SA

3.32

41,000k

Abcam plc

15.42

2,900,000k

Cellectis SA

23.02

Abivax SA

7.55

74,000k

Cellink AB

12.95

110,000k

Abzena plc

0.17

37,000k

Celon Pharma SA

7.69

350,000k

Active Biotech AB

0.36

53,000k

Celyad SA

24.50

290,000k

Addex Therapeutics Ltd

2.17

62,000k

Cerenis Therapeutics SA

1.91

36,000k

Circassia Pharmaceuticals plc

0.81

290,000k

Co.don AG Cosmo Pharmaceuticals NV

the unique and most complete list of share price developments of biotech companies listed in europe – exclusively in european Biotechnology magazine. ADL Bionatur Solutions SA Adocia SAS Advicenne SACA

3.45

57,000k

Cytotools AG

9.24

19,000k

DBV Technologies SA

0.52

10,000k

37.88

1,200,000k

Deinove SA

2.30

35,000k

Destiny Pharma plc

1.01

44,000k

Diamyd Medical AB Diasorin SpA

0.70

39,000k

87.40

5,000,000k

Elanix Technologies AG

3.01

23,000k

e-Therapeutics plc

0.09

25,000k

Ellen AB

0.02

4,700k

Enzymatica AB

0.29

21,000k

Epigenomics AG

2.11

52,000k

Erytech Pharma SA

8.81

160,000k

2.06

80,000k

Esperite NV

0.25

8,900k

16.84

120,000k

Eurobio Scientific SA

4.43

44,000k

Eurofins Scientific SE

466.20

8,300,000k

12.0

97,000k

153.42

1,700,000k

0.27

Alligator Bioscience AB Annexin Pharmaceuticals AB Aqua Bio Technology ASA

ALK-Abelló A/S

120,000k 1,900,000k

Curetis AG Cyxone AB

European Biotech Stocks

5.85 123.76

Evgen Pharma plc

0.18

17,000k

170,000k

Evolva SA

0.26

200,000k

3.08

210,000k

Evotec AG

21.32

3,200,000k

0.36

6,400k

Expedeon AG

1.34

69,000k

0.31

2,200k

Expres2ion Biotech Holding AB

1.13

14,000k

Argenx SE

78.20

2,500,000k

Faron Pharmaceuticals Oy

1.25

39,000k 53,000k

Allergy Therapeutics plc

Arocell AB

0.43

17,000k

Fermentalg SA

3.08

Asit Biotech SA

3.10

54,000k

Fit Biotech Oy

0.0

1,400k

Avacta Group plc

0.31

35,000k

Formycon AG

30.95

280,000k 18,000k

5.65

150,000k

Fusion Antibodies Ltd.

0.81

Basilea Pharmaceutica AG

Avantium Holding NV

53.26

630,000k

Gabather AB

1.36

7,100k

Bavarian Nordic A/S

24.78

800,000k

Galapagos NV

83.0

4,200,000k

Bergenbio ASA

3.72

190,000k

Genedrive plc

0.31

5,800k

Bioarctic AB

10.79

950,000k

Geneuro SA

5.60

82,000k

Bio-On SpA

55.90

1,100,000k

Biocartis NV

12.20

630,000k

Genmab A/S

Biofrontera AG

Genfit SA

22.74

700,000k

140.34

8,800,000k

5.94

270,000k

Genomed SA

5.11

7,100k

48.05

830,000k

Genomic Vision SA

0.90

6,400k

Bioinvent International AB

0.24

85,000k

Genovis AB

0.59

37,000k

Biomed-Lublin SA

0.27

17,000k

Genoway SA

1.92

11,000k

76.30

8,900,000k

Gensight Biologics SA

2.17

54,000k

Biogaia AB

Biomérieux SA Biophytis

2.23

31,000k

Genkyotex SA

Bioporto Diagnostics A/S

0.46

69,000k

Genus plc

1.47

110,000k

27.79

1,700,000k

Biosearch Life SA

1.68

97,000k

Global Bioenergies SA

13.98

63,000k

Biotec Pharmacon ASA

0.50

24,000k

Hansa Medical AB

24.72

940,000k

36.48

190,000k

Heidelberg Pharma AG

2.75

77,000k

1.02

19,000k

Herantis Pharma Oyj

7.20

35,000k

Hofseth Biocare ASA

0.27

75,000k

Horizon Discovery Group plc

2.52

370,000k

Bioventix plc Biovica International AB Bone Therapeutics SA

9.40

72,000k

Brain AG

18.32

320,000k

22-23_EB_Autumn_2018_stock-list_ml.indd 22

52 weeks indicator low high

13.09.2018 14:00:10 Uhr


financial markets

european Biotechnology | autumn edition | Vol. 17 | 2018

COMPANY Hvivo plc

QUOTE 0.70

M-CAP

52 weeks indicator low high

COMPANY

QUOTE

M-CAP

56,000k

PCI Biotech Holding ASA

3.60

92,000k

Pharma Mar SA

1.58

350,000k

Pharming Group NV

1.25

770,000k

10.45

120,000k 130,000k

Hybrigenics SA

0.48

22,000k

Idorsia Ltd.

21.71

2,800,000k

Immunicum AB

0.73

37,000k

Pharnext SA

Immunodiagnostic Systems plc

2.57

74,000k

Photocure ASA

6.18

Immunovia AB

17.39

330,000k

Physiomics plc

0.05

3,700k

0.19

28,000k

Plant Advanced Technologies SA

23.0

21,000k

Polyphor AG

Immupharma plc Index Pharm. Holding AB

0.65

41,000k

29.44

320,000k

Infant Bacterial Therapeutics AB

18.37

210,000k

Poxel SA

6.63

170,000k

Innate Pharma SA

4.58

260,000k

Premaitha Health plc

0.12

47,000k

Integragen SA

2.07

14,000k

Probi AB

41.03

480,000k

Intervacc AB

0.90

34,000k

Probiodrug AG

3.03

24,000k

Inventiva SA

8.52

190,000k

Promore Pharma AB

1.45

29,000k

Isofol Medical AB

3.12

99,000k

ISR Holding AB

0.41

7,700k

Proteome Sciences plc Qiagen NV

0.04

13,000k

32.93

7,500,000k 20,000k

Kancera AB

0.10

19,000k

Quantum Genomics SAS

1.75

Karo Pharma AB

3.27

540,000k

Relief Therapeutics Holding AG

0.01

12,000k

Kiadis Pharma BV

12.80

290,000k

Reneuron Group plc

0.94

30,000k

Kuros Biosciences AG

5.93

51,000k

Salvarx Group plc

0.85

31,000k

Lysogene SA

1.95

24,000k

Saniona AB

3.33

74,000k

Mabion Ltd

26.13

360,000k

Santhera Pharmaceuticals AG

14.74

95,000k

MDxHealth SA

2.86

160,000k

Sareum Holdings plc

0.01

24,000k

Medical Prognosis Institute A/S

1.21

30,000k

Scancell Holdings plc

0.13

53,000k

Selvita SA

11.65

190,000k

Sensorion SA

2.86

37,000k

Shield Therapeutics plc

0.35

40,000k 130,000k

Medigene AG

12.56

310,000k

Medivir AB

3.98

95,000k

Mereo Biopharma Group plc

3.09

220,000k

Metabolic Explorer SA

1.99

47,000k

Silence Therapeutics plc

1.93

Midatech Pharma plc

0.29

19,000k

Simris Alg AB

0.71

6,800k

Molecular Partners AG

17.64

370,000k

Skinbiotherapeutics plc

0.23

28,000k

Molecular Medicine SpA

0.40

190,000k

Stallergenes Greer plc

28.50

560,000k

Mologen AG

4.89

37,000k

94.65

3,000,000k

Morphosys AG

Summit Therapeutics plc Swedish Orphan Biovitrum AB

0.41

33,000k

25.54

7,100,000k

Motif Bio plc

0.36

110,000k

Synairgen Research Ltd

0.22

20,000k

Nanobiotix SA

17.60

340,000k

Targovax ASA

1.13

56,000k

NEL ASA

0.37

400,000k

Theradiag SA

1.47

13,000k

Neol Biosolutions SA

0.25

2,300k

14.64

46,000k

Neovacs SA

0.31

29,000k

Tissue Regenix Group plc

0.10

120,000k

Neuron Biopharma SA

0.30

4,900k

Tiziana Life Sciences plc

1.11

140,000k

Theranexus SADIR

Neurosearch A/S

0.62

15,000k

Transgene SA

2.98

190,000k

Neurovive Pharmaceutical AB

0.40

37,000k

Txcell SA

2.42

56,000k

Newron Pharmaceuticals SpA

9.11

160,000k

Valirx plc

0.03

11,000k

Nicox SA

7.75

230,000k

Valneva SE

3.95

310,000k

Nordic Nanovector ASA Novozymes Biopharma DK A/S

5.67

270,000k

46.67

13,800,000k

Vectura Group plc

0.82

550,000k

Veloxis Pharmaceuticals A/S

0.13

230,000k

Noxxon Pharma NV

2.58

10,000k

Vernalis plc

0.07

36,000k

Nuevolution A/S

1.59

79,000k

Verona Pharma plc

1.34

140,000k

Oncimmune Holdings plc

1.28

79,000k

Virogates A/S

10.59

34,000k

Oncoarendi Therapeutics SA

5.46

72,000k

Vita 34 AG

14.60

61,000k

Oncodesign Biotechnology SA

10.35

71,000k

Xbrane Biopharma AB

5.44

34,000k

Oncopeptides AB

14.44

630,000k

1.09

56,000k

Onxeo SA Optibiotix Health plc

1.17

98,000k

Orphazyme A/S

9.88

190,000k

Oryzon Genomics SA

4.04

140,000k

OSE Pharma SA

3.98

58,000k

Oxford Biodynamics plc

2.35

220,000k

Oxford Biomedica plc

9.09

600,000k

Oxurion NV

6.84

260,000k

Paion AG

2.27

150,000k

22-23_EB_Autumn_2018_stock-list_ml.indd 23

Xintela AB Zealand Pharmaceuticals A/S

0.31

9,500k

14.08

450,000k

23

52 weeks indicator low high

All quotes are listed in euro. All data is provided without guarantee. The effective date is 10 September 2018. These dedicated biotech companies are listed on European stock markets.

13.09.2018 14:00:17 Uhr


24

FinAnciAl MArkEts

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Sustained optimism REPORT

AnAlysis of EuropEAn BiotEch compAniEs on thE stock mArkEt

Biotech stock markets are still appreciated by investors. Whereas the number of IPOs significantly decreased in the first half year of 2018 compared to 2017, follow-on financings doubled. This is particularly true for European stock exchanges. Nurtured by the further progress of breakthrough technologies such as CAR-T for cancer therapies, listed European biotech companies profit from a sustained optimism among investors.

24_33_Studienbeitrag_mr.indd 24

13.09.2018 13:14:33 Uhr


FinAnciAl MArkEts

European Biotechnology | Autumn Edition | Vol. 17 | 2018

B

iotech stockmarkets have developed reasonably well in 2018 so far and iPOs are still a viable route to access further capital. Although there have been no recordbreaking highs, an overall growth trend is still obvious. According to the analysis, which also includes all European biotech firms listed on the US Nasdaq, all of the key figures for 2018 so far show a sustained optimism. the 240 European biotech companies raised a total of €2.47bn in financial proceeds by the half year of 2018 – 36% more than in the same period of time in 2017 (€1.81bn) (see Fig. 1). When it comes to iPOs and listings, however, 2018 showed a lower activity. A to-

€292m Amount of money raised via iPOs by European biotech companies in HY 2018.

tal of five European biotech iPOs took place, raising a total figure of €292m. this means a decrease of 15% compared to the same period in 2017 (see Fig. 2). Four companies opted for one of the 14 European trading centres, and one floated on Us nasdaq.

€2.47bn

tions changed slightly. Paris (47) is still at the top, although it has had no biotech iPOs so far in 2018. currently, stockholm (44) and london (44) share second place; the stock exchange in sweden is now home to three more listed biotech companies. the shares of 39 European companies are currently traded on Us nasdaq. in addition to the iPO, two secondary listings (Morphosys AG and Biofrontera AG) took place.

€1.81bn

+36%

HY 2017

Picture: peshkov/istockphoto.com

24_33_Studienbeitrag_mr.indd 25

HY 2018

Fig. 1: Total financial proceeds of European biotech companies

Follow-on financings in 2018, investors spent even more money on European biotech companies compared to the same period in 2017. in the first half of this year, a total of €2.18bn was dropped into these companies via follow-on financings, a substantial increase of 48% compared to the same period in 2017 (see Fig. 3). the average size of capital increase in 2018 was a bit higher (€28m) compared to €25m in the same period in 2017. Within Europe, Euronext and Alternext together demonstrated the most activity, with 19 financings and total proceeds of €321m, followed by AIM in London (13 financings, €93m) and Frankfurt (11 financings,

€88m). the Us-listed companies brought in a total of €1.21m capital, with 14 financings, a 50% increase compared to half year numbers of 2017.

Oncology in the spotlight the vast majority of companies (85%) are active in the health sector, developing diagnostics or new therapies for which major investments and long-term financial strategies are required. All of the five stock market newcomers in 2018 can be assigned to this category. the most attractive field within the health area is oncology (see Fig. 4). A total of 74 com-

Initial public offerings: total proceeds HY 2018

Average volumes

total number €292m

€58m

5

–15%

Five IPOs in 2018 Whereas swiss company Polyphor sA raised a very high volume of €130m, the other three Europe-based iPOs rested more at the lower end – Polish OncoArendi therapeutics s.A. (€13.7m), Danish ViroGates A/s (€10m), and swedish calliditas therapeutics AB (€8.8m). the nasdaq iPO of Uk-based Autolus therapeutics reached a total of €129.5m. in addition to the iPOs, two new listings that did not raise additional money took place on the nasdaq nordic stock Exchange in stockholm (Fluicell AB and Gabather AB). With this activity, the list of the most attractive stock market loca-

25

HY 2017

€38m

€341m

9

€2,180m

79

Fig. 2: Number of IPOs and capital raised Follow-on and other financings: total proceeds HY 2018

Average volumes

total number

€28m +48%

HY 2017

€25m

€1,471m

58

Fig. 3: Number of financing rounds and capital raised

13.09.2018 13:14:51 Uhr


26

FINANCIAL MARKETS

European Biotechnology | Autumn Edition | Vol. 17 | 2018

REPORT Health/medicine (204 companies)

Agribiotechnology (1 company)

Industrial biotechnology (21 companies)

Non-specific services (14 companies)

Autoimmune diseases

27

Cardiovascular diseases

16

Dermatology

6

Infections

25

Inflammatory diseases

31

Metabolic diseases

29

Neurology

36

Oncology

74

Respiratory diseases

11

Other

48

*Several mentions possible

Fig. 4: Fields of activity and the areas of indications* medical biotech companies address

panies operate in this field, followed by neurology (36), inflammatory (31) and metabolic diseases (29), as well as autoimmune diseases (27). Service providers that offer biotechbased processes for others in the B2B environment have a completely different risk profile than companies focused on biopharma. Although mid- and largecap companies such as bioMérieux and Eurofins fall into this category, only 14 companies overall operate in this field. Another area of listed European companies is industrial biotechnology. A total of 21 firms are involved in the development of new enzyme-based processes or

biobased solutions for various industries. With 14 different trading centres, the variety of stock exchanges relevant to European biotech companies is huge. Analysis of previous years has revealed that the cross-border stock market Euronext is especially attractive for European biotech companies, as it clearly provides a critical mass of listed biotech companies as well as a nurturing environment in terms of innovation and high-risk financing. However, in 2018, less activity took place here and no biotech company went public. But the Euronext-listed companies succeeded with followon financings – in particular those with

Key facts of the European public biotech sector › 240 public European biotech companies* › 39 European biotech companies listed on US Nasdaq › 5 IPOs with €292m capital raised in HY 2018 (-15%) › 79 financings with €2.2bn capital raised in HY 2018 (+48%) › Total financial proceeds of €2.47bn in 2018 (+36%) © BIOCOM AG

24_33_Studienbeitrag_mr.indd 26

a double listing in the US (Cellectis and DBV Technologies). The first half-year of 2018 also demonstrated that the other cross-over exchange in Europe, the Nasdaq Nordic, is catching up. With the IPO of ViroGates A/S in Copenhagen, two new listings at Stockholm First North, and three Swedish companies changing from First North in Stockholm to Nasdaq Nordic Main (Nuevolution A/S, Immunovia AB, Immunicum AB), significant activity took place there in 2018. Another sign for sustained optimism in the European stock market comes from the two well-received IPOs in Switzerland and Poland. That the antibiotics developer Polyphor succeeded in raising €130m in its stockmarket debut on the Swiss Stock Exchange (SIX) demonstrated the high potential of life sciences capital available for attractive biotech stories, even in challenging markets such as anti-infectives. At the same time, it underlined the strong position of SIX in 2018. Reproductive health specialist ObsEva, already listed on Nasdaq, also announced a new listing in Switzerland.* The IPO of Polish drug developer OncoArendi on WSE increased the

13.09.2018 13:15:22 Uhr


SCIENTIST & LAWYER For more than 80 years we are where you are and we deeply understand your business. From all perspectives and in all aspects. In all technical and legal fields of intellectual property. With an interdisciplinary team of patent and legal professionals. www.boehmert.de

27_EB_Autumn_2018_Boehmert.indd 1

14.09.2018 11:06:59 Uhr


FINANCIAL MARKETS

9

8

7

3

2

1

Helsinki **

Milan

Amsterdam *

Madrid

Brussels *

Copenhagen **

6

2018

1

1

6

Warsaw

9

Oslo

12

2018

1 2018

1

17

Zurich

25

Frankfurt

London

240

44

New York

44

47

Stockholm ** 2018

REPORT

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Paris *

28

*Euronext, **Nasdaq Nordic

© BIOCOM

Fig. 5: Overview of trading centres with total numbers of listed European biotech companies and IPOs in 2018

number of listed companies in Warsaw to seven. The company, founded in 2012, focuses on novel therapeutics for neoplastic and inflammatory diseases. They have an asthma-treatment candidate in clinical Phase 1 and an immunothera-

€2.47bn capital raised by European biotech companies on the stock markets in HY 2018.

peutic approach – based on arginase inhibitors to be used as a combination therapy for the treatment of patients with colon, lung, skin, or brain cancer – in preclinical development. The IPO was met with significant demand from both institutional and individual investors and IPO activitiy and volumes in €bn since 2013

Fewer new entries on Nasdaq The first six months of 2018 saw quite modest activit y for new European biotech companies on Nasdaq. The only IPO took place in June, when cancer biotech Autolus Therapeutics plc from UK went public in New York. The company, which is developing blood cancer therapies based on highly targeted CAR T cells, succeeded in raising a total of €129.5m, with a share price at the upper end of the range. In addition, two already-listed German companies decided to go for a secondary listing on Nasdaq this year: MorphoSys AG (€168m) and Biofrontera AG (€10m). Antibody specialist MorphoSys gained much interest due to its late-stage biotech drug candidate MOR208, for which market approval is within reach.

So far, overall activity for 2018 demonstrates a positive stock market development for European biotech companies. But traditionally, the first half year shows lower activity than the second half of the year. For this reason, many experts expect an ongoing positive trend, so that numbers in the upocoming month may possibly exceed those recorded in the first six months. * Please note: Secondary listing took place 13/07/18 and is not included in half-year-data of 2018 for this report.

Report is available online: www.biocom.de/en/analysis2018

For further questions: Sandra Wirsching s.wirsching@biocom.de

Follow-on financings in €bn since 2013 5

0.29

HY 2018

2.18

79 15

0.87

2017

4.30 0.56

2016

123 14

2.75 1.21

2015

141 21

5.08 1.25

2014 2013

the proceeds are aimed at bringing forward licensing agreements and strategic partnerships on an international level.

126 16

2.21 0.11

1.91

109 5 92

Overview of IPO activity and follow-on financings of European listed biotech companies since 2013

24_33_Studienbeitrag_mr.indd 28

13.09.2018 13:15:34 Uhr


33_EB_Autumn_2018_JLABS.indd 1

14.09.2018 12:48:55 Uhr


30

FinAnciAl MArkEts

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Promising company stories attractive for US investors

rEPOrT

Due to its broad spectrum of investors, the US Nasdaq continues to be an attractive stock market for European biotech companies, particularly when they are in late-stage development or active in promising areas such as immunotherapies. In 2018, Nasdaq saw one European biotech IPO, two secondary listings from European companies, and strong follow-on financings. Overall figures are much higher compared to 2017.

EuropEan biotEch companiEs on nasDaQ

Key facts of European listed biotech companies: US vs Europe Nasdaq US

US/Europe

Europe

Total numbers

Number of European biotech companies

25

14

202

240

Capital raised via IPOs/listings in HY 2018

€ 129.5m

€ 178.4m

€ 162.6m

€470.5m

Capital raised via follow-on financings in HY 2018

€ 578.4m

€ 458.3m

€966m

€2.0bn

Total proceeds in HY 2018

€ 707.9m

€ 636.7m

€1.13bn

€2.47bn

iPOs and listings on nasdaq are particularly interesting for companies which need a large amount of capital. this holds true for the field of CAR-T-focused companies at the beginning stage of clinical development, such as Autolus therapeutics. the company was spun out from University of london in 2014, has a pipeline of product candidates in development for the treatment of haematological malignancies and solid tumors, and in June 2018 achieved a successful iPO on nasdaq, raising €129.5m in total at the upper share price range.

Unbroken investors’ appetite

panies were listed on nasdaq at the end of the first half of 2018. They raised total financial proceeds of about €1.3bn via iPOs, secondary listings, and followon financings. This is a significant gain of 50% compared to the same period in 2017 (€897.5m), demonstrating an unbroken investors’ appetite in European biotech companies. For the second year in a row, capital investments show a growth trend not only in numbers, but also in European exchanges

24_33_Studienbeitrag_mr.indd 30

4

374.8

2016

164.6

2015

15

490.7

5 3

806.2

21 4

506.9 59.4 47.0

1

14

391.3 406.6

2014 2013

Us nasdaq

162.6 129.5

HY 2018 2017

compared to last year, the volume increased by 44%. The only IPO in the first half of 2017 was swiss ObsEva, which brought in €90m. However, iPO volumes in 2018 were rather atypical: the largest volumes in the Us and Europe were nearly at the same level – both approximately €130m (Polyphor and Autolus). in total, 39 European biotech com-

volumes. the development is driven by a constant flow of good company news, primarily from technology firms focusing on new therapeutic approaches such as gene therapy, crisPr or cancer immunotherapies. Other more uncertain conditions – such as the Us president’s pharma strategy – apparently had less influence on the stock market. Experts foresee an ongoing positive trend for biotech companies on Us nasdaq in 2018.

740.0

16 9 5 1

Fig. 1: Comparison of IPO numbers and volumes (in €m) raised by European companies

13.09.2018 13:18:47 Uhr


31_EB_Autumn_2018_EuropaBio.indd 1

13.09.2018 13:18:57 Uhr


FINANCIAL MARKETS

European exchanges

US Nasdaq

587

total number

83

total number

2013

1,828

88

2014

1,482

727

2015

3,478

1,602

2016

2,181

566

2017

2,466

1,834

966

1,215

HY 2018

€12,402 €6,032 million

million

Fig. 2: Overview of follow-on financings in €m since 2013

50% increase in total financial proceeds The 39 listed European biotech companies attracted a combined total of €1.215bn in 14 follow-on financings, which means an increase of 50% compared to 2017 at the same time (€807.5m; 9 financings). The numbers also include the two secondary listings of German biotech companies MorphoSys and Biofrontera, which amounted to a total combined capital of €178.4m. Compared to their counterparts that are only listed on European stock exchanges, the firms on the US Nasdaq not only generated more capital in total numbers, but also with much greater average volumes (US: €86.8m vs. Europe: €14.9m). This again demonstrates that US Nasdaq offers a valuable platform for clinical stage companies with a  high capital demand. s.wirsching@biocom.eu

24_33_Studienbeitrag_mr.indd 32

European Biotechnology | Autumn Edition | Vol. 17 | 2018

“Open window will hold on” For private investors, Nasdaq rather than Europe is often the preferred place for a biotech IPO, says Karl Nägler, Partner Health & Care at European investment firm Gimv. VC CAPITAL PERSPECTIVE

EuroBiotech_Do you think at present it’s a good time for a biotech company to go public? Karl Nägler_ Already for

ness models they can understand and are often not interested in early stage companies. This means: if you are planning a stock market debut, your company story should fit into their scheme, otherwise it will be difficult to hold performance levels high in the long-term.

some years now, we see an open IPO window for biotech. This is particularly true for US Nasdaq for which we saw very good performing numbers durKarl Nägler, Partner, ing the recent months and EuroBiotech _ So you Health & Care, Gerpromising companies acwould advise biotech many, joined Gimv in tive in e.g. gene therapy, or companies to have a 2011. Previously, he immunotherapeutics who look at Nasdaq? worked at Ventech in have had positive news Karl Nägler_We at Gimv Paris and Atlas Venture flow. This development always evaluate an IPO in London and Munich. also has an influence on very openly, both in the Nägler holds a PhD in the European stock marUS and in Europe. The demolecular biology. kets: if Nasdaq Biotech incision really depends on indices are going up, Euthe development stage of the respective rope is also well performing. At present, company, its business model, investor no dramatic downswing is visible in the base and origin, its liaison with the US US, although from my perspective curmarket. What speaks for Nasdaq: the lirent indices already tend to reach record quidity is much higher and you will easier levels from 2015. The open window find comparable companies with similar seems to hold on. business models. This makes it easier to reEuroBiotech_How do you evaluate Euceive an adequate market capitalisation. rope as a stock market location? Karl Nägler_Whilst observing the Europe-

an stock market during the recent years, we have seen a quite positive development. At Euronext in particular, a substantial number of biotech IPOs took place, but since 2018 this development decelerated a bit – due to some negative news flow in 2017 about listed companies e.g. at Euronext Paris. For this reason, I think, at the time being, more mature biotech businesses are requested by investors in Europe. In addition, we see less specialist investors active in Europe. Generalists usually look for safer investments and busi-

EuroBiotech_So far, IPO activity for European companies was very modest. Do you see any reasons for that? Karl Nägler_I think there is no empty

pipeline and I expect to see more activity soon. You have to take into account that candidate companies need to be at the right stage of development. Furthermore, it takes time to prepare them for such a step – in particular, if the IPO is planned in the US. You have to make sure that the firm is known by US investors and that the management team is  ready for this transatlantic task.

Picture: Gimv

32

14.09.2018 12:48:34 Uhr


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34

FinAnciAl MArkEts

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Retrospective: Biotech Listings on the Swiss Exchange An IPO is a veritable option for funding biotech companies. This has been proven by the successful listing of a number of companies on SIX in the past two decades.

by Christrian fehr

REPORT

the success of lonza going public in 1999 paved the way for the Actelion listing on siX in the following year. Actelion pioneered biotech company listings and it became the largest European pure-play listed biotech firm over time. In 2016, the Actelion success story culminated in a Us$30 billion takeover bid by Johnson & Johnson. Today, SIX is one of the leading biotech exchanges in Europe and it hosts the highest capitalized European biotech company. things started to take off following the cytos (now kuros Biosciences) iPO in 2002. in the period 2004 to 2007, SIX welcomed four new biotech companies: Basilea, Santhera, Newron and Addex. And it was also around this time that the sXi Bio+Medtech index was created, underpinning the strong commitment of siX to the biotech sector. After the listing of Evolva and Mondobiotech (now relief therapeutics) in

market capitalization of around cHF 1.5 billion on the first trading day.

“it’s very important for idorsia to be quoted on the same stock exchange as big companies such as Novartis, Roche but also Lonza, many suppliers and many companies involved in biotech.” Christian Fehr Relationship Manager Primary Markets, SIX

Jean-Paul Clozel, CEO Idorsia

2009, there was something of a break in biotech listings and then Molecular Partners in 2015 heralded a new era. In 2017, Idorsia, the company spun off as a contribution-in-kind to the former shareholders of Actelion, was listed and achieved a

In the current year 2018, SIX welcomed with Polyphor and ObsEva (dual primary listing) two more pure-play biotech companies. the listing of Polyphor allowed the company to raise cHF 155 million and was one of the largest European biotech

12,000

Polyphor sPi

iPOs

Idorsia

10,000 Newron Pharmaceuticals

Addex Therapeutics

Relief Therapeutics

8,000 Actelion Pharmaceuticals

Cytos Biotechnology

Basilea Pharmaceutica

Kuros Biosciences

6,000

ObsEva

Molecular Partners

4,000 Santhera

Evolva

2,000 01/99 01/00 01/01 01/02 01/03 01/04 01/05 01/06 01/07 01/08 01/09 01/10 01/11 01/12 01/13 01/14 01/15 01/16 01/17 01/18 01/19

Biotech listings on the Swiss Exchange in the past two decades

34-35_EB_Autumn_2018_Advert_Six_Beitrag_mr.indd 34

Picture: SIX, Source: SIX

Lonza

13.09.2018 13:21:19 Uhr


FinAnciAl MArkEts

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Light

Standard

Premium

Deluxe

by one bank

by two banks

by three banks

35

Informatoin, Education & Network by siX Factsheet by Morningstar

Source: SIX

Research Coverage by Baader Helvea, Bank Vontobel, Zürcher Kantonalbank

iPOs in recent years, in terms of proceeds raised by an issuer to finance the development of its pipeline. Obseva, already listed in the US, chose to list on SIX for various reasons including to raise its profile among Swiss and European investors and provide another robust market for any future potential financing activities. This impressively underlines the continuing attractiveness of the Swiss exchange for life sciences and in particular biotech companies – regardless of size. in summary, 14 biotech companies listed on siX in the past two decades and they aggregated a market capitalisation of around cHF 30 billion as per mid-August 2018. There have been other impressive examples of listed companies in the space, which are not counted in this number. For instance Cosmo, which over time developed from its biotech origins into more of a pharmaceutical company. the prominent global pharmaceutical players Novartis and Roche feature in the issuer base of siX and they lay the foundation for a well-diversified peer group whose strong appeal reaches far beyond switzerland’s borders. it therefore comes as no surprise that SIX ranks as Europe's most important life science exchange and leading biotech listing location. switzerland’s capital-rich investor base, powerful banking system and its industry expertise make up the country's dynamic life sciences ecosystem. this allows companies to efficiently raise capital with a view to driving scientific discovery through to market launch. The Lonza experience (see quote) is proof of this. Between January 2017 and August 2018, siX-listed biotech companies raised about cHF 3.5 billion equity capital.

34-35_EB_Autumn_2018_Advert_Six_Beitrag_mr.indd 35

How SIX supports listed biotech companies Achieving trading liquidity and adequate analyst coverage has become more challenging given the increase in regulations. As a result, listed biotech companies need to recognise that these are important issues and address them accordingly. Alongside other initiatives, the SIX Stage Program provides the means for doing so.

“successful iPOs and capital raisings in 2017 and 2018 confirm the deep pools of capital available in Switzerland. For example, Lonza raised over cHF 3.1 billion in two capital increases which marked the largest equity funding by a siX listed non-financial corporate last year.” thomas Zeeb, Head Securities & Exchanges, SIX

One of the most important reasons for listing on an exchange is the facilitated access it gives to the capital market and therefore to growth capital. However, to use capital markets effectively, a company needs to have a minimum volume of trading liquidity. shares of small and medium-sized companies are often less liquid for a variety of reasons. SIX offers several services and initiatives such as the Stage Program to sup-

port companies in the process of building their presence in the market and achieving an appropriate valuation. Companies benefit from a regularly updated factsheet and research reports prepared by experienced partners and can thus reach a larger number of capital market participants.

“We were the first company to join the stage Program in 2016 and have noted increased investor awareness and interest due to the additional analyst coverage, since.” stefan Weber, cEO newron

through siX, companies also gain access to statistics and services that facilitate the “Being Public”. to guarantee the independence of the reports and strengthen the trust of investors in the research, no contractual relationship exists between the listed company and the research provider. SIX acts as a link between the two. in addition, a research committee has been set up to ensure the interests of the different parties are taken into account. It is an advisory body to SIX. Author contact: christian.fehr@six-group.com www.six-group.com

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FINANCIAL MARKETS

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Coming of Age A quick walk through the last 20 years of biotech investing in Europe and a snapshot of the state of the industry today. A new mode of action has been established and the key ingredients for successfully financing innovative therapies and treatments for the benefit of patients in today’s globalised market environment have been defined.

VENTURE CAPITAL

› Dr. Hubert Birner, Managing Partner, TVM Capital Life Science

The biotech industry in Germany and Europe can now claim a history of more than two decades. Looking back at the life cycle of this industry, we can certainly identify some shifts and milestones that triggered major change. In the early days of investment in biotechnology and life sciences – at least in Germany – federal programmes were set up to support acadaemia with promising biotech projects. To facilitate the development of an ‘entrepreneurial spirit’ within these circles, the role of investors, especially venture capital investors, focused on building well-functioning companies around the idea of an entrepreneur. The necessary capital and network of expertise was provided, and syndicates of investors financed within several rounds to finally IPO the company at one of the relevant stock exchanges. The IPO usually was a form of exit and financed the commercialization of at least one product candidate. Risk mitigation was handled on com-

pany level; they were to build a broad, multi-stage product pipeline that ensured the development and growth on a longterm scale.

Venture capitalists had to get disruptive The year 2008 was a memorable year for the global economy at large and inevitably for the biotech industry and all players in the industry – namely venture capital providers. However, the meltdown of the financial markets in late 2008, although it had its well-known implications on all of us, was not the start of a phase of rethinking the finance model in the industry. That started even earlier. The “pharmaceutical ecosystem” was already transforming. Emerging markets were gaining significance, while the established pharmaceutical markets of Western Europe and the U.S. grew more slowly. The pharmaceutical business underwent major reconstruc-

tion and demanded higher capital efficiency. Undoubtedly, the biotech sector also experienced major pressure from private and public capital markets, and the sector was not rewarded for the years of work that management teams and their investors had put into the development of broad pipelines. Therefore, IPOs, if they happened at all, were valued often only slightly above the last private financing round and became financing transactions rather than being an exit. Less money from private and public investors was flowing into the sector. The biotech industry – and above all the venture capital firms – needed to develop new models to finance early-stage development assets. Their limited partners were not willing to accept the overall risks connected to drug development any longer and wanted to see higher capital efficiency, as well as decreased holding periods. TVM Capital Life Science and others started to think about new models of financing life sciences innovation, finding ways of managing drug development in a significantly more cost-effective development setup and governing the necessary development steps in a very different setting. This idea was fuelled by a growing perception on the part of the big pharmaceutical players that their in-house capacity for innovation was not increasing fast enough to fill a widening gap in their products pipelines related to an upcoming patent cliff which significantly would affect overall sales.

Source: TVM Capital Life Sciences Venture Capital

Successful TVM Capital Life Science exits 2000–2018

36-37_EB_Autumn_2018_TVM.indd 36

Global health care expenditures are projected to reach US$8.7tn by 2020, from

Picture: TVM

The investment case in biotech as of today

13.09.2018 13:21:51 Uhr


FINANCIAL MARKETS

Picture: TVM

European Biotechnology | Autumn Edition | Vol. 17 | 2018

36-37_EB_Autumn_2018_TVM.indd 37

Organic

In-licensed

M&A

100% 80% 60% 40% 20%

2014

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2008

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0% 1986

US$7tn in 2015. Growth is driven by improving treatments in key therapeutic areas coupled with rising labour costs and an increased life expectancy. North America, Western Europe, China, and Japan continue to be the largest healthcare markets. As populations age, healthcare will take an ever-larger share of GDP. Urgent unmet medical needs, the need of pharma and big biotech to diversify pipelines through acquiring external innovation, and the promise for high rewards generated by successful drug development projects have the potential to generate good return for all stakeholders: investors, founders, industry, and patients. Although pharma companies continue to deal with the repercussions of patent expiries and payers’ cost control efforts, the growing acceptance of innovative drugs that are either first-in- class or best-in-class, offering clear clinical benefits, are expected to drive sales growth for the next several years. Sales are expected to grow at an average of 4.4% annually to total projected US$1.2tn in 2020. Sales from the top 10 pharmaceutical companies account for ~35% of the global pharma market today. Scientific progress, general increased levels of education, and a more empowered patient population are driving changes in healthcare towards a more personalized experience that demands meaningful health outcomes as the core metric. However, despite the anticipation for steady and long-term growth, the industry faces several inherited challenges. R&D spending grew from US$0.5bn per new drug approval in the mid-1990s to up to US$2.5bn today (this includes the cost of the pipeline products that failed). National reimbursement and insurance policies are increasingly incentivizing the prescription of less costly generic drugs after patent expiration. Pharma is also aiming at a rather narrow set of indications driven by blockbuster economics (>US$1bn in annual revenues). This is in stark contrast with the actual industry average for pharma products of US$522m five years post launch. Within the next five years, until 2022, current annual

37

External innovation now accounts for over 60% of the combined sales of the top 25 companies. Source: TVM Capital Life Sciences Venture Capital

Combined sales of current top 25 pharma companies

sales of approximately US$160bn will be at risk due to patent expirations. The industry will face mounting price pressure driven by governments seeking to control healthcare costs.

A new mode of action to successfully finance innovation in biotech At TVM Capital Life Science a new mode of action of investing in early-stage drug development – as well as later-stage platform and medical technology companies – was installed to handle the above-mentioned requirements and challenges. The company invests in early-stage drug development projects and chaperons them to Proof-of-Concept (PoC) with a team of serial entrepreneurs and advisors and external providers for full-service R&D, specializing in lean development to PoC. This approach ensures reduced timelines and cost while providing big pharma quality for the produced clinical data. We offer our early-stage investees a majority stake outlining a clear path to exit. The management teams, founders, or originators of such projects will benefit from a reliable in-going and out-going equity participation as the capital required to exit is committed upfront and does not depend on future financing rounds with unpredictable dilutive effects. Ensuring exit at

reach of PoC requires a highly skilled investment team with expert knowledge of the pharmaceutical industry‘s future demands. Also, the mitigation of investment risks in this setting is happening within the respective fund, not within the investee company as was the case in the early days of biotech investing. This shift required a new thinking and a new skillset in the investment team; the firm also built up an experienced operational team that can meet the challenges and is very deeply integrated into the global pharmaceutical industry. Now, after a couple of years, the investment firm prides itself on the smooth transition into this new mode of action. The company's recent exit of AurKa Pharma to Eli Lilly is a rewarding proof of the investment rationale. However, it is important to say that this mode of action is not applicable to companies developing a platform technology, or companies offering innovation within the segments of medical technology or ehealth. TVM Capital Life Science continues to invest in promising companies in these segments but will apply a later-stage, minority investment approach in these cases. Again, from the experience of the company‘s current investment activities, it is felt that this two-pronged investment strategy currently is the path of success for a life sciences dedicated venture capital firm like TVM – the emphasis being on ‘currently.’ 

13.09.2018 13:21:57 Uhr


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FINANCIAL MARKETS

European Biotechnology | Autumn Edition | Vol. 17 | 2018

“Liquidity is

key ”

Roche’s US arm Genentech has secured access to Affimed NV’s ROCK platform to add multivalent antibodies to its cancer pipeline. These antibodies engage both NK cells and T cells of the innate and adaptive immune system, respectively. Affimed CEO Adi Hoess talks with EuroBiotech about the US$5bn deal and about Affimed’s financing history. ONCOLOGY

in acute myeloid leukaemia – a very important indication – Amphivena is different. Affimed might be assigned a fraction of the value of Amphivena either when the company is acquired for a certain amount of money, or when differentiating clinical data is generated. At this stage, it’s difficult to set a value for the Phase I asset. But seeing fewer toxicity issues compared to competing bispecific antibody drugs, we are confident that Amphivena has a promising candidate.

make with Genentech was much bigger than we initially envisioned. Serious partnering discussions started in early 2018 but clinical data we presented some months ago clearly helped to accelerate the process. Most investors are interested in companies that develop products. As the value of the company is calculated almost exclusively based on the proprietary drug pipeline, it was important for us to keep the rights for our lead programmes AFM13 and AFM11. That we could sign such a sizable deal indeed was a bit stunning to investors. But as Affimed has shown various times in the past, our technology can generate a significant number of molecules that activate NK cells. And it is these molecules Genentech is interested in to complement its immunooncology pipeline. EuroBiotech_Since the announcement of the Genentech partnership Affimed’s stock has tripled. With a market capitalization of US$300m, is there still some near-term upside potential? Hoess_ We believe there is continued up-

side as, our lead candidate AFM13 showed encouraging efficacy data in two indications: Hodgkin’s lymphoma and T cell lymphoma. After early clinical data in a monotherapy as well as in a combination therapy setting, we now expect updates on these two AFM13 studies later this year. Together with our partner University of Texas MD Anderson Cancer

38_EB_Autumn_2018_InterviewFinance_ml.indd 38

DR. ADI HOESS began his biotech career at Morphosys AG as a scientist. The German native later became Director of Business Development. After Morphosys, he was Chief Commercial Officer at Jerini AG and CEO of Jenowis AG. In 2010, Hoess joined Affimed. Since 2011 he has been the company’s CEO.

Center, we will present preclinical data from a project combining AFM13 with adoptive NK cell transfer. EuroBiotech_ And what about the two companies Amphivena and Abcheck where Affimed owns 18.5% and 100% stakes, respectively? Hoess_Abcheck is extremely important

from a strategic point of view but I don’t see it as a value driver. The Czech company is an expert in antibody-binding domain generation. Developing a product

EuroBiotech_Affimed is based in Heidelberg, Germany. To be listed on the US stock exchange Nasdaq, a Dutch holding company was created. Do you recommend this strategy? Hoess_The German law comes with some

restrictions that are not ideally compatible with a biotech company – especially regarding access to capital. Other than the German AG, the Dutch NV allows us to operate like a US Inc. The structure allows US investors to be easily investible in Affimed. It’s a working template that is reproducible in a straightforward fashion. As US investors can focus on so many companies listed on their stock exchanges, they are less likely to look in detail at European companies. So for easier access to US capital your company is better listed in the US. Additionally, there’s a liquidity issue. The Affimed stock shows a high daily trading volume. Smooth investing and divesting in a stock is important for US short-term traders. If only a few hundred shares of a company are traded every day – as is the case for many Affimed-sized biotech companies listed on European stock exchanges – that’s not  going to work for these investors. m.laqua@biocom.eu

Picture: Affimed

E u r o B i ote c h _ G enente ch is p ay ing US$96m upfront and up to US$5bn, depending on the progress of the collaboration, plus royalties. How did Affimed manage to bag that deal without giving away its clinical-stage lead assets? Hoess_The collaboration we were able to

13.09.2018 13:24:02 Uhr


AdVErtoriAl

European Biotechnology | Autumn Edition | Vol. 17 | 2018

39

A new treatment paradigm TCR CanCeR TheRapy  Medigene is developing the next generation of effective TCR cell therapies 

aimed at establishing better control over cancer at reasonable production cost.  Medigene AG cultivates an in-house entrepreneurial start-up culture based  on deep scientific expertise within the  structures of an established biopharmaceutical company and follows a systematic discovery process in the T cell  receptor (TCR) cell therapy space. With  ongoing research to develop next-generation tools and to find important patient-individualised therapy targets for  those with high medical need, Medigene is navigating toward its goals – to  transform cancer from an incurable disease to a controllable factor and to bring  down production costs for highly innovative T cell therapies.

TCRs vs CAR-T cell therapy

Picture: Medigene AG

CAR-T cells, because they use an antibody fragment to dock the highly active  T cell onto the tumour cell, can only recognise surface proteins. A T cell receptor recognises small peptides that are  brought to the surface by major histocompatibility complex (MHC) molecules  from the intracellular space. Therefore,  a TCR can “look” inside a cell and see  what’s reflected. Many proteins get upregulated by a tumour, to give it growth 

39_EB_Autumn_2018_Advertorial_Medigene.indd 39

and survival advantages. These proteins  provide a differential window to target  such molecules to be seen by TCRs.  TCR therapy works on the basis of a  molecule that a T cell naturally uses.  Auxiliary signaling pathways, which  are coupled to that TCR, are all functioning independently and in parallel.  Therefore, the approach should be safer, more regulated, and more powerful.  Medigene expects to have better regulation and fewer side effects in the T  cells using TCR-based approaches.

Cell therapy production In cellular therapy, the product is a process. Establishment of a robust cell manufacturing process right from the very  beginning of development is crucial, as  it must deal with variations of patientderived material but has to result in a  product consistently delivering the expected therapeutic benefit. Medigene  knows very much about immune cells:   how they behave and how they can be  manipulated to have particular characteristics. This helped tremendously in  setting up the proprietary cell manufacturing process.

Medigene has established a GMP simulation lab onsite that can be used to explore new technologies out of the field  of robotics and automation in the production process. Developing automation improvements have the potential to  substantially reduce costs for cellular  immunotherapies in the future. Medigene is studying how to improve  the characteristics of future cellular  products. Potential side effects are still  a concern with cellular immunotherapies, so new methods with improved  control of T cell activity are needed. Medigene has developed an inducible T cell  receptor that can be turned on and off in  patients as needed. 

First trial started The trial of MDG1011 is the first such TCR  trial in Germany. In order to gain regulatory approval, Medigene contributed to   scientific advice meetings with the authorities to shape what to include with  respect to the production process, and  how the TCR-modified cells should be  characterised, thereby setting the standards for future developments. From a patient and medical point of view, cell therapy is on its way to further revolutionise  cancer treatment, becoming a standard  treatment option, and turning cancer  more into a “chronic,” if not even curable, disease. Contact Medigene AG Business Development bd@medigene.com Tel.: +49-89-20 00 33-33 06

13.09.2018 13:24:29 Uhr


40

ECONOMY

European Biotechnology | Autumn Edition | Vol. 17 | 2018

“A

unique approach to bring open innovation to Europe”

JLABS INCUBATORS In February, Johnson & Johnson Innovation, JLABS opened its first European

open innovation incubator, JLABS @ BE, at the heart of the Beerse Janssen R&D Campus in Belgium. European Biotechnology spoke with Günter Huhle, Head of J & J Innovation EMEA, about J&J’s approach to open innovation and its tremendous global innovation network, currently comprising ten incubators and over 420 companies that have collectively raised over US$10bn in growth capital.

Janssen R&D campus, which hosts JLABS @ BE. We are about to recruit another three companies in the coming weeks and call for more applications from healthcare startups. The ecosystem in Europe looks a bit different compared to the US. We realise you must be very careful in selecting the right talents and residents, which leads us to our selection criteria. First, it needs to be a very strong team and second, very compelling science that addresses areas of unmet medical need – but the team is key. Last but not least, there must be enough funding to enable the talents to meet their next milestone. The selection process normally takes us two weeks.

San Diego in 2012, then another in San Francisco, and it was a great success, so we expanded to the East Coast, Houston and Canada. I think what makes the JLABS concept attractive and unique to entrepreneurs is that there are no-strings attached, which means we are not signing any contracts as an obligation. For the entrepreneurs, this is important because it means they don’t dilute their ownership when they become a JLABS resident company. We open up the entire ecosystem of support for the residents – that means access not only to JLABS laboratories and equipment but also to consumer boards, our entire services, and our networks, as well as educational programmes on whatever you need to bring your enterprise from concept to commercialization. The second point is access to our scientists. We provide every resident with a JPAL. That’s a key expert in the area who can give advice and link them up with our broad J&J network. Last but not least, they are granted access to our Investor Hub. We have more than 45 investors partnering with us. In the past five years, we had 1260 one-to-one investment interactions and more than 98 larger investor events. EuroBiotech_In Europe, JLABS recently created the first in a series of incubators. What’s different compared to the US?

40_EB_Autumn_2018_Interview_JLabs_tg.indd 40

GÜNTER HUHLE heads Johnson & Johnson Innovation, JLABS EMEA. Prior to joining JLABS, he led the Business Development Organisation and the Mature Brands at Janssen. Günter received his MD and PhD from the University of Heidelberg and his Master of Science from the University of Witten/Herdecke. He is board-accredited in internal medicine and haemostaseology and holds a professorship at the University of Heidelberg. Since he moved into the pharmaceutical industry in 2001, Günter has held various leadership positions in R&D, medical, and business; first at Eli Lilly and then at Merck KGaA before joining Janssen and Johnson & Johnson in 2007.

Huhle_Indeed, this year, we announced

the first JLABS in Europe. Since February, seven investors have joined us at the Beerse

EuroBiotech_What’s most important for a start-up company contributing to an open innovation ecosystem? Huhle_It’s most critical that you compile a

team that is able to manage the science as well as oversee the business perspective. Second, experience and fundraising – including bootstrapping and raising public funds – is always a plus. EuroBiotech_Where do you want to go in the future with JLABS? Huhle_We think the ecosystem of science

and business creation in Europe is very scattered and thus so are the investments. So we think that in order to have a critical mass in Europe we need to be where the science and investments are. Thus, we are open to discussing different models, such as a JPOD, which is a scaled down version  of the full existing JLABS incubator. t.gabrielczyk@biocom.eu

Picture: Janssen

EuroBiotech_It took just six years from the launch of JLABS to create a global open innovation network in healthcare. How did it start and what is unique about J&J’s open innovation approach? Huhle_We started with the first JLABS in

13.09.2018 13:25:48 Uhr


Update on clinical trials LIVER CANCER

ˆ

Roche AG has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for its mAb combination therapy for hepatocellular cancer (HCC). Based on data from a Phase Ib study with Roche’s PDL1 blocker Tecentriq (atezolizumab) plus VEGF blocker Avastin (bevacizumab), the FDA granted the status for the antibody combo as a ďŹ rst-line treatment for advanced or metastatic HCC, the most common form of liver cancer. Breakthrough therapy designation is a process to accelerate the FDA review of drugs targeting serious conditions by limiting the amount of evidence normally needed to get drug approval. It is only granted when clinical trials indicate that the drug may offer a substantial improvement over available therapies and in indications with unmet medical need. According to statistics, the requirement to validate the approval through post-authorisation data, however, is often circumvented by companies through delaying the publication of additional data. B-CELL LYMPHOMA

ˆ

In August, Swiss ADC Therapeutics SA dosed the ďŹ rst patient suffering from relapsed or refractory diffuse large B-cell lymphoma with its antibody drug conjugate ADCT-402 (loncastuximab tesirine). In the pivotal Phase II trial the company will evaluate the objective response rate of patients to the CD19-targeting antibody, which is conjugated to a toxic pyrrolobenzodiazepine (PBD) dimer. In April, the company terminated a Phase II programme with an Her2PBD conjugate because of an insufficient safety-to-beneďŹ t ratio. However, in a Phase I trial, 27 of 49 patients responded to ADCT-402 treatment. Secondary endpoints of the Phase II trial include duration of response, complete response rate, relapse-free survival, progression-free survival, and overall survival, as well as safety, pharmacokinetics, and health-related quality of life.

41-43_EB_Autumn_2018_Trial_tg.indd 41

Servier and its development partner CTI BioPharma Corp. failed to show an improvement in progression-free survival through their DNA topoisomerase II blocker pixantrone plus rituximab in a patients with non-Hodgkin’s lymphoma. The DNA intercalator has conditional market authorisation in the EU. CARDIOVASCULAR CALCIFICATION ˆ

In August, Spanish Laboratories SaniďŹ t Sl announced completion of enrollment of patients treated with the company’s lead candidate SNF472 into its Phase IIb CaLIPSO clinical trial. Most patients in end-stage-renal-disease (ESRD) suffer from accelerated cardiovascular calcification, which correlates with higher cardiovascular risk (CVC). In the trial, the company will assess the effects of 300mg and 600mg of SNF472 on the progression of CVC using the coronary artery calciďŹ cation score as a surrogate marker. Results are expected in H2/2019. A Phase III trial in calciďŹ c uraemic arteriolopathy (CUA) with SNF472 is expected to begin in Q4/2018. SAN FILIPPO A SYNDROME

ˆ

Swedish Orphan Biovitrum AB has commenced a one -arm, unblinded Phase I/II study in children aged one to six suffering from San Filippo syndrome (mucopolysaccharidosis type IIIA) with its chemically modified recombinant human sulfamidase SOBI003-001. The modiďŹ cation prolongs halife of the enzyme that cleaves heparan sulfate storage materials in affected cells. The uncurable lysosomal storage defect that results in degeneration of the brain affects 2,000 children worldwide. ANKYLOSING SPONDYLITIS

ˆ

Oxford-based Izana Bioscience plc initiated a Phase IIb study of its licenced (from Takeda) GM-CSF-Targeting antibody namilumab in ankylosing spondylitis. Ankylosing spondylitis is a debilitating arthritic disease of the spine affecting 4 million people worldwide.

OPIS INNOVATION.

European Biotechnology | Autumn Edition | Vol. 17 | 2018

              

 

    

13.09.2018 13:26:04 Uhr


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RegulatoRy affaiRs

european Biotechnology |autumnr edition | Vol. 17 | 2018

News Feel it in one’s water Mologic Ltd has started clinical testing of its Headsup urinebased diagnostic self-monitoring assay which aims to link five urine biomarkers to pulmonary exacerbations in cystic fibrosis patients.

Basket trial I

Clinical milestones AC Immune has started the Phase II study with its Abeta vaccine ACI-24 in patients with mild alzheimer’s disease. furthermore, the company announced at the end of august that it completed recruitment for the highdose cohort of its Phase ib study with ACI-24 for Abeta-related cognitive decline in Down syndrome.

Basket trial II Immatics Biotechnologies GmbH has kicked off a Phase i study with its adoptive T-cell therapy iMa202 in hepatocellular and advanced non-small cell lung cancer. Twelve patients will be enrolled at the MD anderson Cancer Center in Houston.

41-43_EB_Autumn_2018_Trial_tg.indd 42

While Neovacs said it will move its SLe treatment KinoidIFN alpha to phase III testing, new research suggests a VeGFr-driven mechanism between the skin rashes often occurs in SLe patients. Langerhans cells (red) that normally protect keratinocytes (blue) that form the top layer of the skin against sunlight-induced injury do not when VeGF is overexpressed.

usually, it’s treated with tNf-alpha blockers. However, 50% of patientis with advanced disease do not respond to the standard immunosuppressor. in the trial, izana Bioscience will enrol 40 patients with moderate-to-severe disease. Results are expected in 2019. SySteMIC LupuS erytHeMAtoSuS ˆ

Paris-based Neovacs SA has announced its intention to progress its interferon (ifN) alpha blocker ifNalpha-Kinoid to Phase iii testing in patients with systemic lupus erythematosus (sle). in a Phase ii proof-of-concept study, enroling 185 SLE patients with moderate to severe disease, expression rate of IFN alpha was not significantly reduced vs placebo by ifNalpha-Kinoid. the therapy, however, did improve the Composite lupus assessment (BiCla) response rate as well as the lupus low Disease Activity Score response rate vs placebo after 36 weeks. Common SLE symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes,

feeling tired, and a red rash which is most commonly on the face. Currently, there are only symptomatic treatments available. AtopIC DerMAtItIS

ˆ

Cambridge-based Kymab Group Ltd. has presented Phase i dose escalation data on its atopic dermatitis candidate KY1005. The anti-OX40 ligand antibody proved to be well-tolerated in 64 healthy volunteers. Surrogate marker evidence pointed to inhibition of T-cell driven inflammation in the skin. Phase II trials are now prepared to start this year. ACtINIC KerAtoSIS

ˆ

Almirall SA’s licenced topical src signalling blocker KX2-391 has met the endpoint of improving the proportion of patients who achieve complete clearance of actinic keratosis (aK) lesions within the face or scalp in two Phase iii studies enroling 702 patients with actinic keratosis. allmiral licenced the us and eu commercialisation rights for the ointment from Athenex Inc.

Picture: © W.D. Shipman

oxford-based cancer immune therapy developer Immunocore and its commercialisation partner GlaxoSmithKline have started enrolment for a Phase i eu study of a Ny-eso-1-/lage-1-specific immtaC® in patients with NsClC, bladder cancer, melanoma, and synovial sarcoma. According to a 2013 agreement, GSK will have the option to license the candidate after Phase i testing has been completed.

13.09.2018 13:26:12 Uhr


European Biotechnology | Autumn Edition | Vol. 17 | 2018

morBus HuNtIGtoN

ˆ

In August, the European Medicines Agency (EMA) granted PRIME status to roche AG’s antisense nucleotide RG6042 (Ionis-HTTRx), which aims at stopping expression of the neurotoxic mutated version of the huntingtin protein in patients with Huntington’s disease. Roche took over clinical development from Ionis Pharmaceuticals in December 2017 and is now preparing a pivotal Phase III trail. As usual under the PRIME scheme, Phase I/IIa data on relatively few patients, proving safety and giving some hints towards efficacy, were sufficient to accelerate evaluation of the compound, which is believed to act most efficiently when administered in early stages of the disease. Active Biotech AB’s quinoline-3- carboxamide candidate laquinimod has missed the primary endpoint of improving the UHDRS-TM score from baseline to 12 months vs placebo in a Phase II study on 352 patients with Chorea Huntington, but reduced brain atrophy. BreAst CANCer

ˆ

Roche US subsidiary Genentech Inc announced in July that the company’s PDL1 blocker atezolizumab + abraxane improved progression-free survival (PFS) in patients with triple negative breast cancer vs placebo plus the chemotherapeutic. The antibody was given as first-line treatment within the Phase III Impassion130 trial. Details were not provided by the companies. CArDIomyoPAtHy

ˆ

Berlin Cures Holding AG has successfully completed Phase I safety testing of its DNA-based aptamer BC007, which binds to and eliminates pathogenic autoantibodies against against the beta-1 adrenoceptor antagonists, which is expressed in patients with dilated cardiomyopathy interfering with the regulation of the heart’s rate and contraction strength. While young healthy men who had no autoantibodies were initially dosed with low doses of BC007 placebo-controlled, in the further de-

41-43_EB_Autumn_2018_Trial_tg.indd 43

velopment of the study older subjects who tested positive for the autoantibodies were treated with increasing doses of BC007. The optimal dose for complete elimination of autoantibodies was determined without any serious adverse events or any signs of allergic reactions in the 74 treated individuals. The optimal dose will now be tested in a Phase II/III trial with beta1-adrenergic receptor-AAB positive patients suffering from chronic heart failure. According to the company, BC007 also seemed able to neutralise other autoantibodies belonging to the large family of G protein-coupled receptors, which can induce dilated cardiomyopathy and various diseases such as pulmonary hypertension, chronic fatigue syndrome, and glaucoma. GVHD

ˆ

Incyte Corp. and its partner Novartis AG announced in August that its JAK1/2 blocker ruxolitinib plus prednisone or methylprednisolone led to an overall response rate (ORR) of 55% in a Phase II trial in 71 patients with steroid-refractory acute graft-versus-host disease (GvHD). Phase III data of the orphan drug, which has been granted breakthrough status by the FDA for GVHD, are expected to be published next year. PANCreAtItIs

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14.09.2018 12:49:58 Uhr


44

ECONOMY

European Biotechnology | Autumn Edition | Vol. 17 | 2018

“Help to bring

biotech into play” Novozymes’ open innovation initiative HelloScience invites researchers and companies to contribute ideas to solve the global problem of clean water supply. European Biotechnology spoke with Dr Sebastian Søderberg, VP New Business Development, Incubation and Acquisition, about Novozymes’ external innovation activity. HELLOSCIENCE

is dying because of lack of clean water – its an never-ending list. So we wanted to link up with people who have good ideas for new and existing technologies. We see that it is important to have a number of different technologies, industries, and stakeholders to tackle such a problem together.

EuroBiotech_What role does external innovation and bridging to start-ups play for Novozymes? Søderberg_The approach that we are tak-

EuroBiotech_One such open innovation activity you started, with a first call for ideas in 2017, is HelloScience. Could you please describe what HelloScience is? Søderberg_HelloScience is a virtual co-

creation space where we want to invite the world to solve some of the world’s biggest problems. The initial area that we decided to dive into was water. Eighty percent of waste water is untreated today; around 10% of the world population doesn’t have access to clean water; two-thirds could face water scarcity by 2030; every 15 seconds a child

44-45_EB_Autumn_2018_Interview_Novozymes_tg.indd 44

EuroBiotech_Do you have some examples illustrating the outcomes of that first round of ideas? Søderberg _In the first launch of Hello-

SEBASTIAN SØDERBERG is currently, Vice President and leader of Novozymes‘ New Business Development, Incubation & Acquisitions and serves on the Advisory Board for the Disruption Task Force of the Danish Ministry of Industry, Business and Financial Affairs; Copenhagen Business School; Seges Future Farming; and the Novo Nordisk Foundations Bio-Innovation Institute. He joined Novozymes in early 2007, in the acquisition team of the former New Business Development (NBD). Sebastian has the last 11 years worked and led cross functional international teams within business development, sales, marketing, acquisitions, minority investments, early stage innovation and incubations as well as large partnerships.

Science, we got input from over 50 countries across the world and we kept learning new things. It comprised entrepreneurs, start-ups, and large established companies; academic experts, NGOs and governments. It acted as a matchmaking and crowd-problem solving forum to see what ideas do others have and helps to very efficiently bring different disciplines and industries together. To give an example, a Dutch company called NX Filtration has a nanofiltration membrane that captures micropollutants, such as drug residues, pesticides, and chemicals, etc. We established a triangular collaboration between the start-up, Novozymes Biotechnological Solutions, and Grundfos because we believe we can develop a commercial product to solve that problem of micropollutants. EuroBiotech_Are there any additional means to incentivise collaboration and the open exchange of know-how?

Picture: Novozymes

ing in our Business Development Department is to look at how we can solve some of the big challenges that the world is facing – clean water supply, or nutrition, for example. We think biotech can play a role. That means biotech that Novozymes already has in its toolbox but also biotech that we in-license or potentially acquire. Tapping into the many new technologies popping up externally – i.e., by challenging our traditional thinking in collaboration with academic groups, start-ups, and companies in early commercialisation stage – is important in order to position Novozymes as one of the essential collaboration partners of the future early on. That’s the mindset that we are applying to how we work.

13.09.2018 13:27:07 Uhr


european Biotechnology | Autumn edition | Vol. 17 | 2018

Søderberg_HelloScience offers more than

matching people. We link people to our experts and mentors in questions of IP, microbiology, commercialisation of products, etc. We also provide microgrants and we are open to offering our biotech toolbox to be part of the solution. That is free, initially, for experimentation with it. Most people have joined Novozymes not only because its a nice career opportunity but because we are passionate about what biotech can do to master big challenges in sustainability. When it comes to HelloScience, our point of departure is the challenge-solving element. Our working hypothesis is that biotech will play a role – we don’t know how big it will be. And then it’s up to us to make a business out of it – to be agile enough to help our partners grow up a business that sometimes contains elements of Novozymes’ toolbox, other

times completely different technologies. Besides solving some large problems, we are convinced this will deliver a good return for Novozymes’ shareholders. However, it’s important to keep in mind that HelloScience is only one of multiple external innovation activities going on at Novozymes. EuroBiotech_How can policymakers support sustainable vs established solutions? Søderberg _Personally, I think several

things need to be in place. It begins with funding for sustainable technologies at the university level and for sure it depends on which industry you are in, but helping desired solutions and industries to takeoff in their early stage of commercialization is also needed. I think it’s not policy alone but also access to capital, companies like Novozymes that want to

economy

45

contribute, and there is a need for public-private partnerships. EuroBiotech_Where will HelloScience go in the future? Søderberg _We are currently launching

the second version and campaign for HelloScience. The theme is again Water but this time with improved technical features and the expectation of bringing more partners onboard. We are planning a second theme for HelloScience’s “third launch,” i.e. Health and Nutrition, which is another major challenge in the world. We will be available to give more information to people interested in HelloScience during the European Biotech Week (24–30 September) and at the European Forum for Industrial Biotech and the Bioeconomy (EFIB) in Toulouse (16– L 18. October). t.gabrielczyk@biocom.eu

EIB issues first Sustainability Awareness Bond

Picture: EIB

SuStainaBility The european Invest-

ment Bank (EIB) issued its first Sustainability Awareness Bond in September. The €500m (US ($580.80m) transaction represents the first EIB funding intended to directly support sustainable finance. “We have selected the water sector as a starting point,” said Werner Hoyer, President of the EIB. “We look forward to expanding the scope of the Sustainability Awareness Bonds in the coming months to cover health and education,” he added. Proceeds will be put towards water quality and infrastructure projects in countries as diverse as Burkina Faso and Germany. The eIB wants to ensure that the new bond will not cannibalise demand for other Socially Responsible Investment (SRI) bonds, such as its “climate awareness bonds,” or green bonds, of which it sells roughly €4bn annually. “These are two types of bonds that we think can live together without killing each other,” said Bertrand de mazierez, the eIB’s director general responsible for finance. The United nations estimates that US$6,000bn of annual investment is

44-45_EB_Autumn_2018_Interview_Novozymes_tg.indd 45

needed to successfully tackle its 17 Sustainable Development Goals (SDGs) to end poverty, protect the planet, and ensure prosperity by 2030. The SRI bond market has started to evolve far beyond its “green” roots over the last 12 months.

The World Bank, which issues US$5060bn of bonds annually, has placed a series of sustainable development bonds to raise awareness of specific issues, most recently a 1 billion Swedish crown ($110 L m) water and ocean bond.

13.09.2018 13:27:14 Uhr


46

EVEnt profilE

European Biotechnology | Autumn Edition | Vol. 17 | 2018

25–27 March, 2019 Messe Wien Vienna, Austria

BIO-EurOpE sprIng 2019  The 13th annual BIO-Europe Spring® interna-

tional partnering conference will meet in Vienna, Austria, March 25–27,  2019, at the Messe Wien Exhibition and Congress Center. This premier  annual springtime event brings life science executives to Europe’s most  innovative biopharma clusters. The 13th annual BIO-Europe Spring® international partnering conference will  be held in Vienna, Austria, for the first  time, March 25–27, 2019, at the Messe  Wien Exhibition and Congress Center. The event is highly regarded among  companies across the life science value chain, from large biotech and pharma companies to financiers and innovative startups. BIO-Europe  Spring  offers  powerful opportunities for you to network  with  the  right  par tners,  with  over  2,500 attendees from 1,400 companies and 54+ countries. With a focus on   European innovation and global collaboration, the event is the premier 

› Quick fActs Registration   Please visit  ebdgroup.knect365.com/  bioeurope/ 

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springtime  par tnering  conference  bringing together a “who’s who” from  biotech, pharma, and finance in the  most innovative biopharma clusters  in Europe. The event is also sought after by attendees for the variety and high caliber of presenting companies, ranging  from academic innovators and start-up  bio tech companies to mid-size pharma  and biotech, which bring their innovative technologies, therapies, and solutions with the goal of securing development and commercialization partners.  BIO-Europe Spring also features a diverse list of industry leaders speaking  on workshops and panels. Leading pharmaceutical companies,  including all of the big names in pharma, sponsor the event, sending teams  of scouts to discover new and innovative  products. Informal networking events in  stunning local venues lend further dealmaking opportunities.  The 2018 event boasted 15,000 scheduled one-to-one meetings with 3,600+  licensing opportunities posted. L

Join us in Vienna GREEtiNG  BIOE u r o p e   S p r i n g ® ,  held in enticing biotech hotspots every spring, is the best  place to solidify your  str ategies  for  the  next year. This conference is a key event for global biotech, pharma ,and investors who attend  in search of new collaboration partners  and deal opportunities. This year, BIOEurope Spring will be held in Vienna,  Austria, for the first time.  BIO-Europe  Spring  is  expected  to  draw a high caliber of companies to this  vibrant biotech hub, not only from Europe but from across the globe, to fuel  the insatiable drug development industry. The event brings a high quality and  variety of companies to present their licensing opportunities directly to potential partners, resulting in alliances that  literally change the world. Vienna boasts over 450 life science  organizations employing nearly 37,000  people in scientific innovation and medical research. With over 2,500 attendees  last year, BIO-Europe Spring continues  to bring global executives to locations  that drive the industry’s growing demand  for transformational breakthroughs. See you in Vienna in March, 2019! Anna chrisman Managing Director EBD Group & KNect365 Life Sciences

Pictures: EBD Group

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13.09.2018 13:27:45 Uhr


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13.09.2018 13:27:58 Uhr


48

Synthetic Biology

european Biotechnology | Autumn edition | Vol. 17 | 2018

Thermo Fisher Scientific’s CMOS nucleic acid synthesis chip

Pioneers in the synbio revolution Is synthetic biology on the cusp of unlocking the next industrial revolution? A major roadblock is the ability to synthesise DNA for R&D in ways that are both cheap and efficient. Established players in the field believe the answer lies in miniaturising standard chemical processes and running them in parallel systems. But the new kids on the block are betting on a completely new process that involves enzymes. Picture: Thermo Fisher Scientific

DNA SyNtheSiS

48-50_52_54_EB_Autumn_2018_Big shot_DNA-synthesis_fuels_a_revolution_ml.indd 48

13.09.2018 13:28:49 Uhr


european Biotechnology | Autumn edition | Vol. 17 | 2018

n

obel-Prize winning Richard Feynman once famously said: “What i cannot create, i do not understand.” Speaking with EuropEan BiotEchnology, Thermo Fisher Scientific business leader Helge Bastian tipped his cap to the renowned physicist on the trending topic of synthetic biology. “the concept of DnA as a digital code that runs biology and can be read, written and altered hasn’t yet settled in everyone’s mind,” he says. The first step was genome sequencing, followed by genome editing – and now it’s time to make genome synthesis a reality. Synthesising small stretches of DnA or RnA has been a cinch for years, and even synthesising genes up to 2,000 nucleotides has become routine. But if synthetic biology is to bloom, it has to be able to master the challenge of building many genes or even whole genomes from scratch. the VP and general Manager of Synthetic Biology at the lab equipment behemoth says the traditional technology to make DnA is ready for the age of synthesised genomes. others would disagree.

synbio companies by nature of their business concept require numerous DNA-sequences or constructs,” says Bastian. According to the Thermo Fisher VP, ‘true’ synbio companies build pathways or genomes to program cells to produce a certain molecule or compound. the research cycle – design, build, test – is repeated until a solution is found, which can become extremely costly at the current cost per nucleotide. thus, there is a need at companies like ginkgo Bioworks and Zymergen for both high-throughput and more cost-efficient technologies. For synbio researchers like Ybert used to be, the situation translated into: I buy the cheap small segments and assemble them on my own. that time-consuming task is certainly not intellectually satisfying.

Why this is turning into a multi-billion dollar market Fast-forward to 2018, where there’s significant buzz in and around the concept of synthetic biology. Market observer

Picture: Thermo Fisher Scientific

The limits of limited access Thomas Ybert, the CEO of French DNA synthesis start-up DnA Script, has been involved in the synbio community for years. he has this to say about his time in the lab: “I was a metabolic engineer trying to optimise a microbial pathway that leads to a certain, desired end product like a fine chemical or a drug. I was passionate in that, but my day-to-day work was also very frustrating. My progress was limited by my access to synthesised DnA.” Researchers from both academia and industry order tailored DnA constructs from companies like Thermo Fisher Scientific, genscript, genewiz or iDt/Danaher. it’s a process that can take days to weeks – depending on the length and complexity of the product. And with nucleotides costing from US$300-US$1,000 for a molecule with 2,000 building blocks, the process is costly. “All of our customers need highquality, highly accurate products. Many of them work in the biopharma industry and they generally order specific biomolecules like antibodies. in contrast, ‘true’

Dr. Helge Bastian Vice President and general Manager of synthetic Biology, Thermo Fisher Scientific Inc.

?

Will synthetic biology be a major driver for Thermo Fisher Scientific’s gene synthesis business Invitrogen geneart?

!

It’s impressive to see how much money is invested in synthetic bio­ logy these days! Companies are working on manifold applications, and I think the field will become a major industry – one that requires a lot of synthesised DNA.

48-50_52_54_EB_Autumn_2018_Big shot_DNA-synthesis_fuels_a_revolution_ml.indd 49

Synthetic Biology

49

Synbiobeta llc has been recording new funding highs in the field every quarter. 2018 set a blistering pace, with 27 synbio companies raising US$650m in private and public funding in Q1 – twice the amount raised in the same period in 2017. Q2 proved even more impressive: 33 companies raised US$925m, quadrupling 2017 statistics. Synbiobeta now projects the sector will see over US$3bn in funding by the end of the year. that would nearly double 2017 numbers (US$1.7bn). The reason for the boom is obvious: According to Market Research engine, the global synbio market has a compound annual growth rate of 44.2%, and will exceed US$45bn by 2021. “i personally think that synbio is the next revolution, like the one currently being driven by IT companies. It will change the world around us – from energy production to new materials,” ybert told Euro B iotEch . “But to release the brakes on the revolution, we need a faster and cheaper way to write DnA.” that’s why the scientist-turned-entrepreneur is betting on a new technology aimed at stringing together nucleotides – the building blocks of DnA. But first let’s take a look at the status quo. The technological roots of current DnA synthesis methods stretch back a long way. The last major improvement was the introduction of phosphoramidites in 1981. Today, the US$1.3bn DNA synthesis industry continues to rely on a chemical process developed almost 40 years ago. Marvin Caruthers is viewed as the seminal inventor of solid-phase DNA synthesis. His process uses the tools of organic chemistry to attach DnA building blocks one at a time. But it has a big drawback – it requires toxic organic solvents and additives. these substances make the execution of the process in the lab cumbersome, and waste is an issue. Even worse, the solvents limit the accuracy of the synthesis process, because they occasionally intersperse the wrong nucleotide into sequences. For all real intents and purposes, chemical DnA synthesis is limited to building molecules with 200 nucleotides at most. But even a small gene has at least 1,000 of them. So to make longer se-

13.09.2018 13:28:56 Uhr


50

SYNTHETIC BIOLOGY

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Startups that are developing biotech-based DNA synthesis methods.

Company (Location)

Funding

Technology

Founded

› Ansa Biotechnologies, Inc. (Berkeley, US)

unknown

Nucleotide-linked terminal deoxynucleotidyl transferase( TdT)

06/2018

› DNA Script SAS (Paris, France)

€150k family & friends (2014), Agoranov start-up incubator (2015), €2.5m seed round by Sofinnova, Kurma & Idinvest (2016), €11m Series A by Illumina Ventures, Merck Ventures and existing investors (2017), €7.1m in grants from Bpifrance and the European Commission (2018)

Engineered polymerases plus nucleotides with blocking groups

2014

› Evonetix Ltd. (Cambridge, UK)

Explicitly for “a novel enzymatic approach to DNA synthesis”: £1.3m (€1.45m) from Innovate UK (2018); overall funding includes seed funding by Cambridge Consultants & Providence Investment Co. (family office of private investor Hermann Hauser) and £9m (€10m) Series A by seed investors plus DCVC (Data Collective), Draper Esprit, Morningside group, Rising Tide Fund, Civilization Ventures

Targets biopharma market (cells as manufacturing units for specific biopharmaceuticals); silicon arrays with integrated micro-heaters on each of the 10,000 spots, compatible with both conventional chemical synthesis and Evonetix’s proprietary enzymatic DNA synthesis process, which is based on TdT plus nucleotides with blocking groups (thermal deprotection)

12/2015

› Genome Foundry Ltd. (Oxford, UK)

Spin-off of Oxford Nanopore Technologies Ltd.

Not phosphoramidite-based, but involvement of enzymes not confirmed

07/2015

› Molecular Assemblies, Inc. (San Diego, US)

Agilent Technologies, Cavendish Impact Capital Fund, Data Collective Venture Capital, Eleven Two Capital, Genomics Investment Syndicate, Keshif Ventures, Newport Holdings, LP, Alexandria Venture Investments

Terminal deoxynucleotidyl transferase (TdT) plus nucleotides with blocking groups

2013

› Nuclera Nucleics Ltd. (Cambridge, UK)

£500k (€560k) seed, £100k (€112k) Innovate UK grant, £25k (€28k) Ready, Set, Go programme (partly funded by the European Regional Development Fund, all 2014), £250k (€280k) Innovate UK grant (2015)

Engineered terminal deoxynucleotidyl transferases (TdT) and DNA polymerise theta, nucleotides with blocking groups

08/2013

Forget about the templates The core of all enzymatic processes is – of course – the enzyme. Nature is extremely efficient at synthesising DNA. The process can be very fast, with one nucleotide added every millisecond by certain enzymes known as polymerases. But there’s a catch. They need a template. Fortunately, enzymes suitable for template-free de novo nucleic acid synthesis have also been identified. At about 200 bases per minute, they’re not terribly fast, but they beat Caruthers’ chemical method easily. The focus of most enzymatic DNA synthesis companies like

DNA Script is a polymerase called terminal deoxynucleotidyl transferase (TdT, Fig. 1). It’s an enzyme found in the immune system of vertebrates whose function is to add nucleotides randomly to some exons in T cell and B cell receptor genes during antibody gene recombination. The diversity introduced by TdT has played an important role in the evolution of the vertebrate immune system, significantly increasing the variety of antigen receptors that a cell is equipped with to fight pathogens. A second enzyme raising some interest at DNA synthesis companies is DNA polymerase θ. Its big advantage compared to TdT is that it can cope with synthetic size-expanded nucleotides. This is relevant because of the way nucleotides are added to chains in nucleic acid synthesis (see Fig. 2). A key requirement is to make the enzyme add one and only one nucleotide, then stop – and not add the same nucleotide over and over again. To prevent multiple additions, companies like DNA Script, Nuclera and Molecular Assemblies use nucleotides modified with special blocking groups. However, the

48-50_52_54_EB_Autumn_2018_Big shot_DNA-synthesis_fuels_a_revolution_ml.indd 50

problem with that approach is that the catalytic site of TdT is not large enough to accept a nucleotide when a blocking group is attached. Many researchers have tried to use other enzymes like DNA polymerase θ. But as it turns out,

Fig. 1: The crystal structure of murine terminal deoxynucleotidyl transferase (TdT, blueish colours) bound to singlestranded DNA (ssDNA, red) with an incoming nucleoside 5’-triphosphate

Picture: Nuclera/PDB 4I27

quences, researchers have to stitch together shorter sections using a process that is both failure-prone and unable to make certain sequences. Market leaders like Thermo Fisher Scientific are trying to make this stitching process as quick and accurate as possible. But DNA Script and other companies are taking a new path that employs an aqueous process involving enzymes – one that excludes organic solvents altogether.

13.09.2018 13:29:05 Uhr


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SynthEtic Biology

tdt remains the most important hope­ ful. A lot of effort has therefore gone into how to engineer the enzyme to ac­ cept large nucleotide variations without impairing its synthesis activity. “it’s not an easy problem to tackle,” admits Jia­ hao huang, Director & co­founder of British DnA synthesis start­up nuclera. “We took a broad approach in the be­ ginning, essentially surveyed as many or­ thologs as possible and chose the ones that showed significant improvement compared to commercially available tdt in incorporating reversibly terminated nucleotides. our subsequent engineer­ ing rounds were semi­rational, and use a combination of well­known and novel protein engineering methods. the result is that we now have enzyme­nucleotide combinations that essentially can quanti­ tatively get from n to n+1 with a very fast reaction time.” the race is on to find the best en­ zyme for catalysing the addition of single nucleotides to form long DnA sequen­ ces. Everyone involved underlines cer­ tain advantages of the technology, espe­ cially the fact that it’s water­based and toxin­free. ybert thinks that in future, special facilities to synthesise DnA will no longer be necessary. He finds the idea of a DnA printer for every institute or re­ search group very appealing.

“chemical DnA synthesis has been optimised, miniaturised and parallelised over the past few years.” in chemical synthesis, however, the top dogs aren’t just twiddling their thumbs. Agilent technologies is developing a process based on inkjet on glass slides. Roche nimblegen is pursuing a photo­ lithographic process. And Synthomics is looking at a microfluidic process to syn­ thesise DnA via the phosphoramidite path. Small start­ups like Austria’s Brief­ case Biotec are also trying to bring spe­ cial phosphoramidite­based DnA prim­ er synthesis devices into the lab. (the

European Biotechnology | Autumn Edition | Vol. 17 | 2018

addition state

O

O O

O

blocked nucleotide

O

O

O

O

O O O

O

deblock

O

O O O

O O O

O

O O

O

O O

O O

O

engineered tdt

O O O O

O

O O

O

O

controlled state

Fig. 2: Enzyme-based nucleic acid synthesis is a process that requires an initiator sequence. Nucleotide triphosphates with a 3′-O-azidomethyl substituent (or other 3′ protecting group) are added in the presence of a suitable enzyme. After linking the nucleotide to the initiator sequence, the enzyme is removed. A cleavage composition comprising (for example) a photoactive transition metal complex and a suitable electron donor is added. This cleaves the 3′ protecting group after photoactivation. The cleavage composition is removed, and the cycle can begin all over again with the next nucleotide triphosphate.

tagline for their Kilobaser device: “the nespresso machine of DnA synthe­ sis”.) US company Sgi­DnA already in­ troduced what the company called the world’s first DNA printer back in early 2016. however, the BioXp 3200 system isn’t able to synthesise DnA. it’s merely a device for the automated cloning of de novo DnA fragments. But real bench­ top and hands­free DnA printers are no longer a distant dream. “chemical DnA synthesis has been optimised, miniatur­ ised and parallelised over the past few years,” explains thermo Fisher’s helge Bastian. compe ting with Sgi­DnA for the top spot, he sees his company‘s ge­ neart business – based in the german city of Regensburg – as one of the world leaders for large and hard­to­make DnA constructs. “At geneart, 300 people are fully dedicated to gene synthesis, making it Europe’s largest gene synthesis facili­ ty. the company was founded in 2002. We’re actually the pioneer in gene syn­ thesis,” the manager points out.

48-50_52_54_EB_Autumn_2018_Big shot_DNA-synthesis_fuels_a_revolution_ml.indd 52

geneart – along with competitors like twist Bioscience and ginkgo Bioworks subsidiary gen9 – produces oligo­ nucleotides on a semiconductor­based chip. “Each molecule is about 60 nu­ cleotides long, and we do 35,000 of them on a chip the size of your thumb,” says Bastian. “compared to the oligo­ nucleotide industry producing PcR primers and the like, the gene synthesis realm boasts completely different plat­ forms. it copes with femtomole quanti­ ties, resulting in DnA molecules that are almost error­free.” Because of the min­ iaturisation trend, the industry’s tox­ ic chemicals problem is less and less of an issue, he adds. Even though his com­ pany’s technology would remove one of the main advantages of enzymatic DnA synthesis, Bastian insists he’s also a “big fan” of what those companies are try­ ing to achieve: “We haven’t started an R&D project ourselves, but we’re close­ ly watching what’s going on. if the tech­ nology advances to a certain stage, we

Picture: Nuclera Nucleics (top)

52

13.09.2018 13:29:36 Uhr


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13.09.2018 13:29:49 Uhr


Synthetic Biology

european Biotechnology | Autumn edition | Vol. 17 | 2018

hope we can partner with one of the developers to advance it into a successful product.” At this point, the thermo Fisher Scientific business leader thinks all the competitors in the field are “more or less at the same developmental stage.”

Efficiency on par with traditional methods the three most advanced start-ups in the area – DNA Script, Molecular Assemblies and nuclera nucleics – were all founded in 2013 or 2014 (see p. 50). While their big goal at the moment is to make genelength DnA molecules in a single go, one low-hanging fruit is building DNA printers to produce the oligonucleotides needed for various molecular biology tasks in the lab. A benchtop DNA printer would allow researchers to make their PCR primers quickly, instead of waiting for their orders to be processed at firms like Eurofins, Thermo Fisher Scientific, Sigma-Aldrich/Merck or IDT/Danaher. DNA Script ’s Thomas Yber t says progress in making long, flawless molecules has been amazing so far: “Efficiency of enzymatic conversion in our process is better than 99.3% per cycle at the moment. even at this stage, we’re at par with the best existing chemical synthesis methods,” he says. When it comes to the other important parameter – length – the company presented data at a conference in May suggesting it could enzymatically synthesise a strand of DnA with 50 nucleotides. “This result is a world first for enzymatic DNA synthesis and a significant milestone,” says Ybert. “It shows that enzymatic DNA synthesis can compete with the traditional chemical method.” Some nucleotides are easier to incorporate than others, but Ybert confirms that DNA Script’s enzymatic system incorporates nucleotides from each of the four classes containing thymine, adenine, cytosine and guanine. nuclera’s Jiahao Huang acknowledges that the DnA Script result has helped raise confidence in enzymatic DNA synthesis. So what progress has nuclera achieved so far? “Our main focus right now is to improve accuracy and reduce base-bias of

SeBaStian Palluk Co-founder/ CtO of ansa Biotechnologies inc.

?

Extending a primer nucleotide by nucleotide – as your company is attempting – means dumping the enzyme after every cycle. That’s expensive, isn’t it?

!

Since DNA can be amplified easily, synthesis can be performed at small scales where enzyme and reagent costs become negligible. Also Illumina washes away the polymerase in its sequencing process each and every cycle. Additionally, cost-effective ways of producing the enzyme in E.coli have been established.

DNA synthesis. But we’re also working on an automated synthesis platform that will make writing longer length a routine process,” explains Huang.

The UK – a hotbed for synbio Two other enzymatic DNA synthesis companies are based in Britain: Evonetix from Cambridge and Genome Foundry from Oxford are even more close-lipped than other companies in the field. the synbio sector seems to be flourishing in the island nation. over 146 start-ups were founded there between 2000-2016. Synthetic biology also has tremendous political support in the UK. one of the country’s seven innovation and Knowledge centres focuses on promoting the commercial exploitation of synbio research. Established in 2013, SynbiCITE received kickstart funding of £28m. interestingly, some British sequencing pioneers are trying to repeat their prov-

48-50_52_54_EB_Autumn_2018_Big shot_DNA-synthesis_fuels_a_revolution_ml.indd 54

en successes with DnA synthesis. genome Foundry was set on its path by Oxford Nanopore, a company best known for its portable DNA sequencer Minion. And there’s also some history behind Evonetix. Initially headed by Nick McCook and Joe Brennan, former managers of next-generation sequencing pioneer Solexa, Evonetix has been heralded by some in the Cambridge biotech universe as the Next Big Thing. Solexa was bought by Illumina (US) for US$600m in 2006, and it’s still a major employer in Cambridgeshire.

Forget about the enzyme In a surprising twist to the enzymatic DnA synthesis story, the first peerreviewed paper claiming the first successful synthesis of a 10-nucleotide molecule with enzymes was published this summer by newcomers to the field. in setting up the process, researchers David Arlow and Sebastian Palluk (UC Berkeley and Lawrence Berkeley National Laboratory) took a different approach than the companies mentioned so far. instead of engineering the reactive site of tdt to convince it to accept larger modified nucleotides, they simply left the catalyst just as it is. So how did they prevent multiple additions to the molecule in the making? Arlow’s idea was to securely tether an unblocked nucleotide to TdT. After the nucleotide was added to a growing DnA molecule, so the theory, the enzyme would remain attached and protect the end of the chain from further additions. Then after the DNA molecule was extended, they could cut the linking tether to dump the enzyme, re-exposing the end for the next addition. “We demonstrated that we can extend a primer by a single nucleotide in 10–20 seconds,” Palluk told EuroBiotEch. “When we analysed the products, we were able to determine that about 80% of the molecules had the desired 10-base sequence,” he added. “That means, on average, the yield of each step was around 98%, which is not too bad for a first go at L this over 50 year-old problem.” m.laqua@biocom.eu

Picture: Ansa Biotechnologies

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European Biotechnology Autumn 2018

CROs & CDMOs

© Roche AG

SPECIAL 55_EB_Autumn_2018_Special-Title.indd 43

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Passion for Performance

A world-class biopharmaceutical CDMO •���Experts�in�cell�culture�bioprocess� development�and�manufacturing •���Family-owned�company,�thinking�globally�and� focused�exclusively�on�our�client�projects •���Biopharma�pioneer�with�commitment�to� advanced�technology�and�innovation�leadership� •����Extensive�track�record,�40�years�of�experience� and�quality�made�in�Germany

Our partners: one contact – one contract – one quality

Best-in-class�formulations� provide�signifi�cant� competitive�advantages

Best-in-class�facilities� for�aseptic�fi�lling� and�lyophilization�

Rentschler Biopharma SE Erwin-Rentschler-Str.�21�·�88471�Laupheim�·�Germany info@rentschler-biopharma.com�·�www.rentschler-biopharma.com

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57

Vertical integration: time is money Bio-Pharma oursourcing   Financial pressure on Big Pharma and biotechs increases the need 

for drug developers to outsource their development and manufacturing capabilities. The CDMO  and CRO sector, which is further consolidating through M&A, looks well set for continued growth.  As developers have to balance the need to reduce their development risk with time to market or  – for biotechs – time to next financing, contract manufacturing and contract research companies  clearly favour offering fully integrated services. 

Scale

Picture: EY (9/2017)

Service offering focus

The best example to illustrate Big Pharma’s  risk  aversion,  even  in  possibly  highly lucrative future markets, is Sanofi’s recent outsourcing of its anti-infectives R&D to drug discovery service  firm Evotec: Under the licence option  deal, the French pharma major transfered more than 10 early-stage antimicrobial development programmes, plus  its anti-infectives research unit in Lyon  to Evotec while retaining option rights  for development and commercialisation. The highly profitable  CRO received  €60m upfront plus long-term R&D funding and sales royalties for development  of the assets. Evotec's CDO Enno Spill-

ner told EuropEan BiotEchnology that Evotec sees big expansion potential in the  €130bn drug development R&D market,  in which drug developers currently outsource just 10%–30% of their early and  preclinical work, but about 40% of clinical development (see Figure 2).

Find the right expert In the fragmented US$62bn+ CDMO  market, the ten largest players currently control less than 30% of the revenues, according to a EY report published last September. As the CDMO  industry’s annual growth rate of 6% to 

7% is slightly outpacing the growth of  the pharmaceutical sector (5% to 6%  CAGR), the consultancy sees a lot of  space for outsourcing and consolidation. EY point to 2017 mergers, such as  the US$7.2bn deal of Patheon/ThermoFisher or the US$5.5bn acquisition  of Capsugel by Lonza, both aimed at  creating full-service providers.  As manufacturing of new drug formats such as fusion proteins, gene or  cell therapies such as CAR-Ts, modified  or multispecific antibodies is becoming  highly complex, specialised CDMOs are  predestined to become preferred future targets for the handful of integrat-

Drug discovery

Development

API production

Formulation

Target identification

Drug development

Extraction

Solids

Lead discovery

Sourcing

Synthesis

Semi-solid

Medical chemistry

Cell line development

Fermentation:  small molecules

Non-sterile liquids

Preclinical studies: in vitro

Scale up

Fermentation:  large molecules

Sterile liquids

Preclinical studies: in vivo

Tech transfer

Other methods

Other finished dosage  forms (FDF)

Formulation development

Process analytics  development

Packaging Primary packaging

Secondary packaging

Tertiary packaging

Small-scale production (preclinical Phase II) Small-scale Large-scale production (Phase III, commercial)

Overview of the value chain for bio-pharma outsourcing

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

~€30 –36bn

100%

The better way to DNA“

~€85–90bn

~€10bn

∑ ~€130bn

5 (~50%)

not outsourced

5 (~50%)

outsourced

90% 80% 70%

55 (~60%)

~7 (~70%)

60%

~25 (~90%)

50% 40% 30% 20%

~3 (~30%)

10% ~3 (10%)

0% 0%

© 2018 Fotolia.com

35 (~40%)

10% research

20%

30%

preclinic/IND

40%

50%

60%

70%

80%

90%

clinical development & registration

100% other

• Customized minicircle & plasmid production • High Quality Grade DNA for GMP production of viral vectors and RNA • Helper & Packaging plasmids for AAV production In Stock • QC including CGE service for topology analysis

Made in Germany

PlasmidFactory.com PlasmidFactory GmbH & Co. KG Meisenstraße 96 | D-33607 Bielefeld Germany | Fon +49 521 2997350

57-58_EB_Autumn_2018_Special_intro_tg.indd 58

ed providers. Medium-sized biologics CDMOs have also made significant investments to become one-stop-shops. With the establishment of FDA Breakthrough and EMA PRIME status, speed from clinic to market has become even more significant in the commercialisation of biopharmaceuticals. For biotechs, the speed at which a CDMO can achieve milestones is crucial because short development times allow them to achieve next-stage funding. In a way this market pressure is compensated by growing demands for more capacity: scale of production is expected to expand due to longer life expectancy, even in emerging parts of the world, and expansion of drug development markets beyond the US and the EU.

Niche for CAR-T cell- and gene therapy specialists Currently, one of the most targeted fields of expertise is the lucrative field of cancer immunotherapies and gene therapies, with annual cost of treatments of up to US$400,000 per patient. In the highly lucrative field of cancer immune therapies with genetically engineered T-cell receptors (i.e. CAR–T cells), the complex and costly process of production of autologous CAR-T cells is a major roadblock, according to Medi-

Gene’s CFO Thomas Taapken. Everyone in the market thus tries to find ways to reduce cost by trying to establish allogeneic CAR-Ts. According to Taapken, however, “this may take some time.“ Furthermore, the currently used lentiviral gene vectors often integrate into highly expressed coding regions of the T cell genome boosting the risk for cancer. However, tech providers are already working for a solution. The second field of particular interest for M&A, but also for niche player expertise, is gene therapy as shown by the recent Shire-Servier deal (see European Biotechnology, Summer Edition 2018). The dynamic is also demonstrated by the fact that 50% of the eight currently approved gene therapies – Imlygiuc (Amgen), Strimvelis (GlaxoSmithKlaine) Invossa (TissueGene/Kolon Life Sciences/Mitsubishi Tanabe), and Luxturma (Spark Therapeutics) – have been authorised in the past two-and-a-half years. And more than 350 gene therapies are under preclinical and clinical development – the majority of them gene replacement approaches (59%); 10% onkolytic therapies; and 20% cellbased immune therapies. With the first generation of products on the market to guide the way, and supportive regulatory partners, the time is right for new chapL ters on cell and gene therapy. t.gabrielczyk@biocom.eu

Source: Visiongain

Visiongain's analysis of the accessible R&D outsourcing market.

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“Formulation matters” Back in February 2017, CDMO Rentschler Biopharma SE and formulation specialist Leukocare AG joined forces to give biologics and biosimilar makers a competitive edge through significantly stabilised end products. European Biotechnology spoke with Leukocare’s CEO Michael Scholl about the impact of formulation on drug product performance.

RENTSCHLER BIOPHARMA/LEUKOCARE

EuroBiotech_ The industry has had a lot of discussion on, for example, protein aggregation or impurities associated with single-use equipment – so why is the topic still under the radar? Scholl_We can already see a change of attitude in the industry. But it’s still in its beginning. Rentschler Biopharma and Leukocare thus see themselves at the forefront of drug optimisation through advanced formulation technologies. EuroBiotech_ Could you please outline how Leukocare’s SPS® (Stabiliz-

60-61_EB_Autumn_2018_Special_Interview-Scholl_tg.indd 60

MICHAEL SCHOLL is the Chief Executive Officer of Leukocare AG (Martinsried), where he heads the division’s strategy, finance, corporate law, marketing and sales, and human resources. Before co-founding Leukocare in 2003 with Prof. Dr. Martin Scholz, the business engineer worked as a business consultant at Boston Consulting Group and led the foundation and business development of a range of technology and IT companies.

ing and Protecting Solutions) formulation technology works and how it differentiates from the platforms of competitors? Scholl_Basically, the SPS® technology platform consists of two major elements: an excipient librar y and the way we combine fi ve to eight of these

excipients to improve the quality of a biological product. We have approximately 100 well-characterised excipients in our library, which we specifi cally combine towards the degradation pathways, hot spots, and the product needs of our customers. We only use well-established and -approved excipients in order to prevent regulatory complexity. For identification of the optimal combination of excipients for a certain drug, we have a rational algorithm-supported development approach, which starts with a basic characterisation of the molecule and then reduces the design space by using deep learning algorithms before going into the lab. We are currently in the process of strengthening the use of artificial intelligence for automatic preselection of the optimal formulation components. As this approach currently is unique in the industry, it is a differentiator per se. EuroBiotech_How can your technology help biologics and biosimilar developers to get an edge over their competitors? Scholl_There are multiple aspects. First, by increasing thermal stability of protein therapeutics, our technology prevents degradation and allows for room temperature storage in many cases, which is also very relevant for vaccines. Second, many biopharmaceuticals today have to be lyophylised for stability reasons. We can transfer lyophilised to liquid formulations, which reduces manufacturing costs, adds convenience in administration, and comes without any loss of drug

Picture: Leukocare AG

EuroBiotech_ When Rentschler Biopharma joined Leukocare as exclusive partner back in February 2017, you and Rentschler Bio pharma’s CEO Frank Mathias said you hope to elevate the role of formulation strategy on the biopharmaceutical industry’s agenda. Why? Scholl_ We both figured out that formulation or, spoken more generally, drug product development, is underestimated in the schedule of biopharma development. Frank and I concluded that by elevating the awareness about the impact formulation has on the features of therapeutic proteins, we could provide a competitive advantage to Rentschler Biopharma’s clients. Therefore, Rentschler Biopharma and Leukocare commissioned a just recently finished industry survey with the goal to gain strategic insights on the importance, expectations, common challenges and future directions of drug product formulation. Results will be published shortly.

13.09.2018 13:33:23 Uhr


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European Biotechnology | Autumn Edition | Vol. 17 | 2018

Picture: Leukocare AG

activity. We recently announced a collaboration with the Danish peptide anti-infectives developer Xellia, who will switch its lyophilised anti-infectives to liquid products using the SPS ® platform. Third, our technology allows for subcutaneous, instead of intravenous formulations, which are mainly restricted by protein aggregation that occurs at high protein concentrations. Four th, formulation can increase time-to market for bio similar manufacturers such as Leukocare’s partner Laboratorios Liomont. By providing freedom to operate towards originator formulation patents, their biosimilar candidate can reach the market two to three years earlier. Both examples – the case of Xellia and of Laboratorios Liomont – illustrate how advanced formulation technology can create competetive advantages. EuroBiotech_Where do you see the strategic fit of the partnership with Rentschler Biopharma? Scholl_The partnership with Rentschler Biopharma allows us to integrate formulation into the broad range of CMC and CDMO offerings Rentschler Biopharma has to make, providing clients a three to six months acceleration in timeto-clinic and time-to-market and appropriate cost savings. As Leukocare, we benefit from the strong market position

Leukocare’s SPS® technology helps stabilise proteins in liquid formulations. Waterprotein interactions are stronger than SPS®excipient-protein interactions, resulting in a stabilised hydration of the protein. The hydration shell prevents interaction with cosolvents, resulting in lower free energy and thus increased protein stability.

of Rentschler Biopharma. The alliance allows us to reposition formulation as a key success factor in biopharmaceutical development. EuroBiotech_How was the feedback from the sector in the 18 months since the deal has been announced? Scholl_Of course, I cannot disclose exact figures but Leukocare and Rentschler Biopharma have started several new fully integrated projects, particularly with new clients from the US.

COMPETITIVE THROUGH DIVERSITY Discover VTU'ss broad Pichia protein production toolbox

EuroBiotech_W hat are your nex t goals? Scholl_ As the collaboration now is up and running, next we would like to learn more about the formulation needs of potential clients. Formulation is currently still an undeveloped market with some small players around. Our alliance, for the first time, has created some momentum to raise the awareness of formulation development in the drug product development. L t.gabrielczyk@biocom.eu

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Providing future markets with robust technologies CAR-T- & Gene TheRApy  Recent approvals in gene therapies and CAR-T-cell therapies have triggered 

a flood of clinical and translational R&D projects both in industry and in academia. Over the past five  years, US$9.5bn have been invested globally into gene therapy R&D. For the developers of future therapies, one important question is how to overcome limitations and intrinsic safety risks of viral vectors  used to express chimeric antigen receptors in T cells or to transfer therapeutic genes into target cells. › Dr. Martin Schleef, PlasmidFactory GmbH & Co., Bielefeld, Germany

Economies of scale in gene therapy Most industry offers currently involve  use of PlasmidFactory’s plasmids for the  GMP production of AAV vectors for gene  therapy. The reason is that PlasmidFactory has exclusively licenced the global rights on a technology from German  Cancer Centre that makes it possible to  transfect AAV vectors with only two plasmids instead of three – which results in  a 30% reduction in costs-of-goods. The  technology allows for placing all genes  required for virus particle packaging and  propagation into one plasmid instead of 

62_EB_Autumn_2018_Special_Plasmid_Factory_tg.indd 62

PlasmidFactory’s minicircle technology offers efficient transfer of target genes.

using a separate helper plasmid and  plasmid vector for the viral packaging  genes besides the transfer plasmid for  the therapeutic gene. Futhermore, using only two plasmids is more productive. Only a mixture of two vectors must  be optimised to achieve the highest possible yield.

Eliminating safety risks from CAR-T vectors In the CAR-T-cell therapy field, PlasmidFactory is currently expanding its research to eliminate safety risks attached  to the frequently used lentiviral vectors.  Industry is actively testing PlasmidFactory's minicircle-based non-viral vectors  for CAR gene delivery after researchers  at Würzburg University and at the Ger-

man regulatory authority PEI together  with PlasmidFactory demonstrated that  sleeping-beauty transposition of PlasmidFactory's proprietary minicircle DNA  in mice offers advantages over lentiviral  gene transfer. The problem with lentiviral vectors is that they preferentially integrate CAR genes into highly expressed  genes of T cells, a known risk factor for  insertional mutagenesis. In contrast,  the combination of the sleeping-beauty transposition and minicircle DNA integrates almost randomly into the T cell  genome, it's less immungenic, cheaper,  and easier to handle than lentiviral vectors. PlasmidFactory is working to offer the materials in a quality that can  be used in clinical studies by Q4/2018.  The technology is not only suitable for   CAR-Ts but also for vaccines.  L

Pictures: PlasmidFactory

With 354 CAR-T cell therapies currently  under development – 76% thereof in preclinical stage – and about 300 gene therapy projects, both fields are just emerging. Last year, the boom culminated in  the FDA market approval of the CAR-T  therapies Kymriah (Novartis) and Yescarta (Gilead Science) and Spark’s first  gene therapy for retinal dystrophy. Many  companies and research groups are now  jumping on the bandwagon. Since 2016,  the quantity of ordered plasmids needed to engineer lentiviral and AAV vectors  – the current gold-standards for CAR-T  and gene therapies, respectively – has  increased 5 to 10-fold. PlasmidFactory  had to expand its production capacities in  April to keep pace with the demand.

13.09.2018 13:33:48 Uhr


A RE YOU L OOKI N G FOR EX PERTS I N

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Contact us +49 40 55290-436 www.richter-helm.eu

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

Cutting time to market for high quality therapeutics CHOvolutionTM  The demand for the fast and robust development of manufacturing cell lines is  ever growing, with an increasing number of therapeutic proteins in development. To fulfill these  needs, Celonic engineered the cell line kit CHOvolution™, which equips users with everything  required for the development of mammalian cell lines and provides an integrated support system for assistance. › Sebastian Lambert, Senior Scientist, Celonic AG, Switzerland

Reducing time to clinic with CHOvolution™ Bringing a drug from discovery to the  marketplace remains a costly, complex, and time-consuming process, especially in high-stakes races such as to  be first-to-market. Celonic recognises  this and appreciates that improvements  to major bottlenecks and reductions in  timelines add up. For any drug developer or service provider, cell line development is one of the most challenging  phases, especially when subsequent  GMP compliance is required.  To enable the same excellent results  within shortened timelines, Celonic invested in state-of-the-art technologies  and optimised project workflows to  create high-producing cell lines (Fig. 1).  Successful implementation of technolo-

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FACS workflow

Gene synthesis and expression vector cloning

Vector construction

Transfection

FACS Cell printing

Selection and expansion of top/backup clones

Generation of clones

Generation of stable minipool

Single cell cloning

Cell line development (16 weeks)

Standard workflow

Gene synthesis and expression vector cloning

Vector construction

Transfection

Selection of stable minipools

Selection and expansion of top/backup clones

Generation of clones

Cell line development (26 weeks)

Figure 1: Celonic project cell line development timelines.

gies such as FACSAria® Fusion cytometer and cell printing have facilitated fast  track workflow options for high priority projects, bringing the entire timeline  from biological sequence to GMP-compliant material from 18 months down to  approximately 14 months. 

Scalable high-titer production of therapeutic proteins At Celonic, CHOvolution™ forms the  workhorse  for  mAb  production  and 

demonstrates high titers (up to 8 g/L)  with the median productivity of a CHOvolution™ cell line in the 2–4 g/L range  (Fig. 2).  One of the most important characteristic of any cell line is its scalability. Effects such as increased generation cycles and the subtle differences  in the upscaling of processes can often  accumulate  and  sometimes  result in dramatic losses in productivity.  CHOvolution™ cell lines, tested up to  100 generation cycles, retain their ge-

Pictures: Celonic

The CHOvolution™ platform is based on  a CHO-K1 host cell line and its proprietary SEFEX (SErum Free EXpression)  technology platform to provide the best  screening and selection processes.  CHOvolution™ is adapted for creating robust and stable cell lines that  express biologics in serum and protein-free suspension culture and commercially available media. This feature ensures regulatory compliance in  numerous customer projects entering  clinical development phases. 

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›› antibodies of different isotypes (e.g. IgG1, IgG2, IgG4); ›› bispecific and single-chain antibodies; ›› enzymes, growth factors, and hormones.

45 40 35 30 25 20 15 10 5 0 2–4

1–2

4–6

>6

Antibody Titer (g/L)

Figure 2: High productivity of Celonic antibody projects. Scalability of a CHOvolution™ antibody production cell line 100

1.2E+07

90 1.0E+07

80

70 8.0E+06 60

50

6.0E+06

40 4.0E+06

30

20

2.0E+06

10

0.0E+00

Key features include:

Pictures: Celonic

›› cell line adapted to serum-free EMA and FDA-compliant media; ›› high productivity (up to 8 g/L for mABs); ›› high scale-up stability (over the 120 generation cycles and easily scalable from shake flask to 1000L volume); ›› GMP-compliant, from R&D to market manufacturing; ›› tailored workshops and hands-on training to develop the product; ›› technical and scientific support on the CHOvolution™ platform.

64-65_EB_Autumn_2018_Special_Celonic.indd 65

viability (%) (dashed line)

Since July 2015, Celonic has been licensing its CHOvolution platform to drug developers and to other service providers. The license package includes the host cells, vector set, and detailed protocols for the handling, screening, and selection processes necessar y to generate high-performing production cell lines. The license is royaltyfree and with a guarantee to licensees: we will take over the developed cell line from our licensees and upgrade it to a GMP compliant Master Cell Bank. The CHOvolution™ is a proven production cell line technology for:

50 % of Projects (each making a Different Product)

CHOvolutionTM licensing

Antibody concentrations (g/L)

Viable Cell Density (Cells/mL) (solid line)

netic stability, which allows the cells used for development to be used in commercial manufacturing. Combining this stability and in-house expertise results in processes with CHOvolution™ being predictably scalable and displaying almost identical behaviors from the shake flask to 1,000 L bioreactor scales (Fig. 3). This combination of a fully scalable cell line with high titers that can be developed in a competitive time-frame makes CHOvolution™ a powerful tool in the drug developer’s arsenal.

65

0 0

2

4

6

8

10

12

10 L BR Run III

250 L SUB

1000 L SUB

Process time (days) Shake flask 250ml

10 L BR Run I

10 L BR Run II

Figure 3: Scalability of Celonic’s antibody production cell line. Solid lines show Viable Cell Density. Dashed lines show viability. 10 L BR = 10 L stainless steel bioreactor; 250 L SUB = 250 L single-use bioreactor; 1000 L SUB = 1000 L single-use bioreactor.

Celonic is a privately owned CDMO based in Basel, Switzerland. The company provides a range of services from cell line engineering and process development to cGMP manufacturing for new biological entities (NBEs) and biosimiliars worldwide. Celonic’s ethos

focuses on applying empathy, efficiency, and excellence in all business aspects to ensure its clients attain their goals L more efficiently and reliably. www.celonic.com chovolution@celonic.com

13.09.2018 13:34:28 Uhr


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Innovative delivery: dual-chamber systems LyophiLisation  As the global demand for injectables grows, so does the demand for innovative  

delivery systems. For lyophilised forms, dual-chamber systems offer advantages. They have been on  the market since the mid-1980s, mainly for emergency or chronic medication. The systems   have been developed for the convenience of the patients/caregivers, but they also offer benefits for   the pharma/biotech companies in regards to low residual volume and increased API yield.

When considering lyophilisation in a  dual-chamber system, it is important  to understand the development process. A five-step approach can help determine whether it is a viable option for  an injectable drug. 

Step-by-step approach The first step is to determine compatibility utilising a series of lyophilisation cycle feasibility studies. Trials based on existing vial lyophilisation development are  performed, as are concentration/ fill volume studies and cycle options to test the  product viability. The drying process is  governed primarily by convection and ra-

diation rather than direct heat conduction  and needs to be adjusted accordingly.  The second step focusses on process characterisation studies. An assessment of the current process and a variety  of compounding, filtration, and pumping  tests provide guidance for further studies  required for the development in a dualchamber system to identify suitable settings for accurate dosing.    The third step includes design of experiment (DoE) cycle development and  robustness. This is carried out with varying temperature and pressure combinations to test the design space limits  (edge of failure) for both primary and  secondary drying. Visual appearance of 

Simplified presentation of freeze-drying cycle development including the boundaries of DoE.

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the lyo-cake, reconstitution times and  residual moisture, and further critical  quality attributes such as potency, stability, and sterility are analysed. The fourth step involves siliconisation and functionality testing. While  necessary as a lubricant, silicone oil  must be kept to a minimum and evenly distributed to maintain acceptable  break-loose and glide forces. Closure  integrity and stability tests are also  performed with methods like dye-ingress or vacuum decay testing. The fifth step entails engineering  runs to ensure scalability. The first  stage is a non-GMP commercial scaleup testing general feasibility. It also  includes  temperature  mapping  and  sample analyses. The second stage  concentrates on lyophilisation-cycle  adaptation and testing. Trials with a variety of concentrations are performed  under “seeded run conditions.” This  allows for a minimisation of used drug  substance while still obtaining a good  indication of the performance. Finally,  process qualification based on the results from development is performed. In summation, dual-chamber systems offer an innovative delivery option for lyophilised drugs and can also  extend  the shelf-life of complex compounds. Taking the right approach is  essential to determine if such a system  L is suitable for your compound.

Pictures: Vetter Pharma-Fertigung GmbH & Co. K

› Joerg Zimmermann, Vice President Development Service, Vetter Pharma-Fertigung GmbH & Co. KG

13.09.2018 13:34:44 Uhr


Biotechpharma UAB Mokslininku st. 4 !#)'-()#  $(%&"!(

+++$(%&"!(

         

       -t Monoclonal antibodies and microbial proteins -t Drug substance and drug product -t Process development and validation -t Clinical and commercial batches -t Cell banking - -t Fast and reliable -t Strong customer interaction www.biotechpharma.lt bd@biotechpharma.lt 67_EB_Autumn_2018_biotechpharma-UAB.indd EB_Spring_2018_biotechpharma_210x275.indd 11

13.09.2018 28.02.2018 13:34:56 15:59:50 Uhr


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European Biotechnology | Autumn Edition | Vol. 17 | 2018

Data Managers are worth their weight in gold ContraCt researCh  Across industries, end-to-end digitalisation is creating one of the biggest  

value chain transformations in history. However, adopting corporate strategies to sustain the   implementation of often disruptive technology remains a challenge. For most of us, it involves   significant investment of time and resources and re-thinking payment and pricing models. › Dr. Raphaela Schnurbus, Clinical Solutions and BD Director in OPIS S.R.L

In the life science industry, digital health  solutions aim to offer opportunities for  seamless data sharing and highly personalised care. Drug development increasingly relies on highly sophisticated data platforms and clinical trials are  asking for complex study databases, risk  based monitoring, and adequate processes to ensure data integrity, data encryption, and real-time data availability  as standard practices. 

Data: the common denominator

68_EB_Autumn_2018_Special_OPIS.indd 68

ingly inter-connected digital environment,  of diseases will opt for solutions where  '$)$'Ȑ!0''. -1$ Ȑ+#.  Ȑ data handling teams of statisticians, data  an interface with other solutions and/or  managers, and system developers collabmodels become possible. orate closer than ever with scientists and  Strategic re-think the healthcare industry alike.

Data standardisation and sharing An emerging trend to create models that  allow diverse stakeholders to benefit  from shared initiatives is making companies think about forming valuable partnerships with platform owners or investing in developing data sharing platforms.  However, it is quite evident that for such  models to work and contribute toward  establishing opportunities where patients benefit the most, agreement on  standardization of data is urgently needed. Hopefully, all stakeholders involved  in research, treatment, and management 

To conclude, digitalisation is here to stay,  but how much future value we are going  to capture will depend on how skilfully we  implement solutions that unlock the power of data. We rely on infrastructures that  can help predict things and we insist on  data models that feed systems with structured and extractable data. We are talking  about machine learning and artificial intelligence but without clever people able  to create the right concepts in the right  and appropriate contexts, we are not going  to benefit to the full. Investing in a team  of highly skilled data scientists is the best  L move your company will ever make.

Pictures: Opis

It is clear that data and data analytics  have become core capabilities that drive  business decisions, quality and risk management processes and product/service  development. Genomic data and technologies such as voice data entry, eCOA (Electronic Clinical Outcome Assessment),  and Real World Evidence (RWE) generate huge and often very different types of  data to integrate and analyse. Overall, the  industry relies on data: existing data, new  data, personal data, unstructured-dataturned into-structured-data, data in real-time, and data available anywhere. As  a result, the days of thinking about data  management as “boring data entry and  cleaning” are gone forever.  Data scientists are needed in the place  of data managers. Theys are expected  to have programming skills and a good  deal of statistical skills as well. To manage information effectively in an increas-

13.09.2018 13:50:33 Uhr


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13.09.2018 13:35:21 Uhr


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European Biotechnology | Autumn Edition | Vol. 17 | 2018

Managing complexity to bring drugs to clinic faster CDMO  Integrating the disparate stages of drug development is the most time and cost-efficient 

way of turning a promising candidate compound into a pharmaceutical product. A CDMO that offers  coordinated end-to-end services simplifies oversight. › Torkel Gren, Senior Director Scientific & Technology Officer, Recipharm AB

The pharmaceutical contracting sector  is thriving, fuelled by ever-growing  drug industry demand for outsourced  development  and  manuf ac tur ing  solutions. The first CDMOs focused on  the provision of basic manufacturing  services, primarily finished product  formulation, fill/finish, and packaging.

Broad expertise In recent decades, specialist contractors have emerged to cater to the increasing  range  of  work  being  outsourced. However, while such firms  provide the drug industry with access  to expertise, managing the efforts of  multiple  specialist  contractors  is  a  challenge that potentially outweighs  the benefits of outsourcing in the first  place. Taking outsourcing one step further,  Recipharm has added capabilities by 

acquiring  specialists  and  investing  in  in-house  capabilities  to  provide  our  customers  with  a  full  range  of  services. Our approach simplifies and  accelerates drug development.

Managing complexity The development of each drug is different, although there are common stages. All drugs start as compounds that  show therapeutic potential in the laboratory which, if they continue to show  promise in preclinical studies, are selected for clinical development. The  path from laboratory to first-in-human  (FIH) studies involves many different  steps, each requiring expertise. For example, producing a drug product for an FIH study requires both formulation expertise and a detailed understanding of the trial protocol. In  addition, while drug stability and bioa-

vailability are less critical in FIH studies, knowledge of such characteristics  gained during early formulation development can accelerate development  of dosage forms used in later phase  studies. It is possible for multiple contractors  to support each stage of a drug candidate’s journey from laboratory to clinic separately while ensuring materials  and data are transferred. However, it  is far more cost and time efficient if a  contractor with expertise in all stages  carries out such projects in a fully integrated manner. Likewise, a full service contractor that can help with each  step significantly reduces a customer’s  oversight burden. W ith  this  in  mind,  Reciphar m’s  Pathway to Clinic ® service provides  pharmaceutical industry customers  with a comprehensive range of fully  integrated development, manufacturing,  and clinical trial planning and execution  services.

Integration  is  core  to  Recipharm’s  offering. From our early development  through  clinic al  and  commercial  manufacturing, including serialisation,  we focus on providing co-ordinated  expertise that reduces complexity for  our customers and gets high quality  products to market faster and more  L efficiently.

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Picture: Recipharm

CDMO success

13.09.2018 13:36:31 Uhr


SpEciAl

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71

Picture: Fotolia.com/rajcreationzs

Cancer: The long-term downsides of checkpoint inhibition CanCer  Contract Research Organisations (CROs) that conduct clinical  trials with PD1-PDL1 checkpoint inhibitors must consider new safety problems associated with the overhyped  drug class. A retrospective study on  377 patients with advanced non small  cell lung cancer (NSCLC) who received  PD-1 blockers as second-line therapy  indicates that therapy outcomes are  worse than those observed with classical chemotherapeutics (JAMA OncOlOgy,  doi: 10.1001/jamaoncol.2018.3676).    After median follow-up of 12 months,  13.8% of patients had hyperproliferative disease (HPD), which is characterised by accelerated tumour proliferation, tumour outgrowth, and worse  prognosis. 

Patients experiencing HPD within the  first six weeks of PD-1/PD-L1 inhibitor treatment had significantly lower  OS (3.4 months) vs patients with progressive disease (OS 6.2 months). In  contrast, only 3 in 59 patients receiving  chemotherapy (5.1%) developed HPD. “Our  study  suggests  that  HPD  is  more  common  with  PD-1/PD-L1  inhibitors compared with chemotherapy in pretreated patients with NSCLC  and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors,“ conclude the authors, headed by  Caroline Caramella from French Gustave Roussy cancer centre in Villejuif.  As HPD previously was reported in 9%  of advanced cancers  and in 29% of pa-

Lung cancer cells

tients with head and neck cancer, they  say that “additional studies are needed to determine the molecular mechanisms involved.“ Patients investigated had received  either the anti-PD-1 mAbs nivolumab  (Bristol-Myers Squibb) or pembrolizumab (Merck & Co.) or the anti-PD-L1  mAbs atezolizumab (Roche) or durvalumab from AstraZeneca plc.

CRS. Experts. Early Phase. First in Human to Proof of Concept in Patients.

www.crs-group.de

Ina Ott Director Business Development

Dr. Marc Hetzel Senior Director Business Development

ina.ott@crs-group.de +49 171 230 48 49

marc.hetzel@crs-group.de +49 170 574 68 53

e 2018 BIO-Europ ) M e et u s a t R 4 (BIO.N W Booth no. 6

CRS. Your number one CRO for Early Phase in Europe. More than 2.000 successfully completed trials. Five clinical research units. 260 beds. Fourty years of experience (Phase I – IIa). Reliable access to various patient populations and healthy volunteers.

71_EB_Autumn_2018_Special_News_tg.indd 71

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

Fully human antibodies for advanced immunotherapies antibody generation  Answering the increasing demand for novel fully human antibodies in  

immunotherapy, German biotech pioneer YUMAB GmbH accelerates drug discovery and development  with a comprehensive and versatile technology platform. › Dr. Thomas Schirrmann, CEO, YUMAB GmbH

Diverse and safe antibody leads The YUMAB® platform generates fully  human antibodies that are the closest  to natural germline among those available on the market. Unlike animal-derived, chimeric, humanised, or synthetic  antibodies, each YUMAB® antibody combines the maximum epitope diversity of  very large universal antibody libraries  with minimal immunogenicity. This approach is also efficient for difficult targets, such as G-protein coupled receptors  (GPCRs), ion channels, and even whole  cells or virus particles. Additionally, YUMAB optimises antibody properties, such  as affinity, stability, or interspecies X-reactivity in early discovery. First antibody  candidates are identified within weeks  and the versatility of the technology allows flexible manipulation and variable 

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drug formats. YUMAB’s advanced human antibodies cover a broad therapeutic spectrum. Tailored to customer needs,   YUMAB also generates custom libraries,  and offers antibody engineering in fee-forservice or attractive licensing options.

Enleofen – a success story In early 2016, YUMAB started a cooperation with Stuart Cook and Sebastian  Schäfer at the National Heart Centre Singapore and Duke–National University  Singapore Medical School to generate  novel antibody candidates that target interleukin-11 (IL-11) in fibro tic disease.  Their research revealed the critical role  of IL-11 in fibrosis and set the stage for  potential anti-IL-11 therapies that could  transform the treatment of fibrosis of the  lung, heart, liver, kidneys, and other organs[1]. In April 2017, Cook and Schäfer  founded Enleofen Bio Pte. Ltd. with a fo-

cus on the development of first-in-class  antibody therapeutics for the treatment of  fibrotic diseases. Using YUMAB’s expertise in antibody engineering, the start up  rapidly generated high-quality antibodies  as a basis for the development of antifibrotic therapies. “Owing to YUMAB’s rapid and reliable antibody platform, we could  shorten preclinical development and are  now confident to accelerate the translation of a novel antifibrotic antibody candidate from bench to bed,” said Stuart Cook,  Enleofen Bio’s director. “Successful drug  development requires interdisciplinary  expertise and technologies that are most  easily accessed through collaborations,”  added André Frenzel, CSO of YUMAB. “Being able to support our colleagues in Singapore in their quest to rapidly translate  their new insights into fibrosis into a startup company was very rewarding for us,  and we are excited to have played a small  L but crucial part in that process.”

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Fully human antibody candidate Innovative target

Reference [1] Schafer, S. et al. Nature 552, 110–115 (2017)

Immunotherapies based on fully human  monoclonal antibodies have been extremely successful since their first approval in 2002 (AbbVie’s Humira®, adalimumab), and today, the majority of newly  approved antibody drugs are of human origin. This trend calls for a paradigm shift  in antibody discovery and development to  an advanced process that enables flexible  drug design and accelerates translation  into clinics. YUMAB is a pioneer in fully  human antibody development that offers  an optimised discovery process tailored to  the need of the pharmaceutical industry  for a rapid, robust, and reliable generation of novel drug candidates.

13.09.2018 13:37:54 Uhr


RECIPHARM PATHWAY TO CLINIC ®

73_EB_Autumn_2018_Recipharm.indd 1

5HGXFHWKHFRPSOH[LW\RI\RXU¿UVWLQKXPDQ SURMHFWZLWK5HFLSKDUP¶V3DWKZD\WR&OLQLF ®. $IDVWDQGÀH[LEOHVROXWLRQWKDWKHOSVHQKDQFH \RXU$3,¶VSDWKZD\WRFOLQLF)URPIRUPXODWLRQ WRFOLQLFDOWULDOZHWDNHUHVSRQVLELOLW\ Interested in learning more? Book a meeting with us at CPhI Madrid at recipharm.com/cphi

13.09.2018 13:38:07 Uhr


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NorthErN EUroPE

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Testa center up and running

AnAlytics two years after the acquisition of the small biotech company Soft Flow, Danish Foss Group from hillerød laid the cornerstone for Soft Flow’s new hUF2bn (€6.1m) r&D centre in Pécs (hungary) this summer. the investment is supported with a hUF773m (€2.4m) government grant. the centre is expected to be complete by the end of 2019. Creating about 90 new jobs, Soft Flow will grow to 120 employees by 2020. the new facilities will be dedicated to r&D (antibody and assay development), bioanalytical services (mycotoxin reference lab, high-content screening), and reagent production (monoclonal antibodies, ELISA kits) for global distribution. Foss A/S is among the world’s leading providers of analytical instruments for the food and agricultural sector. the group prides itself on analyzing 80% of all traded grain on the world market and 85% of the world’s milk. 

in Uppsala to get its production process ready. the company brought its own staff to the testa Center. After being fully trained, they will set up the process in Stockholm. GE invested €4.5m in the facility – supplying bioreactors and other technology and providing GE employees to staff it. the centre will help the lab equipment specialist to stay involved in the latest breakthrough technologies. “We need to understand what start-ups need because that will drive our business in a couple years,” said Lotta Ljungqvist, GE healthcare’s CEo for the Nordics and for the testa Center. the Testa facility includes four start-to-finish bioprocessing laboratories where researchers can test and evaluate their technical and biological discoveries while keeping the full ownership of their results and IP. L

ge and sweden’s innovation agency vinnova decided to build the centre in 2016.

Feel no pain

CETSA rules

Insulin 2.0

investment German corporate investor trUMPF Venture Gmbh took part in the second closing of the series B funding round of odense-based rSP Systems. Adding €3.85m in September, the round stands at €10.35m. rSP Systems applies raman spectroscopy for human diagnostics. For six years, the company’s focus has been glucose monitoring developing a non-invasive test for diabetic patients. 

drug-tArget interActions After partnering with pharma heavyweight Astra Zeneca in February, Stockholmbased Pelago Bioscience AB managed to also convince Vertex Pharmaceuticals (US) that its CEtSA (Cellular thermal Shift Assay) is a valuable tool in preclinical drug discovery. the companies entered their two-year strategic research collaboration and license agreement in September. 

Acquisition Pharma company Novo Nordisk A/S bets on glucose-responsive insulins as a future growth market. In a €687m deal, the company acquired all of the shares of Ziylo Ltd., a University of Bristol spin-out company, in August. Ziylo owns a glucose-binding molecule platform to develop glucoseresponsive insulins for therapeutic and diagnostic applications. 

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Picture: GE Healthcare

Foss invests

Bioprocessing Beating all timelines, the bioprocess pilot-scale facility testa Center in Uppsala opened its doors for acadaemic groups, start-ups, and established enterprises earlier than expected in mid-August. the newly built innovation centre is supported by GE healthcare and the Swedish government. the inaugural tenant is Biolamina AB. the Stockholmbased company is scaling up production in the newly built facilities. Its bestseller is human recombinant laminin 521, a preferred cell culture substrate for both basic research and for developers of cell therapies. Among Biolamina’s most recent partners are Novo Nordisk A/S (Denmark) for developing novel stem cell based therapies and Cellink AB (Sweden) for promoting a new generation of bioinks for 3D bioprinting. Biolamina will spend six months

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Better than Swiss chocolate Drug Discovery orphan Biovitrum AB (Sobi) paid Swiss drug developer Novimmune SA ChF50m (€43m) for a late-stage antibody targeting a rare haematology disorder. the exclusive licence agreement – completed in August – gives Sobi (SoBI:SS) the rights to emapalumab, a fully human anti-interferon-g monoclonal antibody, which currently is being

sobi headquarters in stockholm

reviewed by the FDA and the eMA for the treatment of primary haemophagocytic lymphohistiocytosis (hLh). emapalumab neutralises the biological activity of IFNg. hLh is a rare life-threatening syndrome of immune activation, for which there is currently no treatment on the market. Including possible payments in the future, the deal is worth €387m. “Novimmune has brought emapalumab all the way from discovery through development to the brink of regulatory approval. Now is the right time to bring in a partner with substantial commercial capabilities to take the next step,” said Novimmune’s Chairman and Ceo eduardo enrico holdener. “In Sobi we see a strong partner with a proven ability to further develop, commercialise, and provide access to innovative treatments for rare disease patients.” Following the announcement, Sobi’s share L price rose about 10%.

Picture: I99pema / Wikimedia Commons (CC BY-SA 4.0)

An odd summer A US$3bn vista Alzheimer’s Bioarctic Neuroscience AB (Nasdaq Stockholm: BIoA B) entered the spotlight in July when the buzz around the topline results of a Phase 2b study of Alzheimer’s Disease (AD) candidate BAN2401 pitchforked Bioarctic’s stock price by 600%. Antibody BAN2401 is the result of a research alliance between eisai and Bioarctic. Japanese eisai Co. Ltd. (tSe: 4523) obtained the global rights in 2007 and entered a BAN2401 collaboration with Biogen Idec (NASDAQ: BIIB) in 2014. Although the July results were initially regarded as promising, doubts came up some weeks later when more details were revealed. Nonetheless, Bioarctic’s shares still traded around €10 in early September – up from €2 back in June. ending another research cooperation with eisai, investigating a new principle for the treatment of AD, Bioarctic and eisai decided to split rights in August. Bioarctic will develop antibody and eisai small molecule therapies against the new molecular target. 

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immuno-oncology A momentous research and licensing partnership was forged in July by German Immatics Biotechnologies Gmbh and Danish antibody specialist Genmab A/S. Bringing next-generation bispecific immunotherapies to life, Immatics receives US$54m upfront and up to US$550m in milestone payments and royalties for each product. Starting off with three programmes, two more could be added later. In a best-case scenario Immatics would earn just under US$3bn. Genmab is responsible for the development, manufacture, and distribution of any new products, but Immatics owns some limited marketing rights in certain eU countries. the goal is to attack the three (or five) new proprietary intracellular cancer target structures identified with Immatics’ XPresident technology. Genmab contributes its in-house antibody development know-how, Immatics its proprietary bispecific T cell receptor technology platform. 

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NewS A new investor Vesalius Biocapital III Partners paid €4m in September and joined the likes of Novo Seeds, Karolinska Development, Novartis Venture Fund, M Ventures, and Innovestor. taken together, these investors propelled turku-based Forendo Pharma with a €16m Series A round into clinical stage. Vesalius manager Stéphane Verdood said: “Forendo is developing truly novel therapies that have the potential to transform the treatment of endometriosis, a disease that affects tens of millions of women across the globe.” the Finnish company also announced that its lead programme For-6219, a hSD17B1 inhibitor, has commenced a Phase Ia study.

Exploring synergies to partner or not to partner? PCI Biotech (oSe: PCIB) and Bavarian Nordic A/S (oMX: BAVA) will try to find an answer in the next months. the companies entered a preclinical research collaboration in August to evaluate technology compatibility and synergy based on in vivo studies.

Orphan drug investor Sickle cell disease drug developer Modus therapeutics AB said it raised SeK140m (€13.2m) in a financing led by new investor healthcap. healthcap invested SeK60m (€5.7m) in a Series A preferred financing; existing shareholders converted outstanding convertible notes into shares. Modus’s lead candidate, orphan drug sevuparin (a polysaccharide drug with anti-adhesive, anti-aggregate and anti-inflammatory effects), is currently in Phase II.

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Fighting oxidative cell stress

ANTIBODIES Belgian Galapagos NV and German MorphoSys AG have exclusively licensed the commercialisation rights of their Phase II IL-17C blocker MOR106 to Swiss pharma giant Novartis AG. Under the deal, the co-developers will equally share an upfront payment of €95m and potential milestones of up to €850m, plus 10-20% in tiered sales royalties. Novartis will finance all R&D and commercialisation. MOR106 is an immunosuppressive mono clonal antibody clinically developed in atopic dermatitis where IL-17C is overexpressed in the skin. MorphoSys and Galapagos will conduct additional · IL-17C target of MOR106 · Dual mode of action · First-in-class · Topline results from Ph1 study H2'17

trials to support development of MOR106 in atopic dermatitis, while Novartis will explore the potential of MOR106 in other undisclosed autoimmune indications in which the IgG1 antibody was evaluated preclinically. While most competitors in the autoimmune field target IL17-A to treat psoriasis and arthritic diseases symptomatically, and IL17-B in blood cancers and solid tumours, IL-17C was first targeted clinically by Galapagos and Morphosys, which designed the antibody in a 2008 co-development deal.

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Expanding the clinical scope The funding will support the design of an open label extension for an ongoing Phase II study with its anti-fibrotic lead compound GKT831 in the orphan liver disease Primary Biliary Cholangitis (PBC) – in which Genkyotex will finish an interim analysis this month. “Enrollment of our ongoing Phase II trial of GKT831 in Primary Biliary Cholangitis (PBC) has reached 86 patients, and to date no serious adverse events or liverrelated adverse events have been reported,” said Elias Papatheodorou, Chief Ex-

ecutive Officer of Genkyotex. In contrast to compounds from competitors such as Genfit Novartis, Allergan or Gilead, which target steatosis and cholestasis, GKT831’s directly counteracts inflammatory and fibrotic effects. GKT831 blocks the enzymes NOX1 and NOX4, major drivers of fibrogenesis in multiple organs, and is being developed in Primary Biliary Cholangitis (PBC) in which the company is in midst of plannings for a Phase III programme. In PBC autoimmune inflammation triggers progressive destruction of the bile ducts so that toxic bile is released and destroys liver tissue which is accompanied by fibrotic remodeling leading to liver cirrhosis – and often – liver cancer. The money will further be used to support CMC activities for an NIHfunded Phase II trial of GKT831 in patients with idiopatic pulmonary fibrosis (IPF). It is also being clinically evaluated in an investigator-initiated Phase II study in Type 1 Diabetes and Kidney Disease (DKD). The product candidate may also be active in other medically underserved fibrotic indications such as NASH or scleroderma, which impact 300 to 700 million people worldwide. The company’s second product candidate, GKT771, a NOX1 inhibitor, will be ready for clinical testing soon. It targets the NGF/TrkA/TRPV1 pain processing pathway and blocks angiogenesis  through the VEGF1 pathway.

Liver fibrosis can be caused by a multitude of liver insults: fat accumulation, cholestasis, and viruses. Associated diseases include cholestasis (primary biliary cholangitis, primary sclerosing cholangitis, progressive familial intra-hepatic cholestasis), non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD and NASH), and liver cirrhosis as well as viral hepatitis (HBV, HCV).

Picture: Genkyotex SA

Cross-licencing

FINANCING Oxidative cell stress is a known trigger of cell processes such as fibrosis, inflammation, angiogenesis, pain processing, cancer, and neurodegeneration. It’s triggered by the NOX enzymes NOX 1 to 7 and involves modulation of several known disease-relevant pathways. French public company Genkyotex SA, which has been under the radar of investors, secured an €7.5m gross financing in August that allows the company to expand clinical testing of its orally-administered NOX inhibitors in different medical indications. The company cashed in €7.5m through the issuance of convertible notes with share subscription warrants attached to YA II PN, LTD, an investment fund managed by Yorkville Advisors Global LP.

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NEWS Immune cell terminator

Small molecule restores liver regeneration

Fountain of youth organ regeneration A team of Scotch, Belgian, and Spanish researchers reported in August that they discovered a way to prevent liver failure caused by toxic drugs by supporting the liver’s natural ability to regenerate. In a study in mice by researchers at the University of Edinburgh MRC Centre for Regenerative Medicine and the Cancer Research UK Beatson Institute in Glasgow, together with Spanish and Belgian co-workers, found liver injury triggers a process – called cellular senescence – usually associated with aging or chronic disease. Cellular senescence occurs when injured cells permanently stop growing.

Liver samples from patients with acute liver injury showed impaired liver regeneration and the expression of several biological markers associated with senescence, and mice with Paracetamol poisoning also displayed senescent liver cells. Notably, two other mouse models showed that senescence could spread from injured liver cells to uninjured cells through the signaling molecule TGF-b. Administering a small-molecule inhibitor of TGF-b to mice 12 hours after Paracetamol poisoning reduced liver injury and increased regeneration, showing that the molecule could be a workable therapeuL tic target for future research efforts.

Picture: fotolia.com/natali_mis

Translational gene therapy r&D Boehringer Ingelheim steps into the lucrative gene therapy field through a licence option agreement with the UK Cystic Fibrosis Gene Therapy Consortium (GTC). The pharma company may licence IP from Imperial Innovations, the tech transfer arm of Imperial College London, and from gene therapy developer and manufacturer Oxford Biomedica to develop replacement therapies compensating for mutations in the CFTR gene that lead to cystic fibrosis. Futhermore, Boe-

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hringer will collaborate in R&D with the UK Cystic Fibrosis Gene Therapy Consortium, which has a clinical track record of six successful early stage CF gene therapies, which has developed a novel inhalable replication-deficient lentiviral vector (rSIV.F/HN) that will serve as a gene therapy development platform within the partnership. According to Boehringer Ingelheim, current treatment approaches do not fix the CFTR mutations (CFTR) but only L slow the progression of disease.

Dutch Xenikos BV has raised €30m in a Series B round led by Medicxi Ventures (Geneva, London, Jersey) and Boston-based RA Capital Management. The company said it will use the proceeds to kick-off pivotal Phase III testing of TGuard for treatment of steroid-resistant acute graft-versus-host disease (GVHD) in early 2019. T-Guard consists of a mix of antibody-drug conjugates (ADCDs), eliminating T and NK cell expressing CD3 and CD7 at their cell surface via apoptosis. GSK, Johnson & Johnson, and Novartis back Medicxi along with Verily, an Alphabet company.

What a combination TxCell SA is set to be acquired by US gene-editing expert Sangamo Therapeutics in an all-cash buyout of €72m on a debt- and cash-free basis. The merger will combine TxCell’s expertise in the field of regulatory T cell (Treg) development for immunological diseases with Sangamo’s ex vivo gene-editing capabilities. The companies plan to evaluate the potential of CAR-Treg – Tregs genetically modified with a chimeric antigen receptor, or CAR – therapies to prevent graft rejection in solid organ transplant and for the treatment of autoimmune diseases such as Crohn’s disease and multiple sclerosis. Sangamo expects that the proposed acquisition of TxCell will accelerate its entry into the clinic with a CAR-Treg therapy. In 2019, Sangamo expects to submit a clinical trial authorisation application in Europe for TxCell’s first CAR-Treg investigational product candidate for solid organ transplant.

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Biontech secures US$425m deal

Drug DiscoVery novo nordisk (NOVOB:DC) and Evotec (EVT:GR) have joined forces to find new drugs in the lucrative diabetes and obesity markets. the companies announced that they will also seek to find drug candidates to treat co-morbidities such as diabetic kidney disease, nonalcoholic steatohepatitis, and cardiovascular diseases. Under the agreement, evotec aG will apply its small molecule drug discovery platform to find promising drug candidates. Once suitable preclinical candidates are selected, novo Nordisk A/S will use Evotec’s INDiGO platform – a tech portfolio to assess ADMET acquired for €62m in 2016 by the acquisition of Cyprotec – to move through preclinical studies to enter IND registration. No financial details of the deal were disclosed. However, usual conditions for similar Evotec deals included €1m-10m R&D grants, €150m in milestones per compound, and 8% tiered royalties on average. the deal adds new projects to evotec’s portfolio of more than 60 R&D coowned projects. novo nordisk is a leader in diabetes medicines. the chronic incapacitating disease, which affected about 425 million people worldwide in 2017 (2015: 415 million), is associated with chronic co-morbidities such as cardiovascular and kidney diseases, nerve damage, and eye diseases. Obesity affects more than 650 million adults worldwide and is often cited as a major risk factor for many diseases such as cardiovascular diseases, diabetes, musculoskeletal disorders, and several cancers.L

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fee – as well as up to US$305m in future milestones plus double digit royalties on sales. Pfizer is now the first strategic investor owning a minor stake in the Biontech holding. With mRNA-based vaccines, Pfizer would challenge the flu world market leaders GlaxoSmithKline, Sanofi Pasteur, and Seqirus – a joint-venture of vaccine giants bioCSl and novartis aG – which more or less have put their development and investment focus on mostly cellbased non-egg-based production methods. Biontech’s mrna vaccines, like those of the company’s competitor Curevac, are expected to create and produce flu vaccines faster than traditional recombinant protein flu vaccines. Most recently, Biontech licenced Genevant Sciences’ directly injected lipid nanoparticle technology originally developed by tekmira L (now arbutus Biopharma).

Going big with little enzymes inDustrial Biotechnology

In early summer, German C-Lecta GmbH said it succeeded in developing a new process to make a new-generation sweetener. rumours are that CocaCola supplier Purecircle is converting stevia-plant-derived molecules with C-Lecta’s enzymes into sweet, aftertastefree rebaudioside M. Back then, the German enzyme specialist also announced its intention to revolutionize the global market for natural sweeteners. those weren’t empty words. a couple of weeks later, CEO Marc Struhalla introduced new investors to ensure that the transition from an R&D-based to a largescale manufacturing company will turn out to be a success. the growth capital comes from lead investor Capricorn Venture Partners (Leuven, Belgium) and from bm|t (Erfurt, Germany). C-Lecta plans to invest these new funds in the approval, launch, and scale-up of products from the project pipeline, further development

at c-lecta’s headquarters in leipzig

of the pipeline, as well as the expansion of international sales. Kevin Reeder, CEO of bm|t, added: “We feel C-Lecta is wellpositioned to transition to a high-value biotechnology product company.” Over the last five years, the company claims it has conducted more than 30 enzyme engineering projects with a success rate higher than 90%. Besides the sweetener project, two further food ingredient products with high market potential are said to be in an advanced development stage. L

Picture: BIOCOM AG

Lucrative goal

Flu Vaccine German Biontech partnered in August with Pfizer Inc. (PFe:US) to develop a mrna-based prophylactic flu vaccine for humans. While the privately held, Mainz-based mRNA immunotherapy specialist Biontech aG will conduct all preclinical development work and a first-in-man trial, Pfizer will be responsible for the later stages of clinical testing and global commercialisation of the vaccine. Biontech has so far focused on the development of cancer vaccines and immunotherapies, but this year began to widen its therapeutics focus by partnering with Genevant Sciences to develop mRNA therapeutics for orphan diseases. the company also has an ongoing research collaboration in the field of animal vaccines with Bayer AG. According to the contract, Pfizer will pay US$120m – partly as an equity investment, an upfront payment, and an R&D

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Merck boots Future Insight Prize AwArd German pharma major Merck KGaa prides itself on being the oldest life sciences company. Celebrating its 350th anniversary at its headquarters in July in Darmstadt, the company introduced the Future Insight Prize. Worth €1m, the research prize will be awarded annually for the next 35 years. the prize will be given to researchers who make “outstanding contributions to enable innovations important for the future of humanity in the categories of health, nutrition and energy.” the new award will be issued for the first time at Merck’s newly established science conference Curious 2019. next year’s topic is “Pandemic Protector,” aiming at solutions to detect or analyze emerging pathogens; agents to protect against or L to combat pathogens.

Picture: Merck

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neWs Agency for jump-starts Germany’s government announced that it will create an agency for breakthrough innovation to foster technology transfer of risky research projects with high market potential into products. It will be funded with roughly €1bn over 10 years. the German agency precedes eU plans to create a similar eU agency within its next research framework programme starting in 2021.

More free days The Future insight Prize was introduced by ceo Stefan oschmann. The inaugural trophy is dubbed “Pandemic Protector.”

Portfolio refresh Spotlight IBD Sequencing Paying CHF54.1m in cash, swiss tecan Group (sIX swiss exchange: teCn) snapped up Us company nugen technologies Inc. in august. With the acquisition, tecan is expanding its range of reagents for high-throughput sequencing (nGs, next-Generation sequencing). nugen is a Californian company founded in 2000 and employing 70 people. It is considered a leading provider of kits and sample preparation reagents for nGs – the fastest-growing segment in genomics. nugen will become part of the life sciences business, tecan said. tecan is strong in nGs sample prep instrumentation. Jointly with nugen, tecan plans to develop complete solutions for automated nGs library preparation. the acquisition price is less than four times the anticipated revenue of nugen for fiscal year 2018. Nugen is currently still in the red, but should turn profitable by 2022 at the latest. Overall, tecan expects sales of more than CHF75m in 2023 through the implementation of its new genomics strategy. 

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MicrobioM e UK company Microbiotica, and Genentech, a swiss roche group member, secured an allaround package to tackle inflammatory bowel disease (IBD) in early summer. the companies will work together to discover, develop, and commercialise biomarkers, targets, and medicines for IBD. For Microbiotica, the multi-year strategic collaboration is worth up to Us$534m and includes an undisclosed upfront payment. the Cambridge Innovation Capital portfolio company was launched in 2016. according to the agreement, Microbiotica will use its precision metagenomics microbiome platform to analyse patient samples from clinical trials of Genentech’s investigational IBD medicines to identify microbiome biomarker signatures of drug response, novel IBD drug targets, and live bacterial therapeutic products. James sabry, Global Head of Genentech Partnering, said he believes that the microbiome represents “a new paradigm in biomedicine both for understanding drug-response and as a novel therapeutic modality.” 

swiss pharma giant novartis announced that its monoclonal antibody for migraine prevention aimovig (erenumab) has received market approval in the eU. In two clinical trials, the once-monthly injection reduced overall migraine days per month considerably. erenumab works by blocking the calcitonin gene-related peptide receptor (CGrP-r), which plays a critical role in migraine attacks.

Phages, not antibiotics Viennese Phagomed Biopharma GmbH works towards a comeback of bacteriophages as weapons against bacterial infections. In august, the start-up presented its seed round investors: the austrian research Promotion agency FGG, the austria Wirtschaftsservice Gesellschaft mbH (aws), and private investors. together they provide Phagomed with more than €4m to further develop these novel therapeutics. FGG also proffered the option of €1.05m more until the year 2021. Currently, Phagomed is evaluating three potential drug candidates.

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Tracking cancer risk genes

Liquid biopsy exOsOme DiagnOstics Even though they’re in the nanometer range, extracellular vesicles (EVs) have started to make it big: According to Market Research Future, the global liquid biopsy market currently values around US$3.9bn and is projected to reach the valuation of US$17.4bn by 2022. “The two major fields for clinical applications will be diagnostics and cell-free regenerative medicine,” believes Antonio Chiesi, the CEO of Italian company Exosomics Siena. “Drug delivery and vaccine applications are also progressing, but I think there will be serious safety and regulatory issues to be addressed before entering clinical use.” Now Exosomics Siena and Swiss pharma company Lonza launched their first proprietary liquid biopsy solution for the selective isolation of tumor-derived nucleic acids from complex biofluids such as plasma or serum. Distinct from current liquid biopsy methods – in which total nucleic acids are harvested from blood with low amounts of tumor-derived genetic material – Exosomics Siena’s technology (SeleCTEV™-DNA and SortEV™-RNA) use a unique affinity method to select tumor-derived exosomes from which the DNA or RNA, respectively, can be extracted. 

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Open Data Cancer may be due to lifestyle or pure chance, but a major cause is genetic predisposition. Three researchers at the Barcelona Centre for Genomic Regulation (CRG) have developed a new statistical method to identify cancer risk genes from tumour sequencing data (Nat. Comm, doi: 10.1038/s41467-018-049007). The publication identifies ten new candidate cancer predisposition genes. Their computational method refers to an old idea that cancer genes often require “two hits“ before they cause cancer. “We applied our method to the genome sequences of more than 10,000 cancer patients with 30 different tumour types and identified known and new possible cancer predisposition genes that have the potential to contribute substantially to cancer risk,” says Ben Lehner, principal investigator for the study. The method allows scientists to find risk variants without a control sample and systematically identify these genes

from existing cancer genome datasets. The researchers worked with genome data from several cancer studies from around the world, including The Cancer Genome Atlas project, among others. Ben Lehner adds: “Our work highlights how important it is to share genomic data. It is a success story for how being open is far more efficient and has a multiplier effect. We combined data from many different projects and by applying a new computational method were able to identify important cancer genes that were not identified by the original studies. Many patient groups lobby for better sharing of genomic data because it is only by comparing data across hospitals, countries, and diseases that we can obtain a deep understanding of many rare and common diseases. Unfortunately, many researchers still do not share their data and this is something we need to L actively change as a society.”

For history’s sake aquisitiOn Since the death of longtime chief executive Giovanniy Recordati in August 2016, his family, which holds 51 percent of the company through its investment vehicle Fimei SpA., has been considering a sale. In June, private equity firm CVC Capital Partners agreed to buy control of the Italian drugmaker. CVC will pay €2.3bn in cash, and €750m in subordinated longterm debt securities to buy the family’s stake, according to a statement from Recordati. “I believe that this is a great outcome for the company and its employees, who will benefit greatly from having CVC as a partner,” states Andrea Recordati, who will remain as CEO and invest alongside the consortium. Recordati’s history began in 1926, when Giovanni Recordati created Laboratorio Farmacologico Reggiano, the predecessor to Recordati SpA, in the northern city of Correggio. Giovanni

died in 1952 and left the company to his son, Arrigo, who moved it to Milan a year later and began expanding research and development, product lines, and access to markets outside of Italy. Arrigo died in 1999, bequeathing the business to his four children, and putting management in the hands of his son Giovanni, who died last year, leaving his share to his wife. “It was important to find a party that would allow Recordati to remain independent, with continuity for management and employees, and accelerate its growth strategy as a leading global consolidator in the pharmaceutical industry,“ states Andrea Recordati. Recordati’s research is focused on the development of new drugs in the therapeutic areas of cardiovascular and urology. Its most important product is Lercanidipine, a new generation calcium channel blocker for the treatment of high L blood pressure.

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NEwS US$50m project started

Look out for America Pharma mar Spanish specialist for sea-derived synthetic oncology drugs, Pharma Mar, wants to start trading in the United States. In September, the company announced its intention to conduct a registered public offering of American Depositary Shares representing its shares in the United States. This initiative was previously announced four yours ago, when Pharma Mar presented the strategy for the merger with Zeltia S.A., a group of pharmaceutical chemical and biotechnology companies of Spanish origin. At that time it did not indicate that the chosen route would be a capital increase without preferential subscription rights for the current shareholders. The company has not yet decided the amount of the operation. Pharma Mar is one of the six Spanish companies listed on the Spanish Stock Exchange (Grifols, Almirall, Rovi, Faes Farma, Reig Jofre). From January to June of this year, all of these pharmaceutical companies, with the exception of Pharma Mar, managed to reduce their debt compared to the same period of the previous year

Pictures: fotolia.de / Tatiana Shepeleva

Licence deal dropped At the end of June, Roche’s Japanese arm Chugai returned all rights from a 2016 licence agreement on the RNA polymerase II blocker lurbinectedin to Spanish oncology specialist PharmaMar SA. As a compensation, PharmaMar received a payment of €3mn from Chugai who had

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announced it will terminate the commercialisation agreement for the alkylating DNA minor groove binder by April 2019. According to the mutual early termination agreement, PharmaMar regains all its rights for Zepsyre ® in Japan with immediate effect. This January, lurbinectedin failed to reach the primary endpoint of progression-free survival for platinum-resistant ovarian cancer patients vs standard chemotherapy in a Phase III trial. However, PharmaMar says the transcription inhibitor is safer than chemotherapy. But there is also positive news for lurbinectedin. In August, the drug was granted orphan drug status by the FDA for the treatment of small cell lung cancer (SCLC). “Receiving orphan drug designation for the treatment of SCLC is a significant regulatory milestone in the development of lurbinectedin,“ states Luis Mora, Managing Director of the Oncology Busines Unit of PharmaMar. In July, the Spanish oncology specialist finalised patient recruitment for its global registration trial ATLANTIS (n=600), which combines lurbinectedin with doxorubicin vs standard therapy. Results for the primary endpoint of overall survival are expected by the second half of 2019. According to data from the Phase I/II Study that will be presented at the wolrd Conference on Lung Cancer (IASLC) in Toronto this year, Pharmamar observed an Overall Survival (OS) of 10.2 months, rising to 11.5 months in platinum-sensitive patients. L

Amyris Bio Products Portugal, Unipessoal, Lda, a fully-owned subsidiar y of Amyris Inc., announced the execution of the Alchemy Project together with the Universidade Católica Portuguesa (UCP) and AICEP Portugal Global (AICEP). It is one of the largest biotechnology programs in Portugal, co-financed by Portugal 2020, and will be based in a new biotech facility on the UCP campus in Porto. The project goals entail collaboration to advance the use of Amyris’s technology platform to explore the means of using waste from fermentation to develop new products and applications from coproducts and increase the production efficiency of biomolecules.

Cannabis for Europe Australian cannabis company MGC Pharmaceuticals has signed a key distribution agreement that will fast track the distribution of its medical cannabis into key target markets in Europe. “This partnership with A.M. Mangion connects us to a well-established Maltese distribution company and fast tracks the distribution of MXC’s medical cannabis pharmaceutical products into Malta, parts of Europe, the MENA region and the UK,” states MGC managing director Roby Zomer. Under the three-year agreement, MGC will supply an initial range of products to Maltese-based A.M. Mangion Ltd for distribution to Malta, Italy, France, Spain, Portugal, the Middle East, North Africa, and the UK. The certification permits the immediate production of CannEpil for the use of epilepsy treatment. CannEpi is already approved for use in Australia.

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Acquisition accomplished

Blocks for drugs Cmo A business trip with the president of the Republic of Estonia to Ukraine in May bore fruit as Andrus Tasa, Chairman of Estonian CMDO TBD Biodiscovery, entered a collaboration with Kiev-based Enamine Ltd. a few weeks later. Enamine will provide protocols to synthesize novel intermediates at laboratory or bulk scale. TBD Biodiscovery will use the developed protocols to manufacture requested products in its Tartu headquarters to GMP standard. Tasa said he has been impressed by the creativity of Enamine’s chemists in designing new chemical syntheses. Enamine is a chemical company producing building blocks and screening libraries. The major asset of the company is the world’s largest collection of building blocks: 150,000 in stock with 2,000 additions synthesized each month. 

Immunotherapy Envisioned two years ago when Czech investor PPF Group participated in a financing of Nantes-based immunotherapy play Cytune Pharma SAS, the staged acquisition of Cytune by PPF was finally completed this August. In 2016, PPF and other investors collected €6m to advance Cytune’s RLI-15 lead programme to Phase I clinical trials. Since then, Cytune has collaborated with Czech biotech company Sotio a.s., another PPF-funded biotech, on the further development of Cytune’s pipeline. Now, it is Sotio that will continue to develop RLI-15 under the new name

Head office of Czech investor PPF Group in the north of Prague

SO-C101. First-in-human clinical trials are expected to start in early 2019 in selected European countries and the US. A key part of this early clinical programme is the combination of SO-C101 with immune checkpoint inhibitors. All Cytune

projects will be developed as part of Sotio’s pipeline. Cytune’s focus is on IL-15 based therapies for the treatment of cancer. SOC101 is a human fusion protein of IL15 and the high-affinity binding domain of IL-15Rα and acts as a specific IL-2/ IL-15Rβγ agonist. Based on preclinical data, SO-C101 is more potent and better tolerated compared to unmodified IL15 or IL-2. “I’m proud that our products, originating from INSERM and the University of Nantes, hold the potential to lead to new therapeutic options for the treatment of cancer patients. They represent a new and very promising class of drugs in the immuno-oncology segment as they have been shown to reinduce responses in patients after failure to checkpoint inhibitors treatment,” added David Bechard, President and COO of Cytune. The most advanced projects in Sotio’s development portfolio have been developed with its proprietary DCVAC platform – an active cellular immunotherapy (ACI) on the basis of dendritic cells. In June, Sotio presented promising results of a primary analysis of its Phase II clinical trial SOV01 with DCVAC/OvCa in patients with ovarian and lung cancer. Sotio CEO Radek Spisek said he wanted to initiate further clinical trials L including a global Phase III study.

award Medical imaging start-up Oxipit was awarded the first offical investment of the Lithuanian Business Angels Network in June. The network, together with Co-Investment Fund Koinvesticinis Fondas, will provide Oxipit with €100,000. The startup’s machine learning systems Chestglass and Chesteye are X-ray search solutions that allow doctors to find radiologically similar images in a given database and to give a fully automatic computer-aided diagnosis solution. 

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GEnomE EDitinG The Norwegian Academy of Science and Letters awarded the 2018 Kavli Prize in the nanoscience category to Virginijus Šikšnys (Vilnius University, Lithuania), Jennifer Doudna (University of California, US), and Emmanuelle Charpentier (Max Planck Institute for Infection Biology, Germany) for their seminal advances in developing the revolutionary genome editing technology CRISPR/Cas9. The three researchers will L share the US$1m prize money.

At the Kavli Prize ceremony in early September: Virginijus Šikšnys, Jennifer Doudna and Emmanuelle Charpentier

Picture: Fredrik Hagen (bottom), PPF Group (top)

AI in radiology Lithuanian CRISPR input honoured

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

AdVErtoriAl

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Advanced blood DNA extraction for less Nucleic Acid purificAtioN  BioEcho Life Sciences develops novel kits for the isolation and processing of 

DNA and RNA. Their proprietary EchoLUTION single-step purification technology simplifies handling and  is significantly faster than commonly used extraction methods. With the new blood DNA kits, inhibitor-free  DNA can be obtained from both small to large sample volumes (60 µl to 1 ml) or dried blood spots. 

With the EchoLUTION Blood DNA Kits,  BioEcho brings new solutions to the  market. No matter if using the EchoLUTION Blood DNA Micro Kit for up to  60 µl blood or dried blood spots or the  brand new EchoLUTION Blood DNA HiYield Kit, with an input range from 200  µl–1 ml blood, both are based on the  same fast and convenient procedure  and result in highly pure and concentrated PCR/NGS-ready genomic DNA.

Inhibitor-free DNA

Pictures:BioEcho Life Sciences

The EchoLUTION Blood technology – unlike common bind-wash-elute methods –  does not include any inhibitory reagents 

and avoids harsh high-salt conditions and  the use of ethanol. The procedure starts  with gentle lysis of stabilized or frozen  blood using TurboLyseTM Protease solution. Then, DNA is separated from the  remaining cellular constituents and from  process components via a single centrifugation step. Purification done! 

Up to 1ml blood – high DNA yield  With the new EchoLUTION Blood DNA  HiYield Kit, up to 20 µg highly concentrated DNA (200 ng/µl) is obtained. This  unique kit solution offers maximal flexibility with 200 µl to 1 ml blood as input. The complete micro-centrifuge-

Flexible blood input, high DNA yield, concentration, and purity. The indicated volumes of blood (the same donor, three samples each) were purified using a common DNA purification kit (Q) or the BE Blood DNA HY Kit (BE). Two µl eluate were loaded onto an agarose gel; key parameters were measured spectrophotometrically (table).

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based procedure takes 20 minutes.  For processing larger sample volumes,  scientists so far had to rely on costly and  inconvenient large-scale kits (e. g., Midi/ Maxi formats). These suffer from a limited binding capacity and low DNA concentration and purity. With the Echo LUTION  Blood DNA HiYield Kit, we avoid all these  obstacles and provide lots of high-quality  DNA (see figure and table).

Reliable PCR and NGS results The  patent-pending  EchoLUTION   process provides DNA of high average  chain length and purity. qPCR reactions  are more sensitive and robust compared  to Silica methods, and the risk of complete assay failure has been eliminated. NGS detection often requires high  DNA concentration and amount. Particularly blood donors with infections, autoimmune diseases, or receiving cancer  treatment suffer from low leucocyte titer and therefore a low amount of DNA.  With the new HiYield DNA Kit, these  samples result in enriched DNA yield  and concentration, enabling sequencing results of the desired coverage and  phred score. Contact Dr. Frank Schäfer BioEcho Life Sciences GmbH Biocampus Cologne f.schaefer@bioecho.de www.bioecho.de Tel. +49 (0)221-99 88 97-0

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BioEconomy

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Copying nature to save the planet Levels of atmospheric carbon dioxide almost doubled over the last century. So why not just take a page out of Mother Nature’s book and harness this immense potential energy source with the help of artificial photosynthesis? Researchers around the world are now trying to produce fuels using just CO2 , water and light. The technology has a long way to go to reach large-scale viability, but in the lab researchers are making decisive progress.

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Pictures: temmuzcan/istockphoto.com

Synthetic Biology

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BioEconomy

European Biotechnology | Autumn Edition | Vol. 17 | 2018

S

even months and a day – in 2018, that’s how long it took us to burn through the resources that nature can restore annually. in other words, humanity is currently living as if it had 1.7 Earths available. Every year, the Global Footprint network launches a campaign for what’s called Earth overshoot Day to raise awareness of how limited resources on the planet actually are. Throughout most of history, humanity has exploited nature to build cities and roads, provide food and create products, and in the process has released carbon dioxide at a rate well within Earth’s potential to compensate. But the amount of co2 in the atmosphere has skyrocketed in the last 150 years, causing global warming and all the negative consequences associated with it. “one important potential risk is the possible amplification of CO2 concentrations through climate feedbacks. in drier years the concentration of carbon dioxide in the atmosphere rises faster because stressed ecosystems absorb less carbon,” says geophysicist Sonia i. Seneviratne from the ETH Zurich’s Department of Environmental Systems Science. The professor has been working on climate extremes for many years, and in August she published results from new satellite observations of water storage that reveal the overall impact of droughts on photosynthesis and ecosystem respiration (Nature , doi:10.1038/ s41586-018-0424-4). “During the driest years, such as 2015, natural ecosystems removed about 30% less carbon from the atmosphere than they do during a normal year,” she warns (see Fig. 2, p. 88).

Pictures: Max Planck Institute for terrestrial Microbiology

Is there a cure for CO2? “if we could turn it into useful compounds for humans,” says Tobias Erb, “this greenhouse gas would be a wonderful and sustainable source of carbon.” The problem is, adds the Director of the Department of Biochemistry and Synthetic metabolism at the max Planck institute for Terrestrial microbiology, that so far no chemical engineering process allows us to efficiently and sustainably bind and convert carbon dioxide on a large scale. However, synthetic biology and the field of genetic engi-

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neering are now creating completely new possibilities for harnessing the resource through artificial photosynthesis (AP). “The vision of artificial photosynthesis is more relevant today than ever before,” says Erb. “Synthetic metabolic pathways, improved light photosynthesis and completely modified photosynthesis in plants … these are things we’ll see in the next 15 years.” For example, he and his research team have developed an artificial – though completely biological – metabolic pathway that binds co2 from the air with 20% greater efficiency than plants can achieve photosynthetically. “The bottleneck is the capture and conversion of co2 into biomass. The enzyme RuBisco is responsible for that. It converts just five to ten CO2 molecules per second on average,” Erb explains. Seeking more efficient solutions, the German scientists discovered a previously un-

Tobias Erb Director of the Department of biochemistry and synthetic Metabolism at the Max Planck institute for Terrestrial Microbiology in Marburg, Germany

? !

How can synthetic biology reduce atmospheric co2 levels?

Carbon fixation is the most important biological process on Earth, literally feeding all life forms. But it’s very inefficient. We’ve built a complete synthetic metabolic biochemical cycle that’s much more efficient than natural photosynthetic cell cycles. With new collaborations, we’re now trying to get this “metabolic heart” into living cells.

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known enzyme from purple bacteria that converts co2 up to ten times faster than RuBisco. “But we couldn’t only replace one enzyme. We had to replace the entire metabolic network,” says Erb. “We designed the so-called cETcH cycle as an imitation of the dark reaction. That’s when plants build up carbohydrates independently of the presence of light.” in march, the Board of Trustees at the Bayer Science & Education Foundation awarded the biochemist a €75,000 prize for his achievements in the field of artificial photosynthesis. The work is done by 17 different enzymes. 14 of these occur in nature, while three others had to be designed virtually and synthesised artificially. The design has already been proven a success in vitro, converting gaseous co2 into the solid organic compound glyoxylic acid (oxoacetic acid) 20% more efficiently than it happens in nature. The acid can be used as a feedstock material for the production of the amino acids glycine or pyruvate – common molecules that can be used in the biotechnological production of many organic compounds (ScieNce, doi: 10.1126/ science aah5237).

“Four years of thinking and lab work against three billion years of evolution” The results published by Erb and his team show that scientists are already able to rebuild complete biological processes from scratch, and reconstruct them. The challenge facing all synthetic approaches to converting sunlight, co2 and water into useful fuels is now to get the artificial metabolic pathways from labs into organisms. “The most obvious way would be to take an existing organism, for example a cyanobacteria or algae, and try to introduce the artificial pathway. But it’s very difficult to get 17 enzymes working in an organism that already has 3,000 others,” says John Glass, professor and leader of the J. craig Venter institute’s (JcVi) Synthetic Biology & Bioenergy group. So one promising idea is to create a cell with as

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BioEconomy

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Photosynthesis” aimed at stimulating the development of usable, innovative systems for the production of fuels from sunlight. outside Europe, major projects like that sponsored by the US Joint Center for Artificial Photosynthesis are aiming to answer the same questions.

Number of companies > 20 10–20 < 20 Top 4 Germany (31) netherlands (28) Sweden (13) United Kingdom (13)

Cells designed to swallow CO2

Fig. 1: Research groups working on artificial photosynthesis. Around 150 teams are working in the field worldwide, 60% of them are active in Europe.

few other biological components as possible.

A number of approaches ‘Artificial photosynthesis’ (AP) means converting co2, H2o and solar energy into high-energy molecules or other compounds, regardless of process. What counts are the fuel or sugar products. There are currently three pathways outside naturally evolved systems for achieving that goal: ›› Synthetic biology & hybrid systems, which mimic existing biological systems. ›› Photoelectrocatalysis, which combines and integrates photovoltaic (PV) technologies to produce hydrogen. CO2 emitted by human activities (+39.2 gigatons/year)

›› co-electrolysis, which also produces hydrogen through energy sources typically considered non-sustainable (nuclear, etc.) Research on AP has grown significantly in the last few years, with 900 articles published in the field since 2014 (A d vAnces in BotAnicAl ReseARch, doi:10.1016/ bs.abr.2016.03.002). With around 400 professionals from over 40 European scientific institutions and around €60m in funding, Europe’s most significant and only truly pan-European-level research network is AmPEA (Advanced materials and Processes for Energy Application). To help foster research in the field, the European commission awarded a €5m prize “Fuel from the Sun: Artificial

CO2 that remains in the atmosphere (+17.3 gigatons/year)

CO2 absorbed by the oceans (+17.3 gigatons/year)

Back in 2016, US scientist and biotech entrepreneur craig Venter reported in science that his team had succeeded in peeling away functions in a naturally occurring bacterium to produce a cell that contains just 473 genes – the bare minimum necessary for life and cell division. Together with the JCVI in the US, the working groups headed by molecular biologist Roland Lill (institute for cytobiology at Philipps University in marburg) and Tobias Erb are trying to create a viable artificial cell that can convert light into chemical energy sources. In June 2018, the consortium received the first part of €1.5m in funding from the Volkswagen Foundation, and will receive the balance over the five years it’s taking part in the “BRILIANCE” project – Bringing Inorganic carbon to Life with Artificial CO2-fixation in a minimal cell (see interview opposite page).

Superboosting RuBisCO Rather than replacing the entire natural metabolic pathway with a synthetic one, scientists from the EU-funded

CO2 absorbed by land ecosystems (+17.3 gigatons/year)

Source: ETH Zurich, https://www.ethz.ch/en/news-and-events/eth-news/news/2018/08/drought-increases-CO2-concentration.html

Fig. 2: Ecosystems planet-wide play a role in the absorption of anthropogenic CO2 emissions.

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Less CO2 is absorbed during global droughts

Pictures: Artificial Photosynthesis: Potential and Reality, Report of the European Commission (2016) / ETH Zurich, Data: Global Carbon Budget 2017, www.globalcarbonproject.com, images: Freepik, Icon Pond

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project Future Agriculture are focusing on shorter artificial pathways with 4-5 enzymes that allow cells to bypass photorespiration, and improve the yield and rate of carbon fixation in plants. In those processes, natural enzymes are recruited to realise these pathways, and novel enzymatic activities have to be engineered. The evolved cascades can then be incorporated into photosynthetic microbes like cyano bacteria, and subsequently tested for advantages. “We have almost completed in silico and in vitro phases of the project, and we’re now moving towards the third phase, where the synthetic pathways are implemented in photosynthetic living organisms,” says Dr. Arren Bar-Even. She’s the research group leader at the Max Planck Institute of Molecular Plant Physiology in Potsdam-Golm and the coordinator of the groundbreaking AP project. Israeli company Evogene will be responsible for checking the activity of the in-plant novel pathways. The goal of the project is to test transformed lines systematically for phenotypic changes like growth rate, overall biomass and leaf size to conditions like light intensity or water/nitrogen availability. Although “there’s still a long way to go” says Bar-Even, “Evogene represents our path towards commercialisation … (and) can commercialise crop plants harbouring our synthetic pathways by itself or in collaboration with its various industrial partners around the world like Bayer, BASF or Biogemma.”

Pictures: J. Craig Venter Institute

Where do we go from here? All the technologies for AP, including synthetic biology approaches, are still in a very early stage of development, so there are still a lot of question marks. But if AP could one day be used to capture massive amounts of CO2 from the atmosphere, it would significantly contribute to climate change mitigation efforts. And according to the Global Footprint Network, halving CO2 emissions would shift the Overshoot date by almost three months. Then we’d  be only around 60 days behind. h.maerzhaeuser@biocom.eu

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BIOECONOMY

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The first principles of cellular life After over 13 years of research, scientists from the J. Craig Venter Institute in 2016 announced the creation of the first minimal synthetic bacterial cell, which contained just 473 genes. John Glass explains how that can help turn artificial photosynthesis into practice.

SYNTHETIC BIOLOGY

EuroBiotech_How did the BRILIANCE project start? Glass_ The introduction to Tobias Erb

was a perfect match. After we created the world’s first bacterial cell with a chemically synthesised genome in 2010 and the near minimal bacterial cell in 2016, we continued working on the minimal cell, trying to understand the biological roles of each of the 149 genes of unknown function, and also starting to look for applications for it. Through the JCVI-Max Planck Institute partnership, Tobias will be able to install his carbon fixation pathway in the worlds simplest cell. That enables him to better understand how the CETCH pathway enzymes interact with fundamental cellular systems. EuroBiotech_What are the next steps? Glass_ In the near term, we simply want

to install the CETCH carbon fixation pathway in a living bacterial cell and learn how it interacts with basic cellular metabolism. Our minimal bacterial cell performs all of the essential functions of cellular metabolism, and as such is an ideal system for investigating how a foreign pathway affects a cell. EuroBiotech_ We’re still doing fundamental research, but CO2 conversion into useful carbon compounds promises to be a billion-dollar market. Have you had any interest from industry yet? Glass_ We have not yet announced that

we are working on this Volkswagen Foundation-funded project. Hopefully, it will ultimately produce organisms capable of more efficient fixation of CO2 than

JOHN GLASS is professor and leader of the J. Craig Venter Institute’s Synthetic Biology & Bioenergy Group. Since June, it’s been working with German researchers to produce a designer cell that can convert light into chemical energy.

current plants are capable of. Should this project go as we hope, we will almost certainly seek industrial collaborations at some point. EuroBiotech_Are there ethical hurdles related to your project? Glass_ The JCVI-syn3.0 – in which the

CETCH carbon fixation pathway will be inserted – is an organism that has lost so many genes that it’s incapable of life outside of a controlled laboratory environment. This first organism will be completely safe: None of the genes we will be expressing will produce virulence factors. The long-term consequences of the knowledge gained from this effort is a more complicated question. Organisms that would be capable of industrial scale photosynthesis likely will be much more complex than the minimal bacterial cell we will be using at the outset of our  project.

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SciEncE & TEchnology

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Asthma needs to be targeted more specifically Up to now, researchers believed that lung remodeling follows an auto­ immune inflammation triggered by components of the extracellular matrix. In August, British scientists provided a more accurate view of the processes in the lung tissue, opening up a way to optimise failed mid­stage clinical candidates.

Allergic AsthmA

in patients with chronic neutrophilic lung diseases such as chronic obstructive pulmonary disease (coPD), cystic Fibrosis (cF) and bronchiolitis obliterans syndrome (BoS), peaking with exacerbation of disease and inversely correlating with lung function.

Selective inhibitors already screened

According to the team of UK, Spanish, and Polish researchers headed by Dhiren Patel (Manchester), unspecific blocking of the extracellular matrix (EcM) enzyme leukotriene A4 hydrolase (lTA4h), which boosts inflammation by epoxide hydrolysis of LTA4 into the highly proinflammatory lipid mediator leukotrien B4 (lTB4), is not enough to cure asthma (Science Transl. Med., doi: 10.1126/scitranslmed. aaq0693). Actually, several potent lTA4h inhibitors failed to show efficacy at various stages of clinical development (see table), including Johnson & Johnson’s recent Phase ii drug candidate JnJ-40929837.

The dual face of LTA4H in S cience TranSlaTional M edicine (doi: 10.1126/scitranslmed.aaq0693) they reported outcomes of experiments in a

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house dust mite model of asthma that prove an overseen second enzymatic activity of LTA4H that interferes with efficacy, a peptidase-binding pocket that overlaps with the hydrolase binding pocket, which binds lTA4 and hydrolyses it into lTB4. its natural binding partner is PgP (Pro-gly-Pro), a leukotrien degradation product of the extracellular matrix, which boosts airway sensivity and EcM remodeling when not degraded by lTA4A. PgP is readily degraded during episodes of acute pulmonary inflammation by extracellular lTA4h to facilitate the resolution of neutrophilic inflammation, and failure of this system culminated in augmented and prolonged inflammation with exacerbated pathology and illness. interestingly, they found PgP accumulation in the sputum of 50 patients with asthma. Significant quantities of PgP have also been found

LTA4H blockers that both block LTB4 formation and PGP degradation

Compound

Company

› SC567461A

Searle/ Pharmacia Johnson & Johnson

› JNJ-20929837 › DG-051

deCode

Failed in

Phase II Phase IIa

Pictures: fotolia.com/Andrej Popov

UK researchers develop the next generation of asthma meds.

When Patel et al blocked lTA4A activity genetically, they found that inflammation ameliorated due to inhibition of the lTA4 hydrolase activity of lTA4h. however, they also found that remodeling of lung tissue was boosted due to accumulation of PgP, which couldn't be degraded by the peptidase activity of lTA4h. Docking and structural analysis of lTA4h bound to its three clinically failed inhibitors clearly showed that they blocked PgP from being degraded. in humans, a structural relative of PgP named AcPgP enhanced mucus production and induced airway remodeling when administered to human bronchial cells in culture. in 2017, the group already reported results from a screening campaign aimed at finding more selective compounds

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

(Sci. rep., doi: 10.1038/srep44449 (2017). Following reports from Haeggstrom et al in 2014, who identified ARM1 as a potential selective LTA4H inhibitor, with the capacity to inhibit LTB4 generation without perturbing PGP hydrolysis, they initially focused on optimisation of resveratril derivatives. After they found they were not druggable, they switched to isoflavone derivatives and identified a promis-

sCiENCE & TECHNoLoGy

ing candidate. “we have developed two distinct chemical series of compounds that can selectively inhibit LTB4 generation with a selectivity that is superior to that of ARM1,“ the researchers write. “These novel compounds could form the basis for the development of selective and safer therapeutics for targeting LTA4H in a broad array of disease moL dalities.“

Pictures: tomozina/istockphoto.com

Fighting Lupus differently Drug Discovery EGFR agonists support the protective effect that Langerhanscell offer against UV-induced damage of skin cells, a hallmark of the autoimmune disease lupus erythematosus and other immunologic and dermatologic conditions, a team of Us and German researchers reported in August. Lupus affects roughly 1.5 million UsAmericans. one of the most common symptoms – besides swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes and fatigue – is photosensitivity, which occurs when the skin becomes highly sensitive to ultraviolet (UV) radiation. Photosensitivity is a major concern for patients because it can result in disfiguring skin rashes. Although strategies such as avoiding the sun and using sunscreen can help prevent lesions from forming, currently there is no causative treatment. A research team headed by Theresa Lu from the Hospital for special surgery in New york has now discovered in a lupus mouse model that light sensitivity arises partly due to malfunction in a cellular protective mechanism. Analyses of mouse models and samples from lupus patients suggest that repairing this distorted interaction between Langerhans cells and skin keratinocytes could bring relief to patients with lupus and other autoimmune disorders. In healthy mice, the researchers discovered that keratinocyte cell death was prevented by Langerhans cell through activation of the EGF receptor. Treating the lupus mice with a topical formulation of an

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EGFR agonist reduced the severity of UVinduced lesions. Mechanistically, Langerhans cells expressed EGFR ligands and metalloprotease 17 (ADAM17), which activates EGFR ligands. Deletion of ADAM17 from Langerhans cells led to photosensitivity, and UV radiation induced ADAM17 activation in Langerhans cells and generation of soluble active EGFR ligands, suggesting that Langerhans cells protect by providing activated EGFR ligands to keratinocytes. As skin samples from lupus patients also showed decreased numbers of Langerhans cells, Lu et al. thus want to elucidate further EGFR’s potential as a workable target in the treatment of lupus. The lupus market, which covers systemic lupus erythematosus (sLE) and lupus nephritis (LN), is set to almost triple from US$1.2bn in 2015 to US$3.2bn by 2025, representing a compound annual growth rate of 10.6%, according to research and L consulting firm GlobalData.

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NEws Sustainable plastics Researchers at ETH Zurich and sulzer AG have developed a process that speeds up synthesis of bio-based polyethylene furanoat (PEF) from days to half an hour. “Usually it takes days to remove water that is formed during the polycondensation of the viscous mixture of monoethylen glycol (MEG) and 2.5-furandicarboxylic acid (FDCA). we now have designed a two-step reaction with a cyclic intermediate in which the water can be removed easily in the first reaction step,“ JanGeorg Rosenboom told European Biotechnology. The major task for the partners is now to limit the amount of solvent needed before upscaling the process. PEF offers several advantages over the bulk plastic PET, which is used in bottle and food foil production. Synvina, a BASF/ Avantium joint-venture formed in 2015, announced they will scale up PEF production this year to 50,000 tons/ year with the classical process. Like PET, PEF can be recycled chemically by solvolysis.

Cross the border Early-onset, fatal neurodegenerative Gaucher disease can be prevented in the womb in mice by delivering an adeno-associated virus (AAV) vector carrying an intact copy of the glucocerebrosidase gene into the fetal brain, reported UK physicians (N ature M ediciNe , 10.1038/ s41591-018-0106-7) at the end of August. Mice treated this way survived 18 weeks. The next step before heading towards testing in humans is ultrasound-controlled AAV delivery into macaque brains, the researchers said.

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Closing a gap at ICUs Diagnostic results must be readily available to diagnose critically ill patients in emergency settings and at ICUs. So far, diagnostic blood tests, which demonstrably could help emergency meds recognise residual congestion in heart failure, septic shock, or acute kidney injury before patients reach critical condition, have not been available in the automated format required at ICUs. After Sphingotec acquired Nexus IB-10 POC testing platform in May, investors wait in line.

POC testing

standing Poc test platform that works with whole blood samples in Q1/2019.” The company has proved in clinical tests on about 30,000 patients that a high plasma penKid level predicts development of AKi in high-risk patients much earlier than other kidney markers routinely used and as precisely as the current gold standard, inulin clearance (true glomerular filtration rate (gFR), that is also expensive and invasive. Blood analysis of kidney function might complement measurement of kidney injury markers in the urine, which provide catheter-use associated risks of urinary infections. Furthermore, serial quantification of penKid allows for monitoring of kidney function, which is not possible with kidney injury markers. clinical studies on more than 20,000 patients showed that elevated levels of

2

1

3

the nexus iB10 point-of care-testing platform supports multiple tests.

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plasma bioADM in patients are an important indication of vascular dysfunction in widely differing indications. BioADM is a regulator of vascular integrity and indicates when patients‘ blood vessels have become so permeable that the risk of septic shock or the formation of dangerous edemas in heart failure patients is greatly increased. clinical test results also indicate that bio-ADM is indicative of the previously undiagnosable residual congestion – one of the leading causes of death after discharge of heart failure patients who appear to be successfully treated with diuretics.

Stepping into big markets For emergency physicians, especially in the numerous smaller hospitals without central diagnostics, Poc tests are good news. They only have to put a little whole blood from the patient on the test slot of the iB10 device in order to prove the acute biomarkers by rapid test and to include the test results in their treatment decision. Every year, eight million people die from sepsis, including 700,000 from acute kidney failure. Sepsis alone costs the US healthcare system US$24bn per year. The current US$31bn annual US health care spent for heart failure is expected to double by 2030. Sphingotec is in talks with the FDA about its tests and new platform. According to Bergmann, Sphingotec plans to market further acute biomarkers on the iB10 platform and is currently building a distributor network. Additionally, distribution partners will offer automated versions of Sphingotecs tests to the cenL tral laboratories of large hospitals. t.gabrielczyk@biocom.eu

Picture: Sphingotec GmbH

At the beginning of September, market observers told EuropEan BiotEchnology that they expect Sphingotec gmbh to close a significant financing round very soon. The german Dx specialist has several cE-marked tests for functional plasma biomarkers in its portfolio, two of them addressing the need of doctors at emergency units and icU to predict and monitor diagnostically underserved conditions such as congestive heart failure and septic shock (bioactive Adrenomedullin, bioADM) as well as AKi (acute kidney injury, pro-enkephalin, penKid). At the end of May, the company acquired the fully automated Nexus IB10 lateral-flow testing platform from Samsung subsidiary nexus Dx inc at an undiclosed price. According to their cEo, Dr. Andreas Bergmann, “we look forward to commencing distribution of our acute care biomarkers on this out-

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ASSOCIATIONS

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Industry attracted €150m ASEBIO REPORT 2017 In July, the Span-

ish Bioindustry Association (ASEBIO) presented figures and data about the Spanish biotechnology sector in 2017. The report includes data related to 2017 and the macroeconomic data from the National Statistics Institute (INE) statistical study on Technological Innovation in Biotechnology Companies. “We’re a special sector: due to our volatility, our levels of risk, and the extension of our cycles. We do believe that we can say, as is found in the conclusions in this report, that it is necessary for the administration to pay attention to certain requests,” explained Jordi Martí, president of ASEBIO, during the presentation of the report. Proposals to resolve the limitations present in the Spanish R+D+I system include: › increasing the public budget dedicated to R+D, both in terms of volume and quality; › increasing the subsidies and non-reimbursable tranches as opposed to loans; › improving how the public budgets dedicated to R+D are formalised; › providing continuity to the debt deferment mechanisms. Financial transactions in the Spanish biotechnology sector have reached a total of €149m – that’s 17% more than last year. The highlights include 27 private capital expansions, valued at €93.7m with MedLumics (€34.4m) and Anaconda Biomed (€15m) as the most important transactions. There have been six capital increases by issuing shares for €41m (Oryzon, Atrys Health, Sygnis, Reig Jofré, and Inkemia), 31 complementary financing operations or participative loans for €10.8m, and various operations in the field of crowdfunding. The acquisitions by Biofabri and the purchase of Biópolis were not considered. More information can be found on the homepage of  ASEBIO www.asebio.com.

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European Biotechnology is published in co-operation with the following organisations: European Biotechnology NET WORK

Europe: european-biotechnology.net

Europe: medtecheurope.org

Europe: europabio.org

Austria: lifescienceaustria.at

Switzerland: swissbiotech.org

Spain: asebio.com

Europe: medicinesforeurope.com

Ireland: ibec.ie/ibia

Denmark: danskbiotek.dk

The Netherlands: hollandbio.nl

Germany: biodeutschland.org

Portugal: www.p-bio.org

UK: biopartner.co.uk

France: france-biotech.org

Council of European BioRegions

CMYK

Italy: assobiotec.it

Sweden: swedenbio.com

Hungary: hungarianbiotech.org

Europe: cebr.net

Europe: ebe-biopharma.org

Norway: biotekforum.no

Finland: finbio.net

Belgium: bio.be

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EBE

White Paper on Personalised Medicine 91_94_EB__Autumn_2018_Associations_HM.indd 91

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AssociAtions

European Biotechnology | Autumn Edition | Vol. 17 | 2018

UPcoMing EVEnt › 14–16 May 2019, Paris the Medtech Forum 2019

Brexit uncertainty puts patients at risk The evolving Brexit uncertainty puts patients and businesses at risk. It’s time to add your voice to our call for an extended transition period and mutual recognition of CE-marked technologies.

sue. Large firms will struggle to deal with the uncertainty and costs that may lie ahead – but they will find a way, even if it hurts their bottom line. For smaller ones, already straining to cope with regulatory changes, it could be the straw that breaks the camel’s back.

Brexit

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Medtech Europe has set out four concrete priorities that we believe would help to guarantee patient safety and public health, and product businesses.

› We are calling for the extension of the transition period until at least 31 December 2020, taking into consideration the current “notified Body re-certification” challenge in the implementation of the new iVDR and MDR. › Mutual recognition of cE marking for medical technologies would bring great relief to hospitals, health professionals, patients, and companies. these are urgent if we are to avoid chaos. › We would like to see a trade agreement for healthcare to prevent the development of trade barriers which would hit industry investment capacity in innovation and industrial development. › We are calling for convergence of regulatory frameworks in the EU and UK. Medtech Europe represents the interests of our sector all year, every year. We need you to add your voice to the growing chorus of medtech companies L pushing politicians to take action.

Pictures: Medtech Europe

the clock is ticking. two years prepare for an unfavouraago, the UK’s decision to leave ble outcome. if you have the European Union sent shockany business interaction waves across European industry. with the UK, the situation Pessimists warned that planes is critical and demands would be grounded, collabourgent attention. ration on energy would cease, this is not an abstract and access to life-saving mediproblem; its impact will cal technologies would grind to be felt by your compaa halt. ny, in your local hosoptimists reasoned that sense Serge Bernasconi, pital, and by people in would prevail. Brexit, they ar- CEO of MedTech your communit y. the gued, would soften in the face Europe numbers of people facof the unpalatable compromising real risks to their es that come with leaving the single health is potentially high – but even if Market and customs Union. self-interjust one person’s care is unduly disruptest would swiftly lead London to proed, it would be one person too many. pose a new relationship that closely reBad timing sembled the status quo. it was too soon to panic. sudden regulatory divergence between i believe that the supply of, and access the EU and UK would have potential to, medical technologies for patients and for chaos at any time. But of course, we healthcare providers across Europe must know it is happening at the worst posbe prioritised by negotiators. sible moment. Medtech companies are Real risks busy preparing to transition to the new Medical Device regulation (2020) and As we hurtle towards the cliff edge, we iVD regulation (2022). still hope solutions will emerge. in the For small and medium-sized businessmeantime, i must urge our members to es (sMEs), all of this is an existential is-

Our priorities

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“WHITE BIOTECHNOLOGY” WORKING GROUP

sector is internationally visible. The project-specific participating companies (most of them young and internationally less savvy) find a comprehensive partner which is helping to put them in the public window. Leading chemical companies are exploring the opportunities that have been opened up by modern bio- The participating Life Science Regions are important internal carriers of the dynamics in the Biotech sectechnology, especially in the field of “white” or industor, thus enhancing the common understanding of the trial biotechnology. And they are also applying these | | | European technologies, Biotechnology Autumn Edition Vol. 17 2018 wherever it makes sense. The SBA takes industry. This and more knowledge is brought into Europa Bio, the European Biotech Association, where such initiatives seriously and has formed a working the SBA is an active member. group specifically dedicated to white biotechnology. The Swiss Industrial Biocatalysis Consortium is an important partner in this effort. The group includes leading multinational companies that support white biotechnology as a pillar of economic growth. The planned activities are in agreement with OECD strategies. In partnership with the Swiss Biotechnet (see pages 14/15) the SBA develops training programmes and useful support tools for the industry. It is of importance that the industry specifies its training needs so that the academic side can create tailor-made education. This strategy ensures that the industry gets the right Domenico Alexakis workforce with the right education. The SBA profits is Executive Director from the marketing alliance “Swiss Biotech” (see box) of the Swiss Biotech in a multiplied form. Thanks to Swiss Biotech, the Association.

Switzerland tops as life sciences site

KPMG’s new site selection report for life sciences companies in Europe compares the attractiveness of different countries for discovering, developing, and commercializing pharmaceutical products in Europe. It shows that the Swiss biotech hub is leading by many accounts.

RepoRt

When entering a new regional market, strategic and meticulous planning is essential for commercial success. the report identified the key success factors in building a successful operating model, and compares the attractiveness of different, mainly European, countries, focusing on the most relevant factors when it comes to site selection for life sciences companies. While there is no one-size-fits-all solution to the location question, switzerland gets the best grades in many aspects, making it a favorable hub for biotech companies.

Pictures: SBA

› Innovation: the European innovation scoreboard shows that switzerland stands out as the clear innovation leader. this is also confirmed by the World intellectual properties organization’s global innovation index. in addition, switzerland has a strong phase iii pipeline as a percentage of the total number of products in development. › Business and political environment: the World Economic Forum’s global competitiveness Report, the imD’s World competitiveness Yearbook, and the Heritage Foundation’s index of Economic Freedom are widely regarded as being particularly useful in comparing countries’ competitiveness. Here, switzerland ranks in positions 1, 2, and 4. in regards to the political environment globally, switzerland is third in political stability and tops the table for overall enterprise resilience to disruptive events.

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SWISS BIOTECH...

...is an alliance of four leading Biotech regions of Switzerland (Bio Alps, BioPolo Ticino, Basel Area and Greater Zurich Area). They have combined efforts to streamline interests of the national biotech sector. The SWX Swiss Exchange holds a leading position in terms of lifescience listings and offers companies from that industry – be they located in Switzerland or abroad – access to an internationally recognised financial marketplace. The initiative was co-founded by the SBA which also manages the executive office of Swiss Biotech.

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@

Upcoming EVEnts For further information please visit www.swissbiotechassociation.ch www.swissbiotech.org

› 27 Sept. 2018, Lausanne swiss Biotech Day Fall tinyurl.com/swiss-biotech-fall

› 7 May 2019, Basel swiss Biotech Day & swiss Biotech success stories celebration swissbiotechday.ch

› Quality of infrastructure: infrastructure quality is of great importance in life sciences, where disruptions in manufacturing or logistics can have a significant impact not only on profits but also patients. switzerland’s overall infrastructure is rated best in the World Economic Forum’s global competitiveness Report 2017-2018. › Qualified workforce and quality of life: in the global comparison, switzerland offers the most attractive overall conditions for highly skilled foreign workers and multinational companies and ranks second in productivity. the mercer Quality of Living index rates switzerland second regarding the standard of living in combination with the typical compensation packages that companies offer their employees. in the global talent competitiveness index, switzerland is right up front with its ability to compete for diverse talent. › Financing: switzerland saw a record total financing volume in 2017 in comparison to the last seven years. it is ranked number three in the European public and private financing of life sciences companies. › Tax Incentives: on a global scale, switzerland ranks third in international corporate and individual tax rates for 2018 and generally provides a wide range of tax incentives and grants to L innovative companies.

Academy TraInIng given the constant need to be up-to-date with current developments in drug discovery and development, clinical research, legislation, and other areas of the drug development procedure, the swiss Biotech Association is expanding its high-quality training program together with selected partners for their members. Aimed at all professionals who have a strong interest in biotechnology and life sciences, the swiss Biotech Association Academy presents a perfect mix of education on a professional level, where thoughts can be exchanged with other experts and the personal network be expanded. the Academy courses are organized throughout the year by the swiss Biotech Association and their Academy partners. 

Cooperations acadeMIa and InduSTry the swiss

Biotech Association supports close cooperation between academia and industry. it is working with Biotechnet and the swiss Biotech national thematic network, and is now exploiting synergies to coordinating its activities with Euresearch in the area of non-dilutive funding. 

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AssociAtions

European Biotechnology | Autumn Edition | Vol. 17 | 2018

Recognising SME biotech innovation EuropaBio invites biotech start-ups and SMEs across Europe to apply for the ninth edition of the Most Innovative European Biotech SME Award – a unique annual initiative recognising biotech innovation and its contribution to society.

EuropE

small and medium-sized enterprises (SMEs) can apply for the Most Innovative European Biotech SME Award in three categories, depending on their

field of activity: healthcare, agricultural, or industrial biotech. Biotech start-ups will compete across all sectors in one special category recognising early stage entrepreneurship. Applications must be submitted online at www.biotechSMEawards.eu by coB sunday 30 september 2018. Two companies will be shortlisted in each category by a jury of biotech and SME experts, with the winners celebrated during a landmark event held later in the year. Each winner will also receive prize money and a free two-year fremembership for EuropaBio (runners-up also receive the latter). According to the European commission, “smEs are the

The EU protein deficit PrOtein CrOPS Growing more protein crops to close the protein gap in the EU would require significant efforts over many years. The EU should invest more in research and recognise that discriminating against innovation and technology has actually widened the gap. A new brochure informs the current debate with the objective of supporting a rational, coherent, and realistic protein strategy. Readers will find all the facts and figures that back a protein strategy based on innovation in local production, gm soybeans, and smooth imports. Given that GM crop technology has been all but expelled from the EU, the hope is that farmers and plant breeders

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will at least be allowed other modern tools of plant-breeding innovation. Read the brochure at europabio.org/agriL cultural-biotech new

UPcoming EVEnts › 24–30 September, europe European Biotech Week www.biotechweek.org › 16–18 October, toulouse European Forum for industrial Biotechnology and the Bioeconomy (EFIB) www.efibforum.com

backbone of Europe’s economy. they represent 90% of all businesses in the EU. In the past five years, they have created around 85% of new jobs and provided two-thirds of the total private sector employment in the EU.” in other words, SMEs matter and the leaders in innovation should be recognised and rewarded. These awards have become one of the highlights in the European biotech calendar, with over 200 SMEs competing over L the years.

Judgment raises hurdles Gene editinG on 25 July the European

court of Justice ruled that organisms obtained by gene-editing techniques such as cRisPR are, in principle, subject to the same regulations as genetically modified organisms. Following more than ten years of discussion, it was hoped that this ruling would provide the legal certainty and predictability needed by EU public and private researchers to deliver solutions to the UN’s Sustainable Development Goals. In the absence of improved legal clarity in this area, Europe could miss out on significant benefits from certain applications of genome editing. 

Pictures: EuropaBio

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

AdVErtoriAl

95

ROBOX makes storable CYPs CytoChrome P450 enzymes  CYPs have a number of disadvantages, including low stability or inactivity.  

The Austrian Centre of Industrial Biotechnology (acib), together with an consortium within the EU-project  ROBOX, created lyophilised CYP biocatalysts that have proven to be very promising for a variety of   industrial applications for the pharma, flavour and fragrance, and material science industries. 

Cytochrome  P450  monooxygenases  (CYPs) are valuable enzymes for the  production  of  drug  metabolites  and  high-priced fine chemicals. Although  such enzymes are already established  on the market, they gave the industry a  bad headache: For decades, CYPs have  suffered from low stability. Even if the  best P450s available get ordered, they  may arrive inactive. To offer the industry robust CYPs for screening and upscaling, the Austrian Centre of Industrial Biotechnology (acib) might have  found a solution: Within the EU project  ROBOX, acib, together with their partners, created lyophilised biocatalysts  that retained full activity – even when  they are awakened from deep slumber  after more than one and a half years in  the fridge. The technology offers a kit  of whole cell biocatalysts in the form of  lyophilised powder, which can be stored  on-site and is ready for immediate and  reliable in-house testing.

Picture: acib GmbH

Important for industry A diverse set of oxidative biocatalysts  covering a broad substrate scope with  unprecedented specificities and activity is now available for everyone. Examples include ROBOX enzymes distributed by the Groningen Enzyme & Cofactor   Collection GECCO biotech, who are offering three types of enzymes for testing: Eugenol oxidase (EUGO), thermostable cyclohexanone monooxygenase  (TmCHMO), and Polycyclic ketone monooxygenase (PockeMO). “Those are  just a few successful examples of the  highly acclaimed H2020 ROBOX project,”  says Anton Glieder, head of protein pro-

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duction at ROBOX and founder of acibstart-up company bisy eU. The consortium, consisting of 17 academic and  industrial collaborators, has one common goal: expanding the industrial use  of robust oxidative biocatalysts and producing novel enzymes for a wide range  of sectors. “In using innovative bio-catalytic oxidation routes simply using molecular oxygen under mild conditions,  such as ambient temperature and pressure, we can improve the sustainability  and economics of processes and applications, where oxygen-functionalities  are key,” explains ROBOX project coordinator Marco Fraaije. “Our results are  of great importance for widening the  industrial use of oxygen-functionalities  for segments like the pharma, flavour  and fragrance, or material science industry.” 

High impact technology Martin Schürmann from InnoSyn B.V.,  also  one  of  industrial  ROBOX-partners, emphasises the impact of the  new biocatalysts: “Stable enzyme formulations, especially for p450, are on  top of the wish-list in industr y, and  we are very happy that after all these  years, our wish was finally fulfilled.  InnoSyn demonstrated that high value speciality chemicals with decadelong market demand can be made by  enzymatic hydroxylation in a singlebatch process.”  Contact Prof. Anton Glieder bisy e.U. anton.glieder@acib.at phone: +43-664-608734074

13.09.2018 13:58:26 Uhr


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CANDOR Bioscience GmbH Phone: +49 7522 795270 info@candor-bioscience.de www.candor-bioscience.com

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European Biotechnology | Autumn Edition | Vol. 17 | 2018

A. m. mangion Ltd. (mt) . . . . . . . . . . . . . . . . . . . . . . . . 81 Ac immune SA (cH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 AciB Austrian center of Biotechnology . . . . . . . . . . . . . 95 Actelion AG (cH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Active Biotech (SE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Adaptimmune Ltd. (uK) . . . . . . . . . . . . . . . . . . . . . . . . . 15 Adc therapeutics (cH) . . . . . . . . . . . . . . . . . . . . . . . . . 41 Addex pharma (cH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Affimed NV (DE). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Agilent technologies (uSA). . . . . . . . . . . . . . . . . . . . . . . 52 Allergan inc. (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Almirall SA (E) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Amgen inc. (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Amyris inc. (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Ansa Biotechnologies inc. (uSA) . . . . . . . . . . . . . . . . . . 54 AstraZeneca AB (SE/uK) . . . . . . . . . . . . . . . . . . . . . . 74, 98 Athenex inc. (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 AurKa pharma inc. (cA) . . . . . . . . . . . . . . . . . . . . . . . . . 37 Austria Wirtschaftsservice GmbH (At) . . . . . . . . . . . . . . 79 Autolus therapeutics Ltd. (uK) . . . . . . . . . . . 13, 25, 28, 30 BASF (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Basilea pharmaceutica (cH) . . . . . . . . . . . . . . . . . . . 21, 34 Bavarian nordic A/S (dK) . . . . . . . . . . . . . . . . . . . . . . . . 75 Bayer AG (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Berlin cures Holding (cH) . . . . . . . . . . . . . . . . . . . . . . . 43 BioArctic neuroscience AB (SE) . . . . . . . . . . . . . . . . . . . 75 Biocom AG (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 BioEcho Life Sciences GmbH (dE) . . . . . . . . . . . . . . . . . 83 Biofrontera AG (dE) . . . . . . . . . . . . . . . . . . . . . . 25, 28, 32 Biolamina AB (SE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Biological industries (Bi) Ltd. (iL) . . . . . . . . . . . . . . . . . . 17 Biomerieux (F) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Biontech AG (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Biotechpharma uAB / member of northway group (Lt) . 67 bluebird bio (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 bm|t (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Boehmert & Boehmert (dE) . . . . . . . . . . . . . . . . . . . . . . 27 Boehringer ingelheim (dE) . . . . . . . . . . . . . . . . . . . . . . . 77 Briefcase Biotec (At). . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 c-LEcta GmbH (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 calliditas therapeutics AB (SE) . . . . . . . . . . . . . . . . . . . . 25 calyxt (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 cambridge innvovation institute (uSA) . . . . . . . . . . . . . . . 7 cAndor Bioscience GmbH (dE) . . . . . . . . . . . . . . . . . 96 capricorn Ventures (B) . . . . . . . . . . . . . . . . . . . . . . . . . . 78 celgene corp. (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 cellectis SA (F) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18, 25 celonic AG (cH) . . . . . . . . . . . . . . . . . . . . . . . . 59, 64, 65 celyad SA (B) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 charles river (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 chugai (Jp) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 cphi / BioLive 2018 (nL) . . . . . . . . . . . . . . . . . . . . . . . . 51 crS clinical research Services Andernach (dE) . . . . . . . 71 cVc capital partners . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 cytune pharma SAS (F) . . . . . . . . . . . . . . . . . . . . . . . . . . 82 danaher Group (uSA) . . . . . . . . . . . . . . . . . . . . . . . 49, 54 dBV technologies (F) . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 deloitte LLp (uK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 deutsche messe AG | Labvolution (dE) . . . . . . . . . . . . . . 9 dnA Script (F) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49, 54 EBd Group (cH) BES Vienna . . . . . . . . . . . . . . . . . . . . . 47 Ecotec AG (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Eisai co. Ltd. (Jp) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Eli Lilly (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Enamine Ltd. (uKr) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Eppendorf AG - Bioprocess center Europe (dE) . . . . . . . 69 Eureka therapeutics (uSA) . . . . . . . . . . . . . . . . . . . . . . . 13 Eurofins Scientific (F) . . . . . . . . . . . . . . . . . . . . . . . . 25, 54 EuropaBio (B) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Evolva A/S (cH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Evonetix (uK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Evotec AG (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Exosomics Siena (it) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 FGK clinical research GmbH (dE) . . . . . . . . . . . . . . . . . 14 Fluicell AB (SE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Fördergesellschaft iZB (dE) . . . . . . . . . . . . . . . . . . . . . . cp3 Forendo pharma oy (Fin) . . . . . . . . . . . . . . . . . . . . . . . . 75 Foss Group (dK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Gabather AB (SE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Galapagos nV (B) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 GE Healthcare (uK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Geneart (dE). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Genentech inc. (uSA) . . . . . . . . . . . . . . . . . . . . . 38, 43, 79 GEnEWiZ (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Genfit SA (F) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Genkyotex S.A. (cH/F) . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Genmab A/S (dK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Genome Foundry (uK) . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Genscript (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Gilead Ltd. (uSA) . . . . . . . . . . . . . . . . . . . . . 13, 15, 16, 76 GimV (B) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 GlaxoSmithKline (uK) . . . . . . . . . . . . . . . . . . . . 42, 77, 98 Grünecker Kinkeldey Stockmair & Schwanhäusser (dE) . 10

Hoffmann Eitle (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 idorsia (cH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21, 34 idt – integrated dnA technologies (uSA) . . . . . . . . 49, 54 immatics biotechnologies GmbH (dE) . . . . . . . . . . . 42, 75 immunicum AB (SE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 immunocore Ltd. (uK) . . . . . . . . . . . . . . . . . . . . . . . 15, 42 immunovia AB (SE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 innovestor oy (Fi) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 izana Bioscience plc (uK). . . . . . . . . . . . . . . . . . . . . . . . 41 JLABS (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Johnson & Johnson (uSA) . . . . . . . . . . . . . . . . . . 34, 40, 77 Kuros Biosurgery AG (cH) . . . . . . . . . . . . . . . . . . . . . . . 34 Kymab Ltd. (uK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Laboratories Sanifit SL (ES) . . . . . . . . . . . . . . . . . . . . . . . 41 Leukocare AG (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . 60, 61 Life Science Austria LiSA . . . . . . . . . . . . . . . . . . . . . . . . 11 Lonza (cH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34, 35, 80 maiwald patentanwalts GmbH (dE) . . . . . . . . . . . . . . . . 10 medicxi Ventures (cH/uK) . . . . . . . . . . . . . . . . . . . . . . . 77 medigene AG (dE) . . . . . . . . . . . . . . . . . . . . . . . . 3, 15, 39 merck & co (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 merck KGaA (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . 43, 79 merck Ventures BV (nL) . . . . . . . . . . . . . . . . . . . . . . 75, 98 mGc pharmaceuticals (Au) . . . . . . . . . . . . . . . . . . . . . . 81 microbiotica (uK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 mirabaud Securities (cH) . . . . . . . . . . . . . . . . . . . . . . . . 21 mLm medical Labs GmbH (dE) . . . . . . . . . . . . . . . . . . . 19 modus therapeutics Holding (SE) . . . . . . . . . . . . . . . . . . 75 mologic Ltd. (uK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 mondobiotech AG (cH) . . . . . . . . . . . . . . . . . . . . . . . . . 34 monsanto (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 morphoSys AG (dE) . . . . . . . . . . . . . . . . . . . 25, 28, 32, 76 neovacs SA (F) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 newron pharmaceuticals S.p.A. (i) . . . . . . . . . . . . . . . . . 34 novartis AG (cH) . . . . . . . . . 13, 15, 16, 35, 43, 76, 77, 79 novartis Venture Fund (cH) . . . . . . . . . . . . . . . . . . . . . . 75 novimmune S.A. (cH) . . . . . . . . . . . . . . . . . . . . . . . . . . 75 novo nordisk A/S (dK) . . . . . . . . . . . . . . . . . . . . . . . 74, 78 novo Seeds (dK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 novozymes A/S (dK) . . . . . . . . . . . . . . . . . . . . . . . . 44, 45 nuclera (uK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52, 54 nuevolutin A/S (dK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 obseva AG (cH) . . . . . . . . . . . . . . . . . . . . . . . . . 30, 34, 35 oncoarendi therapeutics SA (pL) . . . . . . . . . . . . . . . 25, 26 opiS s.r.l. (it) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41, 68 oxford Biomedica (uK) . . . . . . . . . . . . . . . . . . . . . . 21, 77 oxford nanopore technologies Ltd. (uK) . . . . . . . . . . . . 54 oxipit (Lt) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 pci Biotech AS (n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 pelago Bioscience AB (SE) . . . . . . . . . . . . . . . . . . . . . . . 74 Pfizer Inc. (USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18, 78 phagomed Biopharma GmbH (At) . . . . . . . . . . . . . . . . . 79 pharmamar (ES) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 plasmidFactory GmbH & co.KG (dE) . . . . . . . . . . . . 58, 62 polpharma Biologics (pL) . . . . . . . . . . . . . . . . . . . . . . . cp4 polyphor Ltd. (cH) . . . . . . . . . . . . . . . . . 21, 25, 26, 30, 34 ppF Group (cr) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 recipharm AB (SE) . . . . . . . . . . . . . . . . . . . . . . . . . . 70, 73 recordati S.p.A. (i) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 relief therapeutics Holding AG (cH) . . . . . . . . . . . . . . . 34 rentschler Biopharma SE (dE) . . . . . . . . . . . . . . 56, 60, 61 richter-Helm BioLogics GmbH & co. KG (dE) . . . . . . . . 63 roche AG (cH) . . . . . . . . . . . . . . 18, 35, 38, 41, 43, 52, 81 rSp Systems (dK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Samsung Bioepis co. Ltd. (Kr) . . . . . . . . . . . . . . . . . . . . 43 Sangamo Biosciences inc. (uSA) . . . . . . . . . . . . . . . . . . 77 Santhera pharmaceuticals (cH). . . . . . . . . . . . . . . . . . . . 34 Shimadzu Europe GmbH (dE) . . . . . . . . . . . . . . . . . . . cp2 Sigma Aldrich (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Six Swiss Exchange Ltd (cH) . . . . . . . . . . . . . . . . . . 34, 35 Sobi AB (SE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18, 41, 75 Sphingotec GmbH (dE) . . . . . . . . . . . . . . . . . . . . . . . . . 90 Sulzer AG (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Synbiobeta LLc (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . 49 takeda pharma A/S (dK) . . . . . . . . . . . . . . . . . . . . . 41, 43 tBd Biodiscovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 tecan Group AG (cH) . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Thermo Fisher Scientific (UK) . . . . . . . . . . . . . . . 49, 50, 54 trianni, inc. (uSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 tVm capital Life Science (dE) . . . . . . . . . . . . . . . . . 36, 37 txcell S.A. (F). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Vectura Group plc (uK) . . . . . . . . . . . . . . . . . . . . . . . . . 21 Verily Life Scienes (uSA) . . . . . . . . . . . . . . . . . . . . . . . . 77 Vertex pharmaceuticals inc. (uSA) . . . . . . . . . . . . . . . . . 74 Vesalius Biocapital partners S.a (Lu) . . . . . . . . . . . . . . . . 75 Vetter pharma-Fertigung GmbH & co.KG (dE) . . . . . 43, 66 ViroGates A/S (dK) . . . . . . . . . . . . . . . . . . . . . . . . . . 25, 26 Vossius & partner (dE) . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Vtu technology GmbH (At) . . . . . . . . . . . . . . . . . . . . . 61 xenikos BV (nL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 yumAB GmbH (dE). . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Zealand pharmaceuticals A/S (dK) . . . . . . . . . . . . . . . . . 21 Ziylo Ltd. (uK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Pictures: Candor Bioscience

96

14.09.2018 12:56:08 Uhr


EVEnts

European Biotechnology | Autumn Edition | Vol. 17 | 2018

8.–9.10.18

BIOSPAIN 2018 25.–27.09.2018 Seville BIOsPAIn,

the largest biotech event organised by a national bioindustry association in Europe, returns to Andalusia for its 9th edition. AsEBIO expects more then 1.700 attendees from pharma, biotech and medtech companies, professionals from the services and consulting sector and investors. www.biospain2018.org

Synthetic Glycobiology, Chicheley (UK) Info: The Royal Society, https://royalsociety.org

9.–11.10.18

CPhI Worldwide 2018, Madrid (ES) Info: CPhI Global Office, www.cphi.com

9.–11.10.18

bioLIVE, Madrid (ES) Info: UBM, www.bio.live/

97

22.–23.10.18

RMD Europe 2018 – 3rd European Symposium on The New Agreed Regulations on Medical Devices, Brussels (B) Info: BIOEVENTS, http://rmd2018.com

23.–25.10.18

8 th Nordic Wood Biorefinery Conference – NWBC 2018, Helsinki (FIN) Info: VTT (FIN), RISE (SE), http://bioeconomy.vtt.fi/NWBC2018

14.–16.10.18

10 th World Health Summit, Berlin (GER) Info: WHS Foundation GmbH, www.worldhealthsummit.org

10th PEGS Europe

16.–18.10.18

12.–16.11.2018 liSbon the largest

17.–18.10.18

European event covering all aspects of protein and antibody engineering. After record participation by attendees, speakers, sponsors, and exhibitors last year, PEGs Europe will celebrate its 10th anniversary. www.pegsummiteurope.com

EFIB 2018, Toulouse (F) Info: EuropaBio/BIOCOM AG, www.efibforum.com

European Business Development Conference 2018, Hanover (GER) Info: BIO Deutschland, www.biodeutschland.org

17.–19.10.18 24.–30.9.18

European Biotech Week 2018, EU Info: Mélanie Moxhet, EuropaBio, www.biotechweek.org

26.–27.9.18

Life Science Baltics 2018, Vilnius (LT) Info: enterprise Lithuania, https://lsb2018.com

27.–28.9.18

IFIB 2018 – International Forum on Industrial Biotechnology and Bioeconomy, Turin (IT) Info: Assobiotec, https://ifib2018.b2match.io/

27.9.18

Swiss Biotech Day Fall 2018 – The Race to innovate & Pathways to ROI, Lausanne (CH) Info: Swiss Biotech Association, https://swissbiotech.cmail20.com

30.9.–3.10.18

Pictures:ASEBIO/Pixabay/Lisbon Congress Center

HUPO 2018, Orlando (USA) Info: Human Proteome Organization, http://hupo2018.org/

30.9.–2.10.18

LABComplEX. Analytics. Laboratory. Biotechnologies. Hi-Tech., Kyiv (UA) Info: LMT Company, www.labcomplex.com

19.–23.10.18

ESMO 2018, Munich (GER) Info: ESMO – European Society for Medical Oncology, www.esmo.org

BIO-Europe 2018 5.–7.11.2018 Copenhagen the

biotechnology partnering conference features the industry’s most advanced web-based partnering system, enabling delegates from all parts of the biotechnology valuechain to quickly identify, engage and enter into strategic relationships that drive their business forward. www.ebdgroup.com

15.–17.11.18

International Meeting on Optical Biosensors, Ghent (B) Info: VIB, https://vibconferences.be

3.–4.12.18

3rd World Congress on Clinical Trials in Diabetes, Vienna (A) Info: Bioevents, www.wctd2018.com

3.–7.12.18

Zdravookhraneniye 2018, Moscow (RU) Info: Elena Gureeva , www.zdravo-expo.ru/en/

Cell-Nerf Symposium: Neurotechnologies, Leuven (B) Info: VIB, https://vibconferences.be

4.–5.12.18

4.10.18

12.12.18

BioForward, Birmingham (UK) Info: Jane O’Driscoll, OBN/Birmingham Health Partners, www.bioforward.co.uk

97_EB_Autumn_2018_Events_mak.indd 97

Biofit 2018, Lille (F) Info: Margaux Satola, eurosanté, www.biofit-event.com

Pharma Outsourcing – Find the right partner, Stockholm (SE) Info: Maria Eriksson, Kemivärlden Biotech, www.pharmaoutsourcing.eu

13.09.2018 13:58:46 Uhr


ENCORE

Winners & losers

European Biotechnology | Autumn Edition | Vol. 17 | 2018

What fascinates you the most about your job?

Rosehip is hip

TOP ANTIBODY Astra-

NEUROSCIENCE What makes the human

Zeneca plc’s stock has outperformed most of the competing pharma stocks this year. One success story of the British-Swedish pharma is durvalumab (Imfinzi), which showed an overall-survival benefit for a subtset of patients with NSCLS. Durvalumab received EMA approval recommendation in July.

brain so unique? A new track to find an answer – if there is one at all – was opened by researchers led by two teams at the Allen Institute for Brain Science (US) and at the University of Szeged (Hungary), respectively. In a new study published in August in the journal NATURE NEUROSCIENCE (doi: 10.1038/s41593-018-0205-2), the scientists present evidence for a a new type of human brain cell that has never been seen in mice and other well-studied laboratory animals. The Hungarian team dubbed these new cells “rosehip neurons” because the dense bundle each brain cell’s axon forms around the cell’s centre looks just like a rose after it has shed its petals. So far it is still unclear what function these inhibitory neurons might have in the human brain. 

ROEL BULTHUIS Senior Vice President & Managing Director, M. Ventures BV

FLOP ANTIBODY Unlike GlaxoSmith-

Kline’s belimumab, AstraZeneca’s monoclonal antibody anifrolumab will not be an option to treat patients with systemic lupus erythematosus anytime soon. The first of two Phase III trials came back negative in late August. 

“I’m fascinated by the extraordinary entrepreneurs that we get to back in their quest to change the life of patients and their loved ones. Their drive and imagination make them the true rock stars of our world.”

Cell therapy workshops

1 2 3 4 5

British event organizer Clarion Events Ltd. compiled a list of cell and gene therapy manufacturing capacities in Europe (data from early 2018). The size of the CMDO facilities greatly varies – from 150 sqm to more than 3,600 sqm. In 2018, manufacturing experts recorded a trend to bring production in-house. US companies Pfizer and Spark Therapeutics are building new gene therapy production facilities – as is Swiss pharma major Novartis, close to its headquarters in Basel.

6 7 8 9 10 11 12 13 14 15 16 17

Apceth Atvio Biotech Batavia Biosciences Cell & Gene Therapy Catapult Cell for Cure Cobra Biologics Eufets Eurogentec Finvector Fraunhofer IZI Lonza Masthercell Molmed Novasep Oxford Biomedica Roslin Cells Yposkesi

9

16 6

3 11 12 8

15 4 5 17

14

10 7 1 13

Source: Phacilitate

98

2

#ECJ ‘all conquering’ @CRISPRTX Next issue

@Glythera_ rebrand: “Iksuda is derived from the Sumerian word for ‘all conquering’" #ADC #cancer @JocelynOrmond Scientists & citizens ask EU to review #ECJ Ruling on plant genome editing based on scientific expertise, knowledge and facts.

98_EB_Autumn_2018_Encore_ml.indd 98

#IPMB2018 You can sign the petition here https://bit.ly/2OjNbhF @VIBLifeSciences

Please follow us @EuroBiotechNews @carlsberg plans a test run with 10,000 to 20,000 bottles next year; specs: biodegradable in 5 years, returnable #bioeconomy! @EuroBiotechNews

WINTER EDITION The next issue features a

special topic that may misleadingly appear to have a Christmas reference: packaging. Of course, it is all about boxing diagnostics and therapeutics – and not about Christmas presents. And there will be a new Euro BioFairs Compass, too! Publishing date is 13 December 2018; due date for advertisements 26 November. Questions will be answered by Andreas Macht (+4930-264921-54) and Oliver Schnell (-45). Or drop an email: marketing@biocom.de. 

Picture: Merck Ventures

Vertex and @CRISPRTX launch #geneediting clinical trial, treating blood cells for beta-thalassemia in Germany – via @TheScientistLLC @ce_offordt @BCH_Innovation

14.09.2018 12:59:29 Uhr


CONFERENCE LOCATION AT THE INNOVATION UND START-UP CENTER FOR BIOTECHNOLOGY

J Conference Rooms (up to 100 persons) J IZB Residence CAMPUS AT HOME for guests of the Campus Martinsried/ Grosshadern and conference guests only

J Restaurant SEVEN AND MORE Fรถrdergesellschaft IZB mbH Am Klopferspitz 19 82152 Planegg/Martinsried Tel.: + 49 (0)89.55 279 48-27 Fax: + 49 (0)89.55 279 48-29 E-Mail: conference@izb-online.de

99_EB_Autumn_2018_IZB.indd 1

J Catering & Restaurant Freshmaker

www.izb-online.de

13.09.2018 13:59:29 Uhr


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Profile for BIOCOM AG

EBM 3/18 Autumn  

EBM 3/18 Autumn  

Profile for biocom

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