LISAvienna Highlights 01/2015

Connecting Life Sciences

Highlights 01/2015

Future Hospital Trend: Fully Automated Blood Analyses

page 3

Life Science City Vienna: Broad Expertise in Cancer Research

page 7

Invest in Vienna Vienna is a great place to live, but is also great for revolutionizing technologies and innovative services as well as promising products for the future.

Interested in investing in Vienna?

Keep an eye on the inspiring opportunities we present below!

LISAvienna is happy to introduce you to the people in charge.

CVTec Cerebrovascular Technologies GmbH develops software for neurosurgery and neuroradiology to improve life-saving operations like the filling of cerebral aneurysms to avoid ruptures. The first product, CoilControl3D, an occlusion rate measurement system, will be available soon.

EMTensor GmbH develops compact-size devices, information processing systems and services, which will lead to a breakthrough in early stroke recognition. The proactive and preventive approach uses the properties of how electromagnetic waves spread in tissues for medical imaging.

EveliQure Biotechnologies GmbH develops vaccines to combat diarrheal diseases.

The company’s technology platform is based on a live attenuated Shigella vaccine strain able to induce broad protection against shigellosis.

It is suitable for expression of diarrheal antigens from other pathogens.

INOXIA Lifesciences GmbH focuses on peroxidase inhibitor development for the treat-

Š LISAvienna / Markus Schieder

ment of autoenzyme-induced diseases such as bronchial asthma and Ulcerative colitis.

Computer-aided drug design led to the discovery of a substance group with block buster potential.

MITI Biosystems GmbH is specialized in the production of polycyclic peptide libraries for the discovery of peptide drugs and mimotopes. Randomization techniques are applied to natural product peptide scaffolds in order to achieve enormously broad chemical diversity. mySugr Inc. specializes in diabetes education and management. FDA approved, CE marked mobile applications, video based trainings and remote coachings for children appreciated by over 200.000 people worldwide prove that everyday needs of people with diabetes can be combined with style, innovation and even fun.

ORIGIMM Biotechnology GmbH offers a better way to select highly protective antigens for vaccine production. Its protection-based vaccine discovery platform is available for partnering and applied for the development of the world wide first therapeutic vaccine against acne vulgaris.

Continue on page 3 www.cvtec.at www.emtensor.com www.eveliqure.com www.inoxia.at www.mitibio.com www.mysugr.com www.origimm.com

Dear readers!

Highlights – this is what we chose as the new title for our printed news update. It shall point out that we summarize top stories for you and that we put a spotlight on selected life sciences topics in Vienna that you should be familiar with. It of course also acts as a reminder that we do not intend to provide a comprehensive review.

This time, we draw your attention to inspiring business opportunities from biotechnology and medical device companies. We also discuss Vienna’s broad expertise in cancer research both in academia and as regards promising new drug candidates. You are also invited to find out more about how microparticles developed at the Austrian Centre of Industrial Biotechnology in Vienna help to bring protein production at Boehringer Inhgelheim’s BioXcellence to the next level. Innovations linked to fully automated blood analyses in Vienna’s hospitals also take center stage in one of the articles in the spring edition of our biannual publication.

At our initiative, European investors in biotechnology convene at “BioEquity Europe” in Vienna for the first time. Managing to also attract “EuroMedtech Europe” makes us even more proud. These first-class events confirm that the life sciences companies in Vienna have some extraordinarily promising business concepts.

The success stories of the past few months covered on pages 4 and 5 provide wonderful examples. New funding decisions, new deals and the announcement of the construction of a new building for the IMP at the Vienna BioCenter prove that Vienna is succeeding in stabilizing the upward trend in life sciences.

LISAvienna – Connecting Life Sciences LISAvienna is the joint life science platform operated by austria wirtschaftsservice and the Vienna Business Agency. On behalf of the Austrian Federal Ministry of Science, Research and Economy and the city of Vienna, it contributes to the advancement of life sciences in Vienna.

LISAvienna supports innovative biotech, pharmaceutical and medical technology companies in Vienna that develop and market new products, services and processes. The platform links these companies with development partners and key customers. As a central knowledge carrier, LISAvienna provides input for decisions to advance the life sciences in Vienna and contributes to positioning the city of Vienna as one of the leading European innovation centers.

Please visit our website www.LISAvienna.at to learn more about Vienna as a top location for life sciences!

Our Services

• Information & Consulting: Tips and contacts relating to sponsorship, private financing options, infrastructure in Vienna, development partners, leading customers and internationalization • Networking & Matching: Contacts for an improved exchange of experiences and knowledge transfer as well as contact with development partners, leading customers and investors worldwide

But for now, enjoy reading and remember: Starting-up in the heart of Europe and expanding to Vienna pays off!

• Expertise: Analyses, background information, reports and studies relating to life sciences in Vienna

Peter Halwachs and Johannes Sarx LISAvienna Executive Board

• Marketing: Electronic and printed news items from the field of life sciences in Vienna

Life Sciences in Vienna at a Glance

Meet LISAvienna

• 181 biotech/pharma companies with 13,300 employees • 197 medtech companies with 7,731 employees • 9,089 Million Euros revenues in total in 2012 • 25 research organzations employ 14,289 people in the life sciences • 38,290 students in the life sciences, thereof 3,608 graduates • 5,733 publications in international journals

• HIMSS15 Chicago, April 12-16, 2015

• IN3 EuroMedtech 2015 Vienna, June 10-11, 2015

• conhIT – Connecting Healthcare IT Berlin, April 14-16, 2015

• BIO International Convention 2015 Philadelphia, June 15-18, 2015

Statistics on the smart life science city Vienna!

Download the Vienna Life Science Report at www.LISAvienna.at and be invited to order your free print copy at office@LISAvienna.at.

NEW: LISAvienna e-Newsletter Stay updated on hottest news from the life science city Vienna!

Subscribe via e-mail to office@LISAvienna.at!

2

•

LISAvienna goes Asia WKO Austrian Showcase Life Sciences Singapore and Shanghai, May 10-18, 2015

• CMEF Spring 2015 Shanghai, May 15-18, 2015 • BioEquity Europe 2015 Vienna, May 19-20, 2015

In cooperation with:

• WKO Austrian Showcase Biotech/Pharma Israel Tel Aviv, September 6-9, 2015 • BIO-Europe 2015 Munich, November 2-4, 2015 • Medica 2015 Düsseldorf, November 16-19, 2015

Future Hospital Trend: Fully Automated Blood Analyses The quicker the laboratory provides results from blood samples, the better patients are treated. Fully automated “highways” for blood analyses in the background save patients’ blood and time and accelerate diagnosis and treatment in Vienna’s hospitals. They save lives and money.

One hour from the sample transfer to the submission of laboratory-analyzed findings – this is the ambitious goal that has been set and met with the help of new automated systems for blood analyses. At Vienna’s SMZ Ost, one of the large hospitals run by the Wiener Krankenanstaltenverbund (Vienna Hospital Association), such a system has been installed together with Siemens. Numerous technological and organizational innovations paved the way to successful implementation.

220,000 samples and some 5 million analyses

are handled by the blood analyses system at SMZ Ost each year. The system already in place allows routine blood analyses, but due to a joint innovation with Siemens, some special analyses can also be conducted in a fully automated way. Furthermore, a cooled archive has been developed for the storage of blood samples, which even allows for the automated re-analyses of samples several days after drawing blood. To ensure the system works as expected, a day a check is carried out multiple times a day using reference materials

and each analysis result is checked by the experienced team. For safety, the machines along the “analyses highway” are available in pairs and are in a constantly active mode. To make sure that the 1-hour-limit is actually met a large monitor lists all samples. A color code based on the time left for analyses and checks as well as for the approval of results makes it easy for all lab members to check whether everything is on track.

Why Vienna?

Continuation

Invest in Vienna Panoptes Pharma GmbH focuses on novel therapies for the treatment of severe eye diseases.

Panoptes’ clinical candidate is a selective immunemodulating inhibitor for severe and chronic uveitis.

This compound also reduces abnormal blood vessel growth in the back of the eye.

SCARLETRED Biomedicals GmbH links biomedical engineering and ICT. Its SCARLETRED® Vision system is the first e-medical device enabling real time monitoring and objective analysis of cutaneous drug effects and skin diseases in pre-/ clinical trials. It enables to significantly speed up biopharmaceutical drug development.

SIMCharacters GmbH breaks new ground in the development of small training simulators and combines know-how in the medical area, lifelike anatomy and high-class animation technology.

The aim of SIMCharacters is to improve the quality of care of critically ill children, especially term and preterm infants.

TAmiRNA GmbH is a biopharmaceutical R&D company founded to drive the discovery and de-

Highlights 01/2015

velopment of microRNAs (miRNAs) as tools for diagnosis and treatment of age-associated disorders such as osteoporosis, cardiovascular disease and neurodegenerative disease.

Themis Bioscience GmbH recently announced successful phase 1 results for its vaccine candidate to combat Chikungunya. The vaccine was developed in collaboration with the Institut Pasteur and is based upon a measles vaccine vector technology. Tolerability, safety and neutralizing antibodies have been demonstrated.

TUBE Pharmaceuticals GmbH focuses on developing small molecules derived from natural products into safe and efficient drugs. The company combines its toxin platforms with different conjugation-based targeting principles to create products addressing major disease areas with unmet medical needs.

VASEMA GmbH provides the world’s first non-invasive skin analyzer for measuring transepidermal water loss, which is certified as medical product class IIa. DermaMeter allows for quick and objec-

“

Walter Krugluger, head of the Department for Laboratory Medicine, Donauspital SMZ-Ost and coodinator of the Scientific Forum at the Vienna Hospital Association

Beside the treatment of over 400,000 hospitalized patients and over 5 million outpatients, the KAV performs investigator-driven as well as industry-driven research programs.

The large cohorts of well-defined patients with widespread chronic diseases enable the KAV to perform high quality research in many fields and operate as a strong partner in industry-driven clinical research. This led to over 150 publications in peer reviewed journals in 2013.”

www.wienkav.at

tive application, e.g. for the prevention and diagnosis of skin diseases and for monitoring wound healing. www.panoptes-pharma.com www.scarletred.at www.simcharacters.com www.tamirna.com www.themisbio.com www.tubepharma.de www.vasema.com

3

Bulletin d Boar

fund 10 new R&D Vienna Business Agency to iences Call 2014 projects within its Life Sc nted to Akron ion Euros have been gra In total, more than 2.6 mill r & Drbal GmbH, gge sse Gro Vaccines KG, Dr. Molecules AG, Blue Sky hnologie GmbH, GmbH, Marinomed Biotec Labdia Labordiagnostik Austria GmbH. ics GmbH, and Valneva OncoQR ML OG, Platom

additional Systems receives Miracor Medical te clinical validation and ra funding to accele of its PICSO® Impulse n io at iz al commerci System s and the

rfond and aws Gründe s BioMedInvest d tor es inv w ne e lta Th De Partners an Venture Capital, d bir rly Ea s . tor ros llion Eu existing inves estment of 4.5 mi the additional inv multi-center d an SHS – provided gle sin ral conducting seve y ntl rre cu is the PICSO or of Mirac effectiveness ther demonstrate complement in n sio clinical trials, to fur myocardial perfu ing ov pr im in ardial m Impulse Syste CI) in acute myoc ary intervention (P ron co us eo tan with percu . infarction patients

Horizon Discovery Group plc acquire s Haplogen Genomic s GmbH for 7.7 m illion Euros in cash and additional asse ts The business

will be renamed Horizo n Genomics GmbH and function as a wholly ow will ned subsidiary of Ho rizon Discovery Group expanding its laborator plc, y and office space in Vienna.

cy.at www.viennabusinessagen

UCL Cancer Inst itute favors TissueGnostics

“We have been usi ng the TissueGnost ics microscope platfo rm and hardware, and the TissueFax and His toQuest and Tissue Quest software applicatio ns for 3 years now.

I have worked in the field of academic and rou tine pathology and ima ge analysis for alm ost forty years and there is no doubt in my min d that the TissueGnostics sys tem provides the be st option for critical examinatio n of dye-stained sec tions, immunohistochemis try and immunoflu orescence at all levels.”

Geoffrey Boxer, De partment of Onco logy, UCL – Cancer Institu te, London, UK www.TissueGnos tics.com

t t developmen lys to augmen ta u D e ir u q Roche to ac antibodies ific of bi-specific human, bi-spec lopment of fully very and deve n USD izes in the disco of 133.75 millio Dutalys special cash payment nt fro up an e che will mak ts. antibodies. Ro stone paymen million USD mile 5 35 to and up

WWTF grants for 3 outstanding young researchers and 8 new imaging projects Chris Campbell, Martin Leeb and Jillian Peterson will join the University of Vienna and the Max F. Perutz Laboratories operated by the University of Vienna and the Medical University of Vienna. Each position is funded with up to 1.6 millio n Euros. The Vienna Science and Technology Fun d also strengthens the application of novel imaging tech nologies in biological and biomedical research proj ects in Vienna. In total, 4.4 million Euros have been gran ted to 8 research projects in 2014. www.wwtf.at

© TissueGnostics

4

Biomay AG phase IIB d reports positive tive 3rd geata with the innovaallergy va neration grass polle ccine BM3 n 2 B

iomay, a g lobal lead er in allerg announce y immuno d that a la therapy, ndmark P been succ hase IIb st essfully co udy has m p leted with grass polle its 3rd gen n allergy va eration ccine BM designed 32. The st to show su udy was stained alle symptom viation of a s over two llergy consecutiv seasons. e grass po llen

usiness aniel as new B Renée Gallo-D at Pfizer Austria Lead Vaccines rket ap-

eover of the ma mpletion of the tak en Following the co llo-Daniel has be Baxter, Renée Ga m fro s ine cc va proved it Vaccines. zer’s Business Un hired to head Pfi

IMBA: Brain model highli ghted in the “10 Breakthrough Technolog ies List”

The technology to grow three dimensional brain structures from human stem cells, has bee n named a top ten techno logy of the „MIT technology review“ . Each year their list iden tifie s the ten milestones from the past yea r that solve difficult problem s or create powerful new ways of usin g technology.

ts Pathfinder Wellcome Trust gran Award to Apeptico

y developing syneld biotechnology compan Apeptico is a privately-h makes it possible nt gra st The Wellcome Tru thetic protein structures. aritide’ for the ‘En nd pou com of Apeptico’s to further explore the role (PHA type 1b). oaldosteronism type 1b treatment of pseudohyp

© Pfizer

Valneva launches capital increase and enters sale and purchase agr ment with Crucell Holland B.V. ee-

The capital increase for a gross amou nt of approximately 45 million Euros follows the acquisition of Crucell Sweden AB, Dukoral (ETEC vaccine) and a Nordics vaccine distribution business.

noptes Ophthalmology company Pa nounce Pharma and Mediolanum an license agreement

and Mediolanum Laboratoires Panoptes Pharma Ges.m.b.H ts to transfer of the marketing righ Leurquin S.A. agreed on the This um. iolan Med to s ntrie n cou PP-001 over two main Europea y eye ator mm infla for t men elop dev small molecule is in preclinical s uveitis. diseases including non-infectiou

I

More news

For more news please visit our website www.LISAvienna.at

Highlights 01/2015

Vienna

Your news placed here

Vienna-based organizations are invited to e-mail news and press releases to news@LISAvienna.at to contribute to LISAvienna’s digital and print media.

5

austria wirschaftsservice: consistently promoting innovation Austria Wirtschaftsservice GmbH (aws) is the Austrian government promotional bank. aws offers Austrian companies financial assistance in the form of loans, guarantees, grants and/or equity as well as consultancy services from the start-up to the expansion phase.

On behalf of the Federal Ministry of Science, Research and Economy (BMWFW) we help you to profit from Intellectual Property Rights. Contact our consultants and explore support schemes such as the ones introduced here. aws IP.Financing: Support for the internationalization of patents with a non-repayable grant of max. 50% of the application costs resp. the nationalization of a patent in emerging countries and non-European growth markets such as China, USA, Mexico, India, Japan, Brazil and others. Maximum grant per invention/patent family: EUR 18,000, costs are capped for the individual countries.

aws License.IP: Small and medium enterprises are encouraged to profit from intellectual property developed by others, especially by public research organizations. aws offers support in the analysis of technology needs, identification of technological solutions, support in licensing negotiations and funding for the costs of in-licensing or purchase of patents and know-how. Up to 50% of licensing costs can be covered by a non-repayable grant (max EUR 200,000).

markets, locating patenting strategies or planning new business. This service is free of charge to SMEs. Costs for aws market research are generally between EUR 180 and EUR 2,500. www.awsg.at

aws Markt.Chancen.Check (aws Market Research): Market-, technology- or company data and high quality information are the key to identifying new marketing opportunities and new sales

Business Location Vienna.

The ideal location provides the best foundation. The Vienna Business Agency therefore supports relocating and expanding companies.

Apply now for your funding at viennabusinessagency.at Vienna supports economy.

6

Life Science City Vienna: Broad Expertise in Cancer Research Cancer is an undefeated threat. There is a great demand for improved diagnostics and better therapeutic approaches worldwide.

Vienna is Austria’s hot spot for cancer research and product development. Excellency in research is combined with innovative companies offering promising pipelines.

Cancer research represents one of five research clusters set-up by the Medical University of Vienna. MedUni Vienna is not only the largest medical organization in Austria, it is also one of the most important top-level research institutions in Europe and provides Europe’s largest hospital, the AKH in Vienna, with all of its medical staff. A strong bundling of skills from different disciplines is needed to benefit cancer patients. To achieve this, MedUni Vienna runs a Comprehensive Cancer Center.

Brimming pipeline In Vienna, Boehringer Ingelheim employs some 250 scientists at its fully integrated drug discovery center, which is solely focused on cancer. Novel targets, biomarkers, drug candidates and treatment modalities are investigated and both small molecule and biotherapeutic discovery schemes are available. A whole range of novel targeted therapies is in development in the areas of angiogenesis inhibition, signal transduction and cell-cycle inhibition. Within each of these three areas, the company has a substantial pipeline of molecules that are investigated in a number of solid tumors and hematological cancers. These include a signal transduction inhibitor that has been developed in Vienna and which is approved in the EU, the US and in other countries for the treatment of certain types of non-small-cell lung cancer. Additional compounds are currently in stage III trials.

Small but powerful Apeiron Biologics AG is a biotech company with a focus on immunological approaches to treat cancer. The company’s product portfolio includes antibody-based therapies and novel checkpoint blockade approaches: APN311 is a monoclonal chimeric antibody targeting GD2, produced in CHO cells and has shown efficacy against paediatric neuroblastoma. The project is close to submission for marketing authorization in EU and US. APN301 is a recombinant fusion protein of a hu-

manized anti-GD2 antibody and interleukin-2 and in phase II clinical development in neuroblastoma and melanoma. A broad program is pursued to develop therapies to selectively boost the immune system via checkpoint blockade to fight cancer: APN401 is a unique individual cellular therapy based on the cbl-b target, clinical phase I recently has started in the US. APN411 aims at development of low molecular weight compounds to boost immune cells via novel checkpoint blockade mechanisms, and is performed in collaboration with Evotec.

Immunotherapy, targeted toxins & vaccines Personalized cancer immunotherapy is being developed at Activartis Biotech GmbH. A randomized phase II study is ongoing that is investigating the treatment of glioblastoma with interleukin 12 producing dendritic cells charged with tumor antigens as an add-on to standard therapy. This therapy is tailored to individual patients and might be applied for other types of cancerous diseases.

At TUBE Pharmaceuticals GmbH, a variety of conjugation-based approaches is being combined with in-house toxin platforms to create targeted therapies for cancer and other major diseases. In the process, small molecules derived from natural products including tubulysins and their synthetic analogs as well as next generation epothilones

are being developed into safe and efficient drugs.

These highly cytotoxic substances are linked to a polymer to form a nanoparticle or for example to antibodies, peptides or small molecules and only become active within or near the tumor. At Biomedical International R+D GmbH, tumor vaccines are being developed. The aim is to actively stimulate the patients’ immune system to build up own protective antibodies. In a joint project with MediGene, a vaccine has been developed that is targeted against the HER-2 molecule, which is overexpressed in case of breast cancer, but also on many other human and animal tumors. The new vaccine is based on HER-2 mimotopes displayed by Adeno-associated virus particles. www.activartis.com www.apeiron-biologics.com www.boehringer-ingelheim.at www.biomed.cc www.meduniwien.ac.at www.tubepharma.de

Why Vienna?

“

Christoph Zielinski, Maria Sibilia and Michael Gnant Management Team, Comprehensive Cancer Center (CCC) of the Medical University of Vienna and the Vienna General Hospital

The core tasks of the Comprehensive Cancer Center (CCC) Vienna include clinical and translational research as well as basic science and interdisciplinary patient care.

The close interaction between scientists and clinicians allows a fast translation of new findings from bench to bedside and back. As a result, the CCC presently runs 261 trials and keeps developing new research projects.

In addition, about 8.000 patients with cancer are discussed yearly in interdisciplinary tumor boards.” www.ccc.ac.at

7

Innovation in Vienna: ACIB Micoparticles catch Proteins at Boehringer Ingelheim Boehringer Ingelheim, a leading biopharmaceutical contract manufacturer offers tailor-made services covering the entire production chain from DNA to fill and finish under one roof. In Vienna, Boehringer Ingelheim manufactures therapeutically active recombinant proteins and pDNA from microorganisms and yeast.

Boehringer Ingelheim in Vienna

The Austrian Centre of Industrial Biotechnology (acib) is one of the company’s most important R&D partners. To improve the purification process of biopharmaceuticals, special microparticles have been developed that are able to bind up to 150 milligrams of protein per gram of particle material.

The entire binding process is completed within 30 seconds. Traditional chromatographic purification procedures take several hours. To further accelerate biopharmaceutical purification on an industrial scale, a continuous system for routine microparticle application has been established as well.

Five in one step Georg Klima, Head of Biopharmaceutical Process Development at Boehringer Ingelheim Regional Center Vienna GmbH & Co. KG : “The economic relevance of this new procedure is linked to its convenience and speed. We have been able to combine five procedural steps into a single one.

In addition, we expect an even better quality, because the microparticles directly absorb the protein product out of the cells with high specificity. We therefore obtain a much purer product as compared to conventional methods.” A key issue was the transfer of technology from research into corporate labs, which was completed within a few

LISAvienna Life Science Austria Vienna Walcherstrasse 11A 1020 Vienna, Austria

PHONE FAX E-MAIL WEB

oyees

• 1,400 empl

ness aceutical busi tries ility for pharm Boehringer Ingelheim operates a firstthan 30 coun e • Responsib or m in ch ar se re al ic in and cl class biopharmaceutical manufacturch ing facility in Vienna. Several independcancer resear • Center for

rmaceuticals ent fermentation plants are available - for nce for biopha lle ce Ex of r • Cente E. coli and other bacteria as well as for bial systems from micro yeast technologies, and with a flexible facilities extension of scale of up to 6,000 L. Both batch and • Continuous fed-batch fermentations are performed.

On site expertise includes the development and manufacture of non-glycosylated proteins, antibody fragments protein scaffolds, and plasmid DNA (pDNA) according to GMP guidelines. Fill and finish of lyophilized and liquid drug product in vials for clinical supply is offered as well.

Why Austria?

New funding period In January 2015, acib started its second funding period with an overall budget of 65 million Euros.

More than 120 industrial and scientific partners join forces at this international research center to replace conventional industrial processes with new biotechnology-based processes. The center works towards better products and processes that are environmentally friendly and commercially attractive. The city of Vienna acknowledges these attempts and supports acib with up to 4.2 million Euros via the Vienna Business Agency. Styria-based SFG contributes an equal amount and Lower Austria and the Tyrol also support acib financially. The Austrian Federal Ministry of Science, Research and Economy provides some 20.8 million Euros via its COMET program administered by FFG.

Mathias Drexler, CEO acib GmbH

With an experience of 30+ years, acib researchers improve the entire production chain in industrial biotechnology. As a one-stop-shop for the industry, acib tranfers the economic and ecological methods of nature into industrial production.

Environmentally friendly and profitable processes or products are resulted in. These are valuable assets to business, research and society.”

www.acib.at www.boehringer-ingelheim.at www.bioXcellence.com

+ 43 (0) 1 50175 358 + 43 (0) 1 50175 900 office@LISAvienna.at www.LISAvienna.at

LISAvienna is the joint life science platform operated by austria wirtschaftsservice and the Vienna Business Agency. On behalf of the Austrian Federal Ministry of Science, Research and Economy and the city of Vienna, LISAvienna contributes to the advancement of life sciences in Vienna.

crevo.net

Laboratory staff at the biopharmaceutical production plant in Vienna, Austria

eim Farbe/colour: r Ing288elh BoehringePANTONE CV V nter ienna Regional Ce

© acib

© Boehringer Ingelheim

weeks. Georg Klima: “That is one of the reasons why the cooperation with acib is going so well.”