ISSN 2364-2351 | A 60711 |
Life Sciences and Industry Magazine Spring Edition 2018 | Volume 17 | 20 €
Interview Aleks Engel from Novo Holdings on a new fund that will mobilise SMEs in the fight against antibiotic resistance
Antibiotic Resistance
The phage s are back Genome editing
Immunology
Big Bioindustry
GMP bioproduction
EU Court’s Advocate General disappoints GM opponents
How fast food corrupts your immune system permanently
Attracting investment to scale up bio-based production
Which CDMOs will seize the lead in an expanding market?
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Intro
European Biotechnology | Spring Edition | Vol. 17 | 2018
3
We need creative investment to tackle AMR Each year, 700,000 people worldwide die of resistant infections; estimates say this figure will rise to 10 million victims a year by 2050 unless effective action is taken to tackle antimicrobial resistance (AMR).1 From an investment perspective, the main problem is a lack of incentives for the private sector to engage in AMRrelated R&D. The need to use antimicrobials rationally to avoid the development of resistance seriously limits a developer’s expected return on investment (ROI). Antimicrobial R&D is mainly carried out by biotech-oriented small and medium-sized enterprises (SMEs), which face difficulties in attracting the needed investment. One of the reasons for this is national pricing schemes that do not take account of the public health value of new antimicrobials, such as reduced times for treatment and hospitalisation, and the economic value of preventing infections in the first place. Christoph Spennemann oversees the Intellectual Property (IP) Unit at the United Nations Conference on Trade and Development (UNCTAD). Chrisoph will organise a session on fostering investment in the development of new antibacterial prevention technologies at UNCTAD’s 2018 World Investment Forum. He holds a master’s degree in international economic law and European law from the University of Lausanne and practised law in Berlin.
What can be done to address this situation? Action at two levels is needed. First, it is important to identify investors to assist SMEs in their R&D. We should inter alia be looking out for non-traditional investors, such as health insurers and hospital owners, who have an economic interest in reducing resistances. Second, there needs to be a global debate on how to reconcile the industry’s need for ROI with the need to make new antimicrobials accessible to patients, especially in developing countries where currently more people suffer from lack of access to antibiotic treatments than from resistance. Due to global mobility, bacteria in developing countries directly affect European societies. European governments should take the lead in the design of innovative incentive schemes beyond ad hoc projects, i.e. on a more permanent basis.
Picture: EuropaBio
The United Nations Conference on Trade and Development (UNCTAD) through its World Investment Forum (WIF) on 22–25 October 2018 in Geneva provides a platform for both approaches.2 One of its events (“Fostering investment in the development of new antibacterial prevention”, 24 October) will enable partnerships between developers of novel AMR treatments and interested funders, thereby providing investors with a global platform to publicise their contribution to public health. The WIF will also feature a policy dialogue between the industry, investors, payers, and governments to clarify the essential “ground rules” governing investment in AMR. L
1 2
Jim O’Neill, « Tackling Drug-Resistant Infections Globally: Final Report and Recommendations”, May 2016, p. 4. Available at: https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf http://worldinvestmentforum.unctad.org/2018-pre-registration/
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Contents
European Biotechnology | Spring Edition | Vol. 17 | 2018
Cover Story
Insight Europe
regional news
6 Early certainty on examination: EPO bows to pressure from industry
56 Northern Europe: Sweden, Denmark, Norway and Finland
10 EU Court of Justice: Advocate General quells farmer antiGM rebellion on new breeding technologies including genome editing
58 Western Europe: France, Belgium, The Netherlands and the UK 60 Central Europe: Germany, Switzerland and Austria
Economy 20 Latest BIOCOM capital market report: A new wave of optimism swept over European public biotech markets in 2017.
14
Antibiotic resistance: Phages to the rescue? The crisis caused by antimicrobial resistance is growing worse, and in the search for solutions, it makes sense to take a closer look at an alternative that’s already out there – bacteriophages. They’ve been used in Eastern Europe for decades. Now pressure is mounting on global health authorities to see whether bacteria-killing viruses or products based on them could provide a viable option to antibiotics. But guidelines are lacking in Western countries, and many doctors remain cautious about the idea of treating infections with viruses.
22
Interview: Aleks Engel, Partner at Novo Holdings, and George Griffin, Chair of the SAB of the REPAIR impact fund
25 Analyst commentary
62 Southern Europe: Italy, Spain and Portugal 64 Eastern Europe: Poland, Estonia and Hungary
Science & Technology 70 Targeting endothelial dysfunction – an emerging new treatment paradigm
26 Euro Biotech Stocks 74 Scientists keep cancer at bay 30 EMA News 31 Update on clinical trials
Service
34 I P: Balancing generic and innovative medical uses, Ute Kilger, Boehmert & Boehmert
75 News from partner associations: Swiss Biotech Association, ASEBIO, Irish Bioindustry Association (Ibec) and EuropaBio
36 Fine chemicals sector gathers together at Chemspec 49 Biopeople
80 Events 81 Company index 82 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 (Coeditor), Dr. Martin Laqua, Helene Märzhäuser, Sandra Wirsching; Advertising: Oliver Schnell, +49-30-2649-2145, Christian Böhm, +49-30-2649-2149, Andreas Macht, +49-30-2649-2154; Distribution:
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Picture: ktsdesign/fotolia.com
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01.03.2018 12:40:21 Uhr
Contents
European Biotechnology | Spring Edition | Vol. 17 | 2018
Immunology
Financing
Editorial
Cash for going green
Battling infections
Despite several promising biorefinery projects, the finance industry remains largely sceptical about developing businesses that involve bio-based products and power generation. Now the European Investment Bank is pushing financiers to take a bigger stake in the success of the bioeconomy. The newest instrument is dubbed the Circular Bioeconomy Thematic Investment Platform.
After most of the low-hanging fruit was harvested until the 1970s, antibiotics have become a niche market. Big Pharma long ago turned to areas that offer a better return on investment (see Editorial, p. 3). However, after the WHO, G20 and other bodies kicked off initiatives to tackle emerging antibiotic resistance, development activity has revived, particularly in the biotech SME scene. A novel investment fund commissioned by the Novo Nordisk Foundation is aiming to make up for the 30-year pause in antibiotic development by investing in biotechs that have new concepts and modalities (see Interview, p. 22).
50
Fast food epigenetics Everyone knows that too much fast food is unhealthy, but now researchers have discovered that a few burgers early on can actually double the risk of later contracting chronic diseases like diabetes, atherosclerosis, or stroke. And immunologists now say even returning to a healthy diet later in life might not help, because fast food reprogrammes activity in the innate immune system.
The Chair of the fund’s Scientific Advisory Committee believes most new compounds will come from biological sources, including sea organisms and bacteriophages.
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Pictures: iordani/fotolia.com (top), loneroc/shutterstock.com (middle), ABLinc. (bottom)
SPECIAL
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GMP Manufacture 39 42 44 46
Intro: GMP and new processes: Be prepared for hassle Interview: Expanding into the commercial space, Franzpeter Bracht, COO, Celonics AG Statement: “Learning from the small molecule supply chain”, Rutger Oudejans, Brand Director, UBM Biomanufacturing news
The bacteria-specific killers have been used in Eastern Europe and Russia for decades – long before Big Pharma invented the term “targeted therapies”. Phages are now being re-evaluated by Western biopharma alliances (see Cover Story, p 14). However, since old scaling models (“sell as much you can”) won’t apply to novel anti-infectives, new ways have to be found to make profit for developers. And regulators will have to sign off as well.
Thomas Gabrielczyk Editor-in-Chief
02.03.2018 11:30:53 Uhr
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Insight Europe
European Biotechnology | Spring Edition | Vol. 17 | 2018
Early certainty: EPO bows to pressure from industry EU Following harsh criticism from the industry, the European Patent Office has drafted
a proposal to allow exemptions to its Early Certainty Initiative. Industry associations had pressed the EPO not to cut the time to grant a patent to 12 months, arguing it would have detrimental effects on the life sciences sector.
In a draft paper sent to biopharma IP stakeholders in January, the European Patent Office (EPO) proposes substantial improvements to its controversial Early Certainty Initiative, which its outgoing president, Benoit Battistelli, claimed will speed up patent examination time and boost innovation. An addition dubbed User Driven Early Certainty (UDEC), will allow “applicants to postpone the start of substantive examination for a maximum of three years,” the EPO writes. So far, the Early Certain-
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ty Initiative included only elements to speed up examination and granting of a patent, which should benefit sectors with short product development times. The newly added UDEC procedure is designed for applicants who need more time before the start of examination and before a patent is granted. Over the past year, life science leaders have voiced concerns that limiting examination time to as few as twelve months could block innovation within their sector, where applicants typically benefit from longer pe-
Biotech SMEs: apply or die Furthermore, IP experts had warned they expected fewer EU patent applications if Battistelli’s plan went through (see Euro pean Biotechnology, Spring edition 2017) and called for establishing a grace period for sectors with longer product development cycles (see European Biotechnology, Spring edition 2017).
Picture: European Patent OFfice
EPO President Benoît Battistelli, who drafted the Early Certainty Initiative, has made some bitter enemies in his own institution due to a rigorous policy of economy measures and a contentious routine of monitoring his staff. During his outgoing term, the former head of the French patent office fired Laurent Prunier, head of the EPO‘s inhouse staff union Suepo.
riods to prepare for examination before a patent is granted. Industry associations (see European Biotechnology, Spring edition 2017) had called to exempt the life sciences sector from the EPO’s plan to cut the time for examination of a patent from the current standard of 57 months to 12 months. IP experts from Novartis, biotech companies, and EFPIA said they were concerned that the speed-up of examination could come at the expense of quality, or block extensions to patents (see European B iotechnology, Winter edition 2016). Life sciences patents are filed very early in the development stage, with the expectation that confirmatory data will be established later. Granting a patent too early in this process could result in suboptimal drug candidates receiving approval, when they should not. “Early patent issuance would be too early for inventors in 90% of cases to find a licencee,” said biotech industry associations BIO Deutschland and France Biotech, stressing that biotech SMEs or tech transfer offices would not have the resources to pay the national validation and translation costs at the moment a patent is granted.
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Insight Europe
Euro-direct Publication Filling ESR+ESOP
Priority
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European Biotechnology | Spring Edition | Vol. 17 | 2018
Third-party observations or applicant’s request will end postponement
Exam request Reply to search opinion Postponement request
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While 25% of all patent applications come from the life sciences sector, the EPO assumes “that applicants will, in about 10% of cases, make use of the postponement option.” According to the EPO, the UDEC procedure will run starting on 1 July 2018 as follows: Under an “EP direct” application, the (life sciences) applicant pays the examination fee and receives a preliminary option on patentability from the EPO within six months. Within another six months, the applicant can request a postponement of the start of substantive examination using a new online form. If confirmed, the EPO will not begin substantive examination of the application before expiry of three years. The option will be free; however, the applicant has to pay the annual renewal fees for an application to the EPO, which typically total several hundred euros. For divisional applications, the postponement period would be calculated from the filing date
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proposed stay of the examination for three years is a step in the right direction, since it addresses concerns of applicants with long development cycles, such as biotech companies. However, it still remains to be seen whether the EPO will be able to uphold a high quality of patent examination under the shortened examination timelines.” German industry association BIO Deutschland, which published a position paper sharply criticising early certainty for examination last year, stated: “The current proposal of the EPO reflects BIO Deutschland’s suggestion of a DE-PACE procedure in case of 12 months early certainty in examination. Therefore, we would support the idea of a user-driven early certainty approach, because it grants more flexibility to the small and medium sized biotech enterprises.”
of the earliest application with the EPO; in the case of Euro-PCT applications, from valid entry into the EP-phase. Applicants will have the option to initiate examination before expiry of the threeyear postponement. Postponed applications will be marked in the European Patent Register to allow third party observations.
Positive echo from the sector Industry stakeholders from Europe and abroad applauded the EPO’s draft. “This is a welcome development,” Gavin Recchia, Principal at Sydney-based IP office Davies Collison Cave Pty Ltd, told Eu ropean B iotechnology. “It appears the EPO has listened to key stakeholders in the life sciences industry. The UDEC proposal should provide the flexibility the industry needs around patent protection.” Dr. José Pfizer from German drug developer 4SC AG added: “The
Battistelli’s previous determination to push through the Early Certainty Initiative, however, made many stakeholder wonder about his sudden empathy for the concerns of drug developers. Sources told European Biotechnology that it was obvious that the initiative had not been drafted for altruistic motives. In fact, it will lead to a huge shift in fees from the EPO to the national patent offices. On average, the annual renewal fee for a pending patent at the EPO is tenfold lower than the fee payable to the national patent offices after a patent has been granted and nationalised in 30 European countries (which is the standard case). A three year earlier nationalisation of the 96,000 patents issued in 2016 would have resulted in flushing about €1.47bn more into the national patent offices. If the EPO's assumptions are correct – that only 10% of applicants will apply for UDEC – €1.32bn would remain. It’s not clear what benefit the EPO or Battistelli will receive from this effect of the Early Certainty Initiative on examination – except of course to accelerate innovation. L t.gabrielczyk@biocom.eu
01.03.2018 12:42:17 Uhr
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01.03.2018 12:42:33 Uhr
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Insight Europe
European Biotechnology | Spring Edition | Vol. 17 | 2018
Bobek quells anti-GM peasant rebellion EU Court of justice The next round in the fight between GM opponents and proponents is
about targeted mutagenesis approaches that produce the same mutations as random mutagenesis, without using genetic modification. The European Commission is waiting for a decision from the EU Court of Justice in May. Will the advice of its Advocate General, tabled mid-January, be helpful?
created by random mutagenesis, which had a 40-year positive safety record at that time. In contrast, all crops created by in vitro mutagenesis, including the maligned Glyphosate-tolerant rape and others made by novel breeding techniques, should not fall under the exemption, due to potential environmental and health hazards that violate the EU precautionary principle. Aiming for a EU-wide ban of herbicide-tolerant crops, they also questioned if member states may deviate from the EU Directive. The French Conseil d'État requested a legal interpretation of the Directive for a ruling of the case at the EU Court of Justice (EJC).
Scheme of Cibus’ ODM-technology Rapid Trait Development System (RTDS™)
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In mid-January, Michal Bobek, Advocate General and advisor to the EU Court of Justice, rejected the anti-GM coalition’s stance. At the same time, he played back the ball to European decision-makers, who promised to provide a legal opinion on new plant breeding technologies, but have postponed trice since 2015. How is that?
Blow to GM opponents and the European Commission First, Bobek explained that legislation is always designed to prevent problems in the future. So, when drafting new laws, legislators must always consider the potential impact of emerging technologies. In his view, Directive 2001/18/EC says that organisms created by any available mutagenesis technique – whether in vitro or in vivo, state-of-the-art at the time of implementation, or not – are exempted from being classified as GMOs as long as the method only “involves“ recombinant nucleic acids that were either produced by mutagenesis or conventional somatic cell transfer. GM proponents from science and industry welcomed Bobek’s interpretation. Joachim Schiemann from the European Plant Science Organisation's (EPSO) Agricultural Technology Working Group told European Biotechnology: “Though it gives some space for very different interpretations, it’s a step in the right direction.“ GM opponents from the International Federation of Organic Agriculture Movements (IFOAM) said that there are no legal or scientific reasons to exempt
Picture: Cibus Inc
In 2016, members of the French Conféderation Paysanne and seven anti-GM partner organisations hit on the idea to rid the market of Glyphosate-tolerant rape and at the same time ban crops created by novel recombinant methods that cause targeted mutations: The plaintiffs challenged both the French environmental law and the EU Directive 2001/18/EC (Case C528/16), claiming that all crops created by in vitro mutagenesis methods, which were developed after both laws had passed, must be treated as GMOs. They argued that the EU Directive, passed in 2001 to regulate deliberate release of GMOs, only exempted crops
01.03.2018 13:32:57 Uhr
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20 – 21 June 2018 | Koelnmesse Cologne, Germany 01.03.2018 12:44:24 Uhr 06/12/2017 11:55
INSIGHT EUROPE
European Biotechnology | Spring Edition | Vol. 17 | 2018
recently developed genetic engineering methods, which have nothing to do with the mutagenesis of the 1960s, from risk assessment, traceability, and labelling. “Exempting these new genetic engineering [methods] from a risk assessment would be a blatant denial of the precautionary principle and of the citizens’ right to know how their food is produced,“ stated IFOAM EU policy manager, Eric Gall.
Clarification needed? However, Bobek’s convoluted legal phrase that exempts all mutagenesis methods, “on the condition that they do not involve the use of recombinant nucleic acid molecules of GMOs other than those produced with one or more of the methods listed in Annex IB“ – aka “mutagenesis” or “somatic cell transfer” – leaves space for interpretation, Schiemann believes. The former member of the European Food Safety Authority’s (EFSA) GMOs panel has good reason not to agree with Nature, the Guardian, and other leading European media, which reported Bobek wants to exclude genome editing from GMO labeling. In contrast, the Advo-
cate General passed back the decision to policymakers. Since 2015, the European Commission has promised to table a legally watertight interpretation concerning new breeding methods and GMO labeling. Bobek’s formulation leaves it open if indispensable genome editing tools – particularly recombinantly expressed proteins such as meganucleases, zinc finger proteins, TALENs, and Cas9 nucleases, which induce double strand breaks before cellular DNA mismatch repair – are to be labelled as GM or not. It also remains unclear whether nucleic acid templates prepared by gene synthesis, which are introduced into expression vectors of the ODM system, are to be legally evaluated as “obtained by mutagenesis.“ GM opponents have focussed on suggesting that potential off-target effects of the new methods could be more dangerous than those created by random mutagenesis. However, according to Bobek, the safety of the chosen mutagenesis method has not been used as a criterion to decide whether a mutagenesis method may be GM or not. Bobek added that applying “the precautionary principle cannot be based on a purely hypothetical approach to
ZFN-; TALEN-; CRISPR/Cas9-Nuclease
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SDN 3: Targeted mutagenesis Targeted gene replacement
A SDN is introducing a double strand break, which is the starting point for each gene editing approach. When this break is repaired via the host cellular repair mechanisms without the use of an added repair template, the approach is defined as SDN-1.
6-12_EB_Spring_2018_Insight_tg.indd 12
the risk, founded on mere assumptions, which have not yet been scientifically verified.” Second, after having clarified that a EU ban on in vitro mutagenesis methods is not in line with the Directive, Bobek suggested that member states may decide on the use and labeling of new breeding methods on their own; that is, dynamically interpret the Directive. “Directive 2001/18 does not preclude member states from adopting measures governing mutagenesis […],” he writes, adding that since the implementation of national GMO bans through the opt-out clause, there seems to be a trend towards re-nationalisation of GM legislation. This is particularly important because the UK and Greece have made clear that no distinction should be made between various mutagenesis techniques, while Austria, France, the Commission, and the Netherlands want to examine which new mutagenesis techniques can be exempted on a case-by-case basis. Sweden wants to exempt targeted mutagenesis because it believes the procedure produces less offtarget effects, and thus seems safer than random mutagenesis. In 2015, the country’s government decided that the technical and legal issues in favour of non-regulation were crystal clear; last year Finland followed this opinion. And Germany – formerly one of the first European countries that greenlighted ODM as a method that does not produce GMOs – writes in the coalition agreement that consumer protection and the precautionary principle will have priority. As Bobek’s advice to the forthcoming ECJ ruling leaves many open questions, it will now be subject to interest-led interpretation by members of the pro- and anti-GM community. The ECJ is expected to provide clarification this May. Meanwhile, an interesting proposal by Joachim Schiemann and colleagues in a recent issue of Nature is gathering interest across Europe: Given that the optout clause failed to speed up approval times for new GMOs in the EU, why not allow the countries that want to plant GMO crops opt-in instead? L t.gabrielczyk@biocom.eu
Picture: Original from Plant Cell Reports DOI10.1007/s00299-016-1990-2
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01.03.2018 13:33:25 Uhr
April 24th 2018 Radisson BLU Scandinavia Hotel****
Poster Session with Poster Prize / Abstract Submission and Registration on www.stemcellday.de Bioprocessing Technologies in Stem Cell Research
Perspectives on Process Design, Scale-up, and Product Safety Chaired by Prof. Joaquim M. S. Cabral (Instituto Superior Técnico, University of Lisbon, Portugal) Sessions > Bioprocess design — Establishing robust protocols for reproducible stem cell culture > Scale-up vs. scale-out vs. perfusion — The route to commercial quantities > The safety challenge — Stem cell processing and product purity &RQƂUPHG 6SHDNHUV WR GDWH > Dr. Karen Coopman (Loughborough University, UK) > Dr. Robert Zweigerdt (Hannover Medical School, Germany) > 'U 4DVLP 5DƂT (University College London, UK) > Anja Ramme, M.Sc. (TissUse GmbH, Germany)
> Dr. Carlos Rodrigues (Instituto Superior Técnico, University of Lisbon, Portugal) > Ricardo Baptista (Cell and Gene Therapy Catapult, UK)
www.stemcellday.de or stemcellday@eppendorf.de Eppendorf ® and the Eppendorf Brand Design are registered trademarks of Eppendorf AG, Germany. All rights reserved, including graphics and images. Copyright © 2018 by Eppendorf AG.
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28.02.18 12:17 01.03.2018 12:46:35 Uhr
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Cover Story
European Biotechnology | Spring Edition | Vol. 17 | 2018
Fighting AMR: turning the p(h)age
Phage therapy The rapid
development of antibiotic resistance has become a major public health issue that could soon kill 10 million people annually. One promising alternative to ineffective antibiotics has been around for almost a century – bacteriophages. The microbe-killing viruses are used in medicine in Georgia, Poland and Russia, but have been neglected by western doctors. Now pressure is mounting on global health authorities to put the option back on the table.
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01.03.2018 12:47:00 Uhr
Cover Story
European Biotechnology | Spring Edition | Vol. 17 | 2018
W
hen the 33-year- old Ukrainian soldier Dimitry F. badly injured his right knee during a mission, he had to be given a prosthesis. Before long, the area grew infected with a pan-resistant Pseudomonas strain – a potentially fatal diagnosis, because the bacteria was resistant to all currently available antibiotics. Only an old therapy from Georgia that was never really adopted by Western medicine could save his leg. Bacteriophages, also known as phages, are viruses that target specific strains of bacteria and reproduce in them. In the process, they destroy their host so effectively they appear to have eaten it, which explains the Greek origin of the name (phagein = devour). After latching on to a bacteria’s outer surface, phages inject their own nucleic acid and hijack their host’s genetic machinery, effectively turning them into phage factories. Those factories eventually produce so many copies of the phage that they burst. If this process happens inside the human body, the phages produced eventually decay and disappear after lysing all of the target bacteria, while their components are metabolised. The viruses have been widely used for medical purposes in Russia, Georgia and Poland, but for a variety of reasons never took off elsewhere in the world
Picture: ktsdesign/fotolia.com (left), Phagomed Biopharma (right)
Phages – an antibiotic alternative? The Head of Septic Surgery and Infectious Disease Research at Charité University Hospital in Berlin has however built up a library of phages that specifically target the bacteria which produce biofilms. Last year, Andrej Trampuz founded the startup Phagomed Biop harma GmbH. “Our vision is to develop phage therapy for indications where current antibiotic therapy is limited,” says Alexander Belcredi, co-founder and CEO of Phagomed. ”The fact that we had so much knowledge about the experimental and last-resort treatments right from the start is a real asset.” One indication Phagomed is working on is
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for perip rosthetic joint infections like that contracted by Dimitry F. Bacterial infections of hip or knee prostheses are often associated with biofilms. According to Belcredi, the antibiotic dosages needed to eliminate that boundary and effectively destroy the bacteria are typically toxic for humans. Specific phage cocktails, however, could solve the problem. “We’ve already demonstrated strong phage activity against S. aureus biofilms,” Belcredi says. “That allows us to eradicate a mature MRSA biofilm more effectively than with antibiotics, and at doses feasible in humans.” The
Alexander Belcredi CEO of Phagomed Biopharma GmbH
? !
What fascinates you most about phage therapy?
The paradox that exists between the biological principle – that phages infect and lyse bacteria – and the complete lack of human pharmaceutical applications in Western medicine.
results of that study will be published this year. Phagomed was incorporated in November 2017, and is currently completing a seed financing round. The problem of ineffective antibiotics in biofilm-associated infection is one aspect of a much wider problem – that antimicrobial resistance (AMR) as a whole is taking on frightening dimensions. Recently the World Health Organization published a comprehensive report based on data from 500,000 patients in 22 countries on the worldwide status of AMR. The numbers are alarm-
15
ing. Around 50,000 people are currently being killed by antibiotic-resistant infections every year in the EU and the US alone. The WHO estimates that annual costs generated by the problem top €7bn ($8.3bn) in Europe and $6.5bn (€5.5 bn) in the United States. New approaches for tackling the AMR crisis are therefore urgently needed. But do those approaches have to involve traditional antibiotic treatments? Phage therapy proponents say it makes sense to take a closer look at what’s already out there. The first mass medical application of phages took place during the Winter War (1939–1940) between Finland and the former Soviet Union. During the three months of the conflict, around 6,000 soldiers were treated with bacteriophages. Big pharmaceutical companies like Eli Lilly (US) and Behring-Werke (Germany) also focused on the production of phage preparations in large scales at the time. But with the subsequent development of antibiotics, which can be used to treat a broad range of bacteria, phage therapy was soon ignored by pharmaceutical companies on the western side of the Cold War.
A long-forgotten history The therapeutic advantages of phage therapy were first uncovered in 1917, when Felix d’Herelle was working as a research assistant at the Pasteur Institute in Paris. Although the researcher didn’t know what type of microorganism was killing the bacteria in his experiments, his findings opened a new chapter on tackling the infections they cause. In 1936, together with his friend micro biologist George Eliava, d’Herelle would lay the foundations for the George Eliava Institute of Bacteriophage, Microbiology and Virology (EIBMV) in the Georgian capital Tbilisi. The institute still exists today, and has been a last-ditch destination for patients with chronic infections since Western companies stopped phage programmes in favour of antibiotics. In Georgia, over 600 different phages are available in pharmacies in the form of special phage cocktails.
01.03.2018 12:47:08 Uhr
Cover Story
Human health
Animal husbandry
Food safety
Bacteriophage applications
In Central Europe, Poland is the only country that employs phage therapy as a routine treatment for infection. At the Ludwik Hirszfeld Institute of Immunology and Experimental Therapy at the Polish Academy of Sciences (Wrocław), patients who have failed to respond to other treatments can receive phage therapy on compassionate use grounds. In Europe, phage therapy isn’t illegal, but neither is it explicitly defined. The legal framework for the use of medicines in the EU – which is mainly dictated by a directive (2001/83) on medicinal products for human use that is over fifteen years old – does not address the question of phages. Doctors like Andrej Trampuz decide on their own whether a bacteriophage therapy should be allowed in special cases as a last-resort treatment option under the Declaration of Helsinki. “Currently, no phage-based pharmaceutical is on the market in the US or EU,” says Belcredi. “Both the FDA and EMA are actively exploring how to regulate the therapeutic use of phages, but so far no phage product has been authorised for the market.“ To receive
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European Biotechnology | Spring Edition | Vol. 17 | 2018
approval, quality manufacturing standards in particular have to be clarified and established.
The needle in a haystack Phages are everywhere you find bacteria – in food, in puddles and pristine rivers, on computer screens, and of course on and in the human skin and gut. The viruses that prey on bacteria are about 100 times smaller than their hosts, and are thought to be the most abundant free-living entity on the planet. The number of phages all over the world is estimated at one hundred nonillion – 1032. Phages have co-evolved with bacteria for billions of years, which makes them highly specific to different strains of target bugs. “The characteristic feature of bacteriop hages to be more or less specific for bacterial strains within a single bacterial species used to seem a limitation of bacteriophage therapy, but in the era of resistance to broad-spectrum antibiotics, it now looks like a striking advantage,” says Christine Rohde, a microbiologist at the Leibniz Institute DSMZ – German Collection of Micro organisms and Cell Cultures GmbH.
Phage therapy in Europe – getting the ball rolling In September 2017, German joint project Phage4Cure kicked off an attempt to establish bacteriophage therapy within the framework of Western standards. In the project, researchers from the Fraunhofer
Institute for Toxicology and Experimental Medicine (ITEM) and the Leibniz Institute DSMZ have come together with colleagues from Berlin Charité Clinic to attempt to get phages approved as drugs for bacterial infections. The project has received €4m of funding over three years from the German Federal Ministry of Research. The aim is to produce an inhalable product containing bacterio phages that fight infections with hospital-acquired Pseudomonas aeruginosa bacteria. The pneumonia it causes is one of the most common illnesses contracted during treatment in hospitals for respiratory, wound and urinary tract infections. Data from individual therapy applications of phages against P. aeruginosa has shown promising results. “Either phages with broad host coverages can be chosen and produced as sustainable pharmaceutical preparations for human application – for example in clinical trials – or phages might be specifically used in individual cases after a phage-host screening,” says Rohde. Known as a phagogram, that screening is comparable to an antibiogram, with results returned overnight. That’s important for patients and treating physicians, because pathogens like P. aeruginosa multiply fast. Phages attack only bacteria, leaving all other microorganisms and cells intact. That means treatments have very few side effects. The big downside of this specialisation, however, is that a limited number of strains within a bacterial species are targeted by a specific
Electron microscope image of lysed Pseudomonas aeruginosa bacteria in the wake of a bacteriophage attack.
Images: Alila Medical Media/fotolia.com (bacteriophage, top left); Prof. Manfred Rohde, HZI, Braunschweig (bottom)
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Cover Story
phage. According to Rohde, that’s “a curse and blessing at the same time.” The microbiologist adds that preparations which have been imperfectly purified possibly posed the biggest danger when it came to worries about side- effects. In all, the DSMZ currently stores 800 phages that have been fully characterised. For the Phage4Cure project, Rohde and her team have already identified 70 potential therapeutic candidates. Among these are up to four very promising ones that will now be genetically screened and handed over to Holger Ziehr’s research team at the Fraunhofer ITEM. “If you look at phage preparations from the past, they are often barely purified,” says the ITEM Division Manager. “For example, drug products commonly available in Georgia are often made up of microfiltrated supernatants, or have only been partly purified through ultrafiltration,” explains Ziehr. But in the last few decades, he says, “purification systems have matured so much that chromatographic methods can be applied to produce a pharmaceutical clean monophage. Fermenting bacterial hosts to make the phages per se is doable with batch processes.”
European Biotechnology | Spring Edition | Vol. 17 | 2018
Because phages naturally hem bacterial growth, there is also danger that resistance could evolve. That’s why the ITEM team’s long-term goal is to establish phage therapy as a platform technology. It should provide a range of monophages that can be easily interchanged in a phage cocktail that does not have to undergo a full approval procedure by medical agencies. “Someday phage therapy might be treated like a vaccine. They’re updated every year as new flu strains emerge,” says Ziehr. But the current challenges involved in applying existing pharmaceutical quality rules to phage APIs and the potential dangers of resistance could be dampening enthusiasm among potential investors, who are still cautious about investing in phage research.
The first small steps The EMA has not yet published any guidelines for the production of phage therapeutics. Before that can happen, the efficacy and safety of phage therapy in general has to be demonstrated. A promising step towards the legal establishment of phage therapy as an alternative to anti
biotics was achieved in 2009 with the foundation of the Brussels-based international NGO called P.H.A.G.E. (Phages for Human Applications Group Europe, www.p-h-a-g-e.org). Its goal is to increase research on bacteriophages and initiate programs to introduce them as an approved therapy in Europe. Three years ago, the European Union was also willing to spend some attention and money on phage therapy. It contributed €3.8m to the first industrystandard Phase I/II Phagoburn clinical trial, which evaluated phage tolerance and efficacy in fighting sensitive antibioticresistant infections. For the trial, researchers from France, Belgium and the Netherlands recruited 220 burn victims whose wounds had become infected with the common bacteria E. coli or P. aeruginosa. The trial was divided into two parts – 110 patients for each of the two bacterio phage cocktails. Each targeted a specific strain of bacteria, and contained 12–13 monophages identified and developed by French company Pherecydes Pharma. Its COO Jérôme Gabard has great hopes for the firm’s products. “Phagoburn received all the necessary authorisations in
Companies involved in human therapeutic applications of natural, lytic phages or bacteriophage lysins.
Company
Location
Products
Application
Trials
› AmpliPhi Biosciences
Richmond, US
Natural phage cocktails
S. aureus wound and skin infections P. aeruginosa lung and urinary tract infections
Phase I completed Expanded Access
› ContraFect Corporation
Yonkers, US
Bacteriophage lysins
S. aureus bacteremia
Preclinical (FDA Fast Track Designation)
› EnBiotix
Cambridge, US
Engineered phages
S. aureus infections of prosthetic joints
Preclinical
› Fixed-Phage
Glasgow, UK
Natural phages fixed to solid surfaces
MRSA wound infections
Proof of concept, Preclinical
› Intralytix
Baltimore, Maryland
Natural phage cocktails
S. aureus, P. aeruginsa, E. coli wound infections, irritable bowel disease
Clinical (since 2018)
› Micreos
Wageningen, Netherlands
Bacteriophage lysins
S. aureus and MRSA skin infections
Phase I completetd (February 2018)
› Phagelux, Inc.
Shanghai, China
Natural phage cocktails
S. aureus, topical treatments
Preclinical
› Phagomed
Vienna, Austria
Natural phage cocktails
S. aureus and E.coli periprosthetic infections and urinary tract infections
Preclinical
› Pherecydes
Romainville, France
Natural phage cocktails
E. coli and P. aeruginosa burn and skin infections; P. aeruginosa respiratory infections; S. aureus bone/joint/prosthetics
Phase I/II completed
14-20_EBSpring_18_Phagen_hm.indd 18
Preclinical + compassionate use
01.03.2018 12:52:49 Uhr
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France, Switzerland and Belgium – proof of the quality of our phage therapy method and the development invested in the tested products.” The trial is ongoing, and Gabard says results are expected in a few months. Pherecydes has raised €8.7m in a Series B financing round led by Go Capital. With this financial support, the company intends to produce phages for compassionate use and TUA (Temporary Authorization of Use) in accordance with GMP. “We also want to move two programmes into the clinical phase in 2018–2019 for infections with S. aureus and P. aerugino sa respiratory tract infections,” says Gabard. The company is looking at build-
European Biotechnology | Spring Edition | Vol. 17 | 2018
ing its own pharma production unit in Nantes to produce bacteriophages at an industrial scale according to GMP guidelines. In Europe, just two production sites are currently approved to produce phages in line with existing pharmaceutical good manufacturing practices: one in France (Clean Cells SAS) and the other in Slovenia (AmpliPhi Biosciences Corp.). And after decades of ignoring phage therapy, the market isn’t only moving in Europe. Two weeks ago, US-based Intra lytix, Inc. received FDA clearance to initiate Phase I/IIa clinical trials targeting adhesive invasive E. coli (AIEC) pathogens in patients with Crohn’s disease. Intralytix currently has the world’s larg-
est portfolio of FDA-approved phagebased products on commercial markets. In 2015, it entered into a collaboration agreement with Ferring Pharmaceuticals (Switzerland) to develop a proprietary and well-defined set of bacteriophages specifically designed to treat inflammatory bowel diseases. Dimitry F. survived. After five days and periodic treatments with a phage cocktail (Pyo-Phage) his wound healed and he left the hospital on two legs. In the EU, phages can still only be used if there are no other alternatives. And the patient still has to be told that the phage cocktail is not an approved product. At least – not yet. L h.maerzhaeuser@biocom.eu
“It’ll be a game-changer” phage Products At an EU conference in Tallinn, a product utilising
copies of phage lysins was chosen as one of Europe’s most important innovations. Micreos’ CEO explains what’s behind Gladskin.
phages use bacterial metabolism to kill bacteria. This harbours the bacterial re sistance mechanisms, and can trigger de velopment of resistance. Endolysins on the other hand simply puncture the bac terial cell wall, killing the bacteria within milliseconds. Target bacteria don’t have time or defence mechanisms that can be activated that quickly. As endolysins kill only the targeted bacterial species while leaving your microbiome intact, they can be used by patients as long as needed. The first endolysin we developed is called Staphefekt. It specifically kills S. aureus – including the resistant MRSA. We initially thought it would be especially suitable for MRSA infections, but the problems caused by S. aureus in skin conditions like eczema or psoriasis affect many more people. EuroBiotech_ What about regulatory requirements for endolysins?
14-20_EBSpring_18_Phagen_hm.indd 20
Offerhaus_It’s relatively easy to comply
with all regulatory requirements, as endo lysins are enzymes that are registered in many health products. With bacteriophages this is quite a different story, as they are bio logical entities. That doesn’t match most modern regulatory frameworks. EuroBiotech_So phages are the wrong horse to back? Offerhaus_Public understanding and ac
ceptance of phages for human therapy is growing rapidly. There will certainly be therapeutic uses for phages, but I think it’s going to take some time. When we started research on phage enzymes like en dolysins, I immediately thought: ‘This could be a game-changer.’ Since lysins like Staphefekt are not expected to induce drug resistance, they are a superior alter native to antibiotics in many areas. EuroBiotech_Why did you start working with antibacterial lysins? Offerhaus_After applying natural phages
against Salmonella and Listeria in food
Mark Offerhaus is the CEO of Dutch company Micreos, the only European company marketing FDA-approved food safety products that involve natural bacteriophages. Since 2011, Micreos has been developing phage-based enzymes for applications in human therapies.
safety products for several years together with Prof. Loessner’s research groups at ETH Zurich, we unravelled the killing mechanisms developed by phages. This pushed us towards endolysins, the en zymes that actually cut the bacterial cell wall in the process of killing bacteria. Now we don’t need the phages themselves any more. Endolysins represent a quicker and more sustainable way to kill bacteria. L
Picture: Micreos
EuroBiotech_Couldn’t bacteria also grow resistant to phage lysins? Offerhaus_Conventional antibiotics and
02.03.2018 11:32:04 Uhr
Get involved in European Biotech Week! If you are familiar with biotechnology, you know the field provides incredibly innovative solutions for the benefit of mankind despite it often being unknown or misunderstood. That is why the biotech community needs you or your organisation to help raise awareness and make biotech more accessible.
Potential activities are as varied as the supporters themselves, and the organisers of the Week1 always encourage new ideas and feedback. For inspiration, flip through the magazines of the past editions on www.biotechweek.org.
There are no fees or hidden costs involved. All organisers can pool their activities on Now in its VL[WK year, European Biotech Week has www.biotechweek.org for increased visibility offered all supporters of biotechnology the and promotion, and they will later be featured opportunity to host events and develop initia- in a widely-distributed post-week magazine. tives that contribute to an increased dialogue Interested? Please contact Cosmin Popa and understanding of this amazing technology. (hello@biotechweek.org). 1
EuropaBio – the European Association for Bioindustries – together with its member National Biotech Associations
Part of
biotechweek biotechweek www.biotechweek.org
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Financial markets
European Biotechnology | Spring Edition | Vol. 17 | 2018
Making an impact on AMR R&D AMR At the 11th Berlin Conference, Novo Holdings outlined details of a new €135m investment
fund launched to push the development of new drug classes urgently needed to fight antimicrobial resistance. European Biotechnology editors were the first to talk with Aleks Engel, Partner at Novo Holdings, and George Griffin, Chair of the Repair Impact Fund’s Scientific Advisory Board, about the construction and the goal of the fund.
EuroBiotech_Most recently, Novo Holdings announced it will launch a new fund dedicated to the problem of antibiotic resistance. What are you planning, basically? Engel_The initiative is called the Repair
EuroBiotech_So, which kind of pathogens will you focus on? Engel_ The majority of the pathogens
are Gram-negative. However, there are also some Gram-positive and some fungi on the list. When we say early stage, we are talking about lead optimisation through Phase I fully included. We have decided to fund programmes via invest-
22-24_EB_Spring_2018_Economy_Interview_tg.indd 22
Aleks Engel joined Novo Holdings A/S in September 2014. Previously, he was VP at Baxter International, working with M&A licensing, growth strategies, investment prioritisation, and go-to-market planning. Other previous employers include Pfizer Global R&D, Thomson Scientific & Healthcare, and McKinsey & Company.
EuroBiotech_Who will select the most interesting projects? Engel_We have 10 members on our sci-
ments, not grants, because we believe that the problem of a thin pipeline, to a large degree, is caused by a poor commercial outlook for these products. And we believe that, long-term, establishing a sustainable anti-infective therapy space and market place will require bet-
entific selection board, chaired by George Griffin – 50% from the US and 50% from Europe – both from academia and industry. There are a bit more experts from industry because we wished to include people who have seen a lot of failures to pick the winners. Quite a few
Picture: Novo Holdings
Impact Fund. Repair is an acronym and stands for Replenishing and enabling the pipeline for anti-infective resistance. The fund is commissioned by the Novo Nordisk Foundation, which is a charitable fund based in Copenhagen, Denmark, with about US$50bn under management. The foundation has an asset management holding company called Novo Holdings, which invests exclusively in life sciences, and currently has 80 portfolio companies. Novo Nordisk Foundation has asked Holding to create and manage this fund. It will have an investment horizon of DKK1bn or €135m over three to five years and will support early-stage innovation targeting drug-resistant pathogens, particularly the priority pathogens defined by the CDC and the WHO lists.
ter commercial solutions. We have realistic expectations for our own returns, and that’s why it is an impact fund: our principal objective is to make an impact and accelerate therapies to the clinic and eventually to the market. But the investment angle, we believe, will help everybody to focus on the value these potentially life-saving products will create, and hopefully, over time, create a more sustainable situation for all of us. We in our organisation, because we have this prominent capital set-up, can invest for the very long term. So, we do not have a particular time frame for returns and that allows us to look into opportunities that may take a long time to realise. Through this €135m we expect that we can invest in about 20 different programmes. From traditional attrition of that, we would expect somewhere from two to five programmes to get through the end of Phase I and we hope to have at least one of such products eventually get to market.
02.03.2018 11:32:44 Uhr
financial markets
European Biotechnology | Spring Edition | Vol. 17 | 2018
of the industry experts have previously worked in anti-infectives in Big Pharma. They have been instrumental in bringing those drugs to the market at some point in the past. Additionally, there are experts from SMEs contributing to the Scientific Advisory Board.
St Georges Univversity, London
EuroBiotech_What are you looking for? How do you define a novel antimicrobial? Griffin_There are very few new classes
of antimicrobials being investigated at the moment. As Aleks said, this is due to all sorts of reasons, but investment by Big Pharma, particularly, is not strong. So the aim, really, is to get innovative ideas. Biotech, of course, is very strong in Europe and the US at the moment. There are some very good biotech companies, and I suspect that our board will start to look at novel ideas from biotech and choose which – in our scientific opinion – are the best bets. The way that we aim to do it is that there will be a call going out, which is going to be widely publicised. It’s impossible to say exactly how many will come in because this is new. But we certainly hope to see well in excess of 50 applications per semi-annual cycle. First, we’ll draw up a shortlist. Then, we’ll meet at Novo for a couple of days to judge the short-listed applicants on their business cases, followed by interviews and presentations
22-24_EB_Spring_2018_Economy_Interview_tg.indd 23
by the applicants. The final investment will be offered to the applicants who present the best evidence to this experienced team of biomedical and clinical experts. Engel _Our investments have two flavours. One is a royalty-based investment, which means that we provide funding, and if the product eventually is successful, we would get a royalty from the sales at a point in the distant future. The other instrument is a convertible loan. Both of these are easier to handle than equity investments and we hope they will be attractive to companies that we get to interact with. Back to your question: What is a novel antimicrobial treatment? I think what we are targeting here are novel classes and novel modalities. We are certainly working for some diversity in our investments but, as I said, we don’t yet know what we will get. Obviously, there are many start-up enterprises in this field. Even though Novo Holdings has invested in eight anti-infective companies previously, we are looking to find out new places where science is leading us. EuroBiotech_Which directions of AMR research have impressed you most, George? Griffin_As bacteria are not clever, but
highly adaptable through mutations that cause resistance, a novel way to prevent
George Griffin, Chair of the SAB of the Repair Impact Fund. The internationally renowned anti-infectious expert and advisor to Sanofi and Xellia/ Novo established and led the internationally recognised academic unit on host response at St. George’s University of London. Griffin was instrumental in drafting health documents for the G7 2017 summit. He chairs diverse national and international advisory committees on infectious diseases.
set-up of resistance is to use combinations. For example, there are very interesting things going on with drug candidates derived from the sea, producing
02.03.2018 11:32:51 Uhr
financial markets
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European Biotechnology | Spring Edition | Vol. 17 | 2018
CRITICAL
that Novo Nordisk has the first right to license a funded project? Engel _No conditions like that. We in
HIGH
Novo Holdings are completely independent from Novo Nordisk. Novo Nordisk is one of our 80 portfolio companies. We own 26% of it but it is not an antibiotic marketing company.
Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant, ESBL-producing
Enterococcus faecium, vancomycin-resistant Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant Helicobacter pylori, clarithromycin-resistant Campylobacter spp., fluoroquinolone-resistant Salmonellae, fluoroquinolone-resistant Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-resistant
MEDIUM
Streptococcus pneumoniae, penicillin-non-susceptible Haemophilus influenzae, ampicillin-resistant Shigella spp., fluoroquinolone-resistant
WHO priority pathogens list for R&D of new antibiotics
new classes of antimicrobials. Also, antibodies may play a role in targeting highly resistant microorganisms, while approaches targeting the innate immune system are, in my view, in the very early stage. And we need to re-evaluate new therapies, such as phages. However, it’s a sort of approach I am sure the SAB will take. Currently, it looks like new classes are coming from biological sources, rather than from molecular design. We have to think about that. EuroBiotech_How do you differentiate your work from other initiatives, such as Carb-X, Gardp, etc., as they are also targeting the early stage and looking for new classes of antimicrobials? Engel_We are very much inclined to col-
laborate with all of them. I think what sets us apart is that we are, first of all, investing – as opposed to giving away grants. That probably, in some instances, could be seen as less attractive. On the other hand, we have some experience here that we think could be helpful through the people who we have on SAB and in our broader network. And we also believe that our ability and longevity to stay with the companies will be seen as attractive. We hope to have a positive commercial and impact-driven approach to accelerating these therapies. EuroBiotech_Will the fund also include diagnostics that are required to be codeveloped with targeted antimicrobials?
22-24_EB_Spring_2018_Economy_Interview_tg.indd 24
Engel_We may certainly include some diagnostics approaches, but will keep focussed on therapies. Griffin_The partnership concept is what is
really important because neither academia, or biotech, or Big Pharma on its own can now develop major new drugs. There has to be partnership, and then there has to be Phase I testing, and then clinical testing. So the way I look at it: as an experienced clinician and biomedical scientist who has worked with industry, I recognise that a continuum of professional expertise and knowledge is crucial in making the sort of advances we anticipate. EuroBiotech_So is it correct to assume that your fund will be particularly targeting start-ups more than academic groups? Engel_I think this relates to where they
are in development. The earliest possibility is lead optimisation, which is typically beyond what is going on in the academic lab. So we would invest principally in companies and projects that are beyond the academic stage. Griffin_My experience concerning biotech is that there is considerable collaboration with academia, because academics on their own have not the resources for full R&D, but they do have ideas. And those ideas, in collaboration with biotech and then Big Pharma, are very, very powerful. EuroBiotech_ Is your fund completely independent, or are there any conditions
EuroBiotech_Have you thought about establishing a mechanism with other existing projects to bridge the valley of death developers of novel antimicrobial therapies will run into so long as antimicrobial development is not as commercially attractive as, say, oncology? Engel_As a starting point, we believe that
there is funding for projects for which you have proof-of-concept data, which means you have solid Phase I data. We have ourselves a venture capital group called Novo Ventures investing US$300– 500m annually into many therapeutic areas. And we have invested in more than a handful of such companies at that stage and have made money in that area. So, we believe that a company with solid Phase I data has the opportunity to attract venture capital. It might not be the most attractive area because of the commercialisation and market problems mentioned. The objective of the R epair impact fund will be to get companies to that stage. EuroBiotech_You mean extended Phase I trials providing early proof of concept? Griffin_The different Phases have become
blurred recently and a lot of people now think extended Phase I is a very good starting point. So, if you have the safety profile in humans, and you have in vitro efficacy, and may also have some early PK from the extended Phase I, that puts you in a very good position actually. Given the international perspective on the need for new drugs, the organisations will have no trouble getting through these things. As the medical need is so high, the regulatory authorities, whom I have been in discussions with, are thinking about establishing accelerated approval for the most urgently needed antimicrobials. L t.gabrielczyk@biocom.eu
Picture: Biocote Inc.
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European Biotechnology | Spring Edition | Vol. 17 | 2018
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How to benefit from a looming gold rush Marcus Wieprecht Managing Director, Mainfirst Bank AG_As the global pharma
industry copes with a variety of problems, it has put its hopes in the development of new biopharmaceuticals. Some companies are successfully capitalising on this trend.
Investors are increasingly sceptical about the growth prospects of global phar maceutical companies, cit ing public criticism of high drug prices and competitive pressure from generics. Bio pharmaceuticals, however, show great promise, accord ing to market research ex perts at Evaluate Pharma, who predict the global biopharma market will grow almost 9% per year until 2022. The main reason for this growth is the large number of new biologically produced drugs that will come from the bulging development pipeline of the pharma industry, with almost 12,000 new products underway. Growth in the biosimilars market may be even more im pressive – up to 33% per annum. Newer technologies, such as cellular or viral the rapies, are providing additional growth for
the biopharmaceutical mar ket. In short, in the biophar ma market there is current ly something of a gold rush mood. How can investors benefit from this trend? Of course you can rely on sin gle companies, but the indi vidual risk seems quite high. Remember: back in 1848 in California, shovel manufacturing was the safest bet. The gold rush-like prospects for biopharmaceuticals has triggered a mas sive expansion (> 50% by 2021) of pro duction capacity at pharma companies and contract manufacturers, such as Swiss Lonza AG. Even completely new players, such as Samsung Biologics, are trying their luck within this optimistic climate. Biopharmaceuticals are currently main ly produced in large steel tanks. Howev er, production using smaller, more flexible,
cheaper, and thus more efficient, singleuse technologies is increasingly gaining ground. We expect the supply market to grow by 12% annually between now and 2022. Following a wave of consolida tions in 2014/15 (Thermo Fisher bought Life Technologies, Merck KGaA acquired Sigma Aldrich, Danaher bought Pall), the global supply market for disposable pro duction systems is driven by five compa nies: US market leader General Electric, German companies Merck KGaA and Sar torius, and US enterprises Thermo Fisher and Danaher. None of these companies covers all areas – from filtration and liquid management, fermentation, purification to cell culture media – yet. Some are closer to the goal of being a “one-stop shop” for disposable production systems than oth ers. One thing is obvious: true full-serv ice providers will profit disproportionately from the looming gold rush. L
Picture: Mainfirst
News from the floor Prothena Corp. plc Covering Irish late-stage clinical biotech Prothena, Oppenheimer & Co. analyst Jay Olson recommended the stock in February, setting the price target at US$70. Af ter reporting the 2017 financial results and communicating the resignation of the company’s chief medical officer, shares of the developer of antibody therapies were traded for US$35. The management shake-up is seen as crit ical, as it happened in the run-up to a key clinical readout on Prothena’s
25_EB_Spring_2018_Analyst_ml.indd 25
lead pipeline asset NEOD001, due in the second quarter of 2018.
indications, including solid tumours. No wonder that Juske Bank reiterated their “buy“ rating.
Genmab A/S Shares in Europe’s biggest
biotechnology company, Denmark’s Genmab, jumped as much as 19% in late February when it reinsured investors on growing sales of its multiple mye loma therapy Darzalex. Darzalex sales should amount to at least US$2bn in 2018. Genmab hopes for more growth by moving it into earlier therapy lines and, further into the future, brand-new
Morphosys AG Expecting a string of good news in the course of the year, analyst Igor Kim from Franco-Ger man financial services group Oddo BHF continues to recommend buying shares of German antibody special ist Morphosys AG. The shares were worth about €80 in late February, but Kim set his price target at €90.
01.03.2018 12:57:16 Uhr
26
financial markets
COMPANY 4D Pharma plc
QUOTE
European Biotechnology | Spring Edition | Vol. 17 | 2018
M-Cap
2.10
137,000k
4SC AG
7.71
230,000k
A1M Pharma AS
0.62
5,100k
AB Science SA
8.24
336,000k
AB-Biotics SA
1.78
22,400k
52 weeks indicator low high
COMPANY Brain AG
QUOTE 23.45
M-Cap
C4X Discovery Holdings plc
0.82
38,300k
Cantargia AB
0.72
46,500k
Carbios SAS
7.69
35,100k
Cassiopea SpA
32.89
325,000k
Cellectis SA
25.80
953,000k
Cellink AB
14.94
112,000k
Celon Pharma SA
8.06
357,000k
32.60
332,000k
Abcam plc
14.54
2,960,000k
Abivax SA
8.02
79,600k
Ablynx NV
43.94
3,300,000k
Abzena plc
0.29
62,400k
Celyad SA
Acarix AB
0.97
22,200k
Cerenis Therapeutics SA
1.89
35,200k
Circassia Pharmaceuticals plc
1.03
352,000k
CAR-Treg cells line up Cell Therapy ”To the best of our knowledge, this is the
very first CAR-Treg GMP process in the industry,“ said Francois Meyer, Chairman and Head of Research of French bio tech Txcell SA. Intended to make a mark in inflammation, autoimmunity and transplantation, Txcell’s cellular immunotherapies cleared a major hurdle as the company stated that the drug product could be both frozen and thawed with no change in phenotype and function. Transfer of Txcell’s CARTreg GMP process to a contract manufacturer has started in early February. L
Co.don AG
3.08
147,000k
112.19
1,690,000k
Curetis AG
6.64
104,000k
Cytotools AG
9.54
19,700k
Cyxone AB
0.99
16,700k
37.08
928,000k
Cosmo Pharmaceuticals NV
DBV Technologies SA Deinove SA
2.52
29,700k
Destiny Pharma plc
1.52
66,900k
Diamyd Medical AB
0.34
19,500k
69.85
3,890,000k
Diaxonhit Therapeutics SA
4.60
44,700k
Elanix Technologies AG
2.88
20,100k
e-Therapeutics plc
0.10
26,600k
Diasorin SpA
Ellen AB
0.03
5,100k
Enzymatica AB
0.48
35,000k
Epigenomics AG Active Biotech AB Addex Therapeutics Ltd Adocia SAS
0.29
28,000k
Erytech Pharma SA
2.59
39,600k
14.82
103,000k
Eurofins Scientific SE
Esperite NV
4.16
97,500k
16.91
305,000k
0.45
11,200k
474.00
8,450,000k
Advicenne SACA
13.20
106,000k
Evgen Pharma plc
0.15
13,600k
ALK-Abelló A/S
98.18
1,090,000k
Evolva SA
0.24
194,000k
14.78
2,170,000k
Allergy Therapeutics plc
0.29
172,000k
Evotec AG
Alligator Bioscience AB
2.59
180,000k
Expres2ion Biotech Holding AB
1.09
11,800k
Annexin Pharmaceuticals AB
0.53
3,000k
Faron Pharmaceuticals Oy
9.87
300,000k 52,600k
Aqua Bio Technology ASA
0.71
4,900k
Fermentalg SA
3.04
Argenx SE
66.00
2,120,000k
Fit Biotech Oy
0.00
800k
Arocell AB
0.45
12,900k
Formycon AG
32.28
290,000k 4,700,000k
Asit Biotech SA
4.32
64,700k
Galapagos NV
91.50
Avacta Group plc
0.64
43,000k
Genedrive plc
0.38
7,100k
Avantium Holding NV
5.71
148,000k
Geneuro SA
7.40
105,000k
Basilea Pharmaceutica AG
59.38
791,000k
Genfit SA
23.68
761,000k
Bavarian Nordic A/S
32.73
1,040,000k
Genmab A/S
167.88
10,200,000k
Bergenbio ASA
4.82
242,000k
Genomed SA
3.81
5,300k
Bio-On SpA
27.25
506,000k
Genomic Vision SA
2.80
16,400k
Biocartis NV
13.26
681,000k
Genovis AB
0.35
21,400k
6.13
266,000k
Genoway SA
1.91
11,200k
34.26
594,000k
Gensight Biologics SA
6.94
171,000k
Bioinvent International AB
0.21
63,300k
Genkyotex SA
Biomed-Lublin SA
0.37
20,700k
Genus plc
Biomérieux SA
72.10
8,450,000k
Bionaturis SA
2.16
11,000k
Biofrontera AG Biogaia AB
1.69
132,000k
25.90
1,590,000k
Global Bioenergies SA
18.80
83,200k
Hansa Medical AB
23.50
870,000k 88,800k
Biophytis
4.09
54,200k
Heidelberg Pharma AG
3.21
Bioporto Diagnostics A/S
0.46
72,100k
Herantis Pharma Oyj
6.50
31,000k
Biosearch Life SA
0.58
33,500k
Hofseth Biocare ASA
0.18
42,400k
Horizon Discovery Group plc
2.15
326,000k
Biotec Pharmacon ASA
0.64
27,900k
Bioventix plc
24.10
125,000k
1.10 11.46
Biovica International AB Bone Therapeutics SA
26-27_EB_Spring_2018_stockmarketlist_ml_NEW.indd 26
52 weeks indicator low high
420,000k
Hvivo plc
0.60
47,000k
9,000k
Hybrigenics SA
0.57
26,500k
78,100k
Idorsia Ltd.
22.25
2,630,000k
01.03.2018 13:27:28 Uhr
financial markets
European Biotechnology | Spring Edition | Vol. 17 | 2018
COMPANY
QUOTE
Immunicum AB
0.73
M-Cap
52 weeks indicator low high
COMPANY
35,700k
Physiomics plc Plant Advanced Technologies SA
Immunodiagnostic Systems plc
2.53
74,400k
Immunovia AB
8.80
149,000k
Poxel SA
QUOTE 0.06
M-Cap
24.00
22,100k
6.58
163,000k
Immupharma plc
1.50
211,000k
Premaitha Health plc
0.06
18,000k
0.48
30,400k
Probi AB
35.25
412,000k
Infant Bacterial Therapeutics AB
11.35
119,000k
Probiodrug AG
12.70
104,000k
Innate Pharma SA
5.54
324,000k
Promore Pharma AB
1.04
21,100k
Integragen SA
2.45
16,200k
Proteome Sciences plc
0.04
11,900k
Intervacc AB
0.32
5,100k
27.60
6,240,000k
Inventiva SA
5.20
88,100k
Quantum Genomics SAS
2.55
28,000k
Isofol Medical AB
2.53
81,400k
Relief Therapeutics Holding AG
0.01
19,700k
ISR Holding AB
0.86
16,000k
Reneuron Group plc
1.11
35,000k
Kancera AB
0.20
29,300k
Salvarx Group plc
0.24
8,800k
Karo Pharma AB
3.14
335,000k
Saniona AB
2.84
61,200k
Kiadis Pharma BV
11.56
203,000k
23.07
151,000k
Kuros Biosciences AG
10.34
85,900k
Sareum Holdings plc
0.01
31,100k
Lysogene SA
3.60
44,400k
Scancell Holdings plc
0.16
48,700k
Mabion Ltd
Santhera Pharmaceuticals AG
28.02
328,000k
Selvita SA
15.14
208,000k
MDxHealth SA
3.46
172,000k
Sensorion SA
3.20
29,400k
Medical Prognosis Institute A/S
1.08
26,500k
Shield Therapeutics plc
0.28
32,300k
Medigene AG
17.95
410,000k
Silence Therapeutics plc
2.23
156,000k
Medivir AB
3.86
94,000k
Simris Alg AB
1.06
9,800k
Mereo Biopharma Group plc
3.49
248,000k
Skinbiotherapeutics plc
0.10
11,400k
Metabolic Explorer SA
2.20
50,800k
Stallergenes Greer plc
31.60
626,000k
Midatech Pharma plc
0.38
23,600k
Summit Therapeutics plc
2.04
152,000k
Molecular Partners AG
23.37
486,000k
Swedish Orphan Biovitrum AB
13.46
3,690,000k
Molecular Medicine SpA
0.54
240,000k
Sygnis AG
1.42
67,300k
Mologen AG
2.25
78,900k
Synairgen Research Ltd
0.16
14,200k
76.00
2,290,000k
Targovax ASA
1.70
89,300k
Theradiag SA
Morphosys AG Motif Bio plc
0.40
111,000k
1.57
13,600k
Nanobiotix SA
13.24
265,000k
Theranexus SADIR
16.00
49,900k
NEL ASA
0.32
317,000k
Thrombogenics NV
4.07
156,000k
Neol Biosolutions SA
0.25
2,300k
Tigenix NV
1.72
510,000k
Neovacs SA
0.49
30,100k
Tissue Regenix Group plc
0.09
110,000k
Neuron Biopharma SA
0.30
4,700k
Tiziana Life Sciences plc
1.13
142,000k
Neurosearch A/S
0.66
15,500k
Transgene SA
3.05
192,000k
Neurovive Pharmaceutical AB
0.25
12,900k
Txcell SA
1.37
29,200k
Newron Pharmaceuticals SpA
8.92
159,000k
Valirx plc
0.04
15,000k
10.00
294,000k
Valneva SE
3.47
271,000k
7.25
366,000k
Vectura Group plc
0.86
573,000k
42.71
13,200,000k
Veloxis Pharmaceuticals A/S
0.12
203,000k
Nicox SA Nordic Nanovector ASA Novozymes Biopharma DK A/S Noxxon Pharma NV
5.70
12,700k
Vernalis plc
0.07
34,400k
Nuevolution A/S
1.69
73,200k
Verona Pharma plc
1.57
165,000k
Oncimmune Holdings plc
1.64
97,800k
Vita 34 AG
14.55
59,700k
12.00
81,800k
Wilson Therapeutics AB
14.20
398,000k
Oncopeptides AB
7.97
320,000k
Xbrane Biopharma AB
0.31
9,600k
Onxeo SA
1.61
82,600k
Xintela AB
9.66
292,000k
Zealand Pharmaceuticals A/S
13.03
393,000k
Oncodesign Biotechnology SA
Optibiotix Health plc
0.67
53,400k
Orphazyme A/S
9.99
196,000k 88,800k
Oryzon Genomics SA
2.60
OSE Pharma SA
3.61
52,200k
Oxford Biodynamics plc
1.96
170,000k
Oxford Biomedica plc
0.14
423,000k
Paion AG
2.42
149,000k
PCI Biotech Holding ASA
5.94
144,000k
Pharma Mar SA
1.72
384,000k
Pharming Group NV
1.35
788,000k
Pharnext SA
8.26
89,100k
Photocure ASA
2.87
62,600k
26-27_EB_Spring_2018_stockmarketlist_ml_NEW.indd 27
52 weeks indicator low high
3,800k
Index Pharm. Holding AB
Qiagen NV
27
All quotes are listed in euro. All data is provided without guarantee. The effective date is 26 February 2018. These dedicated biotech companies are listed on European stock markets.
01.03.2018 13:27:34 Uhr
28
financial markets
European Biotechnology | Spring Edition | Vol. 17 | 2018
New Wave of Optimism Stock Market Report After a healthy reset in 2016, European public biotech markets
experienced a new wave of optimism with increased volumes of IPOs and financings in 2017. Investors’ appetite was revived on the US Nasdaq in particular, according to the most recent BIOCOM capital market report.
Following the more cautious year 2016, the European biotech sector witnessed a significant volume increase in IPOs and follow-on financings in 2017. Taking all indicators into account – number and volumes of IPOs, follow-on financings, and secondary listings – the 234 European biotech companies raised €5.17bn in 2017, 56% more than in 2016 (€3.30bn). Almost half of the money (43%, €2.21bn) was raised on the US Nasdaq, highlighting the power of biotech-focused investors available through the US stock market. A total of 20 IPOs took place. A majority of 15 firms opted for one of the 14 European trading centres, five firms went public on the US Nasdaq instead. These are the key findings of the “Analysis of European Biotech Companies on the Stock Markets: US vs Europe,“ released by German market analyst BIOCOM AG in mid-January of this year. “Overall figures for 2017 demonstrate that IPOs and listings have become established as an important instrument for European biotech companies to raise capital. With regard to volumes, however, the US stock market is much more
powerful due to a greater diversity and higher number of biotech investors,” says Sandra Wirsching, responsible for the report at BIOCOM.
The analysis also reveals that, in 2017, a new wave of listings took place in Scandinavia, among them one in Oslo and six in Stockholm. For this reason, the Swedish capital has now caught up to Paris and London, with a total of 41 listed biotech firms and 6 new listings, among them Oncopeptides AB, raising €68m, and BioArtic NeuroScience AB with €71.8m. Two British newcomers – Destiny Pharma and SkinBio Therapeutics – performed an IPO at the London Stock Exchange. One listing each took place in Oslo (BerGenBio) and in Copenhagen (OrphaZyme). The five companies already listed – Zealand Pharmaceuticals (Nasdaq Nordic), argenx (Euronext), Verona Pharma (AIM), ERYtech Pharma (Euronext), and Ablynx (Euronext) – went public with a secondary offering on US Nasdaq. The largest European IPO volumes were raised in the US, however, by ObsEva SA (€90m), InflarX (€85.8m), and Nucana Biomed (€84.7m). In Europe, IPOs at Nasdaq Nordic were the most successful in terms of volume: OrphaZyme (€80m, Copenhagen), BioArctic Neuroscience (€71.8m, Stockholm),
Increase of 56% with a total of 20 European biotech IPOs According to the analysis, a total of 20 European biotech IPOs had taken place in 2017, raising a total amount of €866m. This marks an increase of 56% compared to 2016 (€556m). Most of the companies (15) went public in Europe; five firms floated on the US Nasdaq. These include Swiss company ObsEva (€90m), German InflarX (€85.8m), Austrian Arsanis Biosciences (€50.8m), UK-based companies Nightstar Therapeutics (€63.5m), and Nucana Biomed (€84.7m). Among the European trading centres, Paris (47) and London (44) are the top locations with the highest number of listed biotech companies. As stated in the report, cross-border stock market Euronext remains one of the most attractive stock exchanges for European biotech companies. Five of this year’s listings took place here.
Overview of trading centres with total numbers of listed European biotech companies and IPOs in 2017
8
6
2
Helsinki **
© BIOCOM
Infographic + Source: BIOCOM AG
1
*Euronext, **Nasdaq Nordic
28-29_EB_Spring_2018_KMS.indd 28
3
Milan
2017
Brussels *
Zurich
Frankfurt
6
Amsterdam *
1
7
Warsaw
New York
9
Madrid
Stockholm ** 2017
9
Copenhagen **
2017
11
Oslo
5
17
2017
6
London
24
2
5
234
41
2017
44
Paris *
47
01.03.2018 12:59:30 Uhr
financial markets
European Biotechnology | Spring Edition | Vol. 17 | 2018
and Oncopeptides (€68m, Stockholm). When it comes to follow-on financings, 2017 has recovered significantly compared to 2016. A total of €4.3bn was dropped into the companies, a substantial 57% increase compared to 2016. “Investors’ enthusiasm for biotech companies has returned in 2017,” says Wirsching. The average size of capital increase in 2017 almost doubled to €35m, compared to €19m in the same period of 2016. Much of the increase is due to the fact that the climate on Nasdaq ameliorated significantly, whereas in Europe almost the same money was raised with fewer follow-on financings taking place in 2017 (123) compared to 2016 (144). Within Europe, Euronext demonstrated the most activity, with 33 financings and total proceeds of €1.4bn, followed by Frankfurt (23 financings, €312m), and AIM (16 financings, €231m).
Public biotech market 2017 Total financial proceeds of listed European biotech companies 2017
€5.71bn +56%
2016
€3.30bn –48% €6.29bn
2015
Number of IPOs and capital raised by European listed companies Initial public offerings: Total proceeds
2017
Average volumes
Infographic + Source: BIOCOM AG
More information: biocom.de/en/analysis2018
28-29_EB_Spring_2018_KMS.indd 29
Total number €866m
20
€43m
Market revival with 200% increase on the US Nasdaq A significant jump was observed for the US Nasdaq, where the market experienced a revival with a more than 200% increase compared to 2016. The 36 companies listed in the US attracted a combined total of €1.8bn in follow-on financings. One third of the money came in through the five secondary listings from Verona Pharma (UK), argenx (FR), Zealand Pharmaceuticals (DK), ERYtech (FR), and Ablynx (BE), which amounted to a total capital of €553m alone. Drug developers, in particular, opted for a US listing in 2017, which is clearly associated with their high demands for capital. Last year's Nasdaq newcomers are active in the field of reproductive health (ObsEva), cancer therapeutics (Nucana), blinding eye diseases (Nightstar), infections (Arsanis), and inflammation (InflarX). The same applies for the secondary listings: respiratory diseases (Verona), metabolic diseases (Zealand) and cancer/autoimmune diseases (argenx, ERYtech, Ablynx). L
29
+56%
2016
€556m
17
€33m
Number of financing rounds and capital raised by European listed companies Follow-on and other financings: Total proceeds 2017
Average volumes
Total number €4,300m
€35m
123
+57%
2016
€2,746m
€19m
141
Capital raised via IPOs in €m and number of IPOs in Europe and US Nasdaq 2017
374.8
2016
164.6
2015
2012
5 14
391.3 806.2
406.6
2014 2013
15
490.7
506.9 59.4 47.0 110.1 94.0
740.0
21 16 5
3 4 9 1
5 1
01.03.2018 12:59:37 Uhr
30
Regulatory Affairs
European Biotechnology | Spring Edition | Vol. 17 | 2018
EMA wins transparency trial Industry vs EMA The European Medi-
cines Agency (EMA) has won a landmark lawsuit against industry concerning the amount of data from clinical dossiers that may be made public. The European Court of Justice (EJC), citing the EU Transparency Regulation and EMA 2010 policy 0043 on access to documents, rejected the demand of three drug developers not to publish what they claimed to be confidential information.
Transparency: 3 Confidentiality: 0 In all three cases, the EMA, acting under the EU’s transparency policy, granted access to documents that the companies had submitted to attain market authorisation, after that authorisation had been granted. The judgments concern Case T-235/15, Pari Pharma vs EMA; Case T-718/15, PTC Therapeutics International vs EMA; and Case T-729/15, MSD Animal Health Innovation and Intervet International vs EMA. In the PTC Therapeutics International vs EMA case, PTC, with the support of
EUCOPE, wanted to block the EMA from publishing the entire study report, which it claimed was confidential and thus should not be passed on to an undisclosed competitor who, in 2015, requested information under the EMA’s transparency policy. The court, however, dismissed a preliminary order issued in 2016 by its president and vice-president to prevent the release of the report, saying a general presumption of confidentiality would run counter to the letter and spirit of Regulation No 1049/2001. The court confirmed that under EU transparency rules the EMA had the right to use their own judgment for redaction, without consulting the applicant, when determining what information should be considered confidential and personal. Third, the court pointed out that the applicant was not able to specify why the document submitted was confidential as a whole, and that parts of it had been previously published in the public domain. The latter argument also applied to two further cases: In the Pari Pharma vs EMA case, nebulisation specialist Pari GmbH’s
www.ema.europa.eu claimed data from similarity and superiority assessment reports of its cystic fibrosis drug Vantobra should be considered confidential and barred from submission to its competitor Novartis Europharm Ltd. The same applied to five toxicology studies conducted by MSD Animal Health Innovation GmbH and Intervet International BV for the veterinary medicinal product Bravecto, a treatment for tick and flea infestations in dogs. The EMA welcomed the court’s decisions. “We are very pleased that the General Court affirmed that the information contained in these documents cannot be considered commercially confidential in its entirety,” said Stefano Marino, EMA’s Head of Legal Service. “We understand that with these rulings the General Court endorses our implementation of the Transparency Regulation that focuses on the interest of patients and public health.” L
Recommendations from the EMA: MA (market authorisation); cond. MA (conditional MA); e.c. MA (MA under exceptional circumstances); hybrid MA (MA based on preclinical data, results of clinical trials for a reference product, and, in part, on new data).
Drug name
Indication
Company
Status
› Hemlibra (emicizumab)
Treatment of hemophilia A in adult patients with resistance to recombinant factor VIII products
Roche Registration Ltd
MA rec.
› Lamzede (velmanase alpha)
Treatment of patients with mild to moderate forms of alpha-mannosidosis
Chiesi Farmaceutica S.p.A.
e.c. MA
› Shingrix (recombinant, adjuvanted Herpes zoster vaccine)
Prevention of herpes zoster and post-herpetic neuralgia in adults 50 years of age or older
GlaxoSmithKline Trading Services
MA rec.
› Trelegy Ellipta (fluticasone furoate+umeclidinium +vilanterol)
Treatment of hemophilia A in adult patients with resistance to recombinant factor VIII products
GlaxoSmithKline Trading Services
MA rec.
› Segluromet (ertugliflozin / metformin) › Steglatro (ertugliflozin) › Steglujan (ertugliflozin / sitagliptin)
Treatment of type 2 diabetes
Merck Sharp & Dohme Ltd
MA rec.
› EnCyzix (enclomifene)
Treatment of hypogonadotrophic hypogonadism
Renable Pharma Ltd
MA refusal
› Amglidia (glibenclamide)
Treatment of neonatal diabetes mellitus in newborns, infants and children
Ammtek
MA rec.
› Mylotarg (gemtuzumab ozogamicin)
Treatment of acute myeloid leukaemia (AML) in patients aged over 15 years
Pfizer Ltd
MA rec.
› Zydelig (idelalisib)
Treatment of chronic lymphocytic leukaemia (CLL)
Gilead Sciences Int. Ltd
MA withdrawn
30_EB_Spring_2018_EMA_tg.indd 30
01.03.2018 12:59:55 Uhr
European Biotechnology | Spring Edition | Vol. 17 | 2018
Update of ongoing clinical trials Attrial Fibrillation
Danish Acesion Pharma ApS (Copenhagen) has received Phase I approval for its atrial fibrillation treatment AP30663, an inhibitor of SK channels. The company, which received €9.1m funding from Novo Seeds and the Wellcome Trust, hopes that blocking these ion channels with an atrial-selective small molecule drug will help avoid deleterious effects on the ventricles seen with current treatments. The study in healthy subjects will start enrolment at the Centre for Human Drug Research (CHDR) in the Netherlands in March 2018. Antibiotic resistance
French microbiota specialist Da Volterra published Phase I (NCT02176005) results of its colon-targeted adsorbent DAV132 in the Journal of Infectious Diseases (doi. org/10.1093/infdis/jix604). The oral-activated charcoal adsorbent, designed to irreversibly capture residual antibiotics in the gut before they can disrupt the intestinal microbiota, was well-tolerated and showed first signs of efficacy. DAV132 reduced exposure of the intestinal microbiota to moxifloxacin in 28 patients by 99% and maintained 97.8% of the microbiome’s genetic richness without affecting the drug’s therapeutic efficacy. The fluoroquinolone antibiotic has been associated with the antimicrobial resistance (AMR) of Clostridium difficile infections. Melanoma
Prior to the outstanding FDA and EMA decisions on market authorisation of binimetinib/encrofenib as a treatment for BRAF V600-mutant melanoma, Pierre Fabre SA and its partner, Array Biopharma Inc, have presented head-to-head survival data with vemurafenib (Roche AG/Daiichi Sankyo). In 921 patients, the combo clearly outperformed the the approved standard, with a median overall survival time of 33.6 months versus 16.9 months. The combination of encorafenib and binimetinib was generally well-tolerated. Binimetinib (MEK162) is a selective
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MAP kinase 1 and 2 inhibitor. Encorafenib (LGX818) is a small molecule BRAF inhibitor, which showed a median OS of 23.5 months when administered as a daily monotherapy. DNA cancer vaccine specialist Scancell Holdings plc has given an update of its ongoing Phase I/II trial in which the company evaluates safety and efficacy of SCIB1 in stage 3/4 melanoma patients. The vaccine targets gp100 and TRP-2. As of February 2018, Scancell reported that 18 of 20 melanoma patients with resected disease were alive. From the 16 resected patients, who received 2–4 mg doses of SCIB1, six patients relapsed; two of them died. According to Scancell, 14 patients have passed the five-year time point since study entry. Leukemia/Lymphoma
Dutch Acerta Pharma BV (Oss), and its majority stock holder AstraZeneca plc have tabled new Phase II data of the Bruton’s tyrosine kinase blocker acalabrutinib in patients with refractive mantle cell lymphoma. The companies reported a 12-month progression-free survival in 67% of patients and a one-year overall survival rate of 87%. The small molecule drug has been granted US orphan drug status and fast track designation.
Getting the job done right means starting with the right partner. What can you do to help smooth your compound’s path to clinic and beyond? With Vetter, you work with a partner who knows how to take your compound from preclinical to commercial manufacturing: Expertise in the development of a broad range of drugs Technology and resources to achieve decisive milestones Clinical manufacturing facilities in the US and Germany
German Affimed GmbH has tabled initial results of the initial cohort of an open-label Phase I/II dose-escalation study on its bispecific antibody AFM13 plus pembrolizumab (Merck & Co) in nine patients with CD30-positive refractory non-Hodgkin lymphoma. The combination therapy led to an objective response in eight of nine patients and one stable disease, four patients showed complete response, a secondary study endpoint. AFM13 is a tetravalent, bispecific human antibody targeting CD30 and CD16a.
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Norwegian BerGenBio ASA’s (Oslo) AXL receptor tyrosine kinase blocker bemcentinib (BGB324) performed well in a
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Regulatory Affairs
European Biotechnology | Spring Edition | Vol. 17 | 2018
News Iron-fisted Vifor Pharma AG initiated a Phase I study in February to assess safety of its oral ferroportin blocker VIT-2763 designed for treating diseases with impaired iron metabolism. Ferroportin is an iron transporter that plays a key role in regulating iron uptake and distribution in the body.
Vaccines made in DK Nanobiotix’ nano-radiotherapy enhancer NBTXR3
Notch on wood Cellestia Biotech AG (Basel) in January kicked off first-in-man tests of CB-103, which targets the NOTCH oncogenic signalling pathway. Cellestia intends to develop CB-103 as treatment for NOTCHdriven solid tumors, lymphomas, and leukemias.
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Phase II study enroling 35 patients with refractory acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Monotherapy with the small molecule drug triggered two complete responses and five partial responses, plus eight cases in which the disease stabilised for more than four months. BerGenBio acquired rights to the small molecule inhibitor from Rigel Pharmaceuticals Inc. in 2011. Mesothelioma
Oslo-based Targovax ASA (OSE: TRVX) reported preliminary safety and immune activation data of its Phase I/II trial of ONCOS-102 plus chemotherapy (pemetrexed/cisplatin) in patients with unresectable malignant pleural mesothelioma. After a positive outcome in a six-patient safety lead-in cohort receiving the drug combo, a DSMB greenlighted the recruitment of an additional 24 patients to be randomised. In addition, systemic release of pro-inflammatory cytokines was observed in three out of three patients analyzed, demonstrating that the treatment triggers an innate immune response. Also, there was an increase in the relative level of tumour infiltrating cytotoxic CD8+ T-cells (2/2 patients with pre- and post-treatment biopsies analyzed), indicating an activation of the adaptive immune system in the le-
sions. The data show that ONCOS-102 + chemotherapy triggers changes in the tumour microenvironment, making them potentially susceptible to immune system surveillance. Liver cancer
Nanobiotix SA (Paris) has presented preliminary Phase I/II data of its liver cancer radiotherapy enhancer NBTXR3. In seven evaluable out of ten patients enroled with either hepatocellular carcinoma (HCC) or liver metastases, the nanoparticle formulation showed a good preliminary safety profile and objective response rate after administration of two of four dose levels. Out of the seven patients, who got a direct NBTXR3 injection into the tumour followed by Stereotactic Body Radiation Therapy (SBRT), three achieved a complete response and an additional three a partial response. The company is going on to evaluate patients at the outstanding 22% and 33% NBTXR3 dose levels. The two first levels (10 and 15%) have been completed. Hair loss
Swedish Follicum AB (Lund) got the regulatory go-ahead to commence a Phase IIa clinical trial with its lead candidate FOL005 in patients with alopecia (hair loss). The trial will enrol up to 60 patients to evaluate safety and efficacy of injections
Picture: Nanobiotix SA
Bavarian Nordic A/S (Kvistgaard) Imvanex smallpox vaccine met the endpoint of non-inferiority to ACAM2000 vaccine (Emergent BioSolutions Inc) in a Phase III study. Neutralising antibody titers induced by Imvanex vaccination doubled those induced by ACAM2000 as measured by a vaccinia-specific plaque reduction neutralisation test antibody response. In mid-January, the maker of MVA-based vaccines initiated a Phase I trial with its MVA-BN® Brachyury prime-boost vaccine that targets the brachyury transcription factor, which is involved in metastases of several cancer subtypes. The vaccine will be co-administered with co-stimulatory factors B7-1, ICAM-1 and LFA-3, and a fowlpox booster to 10 patients with incurable cancers to check safety and tolerability.
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European Biotechnology | Spring Edition | Vol. 17 | 2018
of different FOL-005 doses, a derivative of the endogenous 300 amino acid protein osteopontin, into the scalp. The study is expected to be completed in 2018. Multiple Sclerosis
LFB S.A. (Les Ulis) spin-out TG Therapeutics Inc. gave an Phase IIa study update of ublituximab (TG-1101), a glycoengineered, defucosylated type 1 mAb targeting the unique site of the CD20 antigen of B cells to treat the relapsing form of multiple sclerosis. Readouts from patients were promising: though ublituximab is infused 2.5-3.5 times faster than its competitor drug, Ocrelizumab from Roche, no grade 3/4 infusion-related reactions occurred. Furthermore 97.5% of patients were relapse-free after 24 weeks and no lesions (o) could be visualised with gadolinum compared to baseline (2.68). Futhermore, B-cells were almost completely absent (99%) in the brain between week four and 24 and their disability score improved. Due to its distinct target site on CD20 and its enhanced ADCC effect, ubilituximab may have some distinct potential compared to other CD20-targeting mAbs such as rituximab, ofatumumab, and obinutuzumab. Orphan Diseases
Roche’s spinal muscular atrophy candidate RG7916 has been well-tolerated in a Phase II dose finding pilot enroling 16 infants (ages one to seven months). The Roche reported interim data from a pivotal Phase II trial of RG7916 at the International Scientific Congress on Spinal Muscular Atrophy in Krakow. In 13 evaluable infants, the oral drug candidate, licenced in 2011 from PCT Therapeutics to treat infants with type 1 spinal muscular atrophy (SMA), was well-tolerated and did not show evidence for renal toxicity, previously observed in monkeys. Two of the sixteen patients enroled with defective homozygotous SMN2 genes died; one was not evaluable. The second part of the study, starting by April, will enrol 40 patients to receive the selected therapeutic dose for 24 months. Primary endpoint is the ability to sit for five seconds after 12 months of treatment.
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InflaRx NV (Jena) has started a Phase IIb study to evaluate the optimal dose of its first-in-class C5a blocker IFX-1 in 175 patients with the rare inflammatory skin disease hidradenitis suppurativa. Endpoints of the trial include patient-reported efficacy and safety of IFX-1. Hidradenitis suppurativa is a disease in which the terminal complement system is highly activated. According to preclinical data, IFX-1 blocks the activation of complement factor C5a while leaving C5b-9-mediated defense intact. Saniona AB (Ballerup) is considering a lower dose of its fixed dose combination of tesofensine and metoprolol (Tesomet) to treat patients with PraderWilli-Syndrome, the most common heritable form of obesity. While Phase II study results either in obese type 2 diabetics or Prader Willi patients revealed that the monoamine reuptake inhibitor tesofensine acts on the brain’s satiety centre, reducing insatiable appetite and craving for food (hyperphagia), Saniona observed a drop-out rate of nearly 50% (four of nine patients) in Prader-Willi patients. An interim analysis of the threemonth study revealed that tesofensine plasma levels increased two- to fourfold compared to obese patients receiving the same dose. As tesofensine induces an increase in heart rate, which is compensated by co-administration of adrenergic receptor beta 1 blocker metoprolol, some of the observed side-effects may be explained by the unexpectedly high tesofensine levels. However, Tesomet reduced mean body weight in the Prader Willi group by 5% at week eight vs 0.5% for placebo. NSCLC
Merck KGaA (Darmstadt) and Pfizer’s PD-L1 checkpoint inhibitor avelumab failed to reach the overall survival endpoint in a Phase III study in Ptchemotherapy pretreated patients with Non-Small Cell Lung Cancer (NSCLC) vs docetaxel. The companies are now looking for subgroups which might benefit from avelumab treatment. L
01.03.2018 13:01:17 Uhr
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economy
European Biotechnology | Spring Edition | Vol. 17 | 2018
Balancing generic and innovative medical uses Repurposing Is cheaper always better when it comes to generics? What about when
it comes to innovative medical uses of them?
Innovative pharmaceutical companies provide new drugs and invest hundreds of millions of Euros to bring them to the market. They have to account for the numerous drug candidates that show promise in animal or early stage clinical trials but ultimately do not reach the stage of regulatory approval. Return on investment (ROI) is secured by market exclusivity limited to a certain time period typically provided by patents and data exclusivity. Thus, originators have time to gain ROI for the short period of time before generics enter the market. This “eco-system” works quite well for new compounds. Currently, the system does not work as well for the development of known and/ or marketed substances to treat a new medical indication. The development of a new medical use for a known substance already marketed for another use typically requires substantial investments of approximately US$500m into development, though clinical trials average five years less than a new compound would require because the existing medicines already have a proven safety track record. However, pharma companies cannot justify the expense and risk of this if generic companies are able to sell the “old” drug also for the new use (leaving no chance of ROI for the originator). It would be detrimental were pharmaceutical companies to cease investigating potential new uses for known medicines. Frequently, medically active compounds are useful in several diseases. The first medical use discovered is not necessarily the one most beneficial to patients but rather the second or third medical use found and developed. Thus, there is
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Dr. UTE KILGER (German Patent Attorney and European Patent and Trademark Attorney, Partner at Boehmert & Boehmert) specialises in all kinds of patent-related issues concerning the obtaining and enforcement of property rights, due diligence, mergers and acquisitions, contract negotiations, and licensing agreements.
a need for a regulatory and legal system that incentivises the development of new uses and yet allows for generic manufacturers to sell the medicines for the use for which legal exclusivity has expired.
The Pregabalin cases Substitution rules and tenders of the health insurer require the pharmacist to dispense the cheapest (generic) medicament without knowing the indications for which it has been prescribed. This inevitably leads to a patent-infringing distribution of generics and destroys the market and the incentives for originators. When
the Pregabalin case was decided by the Danish Courts, Denmark changed its laws to enable a split market where both a generic drug for the old use and the originator drug for the new use could coexist. Other courts in Europe have ruled that the tender of the health insurer is limited to the patent-free indication – but pharmacists in those countries still dispense the generic drug for all uses. This February, Georgetown Law School (D.C.) and Sir Robin Jacob from UCL, London, invited key opinion leaders to a conference in Washington D.C. to discuss ways to balance innovation and thrift, including the potential benefits of creating a split market. But one thing is very clear: this will require more than simply aligning the generic and innovative companies; it also requires the alignment of law makers, politicians, and health insurers. It is not an easy or popular task to explain why the same medicament should be sold at a lower price for the generic indication and a higher price for the new indication. It is easier to state: Hauptsache günstig (the cheaper, the better). The Pregabalin case was recently heard before the UK Supreme Court. Observers reported that, unfortunately, the discussion focused strongly on the potential chilling effect it could have on generics used for patent-free indications. Much less attention was paid to the potential chilling effect on innovators. If originators cease to find and develop new uses for known drugs, it would have a chilling effect on us all. Hopefully, reason will prevail and legislators will find ways to incentivise the development of new uses, while offering cheaper generics for older uses. L
Picture: Boehmert&Boehmert
› Dr. Ute Kilger, Partner at Boehmert & Boehmert
01.03.2018 13:02:07 Uhr
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Economy
European Biotechnology | Spring Edition | Vol. 17 | 2018
Partnering and conferences at Chemspec Europe Sourcing Renowned as a key marketplace for sourcing and trading fine and speciality
chemicals for a wide range of applications and industry sectors, Chemspec Europe 2018 opens its doors from 20–21 June 2018 at Koelnmesse in Cologne, Germany. Next to a large number of international exhibitors, the event offers its visitors a wide choice of workshops and conferences and, for the first time, a targeted partnering programme. › Susanne Neuner, PR & Marketing Director, Mack Brooks Exhibitions Ltd
School of Pharmacy, Temple University, Philadelphia, PA, USA. The presentation will cover the themes: “Discovery of Small Molecule Therapeutics;” “Companion Diagnostics and Targeted Therapies for Cancer;” and “Precision Medicine’s Impact on Pharma and Health Care: Challenges and Future Opportunities.”
Start-ups and careers
Overall trends in the fine and speciality chemicals sector continue to be characterised by intensified competition, a continuous search for innovation, and the demand for sustainable solutions. Biotechnology is key to environmentally friendly and innovative products and thus, biotech-based chemicals play an ever more important role for the global fine and speciality chemicals market. For industry professionals, it is vital to intensify existing contacts with business partners, expand one’s network of suppliers, and form strategic partnerships. With its combination of a substantial international exhibition, a comprehensive conference programme, and targeted networking events, Chemspec Europe offers visitors a unique opportunity to source products, find business partners, and keep up-to-date with the latest findings in R&D. In the following, I will briefly summarise some of the pharma con-
36_EB_Spring_2018_Chemspec_tg.indd 36
ference themes and some of the special features at this year’s event.
Pharma conferences The Pharma Panel on “Outsourcing Best Practices will be of interest to a wide audience from pharma, crop protection, and chemical companies – CROs and CMOs who are engaged in contract research and custom synthesis of Active Pharmaceutical Ingredients (API). The sessions will discuss approaches to developing global outsourcing strategies, identifying outsourcing partners, identifying approaches to mitigate risks, and addressing challenges associated with outsourcing and how to effectively manage partnerships. The Abou-Gharbia lecture theatre will host a talk on “Drug Discovery, Then and Now: The Road to Personalized Medicine” by Dr. Magid Abou-Gharbia, Moulder Center for Drug Discovery Research,
In a cooperation with BCNP Consultants, Chemspec Europe 2018 offers a platform to bring young start-ups, their innovations, and the topic of chemistry founding on stage to discuss prevailing trends, such as renewable raw materials, new production methods, industrial biotechnology, utilization of secondary side streams, and residues or urban mining. The Careers Clinic is organised by Chemical Search International, which specialises in executive search and career development for the global chemicals sector and value-chain, covering polymers, materials, natural resources, and biosciences.
New partnering programme To round-off the visitor experience at Chemspec Europe, we offer all attendees a new Partnering Programme. An online system for personal meetings enables visitors to set up targeted meetings in our new on-site private meeting spaces. L www.chemspeceurope.com
Picture: Mack Brooks Exhibitions
Conference sessions are free to attend for visitors to Chemspec Europe.
01.03.2018 13:02:25 Uhr
European Biotechnology Spring 2018
Bioprocessing cGMP
SPECIAL 37_EB_Spring_2018_Special-Title.indd 43
01.03.2018 13:02:45 Uhr
Passion for Performance
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The Biopharma Manufacturer •��Full-service�provider�from�gene�to�vial�and�from�concept�to�market� •��World-class�biopharmaceutical�CDMO�with�proven�excellence •��Outstanding�expertise�in�mammalian�cell�culture •��Extensive�track�record�with�more�than�40�years�in�biopharma
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Best-in-class�formulations� provide�signifi�cant�competitive� advantages
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Rentschler Biopharma SE Erwin-Rentschler-Str.�21�·�88471�Laupheim�·�Germany info@rentschler-biopharma.com�·�www.rentschler-biopharma.com
Special
European Biotechnology | Spring Edition | Vol. 17 | 2018
39
GMP and new processes: be prepared for hassle GMP Biomanufacturing  Poor aseptic practices can rapidly ruin market supply of products outsourced
Picture: BSP PHARMACEUTICALS S.P.A, Italy
for production. This year, Celltrion came under fire from FDA inspectors. At the end of January, the producer received a warning letter affecting the production of Inflectra biosimilar infliximab-dyyb (CTP13) co-marketed with Pfizer. In mid-February, the FDA added a warning concerning rituximab and trastuzumab biosimilars produced for Teva, as well as for its fast-track migraine mAb fremanezumab. The warning letter resulted from inspections of the South Korean biosimilar specialist's current 140,000-litre production plant in Incheon conducted last summer. According to the FDA, it followed about 140 complaints concerning contaminations in vials due to insufficient sterile filling procedures affecting products marketed in the US. The contamination problem could affect US and EU market approval for Celltrion's trastuzumab biosimilar CT-P6, which had its BLA accepted by the FDA and received recommendation by the CHMP, bothlast year, and FDA approval of the EUauthorised rituximab Truxima. According to Teva, the warning letter could also ruin the planned marketing debut of its anti-CGRP mAb fremanezumab that prevents migraine attacks. In January, the FDA issued a warning letter to Celltrion and its global co-marketing partner Pfizer Inc. concerning infliximabdyyb, a biosimilar of the autoimmune blockbuster Remicade (infliximab) from Johnson & Johnson, the first biosimilar mAb approved by the agency in 2016. For Celltrion, which is playing down any concerns related to its expanding biomanufacturing plant in Incheon, the warning letters could have a huge impact on its business. Celltrion, which will ramp up its capacity to 310,000 litres by 2019, wanted to outperform European CDMO rivals Boehringer Ingelheim (300,000 litres) and Lonza (280,000 litres). Samsung Biologics Co., another
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Korean producer of biologic drugs, has a plan to increase its annual production capacity to 360,000 litres by 2018 (see figure, p. 40). The GMP issues at Celltrion come at a time in which healthcare systems have begun to lobby for adoption of the 1530% cheaper versions of biologics that have lost patent protection. Australia, following the European practice, no longer labels the INN of biosimilars with a unique numerical identifier to differentiate them from the originals. Though the FDA includes the unique INN identifier for biosimilars, the US government wants to boost biosimilar uptake. At the beginning of February, FDA Commissioner Scott Gottlieb announced the agency will facilitate claims of interchangeability in a forthcoming Biosim-
ilars Innovation Plan, which could promote biosimilar uptake.
Find the right expert While most GMP problems are currently limited to Indian, Chinese, and other CDMOs from Asia, some have also hit Western companies, such as Pfizer subsidiary Meridian Medical Technologies Inc., whose QC did not meet cGMP requirements, causing the FDA to to reject AstraZeneca's market approval application for ZS-9, an ion trap to treat hyperkalemia. The cases document what really counts for biopharmaceutical companies: quality and price, but quality first. In Europe, smaller specialised biomanufacturers have found a niche in the inno-
BSP Pharmaceuticals SpA’s validated manufacturing sterilisation department, Sterile 4, was especially designed for anticancer drugs, with the flexibility to manage small molecules and ADC products.
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European Biotechnology | Spring Edition | Vol. 17 | 2018
Projected annual capacity
First plant
Second plant
Third plant
Samsung Biologics
36
3
15
18 1
Celltrion
31
5
9
12 3
2
1) initial operation in 2018 2) +5 by 2019 3) initial operation in 2021
vative biotech SME space, providing special expertise suited to the needs of their customers. CDMOs, such as Celonic, no longer want to remain just the lot-makers for clinical trials but have begun to expand into the high-quality commercial production of personalised meds, orphan drugs, etc. Most recently, Celonic took over the manufacturing business from protein glycosylation specialist Glycotope and is also expanding its production capabilities in Basel (see p. 42). Another tactic to differentiate within the consolidating, but growing, outsourcing market – which had sales of US$5.48bn, according to Visiongain analysts – is to provide novel technologies in selected drug discovery areas for customers. In February, Teva partnered to get access to ProBioGen's Human Artificial Lymph Node Technology, a 3D-micro-organoid model for predicting the effects of Teva’s biopharmaceutical drug candidates on the human immune system in vitro. ProBioGen’s CSO, Dr. Volker Sandig, said, “We have demonstrated effects that were impossible to see in conventional models, bridging the existing gap between animal models and first-in-man applications.“ The technology is based on a patented, miniaturised, and perfused bioreactor for long-term cultivation of immune cells. Human blood-derived dendritic cells,
39-40_EB_Spring_2018_Special_intro_tg.indd 40
lymphocytes, and mesenchymal stem cell-derived stromal cells are inoculated into the bioreactor's 3D hydrogel matrix, which is perfused with cell culture medium and aerated, just as in a real human lymph node. Another technological improvement was announced by ADC Biotechnology Ltd in February. The company has patents (WO2012/140433) and patent applications (WO2014/174316, WO2016/005744, WO2016/067013, and WO 2016/067016) on a novel downstream bioconjugation method expected to save 25% of total costs in ADC (antibody drug conjugate) manufacturing. In contrast to the existing approaches – which undertake bioconjugation after both the mAb/targeting moiety and cytotoxic payload have been manufactured – the new approach moves the conjugation step into the later stages of the downstream processing (DSP), with conjugation and antibody purification carried out concurrently by binding them to a resin. The drug conjugate field got a boost in February when ADC heavyweight Seattle Genetics licensed Pieris' antibodylike anticalins for US$1.2bn. In February, Spanish PharmaMar started its own business that identifies structural diversity from sea organisms and resynthesizes novel toxic payloads for ADCs and anticalinDCs. L t.gabrielczyk@biocom.eu
Picture: Celltrion
Annual capacity of Celltrion’s 140,000-litre biomanufacturing plant in Incheon will be expanded to 310,000 litres by 2019.
01.03.2018 13:03:23 Uhr
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MICROBIAL PRODUCTION?
CONTRACT DEVELOPMENT AND MANUFACTURING OF BIOPHARMACEUTICALS Richter-Helm is a Germany-based GMP manufacturer specialized in products derived from bacteria and yeasts, with a proven 30-year track record. ;gmfl gf mk lg Ʈ ]paZdq hjgna\] Y [gehj]`]f% sive range of services and customized solutions. ;da]flk ogjd\oa\] `Yn] Ydj]Y\q Z]f]ƭ l]\ from our commitment to good manufacturing practice and total transparency. Our work focuses on recombinant proteins, plasmid DNA, antibody fragments, and vaccines. Richter-Helm consistently works to the highest standards of pharmaceutical quality.
Contact us +49 40 55290-436 www.richter-helm.eu
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Special
European Biotechnology | Spring Edition | Vol. 17 | 2018
Expanding into the commercial supply space Celonic Celonic AG has pursued an ambitious expansion strategy in mammalian cell line contract
manufacturing to establish Phase III and commercial supply by mid-2019. A new GMP facility in Heidelberg was acquired, and capacity is also being expanded at the headquarters in Basel. European Biotechnology spoke with Franzpeter Bracht, COO of Celonic, about Celonic’s strategy.
EuroBiotech_ Where does Celonic stand today, and where do you want to p l ace y o ur co mp any in the l o n g term? Bracht_The acquisition of Glycotope’s m a n u f a c t u r in g b u s i n e s s w e a n nounced last winter is the star ting point for a major expansion of our business focus. We have looked for awhile for a strategic acquisition to expand Celonic’s business focus from clinical trial supply to Phase III and commercial GMP manuf ac tur ing, which would allow long-term partnerships from early to commercial phases. In Basel, however, we were very confined, and a capacity expansion was a clear strategic focus for us. So, we thought about how to establish an integrated development site in Basel, where we can do everything from cell line development to tox batches and identify another site, where we can produce GMP-compliantly and accelerate GMP capacity growth. Glycotope’s Heidelberg site was the optimal fit.
Dr. Franzpeter Bracht, (Ph.D.), is Chief Operating Officer at Celonic AG. He has also been COO and Managing Director at Glycotope GmbH, which sold its contract manufacturing business to Celonic in 2017. The pharmacologist co-founded Aplagen GmbH in April 2001 and served as its Chief Executive Officer. Previously he was Principal and Head of Pharma & Life Sciences at Kienbaum Management Consultants and Consultant at EY.
will star t GMP production in three suites there, two with 2-3x2,000 litre fermenters each, and one suite with a 1,000 litre per fusion reactor. This
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EuroBiotech_To what extent will customers be able to benefit from Glycotope’s GEX platform in addition to Celonic’s proprietary CHOvolution cell line? Bracht_Celonic will also benefit from Glycotope’s 20-year successful track record producing highly glycosylated proteins in fed-batch and perfusion processes, and its proprietary human GEX cell line. We acquired a non-exclusive licence. So, we are now able not only to produce monoclonal antibodies at up to 7g/l with Celonic’s proprietary CHOvolution CHO K1 cell line, but also bispecific antibodies, hormones, or other complex biologics products with human glycosylation pattern in GEX cells. So, the acquisition has fairly broadened Celonic’s customer base: we can produce in fed-batch and perfusion, in CHO and in human cell lines, and with the capacity expansion we will serve companies from early development to commercial supply, as well as biosimilar producers looking to be first to the market. That gives Celonic more long-term perspective and allows optimisation of business processes.
Picture: Celonic
EuroBiotech_ Could you describe why? Bracht_With the takeover we added five suites to our biomanufacturing capacit y, with fermenters ranging from 50 to 1,000 litres, both in singleuse and stainless steel. We have already finalised the design for the next growth step in Heidelberg, a 2,500 sqm production hall. By mid-2019, we
expansion of scale marks the change from a CDMO for clinical supply to a manufacturer of Phase III and commercial supply, according to FDA and EMA standards. At the Heidelberg site, Celonic will have enough space for further GMP capacity expansion.
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European Biotechnology | Spring Edition | Vol. 17 | 2018
The better way to DNA“
© 2018 Fotolia.com
„
Production in perfusion reactors at Celonic
Picture: Celonic
EuroBiotech_Celonic has been part of JRS since 2011. What role does the financial backing of the Rettenmaier family play for your company and its strategy? Bracht_Without financial backing from the Rettenmaier family we would not be able to execute an expansion such as currently in Basel and Heidelberg, where we want to start GMP production in mid-2019. It also provides an opportunity to shape business models built around risk sharing for the biotech companies and thus facilitates a real winwin situation. EuroBiotech_Novel molecule formats such as bispecifics currently flood biopharma pipelines for personalised medicines. How does Celonics manage this technological challenge? Bracht_ We already have two bispecifics in production. We have experience with achieving improved yields by switching production from CHO to GEX cells in perfusion reactors. So we are flexible enough and have experience with new formats, such as bispecifics and ADCs, while living up to total quality management.
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EuroBiotech_The CDMO market is characterised by strong demand but also huge competition. Where do you want to go? Bracht_Currently, the market is large enough for all CDMOs. Particularly, the demand for contract manufacturing in the 1,000 to 2,000l range is growing steeply. All projections say that most future products will lie in that production range we are building in the moment. We are focussed on establishing long-term partnerships with biotech SMEs that want to produce orphan drugs, personalised meds, biosimilars etc. Currently, we are producing an invivo-antibody diagnostic commercially. We will add a second commercial product in 2019. EuroBiotech_W hat are your nex t goals? Bracht_This year, we hope to complete the integration of Glycotope and expansion in Heidelberg and the transformation of our Basel site. In the longer term, we will expand our filling capabilities and look for FDA-accepted methods for continous downstream processing. L t.gabrielczyk@biocom.eu
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01.03.2018 13:04:41 Uhr
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Special
European Biotechnology | Spring Edition | Vol. 17 | 2018
Learning from the small molecule supply chain BioLive Rutger Oudejans, Brand Director at bioLIVE, postulates that the bio supply chain could
learn some lessons from the small molecules sector. The bio industry continues to expand at rates above the traditional NCE (New Chemical Entity) sector, yet for the supply chain there are vital synergies that could help further accelerate developments. › Rutger Oudejans, Brand Director at UBM
Growing supply options With the bio industry now forecast by most respected observers to be growing at a mid-teens pace, put simply, more players entering the market means more
44_EB_Spring_2018_Special_bioLIVE_.indd 44
Rutger Oudejans
supply options. But also potentially more complexity as new networks begin to appear to meet demand. It’s how we manage this complexity that will be key to maintaining the bio industry’s impressive ascent. As well as new and increased capabilities within Europe, we are also seeing an even faster predicted growth in the emerging bio economies in China, South Korea, and India. China is especially significant, as with the successful trial of the MAH (Marketing Authorisation Holder) pilot, license holders can now use a CDMO in the country – which potentially means we will see a more rapid increase in the number of bio CDMOs there. Whilst in India, companies have already been successfully producing cost-effective biosimilars, and several South-Korean companies are striving to have production-ready commercial capacity for biopharma (with some of the world’s largest production plants being completed).
So, over the next few years we will see a much larger industry, but also a much more complex one, and how partners meet in the supply chain will be key. The other consideration is that one of the main goals for the bio industry is to simultaneously lower the total cost of production and increase global capacity – which is increasingly becoming a two-tier market of large mammalian capabilities for commercial products, and single-use facilities for newer targets in the pipeline.
Quality and time has an impact One of the key successes in the solid dose sector has been the ability for a global supply chain to come together at events to establish new partnerships and lower costs. It’s also where you are able to find the associated types analytical testing, assays, and partner services so needed to help meet changing commercial requirements. With our new bioprocessing and manufacturing event – bioLIVE – launching alongside CPhI Worldwide this year we will be creating a fully integrated sourcing hub for the industry to facilitate new partnerships. It often said you are ‘only as good as your weakest link,’ but I believe the supply chain will be a strength that sustains its next phase of growth – providing manufacturers and product developers much greater flexibility. L
Pictures:UBM
It’s a key time for bio manufacturing in Europe, as larger supply chains are being built to meet new and rising demand. Thus far, as an industry, we have been pretty successful in adopting to growth in biologicals and biosimilars. But with greater numbers of BLA approvals now coming through (22 in 2017), and many others coming off patent – MAb production is forecasted to grow quickly – there remains a significant challenge for the supply chain to meet. In fact, it is my belief that this year will usher in a new age of increased integration and collaboration across the large and small molecule supply chain. There are many areas in which we can collaborate, from the obvious crossovers like ADCs (antibody drug conjugates) to the softer elements so critical to industry growth, such as supplier directories, talent, and services acquisition. For example, it’s already widely acknowledged that there is an impending bio staffing issue, with the industry struggling to bring enough experienced staff into companies. This staffing strain, at least in the short term, will probably increase and integration could help facilitate shared learning.
01.03.2018 13:04:58 Uhr
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European Biotechnology | Spring Edition | Vol. 17 | 2018
The cGMP Nuclease that cleaves all forms of DNA and RNA
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Packaging  Servier CDMO, the contract manufacturing arm of the French pharma major, is increasing productivity of its preparative chromatography platform at its Bolbec site in Normandy. The expansion will enable chemical purification of 50kg/day, and separation of 10kg/ day of chiral high-value APIs with 90% lower environmental impact and 50% higher speed. Meanwhile, the company announced it will invest US$58m in France to expand into the growing market of biologics. L
jor expansion of its Ravensburg secondary packaging facility, with 32,000 square feet of new state-of-the art packaging lines and assembly equipment for pens and autoinjectors. The company said the expansion is a result of increased customer demand and the company's continuous growth in new filling lines and new lyophilisers. It will also increase Vetter's serialisation capacities. A state-of-the-art syringe blister line will include safety device assembly and equipment for packaging in Japan. The company is also building a new administration building at its Ravensburg headquarters. L
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Business   German biologics CDMO Rentschler Biotechnologie GmbH transitioned into Rentschler Biopharma SE. Rentschler said there will be no operational changes for customers due to the transition. L
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US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) increased from 63 in 2016 to 85 last year, according to a PwC report. It states that of 98 guidance documents planned to be issued this year by the CDER, thirteen will impact pharmaceutical quality and CMC, and two others cGMP rules. L
Targeting expanding markets Gene ther apy   Merck KGa A‘s US CMO arm SigmaMillipore has underscored its capabilities as a commercial manufacturer of viral and gene therapy products, a market expected to grow at a CGAR of 40% over the next ten years. The company announced its Carlsbadbased manufacturing facility for the production of BioReliance viral and gene therapy products has completed both a US Food and Drug Administration (FDA) Pre-License inspection and a European Medicines Agency (EMA) Marketing Authorisation Application inspection. Merck Life Sciences CEO Udit Batra underscored that Merck was “one of the first CMOs in the industry to complete prelicensure inspections for this class of
therapies,“ which will enable one of Merck’s key customers to launch its novel gene therapy in both the US and in Europe. L
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28.02.2018 13:05:39 15:59:50 Uhr 01.03.2018
SWISS BIOTECH DAY 2018
Picture: © Rynacher/ https://commons.wikimedia.org/wiki/File:Basilisk_Wettsteinbrücke.JPG (CC BY-SA 3.0); GNU Free Documentation License
Picture: © Basel Tourismus
The leading Life Sciences Conference in Switzerland and Annual General Assembly of the Swiss Biotech Association
Join the Swiss Biotech Day, the leading biotechnology conference in Switzerland. The event is not just the place to be for members of the Swiss Biotech Association, who traditionally meet there for the association’s Annual General Assembly. As always, the event brings together entrepreneurs, investors, researchers, analysts, political decision makers and industry stakeholders. Don’t miss the keynote by the assigned CEO of Novartis, Vasant Narasimhan, and meet around 600 experts from across Europe.
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All information on programme, exhibitors, sponsoring and registration can be found at www.swissbiotechday.ch.
3 MAY 2018 ...Basel ONE Congress BIOTECHCenter CLUSTER
Sponsors:
“WHITE BIOTECHNOLOGY” WORKING GROUP
Supporting Partners:
European Biotechnology NET WORK
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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 theSingle-Use publicFiltration window. and Mixing The participating Life Science Regions are important internal carriers of the dynamics in the Biotech sector, thus enhancing the common understanding of the industry. This and more knowledge is brought into Europa Bio, the European Biotech Association, where the SBA is an active member.
Leading chemical companies are exploring the opportunities that have been opened up by modern biotechnology, especially in the field of “white” or industrial biotechnology. And they are also applying these technologies, wherever it makes sense. The SBA takes such initiatives seriously and has formed a working 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 Media 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 workforce with the right education. The SBA profits from the marketing alliance “Swiss Biotech” (see box) in a multiplied form. Thanks to Swiss Biotech, the
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Domenico Alexakis is Executive Director of the Swiss Biotech Association.
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-foundedby: by the SBA which also manages Organised the executive office of Swiss Biotech.
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For further information please visit www.swissbiotechassociation.ch www.swissbiotech.org
02.03.2018 11:35:52 Uhr
European Biotechnology | Spring Edition | Vol. 17 | 2018
Clinical master Selvita SA Oncology drug discovery company Selvita SA named Steffen Heeger, MD, PhD, Chief Medical Officer in February. The oncologist will be responsible for the clinical d e ve l o p m e n t o f Selvita’s PIM/FLT3 kinase blocker SEL24 in AML, and the CDK8 kinase blocker SEL120, Steffen Heeger both in blood and solid cancers, as well as all targeted therapeutics, cancer metabolism and immunometabolism, and immune-oncology drug discovery programmes. Prior to Selvita, Heeger was VP Head of Clinical Development and Operations at Morphosys AG. L
Pictures: EuropaBio, Karolinska Development, uniQure, Sabin, GenSight, GammaDelta
Business maker Synpromics Ltd The British synthetic promotor design specialist has hired Sarah Haecker Meeks, PhD, as their new VP for Business Development. Meeks has worked in senior management positions in the biotech sector for more than 20 years. In her previous role as CSO at Adjuvant Partners, she led business development and corporate strategy for clients from Big Pharma, biotech, technoloSarah Haecker Meeks gy providers, and medical centers focused on cell and gene therapy. She helped found Cardiogen Sciences, Inc. and establish the Alliance for Regenerative Medicine’s Gene Therapy Section and Genome Editing Task Force. Prior to Adjuvant Partners, the US molecular biologist and biochemist held the position of VP Business Development for Ora-
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si Medical, Circle Biologics, and BioE. Meeks will work from the newly established US subsidiary, Synpromics Inc. L
Fresh approach Rentschler Biopharma SE Rentschler hired Federico Pollano as their new Senior Vice President for Business Development. Previously, he was Global Director Contract Manufacturing and Business Developmentat at Polypharma. Pollano has an industry track record of more than 25 years, including senior management positions a t R i ch t e r- H e l m BioTec and Helm Federico Pollano Pharmaceuticals. The biologist succeeds Dr. Christoph Winterhalter, who has left the company to pursue new challenges. L
Taking charge Laboratoris sanifit SL Clinical-stage calcification disorders specialist hired Cris Calsada as Chief Financial Officer in January. She joins Sanifit with over 20 years of corporate finance and executive experience in the life sciences and technology industries. She was most recently COO and VP of Finance at Ambrx, where she led the company’s finance organisation during its Series A financing, completed in 2005, through its acquisition in 2015. Previously, the MBA and certified public accountant worked with Sony Online Entertainment. Sanifit is in Phase IIb in ESRD patients and has an orphan drug under d e ve lo p m e n t in calciphylaxis. L Cris Calsada
biopeople
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Money dealer Targovax ASA Michael Bogenstaetter has taken the role of Chief Business Officer (CBO) at the Norwegian clinical cancer immunotherapy specialist. The chemist and MBA’s 25-year track record in Big Pharma and biotech include senior business development and strategy positions with Sanofi, Novartis, and MSD. Bogenstaetter, who started his industry career at The Boston Consulting Group, most recently acted as freelance advisor to top 50 biophar- Michael ma companies. L Bogenstaetter
Old stager Bonesupport AB Emil Billbäck will replace Richard Davies as CEO of the med-tech company. The manager, with over 20 years’ experience in the life science industry, took up his office in March. He joined Bonesupport from Essity AB where he was Senior Advisor following its acquisition of BSN Medical from EQT in 2017. Prior to this, he was a member of the Group Executive Board/Management Commit- Emil Billbäck tee at BSN Medical, where he held the position of Executive Vice President EMEA and Head of Global Commercial Operations. Billbäck spent over 13 years in senior management roles at BSN Medical, including Interim President of North America and Group Director Commercial Operations and R&D. BSN Medical develops, manufactures, markets, and sells products within wound care, compression therapy, and orthopedics. L
01.03.2018 13:07:29 Uhr
Rubrik
European Biotechnology | Winter Edition | Vol. 16 | 2017
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Immunology
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How fast food hijacks young genes trained immunity Americans and Europeans love fast food, even though doctors are now more
certain than ever that the highly processed meals that go hand-in-hand with a hectic Western lifestyle are not a smart health choice. The latest findings suggest that fa(s)t food imprint key genes in the innate immune system, possibly causing the permanent immunological hypersensivity that is at the root of diabetes, atherosclerosis and other common diseases of civilisation.
Pictures: iordani/fotolia.com (left),Universiy of Bonn (right),
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icke Latz is concerned. Especially when the renowned expert for innate immunology from the University of Bonn in Germany speaks of the first worldwide statistics on obesity in children and adolescents. “It’s crucial to educate children on healthy diets,” he stresses. “They can’t be subject to manipulation through food industry advertising. They should be enabled to make informed choices when it comes to nutrition.” According to the very first global meta analysis of Body Mass Index (BMI) development from 1975-2016 across the globe, which was published in the December issue of Lancet (doi: 10.1016/ S0140-6763(17)32129-3), obesity is definitely on the rise. Funded by AstraZeneca, the NCD risk factor collaboration reports that 124 million youngsters between 5-19 years of age have a BMI over 30. Many of those young people live in Europe, high-wage English-speaking countries, or emerging countries (for boys see map p. 54). 60% of the obese youngsters will remain obese in adulthood as well, doubling their risk of developing chronic diseases. In the mid-term, that will have already cash-strapped healthcare budgets on the ropes. In Europe, treating the young obese already makes up 6% of all healthcare costs. The future cost of diabetes alone is ruinous, even for wealthy countries like export world champion Germany. According to Michael Laxy, the head of a study
50-55_EB_Spring_2018_Immunity vs Fastfood_tg.indd 51
group at IGM Munich that analysed diabetes costs from 2012-2015, co-morbidities such as retinopathy drive annual per patient costs of around €2,800. The growth of diabetic incidence and treatment costs like those associated with blindness (€12,000), diabetic ulcers (€5,200), foot amputation (€52,000), renal insufficiency (€92,000) and cardiovascular complications (€10,800-80,000) are expected to contribute dramatically to future healthcare expenses.
For over 10 years, researchers have known that fast food consumption correlates with obesity and impaired metabolism (Lancet, 2005; 365: 36–42). According to a 15-year study conducted by US and Norwegian researchers, people who visited fast food restaurants more than twice a week weighed roughly 4-5 kg more than those who visited them less than once a week. Insulin resistance was also twice as likely in the former.
“Fast food has a lifelong impact on health.”
Eicke Latz Director of the Institute of Innate Immunology at the University of Bonn, Germany
? !
What must be done to prevent a disease-prone Generation XXL? e can achieve a lot through W prevention. We should establish health education in schools to immunise the next generation against food industry temptation.
What concerns Latz most about the fast food-obesity correlation is his own recent findings. Previous research has linked the consumption of Western-style diets to chronic subsymptomatic inflammation, which is believed to trigger diseases such as type 2 diabetes, obesity, atherosclerosis, cardiovascular disease, Alzheimer’s disease and cancer. That’s why “it’s of fundamental importance to understand the mechanisms that link consumption of calorie-rich diets to increased inflammation,” Latz explains. In mid-January, his group reported in Cell (doi: 10.1016/j.cell.2017.12.013) that even transient fast food consumption could lead to permanent epigenetic reprogramming of the innate immune system. The team led by Anette Christ dis-
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Immunology
European Biotechnology | Spring Edition | Vol. 17 | 2018
How the NRLP3 inflammasome senses danger Inflammasomes are oligomer components of the innate immune system expressed in myeloid cells. All are multi protein intracellular complexes for detecting pathogenic microorganisms and sterile stressors which activate proinflammatory cytokines interleukin-1b (IL-1b) and IL-18. Inflammasomes also induce a form of cell death called pyroptosis. Dysregulation of inflammasomes is associated with a number of autoinflammatory syndromes and autoimmune diseases. The exact composition of an inflammasome depends on the activator that initiates its assembly. dsRNA will trigger one inflammasome composition, while asbestos will assemble a different variant.
LRR
NBD
The NLRP3 inflammasome activates caspase-1 using its PYD domain to recruit the ASC protein (see below). Per cell, it forms one oligomer that is about 2 µm in diameter. NLRP3 oligomerisation is activated by a large number of stimuli. Application of an anti-ASC antibody to an Alzheimer’s model blocked the increase in amyloid-b pathology. In type 2 diabetes (T2D), NRLP3 relays signals from glycolysis and mitochondrial metabolism to activate caspase 1. IL-1 inhibits pancreatic b-cell function and causes cell death, while inhibition of IL-1 improves b-cell function in T2D patients. Postprandial hyperglycaemia activates the fat macrophage inflammasome via glucose transporter 1-mediated glucose uptake, glucose oxidation and
Inflammasome
PYD PYD
reactive oxygen species formation to generate mature IL-1, which then potentiates glucose-stimulated insulin secretion. The frequency of chronic morbidity associated with an unhealthy lifestyle, systemic low-grade inflammation and inflammasome activation increases with age – a process called ‘inflammageing’. Ageing is also associated with reduced lipolysis and substrate mobilisation, which explains why elderly individuals develop ectopic visceral fat deposition, impaired exercise capacity and cold intolerance. The underlying mechanisms of impaired lipolysis in ageing, however, cannot be explained by impaired signalling of catecholamines, the major driver of lipolysis.
CARD CARD
ASC large subunit
ProCaspase-1
ligand
PYD
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large subunit ProCaspase-1
Model of inflammasome function: Stress signals trigger a conformal change in NRLP3 that activates its oligomerisation domain (NACHT). Oligomerisation leads to a wheel-shaped signalling hub with LRR domains outside of the wheel and PYD domains forming a disk at the centre. The PYD domains recruit the inflammasome adaptor ASC. ASC binds to the PYD ring. Recruited ASC molecules polymerise and form long helical filaments. The caspase recruitment domain (CARD) of ASC then recruits an inactive caspase-1 precursor , and cleaves it to generate the fully active protease. Caspase-1 then cleaves the precursor molecules proIL18 and pro-IL1b to generate the mature secreted proinflammatory cytokines. Caspase also cleaves pro-gasdermin D, generating N-terminal fragments, which assemble to form gasdermin D pores in the plasma membrane. The pores allow cytokine secretion, and water entering the cell leads to cytolysis. Released alarmins and inflammasome cytokines attract phagocytes to the site, which advance the inflammatory response.
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Picture: Original from https://commons.wikimedia.org/w/index.php?curid=43256589
ligand
01.03.2018 13:09:05 Uhr
The innate immune system never forgets So far, innate immune cell priming – or ‘immunologic memory’ – had been only observed after infections. Called ‘trained immunity’, this is mediated by stress sensors in the innate immune system dubbed inflammasomes (see p. 52). If a pathogen invades the body for a second time, trained immunity leads to a faster and stronger innate immune system reaction compared to the initial invasion. Now, Christ et al have proved for the first time that the sensor molecules in the innate immune system also recognise fast food as ‘pathogenic’ or ‘dangerous’. This in turn alters gene expression patterns in innate immune-cell progenitors in the bone marrow, making the innate immune systeme more prone to activation when a subsequent alarm is sounded. Immune system hyperreactivity is a hallmark for some of the most devasting diseases of civilisation. For the very first time, a detailed analysis of gene expression and chromatin analysis of innate immune cell progenitors carried out by Latz and his research group revealed that some burgers might imprint your immune system in a fashion that boosts your risk of getting seriously ill in adulthood. According to the immunologist, “the resulting immunologic hyper sensivity is a hell of a problem, because it promotes the development of major non-communicable chronic diseases with sub-inflammatory phenotypes.” In mice, the researchers observed activation of the danger sensor (the NRPLP3 inflammasome) by the transient Western diet, as well as a type I interferon response that resembled ones triggered by bacterial infections. Additionally, the animals’ monocyte/granulocyte progenitors overexpressed the proinflammatory cytokine interleukin 6 (IL-6). In cell culture experiments, the pre-primed progenitor cells showed immunological hyperreactivity after experimental exposure to antigens such as bacterial lipopolysaccharide (LPS). Blocking activity of the NLRP3 inflammasome in progenitor cells led to complete protection from the effects of a Western diet on the innate immune system. Earlier publications had suggested that genetic alterations in the adaptor protein ASC and IL-1-RAP, an endogenous inhibitor of interleukin-1 signalling, are essential to trigger trained innate immunity. The researchers therefore speculate that IL-1b might mediate the induction of trained immunity. In fact, previous work has shown that IL-1b inhibitors prevent death in mice chal-
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covered that a four week sugar- and fat-rich diet caused acute inflammation in model mice for atherosclerosis, and that animals subsequently showed elevated levels of innate immune cells like granulocytes and monocytes. The transient fast-food diet also had a long-term effect on health that persisted even after the mice were switched back to a normal chow diet. A first analysis indicated a lasting epigenetically triggered preactivation of the innate immune system. The animals eventually died due to calcified heart vasculature after just 8 weeks.
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European Biotechnology | Spring Edition | Vol. 17 | 2018
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 50-55_EB_Spring_2018_Immunity vs Fastfood_tg.indd 53
01.03.2018 13:09:11 Uhr
Immunology
European Biotechnology | Spring Edition | Vol. 17 | 2018
Source;: NCD risk factor collaboration
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Obesity in boys aged 5-19 around the world as of 2016: The country with the world’s largest market for fast food – the US – leads with a 23.3% obesity rate, followed closely by Argentina (20.8%), China (15.7%) and several Arab/North African countries. In Europe, Generation XXL hits a low in Switzerland (7%) and a high in Greece (16.7%). Recent statistics also indicate that food served in almost all restaurants is increasingly processed, and thus not much better than fast food like burgers, fries and wings.
lenged by experimental infection, and block proliferation of immune progenitor cells. Quantitative trait locus analysis in human monocytes trained with oxidised low-density lipoprotein and stimulated with LPS also suggested inflammasomemediated trained immunity. Small molecules that block inflammasome signalling
might thus help prevent the inflammatory phenotypes triggered by a Western diet that in the end can accelerate the onset of vascular disease. However, finding specific inhibitors is not as easy as it might seem at first glance. NLRP3 inflammasome function is triggered by a wide variety of signals indicat-
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Global incidence (in millions) of obesity in children and adolescents from 1975-2016
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Number of obese boys in millions)
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ing infection, injury, cell stress or exposure to irritants. A long-standing mystery in the field is how NLRP3 coordinates an in vivo response that is appropriate to the nature of its activating signal. The discovery – that neutrophils drive IL-1b production in response to a subset of NLRP3 agonists – provides a potential mechanism
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Immunology
European Biotechnology | Spring Edition | Vol. 17 | 2018
by which in vivo NLRP3 inflammasome responses can be shaped depending on the type of danger encountered.
So can I still eat burgers … ? In February, a group headed by Arthuro Zychlinski from the Max Planck Institute for Infection Biology in Berlin reported that the staphylococcal invasion factor pyocyanin inhibits the NLRP3 inflammasome by producing reactive species that block IL-1b and IL-18 release. It also inhibits pyroptosis by preventing caspase-1 maturation (JBC, doi: 10.1074/jbc.RA117.001105). Danish researchers headed by Thomas MandrupPoulsen reported in 2017 that caffeine counteracts NLRP3 activation (Nature Rev. Endocrinology, doi:10.1038/nrendo.2017.175). And David Brough and Sally Freeman at the University of Manchester have reported the development of a set of boron-containing compounds
F3
U2
TU
that block the JNL1 kinase activity needed to kick-off NLRP3 oligomerisation. Small-molecule inhibitor MCC950 dampens NLRP3 inflammasome signaling in mouse models of MS and other immune diseases. The compound, which blocks IL-1b release, is under development by researchers led by Luke O’Neill at Trinity College Dublin and Matthew Cooper at Australia’s University of Queensland.
… or must I change lifestyles? Latz himself is the co-founder of IFM Therapeutics, which develops anti inflammatory NLR antagonists and cancer drugs targeting the DNA sensor AIM. But when it comes to fast-food-triggered diseases, he’s 100% certain pills won’t cure unhealthy lifestyles. Instead, his focus remains on prevention. Recent analyses suggest that 42% of cancers and 30% of diabetes cases could be pre-
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vented by adopting healthier lifestyles in combination with existing prevention programmes. “Our findings have important societal relevance,” says Latz. “The foundations of a healthy diet need to become a much more prominent aspect of education than they are at present.”
Forget policy support Studies from diabetes research organisation DGG suggest that taxes on highly sugared drinks and fattening foods might help. They argue that the food industry puts over a hundred times more money into advertising junk food than governments do into nutrition education. The EU Commission recently rejected adopting a ‘traffic light’ food labeling system. Currently, only six European countries have a sugary drink tax, and even fewer a fat tax. So the clear health risks of fast food have yet to make a major legislative difference. L t.gabrielczyk@biocom.eu
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Live Lab Hall A3
April 10–13, 2018 I analytica exhibition April 10–12, 2018 I analytica conference 26th International Trade Fair for Laboratory Technology, Analysis, Biotechnology and analytica conference www.analytica.de
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Novo deal for KU Leuven spin-out
Cash refill Immuno-oncology Immunicum AB successfully raised money via a rights issue in December 2017. The company’s proceeds amounted to approximately SEK200m (€20.3m) before transaction costs (SEK168m after cost deduction). “The completion of the rights issue will enable us to conclude the Phase II MERECA (MEtastatic REnal Cell CArcinoma) and the Phase I/II GIST clinical trials for ilixadencel, and to achieve a first decision point in the planned multi-indication study with ilixadencel in combination with checkpoint inhibitors, all important value inflection milestones for the company,” stated Carlos de Sousa, CEO of Immunicum.
Diabetes Belgian Remynd N.V. has out-licenced worldwide commercialisation rights for its small molecule programme ReS39 in diabetes to Da nish biotech Novo Nordisk A/S. The drug impedes death of insulin-producing beta cells by preventing the formation of cytotoxic islet amyloid polypeptide (IAPP) aggregates. The Belgian Catholic University of Leuven spin-out has specialised in small molecules preventing protein misfolding disorders or amyloidoses. Under the terms of the contract, Novo will make an undisclosed upfront payment and will pay milestones and R&D funding totalling €350m. The listed company will gain the rights for ReS39 as a diabetes therapy. Remynd, however, remains the holder of the
rights for ReS39 as a treatment for non-alcoholic steatohepatitis and Parkinson’s di sease. ReS39 doubles the endogenous insulin production capacity of the pancreas by restoring b-cell function in both type 1 and 2 diabetes animal models. Back in 2010, the Belgian start-up entered into a strategic alliance with Swiss Roche, holding out US$637m in payments, to develop first-in-class diseasemodifying treatments, which could slow down neurodegeneration in Parkinson’s and Alzheimer’s patients by inhibiting asynuclein and tau toxicity. The company holds patents on several small molecule compounds that prevent protein aggregation, the underlying cause of a range of neurological and metabolic diseases. L
Aiming for solid tumours
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The University of Leuven’s Central Library on the city’s Ladeuze square
Copper transport decongestion Drug Development Wilson Therapeutics AB is on track with its lead pro duct WTX101. Last December, the US Food and Drug Administration had gran ted WTX101 (bis-choline tetrathiomolybdate) a Fast Track designation for the treatment of Wilson Disease. A couple of weeks later, the first-in-class copper-protein-binding agent was given to the first
patient of the pivotal Phase III Focus trial. The multi-center study involves approximately 100 Wilson Disease patients that receive once-daily WTX101 or standard of care. The primary endpoint will be copper control assessed as the percen tage change in free copper levels in blood from baseline to 48 weeks. Top-line data is expected to be released in late 2019. L
Picture: KU Leuven
Immunicum secured sufficient working capital for the coming twelve months. Hence, the company fulfilled another requirement for the listing of Immunicum’s shares on Nasdaq Stockholm’s main market. Indeed, the small-cap company succeeded in transitioning from Nasdaq First North Premier to the main market of Nasdaq Stockholm in early 2018. Ilixadencel is the lead programme among several allogeneic, off-the-shelf cell-based therapies developed by the company from Gothenburg. It consists of pro-inflammatory allogeneic dendritic cells, and is destined to become a “backbone component of modern cancer combination treatments in a variety of solid tumour indications,” the company states. L
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News Dog service partners
Structure of the ofatumumab Fab-fragment
Novartis ends Arzerra misery cLL Swiss pharma major No vartis AG (Basel) has announced it will end marketing Genmab’s anti-CD20 anti body Arzerra® (ofatumumab) as treatment for chronic lymphocytopenic leukaemia (CLL) outside the US. Officially, the Swiss drug major said there are a huge number of competing CLL treatments, so offer ing Arzerra outside the lead US market doesn’t make sense. However, Novartis will seek advice from regulatory agen cies on how to continue Arzerra supply to patients who benefit from the drug through compassionate use programmes. Antibody developer Genmab A/S will be compensated US$50m for lost poten tial milestones and royalties. But the un official reason may be that Arzerra has failed to set the CLL market alight since
its launch in 2009, where it has strug gled to make headway against Roche’s Mabthera/Rituxan (rituximab), which re ported sales of approximately US$850m in Q1/2017 outside – and US$1.045bn inside – the US, compared to H1/2016 sales of only US$24.8m for Arzerra. What’s worse: While subcutanously ad ministered Mabthera gained EU approval in 2016, Arzerra was rejected. But the misery is not over yet: The an tibody, which is also being developed to treat non-Hodgkin’s lymphoma and re lapsing multiple sclerosis (MS), is com peting in the latter indication against Ro che’s humanised CD20 antibody Ocrevus (ocrelizumab), a first-in-class medicine to treat both the relapsing-remitting and the primary progressive form of MS. L
Picture: nicoletaionescu /fotolia.de
Serving the Nordic region Venture Capital Hadean Ven tures announced the closing of Hadean Capital I, a new fund with a target size of €100m. Particular attention will be given to regions of Europe with worldclass scientific communities and a vi brant start-up community, yet are un der-ser ved from a venture capit al perspective, especially the Nordic re
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gion. “We see an exceptionally strong deal flow of high potential opportuni ties here,” states Ingrid Teigland Akay, Managing Partner of Hadean Ventures. The fund – based in Oslo and Stock holm – is supported by a consortium of blue-chip fund investors, including Ar gentum, Saminvest, Gjensidigestiftelsen, OPF, and Varner. L
After the acquisition of Fin nish Genoscoper Laboratories by US multinational Mars Inc., fellow Finn ish company and Bio-IT expert Medi sapiens Ltd. continues to work with the Mars Petcare unit. The renewed partnership around the My Dog DNA service was announced in February. My Dog DNA is one of the world’s leading dog genetic testing services, which provides pet owners, breeders, and veterinarians with information on genetic traits and diseases.
Liquid biopsy push Danish-US-American molecular diagnostics company Ge nomic Expression Inc. said it re ceived a €3.7m grant in early 2018 to validate its OneRNA™ liquid bio psy platform in bladder cancer. Ac cording to Genomic Expression, the Horizon 2020 grant for the One RNA4Bladder project is one of the largest allocations of support from the European Union ever given to a small biotech company. The key project technol ogy is a patented Urine Cancer Cell Filtration Device that enables the selection of tumour cells from a simple urine sample.
Anti-wart peptide Privately held Cytovation AS an nounced in early 2018 it had raised some additional NOK10m in a pri vate funding round. The biot ech company, developing a topical for mulation of its peptide therapeutic CyPep-H1 for the treatment of cuta neous warts caused by human pa pilloma viruses, already had raised NOK20m back in June 2017.
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French Double Whopper
DMD alliance HTA Patient charitable group Duchenne UK teamed up with seven drug developers and two universities (Leicheister & Sheffield) in February to accelerate post-approval patient access to novel therapies for Duchenne muscular dystropy (DMD). In a project dubbed Hercules, Pfizer, PTC Therapeutics, Roche, Sarepta Therapeutics, Solid Biosciences, Summit Therapeutics, and Wave Life Sciences are going to share disease-level data to help HTA agencies to evaluate DMD drugs much speedier, but at an even higher quality level. The goal of Hercules is to develop a common toolset to provide improved modelling, a broader evidence base, reduction of duplicative or inconsistent work, improved engagement with patients, and better use of patient input. This shared model will include:
›› data analysis, including mapping clinical
M&A Seven years after the acquisition of Genzyme, French drug major Sanofi has added another orphan drug player to its portfolio. The company agreed with the management of US blood disorder expert Bioverativ to pay US$11.6bn in cash, a 64% premium on the company’s share price. In January, Sanofi further complemented its late-stage pipeline by a 3.9bn takeover of Belgian nanobody specialist Ablynx, which earlier in January rejected a €2.3bn takeover bid by Novo. The deals will boost Sanofi’s pipeline in the growing hemophilia and orphan blood disorders market. Ablynx’s most advanced product, caplacizumab, for the treatment of the rare blood disorder acquired thrombotic thrombocytopenic purpura (aTTP), has already filed for market approval in the US and the EU. Additionally, Biogen’s 2015 hemophilia spin-out Bioverativ has two hemophilia treatments on the market: Eloctate (efmoroctocog alfa) – a first-in-class recombinant clotting factor VIII therapy with prolonged half-life licenced from SOBI to treat hemophilia A. The fusion protein of factor VIII to the Fc part of IgG1 benefits from a natural recycling mechanism: IgG1 binds to the neonatal Fc receptor, and is cycled back from lysosomes into the circulation. Alprolix (eftrenonacog alfa), Bioverativ’s treatment for hemophilia B, benefits from the same mecha-
nism, but is a fusion of recombinant clotting factor IX therapy and IgG1. Additionally, Bioverariv has two clinical (Phase I + II/III) and three preclinical programmes in its pipeline, one of which partnered with genome editing pioneer Sangamo Biosciences. The longacting drugs are expected to better prevent bleeding episodes than shorter acting recombinant factors. With approximately US$11bn in annual sales, hemophilia represents the largest market for rare diseases and is expected to grow more than 7% per year through 2022. In 2016, Bioverativ generated $847m in sales and $41m in royalties. Sanofi most recently acquired the global development and commercialization rights to fitusiran, an investigational RNA interference (RNAi) drug to treat hemophilia A and B, from Alnylam Pharmaceuticals. Following a clinical hold for the drug, Sanofi wants Bioverativ to develop the Phase III drug candidate further and bring it to the market. The Ablynx platform includes 45 programmes, nine of which are partnered, and adds significant value to Sanofi’s drug portfolio. Sanofi’s CEO Olivier Brandicourt said that the acquisition helps Sanofi’s transformation plans in R&D, expands the company’s pipeline of candidates in late-stage development, and supports Sanofi’s expansion into rare blood disorders. L
trial endpoints to clinical outcomes;
true burden of illness; ›› a n economic model for individual companies to adapt to their products; ›› training, expert input, and mock appraisal committees. Duchenne UK said the project will allow drug developers to work together to build the evidence base for new therapies required by pricing watchdogs, such as the National Institute of Health and Care Excellence (NICE). The charity will initially contribute £200,000 (€225,446). L
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The precise mechanism that prolongs the half-life of ELOCTATE has not been fully defined: however, preclinical animal studies suggest the following: Unbound protein
ELOCTATE Fc region
FcRn
The Fc region is thought to enable ELOCTATE to bind to the neonatal Fc receptor, or FcRn
FcRn is thought to divert ELOCTATE away from the lsysosome to temporarily delay degradation
Lysosome
It is believed that ELOCTATE can then be cycled back toward the membrane surface and reintroduced into circulation
FcRn cycling pathway Lysosomal degradation pathway
Putative mode of action of Bioverativ's fusion protein Eloctate.
Protein degradation
Picture: Bioverative
›› an HTA-relevant Quality of Life metric; ›› cross-sectional studies looking at the
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News Eat healthy
Sweet partnership Type 2 diabetes Following last year’s €216m licence deal with Japanese Sumitomo Dainippon Pharma (Osaka) for its first-in-class oral type II diabetes treatment imeglimin (PXL008), Lyon-based Poxel S.A. got another pact signed and sealed in mid-February. Roivant Sciences paid €28m upfront for the commercialisation rights in all markets not yet covered, and held out milestones totaling €486m, plus double-digit royalties on net sales in case of approval. In a pilot to Phase III testing in Europe and the US, slated to kick of next year, the companies will pre-evaluate the oral blocker for mitochondrial permeability transition pore (mPTP) opening in patients with chronic kidney disease. Poxel will contribute
€20m to the Phase III programme and has an option for co-promotion. In preclinical and clinical tests, imeglimin inhibited hepatic gluconeogenesis, increased muscle glucose uptake, and restored insulin sensitivity, the hallmarks of type II diabetes, which affects 425 million adults globally. According to Poxel, it might also prevent endothelial and diastolic dysfunction and support beta cell survival and function. Opening of the mitochondrial permeability transition pore (mPTP) is a response to physiological stressors that are associated with insulin resistance. The resulting uncoupling of oxidative phosphorylation leads to ATP depletion and ends up in cell death, a process seemingly inhibited by imeglimin. L
Picture: Africa Studio/fotolia.com
New venture fund Money In January, Truffle Capital (Paris) closed a new BioMedTech venture fund at €85m. The institutional venture fund, which has a €200m target in 2018, is aimed at investments into North American and European medical devices and biotechnology start-ups. According to the VC company, European and Asian institutional and corporate investors, as well as family offic-
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es, invested in this initial closing. The goal is to invest in up to 12 companies, Philippe Pouletty, MD, co-founder and CEO of Truffle Capital, said in a press release. So far, the company has 15 life sciences and med-tech companies in its portfolio. Three French companies already got financing from the new fund: HoliStick Medical, ArteDrone, and Nanosive. L
Seventure Partners has invested US$9m into the nutrition app provider Zipongo, which became the the 17th portfolio company of Seventure’s €160m Health for Life Capital™ fund. US-based Zipongo said it will use the money to market its app in Europe and extend it with prescribable individualised nutritional advice, branded as FoodScripts™. According to the company, food choices are a much cheaper way to treat conditions like hypertension, diabetes, or obesity than drugs. FoodScripts™ will be tested in pilot trials this spring. Zipongo already works with 150 US corporations to reduce chronic disease and improve the health of employees.
Platform conjugation Antibody Drug Conjugate (ADC) specialist Glythera has licensed Actava Group’s Affimer technology in order to develop antibody-like drug conjugates using the combined technologies. Affimers are small, stable synthetic proteins expressed in E.coli that mimic the molecular recognition characteristics of monoclonal antibodies. The companies did not disclose financial details on the deal.
Going clinical French cancer specialist Nanobiotix S.A. (Paris, Boston) raised €27.2m through a placement of 1,941,789 new shares at €0.03 in October. The company will use the proceeds to launch Phase I combination trials of NBTXR3 plus checkpoint inhibitors and prepare EU market launch of the radio-enhancer.
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Servier closes autoantibody deal
Metabolomics Austrian Bio crates Life Sciences AG succeeded in taking over their Berlin-based competitor Metanomics Health GmbH. Everyone involved in the early January deal agreed: The age of clinical metabolome analyses is dawning, and no one is as wellprepared as Biocrates. The merger seems compelling, because heavyweights like Roche and Thermo Fisher are also preparing to enter the lucrative market. BASF Plant Science GmbH, the former owner of Metanomics Health, will keep a minority share of MIG Fonds-backed Biocrates. The Innsbruck-based company claims it is the only one worldwide to provide metabolomics kits, which are capable of multiplex analyses for up to 400 metabolites across ana lyte classes in a single run. Founded in 2002, Biocrates is an expert in targeted metabolomics and offers solutions for the quantitative measurement of certain predefined endogenous metabolites. Although estimates are that so far only about 10% of the sector’s turnover is made up of clincial applications, such as newborn screenings, metabolomics is widely seen as a growth market. After the incorporation of Metanomics Health, Biocrates can offer the sector’s most diverse portfolio of metabolomics services, including untargeted metabolite profiling and the development of companion diagnostics. L
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The Servier Research Centre at the Paris Saclay campus is scheduled to be completed in 2021.
advance the candidate drug through preclinical development and into the clinic, where Servier will assume all responsibilities for its development as a therapeutic to treat diseases driven by elevated levels of IFNα, with emphasis on systemic lupus erythemathosus and Sjögren’s syndrome. The idea of autoantibodies as therapeutic agents came up several years ago when it was discovered that patients with a certain ultra-rare disease leading to increased levels of a set of autoantibodies were less prone to develop certain conditions like diabetes. The disorder is termed APECED/APS-1 and the Finnish patient organisation APECED Ry is among the founding shareholders of Immunoqure. “This is the next stage of our scientific strategy, for which Servier is an ideal partner, having demonstrated their expertise in developing high-potential therapeutics for the treatment of inflammatory diseases,” said Adrian Hayday of London’s King’s College, one of the scientific co-founders of Immunoqure. “Our partnership has the potential to help large numbers of patients in several disease indications, and – very importantly – can directly aid APECED patients by facilitating our greater understanding of their condition.” Other Immunoqure co-founders work at the Universities of Helsinki (Finland) and Tartu (Estonia). The start-up receives its money from Qureinvest II, an entrepreneurial investment fund managed by German HS Lifesciences GmbH. L
Artificial photosynthesis plant Bioeconomy In a joint research project, Evonik AG and Siemens AG plan to convert carbon dioxide into specialty chemicals. The two-year Rheticus project was launched in early 2018. The first test plant is scheduled to go on stream by 2021 at the Evonik facility in Marl, Germany, which produces chemicals such as butanol and hexanol, both feedstocks for special plastics and food supplements,
for example. The technology not only en ables chemicals to be produced sustainably, the partners argue, it also can serve as an energy store that responds to po wer fluctuations and helps to stabilise the grid. Siemens is providing the electrolysis technology to convert carbon dioxide and water into hydrogen and carbon monoxide using electricity. Evonik is contributing the fermentation process. L
Picture: Wilmotte et Associés/Servier
Forming a one-stop shop
Out-Licensing German drug developer Immunoqure AG found its first pharma partner. French Servier said it wants to bring Immunoqure’s lead asset into the clinics. According to the agreement, Servier shall provide Immunoqure with an upfront payment and milestones amounting up to €164m, as well as royalties on net sales. The interesting thing about Immunoqure’s candidates: They are autoantibodies – molecules that are widely known as troublemakers in many autoimmune diseases. The worldwide, exclusive partnership focuses on the development of a therapeutic autoantibody neutralising the cytokine interferon-α (IFNα). Immunoqure and Servier will work collaboratively to
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IPO for Arsanis Big data buy
Unicorn jump
Infectious Diseases After setting up Arsanis Biosciences GmbH 2011 in Vienna, Austrian-born US entrepreneur Tillman Gerngroß led Arsanis Inc., now headquartered in the US, to a successful initial public offering on US stock exchange Nasdaq in late 2017. The 39-employee company raised US$46.0m, falling short of its US$57.5m goal. Arsanis’s lead drug ASN100 is a monoclonal antibody immunotherapy designed to prevent Staphylococcus aureus-induced pneumonia among high-risk patients in intensive care units who are hooked up to ventilators. The drug is currently in a mid-stage study, with data expected in late 2018. After three months, Arsanis shares trade at around US$14 – well above the IPO price of $10.00 per share. L
Financing In January, Biontech AG succeeded in closing the biggest venture capital financing round in German biotech history. The company is estimated to be a biotech unicorn worth at least €2bn. The US$270m Series A round of financing is a follow-up to the fully-integrated biotech’s seed round fundraising in 2008. The round was led by the Redmile Group and joined by Janus Henderson Investors, Invus, Fidelity and several European family offices – including existing investor Struengmann Family Office.
acquisition In a strategic acquisition, Roche has completed its capabilities to use big data to build new business cases in digital diagnostics solutions and personalised healthcare. The pharma major agreed to pay US$1.9bn to take over the US specialist for electronic medical records Flatiron Health Inc. Previously, Roche contributed US$175m to Flatiron’s Series C financing (12.6% of the company’s equity). Now, Roche will acquire the remaining 87.4%. The Swiss pharma will follow the same company autonomy model used at Genentech and Foundation Medicine. Hence, Roche is allowing Flatiron to continue as a separate legal entity that will continue to provide services to the rest of the healthcare industry. L
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Cullinan finds German diamond Drug Development Virtual onco logy company Cullinan Oncology LLC has selected German monoclonal antibody provider MAB Discovery GmbH (MABD) to develop the US company’s first publicly known clinical programme. “We are excited to enter into this collaboration as the MABD development engine provides us with access to highly differentiated monoclonal antibodies,” said Patrick Baeuerle, Cullinan’s Chief Scientific Officer. The partners said they will use MABD’s rabbit platform to generate a “potent, human immune checkpoint agonist”. Last October, 10-employee Cullinan raised
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US$150m from investors with the goal to build a highly diversified portfolio of eight to ten oncology drug development programmes. Under the terms of the agreement, MABD does not receive upfront money, but an undisclosed interest in Cullinan Wittelsbach, a subsidiary of Culli nan formed to fund and guide the deve lopment of the asset. MABD is also eligible to receive milestone-based payments. Set up as a hybrid between a fund and an operating company, Cullinan is backed by the UBS Oncology Impact Fund managed by MPM Capital, a worldwide leader in oncology investing, and F2 Ventures. L
Biontech will use the capital to further advance its clinical pipeline of individualised immunotherapies covering approaches, including mRNA and CAR-T / T-Cell receptors (TCR), for the treatment of cancer and other diseases. Shortly after the raise, Biontech striked a deal with British Scancell. The alliance is about discovering TCRs and includes an option to form a license agreement covering the resulting therapeutics. L
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Help for the heart
Product L aunch Spanish Noventure and Laboratorios Salvat, S.A. entered into an agreement in which Salvat will distribute Noventure’s nasal mucoprotection product in Spain and Portugal. The product is based on the hemicellulose xyloglucan and formulated to control and treat the symptoms of rhinitis and rhinosinusitis from different aetiologies, especially those of an allergic origin. According to the World Allergy Organisation (WAO), allergic rhinitis affects up to 30% of the global population. The partners plan to launch the product in April of this year. L
proved cardiac function without lowering the blood pressure in a rat model with salt-induced high blood pressure that mimicks HFpEF. The disorder occurs in 50% of heart failure patients. In a mouse model of age-related HFpEF, Givinostat (TF2357) alleviated diastolic dysfunction, a decline in performance
Next generation chaperons Spin- Off In February, Spanish biopharmaceutical company Minoryx Therapeutics established a spin-off in Switzerland. Gain Therapeutics will focus on marketing Minoryx’ Site-directed Enzyme Enhancement Therapy (SEE-Tx). “This deal validates the SEE-Tx platform and its great potential for identifying a new generation of pharmacological chaperones with improved properties,” said Dr Marc Martinell, CEO of Minoryx Therapeutics. “It will also allow Minoryx to focus on its clinical candidate, MIN102, which is now in Phase II/III clinical trials for the treatment of X-linked adrenoleukodystrophy and in preclinical de-
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velopment for other orphan CNS diseases.” SEE-Tx uses the three-dimensional structure of proteins originating from a patented computational technology initially discovered by the Barril Lab (University of Barcelona) Gain Therapeutics was funded by private Swiss investors and by the TiVenture fund and has its headquarters in Lugano (Switzerland), with a branch operating site in Barcelona (Spain). Several researchers from the Minoryx laboratory at the Barcelona Science Park will join the new spin-off, including Xavier Barril, cofounder of Minoryx and inventor of the technology. L
of one or both ventricles. Until now, the cause of HFpEF was not known. Although there are speculations that cardiac hypertrophy causes HFpEF, the researcher from Colorado didn’t observe any effect of givinostat treatment on the sizes of the rats’ hearts. Instead, they noted that givinostat treatment improved the ability of heart muscle cells to relax. The cardiologists found that givinostat prevented muscle fibers from becoming modified by HDACs, which preserved relaxation capabilities. Interestingly, samples of heart muscle fibers from two patients with HFpEH had similar problems relaxing as observed in the rodents. According to the authors, HDAC-dependent muscle fiber modifications represent a previously unappreciated cause for HFpEF, paving the way to potential treatments. Givinostat is in Phase II clinical trials for Becker’s Muscular Dystrophy and in in Phase III studies for Duchenne Muscular Dystrophy. The drug, originally patented in 1997, has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis and polycythaemia vera. L
€300m deal Aquisition Shanghai’s SARI will pay around €300m to acquire a 90% interest in Group NMS, a Milan oncology biopharma company. SARI is a biopharma investment firm affiliated with the Chinese Academy of Science research organisation with the same name. SARI intends to bring NMS oncology drug candidates to China and integrate the features of the NMS development technology into its own. “We welcome the opportunity to become part of the Sari network if companies and research centers and we look forward to the continued evolution of our pipeline of molecules,” states Andrea Agazzi, NMS Chairman. L
Picture: Yodiyim/fotolia.com
Hope for the allergic
Study Givinostat, a small molecule histone deacetylase (HDAC) inhibitor developed by Milan-based company Italfarmaco SpA, is also an option to treat heart failure with preserved ejection fraction (HFpEF). In February, researchers from the University of Colorado and Italfarmaco reported in Science Translational Medicine (doi:10.1126/scitranslmed. aao0144 ) that Givinostat (TF2357) im-
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Slight recovery for PharmaMar
Picture: Pixabay
Licence Agr e e m ent 2017 didn’t end well for the Spanish specialist for sea-derived synthetic oncology drugs PharmaMar, and hasn’t started well this year. But a licence deal with US antibody drug conjugate (ADC) company Seattle Genetics Inc gives a small glimmer of hope. In January, PharmaMar announced the failure of its cancer drug lurbinectedin (Zepsyre). In a Phase III trial, the drug didn’t demonstrate better efficacy than chemotherapy in treating ovarian cancer (CORAIL). Zepsyre was compared to topotecan or PLD (liposomal doxorubicin) in platinum-resistant ovarian cancer patients. The announcement made PharmaMar stock fall by 39% on Madrid’s exchange market. It was a big blow for PharmaMar, especially after another of its late-stage candidates, plitidepsin (Aplidin), was rejected as a treatment for multiple myeloma by the EMA last December. In the Spanish newspaper Bolsamanía, Luis Mora Capitán, managing director of PharmaMar’s oncology unit, maintains that what has happened with Zepsyre and Aplidin, although it is bad news, does not leave PharmaMar “on the ropes.“ Maybe Mora is right. At its January 2018 meeting, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) announced it would re-examine Aplidin. Furthermore, PharmaMar could announce more pleasant news in February. It inked a licence agreement with US an-
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tibody drug conjugate (ADC) company Seattle Genetics Inc. that secures PharmaMar upfront payment of US$5m and an undefined milestone payment when the product enters clinical development. In addition, PharmaMar is eligible for potential milestone payments for approval and achievement of revenue targets and royalties once a product receives regulatory approval and is marketed. Seattle Genetics received the exclusive worldwide rights to some proprietary sea-derived toxic payloads of PharmaMar for the development, manufacture, and commercialisation of targeted drug conjugates. PharmaMar’s recently launched business division for payloads has already developed an tubulin inhibitor for Her2-targeting antibody-drug conjugates (ADCs), which impairs tubulin polymerisation, causing disorganisation of the microtubule network leading to mitotic failures and halting cell division in cells. However, according to the company, there are further novel, structurally diverse molecules with novel mechanisms of action and nanomolar cytotoxicity under development for next-generation ADCs. The announcement of the deal led to a slight recovery of PharmaMar’s stock on Madrid’s exchange market, which had plunged by around 39% in January after the failure of Zepsyre. Currently, the pipeline of PharmaMar includes the EUmarketed product Yondelis, and three clinical drugs including lurbinectedin, plitidepsin, PM184, and PM14. L
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News Entering China In January, Fosun Pharma acquired Chinese marketing rights for a novel treatment for Parkinson’s disease from Portugal’s BIAL in an $18 million agreement. BIAL developed Ongentys (opicapone) as a once-daily adjunctive therapy to levodopa/DOPA decarboxylase inhibitors. It was approved in the EU in 2016. Wanbang Biopharma, a Fosun Pharma subsidiary, will commercialise the drug in China, paying $3m upfront and up to $15m in milestone payments.
Pancreatic Cancer The Spanish center Santiage de Compostela has become the latest pancreatic disease center participating in Immunovias’ PanFAM-1 study. The multicenter study was designed to verify Immunovias IMMrayTM PanCan-d, a blood-based test for early detection of pancreatic cancer.
Spanish Bioinformatics The Spanish computational drug discovery company Mynd the Byte aquired 100% of Intelligent Pharma, a provider of chemoinformatics services for the pharmaceutical and biotechnology industry. “The integration will allow us to round off our portfolio of tools for designing drugs with the know-how built up by Intelligent Pharma over more than 10 years,” states Alfons Nonell-Canals, CEO of Mynd the Byte. Terms of the agreement have not yet been made public. Mynd the Byte is headquartered in Barcelona Science Park.
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Oncoarendi aims for an IPO
Blue Biotechnology Esto nian company Furcella OÜ from Tallinn has developed Baltic algae-based cos metics for day and night use. Dubbed Berrichi, the facial creams of the cosmet ics line include a key antioxidant ingre dient obtained from the Baltic red algae Furcellaria lumbricalis: the polysaccharide furcellaran. The product is the first one to emerge from the Interreg Baltic Blue Bio technology Alliance Consortium’s ALLI
Furcellaria lumbricalis
ANCE mentoring programme. Led by the German GEOMAR Helmholtz Centre for Ocean Research Kiel and funded by the Interreg Baltic Sea Region, the consorti um brings together about 30 research in stitutes and biotechnology hubs as well as business parks. The fourth call for ide as has been initiated and projects apply ing for the mentoring programme will be presented to an international expert pan el in Copenhagen in April 2018.
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Headquarters of the Warsaw Stock Exchange GPW
In demand
Equity in Evestra
Public offering Shares of Polish drug discovery company Selvita SA claimed an all-time high of PLN64.30 af ter a secondary share offering in February. Priced at PLN61.00, Selvita could place all 2,200,000 shares offered. The amount of gross proceeds raised in the offering is ap proximately PLN134.2m (€32.2m). “The demand for Selvita shares at the maxi mum price was significantly higher than the number of shares offered. We are glad to see many of the current shareholders interested in increasing their stake in Selvi ta, as well as welcome new strong capi tal market funds to our shareholder base,“ said Pawel Przewiezlikowski, co-founder, the largest shareholder and CEO of Selvita. Among the investments planned is a new research facility which will allow Selvita to grow from 446 to 770 people.
Pharma After providing UScompany Evestra with a US$5m loan in 2015, Hungarian pharma company Gede on Richter chose to receive in exchange equity in the Texas-based firm in ear ly 2018. Last year, Evestra’s Polish-based subsidiary Evestra Onkologia Sp. z o.o – focused on oncology therapeutics – had received a US$4.6m grant from the Polish National Centre for Research and Devel opment and the European Union Regional Development Fund to develop an experi mental drug for endometriosis. On a sour note, the Gedeon’s stock price plunged in February after the Eu ropean Medicines Agency had recom mended to temporarily restrict prescrip tions of Gedeon’s uterine fibroid drug Esmya until potentially related liver dam ages have been reviewed.
Picture: Anna Mościcka/Wikimedia Commons (top), Terje Atonen (left)
Algae-based cosmetics
Marcin Szumowski, CEO, President of the Board and significant shareholder of Oncoarendi. Oncoarendi is developing small mole cule drugs in two therapeutic areas. The first one is inflammation-induced diseases that lead to tissue remodelling and fibro sis, in particular in lungs and the respirato ry system. The most advanced candidate, OATD-01, is in Phase I development. The second therapeutic area pursued is onco logy. Here, the lead asset, an arginase in hibitor, is in preclinical stage. L
Stock Market Debut Founded in 2012, Oncoarendi Therapeutics SA will pursue a listing on the Warsaw Stock Ex change in the first half of 2018, the com pany announced in late 2017. Following the founders’ seed and in-kind contribu tions, Oncoarendi closed an angel and two investment rounds totalling about PLN34m (€8.2m). In addition, it received non-dilutive capital, with total funding exceeding PLN100m (€24m). Oncoarendi has filed documents with the Financial Supervision Authori ty, kicking off the process aiming for the initial public offering (IPO) of its shares on the Warsaw Stock Exchange’s regu lated market. “We have decided to issue shares in an IPO in order to raise funds needed for the execution of our ongo ing research and development projects and for launching new drug discov ery projects. Our strategic aim is to ad vance our projects to the commerciali sation stage sufficient for entering into a licensing agreement or partnership with global pharmaceutical companies,” says
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Finland’s Archipelago Sea will be the focus of the first Environmental Impact Bond.
Follow the money – from niche to norm Bioeconomy Despite seemingly insurmountable environmental challenges ahead and the
Picture: loneroc/shutterstock.com
many ‘successes’ flaunted by big biorefinery projects, the wider business community remains stubbornly sceptical about developing business within the bio-based paradigm. Now policymakers are pushing financiers to take a bigger stake in its success. New efforts are underway to drive private investment in bioeconomy ventures.
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W
ith approximately 40,000 islands and islets, Fin land’s ‘Archipelago Sea’ is one of the largest is land groups in the world. A top spot for tourism and agriculture, the region’s big gest environmental problem is the quality of the shallow Baltic sea. The Archipelago Sea’s drainage basin has been studied ex tensively in the past to calculate the im pact of manure from domestic animals, sludge from water treatment plants, or ganic industrial waste, biowaste, field bio mass and reeds. With the problem still un solved, the Finnish region is taking centre stage in a new Circular Economy initiative that’s being closely watched by funding experts. In focus are Environmental Im pact Bonds (EIB) – a type of payment-byresults environmental fund. The idea is that private investors finance efforts nec essary to achieve a given goal, and the public sector only pays for results.
Picture: James Cogan
From social to environmental Finland already has experience with So cial Impact Bonds (SIBs). Six such funds are currently in progress, under construc tion or planned, with targets ranging from rapidly integrating immigrants to promot ing the well-being of children and young people. “We believe very strongly that SIBs are very useful tools for making systemic changes in the use of taxpayer money,“ says Mika Pyykkö. The Project Director for Impact Investing from Finnish Innova tion Fund Sitra told EuroBiotech there’s a concerted effort to prove that the con cept also works for environmental protec tion goals. Finland now wants to launch Europe’s first EIB in 2019. There are two specific projects so far. The first is the eu trophication of the Archipelago Sea. Fin land produces more than 17 million tonnes of livestock manure each year, and it con tains huge amounts of nitrogen and phos phorous. So why not kill two birds with one stone? Significantly reducing nutri ent emissions into the Archipelago Sea goes hand-in-hand with the production of new, highly-refined manure products. Major benefits created by the project in clude upsides for recycled manure and
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tourism businesses. The second idea put forward by an EIB is related to municipali ties, and how to help them switch to serv ices produced in a carbon-neutral and re source-wise way. The project will include a group of municipalities willing to coop erate with companies and service provid ers. The aim is to cut greenhouse gas emis sions in the participating towns and cities by 80%, while simultaneously decreasing the use of natural resources. As bonds are a fixed income investments, stakeholders loaning the money usually aren’t chasing high profits. Pyykkö expects investors in terested in EIB to be similar to SIB inves tors: “They have some kind of social or environmental vision. In our case, SIB in vestors include, for example, the Europe an Investment Fund, Finnish retail cooper ative SOK Corp., the Orthodox Church of Finland and the City of Espoo.” Northern Europe is a motor in the drive to establish the sustainable use of bio resources. In 2015, the Nordic Bioeco nomy Panel was set up with a mandate to develop a proposal for a joint Nordic bio
James Cogan Industry, technology and policy analyst, Ethanol Europe Renewables Ltd, Ireland
?
Could the Circular Bioeconomy Thematic Investment Platform turn out to be a full-blown success?
!
The new initiative of the EIB is an excellent idea. Creating a thema tic area is a good thing as it allows focus and action. If this initiative in cludes a monitoring and measuring system allowing people like us to see how much money really got to the field, then I’d really love it.
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economy strategy. One of its first actions was collecting 25 Nordic examples of the ‘new’ Nordic bioeconomy. Among them is Exilva, made by Norwegian firm Bor regaard – a multifunctional additive for adhesives, coatings, agricultural chem icals and cosmetics. Made from micro fibrillated cellulose, the aim behind its development was to replace petroleumbased additives. Another example is Mac ro Cascade, aimed at proving the concept of the cascading marine macroalgal bio refinery. Set up on the Faroe Islands, the project’s goal is to expand current bio mass portfolios by adding seaweed. At the UN Climate Summit in Bonn last au tumn, the Panel presented its five prin ciples for a sustainable bioeconomy, and also commented on policy measures for driving change and business in the bio economy. Targeted public procurement is one of them. A label indicating levels of sustainable content in products might be another. To establish bio-based start-ups and help them scale, the Panel suggest ed establishing a cross-Nordic/Baltic fund for transformational bioeconomy startups that also issues specific “bioecono my bonds or something similar”. Both push and pull forces are seeking to encourage a sustainability financing sec tor in Scandinavia. At the Bioeconomy In vestment Summit in Helsinki in late 2017, Nordea Bank AB’s Head of Responsible Investments, Sasja Beslik, said the finance industry is starting to bond in whole new ways with the bioeconomy: “People dis cuss this subject with a verve that was un thinkable five years ago. People are talk ing about a revolution in financing – and the bioeconomy is a big part of that.”
A new InnovFin facility The European Commission and Euro pean Investment Bank (EIB) are also set ting up a new fund to stimulate private investment in the bioeconomy: The Cir cular Bioeconomy Thematic Investment Platform has been implemented within the InnovFin risk-sharing finance facility. Since its launch in 2014, tailored InnovFin products have been set up to serve niche markets with little access to financing – a
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Financial instrument
Regional research grants
European Biotechnology | Spring Edition | Vol. 17 | 2018
Type
Bio-based industry
Financial instrument
Type
InnovFin
Corporate loans Equity financing Advisory servics
Innovative
EFSI
Venture capital Mezzanine Growth
Traditional
EFSI
Venture capital Mezzanine Growth
ESIF
EU collaborative research grants
BBI JU H2020
Loans for innovation deployment advisory services
InnovFin
Loans for investment projects
EFSI
Additional Activities
Education and training programmes Implementation Regional Dev.ment
ESIF
Operation
Innovative Core Activity Projects Companies
Overview of financial instruments available to support the development of the European bioeconomy
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bioeconomy projects that use terrestrial or aquatic biomass that is turned into biobased products. Circularity is a plus, but not a must. Projects focussing mainly on renewable energy generation are not a priority. Time will show whether the Innov Fin TIP can succeed at crowding-in private capital. Politicians appear confident they’ve found a way to de-risk new technologies, processes and business models: “The bioeconomy for me really is green alchemy,” said John Bell, Director of Bioeconomy at the European Commission’s Directorate-General for Research and Innovation. “And we want to help it go from niche to norm.”
“ InnovFin products so far don’t reach the field.” James Cogan, a Bioeconomy Industry & Policy Analyst working for Irish Ethanol Europe Renewables Ltd (EERL), applauds the new initiative, but also gives food for thought: “My research has led me to believe that InnovFin products are not reaching the field. Many of the banks the EIB lists as intermediaries had never heard of InnovFin when I called them, and clearly weren’t delivering the prod-
ucts to market.“ His verdict is likely being used by many banks as cheap finance for traditional lending secured by property and other near-cash assets. According to Cogan, what a refurbished InnovFin product like the TIP needs are effective delivery mechanisms, along with checks and balances on how they work.
Commercial-scale plants needed The new fund is rooted in an EIB ana lysis published last June which found that, while money is available in Europe for the R&D phase of bioeconomy projects, it’s much harder to attract funding for la ter demonstration and commercialisation phases. Realisation of bioeconomy-related projects like the construction of new bio refineries is still risky in financial terms. At the same time, commercial-scale plants are needed to overcome bottlenecks and showcase how interesting returns on investments are possible. The new fund complements other recent European Commission initiatives to foster a bioeconomy – most notably the Biobased Industries Joint Undertaking (BBI JU). It’s a public-private partnership between the EC and the Bio-based Industries Consortium (BIC), a Brussels-based nonprofit organisation with nearly 200 mem-
Picture: BIOCOM AG/modified from Bio-based Industry Consortium‘s “Access to EU Financial Instruments” report
complementary programme to the European Fund for Strategic Investments (EFSI). After an interim evaluation published in mid-2017, the InnovFin strategy is now set to be altered to better align with EFSI activities. InnovFin products are now subject to regular updates to reflect market evolution. The Thematic Investment Platform (TIP) is one such update. Financing deployed by a TIP can include grants, loans, venture capital, venture debt, bridge equity and blends of all of the above. The European Commission has pledged to direct €100m from Horizon 2020 sources to the first installation: the Circular Bioeconomy TIP (CBTIP). “The platform will be established in 2018,” says Alexander Stubb. The EIB’s Vice President is also quick to point out the merits of his employer. “Together with the World Bank, we kickedoff the green bond market in 2007 with an AAA-rated issuance.” For the new platform, the EC and EIB are aiming to attract diverse sources of capital. It hopes banks, pension funds and venture capitalists will invest in a large public-private pot, along with Member States. The CBTIP will be managed by independent fund managers being scouted in early 2018, and the aim is to have it up and running by the end of the year. Thematically, the focus is on
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ber companies. Executive Director Dirk Carrez regards the BIC as an “important bio-based platform for bringing together different sectors and entire value chains to collaborate on the bioeconomy.”
BBI JU on repeat The BBI JU has a total budget of €3.7bn. About €1bn comes from the EU‘s Horizon 2020 programme, the remainder from the industry. Discussions about a Horizon 2020 successor are already underway. The BIC, for example, called for a continued partnership with the European Commission in late 2017. The aim is to set up a Bio-based Industries Joint Undertaking 2.0: “A BBI JU 2.0 contributes to international and European objectives such as the Sustainable Development Goals and the Paris Agreement, as well as the Juncker Priorities, EU Circular Economy initiatives, the bioeconomy strategy, EU industrial policy, the Energy Union and the upcoming reform of the Common Agricultural Policy,” the statement reads. After three years of existence, the up-and-running BBI JU already has over 65 projects in 30 countries. They represent grants totalling €414m in public funding and €1.95bn of announced private investment in the European bioeconomy. In other words, for every €1 contributed so far by the EU,
the private sector has invested €4.71. In terms of the goals stated when it was set up, the BBI JU is therefore a clear success. Since the joint undertaking began in 2014, 45 new bio-based building blocks have been developed, exceeding the 2020 target of 30. 90 new biobased materials have also been developed (target of 50). Additionally, some 40 new bio-based consumer products were launched (target: 30). The package of loan and equity instruments under the InnovFin brand are intended to make money available to technology and business innovators. However, when Cogan’s firm EERL was developing its first investment – Pannonia Ethanol at Dunaföldvár in Hungary – InnovFin and other EIB products were simply not an option. The plant‘s costs were about €150m, and financing was accomplished by a combination of equity from the company‘s Irish founders, equity from the owners of a US-based biorefinery engineering company, and loans from two US development banks. According to Cogan, the plant produces enough climate-friendly ethanol to fuel five million cars and enough proteinrich GMO-free feed supplement for 300 thousand head of cattle. “When EERL was first launched, the US provided most of the finance. With several years of solid results behind it, , and with all the risk and innovation behind them, European loan
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and equity providers have stepped in to replace them,” Cogan reports. Kari Jordan, President and CEO of Finland’s Metsä Group, has a positive opinion about the investment landscape in Europe: “I’ve been working together with the EIB on financing our bioproduct mill project, and can only give high marks for the work done so far.” Project costs of €1.2bn include a €275m EIB loan and €75m guaranteed by the EFSI. That was topped up by a Horizon 2020 grant of €2.2m and a Finnish government grant of €32.1m. What’s glaringly absent from that list is InnovFin funding. But if the new TIP lives up to its promise and can be used to enhance the EFSI instrument, chances are good that in the future, higher-risk circular economy ventures can also count on financing later in the game. “Again, the pledge to direct €100m from Horizon 2020 sources to the CBTIP to attract the financing sector is very good,” Cogan says. “But people in Brussels sometimes convince themselves that their efforts are big enough to turn around the supertankers in society. I’m not sure they can. Instead, these efforts are not even seen by the supertankers.” To get real progress, he says, you need EU policy expert campaigns for changes in legislation and EU member state policy: “These two levers (and market forces) are what turn the supertankers.” L m.laqua@biocom.eu
Bio meets Economy – Science meets Industry
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Endothelial disruption Physiology Is endothelial targeting the Next Big Thing in patient stratification and pharma
Participants from the meeting on endothelial dysfunction.
Although it’s still under the radar of an alysts, the vasoactive peptide adreno medullin could become the Next Big Thing in therapy monitoring and the treat ment of disorders caused by endothelial dysfunction, such as acute heart failure or septic shock. During an invitation-on ly symposium titled Endothelial Dysfunc tion, held shortly before the JP Morgan Conference, 15 key medical opinion lead ers from ICU/EDs compiled, for the first time, clinical data from more than 10,000 patients, underscoring that the vasoregu latory protein could shift diagnosis, thera py monitoring, and the treatment of disor ders linked to endothelial dysfunction. “Adrenomedullin indicates endothelial dysfunction and thus the need for vascu lar repair,” said serial entrepreneur An
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dreas Bergmann, co-founder of diagnos tics companies BRAHMS, Sphingotec, and the antibody developer Adrenomed AG. “The marker is a general indicator of endothelial dysfunction – in heart failure but also in other medically underserved areas, such as septic shock.”
A new paradigm Data presented by clinicians in Berlin support the view that adrenomedullin could serve as a biomarker and a thera peutic target in disorders linked to leaky blood vessels, including peripheral vascu lar disease, stroke, heart disease, diabetes, chronic kidney failure, and metastasis. Studies on different patient groups with sepsis suggest that high plasma levels of
the active, amydated form of adrenom edullin (bio-ADM) predict negative out comes. Using the only available com mercial assay (Sphingotec GmbH, Berlin, Germany) that detects bio-ADM, a pilot study on 100 sepsis patients with heter ogeneous disease etiology, conducted by Salvatore Di Somma (University La Sa pienza, Rome), showed that serum con centrations above 70pg/ml accurately pre dicted the development of septic shock. Larger trials, such as ALBIOS (N=1,000) conducted by Roberto Latini (Head Car diovascular Research, Mario Negri In stitute, Milan), confirmed that high bioADM plasma levels were predictive of organ dysfunction and shock. Data from the AdrenOSS-1 (N=583) and FROG-ICU (N=2084) studies, headed by Prof. Dr. Al exandre Mebazaa (Hôpital Lariboisière, Paris), clearly qualified baseline bioADM levels as a predictor for vasopres sor demand. Results from Olle Melland er, who compared mortality of patients above and below the adrenomedullin cut-off, showed that adrenomedullin in dicates ICU requirement. He found a 13fold higher mortality in patients with high bio-ADM levels admitted to the hospital. Clinical data on a 30-day mortality and organ dysfunction in sepsis patients from South Korea (Mina Hur, N=215) indicate that the findings also apply to Asians. Data on surgical sepsis patients (Gernot Marx, Aachen) confirmed the same for this patient group. “A predictive biomarker that identi fies patients at the highest risk to develop endothelial leakage, impaired organ cir culation, multi-organ failure, and shock would help start supportive therapy ear lier, which might save many lives,” Kon rad Reinhart, chairman of the Global Sep
Picture: Adrenomed
development? At a small meeting in Berlin, medical leaders and decision-makers from diagnostics and pharma majors excitedly discussed the potential paradigm shift in the diagnosis and treatment of common diseases.
01.03.2018 13:15:35 Uhr
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ADM Interstitium Endothelium
Vascular integrity
Blood
ADM
Mode of action of intravascular adrenomedullin
sis Alliance, told European Biotechnogy. It could also bring drug developers back to the field, which suffered from a huge array of Phase III failures due to the lack of stratification of the highly heterogenous patient group. In 2016, systemic inflammation caused nearly US$24bn in direct annual costs for the US healthcare system alone.
Heading for stratification However, as most players in the sector link sepsis to failure, it was no surprise that decision-makers from diagnostics and therapeutic companies at the meeting were more thrilled by the results in another medically underserved area: congestive heart failure, which also seems linked to endothelial dysfunction. Low pump efficiency of the heart caused by cardiac remodeling results in congestion – high venous pressure cause the microvasculature to get leaky and fluids to build up in the tissues (edema) in up to 80% of patients. While therapy with loop diuretics helps most patients, a significant group – 2030% – relapses; most of them die. Currently, there is no biomarker to diagnose residual congestion. Re-admissions of therapy-resistant patients make up a good part of the $31bn heart failure currently costs healthcare systems. Two large studies (PROTECT and BIO STAT) conducted on 4,000 patients with decompensated acute heart failure (AHF), presented by Prof. Dr. Adriaan Voors from
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UMC Groningen, demonstrate that high bio-ADM levels were predictive of 180day mortality. Voors’s team confirmed that among 160 biomarkers, bio-ADM had the best predictive power related to the probability of rehospitalisation due to congestion, residual congestion, and mortality. His findings are backed by results of the GREAT study (Paris, Basel, Leicester) on 1,884 patients. According to study head Leong Ng (Leicester), bio-ADM levels on the day of discharge identified the need to continue decongestive therapy. Results from another study (Val-HeFT, N=583), reported by Inder Anand, Head of Cardiovascular Medicine at the University of Minnesota, confirmed that bio-ADM is also a marker for congestion in patients with chronic congestive heart failure. Fernando Chavez, Global Head at Ortho Clinical Diagnostics, said the economic impact of the findings could be huge, as residual congestion affects 1.1 million AHF patients in the US alone. Representatives of Siemens Healthineers and Biomerieux confirmed that the biomarker has high medical and economic potential.
Go one step beyond Discussing the primary clinical utility of bio-ADM, KOLs at the meeting agreed that monitoring treatment success in patients with endothelial dysfuntion must have priority, followed by stratification and early treatment of patients at high risk of life-threatening events and re-hospital-
isation. Indeed, clinical trials suggest that bio-adrenomedullin might also be an attractive therapeutic target. According to Prof. Dr. Peter Pickkers (Radboud University, Nijmegen), targeting adrenomedullin with a humanized antibody (Adrecizumab, Adrenomed AG, Hennigsdorf/Berlin) that targets the N-terminus instead of its receptor-binding C-terminus improved fluid balance and blood pressure in resuscitated rat and pig models for sepsis. In a mouse model for sepsis, Adrecizumab led to a 40% overall survival benefit. Preclinical results suggest that the antibody leads to an immediate re-distribution of adrenomedullin from the interstitial space to the vessel lumen, without increasing its production. The shift from tissue to the vessel promotes stabilization of the endothelial barrier and prevents vasodilation, adrenomedullin’s extravascular effect on smooth muscle cells.
Therapeutic potential So far, Adrecizumab has proven safe in two Phase I trials. In December 2017, it entered a Phase II proof of concept study in 300 patients with early septic shock. According to Prof. Pierre-François Laterre (St. Luc Hospital, Brussels), only patients with high bio-ADM levels will be included. Besides mortality, endpoints include the number of days with organ support (SSI) and 90-day safety. In 2018, Adrenomed will start a multicentre Phase II trial with Adrecizumab in up to 360 patients with worsening heart failure. According to study head Prof. Dr. Adriaan Voors, an antibody that triggers redistribution of adrenomedullin from tissue to the intravascular space by factor 10 like Adrecizumab does, should counteract tissue congestion. Endpoints under discussion include safety, time to rehospitalisation, clinical congestion score, clinical lab parameters etc. Representatives from diagnostic and pharma companies said at the meeting that they see great potential in the new approach to stratify patients based on bioADM levels and subsequently target endothelial dysfunction. L t.gabrielczyk@biocom.eu
Pictures: Biocom, Source Adrenomed
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European Biotechnology | Spring Edition | Vol. 17 | 2018
Advertorial
73
Inhibitor-free DNA for PCR PCR BioEcho develops kits for the isolation and processing of DNA and RNA. Their proprietary Echo-
LUTION single-step purification technology simplifies handling and is significantly faster than commonly used extraction methods. BioEcho avoids the use of inhibitory process reagents, resulting in increased robustness of downstream analyses. The risk of complete failure of PCR applications is eliminated.
The EchoLUTION spin column process works under native conditions in the absence of denaturing salts and organic solvents such as ethanol used in common Silica-based bind-wash-elute methods, which may be carried over into the DNA preparation and lead to inhibition of enzymatic reactions like PCR or even to complete failure of analyses.
Pictures: BioEcho GmbH
Quick lysis and single-step purification The EchoLUTION technology starts with lysis of cells or tissues under aqueous conditions. For the development of new kits, the lytic activities most suited to quickly and gently release DNA (i.e. proteases or lipases) are selected as a tailor-made TurboLyseTM lysis solution. In contrast, common procedures rely on DNA binding to a silica membrane in a denaturing environment at 7M guanidine hydrochloride. Since lysis needs to work under these harsh conditions, the silica principle is restricted to only a single commercially available enzyme: Proteinase K. The broader substrate spectra of the TurboLyse enzymes allow for a faster and more complete lysis in a neutral environment and nucleolytic activities are concurrently suppressed. Lysis for most tissue types (epithelial, connective, nervous and other fatty tissues) is complete after 15 minutes and for fibrous samples after 30 minutes. For separation of the target nucleic acid from the remaining cellular constituents and from process components (enzymes, salts, detergents), the lysate is processed in a single centrifugation step. Bioecho’s purification ma-
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Improved sensitivity in real-time PCR. Genomic DNA from 5 mg mouse tails was purified using the Echolution Tissue DNA Micro Kit (red) and a common silica kit (blue) and used in qPCR reactions (HOX D9 amplicon) in dilutions as indicated. The table insert shows the resulting Ct values and the difference by which the Echolution DNA template was detected earlier.
trix is a proprietary formulated bead suspension with various functionalities. The matrix is tuned to make sure that all unwanted components are retained. Free from inhibitors of downstream reactions, the DNA is collected in the elution tube – purified, desalted and buffered. Since DNA remains in solution during the entire process, shearing forces are minimized.
Highly sensitive PCR detection
echo kit is detected by one to five cycles (Ct) earlier. This represents a clear improvement compared to the current state of the art. The BioEcho development team is positive that the Echolution technology is a valuable addition to available methods in molecular biology which will stand up to current approaches. Sustainability is an additional advantage: 70% less plastic and no organic liquid waste is generated, plus packaging volumes have been significantly reduced.
The patent-pending EchoLUTION process provides DNA of high average chain length. Due to the maximized purity, detection reactions via qPCR are more sensitive and robust compared to silica methods. The figure shows a typical qPCR result: DNA obtained using a Bio-
Contact Dr. Frank Schäfer BioEcho Life Sciences GmbH Biocampus Cologne frank.schaefer@bioecho.de www.bioecho.de Tel. +49 (0)221-99 88 97-0
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News Cancer blocker
Blocking glycolysis An US-Italian research team has identified the immune cells that trigger fibrosis. In January, the team reported that abnormal activity of plasmacytoid dendritic cells (pDCs) trigger inflammation and fibrotic remodelling in mouse models and tissue from patients with the autoimmune disease systemic sclerosis (SSc). They suggest that SSc patients may benefit from therapies that remove or attenuate chronically activated pDCs, a subset of blood-roaming innate immune cells that trigger type I interferon immune responses.
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Preventing metastases Breast Cancer Spanish and German re-
searchers have identified two proteins that keep cancer at bay. In mid-January, the team, headed by Roger Gomez at IRB Barcelona, reported they found a factor capable of keeping breast cancer stem cells in a dormant state, preventing them from forming metastases. A team at German Cancer Centre in Heidelberg found an endothelial receptor protein that prevents dormant micrometastases in the blood from invading into tissue.
No angst anymore Three years ago, the team headed by Gomez discovered that certain mutations in the MAF gene of breast cancer patients correlated with a 14-fold higher risk to develop bone metastases. An early stage diagnostic test under development by Gomez’ spin-out company Inbiomotion identifies primary tumours at high risk of metastasis relapse, which would benefit from bisphosphonate adjuvant treatment. In January, the same team reported in Nature Chemical Biology (doi:10.1038/ s41556-017-0021-z ) that it found a target protein in estrogen-receptor (ER) positive breast cancer patients that might help prevent formation of bone metastases. Most of the 76% of breast cancer patients that express either the progesterone or estrogen receptor are ER-positive. In patients with ER-positive breast cancer, low MSK1 expression associated with early metastasis by increasing bone homing and growth capacities. In
cell culture, MSK1 controlled the expression of cancer stem cell differentiation genes GATA3 and FOXA1 epigenetically. MSK1 controls metastatic progression by regulating chromatin accessibility of the genes at the level of phosphorylation and acetylation state of histone H3. The researchers believe their findings may benefit patients in two ways: ›› To identify those patients with an imminent risk of relapse and to adjust their treatment. ›› To design functional MSK1 kinase analogues with the aim to maintain metastatic lesions in a latent and asymptomatic state for as long as possible.
Blocking angiogenesis stops tumours from spreading The approach of the German onocologist is early stage but might be more far-reaching. When they blocked the endothelial protein receptor Tie1 in mice xenografted with human tumours in advanced stage, most tumours grew more slowly and lost the capacity to form metastases. Tie1 expression normally increases the size of endothelial gaps, letting tumours cells pass into tissue. The anti-metastatic effect the oncologists saw in mice was tremendous. While 10 out of 14 mice that expressed Tie1 developed metastases, it was only 1 out of 14 in Tie1 knock-out mice. Tie1 is an orphan receptor: it has no ligand. “This time, we switched off Tie1 genetically,“ announced first author Silvia La Porta. "Next, we’ll try to prevent metastases and tumour proliferation by doing it with drug candidates.“ L
Picture: La porta, German Cancer Research Centre, heidelberg
Italian, US, and Australian researchers say they have developed a blood screening test to detect eight different cancers prior to metastasis (S cience , doi: 10.1126/ science.aar3247). Its sensitivity is among the best performances yet for a universal cancer blood test. In 1,005 patients with stage I-III cancers, the assay, dubbed CancerSEEK, showed sensitivities ranging from 33% for breast cancer to 98% for ovarian cancer, and a specificity of 99%. The assay detects 16 typical mutations as well as eight cancer proteins, which together point to cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. Using machine learning, the researchers enabled the test to accurately determine the location of a tumour down to a small number of anatomic sites in 83% of patients. The researchers estimate that the cost of this single blood test for eight cancer types may be less than US$500. Larger studies of the test are currently under way.
01.03.2018 13:18:36 Uhr
associations
European Biotechnology | Spring Edition | Vol. 17 | 2018
Export record Ireland The biopharmachem sector maintained its position as the largest exporter of goods from Ireland in 2017. It has increased its exports to a total amount of €67.8 billion, up 2% on the previous year. The sector now accounts for 55% of overall Irish exports of goods (excluding services). The results were published in February at the BioPharma Ambition Conference 2018 in Dublin. The event was hosted by the Irish Pharmaceutical Healthcare Association (IPHA), BioPharmaChem Ireland (part of Ibec), and the National Institute for Bioprocessing Research and Training (NIBRT). During the event, NIBRT announced their strategic partnership with Jefferson (Philadelphia University and Thomas Jefferson University in Philadelphia, USA). The Joint Venture, Jefferson Institute for Bioprocessing, was established to educate graduate and undergraduate students in biologic engineering. It will be the first education and training institute for biopharmaceutical processing in North America. “The NIBRT and Jefferson teams have been working closely over the last 18 months, and we look forward to the successful launch of this groundbreaking project," states aid Dominic Carolan, CEO of NIBRT.
Strengthen R&D Strategy In December, the Spanish
Bioindustry Association (ASEBIO) renewed its president, vice-presidents, and board of directors. Now it has made the focus of its institutional strategy to bring science and innovation to the public and political debate. The new board of directors aims to improve the development of biotechnology and the growth capacity of companies, proactively strengthening the institutional position of the association, especially in the field of R & D, to promote the necessary financing of companies from both the public and private sectors.
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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
Blue: 100/15/0/35 Orange: 0/75/90/0
European Biotechnology covers the biotechnology sector of the current 28 EU member states, Norway and Switzerland. If you would like to subscribe, please refer to european-biotechnology.com
EBE
White Paper on Personalised Medicine 75_78_EB_Spring_2018_Associations_HM.indd 75
01.03.2018 13:19:32 Uhr
associations
European Biotechnology | Spring Edition | Vol. 17 | 2018
Genome editing: Achieve the potential Position Paper EuropaBio calls upon European decision-makers
to create platforms to ensure consumer confidence and to provide regulatory clarity to enable innovation for developing products by genome editing methods.
Genome editing is an umbrella term for a range of tools that enable precise changes to the genome of an organism. Researchers in public and private institutions across Europe and the globe have embraced genome editing because it is precise, efficient, versatile, and provides ample opportunities to develop new products.
A variety of applications A host of potential fields of application exist for genome editing, from the development and production of medicines and therapies, diagnostic agents, and vaccines for treatment of human diseases; to bio-based chemicals and bio-energy for better environmental stewardship; to nutrient-enriched and stress-resilient crops for fighting food waste and food insufficiency, and beyond. Previously developed technologies include: therapeutic tools for recognising specific viral DNA and eradicating HIV proviruses; production of bio-based chemicals, like lactic acid and succinic acid, for replacing petrochemical building blocks: and non-bruising potatoes for reducing food waste. Regulatory clarity on genome editing is increasingly being established across the globe. Guided by the needs of society and supported by the science, EU decision-makers should engage with public and private researchers in communicating to citizens on the uses of these tools to raise the societal awareness of the benefits. It should be recognised that with needed medical breakthroughs, im-
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proved food and feedstuffs and industrial production methods, and products that are environmentally beneficial, genome editing is a vital part of securing Europe’s place as a global leader in science, innovation and competitiveness. To this end EuropaBio calls for:
ACHIEVING THE POTENTIAL OF GENOME EDITING The perspective of the European Biotech Industry
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
In a recent position paper, EuropaBio called upon European decision-makers to create platforms to ensure consumer confidence and to provide regulatory clarity to enable innovation for developing products by genome editing methods. This paper seeks to support the ongoing discussion about how to increase the public understanding of these tools and the solutions that come with them, as well as how to best develop any needed regulatory policies to enable their potential.The paper is available on www. europabio.org. L
Brexit: impact on medicines JANUARY 2018
›› an inclusive, fact-based platform for dialogue, information sharing, and trust building to be set up by the European Commission that brings together the EU Member States, industry, public researchers, academia, and civil society ›› a risk-proportionate, predictable, science-based, and non-discriminatory application of the existing policy approaches to allow innovation to benefit European society and the environment.
Policy Paper A broad coalition of players representing the European and UK life science industry (EuropaBio, AESGP, ABPI, BGMA, BIA, EFPIA, EUCOPE, Medicines for Europe, PAGB) have recently published a Joint Life Science Industry Policy Paper on the Potential Impact of Brexit. The paper presents a common UK-EU life science position on key challenges that lie ahead in the Brexit negotiations and proposed solutions to safeguard public health. Read more on www.europabio.org/healthcare-biotech.
Pictures: Spectral-Design - fotolia / ©SL (above), EuropaBio
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01.03.2018 13:19:42 Uhr
9th INTERNATIONAL CONGRESS ON BIOCATALYSIS
26–30 AUGUST 2018 HAMBURG UNIVERSITY OF TECHNOLOGY l GERMANY © Technische Universität Hamburg-Harburg
MAJOR TOPICS Enzyme discovery, production and application Structure-function analysis and enzyme design Enzymatic and whole cell biotransformations Bioprocess engineering and downstream processing Sustainable industrial processes, biorefinery and bioeconomy
Abstract deadline 23 March 2018 www.biocat-conference.de 77_EB_Spring_2018_Biocatalysis-Conventus.indd 1
01.03.2018 13:22:18 Uhr
“WHITE BIOTECHNOLOGY” WORKING GROUP
associations
SBA celebrates 20th anniversary in Basel
Domenico Alexakis is Executive Director of the Swiss Biotech Association.
Swiss Biotech Day At this year’s Swiss Biotech Day, entrepreneurs,
investors, researchers, analysts, political decision-makers, and industry stakeholders will meet in Basel, celebrating the 20 th anniversary of the Swiss Biotech Association.
“The SBD has proven to be a lot more than the Annual General Assembly of the Swiss Biotech Association. It has become one of the key meeting points for biotech entrepreneurs, investors, researchers, analysts, political decision makers, and industry stakeholders in Switzerland,” states Michael Altorfer, newly appointed Chief Executive Officer of the Swiss Biotech Association.
Come together in Basel On May 3, 2018, senior executives from Swiss and European biotech companies and senior scientists from leading academic institutions are invited to come together at the Congress Centre Basel. Each year, the event traditionally begins with the General Assembly of the Swiss Biotech Association (SBA), which currently has more than 200 member companies representing the interests of SMEs within the biotechnology sector. In 2018, the Assembly will be followed by a keynote address from Vasant Narasimham, assigned CEO of Novartis. Next, the Swiss Biotech Report 2018
75_78_EB_Spring_2018_Associations_HM.indd 78
will be released, providing an opportunity for interesting discussions on potential future developments within the Swiss biotechnology field. During the afternoon, partners of Swiss Biotech Day will present parallel sessions offering insights into specific life sciences topics, such as analyses and predictions for publicly listed biotech companies, and financing opportunities in the Analyst and Investor track. After the afternoon sessions, attendees and partners are welcome to celebrate the 20th anniversary of the Swiss Biotech Association.
@
Upcoming events For further information please visit www.swissbiotechassociation.ch www.swissbiotech.org
› 3 May 2018, Basel Swiss Biotech Day swissbiotechday.ch
New CEO appointed Management Since January, Michael Altorfer has taken over as the new CEO of Swiss Biotech Association. Michael has more than 20 years of experience in the life science industry, comprising postions at both big pharma and smaller biotech organizations. As a member of the executive committee, he supported the build-up of Polyphor Ltd in many different roles (Head BD&L, CFO, COO and CEO). Michael started his career as a scientist in pharmaceutical research at Sandoz, Ciba-Geigy (Summit, NJ, USA), and Roche. From 1996 to 2001, he held program management and line management roles at the investment bank UBS Warburg. Michael studied Natural Sciences at the ETH, and he obtained his Ph.D. in Chemistry under the supervision of Prof. Dr. H.-J. Hansen (University of Zurich) and Prof. Dr. K. Müller (Roche), and holds an MBA degree from the University of Rochester, NY, USA. L
Vivid heart in Basel There are only a few spaces in the world where so many life sciences jobs are concentrated in one place with the density seen in Basel. From worldleading research groups, biotech entrepreneurs, start-ups, and patent specialists – the region covers the entire value chain. That’s why the Swiss Biotech Day 2018 will once again take place in the vivid heart of the Swiss life sciences industry. L
Pictures: Pixabay, Swiss biotech Association
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Leading chemical companies are exploring the opportunities that have been opened up by modern biotechnology, especially in the field of “white” or industrial biotechnology. And they are also applying these technologies, wherever it makes sense. The SBA takes such initiatives seriously and has formed a working 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 workforce with the right education. The SBA profits from the marketing alliance “Swiss Biotech” (see box) in a multiplied form. Thanks to Swiss Biotech, the
sector is internationally visible. The project-specific participating companies (most of them young and inSWISS BIOTECH... ternationally less savvy) find a comprehensive partner which is helping to put them in the public window. ...is an alliance of four leading Biotech regions of The participating Life Science Regions are important Switzerland (Bio Alps, BioPolo Ticino, Basel Area internal carriers of the dynamics in the Biotech secand Greater Zurich Area). They have combined eftor, thus enhancing the common understanding of European the fortsBiotechnology to streamline interests of Edition the national biotech | Spring | Vol. 17 | 2018 industry. This and more knowledge is brought into sector. The SWX Swiss Exchange holds a leading Europa Bio, the European Biotech Association, where position in terms of lifescience listings and offers the SBA is an active member. 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.
01.03.2018 13:22:35 Uhr
nordic partnering at its best
a
event, produced by
invest partner network
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Events
Analytica 2018 10 –13 April, Munich Whether you are looking for tips regarding safety in the laboratory, financing trends for biotech start-ups, or want to explore actual laboratory worlds in the Live Labs, the Analytica offers all of the above to its visitors. Find out about the highlights that await you in Munich from April 10 to 13. https://www.analytica.de
European Biotechnology | Spring Edition | Vol. 17 | 2018
20.–22.3.18
7th Int. Bioeconomy Conference
Bioprocessing Summit Europe, Lisbon (PT) Info: Cambridge Innovation Institute http://bioprocessingeurope.com/
21.3.18
New Updates in Drug Formulation & Bioavailability, Copenhagen (DK) Info: Kemivärlden Biotech Kemisk Tidskrift http://www.trippus.se
26.–28.3.18
World ADC Berlin 2018, Berlin (GER) Info: Hanson Wade, http://worldadc-europe.com/
9.4.18
Genome Editing 2018, Oxford (UK) Info: LPMHealthcare http://lpmhealthcare.com/genome-editing-2018/
10.–13.4.17
Analytica 2018, München Info: Katja Stolle, Messe München GmbH www.analytica.de
6–7 June, Halle The ScienceCampus Halle and the BioEconomy Cluster cordially invite you to the 7th International Bioeconomy Conference “Bio meets Economy – Science meets Industry,“ one of the most important bioeconomy events in Germany, held in Halle (Saale). Internationally renowned representatives from science and industry meet to intensively and productively exchange ideas on the latest research findings, innovations and market developments. This year’s partner region is Scandinavia.
www.bioeconomy-conference.de
10.–12.4.18
BIO-Europe Spring 2018, Amsterdam (NL) Info: Tom Voigt, EBD Group www.ebdgroup.com/bes
13.–14.3.18
Industrial Biotechnology Forum 2018, Munich (GER) Info: Heidi Roesler, IBB Netzwerk GmbH/Technical University Munich http://ibf-conference.org
13.–14.03.2018
Nano and MicroFormulations – Joint Conference, Berlin (GER) Info: Wolfgang Heimes https://www.gmp-compliance.org
14.–15.3.18
European Food & Beverage Plastic Packaging, Amsterdam (NL) Info: Mado Lampropoulou, ACI www.wplgroup.com
15.–16.3.18
6th Conference on Carbon Dioxide as Feedstock for Fuels, Chemistry, and Polymers, Köln Info: Dominik Vogt, nova-Institut www.co2-chemistry.eu/
19.–20.3.18
Immuno-Oncology Summit Europe, London (UK) Info: Nicole Lyscom, CHI – Cambridge Healthtech Institute www.immuno-oncologyeurope.com/
20.–22.3.18
World Bio Markets, Amsterdam (NL) Info: Robert Wilson, Green Power Conferences http://worldbiomarkets.com
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19.–20.4.18
Global Bioeconomy Summit 2018, Berlin Info: Bioökonomiera,www.gbs2018.com
23.–24.4.18
BioVaria 2018, München Info: Esther Lange, Ascenion GmbH, www.biovaria.org
26.–27.4.18
Swiss Biotech Day 3 May, B asel The Swiss Biotech Day will gather more than 600 senior life sciences executives from across Europe within the Basel bio pharma hub. Programme highlights will again include keynotes from renowned industry experts, the presentation of the Swiss biotech report, the annual general assembly of the SBA, and, of course, networking. www.swissbiotechday.ch
16th Biosimilar Medicines Conference, London (UK) Info: Medicines for Europe AISBL, www.medicinesforeurope.com/events/bios2018/
3.5.18
Swiss Biotech Day 2018, Basel (CH) Info: Uta Holmer, Swiss Biotech Association/BIOCOM AG, www.swissbiotechday.ch
14.–16.5.18
BioEquity Europe 2018, Ghent (B) Info: EBD Group www.biocentury.com
15.–16.5.18
11th International Conference on Bio-based Materials, Cologne (DE) Info: Nova Institut, www.bio-based.eu/conference
22.–25.5.18
Global Genome Biodiversity Network Conference 2018, Vienna (AT) Info: AIT Austrian Institute of Technology https://meetings.ggbn.org/conference/ggbn/2018/
4.–7.6.18
BIO 2018, Boston (USA) Info: Biotechnology Industry Organization, http://convention.bio.org/2018/
Pictures: Messe München (left), SBA (mid), Bioeconomy e.V. (right)
12.–14.3.18
International Conference on Nanobiotechnology – ICNB 2018, Budapest (HUN) Info: International ASET Inc. http://nbconference.com/
01.03.2018 13:35:50 Uhr
European Biotechnology | Spring Edition | Vol. 17 | 2018
1st Ricerca Cesare Serono (IT) . . . . . . . . . . . . . . 56 4SC (DE). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Ablynx NV (BE) . . . . . . . . . . . . . . . . . . . 28, 29, 58 Acerta Pharma BV (NL). . . . . . . . . . . . . . . . . . . . 31 Acesion Pharma ApS (DK) . . . . . . . . . . . . . . . . . 31 ADC Biotechnology Ltd. (GB). . . . . . . . . . . . . . . 40 AdrenoMed AG (DE). . . . . . . . . . . . . . . . . . . . . . 70 Affimed GmbH (DE). . . . . . . . . . . . . . . . . . . . . . 31 Alnylam Pharmaceuticals Inc. (USA) . . . . . . . . . 58 Ammtek Ltd. (GB). . . . . . . . . . . . . . . . . . . . . . . . 30 AmpliPhi Biosciences (US). . . . . . . . . . . . . . . . . 18 Argenx BV (BE). . . . . . . . . . . . . . . . . . . . . . . . . . 28 Array Biopharma Inc (US). . . . . . . . . . . . . . . . . . 31 Arsanis Biosciences (AT). . . . . . . . . . . . . 28, 29, 61 ArteDone (FR). . . . . . . . . . . . . . . . . . . . . . . . . . . 59 AstraZeneca plc (GB). . . . . . . . . . . . . . . . . . . . . 31 Axovant Sciences Ltd. (US). . . . . . . . . . . . . . . . . 82 BASF Plant Science GmbH (DE). . . . . . . . . . . . . 60 Bavarian Nordic A/S (DK). . . . . . . . . . . . . . . . . . 32 Baxter International (US). . . . . . . . . . . . . . . . . . . 22 BCNP Consultants GmbH (DE). . . . . . . . . . . . . . 36 BerGenBio AS (NO). . . . . . . . . . . . . . . . . . . 28, 31 Bial-Portela & CA SA (PT). . . . . . . . . . . . . . . . . . 63 BioArctic Neuroscience AB (SE). . . . . . . . . . . . . 28 Biocrates Life Sciences AG (AT) . . . . . . . . . . . . . 60 BioEcho Life Sciences GmbH (DE). . . . . . . . . . . 73 Bioeconomy e.V. (DE). . . . . . . . . . . . . . . . . . . . . 69 Biogen Idec (USA) . . . . . . . . . . . . . . . . . . . . . . . 58 BioGenes GmbH (DE) . . . . . . . . . . . . . . . . . . . . 40 BioJapan Expo (JP) . . . . . . . . . . . . . . . . . . . . . . . 35 Biological Industries (BI) Ltd. (US). . . . . . . . . . . . 17 Biomerieux (FR). . . . . . . . . . . . . . . . . . . . . . . . . 72 Bionordic Services AB / NLSDays 2018 (SE) . . . . 79 BioNTech AG (DE). . . . . . . . . . . . . . . . . . . . . . . 61 Biotechpharma UAB (LT) . . . . . . . . . . . . . . . . . . 47 Boehmert & Boehmert (DE) . . . . . . . . . . . . . . 9, 34 Boehringer Ingelheim (DE). . . . . . . . . . . . . . . . . 39 Bonesupport AB (SE). . . . . . . . . . . . . . . . . . . . . . 49 BRAHMS AG (DE) . . . . . . . . . . . . . . . . . . . . . . . 70 c-LEcta GmbH (DE) . . . . . . . . . . . . . . . . . . . . . . 46 Cardiogen Sciences, Inc. (US). . . . . . . . . . . . . . . 49 Cellestia Biotech AG (CH). . . . . . . . . . . . . . . . . . 32 Celonic AG (CH) . . . . . . . . . . . . . . . . . . 40, 42, 45 Central BioHub GmbH (DE). . . . . . . . . . . . . . . . 61 Chiesi Farmaceutici S.p.A. (IT) . . . . . . . . . . . . . . 30 Cibus Inc. (US). . . . . . . . . . . . . . . . . . . . . . . . . . 10 Conventus GmbH / Biocat 2018 (DE). . . . . . . . . 77 ContraFect Corporation (US). . . . . . . . . . . . . . . . 18 Cytovation AS (SE) . . . . . . . . . . . . . . . . . . . . . . . 57 Da Volterra SAS (FR). . . . . . . . . . . . . . . . . . . 31, 82 Daiichi Sankyo (JP). . . . . . . . . . . . . . . . . . . . . . . 31 Danaher Group (US). . . . . . . . . . . . . . . . . . . . . . 25 Davies Collison Cave Pty Ltd (AU) . . . . . . . . . . . . 8 Destiny Pharma Ltd (GB). . . . . . . . . . . . . . . . . . 28 Eli Lilly (US). . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Emergent Biosolutions (US). . . . . . . . . . . . . . . . . 32 EnBiotix (US) . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Eppendorf AG (DE). . . . . . . . . . . . . . . . . . . . . . . 13 Erytech Pharma SA (FR) . . . . . . . . . . . . . . . . 28, 29 Essity AB (SE) . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Ethanol Europe Renewables Ltd (IE) . . . . . . . 67, 68 EuropaBio / EFIB 2018 . . . . . . . . . . . . . . . . . . . . 65 EuropaBio / European Biotech Week (BE). . . . . . 21 Evestra Inc. (US). . . . . . . . . . . . . . . . . . . . . . . . . 64 Evonik AG (DE). . . . . . . . . . . . . . . . . . . . . . . . . . 60
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FGK Clinical Research GmbH (DE). . . . . . . . . . . 23 Fixed-Phage (GB). . . . . . . . . . . . . . . . . . . . . . . . 18 Flatiron Health Inc. (US). . . . . . . . . . . . . . . . . . . 61 Fördergesellschaft IZB (DE). . . . . . . . . . . . . . . . . U2 Follicum AB (SE). . . . . . . . . . . . . . . . . . . . . . . . . 32 Fosun Pharma (CN). . . . . . . . . . . . . . . . . . . . . . . 63 Furcella OÜ (EE). . . . . . . . . . . . . . . . . . . . . . . . . 64 Gain Therapeutics (CH) . . . . . . . . . . . . . . . . . . . 62 Gedeon Richter Ltd. (HU). . . . . . . . . . . . . . . . . . 64 Genentech Inc. (US). . . . . . . . . . . . . . . . . . . . . . 61 Genmab A/S (DK). . . . . . . . . . . . . . . . . . . . . 25, 57 Genomic Expression inc. (US) . . . . . . . . . . . . . . 57 Genzyme (US) . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Gilead Sciences Limited (US). . . . . . . . . . . . . . . 30 GlaxoSmithKline Trading Services Ltd. (IE) . . . . . 30 Glycotope GmbH (DE). . . . . . . . . . . . . . . . . 40, 42 Glythera Ltd. (UK) . . . . . . . . . . . . . . . . . . . . . . . 59 Group MNS (IT). . . . . . . . . . . . . . . . . . . . . . . . . 62 Hadean Ventures (NO). . . . . . . . . . . . . . . . . . . . 57 Hemogenyx (GB). . . . . . . . . . . . . . . . . . . . . . . . 82 HS Life Sciences (DE). . . . . . . . . . . . . . . . . . . . . 60 IFM Therapeutics, Inc. (US). . . . . . . . . . . . . . . . . 55 Immunicum AB (SE). . . . . . . . . . . . . . . . . . . . . . 56 Inflarx NV (DE). . . . . . . . . . . . . . . . . . . . 28, 29, 33 Intelligent Pharma (ES). . . . . . . . . . . . . . . . . . . . 63 Intervet International BV (NL). . . . . . . . . . . . . . . 30 Intralytix (US). . . . . . . . . . . . . . . . . . . . . . . . 18, 20 Italfarmaco (IT). . . . . . . . . . . . . . . . . . . . . . . . . . 62 Johnson & Johnson (US). . . . . . . . . . . . . . . . . . . 39 Laboratorios Salvat, S.A. (ES). . . . . . . . . . . . . . . . 62 Laboratoris Sanifit S.L. (ES). . . . . . . . . . . . . . . . . 49 LFB SA (FR). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Life Science Austria LISA (AT). . . . . . . . . . . . . . . U3 Lonza AG (CH). . . . . . . . . . . . . . . . . . . . . . . 25, 39 Mack Brooks Group / Chemspec Europe 2018 (GB) . . . . . . . . . . . . 11, 36 Medisapiens Ltd. (FI). . . . . . . . . . . . . . . . . . . . . . 57 Merck KGaA (DE). . . . . . . . . . . . . . . . . . 25, 33, 46 Merck Sharp & Dohme Ltd (US). . . . . . . . . . . . . 30 Meridian Medical Technologies Inc. (US). . . . . . 39 Messe München / analytica 2018 (DE). . . . . . . . 55 Metanomics Health GmbH (DE). . . . . . . . . . . . . 60 Micreos (NL). . . . . . . . . . . . . . . . . . . . . . . . . 18, 20 Mind the Byte (ES) . . . . . . . . . . . . . . . . . . . . . . . 63 Minoryx Therapeutics S.L. (ES) . . . . . . . . . . . . . . 62 MLM Medical Labs GmbH (DE). . . . . . . . . . . . . 19 Morgan Sindall Professional Services AG (CH). . . 7 MorphoSys AG (DE). . . . . . . . . . . . . . . . . . . 25, 49 MSD Animal Health Innovation GmbH (DE). . . . 30 Nanobiotix SA (FR). . . . . . . . . . . . . . . . . . . . 32, 59 Nanosive (FR). . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Nightstar Therapeutics Ltd. (GB). . . . . . . . . . 28, 29 Novartis AG (CH). . . . . . . . . . . . . . . . . . . . . . . . 57 Novartis Europharm Ltd. (GB). . . . . . . . . . . . . . . 30 Noventure (ES). . . . . . . . . . . . . . . . . . . . . . . . . . 62 Novo Holdings (DK). . . . . . . . . . . . . . . . . . . . . . 22 Novo Nordisk A/S (DK). . . . . . . . . . . . . . . . . 24, 56 Novo Seeds (DK) . . . . . . . . . . . . . . . . . . . . . . . . 31 Nucana Biomed (GB). . . . . . . . . . . . . . . . . . . . . 28
company index
81
OPIS s.r.l. (IT). . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Orphazyme AS (DK). . . . . . . . . . . . . . . . . . . . . . 28 Ortho Clinical Diagnostics (US). . . . . . . . . . . . . 72 Pari Pharma GmbH (DE). . . . . . . . . . . . . . . . . . . 30 Pfizer Ltd. (US). . . . . . . . . . . . . . . . . 22, 30, 33, 58 Phagelux, Inc. (CN) . . . . . . . . . . . . . . . . . . . . . . 18 PhagoMed Biopharma GmbH (AT). . . . . . . . 15, 18 PharmaMar S.A. (ES). . . . . . . . . . . . . . . . . . . 40, 63 Pherecydes Pharma (FR). . . . . . . . . . . . . . . . . . . 18 PIERIS AG (DE). . . . . . . . . . . . . . . . . . . . . . . . . . 40 Pierre Fabre (FR). . . . . . . . . . . . . . . . . . . . . . . . . 31 PlasmidFactory GmbH & Co.KG (DE). . . . . . . . . 43 Polpharma Biologics (PL) . . . . . . . . . . . . . . . . . . U4 Poxel SA (FR) . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 ProBioGen AG (DE) . . . . . . . . . . . . . . . . . . . . . . 40 Prothena Corp. plc (IE). . . . . . . . . . . . . . . . . . . . 25 PTC Therapeutics Ltd (US) . . . . . . . . . . . . . . 30, 58 Remynd N.V. (BE). . . . . . . . . . . . . . . . . . . . . . . . 56 Renable Pharma Ltd. (GB) . . . . . . . . . . . . . . . . . 30 Rentschler Biopharma SE (DE) . . . . . . . . . . . . . . 49 Rentschler Biotechnologie GmbH (DE). . . . . 38, 46 Richter-Helm BioLogics GmbH & Co. KG (DE). 41, 49 Rigel Pharmaceuticals Inc. (US) . . . . . . . . . . . . . 32 Roche AG (CH). . . . . . . . . . . . . . 31, 33, 57, 60, 61 Roche Registration Ltd. (GB). . . . . . . . . . . . . . . . 30 Samsung Biologics (KR) . . . . . . . . . . . . . . . . 25, 39 Sangamo Biosciences Inc. (US). . . . . . . . . . . . . . 58 Saniona AB (DK). . . . . . . . . . . . . . . . . . . . . . . . . 33 Sanofi SA (FR). . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Sarepta Therapeutics Inc. (US) . . . . . . . . . . . . . . 58 Sartorius AG (DE). . . . . . . . . . . . . . . . . . . . . . . . 25 Scancell Holding plc. (GB). . . . . . . . . . . . . . 31, 61 Seattle Genetics, Inc. (US) . . . . . . . . . . . . . . 40, 63 Selvita S.A. (PL) . . . . . . . . . . . . . . . . . . . . . . 49, 64 Servier (FR). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Seventure Partners (FR). . . . . . . . . . . . . . . . . . . . 59 Siemens AG (DE) . . . . . . . . . . . . . . . . . . . . . . . . 60 Siemens Healthineers (DE). . . . . . . . . . . . . . . . . 72 Sigma Aldrich (US). . . . . . . . . . . . . . . . . . . . . . . 25 SkinBio Therapeutics PLC (GB). . . . . . . . . . . . . . 28 Solid Biosciences Inc. (US). . . . . . . . . . . . . . . . . 58 SphingoTec GmbH (DE). . . . . . . . . . . . . . . . . . . 70 Sumitomo Dainippon Pharma (JP) . . . . . . . . . . . 59 Summit Therapeutics plc (IE). . . . . . . . . . . . . . . . 58 Swiss Biotech Association (CH). . . . . . . . . . . . . . 48 Synpromics Ltd. (GB). . . . . . . . . . . . . . . . . . . . . 49 Targovax AS (NO). . . . . . . . . . . . . . . . . . . . . 32, 49 Teva Pharma (IL). . . . . . . . . . . . . . . . . . . . . . . . . 40 TG Therapeutics Inc. (US). . . . . . . . . . . . . . . . . . 33 ThermoFisher Scientific (US). . . . . . . . . . . . . . . . 25 Trianni, Inc. (US) . . . . . . . . . . . . . . . . . . . . . . . . 53 Truffle Capital (FR). . . . . . . . . . . . . . . . . . . . . . . 59 UBM (BE). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Verona Pharma plc (GB). . . . . . . . . . . . . . . . 28, 29 Vetter Pharma (DE). . . . . . . . . . . . . . . . . . . . 31, 46 Vifor Pharma AG (AT). . . . . . . . . . . . . . . . . . . . . 32 Wellcome Trust (GB). . . . . . . . . . . . . . . . . . . . . . 31 Wilhelm Bähren GmbH & Co. KG (DE) . . . . . . . 71 Xellia Pharmaceuticals ApS (DK) . . . . . . . . . . . . 23
Obseva AG (CH). . . . . . . . . . . . . . . . . . . . . . . . . 28 Oncoarendi Therapeutics SA (PL). . . . . . . . . . . . 64 Oncopeptides AB (SE). . . . . . . . . . . . . . . . . . 28, 29
Zealand Pharmaceuticals A/S (DK). . . . . . . . 28, 29 Zipongo (US) . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
02.03.2018 11:40:26 Uhr
82
Encore
Winners & losers
European Biotechnology | Spring Edition | Vol. 17 | 2018
I’m in biotechnology because …
T w ee t- o - Ta s t i c A
tweet hinting at a clinical breakthrough triggered a tripling of the stock price for British bi-specific antibody developer Hemogenyx. Even after the company revealed that the fuss was just about a patent application (and said sorry for the tweet), the price stuck at the dizzy new height.
Florence Séjourné CEO of Da Volterra SAS; President BEAM Alliance
Tweet-o-Dopey The stock price of Ax-
ova n t S c i e n c e s wa s slashed by 75% in January after the Swiss-based company said it will mothball its lead candidate. The corresponding tweet is rather straightforward: “Today, we announced negative results for intepirdine.”
“… it’s an incredible chance to wake up every morning looking forward to patients' improvement and life sciences contribution. In antimicrobial resistance, biotechs have an essential role in developing breakthrough innovations.”
Corporate VC big in UK
Dad’s age counts Epigenetics Working with mice, German researchers found age-associated traits in 19-month-olds differed depending on the age of their fathers. “Statistically, certain diseases occur more often in children of older fathers than in the offspring of young men. This is the case, for example, for autism or schizophrenia,” says Dan Ehninger, lab head at the German Center for Neurodegenerative Disease in Bonn, who addresses this observation with his expe riments. He observed, for example, differences in lifespan: Offspring of young fathers lived about two months longer than peers with older fathers. The scientists attribute these effects to epigenetic alterations in the sperm that are not completely erased upon fusion of sperm and egg cell (doi: 10.1073/pnas.1707337115).
average Europe United Kingdom
600
in million US$
400
200
2006
M&A fight @nature #minION Plasma biomarkers that can predict amyloid beta deposition in the brain — the earliest pathological signature of Alzheimer’s disease — are reported this week go.nature.com/2GVxqdG @nature Sanofi inks €3.9bn Ablynx buyout to pip Novo in M&A fight @BiotechSweden Convert Pharmaceuticals secures EUR 13,6 million to develop anti-cancer drugs @flandersbio
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After years of international collaboration, in 2001 we celebrated the 1st human
Please follow us @EuroBiotechNews genome. 17 years later, we‘ve got sequen cers the size of a smartphone & can read a human genome in 26h. Talk about progress. #minION @nanopore @sciencepractice
2008
2010
2012
2014
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Next issue summer edition Time flies and before you know it the autumn event season is at the door. Educated cherry-pickers trust the semi-annual Euro BioFairs Compass, which will accompany the summer issue of Euro Biotech. The magazine will be published on 21 June 2018. Due date for advertisements is 4 June. Questions will be answered by Andreas Macht (+49-30-264921-54) and Oliver Schnell (+49-30-264921-45). Or drop an email: marketing@biocom.de.
Picture: Europabio/Veldemanphoto; FARBAI/fotolia.com (bacteria icons)
0 2004
Source: ABPI
Corporate venture capital (CVC) plays an important role in the UK financing landscape. According to an analysis by the Association of the British Pharmaceutical Industry (ABPI), corporate related capital has been deployed in 101 financing rounds in the UK in 67 companies since 2001, with CVCs and their syndicate partners investing a total of US$2.5bn. Comparing European and UK financings with one or more CVC participants since 2004, increased CVC interest in UK financings is apparent.
01.03.2018 13:26:43 Uhr
Meet us at BIO-Europe Spring m in Amsterda14 March 12 –
Advancing Austrian life science // at the heart of Europe 2018 meet LISA at
HIMSS Annual Conference & Exhibition Las Vegas, 05.– 09.03 BIO-Europe Spring Amsterdam, 12.– 14.03. MT Connect Nuremberg, 25.– 06.04. BIO International Convention Boston, 04.– 07.06. CPhI Worldwide Madrid, 09.– 11.10. BIO-Europe Kopenhagen, 05.– 07.11. Medica Duesseldorf, 12.– 15.11. www.lifescienceaustria.at
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