Meet the Biosimilar Believers

MAY 2018 #41

Upfront In My View NextGen Sitting Down With Grand challenge issued for Repurposing drugs with What drug discovery can gain Biosimilar backer a universal flu vaccine computational tools from artificial intelligence Cyrus Krakaria

12 20 38 – 39 50 – 51

Can copycat biologics really change the world? Or will disappointment haunt all our dreams?

26 – 35

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7. SHINYA 26 Feature YAMANAKA

D IREC T O R AND P R O FESSOR , C ENTER FO R IPS C ELL RESEARCH 2. CHRISTOPHER J.H. PORTER 5. RODERICK MACKINNON Shinya’s pioneering work on stem cells has gained him huge scientific PROFESSOR ANDND DIRECTOR, SCIENTIFIC CO-FO UNDER recognition. After reprogramming MONASH INSSTITUTE OF A ND CO-CHAIR, adult mouse (2006) and human (2007) PHARMACEEUTICAL SCIENCES MASTERS FLEX PHARMA somatic cells into what are now called “I’m motivvated by my next discovery; induced pluripotent stem (iPS) cells, OF THE however big or small. I became an A Nobel laureate and an endurance he was awarded a Nobel Prize in 2012. 9. ANDREAS SEIDEL- academicc because of the excitement, athlete, Roderick’s 2003 Nobel “Working on the medical applications MORGENSTERN BENCH wonder – and sometime panic! – that Prize was awarded for his work on of iPS cells is still my focus,” says discoveryy can bring. I now have ion channel activation. Thisw ork Shinya, “and I would like to see the DIREC T O R, MAX PLANC K scientific awards, including the United many differerent tasks to get through, went on to become the foundation of pharma industry collaborate more with I N S TITU TE FO R DYNAMICS States National Medal of Science, and but the bestt ppart of every day is still Flex Pharma’s clinical approach to academia to develop drugs for intractable O F COMPLEX TEC HNIC AL the 2002 Charles Stark Draper Prize the anticipationion of what the next muscle cramping – and the company diseases.” Asked what piece of advice S YSTEMS, MAGDEBURG (often considered the equivalent of the graph might show.w. I realize that this hopes to translate their findings into he would offer young researchers, 1. ROBERT SAMUEL treatments for patients with a range of he says “I wish I had improved my Andreas’ research focuses on LANGER Nobel Prize for engineers). is a utopian and perhapshaps unrealisticun It has been estimated that as many as aim, but I’d like to see a greater neuromuscular disorders which cause English communication skills in my developing concepts to better INSTITUTE PROFESSOR, two billion people may have had their emphasis on addressing unmet muscle cramps and spasms. 20s, because English proficiency is link the various steps involved in MASSA C HUS ETTS INS TITUTE O F lives touched by the technologies created medical need in a manner that is not crucial for scientists to better compete drug production. “I have a lot of T E C HNO L OGY , LANG ER LAB by Robert and his fellow researchers, driven by market size. Philanthropy 6. NICHOLAS A. PEPPAS or collaborate with researchers overseas.” ideas, and I am driven to evaluate and many of his former students have and public/private partnerships are their potential. This includes both The most cited engineer in history and gone on to great success in academia increasingly trying to redress this P R O FESSOR AND DIREC T O R theoretical concepts as well as one of the most prolific inventors in all and industry. “Working with wonderful balance, and have been successful 8.MICHAEL N. OF THETH INSTITUTE LIEBMAN practical implementations. I see it as of medicine, Robert has nearly 1,300 students and doing work that can make in certain areas, but there is much FOR BIOMOMATERIALS, a privilege that I can do this together issued and pending patents, many of the world a better place is what drives more that can be done.” DRUG DELIIVERY AND M ANAGING DIRECTOR AND with so many talented young people” which have been licensed or sublicensed me,” says Robert. “If I could change one REGENERATITIVE MEDICINE, F O UNDER, IPQ ANALYTICS LLC says Andreas. “I would like to see to over 350 pharma, chemical, biotech thing about the industry, it would be to 4. DAVID BALTIMORE THE UNIVERSSITY OF TEXAS more continuous production process and medical device companies. He find a way to get more funding for basic A T AUSTIN “There is an increasing need to applied in the pharma industry.” has been honored with over 200 major research that could help pharma.” PRES IDENT EMERITUS AND understand and address the complexities R O BERT ANDREWS MILLIKAN “This has been a banner year for my of disease in terms of clinical 10. CHI VAN DANG PROFESSOR OF BIOLOGY, team, with achieievements including presentation, patient diversity and C ALIFO RNIA INS TITU TE O F our new treatmment for hemophilia physician practice and this can only be SCIENTIFIC DIREC T O R , T ECHNOLOGY using oral delielivery of hematological achieved through more critical analysis LUDWIG C ANC ER RES EARC H and his fellow “CRISPR Pioneers” were 3. CARL JUNE factor IX, anand our work developing and less dependency on technology. named as runners up in Time Magazine’s David Baltimore’s love for research drug deliverydeliv systems of siRNA and My career advice? There are no bad Chi is well-known for his contributions R I C HARD W. VAG UE PRO FESSOR Person of the Year. “Success is the sum of was born after spending a summer interferons.inter I am driven by a continuous experiences, only new opportunities to to the understanding of the Myc I N IMMUNOTHERAPY, intelligence, energy and persistence – and seeing scientists at work at the excitement to devise new treatments, learn and improve.” oncogene – his research has led to studies UNIVERS ITY O F PENNS YLVANIA ending the cancer epidemic is what drives Jackson Laboratory in 1955. Since new therapeutic agents, and dedicated to the targeted disruption of me to succeed. In pharma, I’d like to see then, his achievements include Carl is also Director of the Center for more long-term vision, rather than quarter- a National medal of Science and new medical devices that aberrant cell metabolic pathways, with Cellular Immunotherapies at the Perelman to-quarter milestones.” a Nobel Prize in 1975 for will help patients who the aim of developing drugs to inhibit School of Medicine, Medicine Director of the discovery of reverse suffer from debilitating cancer. “Patients dying of cancer remind Translational Research Programs and transcriptase, which implied d i seases. I a m me every day why I do what I do. As with Director of the Parker Institute for that cancer could be caused particularly interested everyone else, my life has been personally Cancer Immunotherapy, both at by genetic means – a wide- in understanding touched by cancer, and as a trained the University of Pennsylvania. open question at the time. the mechanisms medical oncologist, I am humbled by He is also Co-Founder and He has played a significant a nd providing cancer as a formidable foe. A career is chief scientific advisor of role in the development of innovative treatments a journey in continuous learning – I Tmunity Therapeutics. Carl biotechnology since the 1970s.970s. for autoimmune diseases.” learn something new every day.”

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The Power List 2018

Did you miss out on the April 2018 print issue of The Medicine Maker? Our April issue included our annual Power List of the top one hundred professionals in drug development divided into four categories: Masters of the And Coming Up Next Month…. Bench, Industry Influencers, Business Captains, and Champions of Change. Want to find out who topped each category? You can view the full list on The three top winners of The our website: https://themedicinemaker.com/power-list/2018/ Medicine Maker 2017 Innovation Or check out our social media coverage of the Power List: Awards – SGS, OUAT! and GE Healthcare – share the stories behind Twitter @medicinemaker their technologies. And look forward LinkedIn Showcase The Medicine Maker to the opening of nominations for Facebook themedicinemakermag the 2018 Innovation Awards!

www.themedicinemaker.com ISSUE 41 - MAY 2018 Contents Editor - Stephanie Sutton [email protected] Deputy Editor - James Strachan [email protected] Deputy Editor - Roisin Mcguigan [email protected] Content Director - Rich Whitworth [email protected] 13 Publisher - Richard Hodson [email protected] Sales Manager - Helen Conyngham [email protected] Business Development Executive - Sarah Griffith [email protected] Head of Design - Marc Bird [email protected] Junior Designer - Hannah Ennis [email protected] Digital Team Lead - David Roberts [email protected] Digital Producer Web/Email - Peter Bartley [email protected] Digital Producer Web/App - Abygail Bradley [email protected] Audience Insight Manager - Tracey Nicholls [email protected] Traffic & Audience Database Coordinator- Hayley Atiz [email protected] Traffic and Audience Associate- Lindsey Vickers [email protected] Traffic and Audience Manager Jody- Fryett [email protected] Traffic Assistant Dan- Marr [email protected] Events Manager - Alice Daniels-Wright [email protected] Marketing Manager - Katy Pearson [email protected] Financial Controller - Phil Dale [email protected] Accounts Assistant - Kerri Benson [email protected] Chief Executive Officer - Andy Davies [email protected] 10 Chief Operating Officer - Tracey Peers [email protected] Senior Vice President, North America - Fedra Pavlou [email protected] Change of address: [email protected] 03 Online This Month Upfront Hayley Atiz, The Medicine Maker, Texere Publishing, Haig House, Haig Road, Knutsford, Cheshire, WA16 8DX, UK 10 Print it, Eat it General enquiries: 09 Editorial www.texerepublishing.com [email protected] Open Your Mind, 11 Wake Up and Smell the Polymer +44 (0) 1565 745200 by Roisin McGuigan [email protected] 11 Trials of a Medicine Maker Distribution: The Medicine Maker (ISSN 2055-8201), is published monthly by Texere Publishing, Haig House, Haig Road, Knutsford, Cheshire 12 Go Forth and Find a Flu Vaccine WA16 8DX, UK Single copy sales £15 (plus postage, cost available on request On The Cover Cover 13 A Life Too Short [email protected]) Non-qualified annual subscription cost is £110 plus postage MAY 2018 #41 Biosimilars seek to change the 14 Staying on Target Reprints & Permissions – [email protected]

Upfront In My View NextGen Profession Grand challenge issued for Repurposing drugs with What drug discovery can gain Top career tips from CEO a universal flu vaccine computational tools from artificial intelligence Annalisa Jenkins The opinions presented within this publication are those of the authors 12 20 38 – 39 46 – 49 world through love, lower drug Then I Saw the Biosimilars and do not reflect the opinions of The Medicine Maker or its publishers, Data…

Now I’m a Believer

26 – 235 costs and improved access for all. Texere Publishing. Authors are required to disclose any relevant financial 16 Business-in-Brief arrangements, which are presented at the end of each article, where relevant. © 2018 Texere Publishing Limited. All rights reserved. Reproduction in whole or in parts is prohibited. www.themedicinemaker.com 16 Get ’Em While They’re Young ARE YOU LOOKING FOR EXPERTS IN

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In My View Reports

20 Computational tools can help us 18 Stay Ahead. Smart repurpose old drugs for rare Risk Management diseases, says Misagh Naderi. 24 Industrializing Cell Therapy 22 Jeremy Drummond believes that breathing new life into old drugs could benefit those with eye disease. NextGen

40 Medicina Ex Machina Pharma drug discovery can be 50 Feature incredibly inefficient, but artificial intelligence and deep 26 I’m a (Biosimilars) Believer! learning can help. Is it time to end the skepticism around biosimilars? Our gurus 46 Recognizing Friend from Foe Sitting Down With say these medicines are safe, will How can we teach the bring down drug costs and immune system to recognize 50 Cyrus Krakaria, President increase access to much-needed biological drugs as partners of Biotechnology for Lupin treatments. rather than invaders? Limited, Biotech Division, India.

www.themedicinemaker.comwwww.t.ththemedicinemakerm ker.ccomm

Open Your Mind Is the pharmaceutical industry overly reluctant Editorial to accept new ideas?

t is universally acknowledged that the pharmaceutical industry can be conservative and slow to embrace change. With the health and safety of patients at Istake if something should go wrong, this is hardly surprising. But does pharma’s skepticism run too deep? I recently had the pleasure of speaking with Alex Zhavoronkov, CEO of Insilico Medicine – a passionate supporter of artificial intelligence (read more on page 40) and a true believer of its transformative potential in drug discovery. Insilico Medicine is working with Juvenescence to identify preclinical compounds, but there are other companies grabbing headlines in the AI/pharma space; take BenevolentAI, which is attempting to gain new insight into the molecular mechanisms of disease and to match patients to the right drug. The company was valued at $2 billion after its latest round of funding (1). AI has been touted as a technology to watch for some time across diverse industries, so I was a little surprised when Alex told me about the skepticism and disinterest he’d encountered within big pharma. “AI is moving too fast.” “AI isn’t ready for primetime.” References AI is certainly new ground for pharma, so perhaps (healthy) 1. CNBC, “AI pharma start-up BenevolentAI skepticism is to be expected. But what about more established now worth $2 billion after $115 million industry innovations, such as biosimilars? Biosimilars have funding boost”, (2018). Available at: bit.ly/ been available in Europe for years but skepticism remains. In BenevAI. Accessed May 4, 2018. our cover feature on page 26, several experts tackle common safety “myths” and lay out the path towards more rapid adoption – in a word: education. Both AI approaches and biosimilars have the potential to transform our industry. So it seems a shame that proponents must waste time and energy on the seemingly Sisyphean task of “arguing the case” rather than developing innovative lines of thinking. Though there will always be those who are ahead of the curve in science, perhaps pharma as a whole could benefit from keeping a more open mind – providing patient safety comes first, of course.

Roisin McGuigan Deputy Editor

www.themedicinemaker.com 10 Upfront

Print it, Upfront Eat it Reporting on research, Could drug-containing QR personalities, policies and codes ﬁght fakes and avoid partnerships that are medication errors? shaping pharmaceutical development and With the rise of the smartphone, we have all become familiar with the QR code manufacture. – used for everything from boarding an aircraft to paying for a service. But what information and expiration dates, and more. We welcome information if you could eat one and receive a dose “On average, it takes around 4 to 7 minutes on any developments in of medicine? to print therapeutically relevant doses with A team from the University of the advanced printer we used in this study,” the industry that have Copenhagen have taken the QR code a adds Magnus Edinger, a PhD fellow who really caught your eye, step further, creating a system to print worked on the project. in a good or bad way. QR codes on to an edible material as a Genina says the system has the potential Email: stephanie.sutton@ means to create personalized medicines. to tackle counterfeit medicines and “It actually started out as a funny idea medication errors. “Current medicines texerepublishing.com briefly discussed over lunch,” says Natalja are mostly in the form of plain white Genina, co-author of the associated tablets with few, if any, distinguishing paper (1) and assistant professor in the characteristics. This can potentially allow Group of Manufacturing and Materials counterfeits to enter the supply chain. at the University of Copenhagen. “Then Incorporation of QR codes as anti- we realized that it could actually be counterfeiting features can help minimize used. First, we identified the gaps in the risk of getting a fake medicine. The conventional medicines. Second, we encoded information will also ensure that pinpointed the unique possibilities the patient takes the right medication at of inkjet printing technology that the right time and in the right way. For can be used in the production of example, an alarm can be encoded into a medicine. And, as the world is mobile phone, reminding the patient to now driven by digital devices scan and administer the QR code dose,” and interconnected through explains Genina. the Internet of Things, we used Genina and her team believe the our creativity and knowledge technology is ready for implementation, to combine all the factors and but it will be difficult to predict when it came up with the idea of the may hit the market. She adds, “We are edible QR code”. now studying the following scenarios: The team uses ink-containing manufacturing of patient-oriented active pharmaceutical medicine at the pharmacy, in the ingredients, which are placed pharmaceutical industry, and even in the on an edible “paper” in the form patients’ home.” of a QR code using inkjet printing. The QR code is resized to produce Reference the right dose, and contains a host of 1. M Edinger et al., “QR encoded smart oral dosage relevant information – which can include forms by inkjet printing”, Int J Pharm, 536, the patient name, the dose, manufacturing 138–145 (2018), PMID: 29183858. Upfront 11

collaborators at the Massachusetts Institute of applications, particularly for patient Wake Up and of Technology, is working to develop new populations who have difficulty swallowing polymer gels with improved safety profiles. capsules and tablets. It’s also possible to Smell the Polymer The majority of gels are created using fine-tune the properties of the gels. “We traditional metal catalysts, which can pose have demonstrated the capacity to tune Caffeine isn’t just a catalyst to a toxicity risk if any of the catalyst remains the surface properties of these gels by get you moving in the morning in the gel after it is formed. recreating the surface pattern of the lotus – it can also help create In particular, Traverso and his team leaf on the gels and thereby modulating polymers for drug delivery have hit upon a novel catalyst with low the hydrophobicity of the material,” says toxicity in the form of the well-loved Traverso. Altering the gels in this way could Biocompatible gels have a range of friend of the coffee drinker: caffeine (1). be used to impact how quickly or slowly they applications in the pharma industry, “We used caffeine, a weak base, to catalyze move through the patient’s digestive tract. including drug delivery. Giovanni Traverso, anhydrous carboxylate ring-opening of assistant Professor of Medicine at Harvard diglycidyl-ether functionalized monomers Reference Medical School and a gastroenterologist in with citric acid,” explains Traverso. 1. AM DiCiccio et al., “Caffeine-catalyzed gels”, the division of gastroenterology at Brigham The gummy polymer gels created Biomaterials, 170, 127–135 (2018). PMID: and Women’s Hospital, along with his using this method could have a range 29660635.

For more adventures featuring Gene and Eva check out our website themedicinemaker.com/additional-data/cartoons If you have any ideas you’d like to see in future comic strips about bioprocessing then get in touch with us at [email protected] or look up #TrialsOfAMedicineMaker on Twitter.

Brought to you by GE Healthcare 12 Upfront Kjetil Ree Kjetil

from morbidity and mortality caused by understanding about the nature Go Forth and all subtypes of circulating and emerging of the influenza or immune (drifted and shifted) Influenza A subtype response; and applications of new Find a Flu viruses and Influenza B lineage viruses technologies for disease protection. for at least three to five years”. • Enabling advances: including Vaccine The foundation is looking for “bold challenge models to quickly ideas” and “unconventional approaches” demonstrate safety and proof-of- Bill Gates has issued a – not marginal improvements or concept for influenza vaccines. challenge – and signiﬁcant precedential approaches, such as the use funding – to help researchers of biosimilars, monoclonal antibodies, The aim is to develop a vaccine that push for a universal ﬂu or the development of new assays, is ready to start clinical trials by 2021. vaccine adjuvants, and so on. Examples of what Pilot funding will be offered in the the foundation is looking for include: region of $250,000 to $2 million. Upon The year 2018 marks the centenary of the demonstration of proof-of-concept, a flu pandemic that killed around 50 • Antigen-centric: discovering new projects will be invited to apply for a full million people worldwide. Since then, antigens/targets through artificial award of up to $10 million. Applicants significant efforts have been made to intelligence or deep learning. don’t need to have an industry partner, fight the flu, but a universal flu vaccine • Host-centric: approaches that but such collaborations will be still eludes us – and thousands continue generate, enhance, or modify considered. Industry is also welcome to die every year. In late April, the Bill human immune protection, or to apply. and Melinda Gates Foundation launched that ensure longer term immune a $12 million Grand Challenge: “[to] response. If you think you’re up to the challenge, identify novel, transformative concepts • Technology-centric: including bear in mind that the deadline for that will lead to development of universal novel vaccine concepts, targets submissions is June 22, 2018: influenza vaccines offering protection and constructs inspired by new https://bit.ly/2HwEI7F. Upfront 13

processing. “There is a real biological group, it was theorized that they could A Life Too Short link between progeria and normal aging. help progeria patients. We now know that progerin is made in Treatment with lonafarnib alone Researchers celebrate a new all of us, but at a much lower rate than compared with no treatment was breakthrough into progeria, in children with progeria. Progerin associated with a significantly lower and urge others to help them is found in cells of the cardiovascular mortality rate (3.7 percent versus 33.3 ﬁnd a cure system and increases at about 3 percent percent) after a median of 2.2 years each year that we age,” says Gordon. of follow up (1). “This is an incredibly Countless rare diseases remain short amount of time to achieve uninvestigated by big pharma, leading statistical significance. And we also have non-profit organizations to step up to supportive data that we have previously the challenge themselves. In the case published showing lonafarnib’s influence of the Progeria Research Foundation on the cardiovascular system and skeletal (PRF), their efforts have resulted in systems. It shows us that gold – for the first time ever a drug we can make progress,” has been shown to increase survival. says Gordon. Clinical trials that increase survival But she also stresses are always heartening, but even that pharma needs to more so when the patients do more to support rare are children. diseases. PRF is hoping “Progeria is a rare, to eventually see lonafarnib fatal, pediatric disease become FDA approved – but that causes rapid aging. that’s a huge challenge for a Without progeria-specific non-profit organization and its treatment, children with collaborators. “We need to progeria will die of heart fund much more research disease at an average age of into progeria. There are 14 years,” says Leslie Gordon, brilliant scientists that medical director and co-founder can help us make big of PRF. “The Progeria Research breakthroughs, but we need Foundation was founded in to support their efforts,” says 1999 by the parents of a child Gordon. “The only way to treat with progeria, in response to and cure these fatal diseases is a complete lack of medical to work together – the rare and scientific progress to help disease communities, patient these children.” organizations, academia, the Working with patient National Institutes of Health, families, pediatricians, and the FDA and pharma. I’ve academic researchers, PRF has love to see more incentives and rewards uncovered a number of scientific insights for pharma to get involved with rare into progeria.over the last two decades. diseases. This is an opportunity to save The disease is caused by a genetic The discovery led researchers to children – and make new discoveries in mutation in the LMNA (lamin A) gene, investigate Farnesyltransferase inhibitors aging and atherosclerosis.” and results in the over-production of a (FTIs), particularly FTI lonafarnib, protein called progerin, which causes which has mainly been studied in solid Reference premature aging of the body’s cells. tumors. To block normal cell function 1. LB Gordon et al., “Association of Lonafarnib After the gene discovery, PRF-funded and cause progeria, a farnesyl group Treatment vs No Treatment With Mortality researchers began an intense study of attaches to the progerin protein. Since Rate in Patients With Hutchinson-Gilford progerin and its post-translational FTIs inhibit attachment of the farnesyl Progeria Syndrome”, JAMA (2018).

www.themedicinemaker.com 14 Upfront

of the Rejniak Lab at the Integrated tissue histology images or fluorescent Staying on Mathematical Oncology Department images as a domain for mathematical at the H. Lee Moffitt Cancer Center & models and to test whether drugs or Target Research Institute in Tampa, Florida, imaging agents will penetrate tumor are part of a team that has combined tissue differently depending on cellular What characteristics make a mathematical modeling and single- and stromal architecture. cancer therapy more likely to cell imaging of cancer cells to better effectively treat disease? understand what drug properties make How does your approach work? for more efficient drug uptake (1). Here, KAR: The Analytic Microscopy Core Targeted therapies have had a huge we find out more. at our Cancer Center provide us with impact on cancer treatment, in some digital images of tumor histology. We cases significantly improving patient What inspired you to investigate then develop computational routines to survival – but not in all cases. To treat this problem? discretize these images, select tumor the cancer, the drug must, of course, Katarzyna A. Rejniak (KAR): cells, determine their sizes and shapes, reach the tumor tissue and be taken up Our extended team combines and use them in our computational by cells, but this doesn’t always happen mathematicians, chemists, biologists models. Our models also contain effectively despite targeting efforts. and image analysis experts. Working in drug molecules with pharmacokinetic Why not? the Cancer Research Institute allowed and pharmacodynamic properties of Tumors and their surrounding us to participate in seminars in which experimental drugs or biomarkers. environments are complex and pathologists and cancer biologists We run multiple simulations in which heterogeneous – resulting in different discussed the use of medical images we change some drug properties or responses to the same drug. Katarzyna in cancer diagnosis and treatment drug administration schedules to see A. Rejniak and Aleksandra Karolak monitoring. We decided to use tumor if we can achieve more efficient drug ALL YOU NEED FOR MABS, FABS & scFvs PROTEIN A & PROTEIN L CAPTURE MEDIA PROTEIN A - FOR FAST TITER DETERMINATION IEC, HIC & MULTIMODAL POLISHING MEDIA TSKgel UP-SW - FOR AGGREGATE ANALYSIS

VISIT US ON WWW.TOSOHBIOSCIENCE.DE OR CHECK OUT OUR CLIPS ON mAb PURIFICATION & ANALYSIS ON WW.YOUTUBE.COM/USER/TOSOHBIOSCIENCEGMBH distribution within the tumor tissue and individual cells.

What drug characteristics did you find to be most important for uptake? Aleksandra Karolak: The answer is some biophysical and biochemical drug current plan is for animal studies first, complex… The successful recognition properties including size, molecular weight, but we hope that this approach will of drug molecules by receptors and high charge, hydrophobicity, or conformation have translational potential. One of the affinity binding plays a pivotal role in the must be adjusted. In our model, we vary outcomes of our published work was that formation of drug-receptor complexes. these drug properties to explain on the by changing the way the same drug was However, we didn’t quite expect to see single cell level why certain drugs could be administered (slow or fast release) it was that the fast release scheme of a drug more successful in reaching distant cells possible to either saturate cells located could lead to increased uptake for moderate than others. near the vasculature or far from the affinity drugs. On the other hand, because vasculature. Thus, we proposed a way of multifaceted barriers, efficient drug What’s next? to predict how to administer a drug to uptake by cells with limited access to KAR: We hope that micro-pharmacolog y increase its effectiveness. drug molecules won’t be improved until techniques developed by us and others receptor-ligand contact takes place. will allow drug efficacy to be tested Reference Here, the impact of affinity and within the tumor tissue before the drugs 1. A Karolak et al., “Targetingg ligand specificity release scheme becomes less are tested in animals. We are starting to linked to tumor tissue topologicalopologica heterogeneity important, at least until drug examine how to stratify tumors to match via single-cell micro-pharmacologicalpharm cological molecules reach the distant them with the most effective treatment modeling”, Sci Rep, 8, 363836 8 (201(2018).8). cells. For this to happen, based on our simulation studies. The PMID: 29483578.

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Business Biosimilars in Brief • Sandoz’s rituximab biosimilar application to A knockback for the FDA has been rejected. The biosimilars in the US, company received a completete patient engagement, response letter in early May.ayy. and contaminated blood The reasons for the rejectionon products… What’s new for have not been disclosed. “WhileWhW ile mamakeke “meaningful“meaningful pharma in business? disappointed, Sandoz remainsains papatienttient engagementengageme in the life committed to further discussionsssions cycycleclle of medicinesmedicine a reality”. Facilities with FDA in order to bring this PAPARADIGMRADIGMM stands for Patients important medicine to US patientsents Active iinn ReResearchs and Dialogues • The UK’s Cell and Gene as soon as possible,” Sandoz said for an ImprovedIm Generation of Therapy Catapult has opened in a statement. Rituximab was Medicines, and is funded by a manufacturing center in approved by the EMA in June the EU’s Innovative Medicines Stevenage, UK. The center was 2017 and is marketed as Rixathon. Initiative. It is described as an open backed by over £60 million from • Herzuma, a biosimilar forum on patient engagement. the UK government and has trastuzumab (Herceptin), is • AstraZeneca is collaborating the infrastructure to develop now available in Europe for the with Lucy Cavendish College manufacturing capability for large treatment of early breast cancer. at Cambridge University to help scale cell and gene therapy clinical It is the third biosimilar to be women advance in science and studies. The center will also marketed and distributed by the business leadership. Employees supply the network of world-first, Mundipharma network in Europe. will mentor students by supporting UK-based Advanced Therapies Marketing authorization was their scientific developments Treatment Centers, which will granted in February 2018. and offering career and personal develop and deliver the therapies. • A report from development advice. • A new R&D center is on the cards ResearchAndMarkets.com for WuXi AppTec, which has just (Biosimilars Market by Product, Controversy signed an investment agreement Manufacturing Type and by with the government of Shanghai Disease – Global Forecast to • A public inquiry will begin in the Jinshan District in China. The 2023) has forecast the global UK later this year on the tainted new center will be located next market for biosimilars to grow at blood scandal of the 1970s and 1980s, to the existing Jinshan drug a CAGR of 31.7 percent, to reach when more than 3000 people were substance manufacturing site, and $23.63 billion by 2023. The non- infected with HIV and Hepatitis will add more than 30,000 square glycosylated proteins segment C. Campaigners are pushing for meters of laboratory space and accounted for the largest market the inquiry to examine the role of 500 scientists. share of the market in 2017; pharmaceutical companies. • In the US, Mayne Pharma however, recombinant glycosylated • Biohacker Aaron Traywick, CEO has opened a new $80-million proteins are expected to hold the of Ascendance Biomedical, has facility, which will quadruple largest share of the market during died. Traywick was known for the company’s capacity to the forecast period. developing and self-administering manufacture oral solid-dose CRISPR-Cas9 gene editing pharmaceuticals. The facility Collaboration technologies – and even injected is located in Greenville, North himself with an untested herpes cell Carolina, and can also cope with • PARADIGM is a new therapy in front of a live audience the commercial scale manufacture collaboration between 34 public earlier this year. The cause of death of potent compounds. and private partners, launched to has not yet been revealed. Upfront 17

of the right amount of medicine, information on labels, expiry dates and storage of medicines. Some workshops have also included discussions about different types of medicines, such as inhalers that deliver drug directly to the lungs, and the production process for making medicines. “There are already mechanisms in place to support medicines safety with children, but a lot of this is often aimed at the parent. If we can build things like this into education curriculums in a supported way, then we know we are getting the message to those most at risk,” says Brown. “It’s also been good for the pharmacy students, who learn to ‘pitch’ medical information at different levels to a diverse audience.” The big question is, should pharma get involved? Brown urges companies to consider reaching out to local schools. “Schools are always welcoming of initiatives like this where they can engage with external ‘experts’ and deliver on a key aspect of the curriculum, and I think companies have that expertise and can deliver interactive sessions which would allow children to experience some of the ‘real life’ science in the context of their learning,” she says. “It’s also a great way to promote science and encourage children to get involved.” Get ‘Em While They’re Young

Pharmacy students take medicine safety lessons to school classrooms

Pharma companies and pharmacists go a long way to try and teach patients to be safe around medicines and to read medicine labels and leaflets. But let’s be honest: human nature means that people often don’t pay much attention. At Robert Gordon University in Scotland, pharmacy students have found that children are very keen to soak up information about medicine safety, and so the university has partnered with local schools in Aberdeenshire to conduct workshops. “Increasing use of social media and the accessibility of information means that children and adults have developed a wider understanding of some of the issues around medicine, but not everything on the Internet is correct so we need to communicate messages in others ways too,” says Alyson Brown, Pharmacy lecturer at Robert Gordon University. “We tried to make it as fun and interactive as possible. We used placebo or pretend tablets for the pupils to count and label, and they measured liquids using different types of apparatus.” The agenda covers more than simply explaining why medicines are kept out of reach, by delving into the importance 18  SponsoredSponnsored FeatureFFeaturre

StayStay AAhead.head. SmartSmart Risk Management

As supply chains become increasingly complex, collaboration between biopharmaceutical customers and suppliers is crucial for supply continuity and control.

By Dawn MacNeill

There is tremendous growth within the biopharmaceutical industry. Patient demand for life-saving and life-enhancing medicines is MRGVIEWMRK HVMZMRKWGMIRXM½GERHXIGLRSPSKMGEP advances in drug discovery, development and supply gaps, and inform our manufacturing. As a result, biopharmaceutical Meet the capacity plans and capital manufacturers are intensifying their speed Expert: Aida investments. The S&OP to market, increasing their capacity and Tsouroukdissian process is the basis of optimizing their productivity. With rapid our monthly “consensus” growth and geographic expansion comes I am Head of Demand demand plan for the an extended supply chain with more Planning, Integrated Supply next 18-24 months. complexity and vulnerability to supply chain Chain Operations, at Merck. On a quarterly and bi- disruptions, such as natural disasters. At the My team focuses on attaining annual basis, we review our same time, there is strengthened regulatory an accurate demand and forecast to TSVXJSPMSW[MXLQEVOIXMRKXSHI½RI oversight of supply chains to assure patient drive the right supply chain activities a 5-year long range plan and a 10-year access to quality drug products. To stay at the right times to meet customer strategic plan, respectively. ahead, manufacturers and suppliers must requirements. We are responsible This S&OP process has also been collaborate to ensure continuity of supply. for securing and managing the global extended to some of our customers Together, we must make “risk-smart” demand of our Process Solutions and critical suppliers directly, with decisions to strategically balance the portfolio through a collaborative whom we have partnered to increase need to invest in capacity expansions and effort with our commercial, marketing transparency and reduce the risk of supply chain innovations to continuously and operations teams. The portfolio a supply disruption. These supplier- supply customers with the right, high includes single-use systems, assemblies partner relationships are becoming quality products in the right place at the and components, aseptic, virus and TFF more important to maintain service right time with the need to continually ½PXIVW GLVSQEXSKVETL] GIPP GYPXYVI levels that keep pace with the mitigate risks and minimize supply media, chemicals and more. anticipated ramp-up in the industry. disruptions. The routine, reliable supply We use a Sales and Operations I find it very interesting and of products depends upon a disciplined Planning (S&OP) decision making rewarding to collaborate with approach to supply chain management, process to understand the market customers, suppliers and colleagues from demand planning, materials/supplier dynamics, drive production planning in this way. It’s all about preparing for management, production planning, and requirements, reconcile our demand- the future and mitigating risks! manufacturinggyg to inventory management, warehousing,warehousing, didistribution,stribution, andand llogistics.ogistics. andannd more importantly,importanttlly, MeetMeet thethe collaboratecoc llaborate withwith themthem to Expert:p MichaelMichael developdevelop rriskisk mitigationmitigation pplanslans DonahueDonahue – rereducingducing rriskisk uupstreampstream greatlygreatly improvesimproves tthehe ToTo maximizemaximize resresiliency,iliency, we execute a I am HHeadead of PProductionroduction TVIHMGXEFMPMX]SJSYV½RMWLIHTVIHMGXEFMPMX]SJSYV½RMWLIH multi-faceted, “risk-smart” aapproachpproach to Planning,Planning, InteIntegratedgrated SSupplyupply goodsgoods outoutputput ddownstream!ownstream! supplysupply cchainhain rriskisk mmitigation.itigation. LLeveragingeveraging ChainChain Operations, at Merck. MMyy ToTo mitigatemitigate suppsupplyly didisruptions,sruptions, yearsyears ofof exexperience,perience, market intelliintelligence,gence, teamteam focuses on our upstream supplsupplyy supplysupply chainchain mappingmapping isis essential.essential. WWee use productdt and d process knowledge, k ld we chainh i ffrom materialst i l managementt an effectiveff ti ttooll fromf a lleadingdi supplyl proactively identify and prevent potential XS½RMWLIHKSSHWQERYJEGXYVMRK chain mapping/resiliency company. risks through effective capacity planning, We’re responsible for buying raw Some customers and several suppliers business continuity planning, supplier quality materials, managing inbound material use the same tool, which provides alerts management, change control management, ¾S[[EVILSYWMRKVE[QEXIVMEPW on relevant world events. For example, disaster recovery planning, supply chain scheduling manufacturing on the if a man-made or a natural disaster mapping and continuous improvement. TVSHYGXMSR ¾SSV ERH WYFWIUYIRXP] strikes a manufacturing site location of a Data transparency and real-time, shared QEREKMRKSYXFSYRHQEXIVMEP¾S[%W supplier, we will receive an early warning information between biopharmaceutical a result, my team is responsible for event alert that enables us to act, such manufacturers and their suppliers is developing and executing the materials as decide to re-route materials from a critical to effective capacity planning. management program at several of different warehouse. An extremely crucial element of “risk- the manufacturing sites. Essentially, Of course, we have several other smart” mitigation is the provision of up- the program is about evaluating risk mitigations in place. We may have to-date, accurate customer forecasts. and mitigating risks related to raw dual sources and/or dual suppliers. Ideally, forecasts will evolve from those materials, and therefore, our suppliers. However, this isn’t practical for many currently based on single raw materials In production planning and materials/ single-sourced raw materials. We would to the sharing of molecule BOMs (bills- supplier management, predictability hold safety stocks – often at separate of-materials) and critical products. is very important. When we commit locations in case of a disaster. Another important element of “risk- XSLEZMRK½RMWLIHKSSHWEZEMPEFPISRE I am very passionate about our smart” mitigation is business continuity certain date, we want to be reliable in upstream supply chain and making sure planning (BCP). BCP is the process for meeting that commitment. We work that we have suppliers who understand identifying, preventing, mitigating and closely with our suppliers to ensure we our customers’ requirements. I think of VIWTSRHMRKXSWYTTP]VMWOWJSVWTIGM½G have robust supplier quality agreements raw materials as an enabler (or disabler). products. Prioritization of BCP’s is based in place that include quality controls. For If you do an excellent job, nobody on a business impact analysis. During the our critical suppliers, we use specialized notices. But, if you are not doing a BCP process, a risk priority number (RPN) tools to perform risk assessments decent job, then everybody notices! is assigned to a product or a process that UYERXM½IW XLI PMOIPMLSSH SJ SGGYVVIRGI likelihood of detection, and severity of impact. Risks above a certain RPN must be mitigated. Business continuity many include considers the complexity of technology, sites control decisions, and more. Disaster Recovery Planning for the site in impacted, country of origin, compliance and Ultimately, collaboration is key to being which the product is manufactured. corporate social responsibility (i.e., REACH, more predictable and reliable with improved Yet another important element to GSR¾MGXQMRIVEPWERHERMQEP[IPJEVI WEPIW delivery metrics. In turn, biopharmaceutical “risk-smart” mitigation is supplier quality and more. The categorization determines customers can better meet the demands management, which is designed to manage the assessment frequency and method, such of their growing patient populations and the quality of all procured products and as audits. comply with regulations, such as FDASIA. services that directly and indirectly support Agreements, in which we are given QERYJEGXYVMRKSJ½RMWLIHKSSHW;I visibility into customers’ biologics pipelines Dawn MacNeill is Marketing Operations categorize suppliers as critical, essential and critical product needs, enable us to Manager at Merck. and non-critical. Although every procured prepare for capital investments, reduce product and supplier could be categorized concerns over capacity constraints, enhance Merck is a trademark of Merck KGaA, Darmstadt, Germany or its EJ½PMEXIW%PPSXLIVXVEHIQEVOWEVIXLITVSTIVX]SJXLIMVVIWTIGXMZI as critical (after all, we cannot make the relationships with our respective suppliers, S[RIVW(IXEMPIHMRJSVQEXMSRSRXVEHIQEVOWMWEZEMPEFPIZME improvepyp inventory replenishment, TYFPMGP]EGGIWWMFPIVIWSYVGIW ½RMWLIHKU KSSH [MXLSYX EPP XLI VIUYMVIH 8LI8LIPMJIWGMIRGIFYWMRIWWSJ1IVGOSTIVEXIWEW1MPPMTSVI7MKQEMPMJIWGMIRGIFYWMRIWWSJ1IVGOSTIVEXIWEW1MPPMTSVI7MKQEMRR rawraw materials), our categorization process prioritizeprioritize businessbusiness continuitycontinuity andand changechange XLIXLI97ERH'EREHE97ERH'EREHE 20  In My View

bind to multiple proteins – on average Old Drugs, New they can bind to as many as six targets In My – which is the cause of unwanted side Computational effects; on the other hand, it also means that one drug has the potential to affect View Tools multiple targets, and therefore to treat multiple diseases. Drug repurposing can beneﬁt This potential inspired us to devise a In this opinion section, many areas of drug discovery rational way to find the possible protein experts from across the – particularly rare diseases. targets for drugs that have already world share a single been developed, using computational tools (1). Our Computational Systems strongly held view or Biology Group strategically bridges key idea. Biological Sciences and the Center for Computation and Technology at Submissions are welcome. Louisiana State University, which allows us to use very powerful super computers Articles should be short, to investigate biological questions on a focused, personal and large scale. With eThread, eFindSite passionate, and may By Misagh Naderi, PhD Graduand, and eMatchSite, three software tools Computational Biochemistry Research developed in-house, we can predict the deal with any aspect Assistant, Department of Biological structure of proteins, annotate within of pharmaceutical Sciences, Louisiana State University, the protein the drug-binding sites, development or USA. and match those with known pockets that available drugs bind to – and manufacture. There are about 7,000 rare or orphan subsequently figure out if the pockets They can be up to 600 diseases. But, perhaps counterintuitively, match or not. The obvious usage for words in length and around 1 in 10 people are affected by one such a pipeline is drug repurposing, and – so although the diseases themselves applying this strategy to rare diseases written in the first person. are rare, they are certainly not rare in to help with rational drug repositioning terms of their collective impact! But as for such a vulnerable and underserved Contact the editor at: each of the individual conditions affects population was a no-brainer. stephanie.sutton a small population, each represents just Structure-based drug discovery from a small market. Unfortunately, this is scratch might not always be the most @texerepublishing.com what leads to these disease areas being neglected, as this small market doesn’t justify the billion-dollar drug discovery process that big pharma needs to go “One drug has the through to find a new drug. But of course, the human impact is huge, and potential to affect the psychological and financial burden of these diseases on society, patients and multiple targets, their family members is immense. The pharmaceutical industry relies and therefore to on basic scientific research that is performed by universities to provide treat multiple leads, and we realized that we could help find a solution to the problem. It diseases.” is well known that approved drugs can In My View  21

effective path, but in the case of rare process. However, the project is an medical needs, such as orphan diseases. diseases it is a solid approach to finding ongoing effort – as new information Research such as ours coupled with fewer a solution to a problem that has limited on protein structures is deposited into complications in the approval process options. Keep in mind that we are not our database, and new proteins and makes it less expensive to develop a prescribing these drugs to patients; we pathways in rare diseases are discovered product, which means profitability are identifying proteins that are involved every day, we will continuously have new even with a small market size. Our in a rare disease that can possibly be and better predictions. work has the potential to streamline an ancillary target for a known drug. Personally, I am excited to complete the repositioning process, and hopefully At best, our prediction can identify a my PhD in Biochemistry and Master’s attract more pharma companies to the drug that can be repurposed directly to degree in Virology and Veterinary area of rare and orphan disease. alleviate the symptoms or treat a disease, Medical Sciences in May 2018, and but most probably it would be used as I am looking forward to joining the References the first lead for drug discovery. We are biotech and pharma industry, as I 1. RG Govindaraj et al., “Large-scale hopeful about a few cases in the database hope to continue to be part of work computational drug repositioning to find that we have already published (2), and that aims to improve human health. treatments for rare diseases”, NPJ Syst Biol there are a few drug candidates that we Governments incentivize drug discovery Appl, 4, 13 (2018). PMID: 29560273. are currently working on. We are also for orphan diseases, and the process of 2. M Brylinski et al., “eRepo-ORP: Exploring collaborating with experts in structural repositioning a drug is less cumbersome the Opportunity Space to Combat Orphan biology and biochemistry to test these than gaining approval for a new one. The Diseases with Existing Drugs”, J Mol Biol, drugs in vitro and provide the initial US FDA provides a fast-track process [Epub ahead of print], (2017). PMID: results needed to start the repurposing for treatment of conditions to fill unmet 29237557. 22  In My View

• existing drugs are likely to have and the sclera. Often, this challenge It Doesn’t large portion of their non-clinical is too great and developers turn to packages in place intravitreal injection (especially if Have To End • regulatory authorities offer controlled release of the drug could simpler submissions (e.g., FDA benefit the patient). In Tears via 505b(II) submission) • greater understanding of basic Rare diseases aren’t the only biology in other therapeutic areas ﬁeld that can beneﬁt from is uncovering overlaps in certain repurposing – companies pathways and targets, especially “Repurposing an should also consider in immunology and inflammation breathing new life into old • legislation and social media has existing drug for drugs for a much overlooked made orphan indications more organ: the eye. attractive. an ophthalmic

Diseases of the eye are one area condition at least receiving increased attention from this approach, which is very good news for gives developers a patients as not all ocular diseases have effective and non-invasive treatments. head start rather However, developing drugs for the eye is a significant challenge – the eye is than developing a a complex organ with unique anatomy and physiology, and it can be difficult whole new drug to overcome its natural protective barriers. Repurposing an existing drug from scratch.” for an ophthalmic condition at least gives developers a head start rather than developing a whole new drug from scratch. Tears are one of the biggest obstacles The desired site of action for drug to overcome when it comes to delivery to the eye may be the cornea, delivering drugs to the eye, but there conjunctiva, sclera, or other tissues of are approaches that can significantly By Jeremy Drummond PhD, Senior the anterior segment such as the iris, improve the chances of success. First, Vice President, Business Development, retina and ciliary body. If the back of the formulation must be optimized MedPharm Ltd, UK. the eye is the desired site of action, for the desired target site. This may the blood retinal barrier is an obstacle sound obvious but it is amazing how Pharma companies are closely to systemic delivery so a topical route many companies fail to truly optimize scrutinizing existing products to may offer the best solution. Topical their formulations. When repurposing discover if they have activity for delivery to the eye is the least invasive a drug, developers should already have new indications, possibly through and most flexible option compared to a lot of data about the characteristics new routes of delivery. Repurposing injection but the formulation has to of the API – and use these data to comes with challenges as developers battle a waterfall of tears induced by decide on whether a topical, systemic must go back to the drawing board the drug’s application and blinking to or periocular will be the best route of to optimize the product for its new reach the site of action, which could delivery. From there, formulators will purpose, which may require a new be on, in or through the surface of the need to look at product development formulation or delivery mechanism. eye. The formulator has to anticipate with fresh eyes, beginning with pre- However, repurposing also has many that any permeation and penetration formulation work. For ocular delivery, advantages: will be through the cornea, conjunctiva it is imperative to consider how a drug In My View  23

adheres to and penetrates corneal tear flow. In addition, muco-adhesion “With new models or scleral surfaces whilst in a heavy models specifically tailored for tear turnover environment. Specific corneal or sclera drug delivery can and growing excipients may be required that demonstrate sufficient retention on enhance a drug’s adhesive properties, the eye surface. knowledge around allowing sufficient time for drug These models are making drug retention and delivery. development for the eye much easier ocular formulations, Secondly, I strongly recommend and more attractive – and this is identifying effective performance exactly what the field needs. Any eye there is a better models and using these throughout the disease can be extremely distressing for product development process to ensure patients. If you have an eye disease, you chance that more your drug is reaching the correct part don’t care if it is rare or not – you want of the eye, and is bioavailable. You need the best treatment. Drug development pharma companies to understand the pharmacokinetics for the eye is challenging, but with new and pharmacodynamics of your drug models and growing knowledge around will consider product before significant money ocular formulations, there is a better is invested in clinical trials. Ex chance that more pharma companies repurposing drugs vivo models are developing rapidly will consider repurposing drugs for the for assessing drug permeation and eye. I believe the industry has a duty to for the eye.” penetration through the cornea/sclera, ensure that patients smile, rather than and can also consider the impact of end up in tears.

HEALTH FROM A DIFFERENT ANGLE

CAPSULES ARE THE VERY ESSENCE OF QUALICAPS®

As a company dedicated to capsules we have a unique perspective on how to contribute to health. Qualicaps® delivers pharmaceutical-grade capsules together with a comprehensive service along the drug product life cycle through our global team of commercial, scientiﬁc and technical experts.

www.qualicaps.com 24  Sponsored Feature

Industrializing Cell Therapy

We know that cell therapies work; now, we need to learn to manufacture them efficiently on an industrial scale.

Many see the growth of the cell and KIRIXLIVET]½IPHEWXLIGYPQMREXMSRSJ a healthcare revolution – a move away JVSQSRIWM^I½XWEPPETTVSEGLIWXSXVYP] individualized and personalized treatments. Over the past few decades, increased understanding of immunology and genomics has generated an unprecedented amount of biological information, which scientists are now beginning to translate into a new calibre of medicine. It’s an especially exciting time JSVXLI½IPH XLI½VWXX[SETTVSZIH'%68 says Phil Vanek, Ph.D., General Manager therapies are already treating patients in the of GE Healthcare’s Cell Therapy Strategy. “Finding ways to US and Europe. “Autologous cell therapies are different – for “The complete response rates being seen a start, they can’t be lyophilized or formulated VIQSZIVMWOJVSQ for these kind of therapies are inspiring,” as a traditional tablet! But most of all, they explains Madhusudan Peshwa, Ph.D., Chief require manufacturers to take a “scale XLITVSGIWWMWSRI 8IGLRSPSK]3J½GIV'IPP8LIVET]FYWMRIWW out” approach. Every patient needs their at GE Healthcare. “I am not aware of any treatment to be manufactured individually, SJXLIQEMRJSGYWIW small molecule drug or any biological drug so if a manufacturer needs to produce 5000 having the ability to deliver such phenomenal patient batches, or doses, a year, they must JSVGIPPXLIVET] outcomes for patients. This is stimulating the run each batch in serially or in parallel.” growth of the cell and gene therapy industry.” As the starting material for cell therapies manufacturers.” %WXLI½IPHGSRXMRYIWXSXVERWMXMSRJVSQ is derived from patients themselves, the discovery stage to therapeutic reality, Peshwa also points to another challenge: with further approvals sure to come, “There is a wide range of variability from multi-step process involving collection of the new challenges are emerging. The search person to person, in terms of the attributes material from the patient, transportation to for answers has quickly shifted from the and properties of the starting material, the manufacturing site, manufacturing the mainly biological questions facing early- [LMGLQEOIWMXHMJ½GYPXXSIRWYVIXLEXXLI product, and then shipping it back to the stage research scientists, to the challenges manufacturing process always delivers within patient, but there are also dozens of other of industrializing and commercializing such EHI½RIHVERKISJEXXVMFYXIW;IRIIH process steps in between – and when you therapies. “The industry is starting to realize manufacturing methods that can increase are working with biological material and that coming to grips with the manufacture XLIVIPMEFMPMX]ERHGSRWMWXIRG]SJXLI½REP processing steps that require biological of cell therapies involves a change in mindset product, no matter the starting material.” activity, the process does not discriminate and approach. With small-molecule drugs between the cells of interest and bacterial and biologics, manufacturers synthesize a Close and automate contamination. The material must be treated batch of product in a “scale up” process, Finding ways to remove risk from the carefully throughout – and the best way to which often involves lyophilization, followed process is one of the main focuses for cell prevent contamination is to automate a by conventional distribution and marketing,” therapy manufacturers. Cell therapies are a closed process. Sponsored Feature  25

when it comes to cell therapies. Right “Looking at the process workflow and now, the industry is learning many lessons identifying steps that have the highest risk, about developing and manufacturing and then finding an effective way to automate these therapies – and knowledge will these steps is a low-hanging fruit in terms of only increase. In a few years, it is likely that reducing the risk of contamination,” adds processes will be very different, so deploying Peshwa. “Right now the industry relies heavily flexible technologies now, which have the on aseptic process qualification operator capability to be adapted in the future, is a training and environmental monitoring wise precaution. “In the future, I expect in being able to deliver an unautomated that we’ll have much smarter methods to manual process – and cer tainly this has been a engineer our cells so that they are much success – but automation would bring about more potent, which will change therapeutic a significant reduction in cost of goods and doses and the amount of product that must help make product quality more reliable. be manufactured,” says Peshwa. Does this Every time a human performs a step in a mean that companies should hold back complicated process, there is the potential on implementing new technology? Not for a mistake to be made.” at all – there are huge opportunities for cell therapies today, and first movers will Finger on the pulse certainly reap the benefits. Peshwa describes GE Healthcare as a “And there are a lot of fantastic solutions company that likes to “keep its finger on the already available,” says Vanek. “We’ve been pulse”. Indeed, the company is always looking “Historically, people have done whatever approached by a number of customers out for technologies in the marketplace they needed in the clinical center to make looking to accelerate their path to market. that could lead to more effective ways of these therapies happen, but given the They explain their basic process and then engineering cells, enhancing their potency, expected growth of the cell therapy market, ask us to equip a factory for them. We’ve and assessing the biological attributes or the industry will need to think more about leveraged all of our experience gained “fingerprints” of a therapy. “But most of all, an automated, industrial environment that with KUBioTM facility and our Enterprise GE Healthcare is not just a vendor, but a can cope with larger patient numbers,” says Solutions to develop a solution for cell and value-added partner,” says Peshwa. “We Vanek. “Manufacturers will need to consider gene therapies – it is basically a prepackaged work with customers to understand the consistent manufacturing and product quality, factory ready to go.” product attributes that will drive clinical utilization of space, operational effectiveness But for cell therapies to truly be mass success and then we consult with customers and cost efficiency. Use of data – via smart manufactured, there is also a need to make through their stages to ensure they are systems based on digital and analytical processing steps less specialized so that they optimizing their process. We’ll also make technology – will also be key as it will offer can be carried out by non-experts. Given sure that requirements from a robustness insights into controlling manufacturing the cutting-edge nature of these therapies, and scalability perspective are addressed processes and ensuring product quality many of the processes are comprehensible early on – this is incredibly important to consistency. In time, we’ll be able to use this only to the specific scientists and technicians ensure smooth scale up.” knowledge to further automate processes, who worked on them at the clinical stage – Vanek adds, “GE has demonstrated real reduce the number of manufacturing steps and this small number of experts will not be commitment to the field of personalized and allow for aseptic transfers without enough to scale a therapy to thousands of medicine and now is the time to move manual interventions or a high degree of risk patients. “When we work with customers, forward and help manufacturers overcome of exposure to the external environment.” we look at their processes and investigate the challenges in the field. As an industry, we GE has developed a number of tools and whether any steps can be simplified into have more understanding of the causation techniques that can be used to automate sub-routines or made more efficient by and progression of cancer than we’ve ever and close the manufacturing process – removing certain steps. We also look at had before, as well as developing a capability most of which are based on established trying to introduce new technologies or to effectively stratify patients in the future. flexible bioprocessing technologies, such methods that can accomplish those sub- Coupled with the genomics revolution, as single use systems, or WAVE™/Xuri™ routines as opposed to thinking about all the we are moving towards a whole new era bioreactors. The word “flexibility” is crucial unit operations independently,” says Vanek. of medicine.”

Feature 27

I’m a (Biosimilars) Believer! It’s been a long winding journey, but biosimilars are finally starting to shake up the biopharma market. Their true potential remains untapped, however – hindered by market access and myths around safety. Here, four biosimilar gurus discuss successes and tackle the issues head on.

By Stephanie Sutton

What do you consider to be the biggest success biomolecules, such as monoclonal antibodies, were considered stories for biosimilars in recent years? impossible, but such molecules have now been approved. The prospect of biosimilars in oncology is particularly exciting, and Hoss Dowlat: I think the biggest success stories are the first the WHO is already working to prequalify biosimilars for cancer. wave of oncology monoclonal antibody approvals, trastuzumab (US and EU), bevacizumab (US) and rituximab (EU) and with Rick Lozano: It’s been a little different in the US – there are only extrapolation of all indications. These are long awaited and were a small number of approved biosimilars in the market and while developed by biosimilar leaders ahead of immunomodulatory there is no single “success story” that sticks out to date, there are products, such as infliximab and etanercept, but it proved very elements of each that have been successful. For example, we are difficult to satisfy regulatory clinical requirements earlier. starting to see the first biosimilar in the US, Zarxio, gain market share as it has now found the appropriate channel strategy. We’re Carsten Brockmeyer: I agree with Hoss – and would, in particular, also seeing each product learn from one another. I believe that highlight the successful launch of the first European oncology when more biosimilars are approved for oncology as opposed to biosimilar medicine, rituximab, which captured a 50 percent supportive care, there will be even more interest and adoption market share in Germany within 8 months. of affordable biologics, leading to more successful launches and greater insights. Fiona Greer: Although there are inconsistencies among different It’s important to remember that about a decade ago we saw the nations, the EU overall has made great progress when it comes same challenges that biosimilars are facing today with the generics to the uptake of biosimilars. Over the past 10 years, we have seen market, and, in that time, generics have been able to establish a the evolution of a science-based regulatory framework that has good foothold on the market. Though we consider biosimilars led to over 30 marketing authorizations in the EU and has driven to be a unique and distinct class compared to generics, the good development of biosimilar regulatory guidelines internationally. At news is that we see a similar trajectory with biosimilars as policy the beginning of the “revolution,” biosimilar versions of complex and reimbursement continue to advance.

www.themedicinemaker.com 28 Feature

The Gurus of Biosimilars

Hoss Dowlat Carsten Vice President, Regulatory Brockmeyer Affairs, PharmaBio Consulting CEO, Formycon AG

Rick Lozano Fiona Greer Vice President, Life Sciences Biosimilars & Integrated Global Director, Business Development, Biopharmaceutical Services Amerisource Bergen Development, SGS

And what about low points for the industry? that there is a need to focus on responsible pricing. Biosimilar manufacturers need to be careful when devising their pricing HD: There have been some biosimilar development programs strategy, as collectively it is what upholds the market. that have not gone as hoped, particularly for insulin. Today The manufacturing process for a branded biologic and a there is only one biosimilar insulin on the EU market and there biosimilar will be different – what does this mean for the final have been a number of setbacks and failures for recombinant product? And, ultimately, does it really matter? human insulins, immediate rHu-insulin, medium rHu-insulin and biphasic rHu-insulin. Many companies have also tried to HD: The manufacturing process for a branded biologic and develop a biosimilar PEG filgrastim, but this has not gone a biosimilar can be very different; for example, different well. The regulatory barriers have exceeded expectations expression systems may be used in the fermentation process. causing delays, while further development is leading to new In Samsung’s biosimilar etarnecept, the expression system used filings of data with both FDA and EMA. for the originator molecule was replaced by a more modern approach using CHO cells – without any effect on safety, FG: It’s certainly not been smooth sailing. There have been a efficacy or immunogenicity. Voltropin (biosimilar somatropin) couple of high-profile instances where GMP-related issues at some used a yeast expression system rather than bacteria, with manufacturing sites have delayed approval for biosimilars until no negative impact on similarity (Voltropin was ultimately supplementary information is provided to the authorities. Instances withdrawn from the EU market, but this was for commercial like this can put the biosimilars industry in a negative light. reasons, rather than safety conerns). In most cases, the same expression system is used to make RL: Biosimilars have had many challenges coming to the justifying similarity easier. As the biological process is complex US market, including struggles with channel, payer and with many upstream and downstream processes, involving pricing strategies. Though we’ve worked extensively with our many reagents and materials and a range of equipment and manufacturer partners on all three, right now, we are finding conditions, the end product will never be exactly the same WHO Wants to Put Biosimilars to the Test

The newest cancer medicines are considered expensive for developed countries – and they are completely out of reach – but it will be... similar! Based on my experience with for most low- and middle-income countries. In 2017, the many biosimilars from different sponsors, I’ve found that WHO announced a pilot project for prequalifying two manufacturing and testing is often more tightly controlled biosimilar medicines for cancer (1) – with the hopes of for biosimilars – because they are so closely scrutinized by increasing access to treatment. regulators – sometimes leading to narrower limits than the The WHO’s prequalification programs ensure that originator. The nonclinical and clinical results are the same, medicines meet acceptable standards of quality, safety so I don’t think it matters. and efficacy – and their lists of prequalified medicines are frequently used by international procurement agencies and CB: Biosimilar medicines are 21st century biopharmaceuticals. countries to guide their decisions around bulk purchases The development of a biosimilar medicine provides an of medicines. WHO prequalification (launched in 2001) opportunity to introduce manufacturing innovations and initially focused on treatments for HIV, tuberculosis and state-of-the-art technologies. The reference products, in malaria, but the remit was extended in 2006 and 2008 contrast, often tend to be locked in older process technologies. to cover medicines for reproductive health, and zinc for Significant advances have been made in biomanufacturing over managing acute diarrhea in children, respectively. the last two decades, resulting in the reduction or avoidance The decision to investigate prequalification of biosimilars of non-desired materials, such as animal or human derived was made following a two-day meeting in Geneva in proteins, latex, silicone oil, or heavy metals, in biosimilar 2017 between WHO, national regulators, pharma medicines. Safer, more user friendly drug delivery devices industry groups, patient and civil society groups, payers have also been made possible by technological advances. and policymakers. Discussions focused on how to increase Ultimately, the same chemistry, manufacturing, and access to biotherapeutic medicines. The first two biosimilar control standards apply for biosimilar medicines and reference cancer drugs to be studied for prequalification are rituximab products. Approved biosimilar medicines in the EU and the (non-Hodgkin’s lymphoma and chronic lymphocytic US have demonstrated similarity to the reference product in leukemia) and trastuzumab (breast cancer). The WHO is terms of quality, biological activity, safety and efficacy, and also exploring options for prequalifying insulin. thus provide a safe and efficient, state-of-the-art medicine According to the WHO, draft guidelines have been to patients. prepared and shared with stakeholders for consultation. “After the consultation process is over, WHO will issue an FG: What is not widely appreciated is the fact that because expression of interest letter inviting interested manufacturers biologicals are “manufactured” in living systems, even different to submit the two cancer medicines for assessment by batches of the original product, itself, will not be identical. The WHO. We’re expecting this to happen originator, under specific regulatory oversight, may also modify by the end of June, and then it will their manufacturing process over the lifetime of the product, depend on the quality of the which may introduce slight variations in the range of product information submitted as to attributes. So, it doesn’t matter if the biosimilar process is how fast WHO can assess different, providing that the final product is demonstrated to the products, inspect the have no meaningful differences to the originator. manufacturing sites and make a final decision on RL: There are still large gaps in clinician understanding of, whether to prequalify and confidence in, the manufacturing and approval process for or not,” explained the biosimilars. The nomenclature – “similar” – perpetuates the WHO in an emailed myth that biosimilars are not as safe or effective as biologics. statement. However, comparative studies leveraging research from innovator products are an accepted method of FDA approval. Reference Additionally, FDA-approved biosimilars have proven to have 1. World Health the same mechanism of action as the innovator product. In Organization, “WHO to fact, more than 10 years of biosimilars patient-use in the EU begin pilot prequalification of has shown no difference in health outcomes between patients biosimilars for cancer treatment” who use a biosimilar and those who take the original branded (2017). Available at https://bit. biologic medicine. ly/2vOcSCn. Accessed April 26, 2018. 30 Feature

How have techniques and technologies for the FG: The biggest myth is that they are less “pure, safe or efficacious” manufacture, development, and analysis of than the originator. Education that biosimilars are subjected to biosimilars advanced in recent years? rigorous regulatory oversight, including clinical assessment, is needed to overcome these prejudices. HD: Some of the biggest advances have been seen in the analytical field – sensitivities have improved significantly and HD: There is no safety issue with biosimilars. In fact, my increasingly sophisticated systems continue to emerge. As Carsten experience is that a biosimilar is often purer than the originator mentioned earlier on, biosimilars are often able to benefit from medicine and, more practically, more consistent batch-to-batch new technologies. I see a lot of biosimilars using more modern because the biosimilar manufacturer can benefit from recent processes compared with the originator. technological advances, or new scientific understanding. Regulatory scrutiny of biosimilars has been intense because CB: I agree that analytics have they are a new class of product, progressed significantly; the ability but many have now accepted that to analyze and characterize large there is nothing controversial glycosylated proteins has greatly “There is no about biosimilars. The FDA has improved. For example, significant safety issue established the practice of approving advances have been made in high- all first entry new biosimilars throughput methods for glycan with biosimilars. by presenting the case for safety analytics, capillary-based protein and efficacy and extrapolation of analytics, and reporter gene In fact, my indications to an external advisory cell assays. experience committee and holding an associated Cycle-time reduction in process public hearing, for an extra level of development has also been is that a scrutiny and evaluation. achieved by increased use of high- biosimilar is throughput platforms, including CB: Biosimilar medicines approved miniaturization, automation, and often purer than in the EU or the US have the same parallelization, in combination the originator quality, safety and efficacy as the with single use upstream and reference products – this has been downstream technologies. Some of medicine” proven by more than 12 years of real these developments have improved world experience in Europe, with our ability to screen large numbers more than 700 million patient days of cell pools and clones, and speed up timelines. experience under the control of the stringent pharmacovigilance systems. Patients can also be safely switched from the reference FG: Over the last 20 years, advanced technologies have been product to the biosimilar medicine, as many studies have shown. developed for structural characterization of biological molecules. Providing educational information about biosimilar medicines Indeed, the challenges of demonstrating biosimilarity have driven to patients, physicians, and pharmacists is high on the agenda this development in part, with emerging novel technologies and of many public and private organizations, and will increase improvements in older “classical methods”. There is also a greater understanding and acceptance of biosimilar medicines. appreciation of methods that can link structure with biological activity or predict how the molecule might interact within the RL: We have a community oncology group purchasing biological system; for example, HDX-MS. Essentially, regulators organization – ION Solutions (an AmerisourceBergen company) are looking for multiple orthogonal assessments to build a total – and we’ve had conversations with more than 5,000 community profile of the molecule. In the US, the FDA has introduced the oncologists across the US. Certainly, biosimilar manufacturers concept of “fingerprint-like” analyses. need to educate more around safety, but I would also add that they need to look at other areas too. For example, biosimilars Biosimilars have been available for years and yet companies should match patient support services offered by the articles are still being written in 2018 that question innovator, such as patient support programs. their safety. What do you think are the biggest myths Community oncologists do not move for price; rather, they look in the ﬁeld? for support from their group purchasing organization contracts What Regulators Want about how analytical data have between the biosimilar and the originator been validated. product – and you need more participants By Bruno Speder, Head Clinical This head-to-head comparison is often to ensure the statistical relevance of results. Regulatory Affairs & Consultancy made more difficult as data are rarely Study design should be agreed with at SGS available for the originator products, the relevant regulatory authority to which, in any case, may have changed establish its acceptability and whether, Unlike small molecule drugs, through authorized manufacturing based on the CMC dossier, the product biosimilars are “manufactured” from changes. In some cases, entire analytical may be considered biologically similar to living material and have a much more exercises must be performed multiple the originator. Without this agreement, complex and intricate structure, so it times on different batches to enable there is little point in continuing with is not as easy as classifying them as comparisons to be made. development as it will be unlikely to generic biologic drugs. This difference A comprehensive set of preclinical gain marketing authorization via the is acknowledged in the greater safety studies must also be carried biosimilar pathway. In addition to requirements of the various regulatory out before any human volunteers or the phase I comparative safety study, agencies for biosimilar approvals. The patients are dosed with the potential a phase III study to prove equivalent path to market for a biosimilar involves biosimilar, including in vitro assays efficacy is essential and the design an abbreviated approval process, and appropriate animal models, which of this study should be carefully focused on proving “biosimilarity” are designed to predict whether those coordinated with regulators to establish to the reference originator product small differences may have an impact the necessary endpoints. with physicochemical, biological and on safety or efficacy. Immunogenicity A biosimilar must have the same clinical data. is a particular concern, but both in route of administration as the reference silico tools and in vitro assessments product and any changes to strength, Head to head using animal tissue can be used to pharmaceutical form or formulation, for The Chemistry, Manufacturing and predict whether it is likely to occur example, will need to be justified to the Control (CMC) dossier is an essential in humans. Some regulations require regulators. Other changes, for example, part of the submission package for animal immunogenicity studies be optimizing the glycosylation pattern any pharmaceutical product to enter a carried out before humans are dosed of the drug to improve efficacy, will clinical trial and, in a later stage, for an for the first time. not be compatible with biosimilarity. application for market authorization. However,However, changes designed to For a biosimilar, the CMC part is Clinical studiesstudies improveimprove safesafety,ty, for examexample,ple, even more important and the core of a For an originatororiginator pproduct,roduct, reducingreducing levels of known biosimilar’s dossier is a comprehensive phase I studiesstudies are typicallytypically impuritiesimpurities or reducingreducing head-to-head comparison of the carried ooutut on somesomewherewhere immunogenicity,immunog enicity, biosimilar and the originator product, between 30 and 48 healthyhealthy may not precludepreclude a including points of difference between volunteerss to establish safety;safety; biosimilarbiosimilar ddecision.ecision. the two products, and how these will however, a biosimilarbiosimilar phasephase affect the product. The dossier must also I study wiwillll invoinvolvelve include all details of the analytical (and anywhereere between other) methods that have been used to 120 andd 200 healthyhealthy identify these differences (allowing the volunteersrs dosed with assessor at the regulatory agency to either thee originator decide just how similar the two products or the biosimilariosimilar actually are), as well as manufacturing drug. TheThe trialtrial details (including cell lines and sources will aim toto detectdetect of material), a description of the process differencesces inin control methods used, and information safety signalsnals A New Supporter Worcester, and another author of may be kept off formularies precisely the paper. “Thus, any differences in because they are less expensive! Initially, The American College of manufacturing processes between an This is paradoxical and may prevent Rheumatology urged caution around approved biosimilar and its reference biosimilars from realizing their the use of biosimilars. Information product do not result in ‘clinically promise of lower prices and increased about the manufacturing process for meaningful differences’. Patients access to treatment,” says Worthing. a branded biologic is proprietary; receiving treatment with an approved To help patients get better access a biosimilar manufacturer will not biosimilar should not experience any to biosimilars, Worthing would like have access to the details of the difference in response than that which to see the FDA quickly finalize its process so how could they guarantee would be expected when using another interchangeability approval pathway their product would be the same? It lot of the branded reference product.” so that manufacturers can perform is now well accepted by the scientific Despite the fact that biosimilars are clinical trials to demonstrate safety community that biosimilars are safe, safe and effective, uptake in the US and efficacy of alternating back and and in February 2018 ACR published has been slow. According to Angus forth between reference products and a white paper, The Science Behind Worthing, a doctor with Arthritis biosimilars. In addition, he believes it Biosimilars – Entering a New Era and Rheumatism Associates and would be beneficial for Congress to of Biologic Therapy (1), which aims chairman of the American College reform the drug distribution system to educate ACR members about and of Rheumatology’s Government to create more transparency in the support the use of biosimilars. Affairs Committee, “Only two of rebate system. Boosting the supply of “Increased real-world experience the six FDA-approved biosimilars for biosimilars – including interchangeable with biosimilars in Europe, new data rheumatologic diseases are available; biosimilars – and improving incentives including a prospective switching study the biggest obstacle is patent disputes to bring them onto formularies should (NOR-SWITCH), and increasing and manufacturer decisions that improve access to biosimilars and help clarity around FDA policies (naming, prevent their use. One important long- lower biologic drug prices. switching) have all served to increase term barrier is insurance coverage. confidence in biosimilars,” explains Ironically, despite being priced 15-30 Reference Doug White, one of the authors of percent lower than reference products, 1. American College of Rheumatology, the paper and ACR Board of Directors we’re seeing some biosimilars kept off “American College of Rheumatology member at large. formularies.” Recommends Biosimilar Use in New White The paper explains that a biosimilar This appears to be a result of the Paper,” (2018). Available at: https://bit. and its reference product must have US drug distribution system in which ly/2jhtZn8. Accessed May 1, 2018. identical amino acid sequences and must medication formularies are dictated be ‘highly similar… notwithstanding by interactions between pharmacy minor differences in clinically inactive benefits managers (PBMs) and components’ in many analytical assays. manufacturers. The larger “The biosimilar must be equivalent the rebate or price to its reference product in clinical concession paid trials assessing pharmacokinetics/ by manufacturers pharmacodynamics and clinical to PBMs, the efficacy and must have comparable more likely a safety and immunogenicity to its drug will be on reference product,” says Jonathan Kay, formulary, and Professor of Medicine and Timothy a lower-priced S. and Elaine L. Peterson Chair in drug may result Rheumatology at the University of in a lower rebate Massachusetts Medical School in payment. “Biosimilars Feature 33

to ensure they are able to stay viable in today’s competitive and that bring down healthcare costs. However, without sufficient often unpredictable market. Clinical education about biosimilars biosimilar competition, uptake has been slow, and as a result, may facilitate informed decision making, promote acceptance providers continue to choose biologics. of biosimilars into clinical practice, increase accessibility, and expedite associated health and economic benefits. If you had the power to make one big change in the biosimilars industry, what would it be? What other big hurdles do you think face the ﬁeld? HD: Reduce the burden of testing by regulatory agencies – it HD: There are huge data demands in terms of quality when it would make it much easier for companies to develop biosimilars. comes to developing a biosimilar; the FDA, for example, has I think we should carefully rationalize and justify all regulatory precise requirements for analysis using statistical models – and this requirements. Harmonizing the FDA requirements with the can be an insurmountable barrier for smaller biosimilar players. EMA could also be beneficial. I find that the EMA sometimes has Also, both the FDA and EMA have requirements for phase III a lower regulatory burden, based on their significant experience studies with at least one year of safety data. Major companies rely with assessing and approving biosimilars. on their financial strength to conduct more studies and to generate more data than the minimum EMA or FDA requirements; partly, CB: Carrying on from Hoss’ comment, I would add that this is for exploratory reasons but also to fulfil what they perceive experience gained during the last 12 years in Europe has as the expectations of the medical community. However, the provided confidence in the ability to analyze and characterize additional work escalates the cost of development and prevents small and large proteins. The need for large clinical studies will some smaller companies from ever getting involved. likely decrease in the coming years for a number of biosimilar medicines. Whether this will also include monoclonal antibodies CB: There is no one hurdle facing the industry – there are several will largely depend on the future progress in functional assays elements that can be addressed to further increase the uptake of and pharmacodynamic markers. biosimilar medicines. Right now, it is a bit like the early days For me, the big change I would make is to increase competition of the generic industry when healthcare providers and patients between biosimilar medicines and off-patent branded drugs by were used to brand name drugs and were reluctant to use new providing a level playing field with fair and equal conditions for generics. There is often rapid uptake today in some markets for all players. newly launched biosimilar medicines, but not all biosimilars are equally successful. Awareness and education initiatives will help, FG: I certainly agree with the previous comments, but would and so will benefit-sharing models, incentives schemes, and, last also highlight the importance in educating the market as to the but not least, improvement of tendering mechanisms. benefits of biosimilars. The biosimilars industry must step up efforts to market themselves as an industry group to stakeholders FG: A major challenge for biosimilar companies is to make with the same dedication as originators – and this group must the biosimilar economically viable. The main “advantage” for educate clinicians and patients about biosimilars to counter the biosimilar developers is that the regulatory process is “shortened” “negative” image. Many individual companies, and some industry because a phase II clinical trial is not typically required. However, organizations, do this already, but if forces and resources were these regulatory pathways also require extensive, head-to-head combined, the message would have greater reach. comparability against the originator product. At the outset, obtaining batches of originator molecules is not easy and is very RL: For significant cost savings to happen, we need to dramatically expensive as multiple batches are required for the biosimilarity expand patient access and bring more biosimilars to market. I exercise. That said, there are considerable financial incentives in would change one of two things. The first option is to either that biological products tend to generate blockbuster revenues. If shorten the length of biologic patents or change the laws to biosimilars can be marketed at a cheaper cost, they will attract shorten the length of the exclusivity period. We see products in considerable sales. the immunology space that have several hundred patents on one product with four or five indications, and companies can hang RL: I think we have everything in place to have a strong market on to these patents for a significant amount of time. The second for biosimilars, but the incentives that are crucial for the success option is to allow biosimilars to come to market without the 180- of biosimilars, including rebates in the US, remain reserved for day notice period to innovators in the US, which would help branded biologics. There is a tremendous need to find solutions eliminate a patent dance and time (and money) spent on litigation.

www.themedicinemaker.com 34 Feature

A Vendor’s View On making biosimilars

With Nigel Darby, Advisor, GE Biosimilars need to be as “similar” as possible to the original Healthcare Life Sciences drug in molecular, therapeutic and safety characteristics. This is a challenge with something as complex as a biological molecule, so On market competition careful control and characterization of the production process is key – and tools that allow comparison of originator and biosimilar There are over 100 projects to deliver molecules are of major importance. Achieving acceptable biosimilars for the top ten biopharmaceuticals that have similarity to some of the “subtleties” of originator molecules, such gone off-patent or will be going off-patent in the next few as glycosylation profiles, can be particularly challenging, requiring years. Participants range from small regional start-ups, all a significant focus on cell culture and media development. the way through to major pharmaceutical manufacturers. To gain a competitive advantage, cost-effective manufacturing Perhaps surprisingly, some companies with strong portfolios of biosimilars is important. In particular, there needs to be a of original molecules, such as Amgen, have also chosen to strong focus on maximizing manufacturing plant utilization and develop biosimilars programs. Biosimilar manufacturing is productivity, as these are major drivers of manufacturing costs. highly competitive, with the most popular originator molecules potentially spawning over 20 biosimilar projects each. This On manufacturing strategies intense level of competition creates significant uncertainty in manufacturing capacity demand and the dimensioning of Many biosimilars are intended to be manufactured in emerging facilities to achieve it. markets, which may not have appropriate manufacturing With so many biosimilars competing for the same market, infrastructure available or the necessary expertise at all levels it’s obvious that the first products launched will have a (managers, scientists, process developers, manufacturing operators) significant advantage. Given the level of competition around to develop biopharmaceuticals. Even basic requirements that certain molecules and therapeutic indications, it’s impossible to are normally taken for granted, such as stable power and water believe that all these projects can be commercially successful. supplies, may be a challenge in certain countries (that said, many For example, in terms of the latter, I’m guessing there may manufacturers in markets such as China have the stated goal of be twenty different biologics targeting psoriasis by 2020 selling their products to Western markets, making them sensitive compared with perhaps just three ten years ago… and perhaps conservative in terms of satisfying Western regulators). Companies wanting to get into the biosimilars market need

Nigel’s Dream There would be maximum flexibility Biosimilars Facility in terms of the types of products that could be handled and production would It would be a multi-product facility, need to be easily reconfigured. I would given the commercial uncertainty that like an open architecture “ballroom” may surround an individual product, type facility that enables flexibility in as well as the fact that the ability deploying equipment. to drive multiple products through The costs for low added-value a facility is a key requirement for activities, such as cleaning and economically efficient manufacturing. maintenance, would be minimized, and The facility would need to be the right uptime for manufacturing maximized. size – appropriate for the likely market Also, technology would be adapted to demands and risks, but future proofed intensify all parts of the process, reducing so that capacity can be rapidly expanded both upstream and downstream cycle if drug demand is sufficient. times to increase batch throughput. Feature 35

“Although single- products for a global market, especially if it increases use of existing use and modular infrastructure. This is the strategy adopted by companies such as Celltrion and Samsung, and it is worth noting that the Remsima manufacturing biosimilar is manufactured in a more traditional type facility. The methods have many choice between “big traditional” and “single use” (modular) depends beneﬁts, there is still on the market, risk appetite and commercial expectations. an active debate as On the future to the ‘right way’ Biosimilars have been around in Europe for many years and are to manufacture already a significant part of the market. The first biosimilar on the US market, Zarxio, was introduced a couple of years ago biosimilars.” and has been steadily gaining market share. But I think the big question is how successful monoclonal antibody biosimilars will be. Uptake of Remsima, a biosimilar of Remicade, has been strong to carefully consider their manufacturing strategy – and perhaps in Europe, driven by aggressive pricing. The development of the look to using flexible technologies, such as single-use systems and mAb biosimilars market in the US is expected to be slower; though, modular systems, that can get manufacturing operations up and given its novelty, it is hard to assess. Will payors and patients drive running quickly, with reduced capital investment. Overall, costs uptake in the absence of the strong government influence that has shift towards variable costs (in other words, costs only incurred been so important in Europe? And exactly how much discount when the drug is manufactured) compared with traditional (compared with the originator) will be required? infrastructure, where fixed and capital costs predominate and are incurred irrespective of whether manufacturing is taking place. Single-use technologies are also very appropriate for the required levels of product output of a biosimilar. For example, predominantly single-use modular facilities can deliver amounts of monoclonal antibody in the 20-1000 kg range, which is appropriate for serving individual countries or regions and fragmented markets. If a drug proves to be particularly successful, increasing supply can be achieved by building further manufacturing lines – this is a comparatively cheap and quick process with modular type facilities based on single-use technology. If there is significant commercial VISIT US AT uncertainty (the case for many biosimilars), it often makes sense ACHEMA 2018 to launch the product from the smallest, lowest capital cost facility 11 – 15 JUNE possible, and then scale out, if the molecule is successful. WE DO IT ALL HALL 3.1 Logistically, modular facilities are readily deployable in STAND A75 emerging markets in a rapid and cost-effective manner, whilst at the same time achieving high quality standards. The bulk of the construction and fitting out can be carried out remotely Systems and be assembled quickly on top of a foundation with basic services at the final location in a period of a few months.

On single use versus stainless steel Handling Although single-use and modular manufacturing methods have many benefits, there is still an active debate as to the “right way” to manufacture biosimilars, with many arguments suggesting that large, well-utilized fixed infrastructure can also deliver favourable Containment economics. The key is high facility utilization, targeting big

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NextGen R&D pipeline New technology Future trends

40-45 Medicina Ex Machina Is artificial intelligence coming to pharma? We interview Gregory Bailey ( Juvenescence) and Alex Zhavoronkov (Insilico Medicine) to find out why they are using AI to generate preclinical candidates.

46-49 Recognizing Friend from Foe Life-saving biologic drugs can sometimes trigger the immune system to produce anti-drug antibodies. These can be lethal, so the industry needs to find a solution. 40 NextGen

Medicina Ex Machina

The sci-ﬁ inspired concern that artiﬁcial intelligence will one day rule the world is (mostly) unfounded, but it certainly could have a huge impact on drug discovery.

By Roisin McGuigan

Traditionally, pharma companies have been skeptical about the promise of artificial intelligence (AI). But with its potential to bring powerful new tools to the often slow and expensive drug discovery process – and its ability to predict which drugs are most likely to successfully run the clinical trial gauntlet, pharma companies are waking up to the Juvenescence and Insilico Medicine, because of recent advances in deep fact that it really could be the future. respectively – to find out more about the learning and deep reinforcement In 2017, a collaboration began collaboration, and the potential of AI. learning. AI techniques started between Insilico Medicine, an AI outperforming humans in many tasks company specializing in deep learning What drew you to AI? starting in 2014 and 2015 – examples for drug discovery, and Juvenescence Gregory Bailey: Juvenescence is a include superhuman image recognition, – a company focused on investing in relatively new company – but we are autonomous driving, and the famous treatments for age-related diseases and fortunate to have attracted a team of defeat of the human champion of the longevity. The aim of the partnership? seasoned drug developers from big ancient Chinese board game, Go. To find out if AI techniques could pharma and biotech. Having seen Pharma is perhaps one of the most enhance drug discovery in the tricky millions of compounds sent through inefficient industries, with about 90 area of age-related diseases, including high-throughput screening to generate percent of new drugs failing in clinical dementia, diabetes, and cancer, as well a single lead, our team was captivated trials. The industry spends over $150 as the aging process itself. by the idea of replacing a time- billion annually on research and only In 2018, the companies announced consuming and wasteful process with 40–50 drugs are approved every year. that a handful of promising molecules AI-driven compound development. The However, pharma companies also generated by Insilico’s deep-learned potential to generate lead compounds generate enormous amounts of data drug discovery engines would be without high-throughput screening that could be used to train AI systems. heading into preclinical and clinical was enough of a draw for us to want to We were very impressed by the results development, headed by Juvenescence partner with Insilico, but we were even of deep learning in images; specifically, AI, a joint venture between the two more excited by the prospect of using Andrej Karpathy’s work on computer companies. Juvenescence AI is also AI and machine learning techniques vision back in 2014 – and now powering seeking to independently develop its to parse through existing genetic and the Tesla’s Autopilot project. He own AI engine focused on accelerating transcriptomic data to identify exciting demonstrated how deep neural networks the clinical development of novel drugs. new targets for drug development. could describe pictures in natural Here, we speak with Gregory Bailey Alex Zhavoronkov: There is a lot language. Some of these descriptions and Alex Zhavoronkov – CEOs of of hype around AI, and most of it is were better than mine. And when he NextGen 41

big pharma company did not follow • Generate completely novel up on the meeting, so I guess they molecules that can bind to “There is a lot of missed the boat in deep learning just a specific target using our like they missed it in IO. Ironically, GANs. GANs are trained on hype around AI, we do a lot of work in IO with deep multiple data sets to “imagine” learning nowadays! molecular structures that have the and most of it is characteristics of a good drug. We How does AI work in drug discovery? also introduce a reinforcement because of recent AZ: The most difficult part of the learning (RL) component, which application of deep learning to drug helps build the molecules with a advances in deep discovery is the pace of progress. In specific objective. We have a large deep learning, there are several papers zoo of these GAN-RL models and learning and deep published every week with ideas that we are building new ones almost can be incorporated into the drug every week. reinforcement discovery pipeline, and our team is coming up with new ideas on a daily The most promising leads are then learning.” basis. If we were to turn our pipelines scored using a predictor of clinical into a software product, in a month it trial outcome. For disease areas with would be obsolete. That’s why we keep sufficient data available, we created showed these results at the NVIDIA all stages of our pipeline in a flexible predictors of success or failure using GTC2015 conference, where Insilico “Lego-like” mode and run the entire the “omics” data and the structure also presented, I decided to invest pipeline only when we absolutely need of the molecule. The highest-scoring everything we had into deep learning to churn out new targets and molecules molecules are then synthesized and for drug discovery. I co-founded Insilco for partnering and licensing. tested experimentally. Medicine with the ultimate aim of The current pipeline starts with deep harnessing available data to minimize learned and pathway scoring algorithms How did this collaboration come about? the need for animal testing and clinical applied to massive “omics” databases for AZ: We met the Juvenescence team when trials by using AI and deep learning target identification. We use generative Jim Mellon, one of the core founders of to identify new therapeutic compounds adversarial networks (GANs) to Juvenescence, was doing research for his and predict biological activity. Back reconstruct the missing or erroneous book “Juvenescence” – which discusses then (this was around 2014), nobody in values or to generate diverse data sets the science of longevity. This is where pharma was using deep learning and it that we may be lacking. We heavily rely we connected, because we were also was extremely difficult to explain what on the predictors of disease state, or in interested in developing biomarkers of we were doing to big companies! the case of aging, age of the patient, aging and linking the targets implicated In 2015, I was invited to give a talk where we extract the most relevant in aging with disease. Jim is often referred in Boston at a closed-door immune- targets and pathways of the disease or to as the “British Warren Buffett” (even oncology (IO) event organized by a aging. We then engage a second part though he may not like it!) because he big pharma company, which wanted of our pipeline, where we look for the makes some bets very early on, and these to understand why it missed the IO molecules that may effectively inhibit bets often turn into multibillion-dollar revolution and how it should move or modulate some of these targets businesses. Gregory Bailey has a similar forward. All of the research executives or pathways. track record in the biopharmaceutical were there, and for the first time I We do this in three ways: industry, so it’s a good combination. presented our work in deep learning. We really liked the team and worked No one was interested except for • Screen the existing molecular very hard to establish this collaboration. the executive editor of Molecular libraries for molecules that are Juvenescence invested in Insilico and Pharmaceutics, Carston Wagner, likely to bind to a specific target. now has the right to license up to five of who invited us to submit a paper. It is • Screen for molecules that can the best molecules discovered using our now an extremely popular paper with effectively reverse a disease deep learning engine annually. an Altmetric score over 750. But the pathway signature. GB: Jim Mellon introduced Alex to

www.themedicinemaker.com 42 NextGen

Figure 1. Integrated top-down and bottom-up target ID and drug discovery pipelines. the rest of the Juvenescence team, and investment, and by using AI to situations it can generate compounds we were fascinated by the potential of massively reduce the long and expensive that are predicted to interact with a Insilico’s drug discovery engine to shorten drug discovery process we hope to given target. Our goal is to build a tight the time between target identification eventually develop drugs to treat feedback loop between Insilico’s AI and lead candidate selection. We decided both aging itself and diseases of aging engine and the biological experiments to make an investment into the company including diabetes, dementia, cancer, conducted based on its output. and to create a joint venture to develop and respiratory disease. AZ: When you really delve into AI and five drug families per year, playing to begin to understand how to combine AI our strength in drug development – and What advantages does an AI tools with advanced machine learning Insilico’s strength in drug discovery. approach offer? and bioinformatics, you should be able This led to the creation of Juvenescence GB: AI approaches to drug discovery to look at complex diseases and narrow AI, a subsidiary of Juvenescence Limited offer three major benefits: enabling them down to a set of actionable and dedicated to combining advances in AI drug discovery programs against druggable targets. It can also help us with our classical techniques, to develop targets for which no high-throughput to understand the population-level compounds sourced from Insilico assay is available, reducing time to lead response and generate new molecules Medicine’s drug discovery pipeline and candidate selection, and identifying with a specific set of characteristics for take them through to clinical proof-of- new targets of interest. How we apply the individual targets using GANs and concept. AI depends on the task; in some RL. Such generation was not possible The team behind our company situations, it is used to identify a target just two years ago, as GANs are a very have an extensive track record in of interest that can be explored using new concept – we were the first to drug development and biotechnology known biological tools, and in some publish and validate the applications NextGen 43

viable drugs that fail due to a spuriously high placebo effect, or improper patient selection for clinical trials. AI will help drug developers sort out these problems, and therefore have an effect in many different areas. AZ: I personally have always been fascinated by the idea of extending healthy longevity, but aging is an extremely complex and multifactorial process. As a result, we have taken a wide view of the field, with a variety of projects and collaborators. Aging is also a very important component in many diseases and it is extremely important to study it in both biomarker development and drug discovery, as people of different biological age simply do not respond to therapies in the same way. We intend to publish many “firsts” this year in multiple areas, ranging from cancer immunotherapy to novel in the industry. AI can be used for a molecular structures generated using top-down approach and can work with AI – and we’ve already started. For “We are also multiple omics data types to identify example, we were the first to publish targets for individual diseases, and a deep-learned predictor of human interested in a bottom-up approach to identify biological age using simple and or generate the best molecules for inexpensive blood test results. So far investments that individual or multiple targets. We can we have three papers describing this then use AI to assess the probability of methodology, and we use it internally use AI technology passing the clinical trials for some of on other data types like gene expression the molecules (see Figure 1). and genomic data (3). We were also one to solve other of the first to publish on the applications Why focus on aging? of the adversarial autoencoder (AAE), problems in the GB: I think that finding therapeutics a form of GAN, in a peer-reviewed for aging and age-related diseases journal (2). We submitted in June 2016 pharmaceutical presents us with the opportunity to and published in December 2016, as it have the most dramatic effect on the took two months to find the relevant industry, largest population – potentially 7.8 reviewers. In the meantime, another billion people. We are also interested group, led by Alan Aspuru-Guzik from particularly in in investments that use AI technology Harvard published the application of to solve other problems in the the variational autoencoder (VAE) in drug development.” pharmaceutical industry, particularly in October 2016. So we can say that we drug development. AI is a very exciting were first to submit, but they were the new tool that gives us the ability to do first to publish. The Aspuru-Guzik of GANs in both medicinal chemistry work that is too time consuming or group is our main competitor in this and biology (1, 2). even impossible for a human. It can area – and a pretty formidable one I really believe that our AI pipelines also assist us with many of the issues we at that! We have a lot of respect for are among the most comprehensive confront in drug development, such as their team.

www.themedicinemaker.com 44 NextGenNex tGen

build a continually-renewed pipeline of of, which have the potential to change therapeutic candidates. Acknowledging the therapeutic compendium. AI is an “We can use AI the odds of drug development, we amazing tool; it is not yet a stand-alone would be delighted if two compounds solution to all problems in medicine and to assess the achieved clinical proof-of-concept in an drug development but certainly it can aging-related disease every year! help humans deal with the extraordinary probability of AZ: We plan to provide Juvenescence complexity of biological systems and with safe and effective molecules at the help us to solve some of the biggest passing the clinical early preclinical level that can potentially mysteries and challenges in biology. turn into new drugs targeting both age- AZ: Many large pharma companies trials for some of related disease and aging itself. Together, are still saying that AI is overhyped we aim to become the core of what will and we need to slow down. They claim the molecules.” be called the longevity biotechnology that the AI field is overpromising industry. The current pharmaceutical and will under-deliver, and refer to model is focused on treatment and, similar claims made by computational What successes have you seen so far? initially, we will need to play by this rule. biologists and chemists in the 1990s. GB: In terms of drug development, our But in the future, we hope to prevent Some older-school computational collaboration has only just begun, and diseases from occurring, and to help discovery scientists and even some we are in the process of learning about people live longer in a healthier and more younger academics from the top the strengths and limitations of the AI youthful state. institutions, who are just entering the engine. Similarly, Insilico is learning deep learning field and want to make how to interact with the culture of How do you think AI will alter the a name for themselves, often refer biotech drug development. We have pharma industry as it advances? to how easy it is to fool deep neural selected a family of geroprotective GB: Although AI has the potential networks, and how difficult they compounds for development as our to open up new landscapes of targets, are to interpret. These people often first license, and we are also seriously drugs against these targets will need support each other at conferences exploring the biology behind four other to fit into the current therapeutic and in the press claiming that AI is potential programs. development paradigm. We think overhyped and that pharma companies AZ: So far, we have had many proofs- the key near-term structural change should limit their investments in of-concept, some of which are published. that AI will bring to drug discovery this field. After the driverless Tesla We were also involved in another is a reduced need for the capital- demonstrations they switched gears collaboration in which we applied our intensive, high-throughput screening and started making arguments for the AI methods to the development of process. The collection and collation human-machine union, where deep nutraceuticals, which helped us learn of more biological data, however, learning techniques can act as useful how to work with large population data. and maturation of machine learning tools, while still claiming that AI We have also had multiple pilots with and AI techniques will enable more is overhyped. large pharma companies, and some of profound changes to the therapeutics My response to these people is these will be published in the near future. industry, but the structure of the simple – AI in drug discovery is not But I would consider our real success pharma industry is largely a product overhyped. In entertainment, robotics the partnership with Juvenescence – the of its regulatory environment. I hope and consumer businesses, investors are successful licensing of our compounds is that as AI techniques prove themselves, pouring billions into AI, but this is a major milestone for us! But in pharma, regulators will embrace them for drug not the case in the pharma space. Our the only outcome that you can truly call discovery and development. We assume company struggled to fundraise until a success is the completion of a phase III that for now change will be slow, and 2017, and even after the investment we clinical trial for a blockbuster drug – and we will need to see multiple successes remain very lean and I do not receive we’re still quite far away from that! before regulatory processes are updated. a salary. Many other companies are I firmly believe that AI has unique finding it hard to fundraise as well, What’s next? potential to open up new drug targets and pharmaceutical companies are GB: Our goal for Juvenescence AI is to that humans would not have conceived trying to build internal expertise in NextGen 45

this area but failing to attract the right I personally think that AI will 3. P Mamoshina et al., “Population specific talent. My guess is that in 2016 the transform the way we discover drugs, biomarkers of human aging: a big data study total capitalization of the entire AI and diagnose and treat diseases. To quote using South Korean, Canadian and Eastern for drug discovery market was under Bill Gates, “We always overestimate the European patient populations”, J Gerontol A $300 million with the exception of one change that will occur in the next two Biol Sci Med Sci, [Epub ahead of print] company, which managed to get into years and underestimate the change (2018). PMID: 29340580. unicorn territory. that will occur in the next ten. Don’t let The CEOs of the top pharma yourself be lulled into inaction.” I think Alex Zhavoronkov is CEO of companies do not yet see AI impacting we need to act now, and act fast. Insilico Medicine, Inc, a company their bottom lines, at least on the specializing in the development of next- discovery front. These people are busy References generation artificial intelligence and with the products they have on the 1. A Kadurin et al., “druGAN: an advanced Blockchain technologies for drug discovery, market and with what can be acquired in generative adversarial autoencoder model for de biomarker development and aging research. late-stage clinical trials. But considering novo generation of new molecules with desired the potential, the results we see in the molecular properties in silico”, Mol Pharm, 14, Gregory Bailey is CEO of Juvenescence lab and the lag between virtual and 3098–3104 (2017). PMID: 28703000. Limited, an investment company focused real experiments, promoting AI in the 2. A Kadurin et al., “The cornucopia of on developing therapies for anti-aging pharma space and educating executives meaningful leads: applying deep adversarial and age-related diseases, which will be on the differences between traditional autoencoders for new molecule development in using AI to augment its drug discovery machine learning and next-generation oncology”, Oncotarget, 8, 10882–10890 and drug development programs in AI is a very logical thing to do. (2017). PMID: 28029644. partnership with Insilico Medicine.

www.themedicinemaker.com 464 NextGenNextGen

When I started my career, most to broadly immunosuppress patients Recognizing therapeutics were small chemical comes with clear drawbacks and risks. molecules, but today the focus has We have been aiming to improve Friend from Foe shifted to biologics. The immune system the efficacy and safety of biologic does not react to small molecules, but it medications by resolving the ADA The immune system can often react to biologic drugs, such issue. One of our cofounders, Ulrich von scrambles into action when as proteins, monoclonal antibodies Andrian (the Mallinckrodt Professor of a foreign entity is detected, and enzymes. A surprisingly large Immunopathology at Harvard Medical but not all foreign entities number of biologics already on the School) is one of the world’s leading mean harm. New solutions are market induce the production of immunologists, and much of his work has needed to teach the immune ADAs in many patients. Not only focused on the role of dendritic immune system to recognize biological can ADAs reduce drug efficacy cells. The dendritic cell acts as the teacher drugs as partners rather than and modify pharmacokinetics and and sentinel of the immune system. plunderers. pharmacodynamics, they can also cause They sample viruses and nanoparticles allergic responses. Over 100 approved in general and, if they sense danger, they By Werner Cautreels biologics already list immune responses activate the immune system to respond by on their labels. As one example, a inducing the activation of virus-specific The human immune system is an majority of patients taking Humira T cells and B cells, which leads to the incredible defense mechanism that has make ADAs (1). It often takes several production of specific antibodies to fight the ability to interrogate and respond months to a year for antibodies to build the danger. Von Adrian demonstrated to any harmful entity (or ‘antigen’) that up and become a problem, but it is a key that you can also achieve the opposite it is exposed to. When we are exposed reason why patients on anti- TNF alpha result by taking dendritic cells out of to viruses, our dendritic cells sample inhibitors are often forced to switch an animal and teaching them to induce the particles, process them, and then medications. immune tolerance to an antigen. He mobilize the immune system into The real problem arises when there is then reinjected those dendritic cells into action, resulting in the production of no alternative treatment. For instance, another animal, which prevented the antibodies against the virus. The same for patients with Pompe disease, animal from making antibodies against mechanism has been exploited for there is only one approved enzyme: the specific antigen. vaccination, of course. alglucosidase alfa. If patients develop We believe that it is also possible But the immune system also has ADAs to alglucosidase alfa – and the to combat ADAs in vivo by using a darker side – antibodies can form vast majority of patients do – the loss of synthetic vaccine particles (SVPs). We in response to anything deemed as alglucosidase alfa efficacy can prove to have designed these nanoparticles with ‘foreign,’ including biological medicines be fatal. ADAs also prevent a number the goal of permitting them to “talk” that are intended to improve – or to of drugs from even reaching the market. to the immune system – telling it when save – the patient’s life. A well-known to fight and, just as importantly, when example is coagulation factor VIII – a Antibody action clotting protein required by patients We need an approach to deal with with hemophilia A. In a surprisingly ADAs that goes beyond “wait and large percentage of patients (over 30 see”. At present, some physicians are “The need to percent), the immune system treats avoiding certain approved medications factor VIII as if it were a harmful entity because of the drug’s immunogenic broadly and starts to make anti-drug antibodies profile or are unaware that a patient (ADAs). This often results in a loss has developed ADAs because they immunosuppress of efficacy and may also cause severe are not routinely monitored. Other hypersensitivity reactions, including physicians are experimenting with patients comes with anaphylaxis. immunosuppressive cocktails to overwhelm the immune system to clear drawbacks Arrested development and keep the ADAs at bay and allow the allergic responses medication to work. However, the need and risks.” NextGen 47

not to fight. We hope to use SVPs – to take place within the patient to by the dendritic cells. We designed the to program the immune system to induce longer term immune tolerance. nanoparticles to remain intact once they elicit tolerance to a specific antigen, The design of SVP-Rapamycin took were injected and to only release their without impacting the rest of the a significant time as we were looking to payload once they were taken up by the immune system. Rather than taking overcome serious scientific challenges dendritic cells. In addition, of course, the dendritic cells out of the patient and had to meet many important criteria. we had to develop a means to produce and dosing them with a biologic and For instance, we wanted them to work the particles in a way that made business an immunomodulator in a petri dish when dosed both subcutaneously or sense and could facilitate our scale-up. We to prevent ADAs, we enable the critical intravenously. We wanted to ensure that have already translated our SVPs from in process – specifically SVP-Rapamycin these nanoparticles resembled viruses so vitro, to mice and to non-human primates dosed in combination with a biologic that they would be taken up selectively – and this research has been published (2).

www.themedicinemaker.com candidate, studied it in clinical after his treatment (5). Teaching trials – and found that almost all Roche licensed the technology and Old Drugs New patients developed antibodies against reengineered the immunotoxin with NCI the immunotoxin, rendering the to make it less immunogenic by removing Tricks drug useless. certain epitopes, creating a product Many promising treatments do not reach NCI then opened a small new Phase I candidate known as LMB-100. Roche the market because of immunogenicity. trial in which a small number of terminal initiated a new clinical trial with LMB- As one example, Ira Pastan, a senior patients with a rare form of cancer known 100, but found that the compound was investigator with the US National Cancer as mesothelioma were dosed with the still highly immunogenic. Roche then Institute (NCI), discovered mesothelin, immunotoxin and a potent cocktail of returned the product and technology to a protein that is overexpressed in immunosuppressant drugs. The results NCI. In 2016, NCI and Selecta generated mesothelioma, pancreatic cancer and were compelling. While the vast majority compelling preclinical data showing how other solid tumors. After identifying of patients still formed ADAs and were SVP can prevent the formation of ADAs the target, Pastan started to work on forced off therapy, one patient was able to to LMB-100, which led Selecta to in- recombinant immunotoxins consisting receive four treatment cycles and another license the product candidate in 2017. of an antibody fragment fused to a was able to receive six treatment cycles. Selecta and NCI are currently planning bacterial toxin payload intended to kill Both of these patients saw marked tumor a Phase 1b clinical trial for this new mesothelin-expressing tumor cells. regression, and one of these patients combination product candidate, known NCI subsequently developed a product remains alive today more than five years as SEL-403.

But, of course, we needed to make the we would have full control of the many other drugs, ADAs build most important translational step of all – development path and timeline. up more slowly over the course of demonstrating that our approach would • At the same time, we needed many months. work in humans. this to be a real commercial • We also wanted to find a opportunity to address real unmet medication that had clear The right indication patient needs. biomarkers of efficacy as opposed In order to pursue our first commercial • We also wanted a product that to a longer-term clinical outcome. path for SVP-Rapamycin, we needed a would enable us to demonstrate a • Lastly, we wanted to work suitable biologic candidate to showcase benefit very rapidly – both from with adult patients for our first the potential of SVPs, and we had the an efficacy and from an ADA- indication. With hemophilia following criteria: mitigation aspect. and other genetic diseases, the • In some cases, immunogenicity is focus is often on treating young • It had to be a product that we built up immediately; flu shots are patients. However, as SVP is a new owned; we could have chosen to designed so that you only need one technology, starting with children license out our technology, but shot to have an immune reaction, would have erected high hurdles we wanted to own the product and some biologic drugs provoke from regulatory agencies, parents for the first applications so that an equally strong response. With and ethics committees. NextGenNextGen 49

Our screen led us to the chronic severe markets will begin to requireuire companiescompanies gout market. Gout is a very prevalent to not only study immunogenicityogenicity during disease – there are around eight million “Currently, it is clinical trials, but also afterfter a drugdrug has patients in the US alone. It is caused by been approved and is in regularegular metabolites from proteins; specifically not possible to re- use on the market. WWee uric acid, which normally circulates in urgently need to address thishis the blood at healthy levels below 6 mg/ administer gene issue as the next generationon dL. Gout patients have an imbalance of biologic therapies are between how much uric acid is formed therapy because the developed. Particularly inn the case and how much is excreted through of gene therapies, retreatmenteatment the kidney. If the concentration goes immune system will be incredibly importantant fforor above 6.8 mg/dL, uric acid is no longer a number of inborn diseasesases fforor soluble, leading to the formation of will have made which no treatments existist today.today. crystals that can cause inflammation If we want to progress medicinemedicine to the in joints and tissues. To get rid of the ADAs after the next level, we need to tackle AADAs.DAs. imbalance, you may need an enzyme And I believe that the mostost effective wayway called a uricase that targets uric acid. first injection.” to do this is through antigen-specific However, as the human body doesn’t immune tolerance. make uricase, it is viewed as foreign by the immune system, and ADAs form in patient’s liver cells to make the missing Werner Cautreels is Chairman, the vast majority of patients (3). coagulation factor? Gene therapy would President and CEO of Selecta We licensed one such enzyme, involve delivering genetic information Biosciences, Inc. pegsiticase, and then combined it with encoding the coagulation factor into our technology. By co-administering the the liver cells, but to do that you need This article was originally published enzyme drug with our SVP technology, a vehicle, such as a viral vector. Of in The Translational Scientist (www. we have generated data that show that we course, as these vectors are “viral,” they thetranslationalscientist.com), a sister can prevent the formation of ADAs in are always immunogenic when you dose publication to The Medicine Maker. human patients (4). I like to describe SVP- them systemically. Initially, the viral Rapamycin as a “negative vaccination.” vector should induce liver cells to start References With a vaccination, you are sending a making the missing protein. But, over 1. NK Bender et al., “Immunogenicity, efficacy danger signal to the immune system to time, expression may wane due to cell and adverse events of adalimumab in RA induce the formation of antibodies to turnover in the liver. Currently, it is not patients”, Rheumatol Int, 27, 269–274 fight an antigen. With SVP-Rapamycin, possible to re-administer gene therapy (2007). PMID: 17006705. we seek to teach the immune system that because the immune system will have 2. RA Maldonado et al., “Improving the efficacy the biologic is not dangerous and that made ADAs after the first injection. This and safety of biologic drugs with tolerogenic ADAs should not be formed. We have is a particularly challenging issue for nanoparticles”, Nat Nanotechnol, 11, already generated clinical data in support pediatric patients, as cell turnover in the 890–899 (2016). PMID: 27479756. of the idea that SVP-Rapamycin that is liver will be high as the children grow. 3. FDA, “Krystexxa (pegloticase) injection administered with pegsiticase mitigates As a result, systemic gene therapy dosing label”, (2012). Available at: bit.ly/2y5ArHc. the formation of ADAs to pegsiticase. has been mostly limited to adult patients Accessed May 1, 2018. We are now in the middle of a phase II thus far. In preclinical studies; however, 4. Selecta Biosciences, “Selecta Biosciences reports study and we have already started looking we have shown that by combining viral data from ongoing phase 2 trial of lead at the design of our phase III program, vectors with our SVP technology, ADAs candidate, SEL-212, in development for which we plan to begin soon. can be prevented, making it possible to chronic severe gout”, (2017). Available at: re-administer gene therapy. bit.ly/2fO11d8. Accessed May 1, 2018. Treat and retreat As the problem of ADAs becomes 5. I Pastan, R Hassan, “Discovery of mesothelin Gene therapy could be a particularly more understood, I expect to see greater and exploiting it as a target for promising area for SVP. Going back to regulatory oversight – and perhaps immunotherapy”, Cancer Res, 74, 2907– hemophilia; what if we could teach a agencies in the US and other developed 2912 (2014). PMID: 24824231.

www.themedicinemaker.com Biosimilar Backer Sitting Down With… Cyrus Krakaria, President of Biotechnology at Lupin Limited, Biotech Division, India. Sitting Down With  51

You’re passionate about the benefits of was a fascinating opportunity given that based in the US, and they’ve had a huge biosimilars – why? most of my career had been based in the influence on legislation. The hurdles There is no country on earth right now US. And because India is relatively poor, for launching biosimilars in the US are where medical systems are not under many biopharmaceuticals are completely significant. Even big pharma companies strain. Yes, biologics have revolutionized out of reach. What a difference it would are struggling to launch biosimilars – medicine by providing treatments for make to be able to bring these essential forget about small companies like us! incurable diseases, but these medicines medicines to a point where wider numbers Things will remain difficult until there is are expensive. However, it is possible to of patients can afford them… an even playing field. Right now, contracts produce the same medicines at lower costs. And actually, it isn’t just a problem for and rebates are preventing insurers from And once the price point is adjusted, we can countries like India. Think of the US; if choosing biosimilars – so they aren’t being reduce the pressure on medical budgets. someone is unlucky enough not to have used. And this does not incentivize the The money saved can be used for other insurance, then they are “written off.” development of biosimilars, particularly (newer) life-saving drugs. Some people in In a way, India is in a better position for small companies. It is very expensive the industry are against biosimilars, with because biosimilars have really taken off to get a biosimilar approved in the US, some innovators scare mongering so that so there is a lot of competition to bring which means there is little leverage to they can hang on to a monopoly, but we prices right down. reduce the cost of a biosimilar compared need biosimilars! Like it or not, biosimilars with an innovator product. Despite all are an effective solution to healthcare Some people in industry have made of this, I am optimistic. It will change costs – and will become universal as more comments about the safety of medicines because things have to change. We have governments start acting. made in India… our eyes on the US market at Lupin. We A significant percentage of all the world’s have a pipeline of around 10 biologics How did you get involved with the generic medicines are made in India – and we want to take some of these to the biosimilars industry? patients all over the world benefit from global market. At some point we will I’ve worked in biotech for over 25 years. medicines that come from India and I crack the US market too. Much of my career was spent working don’t think a lot of people know how for companies that produce biological well these drugs have been made! All How do you think the industry needs entities, including Biogen, one of the the major companies follow cGMP to change? oldest biotech companies around. I’ve and the regulatory climate here is very I would like to see a change in the way had the good fortune to be involved in effective for generics and biosimilars as that biosimilar molecules are scrutinized taking three biological drugs all the way regulators don’t discriminate between and a simplification of the requirements from the clinic to commercialization, so I innovator and copycat drugs – the final for demonstrating biosimilarity. Science know the hard work that is involved. But decision will be made based on quality. has improved a great deal – and will at some point I began wondering about There are many misconceptions about the continue to improve in the future. We what comes next. safety of biosimilars and manufacturing can clearly show whether a biosimilar has When I first heard about the concept processes, but biosimilars tend to use the same route or mechanism of action of biosimilars, I must admit I was a newer manufacturing technologies than as an innovator drug – no matter how little skeptical. I thought it would be the innovator. I’ve seen head-to-head “dissimilar” it may be. And a lowering of very difficult – perhaps impossible – to studies where the biosimilar drug could regulatory hurdles does not mean we have copy a biologic considering that most be better than the innovator drug because to compromise safety and efficacy (which biologics are made in natural systems. of the use of more modern technologies should never happen). It would be great How do you engineer a different cell to and high-end analytics. to make it easier for biobetters to come to produce the same biologic with the same market. Right now a biosimilar must be post-translational modifications? I was Do you think biosimilars will ever take similar, but it can’t be better. If it’s more intrigued and did more research – and I hold in the US? potent than the originator then you’ll took it on as a challenge, because it would Yes – eventually. Because someone need to spend more money on additional bring enormous benefits to patients. somewhere is paying for the current trials. But most companies cannot afford India-based Lupin has traditionally system and that is not sustainable. I think to do that. What a shame there is not focused on generics, but biosimilars are uptake has been slow in the US because more incentive to develop products that a natural progression. Joining Lupin many of the innovator companies are offer improvements for patients!

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