HUMIRA BIOSIMILARS: Battle Lines Shift from Education to Sustainability by MELANIE SENIOR

invivo.pharmaintelligence.informa.com OCTOBER 2018

Invol. 36 ❚ no. 09 Vivopharma intelligence ❚ informa HUMIRA BIOSIMILARS: Battle Lines Shift From Education To Sustainability BY MELANIE SENIOR

A Phoenix Turn For Tonix: Immuno-Oncology: Unicorns, Aetion: Sealing The Deal With Rising From Phase III Ashes China And The Perfect Storm Payers On Real-World Research PAGE LEFT BLANK INTENTIONALLY invivo.pharmaintelligence.informa.com STRATEGIC INSIGHTS FOR LIFE SCIENCES DECISION-MAKERS CONTENTS ❚

In Vivo Pharma intelligence | October 2018

8 COVER ❚ HUMIRA BIOSIMILARS: Battle Lines Shift From Education To Sustainability Melanie Senior

In October 2018 a handful of biosimilars of the world’s top-selling drug, Humira (adalimumab), were due to launch in Europe. They will not topple the $18 billion behemoth. But they will do some damage, as Europe’s cash-strapped payers ready themselves to embrace these cheaper lookalikes.

16 20 24 A Phoenix Turn For Tonix: Twist Bioscience: Aetion: Sealing The Deal With Rising From Phase III Ashes DNA Research Tools Put Fresh Payers On Real-World Research With New PTSD Approach Spin On Drug Discovery WILLIAM LOONEY LUCIE ELLIS WILLIAM LOONEY As biopharma’s embrace of real-world In an exclusive interview, Seth Lederman, Speed and efficiency are fundamental to evidence (RWE) gathers speed, In Vivo CEO of New York-based Tonix the success of today’s biopharmaceutical looks at one company that is using a mix Pharmaceuticals, talks about the enterprise, but the hunt is still on for of prestigious academic, government and company’s R&D rollercoaster ride and transformative technologies to boost non-profit partners to build a credible how it plans to keep its lead asset on pipeline productivity and growth. One foundation for acceptance of this research track for approval as a treatment for answer may lie in the arrival of replicable, tool in the wider commercial space. post-traumatic stress disorder. synthetic versions of DNA.

28 34 Immuno-Oncology: Unicorns, STEM CELL RESEARCH PROGRESS China And The Perfect Storm IN THE US: WHERE ARE WE NOW? SWARNA MEHROTRA, SPONSORED BY: SYNEOS HEALTH ODED BEN-JOSEPH AND The history of stem cell research has ELLEN BARON been marked by a combination of great There is a unique phenomenon being promise, disappointment and realized in immuno-oncology deal- controversy. But progress is being making compared with other segments in made, with a number of stem cell the life sciences sector – an apparent therapies approved and many more in uncoupling between risk and return on the late-stage pipeline. invested capital, as early assets provide similar liquidity to more mature assets.

DEPARTMENTS ❚ From The Editor AROUND THE INDUSTRY This month, In Vivo’s lead story from Melanie 4 Japan’s Healios Eyes First Senior looks at the huge market shift for biosimilars Approvals As It Progresses now that patents protecting the world’s best-selling Regenerative Therapies drug have expired in Europe. In October 2018, over a IAN HAYDOCK decade since the first biological copycat product was approved in Europe, a handful of biosimilars of 6 A Chance To Own The Venous AbbVie’s Humira (adalimumab) were able to launch Space: BTG Acquires Novate in the region. ASHLEY YEO This article explores the changing attitudes to- 38 ON THE MOVE ward biosimilars in Europe and further afield, and sheds light on how different countries are Recent executive appointments preparing for switching once multiple biosimilar LUCIE ELLIS in the life sciences industry versions of Humira become available. Biosimilars REGINA PALESKI are here to stay, but when it comes to pricing, the key question is: how low is too low? Melanie explores the issue of sustainability in this emerging and 42 DEAL-MAKING changing market. Deals Shaping The Medical Industry, September 2018 Meanwhile, we have been busy at In Vivo headquarters and have recently made THE STRATEGIC TRANSACTIONS TEAM changes to some of our regular features. You may have spotted in September that we published for the first time our redesigned On The Move column. This is orga- nized in a new, easy-to-view table and includes more entries than the previous format. An even more comprehensive monthly roundup of executive changes across the biopharma and medtech sectors is published on our website in a EXCLUSIVE ONLINE CONTENT searchable, interactive table. invivo.pharmaintelligence.informa.com We have also updated the Up-front page; this section allows our print readers to quickly assess some key points from that month’s content. The In Vivo team ❚ Partnering In Cell And Gene would appreciate any feedback on these changes and looks forward to hearing Therapy Is A Unique Endeavor from our readers. AMANDA MICKLUS In other news, Barbara Freischem has joined the In Vivo Editorial Advisory Board. Ms. Freischem is the executive director of European Biopharmaceutical ❚ Device/Diagnostics Quarterly Enterprises (EBE), a specialized group of EFPIA, the European association for Dealmaking Statistics, Q2 2018 the pharmaceutical industry. She is a qualified veterinarian and has significant AMANDA MICKLUS & experience both on the side of regulatory authorities as well as the regulated industry in a variety of technical and leadership roles. MAUREEN RIORDAN

❚ VistaGen Stocks Neuro- psychiatry Pipeline And Takes In Vivo: Always Online First Aim At Depression Market Relevant and exclusive online-only Don’t have an online user account? LUCIE ELLIS content at your fingertips 24/7. Quickly and easily create one by clicking on the “Create your Full access to our 35-year archive. ❚ Deals In Depth, August 2018 account” link at the top of the page. AMANDA MICKLUS Access your subscription by visiting: Contact: invivo.pharmaintelligence.informa. [email protected] com and log in. or call: (888) 670-8900 or +1 (908) 748-1221 for additional information.

All stock images in this publication courtesy of www.shutterstock.com unless otherwise stated. /invivo @invivo /invivo

2 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com CONTENTS ❚

❚ Up-Front SNAPSHOTS FROM OCTOBER'S CONTENT

“I have never seen such a coordinated push for speed, depth and breadth of uptake.”

OMAR ALI, FORMULARY ADVISOR SURREY & SUSSEX HEALTHCARE NHS TRUST

AS TOLD TO IN VIVO WHEN DISCUSSING THE INFLUX OF HUMIRA BIOSIMILARS. PAGE 8 1H/2018 saw larger venture investments with a VC investors like synthetic There is a growing consensus DNA because it is “platform in the research community agnostic.” More than two that a more inclusive stance 27% dozen US companies and involving both clinical trial INCREASE start-ups are presently data and real-world evidence in average investment active in the field, which will spur efficiencies in drug is on track to surpass $1 development, raise industry size compared with billion in investor funding returns on its massive the prior year and a commitments from the VC investments in R&D and robust VC appetite and public markets this year. possibly ease pressures on PAGE 20 drug pricing. PAGE 24 for early-stage companies, investing heavily “Psychiatry drug development8 080 in Series A and B. is a journey, and the path7 070 PAGE 28 6060 certainly does not follow 5050

a straight line.”4040

SETH LEDERMAN, CEO 3030 TONIX PHARMACEUTICALS 2020

He talks to In Vivo about 1010 getting the company back onAverage Investment Capital ($M) Average Investment Capital ($M) track after a Phase III setback 0 0 SeriesSeries A A SeriesSeries B B SeriesSeries C C for its lead compound in PTSD. 20152015 20162016 20172017 1H/20181H/2018

Barryfc101_Wikimedia Commons Barryfc101_Wikimedia PAGE 16 CREDIT: CREDIT:

Japan’s Healios Eyes First Approvals As It Progresses Regenerative Therapies

Following the modification and introduction of legislation governing the safety, devel- The firm’s lead project is HLCM051, a opment and use of regenerative and cell therapies in Japan in late 2014, companies somatic stem cell regenerative medicine in the space have been generally positive on the shape and impact of the supportive that is being tested in a Phase II/III trial regulatory environment in the country – which has already led to the reimbursement in Japan for ischemic stroke. HLCM051 is and launch of several therapies. also set to move into the clinic for acute respiratory distress syndrome (ARDS); Tokyo-based Healios K.K. is one such have already received high prices. For Dr. Kagimoto disclosed that discussions company. Formed in 2011 as Retina Institute example, JCR’s mesenchymal stem cell with Japan’s regulatory agency, the PMDA, Japan, a Fukuoka-based venture under Rik- therapy Temcell (licensed from Meso- were already underway for exploration of en (Japan’s largest research organization blast), conditionally approved for acute the treatment in this area. for basic and applied science), the company graft-versus-host disease after allogeneic Behind this are various iPSC-based listed on the Mothers high-tech market of bone marrow transplants in September therapies including HLCR011 for wet age- the Tokyo Stock Exchange in 2015. It now 2015, was given an initial price equivalent related macular degeneration (AMD), also has around 110 employees (up from around to around $125,000 per treatment course. set to move into Phase I soon. Also, an in- 40 at the time of the initial public offering) “The regulatory framework in Japan ternational clinical program for HLCR012, an and affiliated research and company opera- is very clear,” Dr. Kagimoto continues. allogeneic iPSC-derived retinal pigment epi- tions in both Japan and the US. “Although there is a strong emphasis on thelium cell therapy for dry AMD, based on a “The deregulation of the laws for re- safety, a major aim is to accelerate in- US Phase III trial, is being considered. This generative medicine required companies novation, and I expect companies will be is being progressed in the US under a May primarily to show safety, but there was required to show benefits [of their regen- 2018 CRADA (Cooperative R&D Agreement) also flexibility around efficacy – statistical erative therapies] due to the high prices.” with the National Eye Institute. In support of significance does not need to be p<0.05 for Furthermore, Japan’s government has these projects, Healios has built allogeneic example – and this can be demonstrated realized it needs to encourage the domestic iPSC master cell banks that the institute is later on [after a possible conditional ap- industry to support cell and regenerative assessing under the collaboration. proval],” highlights Dr. Hardy Kagimoto, therapies, where it has the chance to Wet or dry AMD is estimated to affect chair and CEO of Healios. become a global leader, building on the around 9.2 million people in Japan, where “The regulations have been very 2012 Nobel Prize-winning work of Kyoto the anti-VEGF market for wet disease is positive. There is now a really supportive University’s Professor Shinya Yamanaka in estimated by Healios at about $496 mil- regulatory environment in Japan for unmet induced pluripotent stem cells (iPSCs). The lion. Still, Healios notes that relapse rates medical needs,” he says. “The motivation Laureate’s work in developing open-access on VEGF therapy are high (92% within a behind the changes [for the government] methods for directing iPSCs to develop into year). For HLCR011, preliminary studies in has been a rapidly aging society and almost any cell type laid the foundation for one patient at Riken have shown no recur- increasing health costs, including for im- the techniques now being progressed by a rence of disease and “there is expected ported drugs.” The new framework is based number of companies in the space in Japan. to be no need for continued anti-VEGF mainly on early conditional approvals using treatment” when the cell therapy is used, limited clinical data, and reimbursement KEY PIPELINE ASSETS Dr. Kagimoto says. and launch to expedite patient access, Healios’ hope is to gain Japanese ap- Another pillar of Healios’ technology with the allowance of rolling submissions proval for three therapies over the next is the generation of organ “buds” from of further data within certain time limits to three years. The key mid-term assets three types of iPSC-derived cells, which support a subsequent full approval. expected to drive future growth are being early tests have shown can improve sur- Speaking in an exclusive interview at progressed through a “hybrid strategy” vival in animal models of liver failure. The Healios’ head office in Tokyo, Dr. Kagi- comprising both in-house intellectual technology was exclusively licensed from moto noted that Japan’s National Health property and in-licensed projects. “We Yokohama University in Japan. Under a Insurance (NHI) scheme was also being were able to select assets that will give partnership agreement, the university is supportive of reimbursement for regen- us revenues and profit, and are aiming for planning to start a clinical study in 2019 erative therapies. Indeed, some products unmet needs,” Dr. Kagimoto says. in patients with ammonia-producing urea

4 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com AROUND THE INDUSTRY ❚

cycle defects, which currently require hours of stroke onset. Enrolment in the Europe an adjuvant surgical dye product expensive enzyme replacement therapy 220-patient Phase II/III TREASURE study used in ophthalmic surgery. “There was or liver transplantation. in the indication is also ongoing and something about where I grew up and the completion is expected in fiscal 2020. school I went to that seemed to encourage ATHERSYS RELATIONSHIP For potential commercial production, an entrepreneurial spirit,” he observes. Healios became the largest shareholder Nikon CeLL innovation, a wholly owned Relocating the budding Healios to Tokyo in Nasdaq-listed US stem cell venture subsidiary of imaging company Nikon enabled the growing company to tap into Athersys Inc. in March 2018, acquiring – which also has a capital alliance with the large pool of pharma industry talent an 8.7% stake. The deal provided access Healios – has already concluded a cell cul- in the capital, given that this is where the to Athersys’ MultiStem platform for off- turing manufacturing service agreement “money, tech, and people” are, and it was the-shelf cell therapies for tissue repair, with Athersys, which will make supplies this that helped to create a positive spiral which do not require tissue matching. for Healios’ sales. On the iPSC side, a as the venture developed. “Athersys has a particularly good pipeline joint venture with Sumitomo Dainippon and matches well for us,” Dr. Kagimoto Pharma, known as Sighregen, is establish- FUTURE STRATEGY notes. Its technology forms the basis for ing a production facility in the big pharma While Healios already has multiple alli- HLCM051, derived from bone marrow, and firm’s now-completed SMaRT regenerative ances with a range of academic and com- Healios now has a license in Japan, and and cell therapy plant in Osaka. pany partners, “It doesn’t make sense to also globally, to explore the MultiStem Given the criticality of production in the partner [for commercialization] as we want platform for organ bud therapies, ophthal- cell therapy sector to ensure quality and to achieve the highest profit and feed this mology indications, and in combination consistency, working with external vendors back in to the business,” Dr. Kagimoto ex- with iPSCs and embryonic cells in this latter (and perhaps competing with their other plains. “We will focus on the Japan market area. An option right being discussed for clients) can present challenges, so Healios for the present, which is the best country China would cover potential applications in will “keep its options open” in this area. for our type of business, but we may then ischemic stroke, ARDS, and trauma. look at the US and other markets.” ARDS – often caused by pneumonia or JAPAN BIOTECH, One other approach may be to move septicaemia – has a mortality rate of up to FUNDING ENVIRONMENT from developing a pipeline and more 58% and has no existing therapeutic drug Dr. Kagimoto emphasized that Healios had into platform technologies “to leverage treatment; the condition affects around not encountered any problems in securing the strengths that we have,” he adds. 12,000 people in Japan. Intravenously funding, having raised around $30 mil- Healios, however, will continue to work administered HLCM051 acts to control lion in a series A, $76 million through the with its existing partners in Japan, includ- inflammatory cells and hypoxia, and to IPO, and a total of around $300 million ing Sumitomo Dainippon, with which protect damaged tissue to promote heal- combined from these and other sources it is conducting joint R&D related to a ing. Cleveland, Ohio-based Athersys has and alliances. pre-transplant immune reaction testing been conducting small trials in the US and On an operating basis, Healios re- method in the wet AMD area. Europe in this setting since early 2016. ported a net loss of around JPY3 billion It is also working with industry giant Dr. Kagimoto described the potential ($27 million) in the 2018 fiscal second Takeda under a non-exclusive licence for market in Japan for HLCM051 in acute brain quarter and had cash of JPY14.8 billion as its 3D organ bud technology. stroke as “big,” given that ischemic stroke of June 30, 2018. Dr. Kagimoto is upbeat about the future accounts for around 75% of cases in Japan, Nevertheless, “One question is whether prospects for the company, given that affecting 230-330,000 patients. Another Japanese companies are using the support- the foundations for product filings and advantage is that the cell therapy may offer ive regulatory environment [in the country] hopefully approvals from the advancing a longer treatment window following onset well,” he says. His view is that “it is not pipeline – and subsequently the genera- than existing clot-dissolving agents (due to about money. It is more about the qual- tion of larger revenues – are now in place. the risk of cerebral hemorrhage). Healios ity and quantity of entrepreneurs. Money The CEO is confident that Helios is pursu- estimates that about 47% (around 62,000) chases people, but people [in Japan] can ing a sound strategy and is bullish that the of Japan's 130,000 severe stroke patients still be quite reserved” when it comes to venture “will be a really strong profitable will reach a hospital within 36 hours. setting up and managing new businesses. company” in a few years. In this indication, the therapy would As for his own background, Dr. Kagi- He says, “We believe we are making act to down-regulate hyper-inflammatory moto’s parents were also medical doctors, good decisions, and we want to build in- response and lymphocyte release in the and it was his own experiences at Kyushu house development and sales capability spleen (which exacerbate neuronal dam- University Hospital with several patients going forward… My hope is to create a ‘ma- age), promoting neuroprotection through with serious illnesses that convinced him chine’ that lasts beyond a single lifetime. the activation of anti-inflammatory cells about his desire to meet medical needs. Our ultimate aim is to be like a Japanese and growth factors. Athersys’ 300-pa- “Something was ‘off’ and bioventures version of Amgen or Genentech.” tient, Phase III MASTERS-2 trial in this were lacking in Japan,” he notes. IV123561 setting started enrolment in July and So, at just 28, he started his first com- IAN HAYDOCK patients will be treated within 18-36 pany, which developed and launched in [email protected]

A Chance To Own The Venous Space: BTG Acquires Novate

BTG PLC has continued to do selective bolt-ons to its growing portfolio of interventional products from the ranges currently avail- medicine (IM) technologies, adding Novatek Medical’s Sentry inferior vena cava (IVC) filter able, and avoid picking products where to its product mix. The technology will boost the group's vascular business, which has there is saturation or a lot of competitors. tended to be overshadowed somewhat by BTG's expanding oncology franchise of late. Bolt-ons are a major part of BTG’s growth strategy, and Novate follows the Oct. 2017 The Sept. 7 acquisition announcement acquisition of Roxwood Medical Inc., has also restored some balance to BTG's which joined Ekos Corp. in BTG's vascular newsflow, which was dealt a blow in portfolio. In addition, there has not been June when a US FDA advisory committee ‘There has not been a company in the past that has differenti- declared PneumRX’s Elevair endobron- ated themselves in the venous space, chial coil system not approvable. BTG is a company focused says Hahn. Plentiful efforts have been reviewing options of how best to proceed made in the arterial space, with coronary with the FDA on this front (Also see “FDA on developing a range angioplasty, stenting and atherectomy, Panel: Benefits Unproven For BTG Em- of products in the Hahn observes. “But there hasn't been a physema Treatment” - Medtech Insight, company that has really focused on devel- June 16, 2018.) venous space; oping a range of products in the venous In buying Novate for up to $150 million space; with Novate, BTG has announced (milestone dependent), BTG has regained with Novate, BTG itself as a player who could do that”. positive momentum behind its decision As to Sentry, BTG points to 12-month to augment its mainly royalties-based has announced itself clinical trial data that have demonstrated income generation commercial model no new symptomatic PE, and no evidence by owning and developing its own prod- as a player who could of device migration, tilt, fracture, perfora- ucts. (Also see “BTG Enters IVC Market tion or embolization; complications that With $150M Novate Bolt-On” - Medtech do that’ have been associated with some other IVC Insight, September 7, 2018.) That strategic – BTG’s David Hahn filters. One-year clinical outcomes from the decision came under CEO Louise Makin, 129-patient Sentry trial were published and began with the purchase of Biocom- online on Aug. 31 by the Journal of Vascular patibles International in 2010. Arguably it need in the population where permanent and Interventional Radiology (JIVR). has not looked back since – and CER sales caval filtration has traditionally been The clinical trial has been a one-year up 10%, for the year ended June 30, 2018, used, but is not always seen as neces- prospective analysis of safety and efficacy. underlines that notion. sary. Sentry represents the next step in Two-year data will be presented at the up- Sentry is a bioconvertible IVC filter that addressing this market of temporary caval coming VIVA meeting, in November 2018. aims to prevent pulmonary embolism (PE) filtration, he believes. The device was granted 510(k) regula- in patients at high risk of venous throm- Implanting Sentry, the first biocon- tory clearance in the US in 2017, and BTG boembolic events (VTE's), and will join vertible IVC filter, would obviate the need plans to launch it there in the second half other PE assets in the BTG stable. Other for filter removal, thereby avoiding both of FY2018/19, selling it through the exist- manufacturers have had issues with IVC the potential complications associated ing vascular sales force that is attached filter technologies, and some, including with the second procedure and with the to EKOS. CR Bard Inc. and Cook Medical Inc., face retrievable device itself. “Bioconversion” Novate was the first bioconvertible thousands of patient-injury lawsuits as means that the device changes configura- filter on the market, ahead ofB. Braun a result of complications tied to device tion over time, such that when the patient Melsungen AG's VenaTech, a device that migration, fractures and other issues. no longer needs caval filtration, the filter requires a secondary procedure to convert auto-converts and opens up the cava to it into an open configuration. In develop- NEXT STEP BEYOND free flow. The technology is targeted at ing Sentry, Novate learnt how to steer CAVAL FILTRATION providing patients with protection against clear of the patient event issues that have BTG’s senior vice-president of medical and PE during transient periods of high risk. beset some IVC filter competitors, includ- clinical affairs, interventional vascular, After about 60 days, hydrolysis of the fila- ing Argon Medical Devices Inc., Boston David Hahn explains to In Vivo that there ment enables the arms to retract against Scientific Corp. and Cordis Corp. are many devices in the IVC filter market, the IVC, leaving a patent lumen. Hahn stresses the point that retriev- and recently there has been a trend to- Hahn says that BTG's policy as an in- able filters must be designed to be col- wards retrievable devices to meet unmet novator is to seek to buy differentiated lapsible and retrieved through a small

6 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com AROUND THE INDUSTRY ❚

sheath. “Those design issues lie at the cedure. It's fantastic for a physician to be core of the problem – if the device frac- able to tell a patient who would otherwise tures, tilts, or perforates the vessel wall, have received a retrievable filter that they they become difficult to remove. In such ‘BTG’s DNA is do not have to come back for a procedure cases, the procedure can be fraught with with any degree of risk or hardship for problems, and that is the basis of a num- innovative and is them”. And the hospital saves on the cost ber of patient litigation issues being seen rolling back the of the second procedure. around retrievable filters”. On the other hand, Sentry has none boundaries of LEARNING CURVES FOR SENTRY of these design compromises and merely AND ELEVAIR opens up, becoming stent-like. Hahn said, what physicians Sentry represents a learning curve for “Its whole design is intended to sidestep physicians and patients. And BTG is on the retrieval issues that can potentially can do for its own learning curve with its Elevair lead to complications. A filter designed endobronchial coil system. Hahn explains for retrieval can be problematic even if the patients in a that in the wake of the FDA's decision, it concept is good” (as is evidenced in the is clear that more data are necessary for physician hashtag #filterout). minimally-invasive the PneumRx product, and BTG is currently The IVC filter market is very well under- in the process of understanding precisely fashion’ stood and differentiated. Around 100,000 what data will be needed to help in the filters are placed in the US per year. The US US regulatory process. The company is has a trend towards management of DVT, filtration for the rest of their lives. Sentry running a trial in Europe, Elevate, and although Europe sees an approach based is likely to address the subset of the popu- has already been generating new clinical more on anticoagulation than filters. Nev- lation that will benefit from having caval evidence. “What we are understanding ertheless, BTG sees Sentry as properly filtration during the short period when in the wake of the FDA decision is that addressing the disease state around DVT they are at risk of having a PE. “That's we need to increase the body of clinical and PE. Hahn observes that BTG has EKOS, probably the majority of the population”, evidence around the efficacy and safety of to treat DVT and PE, and now, with Novate, says Hahn. “My guess is this will be used coil therapy”. He adds that is is too early has a preventive option for PE by catching by a lot of physicians who have migrated in the process for timelines. DVT. “It rounds out our understanding of to the retrievable filter market because In Sentry, BTG has brought in another the entire venous space”, he says. they wanted to avoid lifelong caval filtra- technology that will be central to its prod- The product is not yet launched, but tion. This will transform that space”. uct mix. Firstly, it is a novel solution that BTG already has the sales force and the This seems to fit the rationale and new has the potential to really be a differen- relationship with physicians around VTE. mission statement – “imaginative solu- tiator, says Hahn. Secondly, CEO Makin “The investigators in the multicenter tri- tions that make a difference to patients wants to leverage BTG's highly comple- als are extremely optimistic about the and physicians” – of BTG. Hahn adds, “The mentary vascular portfolio around PE and technology, and their opinion matters”, intent of the company is to be an innovator seek out opportunities for cross-working says Hahn. He continues, “They very in IM, a space that requires creativity and and spin-offs within the company. And much understand the issues around caval innovation within its core. BTG’s DNA is thirdly, it will augment the vascular offer- filtration, and for them the product makes innovative by nature: a drive to transform ing that BTG can present to interventional sense”. The main training and education medicine and push in a new direction – radiologists – who place three-quarters of required for Sentry is around the time to better, faster and in a non-invasive man- all filters – at key events like CIRSE (Car- bioconversion, and the clinical advantage ner – and rolling back the boundaries of diovascular and Interventional Radiologi- and expectations of placing a filter that what physicians can do for patients in a cal Society of Europe). The acquisition of auto-converts. minimally-invasive fashion”. Novate's Sentry is a prime example of how Accordingly, BTG will play strongly on BTG distinguishes itself in the market, SENTRY'S TARGET DEVICE MARKET the “unique” bioconversion properties says Hahn. As to how much of the market converts, of Sentry. Hahn says, “The beauty of IV123570 BTG believes that there is a population bioconversion is that essentially it saves ASHLEY YEO that will still require an IVC filter and caval the patient from undergoing a second pro- [email protected] LET’S GET SOCIAL In Vivo Pharma intelligence | @INVIVOnow

HUMIRA BIOSIMILARS: Battle Lines Shift From Education To Sustainability BY MELANIE SENIOR Shutterstock: Copyright Info Copyright Shutterstock: Gayle Rembold Furbert Rembold Gayle

Copies of the world’s top-selling Many of Europe’s payers are poised to So what? Sponsors fear downward drug, Humira, will hit Europe in swiftly adopt these cheaper price-spirals may threaten the sector’s mid-October, launching the biggest medicines. Their challenge has shifted sustainability. Yet, longer-term, biosimilars’ biosimilar battle yet. from whether to use biosimilars, to impact may stretch beyond price and how to use them. access, to change treatment pathways.

8 | In Vivo | October 2018 pharmamedtechbi.com invivo.pharmaintelligence.informa.com BIOSIMILAR MARKET VIEW ❚

IN OCTOBER 2018 A HANDFUL OF BIOSIMILARS OF THE WORLD’S TOP-SELLING DRUG, HUMIRA (ADALIMUMAB), WERE DUE TO LAUNCH IN EUROPE. THEY WILL NOT TOPPLE THE $18 BILLION BEHEMOTH. BUT THEY WILL DO SOME DAMAGE, AS EUROPE’S CASH-STRAPPED PAYERS READY THEMSELVES TO EMBRACE THESE CHEAPER LOOKALIKES.

ver a decade since (UK, Germany, France, Spain and Italy) figuring out the pricing and procurement the first biosimi- could save €10 billion ($11.6 billion) from dynamics that enable meaningful health lar was approved biosimilars between 2016 and 2020. system savings and increased patient in Europe, these As well as being critical to health access, but which also sustain a vibrant, near-copies of system sustainability, biosimilars are competitive biosimilar market. large molecule increasing patient access to biologics in drugs have taken certain countries and conditions. They Not Whether, But How hold. Physician have boosted European sales volumes: Europe’s payers and physicians have cut confidence has grown as evidence accu- since biosimilars of infliximab and their teeth on other monoclonal antibody mulatesO to show biosimilars’ equivalence etanercept (Amgen Inc./Pfizer Inc.’s biosimilars, including infliximab, in the to branded originals. Payers are saving Enbrel) were launched, these medicines same anti-TNF class as Humira and used money. Prices of medicines that can cost have grown at compound annual growth across a similar range of inflammatory many tens of thousands of dollars per rates of 10% and 4% respectively, having diseases, and, most recently, biosimilar patient per year are falling by between been flat before, according to IQVIA data. trastuzumab (Herceptin) in cancer. There 40-80% in some markets. And the sav- And there are signs that biosimilars are is a strong foundation of clinical and ings are rolling in faster with each new opening up use of biologics earlier in the real-world data supporting the equiva- biosimilar launch: Europe’s first complex treatment pathway. lence of biosimilars to their originator. biosimilar, infliximab (a copy ofMerck So while the nascent US biosimilars “Biosimilars work. They are equivalent & Co. Inc./Johnson & Johnson’s TNF- market remains hamstrung by patent enough” to the originator molecule, as- blocker Remicade, used in a range of disputes, topsy-turvy market incentives serts Justin Stebbing, Professor of Cancer inflammatory conditions), took a couple and a mind-boggling naming policy (see Medicine and Medical Oncology at the of years after its 2015 launch to get off the Box US Biosimilars: Close To Lift-Off?), Imperial College Healthcare NHS Trust ground. Biosimilar versions of Roche’s Europe is bracing for its biggest biosimi- in England. Stebbing is lead author on cancer and rheumatoid arthritis treat- lar launch-party yet. An unprecedented a Celltrion-funded equivalence study of ment MabThera (rituximab), however, number of competitors are vying for a biosimilar trastuzumab, which showed launched in 2017, captured almost 40% share of Humira’s $4.4 billion European that the Korean group’s biosimilar, now volume share in Europe within a year. sales (over $12 million per day), across available as Herzuma, was therapeuti- In the UK, that share is now over 80%, its dozen or so indications. Many of Eu- cally equal to Herceptin in patients with according to IQVIA. rope’s payers have geared up to take full early-stage HER-2 positive breast cancer. After a slow start, Europe is now advantage of biosimilar adalimumabs the But he suggests that, as comfort with adopting biosimilars “at the high end of minute they become available. biosimilars grows, full-blown clinical expectations,” says Ronny Gal, senior There are still challenges. But those trials may not be necessary across all analyst at Bernstein. Biologics make up challenges have shifted. They are no longer indications. In some situations, such as the largest, and fastest-growing share about informing and convincing physicians metastatic cancer, “we can extrapolate,” of drug spend in most systems. IQVIA and other stakeholders of biosimilars’ he says (see box: Changing Attitudes). estimates that Europe’s top five markets safety and efficacy. They are now about Indeed, “extrapolation [relying on

Exhibit 1 ❚ US BIOSIMILARS: Europe Market Overview: Biosimilars As Volume Share Of The CLOSE TO LIFT OFF? Reference Molecule Market

The FDA has approved over a dozen EU Biosimilar Market Share biosimilars, but most are caught up (by standard units) in patent disputes. And even if they 100 were not, the US health system’s web 93 Neupogen (lgrastim) of rebates and reimbursement con- 90 tracts is not designed to encourage 80 76 Epogen (epoetin) more careful purchasing – indeed, 70 many hospital systems benefit from 60 buying more expensive drugs. The 60 Remicade (infliximab) result is “anemic” biosimilar com- 50 petition and a missed opportunity to 40 38 Rituxan (rituximab) save what could have been over $4.5 37 Enbrel (etanercept) billion in 2017 alone, lamented FDA 30 Commissioner Scott Gottlieb in a July 20 Herceptin just showed up 2018 speech. (2nd month with data) 10 July 2014 July 2018 Momentum is building behind efforts to boost biosimilar adoption, SOURCE: IQVIA; Bernstein however. Gottlieb’s July speech was Payers Poised To Embrace to launch the FDA’s 11-point plan September 26, 2018. Cummings acknowl- Biosimilar Humira to promote biosimilar uptake and edges, though, that some clinicians still competition. This included a more want to see clinical data in a relevant The onslaught of Humira biosimilars will efficient approval process, better population. And indeed, for now, “we test how well health systems and spon- communication, finalized labeling still need clinical studies, including sors are facing up to those challenges. guidance and steps to tackle anti- combination and switch studies, as well As of late September 2018, eight competitive behavior. as more long-term data,” says Stebbing. biosimilar brands (five different mol- Real-world data and pharmacovigilance ecules) had been approved in Europe, Forthcoming guidance around inter- remain critical: systems must handle with several more in development (see changeability could be the most im- growing volumes of data, and be suf- Exhibit 2). AbbVie’s CEO Rick Gonzalez portant catalyst for change, however. ficiently sensitive to pick up signals as has predicted that ex-US sales of the drug Most US states have passed laws that patients are switched from reference will fall by no more than 20% by the end would allow pharmacists to substi- drugs to biosimilars, and, increasingly, of 2019. This may be optimistic (even if tute biosimilars that are designated between biosimilars. ex-US includes other markets where bio- interchangeable, significantly boost- Yet while these data accumulate, the similars are not available, such as Brazil ing uptake. Credit Suisse analysts question for many health systems has and Japan). Sales of branded Remicade expect the first interchangeable bio- moved from whether to use biosimilars, have dropped almost 70%, albeit three similar to be approved in 2019-2020. to how to use them. Providers are now years after launch. Humira sales could Meanwhile, AbbVie’s lawyers have grappling with the practicalities of staff- drop farther and faster, since there are held off biosimilar Humira in the US ing and setting up patient-switching more competitors at the outset, and far until 2023. programs, and working out what, if more rigorous preparations among some anything, to tell patients as they move European payers. “I think uptake of [bio- onto a medicine that might look slightly similar] adalimumab will be massive,” different. They are having to balance predicted Michael Muenzberg, biosimilar budgetary priorities with patients’ needs consultant and former medical director and concerns, and ensure that decisions of EU biosimilars for Amgen, at SMi’s data in one indication to support use are understood and supported by all Biosimilars & Biobetters conference. in another] is now better understood, stakeholders. Several European health systems, in- and accepted,” says Fraser Cummings, Biosimilar sponsors, meanwhile, must cluding in the UK and Germany, have in- consultant gastroenterologist and Honor- continue to navigate (and influence) creasingly aggressive national or regional ary Associate Professor at the University complex, fragmented and fast-evolving biosimilar prescription targets or quotas Hospital Southampton NHS Foundation procurement systems alongside a grow- in place to encourage uptake, sometimes Trust, speaking at SMi’s Biosimilars ing number of competitors – including linked to financial or non-financial incen- & Biobetters conference in London on the originator. tives. In the UK, preparations have gone

10 | In Vivo | October 2018 pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com BIOSIMILAR MARKET VIEW ❚

deeper still. NHS England’s Regional the UK. England already has the highest Medicines Optimisation Committee, biosimilar penetration across the EU 5 charged with ensuring the national countries, and saved £324 million ($423 ❚ CHANGING ATTITUDES payer obtains good-value medicines, million) from biosimilars last year. The Attitudes across professional soci- urged local medicines purchasers back NHS hopes to make regular annual sav- eties in Europe, too, have evolved in May 2018 to avoid entering into new ings of £300 million by 2021. to encourage use of better-value adalimumab contracts lasting beyond Some German payers have been avoid- medicines. This is critically impor- 16 October 2018. Instead, NHS England’s ing high-priced Humira since 2016, even tant in convincing physicians to use Commercial Medicines Unit will use a without a biosimilar to that particular biosimilars. The positions of groups price-based national tender to select a molecule. Instead, in areas such as such as the Association of German short-list of adalimumab formulations Westfalen-Lippe, physicians and hospi- Rheumatologists, the British Soci- under a ‘framework agreement’. Regional tals are encouraged to use biosimilar ver- ety of Gastroenterology, and many players can then select from and negoti- sions of other anti-TNF medicines such others have shifted from cautious ate further discounts around these for- as infliximab or etanercept (Benepali) skepticism two or three years ago, to mulations, according to local priorities. – especially for new patients. Potential positive endorsement today. Importantly, given that adalimumab is annual savings from using cheaper bio- often administered at home or in an out- similars – up to 20%, or over €4,000 per Even in France, where strong physi- patient setting, shared savings schemes patient – are spelled out. The share of cian lobbies and a law that prohibits are being set up to ensure that incentives infliximab biosimilars in Germany is now patient switching have slowed bio- for hospital systems and primary care about 80%, although regional variation similar uptake, things are changing. providers are aligned to use cheaper is high. Marc Bardou, a gastroenterologist biosimilars. Advice is also provided and professor of clinical pharma- Speeding Up Switching to hospitals and general practitioner cology at the Centre Hospitalier practices on updating agreements with Switching is key to biosimilars’ success: with- Universitaire (CHU) Dijon, Northern local homecare providers. Even letter out it, their markets would be limited to new France, was highly skeptical of using templates are available for providers and patients. Here too, attitudes are shifting as sav- biosimilar infliximab in GI indications clinicians to send to patients, informing ings materialize and study data accumulates when it first became available. Now, them of why they are being switched to a to support the safety of switching (see Exhibit reassured by data from a national biosimilar medicine and what it means. 3 for study examples). switching trial, “my and many of Online savings calculators will enable Many of Europe’s healthcare providers my colleagues’ attitudes have com- regional providers (Trusts) to work out are being urged by their funders to pre- pletely shifted,” he says. the savings available from switching a pare for extensive switching from Humira certain proportion of their patients. onto biosimilar adalimumabs. Patient “I have never seen such a coordinated switching is already a well-oiled process push for speed, depth and breadth of up- in many markets and hospital systems, take,” says Omar Ali, formulary advisor though. In Norway and Denmark, which for Surrey & Sussex Healthcare NHS Trust run nationwide tenders for biosimilars, and visiting lecturer, value based pricing mandated patient-switching may oc- & outcomes based innovative contract- cur across the entire country. Patients switched within two months to biosimilar ing at the University of Portsmouth in in Sweden’s capital, Stockholm, were infliximab, with few complaints according to Gustaf Befrits, a health economist Exhibit 2 with the Stockholm County Council, Biosimilar Humira Products Ready To Launch In The EU In October 2018 speaking at a conference earlier in 2018. In June 2018, the European Specialist MANUFACTURER BIOSIMILAR ADALIMUMAB BRAND NAMES (APPROVAL DATE) Nurses Organisation (ESNO) launched a guide on how to support patients switch- Amgen Amgevita and Solymbi (Mar. 2017) ing from reference to biosimilar drugs, or vice versa. Samsung Bioepis Imraldi (Aug. 2017) The most recent switch underway across many Trusts in England, onto bio- Boehringer Ingelheim Cyltezo (Nov. 2017) similar trastuzumab, appears to be going smoothly. Patients at the Royal Marsden Hospital in London were switched in Sandoz Halimatoz, Hefiya and Hymrioz (July 2018) September 2018 to a biosimilar trastuzumab that “cost about half the price of Fujifilm/Mylan Hulio (Sept. 2018) the original,” says Jatinder Harchowal, SOURCE: News releases chief pharmacist at the Royal Marsden

Hospital in London. “We didn’t have to offered incentives to use cheaper medi- support education and uptake in these do an intense amount of training,” he cines if they fall within a diagnosis re- retail settings, too. Chrys Kokino, head of continues, “because people understand lated group (DRG) tariff, which provides biologics at Mylan NV, whose biosimilar and accept” biosimilars. Patients at the fixed payments for certain activities and adalimumab Hulio is the most recent to Imperial College Healthcare NHS Trust procedures, many expensive medicines, gain European approval, is not concerned are also being switched to Ontruzant, including biologics, are reimbursed about the retail versus hospital distinc- a biosimilar trastuzumab developed separately. In Germany, hospitals in some tion, given the overall variation between by Samsung Bioepis Co. Ltd. and mar- regions may still profit from using inno- European markets. “Every European keted by MSD in Europe. The switch is vator biologics, because of contracts with market is different. As long as we are able mandatory for all patients on the IV for- insurers that simply reimburse list price to improve patient access, we are not as mulation of the drug (the branded version minus a fixed percentage discount. So concerned about where the prescription is also available in sub-cutaneous form), they have little interest in changing doc- originates as uptake will be dependent but patients are informed. The timing tors’ behavior. But the hospital-insurer on recognition of the product’s efficacy, and depth of information provided is at contracts are evolving to encourage great- safety and utility,” he says. the discretion of the Trust and clinicians, er biosimilar uptake, including through however. Some clinicians feel the change introducing flat-funding for all products How Low Is Too Low? should be kept as low-key as possible to with the same international non-propri- The Sustainability Question avoid unnecessary stress among patients. etary name (INN), set at the level of the Biosimilar sponsors have spent over a de- Switching is likely to become more cheapest drug in that category. cade trying to persuade Europe’s payers frequent as more biosimilars reach the to use biosimilars. Now they are worried market, each offering payers a better Retail Versus Hospital that those payers, in their new-found en- price. The limiting factor in many systems Biosimilar uptake also varies widely thusiasm, might become too aggressive in will be clinical and nursing resources. across the hospital and retail (communi- pushing down prices. Sponsors are now “We have over 600 patients on Humira” ty) settings. Some biologics, particularly worried about sustainability. “The way across our hospitals, says Southamption those for chronic conditions, are admin- things are going right now, driven only NHS Foundation’s Cummings. “Even with istered and paid for outside hospitals by price, will mean less competition, less the slickest switch, each patient will need (even if they are prescribed by hospital choice, and patients will lose as a result,” 30 minutes at least.” He predicts no more doctors). Humira is one example: in most warns Paul Harmon, senior director and than one switch per year in any given indications, it is administered at home or oncology biologics lead at Mylan Europe. indication as a result. at least in the community setting. In the With so many adalimumab competi- retail sector, choice of medicine is often tors, the risk is that prices dive deeply Doctors Take A Back Seat less constrained by institutional prac- and rapidly, making it un-economic for In future, doctors in UK hospitals may tices and policies, and some analysts pre- some players to remain in the game. Al- play even less of a role in determining dict a slower-than-anticipated uptake of ready, biosimilar discounts have reached which version of a particular biologic biosimilar adalimumab as a result. They depths that few thought possible – like patients actually receive. “It is going to be speculate that patients in the home set- Denmark’s 70% discount on branded the Trust’s decision,” predicts Imperial’s ting may be more resistant to switching Herceptin, or Norway’s 72% discount on Stebbing. For him, that is fine. “We’re from a more familiar reference product. branded Remicade in 2015. busy. We don’t have time to ask where But the influence of many of Europe’s At what point the price becomes un- the trastuzumab comes from.” payers is spreading into retail, where economic will vary by company, molecule Hospital physicians in Norway and incentives for using biosimilars are evolv- and market. “I don’t know what the ap- Denmark have already relinquished such ing fast. In Germany, insurance funds run propriate price is. Is it 10%, 20%, 30% decisions. These markets use price-based ‘open-house’ contracts for biosimilars less than the originator? I don’t know. tendering to select a single winner, which in the retail setting, with conditions But it definitely isn’t 90%,” says Harmon. becomes the preferred medicine across such as minimum list-price discounts or The Humira gold-rush will begin to the entire country. According to IQVIA, maximum prices pegged to that of the force answers to this question, and oth- this system has led to biosimilar pen- cheapest or second-cheapest candidate. ers around what a healthy and sustain- etration of 98% and 100% for biosimilar As biosimilar competition increases, the able biosimilar marketplace looks like. infliximab in Norway and Denmark, screws are being tightened, notes Pro- Granted, it costs a considerable amount – respectively – and some of the fastest Biosimilars, a national industry associa- in the $100 million to $200 million range and strongest price erosion. (Physicians tion. Even in France, economic pressures – to bring a biosimilar to market, and it can prescribe an alternative, but may face compelled the health ministry in August can take 10 years. If prices drop too low, financial penalties for doing so.) 2018 to call for proposals for new ways there could be fewer competitors, which, The picture is less clear-cut in other to encourage uptake of biosimilar etan- as well as restricting choice, could also markets. In France, hospital doctors ercept and insulin glargine in the com- potentially threaten supply. can still specify a particular brand if munity setting. Meanwhile, biosimilar The huge margins on biologics mean they wish. And although hospitals are sponsors are bending over backwards to there is plenty of scope for generous

12 | In Vivo | October 2018 pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com BIOSIMILAR MARKET VIEW ❚

discounts, however. Modern manufac- potentially the originator – and offer form of infliximab, for example. Others turing technologies are pushing down patients and prescribers a range of op- are finding new, more convenient and unit production costs. “They might make tions. Such systems are in place in the faster ways to deliver I.V. medicines, and gross margins that are less than 80-90%, UK and Germany, and in France, where, to offer support. “We are looking at pa- but there’s no reason [profit] margins according to Sandoz’ Turk, “only 40% tient services, devices and other means won’t still be in the 30-50% range in five of the decision is based on price; 50% to further differentiate ourselves in the years’ time,” making it a nice business is qualitative criteria.” Those qualitative marketplace,” says Mylan’s Kokino. still, says Bernstein’s Gal. Muenzberg criteria extend to education, support and also dismisses sponsors’ sustainability logistics, inventory management and Thriving In Complexity concerns. “There’s a lot of room for prof- even environmental impact of produc- Europe’s biosimilar practices will contin- it,” he says. And indeed companies like tion, as well as excipients, delivery device ue to evolve, but they will not harmonize. Orion Pharma, distributing biosimilars and administration mode. Optimal procurement systems, number of in the Nordic countries, are doing nicely The weighting of such criteria var- competitors, average price drops and the on their formula of large discounts and ies by country and region and even, in extent to which factors like product sta- large market share. some markets, by individual insurers or bility, dosage, formulation and delivery Europe’s patchwork of national and even hospitals. Price predominates in trump pricing will continue to vary by regional reimbursement policies, pro- most cases. But once a certain level of molecule, indication, country and even curement processes, cultures and even discount is achieved – for instance, in region. This fragmentation may be pre- intellectual property protection mean the UK framework agreements – there is cisely what allows the biosimilar market prices are not going to fall by the same room around the edges. Priorities will be to thrive, sustaining multiple competitors degree all at once. Despite a common based on individual institutions’ patient across the region as a whole, and a wide quest for value, biosimilar uptake and numbers, storage capacity, resources and choice for patients. utilization is highly variable across differ- more. “Some [biosimilar trastuzumabs] Europe’s complexity has played di- ent molecules and markets. Indeed, the have longer stability data than others,” rectly into the hands of groups like Mun- region offers a convenient suite of case illustrates Royal Marsden’s Harchowal. dipharma, which commercializes three studies showing the impact of different That can help avoid wastage. For other of Celltrion’s biosimilars across several biosimilar procurement strategies and hospitals, guarantee of supply may be a European markets. Mundipharma is a physician incentives. Although no single priority, for example when usage is high network of associated, yet independent country provides a perfect example of a and/or in acute settings. (Sandoz hit ca- organisations across Europe (and be- healthy biosimilars market – if indeed pacity issues for its Rixathon [biosimilar yond). Each has deep knowledge of local anyone knows what that is – “there are rituximab] after its mid-2017 launch, giv- systems, stakeholders, priorities and lots of individual best-practices you can ing the lead in some markets to rival Cell- culture, and each has the freedom to use learn from specific markets, regions, even trion Inc./Mundipharma International that expertise to maximize patient access. specific hospitals,” says Florian Turk, Corp. Ltd.’s Truxima.) This local-first philosophy and structure head global payer, marketing, sales and Not all formulations of a given molecule is particularly well-suited for biosimilars. relations at Sandoz International GmbH. are available as biosimilars: Roche’s sub- After extensive education campaigns, And worst practice: many biosimilar cutaneous MabThera (rituximab) has seen working closely with stakeholders, and sponsors hate the aggressively price- minimal sales erosion from biosimilars, sharing early lessons, “we understand focused, single-winner national tenders according to IQVIA data. Roche also has how biosimilars are procured and how seen in some Nordic countries, that cut a (still-patented) sub-cutaneous version physicians prescribe them” in each mar- out all but one player. Such tenders “are of Herceptin, which is much quicker and ket, says Warren Cook, senior commercial negative for both originator and biosimi- cheaper to administer than the intrave- lead, biosimilars at Mundipharma. lar manufacturers…and may eliminate nous version. In England, patients on Today, infliximab biosimlarRemsima manufacturers’ incentives to innovate in sub-cutaneous Herceptin are, for now, remains the number one infliximab brand areas of added value, such as administra- allowed to remain on it. There is even in Mundipharma’s seven territories, tion route, device design, patient support reverse-switching in some English Trusts: which include Germany, Italy, the UK programs,” declare the authors of a Pfizer patients may be started on biosimilar and the Netherlands. Mundipharma also Inc.-sponsored IQVIA report, Advancing trastuzumab by infusion, but once they sells Celltrion’s rituximab (Truxima), Biosimilar Sustainability in Europe, pub- are stable, they are sent home with a which grabbed 75% market share in the lished in September 2018. prescription for sub-cutaneous Herceptin. Netherlands six months post-launch, and “It actually saves money to keep them out trastuzumab (Herzuma), launched in Multiple Winners of hospital, even with the more expensive May 2018. As In Vivo went to press, Mun- They instead favor multi-winner ten- formulation,” says Omar Ali. dipharma announced plans to acquire ders, and/or sub-national tendering (at These dynamics allow innovators to Cinfa Biotech, which received a positive the hospital or regional level) based on hold onto a slice of the market; they also recommendation in Europe last month other criteria as well as price, that may drive innovation among the followers. for approval of its biosimilar version of sustain several competitors – including Celltrion is working on a sub-cutaneous Amgen’s Neulasta (pegfilgrastim).

Exhibit 3 Switching Studies Show Few Concerns

The Norwegian government-sponsored NOR-SWITCH trial See The Lancet, June 2017 for study results. of infliximab found the biosimilar to be non-inferior to the https://www.thelancet.com/journals/lancet/article/ reference molecule. PIIS0140-6736%2817%2930068-5/fulltext

A Danish study of over 800 patients with inflammatory See Annals of the Rheumatic Diseases, 2016 for full study arthritis, switched from Remicade to Celltrion’s biosimilar results. https://ard.bmj.com/content/76/8/1426.long Remsima, also showed non-inferiority.

A Sandoz-sponsored systematic literature review of switching See Drugs, March 2018 Vol. 78 (4), for full study results. studies, published in March 2018, found no differences in https://link.springer.com/article/10.1007%2Fs40265-%20 immunogenicity, safety or efficacy following switching. 018-0881-y

Celltrion and other biosimilar-makers to afford. They are expanding treatment gradually lift. Meanwhile, adoption of are also using multi-branding strategies choice as competition forces biosimilar new biologics may slow further, certainly to address (and benefit from) Europe’s and originator sponsors to differentiate in the first-line setting. “It will be [even] complexities. Multi-branding refers to their medicines, for instance through tougher for originator drugs to access marketing the same molecule under new more convenient formulations, biologic-naïve patients,” says Southamp- distinct brand names. The eight brands delivery devices or dosages. ton’s Cummings. of adalimumab biosimilar are in part But so far, there is only limited The arrival of biosimilar adalimumabs about overcoming divergent national evidence that biosimilars are actually in Europe marks the end of a decade- patent constraints (patents are national changing treatment pathways through long transition period as these medicines affairs; the concept of an EU-wide pat- allowing earlier use of biologics. UK proved their therapeutic equivalence, and ent extends to name only). Molecules guidelines around the use of filgrastim their potential to help save costs while like adalimumab, approved for a dozen (granulocyte-colony stimulating fac- driving access. The next phase will see or more indications, are more likely to tor, G-CSF) in chemotherapy patients greater penetration of biosimilars in the bump up against such patent barriers. changed to include first-line/prophylactic slower-adopting European markets. Dy- Amgen’s biosimilar adalimumabs Am- use following the introduction in 2008 of namics among front-runner regions such gevita and Solymbic are identical other biosimilar versions of Amgen’s original, as the Nordic countries, the UK and some than in one of the nine indications each Neupogen. Other than that, “the evidence parts of Germany will begin to determine is indicated for. is mostly only anecdotal,” says Turk. whether sponsors’ sustainability fears Multiple brands may also enable It is a start, though. As biosimilars sav- are justified, and how many competitors sponsors to hand out distribution rights ings accumulate, specialists are likely to the region’s disparate – yet increasingly to different partners, and increase their push for a loosening of treatment guide- value-seeking-- markets can sustain. share of voice through having two sales lines, narrowed over recent decades by There are further biosimilars to come, forces. They may position one brand more increasingly widespread health technol- including a handful of copies of Amgen’s aggressively to compete in government- ogy assessment amid soaring drug costs. long-acting Neulasta in Europe, likely to backed tender processes, for instance, “We have no data to support changes in see rapid uptake given the high adop- reserving another for commercial con- treatment pathways, but we do see faster tion of biosimilar filgrastims. A further tracts, which may include a service ele- [volume] growth among biologics with $52 billion (€44 billion) of biologics are ment (e.g. home-care). There may also be biosimilar competition than those with- expected to go off patent in the top ten de- cultural nuances around particular brand out,” says Pontus Johansson, head of unit veloped markets between 2019 and 2022. names. In short, sponsors are “playing at Sweden’s medicines reimbursement As the category matures, biosimilars’ with patents, and pricing to different agency, TLV. “This could be due to lower impact will likely stretch beyond pricing games” in a bid to maximize market prices. But it could also indicate that and volumes, potentially changing how share, says Bernstein’s Gal. patients are being put on the treatment patients are treated, and raising entry earlier, because of affordability.” thresholds for novel biologics. First, Are Biosimilars Changing In future, “I can see the availability though, comes the battle for Humira’s Treatment Pathways? of biosimilars changing the sequence of billions and the many lessons from that. Biosimilars are already saving health drugs we use, and how we use them,” “I’m fascinated to see what’s going to systems money and enabling more peo- says Cummings. Cost-driven restrictions happen,” says Cummings. “Hold onto ple to access specialist treatments that on the use of drugs like infliximab, now your hats.” they may not otherwise have been able baked into treatment pathways, should IV123573

14 | In Vivo | October 2018 pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com BIOSIMILAR MARKET VIEW ❚ Pharma intelligence

Intelligence with a Global Perspective

The Premier Resource In The Life Sciences Industry Biomedtracker Pink Sheet Datamonitor Healthcare Pharmaprojects In Vivo RxScorecard Meddevicetracker Scrip Medtrack Sitetrove Medtech Insight Trialtrove

Pharmaintelligence.informa.com ©2017 Informa Business Information, Inc., an Informa company October 2018 | In Vivo | 15 ❚ R&D STRATEGY A Phoenix Turn For Tonix: Rising From Phase III Ashes With New PTSD Approach

In an exclusive interview, Seth Lederman, CEO of New York- based Tonix Pharmaceuticals, talks about the company’s R&D rollercoaster ride and how it plans to keep its lead asset on track for approval as a treatment for post-traumatic stress disorder.

BY LUCIE ELLIS t has been a bumpy journey for Tonix Pharmaceuticals Holding Corp. trying to get its lead investigational compound, TNX-102 SL, to market – despite the drug Tonix hopes to break new ground with having Breakthrough Therapy status in the US for the treatment of post-traumatic a second Phase III trial in PTSD that will stress disorder (PTSD). In an exclusive interview with In Vivo, CEO of the New focus on a specific patient population York-based company, Seth Lederman, talks about Tonix’s R&D rollercoaster ride defined by time since trauma. Iand how it hopes to keep its lead asset on track for approval. In July 2018, Tonix was forced to stop early a Phase III trial for TNX-102 SL, also known As CEO, Lederman is focused on telling as Tonmya (cyclobenzaprine HCl sublingual tablets). Preliminary safety data did not a new story for Tonix based on clinical reveal any serious or unexpected adverse events in the trial, but benefit to patients data he believes will disrupt how the was not significant over placebo. The HONOR study, a randomized, placebo-controlled R&D sector and physicians view PTSD patients. study of up to 550 participants with PTSD at 40 US clinical sites, enrolled only active or veteran US army members. After compelling Phase II data for Tonmya as a treatment for military PTSD, Lederman So what? Tonix needs to secure its new message and quickly embark on a said the company thought it was in a position to intelligently design a Phase III study. different late-stage strategy for its lead However, he says that after the Phase III setback, Tonix has “learned more about how compound in order to retain positive to design an excellent Phase III study.” investor sentiment and educate the An Independent Data Monitoring Committee reviewed the results of the first 50% of market about its fresh action plan. participants (n=274) randomized in the HONOR study before recommending the trial be stopped. The primary analysis was the change from baseline in the severity of PTSD symptoms as measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). “Psychiatry drug development is a journey, and the path certainly does not follow

16 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com R&D STRATEGY ❚

a straight line,” notes Lederman, who is and those with a longer time since trau- also co-founder and chair of Tonix. ma, Tonix thinks there is a fundamental ❚ WHAT IS PTSD? Despite success in Phase II, where a difference in how these patients should Post-traumatic stress disorder is dose of 5.6mg for the oral PTSD therapy be treated. Lederman says the general an anxiety disorder caused by very was confirmed and selected, Tonix was concept that PTSD evolves in different stressful, frightening or distressing unable to replicate results in a large- phases is very appealing. Tonix are not events. Potential causes of PTSD scale study. Still, Lederman thinks the the first to propose this theory, but the include: serious road accidents, company has the information it needs to idea that drug responsiveness may be violent assaults or prolonged abuse, take the drug into another Phase III and related to these different phases of PTSD witnessing violent deaths, military to the market. “We have learned that we is a new concept for drug development combat, terrorist attacks and natural should study trauma closer to the time… in this space. “It will take time for that disasters. we’ve had the opportunity to get feedback to become an accepted idea,” Lederman from a lot of experts about this.” Moving says. “The scientific community typically Physicians use a scale to breakdown forward with Tonmya, Tonix will look responds to new paradigms like this with PTSD: normal stress response, acute at PTSD “as a condition where there are both interest and scepticism.” stress response, uncomplicated different phases.” PTSD, comorbid PTSD and complex Lederman says there is an acceptance Phases Of PTSD PTSD. The latter is characterized as of this concept. “PTSD had been viewed Tonix is proposing the earlier trauma a response from repeated experi- as a single condition. So, we think that population could be called “remitting ences of traumatic situations, such the idea of looking at it as something PTSD” and that the longer-term popula- as severe neglect. that has at least two phases is a step in tion, with a longer period since trauma, the direction of precision medicine,” he might be called “persistent PTSD.” According to the UK’s National Health notes. Tonix believes there are biologi- “Those terms were in the literature Service’s recommendations, any of cal reasons why a treatment might have before… but we think these phases that the following treatment options may better activity in PTSD closer to the time have been described by other people be considered: of trauma. may correspond to a biological state that • Watchful waiting – monitoring relates to responsiveness,” Lederman symptoms to see whether they im- Retrospective Analysis says. The executive adds that he thinks prove or get worse without treatment Tonix presented a poster at the 2018 Mili- the company has the necessary informa- tary Health System Research Symposium tion internally now to intelligently design • Antidepressants – such as parox- (MHSRS) in August 2018, entitled “Effect another Phase III study. In more than 600 etine or mirtazapine of Time Since Trauma on Response to people with moderate to severe PTSD, the • Psychological therapies – such as TNX-102 SL in Military-Related PTSD: tolerability profile for Tonmya has been trauma-focused cognitive behav- Results of Two Double-Blind Randomized “encouraging,” Lederman says. “This is ioural therapy (CBT) or eye move- Placebo-Controlled Studies.” The presen- a drug that could benefit a lot of people. ment desensitisation and reprocess- tation included results and retrospective Everything we’ve learned about the drug ing (EMDR) analyses from the Phase III HONOR trial indicates that it could be an approved and the Phase II AtEase study. product for PTSD.” According to NHS resources, cases of Lederman says this was a critical op- PTSD were first documented during portunity for Tonix to explain its decision PTSD Pipeline the First World War when soldiers to halt the Phase III trial but continue There are only two approved PTSD drugs developed shell shock as a result clinical research for Tonmya in PTSD. “In- on the US market, Vectura’s Paxil (par- of the harrowing conditions in the vestors were confused by our decision to oxetine) and Pfizer’s Zoloft (sertraline), trenches. Still, the condition was stop the study, but then to announce that though other treatments are used off- not officially recognized as a mental management was still optimistic about label to treat the condition or to treat health condition until 1980, when it the drug,” he notes. “It’s challenging to PTSD-related issues. The development was included in the Diagnostic and be in that kind of position.” pipeline is also very limited. Tonix’s Statistical Manual of Mental Disor- He adds that the conference was a program was the most advanced, prior ders, developed by the American well-timed moment for Tonix to address to the disappointment for Tonmya in Psychiatric Association. questions about the future of its PTSD the HONOR study. As the company is PTSD symptoms are generally program. “For a large Phase III study like continuing the program it remains at the grouped into four types: intrusive the HONOR trial, there is a treasure trove top of the table. There are also a handful memories, avoidance, negative of data. We were simply not prepared to of therapy candidates in Phase II and changes in thinking and mood, and understand what happened in the study an NMDA glutamate receptor in Phase I changes in physical and emotional the morning after un-blinding.” testing from Aptinyx Inc. reactions. Based on data from two studies that in- Earlier in the pipeline, there are less cluded patients within 9 years of trauma than 10 drugs being tested in preclinical

Exhibit 1 Majority Of PTSD Programs Are In Phase II

Approved

Phase I

Phase II

Phase III

Preclinical

Suspended Programs

0 1 2 3 4 5 6 7

SOURCE: Biomedtracker | Pharma Intelligence

studies as options for treating PTSD. which is associated with an increase in thinks it is noteworthy that this study The two approved treatments for PTSD restorative slow-wave sleep; the alpha-1 took place within nine years of a period in the US, both serotonin reuptake inhibi- adrenergic receptor, associated with re- of time when the US had millions of ac- tors, have been on the market for many ducing trauma-related nightmares and tive duty personnel deployed in Iraq and years and no longer have patent exclusiv- sleep disturbance; and the histamine-1 Afghanistan. The protocol devised for ity. There has not been a novel therapy ap- receptor, associated with the reversal the Phase II study was military-related proved in the US for the treatment of PTSD of stress-induced increases in rapid eye trauma that occurred in 2001 and later. since 2001. “It’s difficult to be a pioneer,” movement (REM) sleep. The drug is a The concept was to capture the genera- Lederman says. “We certainly have our long-term medicine that does not start tion of post-9/11 military trauma. bumps and bruises from the two trials that impacting sleep until approximately two In the Phase II AtEase study, the median we’ve done… but we have never known as weeks after patients start taking it. time since trauma was 6 years. In the much about PTSD as we do now.” Tonix originally tested TNX-102 SL as a Phase III HONOR trial the median time Tonix’s drug, a novel low-dose for- treatment for fibromyalgia, where Phase since trauma was 9.5 years. In the larger mulation of cyclobenzaprine, a widely III studies were also initiated. However, study, there was also a significant number prescribed muscle relaxant with an this program was suspended in 2016 after of people who had experienced trauma established safety profile, targets se- the AFFIRM trial failed to meet its pri- between 14 and 17 years ago. “There were rotonin receptor type 2a (5HT2a) and mary endpoint. Tonix said at the time that no protocol violations, it was just that we alpha-1 adrenergic receptors. The drug it would end activities in fibromyalgia to didn’t know that this would be an impor- is designed for under-the-tongue ad- concentrate its resources in PTSD – add- tant parameter,” Lederman says. ministration, facilitating transmucosal ing pressure to Tonix’s need for success In the next planned Phase III for absorption of cyclobenzaprine, which in this indication. When the company Tonmya, Tonix does not believe it will bypasses first pass liver metabolism that started to investigate its compound in be possible, in the US only, to recruit a is necessary for orally ingested cycloben- PTSD, around 2014, the number of ongo- population of military-related PTSD that zaprine drug products. ing studies for new therapies was very is less than 9 years since trauma. “We are Tonix won a breakthrough therapy limited. “When we started, it was almost likely going to propose to the FDA a trial designation from the US FDA in December like a new field.” that will be more all-comers. Meaning 2016 for the development of Tonmya in that we will certainly look for military PTSD. The drug works by improving a pa- Next Steps For Tonmya PTSD because of our commitment to that tient’s quality of sleep in order to lessen Tonix is meeting with the FDA this month group of people, but we hope to look at the the symptoms of PTSD. This is a different to discuss the next steps for its PTSD pro- civilian population as well in that study.” strategy for treatment than how PTSD gram. In its Phase II trial, the company Lederman notes that the civilian is presently managed. The drug is not a recruited veterans, reservists and active population with PTSD in the US is around sedative, instead it interacts with three duty members of the US military who four-times the size of the military PTSD receptors: the serotonin 2A receptor, were relatively close to trauma. Lederman population. He adds that Tonix has no

18 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com R&D STRATEGY ❚

Exhibit 2 MoA Variation Is Apparent In PTSD Drug Pipeline

DRUG NAME LEAD COMPANY CURRENT PHASE TARGET NYX-783 Aptinyx I NMDA Glutamate Receptor BNC210 Bionomics II Nicotinic Acetylcholine Receptor Multidisciplinary Association Midomafetamine II Trace Amine Associated Receptor 1 For Psychedelic Studies PRX-3140 Nanotherapeutics II Serotonin 5-HT4 receptor Rexulti Otsuka II Dopamine 2 Receptor SLS-002 Seelos Therapeutics II NMDA Glutamate Receptor PF-04457845 SpringWorks Therapeutics II Fatty Acid Amide Hydrolase Tonmya Alpha-1 Adrenergic Receptor/Serotonin Tonix Pharmaceuticals III (TNX-102 SL) 5-HT2A receptor Approved Paxil Vectura Group Serotonin Reuptake (Generic Competition) Approved Zoloft Pfizer Serotonin Reuptake (Generic Competition)

SOURCE: Biomedtracker | Pharma Intelligence reason to think the civilian population will as a development area has historically intends to use the net proceeds, together be harder to treat. “In fact, as a general been reliant on companies that have a with existing cash, to fund the new Phase concept, existing studies show that civil- long-term view, patience and the ability III study using a modified design. ian PTSD is more responsive to treatment.” to learn from trial-to-trial. Lederman is hopeful that Tonix will be Tonix is also investigating Tonmya in If the company is unable to secure a able to lead the emerging wave of PTSD Alzheimer’s disease, but research is at partner for the next Phase III study of drug development and be the first to get a much earlier stage for this indication Tonmya, Lederman is optimistic Tonix an approved product to market in the US than the PTSD program. The company can afford to continue alone. Once Tonix in almost two decades. believes its drug has potential as a treat- has a clear direction from the FDA, it IV123563 ment for Alzheimer’s agitation, however will have more information on the risk, Comments: clinical studies in this area have been put reward and cost of a new Phase III. “An Email the author: [email protected] on hold for the time being until Tonix can all comers-style will make the trial faster get the PTSD program back on track. Be- and less expensive to enrol,” Tonix’s CEO fore the failure of the HONOR trial, Tonix adds. He notes that it was challenging READ MORE ONLINE had been planning a Phase II for Tonmya to study only military PTSD and enroll in Alzheimer’s agitation. enough patients into the previous trials because of the culture of stoicism in Just The Tonix: New York Biotech Fund Raising the veterans, reservists and active duty Has Breakthrough Drug For PTSD Prior to the Phase III setback, Tonix had people. Tonix had to invest in education Tonix Pharmaceuticals has won a been seeking potential partners for the and training to figure out the best way breakthrough therapy designation drug. The company has not given up on to engage and recruit military members. this month for its post-traumatic this strategy, “It’s not uncommon for “From what we understand of civilian stress disorder drug – the most partners to have a different view on a PTSD, the challenges of enrolling patients advanced product in development program than, for example, investors,” will still be present, but they will not be specifically for the condition Lederman says. “At least some potential as challenging as military PTSD.” and potentially the first ever to partners understand that our program In September 2018, the company filed market targeting PTSD as its lead has never been more valuable… we have an S-1 with the SEC to raise up to $12 indication. more human exposure, more data and million in a secondary public offering. we are essentially closer to approval than Pricing terms had not been disclosed https://bit.ly/2DnFoyC before we got these data.” Psychiatry at the time of publishing. The company

Speed and efficiency are fundamental to the success of today’s biopharmaceutical enterprise, but the hunt is still on for transformative technologies to boost pipeline productivity and growth. One answer may lie in the arrival of replicable, synthetic versions of DNA.

BY WILLIAM LOONEY peed and efficiency – from discovery to approval to market and beyond – are fundamental to the success of today’s biopharmaceutical enterprise. Mak- Only five years old, Silicon Valley starting decisions faster and introducing efficiencies at every stage of the drug up Twist Bioscience Corp. is the leading development cycle is now accepted dogma, but the search continues for privately held producer of synthetic DNA something more transformative to boost pipeline productivity and growth. for commercial research applications in One answer may lie in the arrival of replicable, synthetic versions of DNA, the design multiple industries. S atelier behind the most cost-effective, perfectly engineered structure of all: the human body. By replicating the processing and storage power latent in individual strands of CEO Emily Leproust outlines her DNA, scalable volumes of genes, proteins and other genetic material can be engineered company’s ambitions to make the “code by scientists in the lab to help drug developers design and test novel, personalized of life” a benchmark for scale, efficiency and lower cost at virtually every stage medicines more cheaply and at a faster rate than conventional search and discover of the R&D cycle, with the added methods. But although the science seems viable, and investors are putting real money advantage of serving as a tool for storing behind synthesized DNA’s potential as a productivity game-changer, you can’t discount and accessing vast amounts of data. the hype factor that accompanies any disruptive challenge to the status quo. Will technology’s latest shiny object spark that third industrial revolution – in bio- So what? While there is yet no accurate technology – forecasters have been promising for much of the century thus far? And measure of its true potential, synthetic will re-engineering drug development with DNA as host create a better business model DNA is a booster rocket against the for making drugs? The answer to both questions is unclear, because for biopharma the archaic, underpowered processes that commercial landscape of DNA has yet to be fully mapped. characterize much of biopharma R&D But it’s not for lack of trying. DNA’s computerization at scale of what used to be a today. The need for progress in removing manual, time-consuming process carries benefits not just in biopharma, but in many barriers to research productivity puts other industries too. Indeed, VC investors like it because synthetic DNA is “platform DNA-based process technology squarely agnostic.” More than two dozen US companies and start-ups are presently active in in the sightlines of the future. the field, which is on track to surpass $1 billion in investor funding commitments from

20 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com BREAKTHROUGH SCIENCE ❚

the VC and public markets this year. As miniaturization where we can produce costs go down and capacities accelerate synthetic versions of as many as 10,000 in conformity to Moore’s Law of continu- genes on a single silicon chip – at higher ous improvement in technology, analysts volumes, faster and more cheaply than predict the synthetic DNA business to these other methods of production.” reach $25 billion in annual global rev- Leproust explains there are two charac- enues by 2025, with direct applications in teristics that make synthetic DNA optimal agriculture, energy and the environment, for drug discovery and development: in addition to biopharma and health care. precise, high-throughput engineering, and manufacture at very high volumes. Twist: Start-Up On The Move? “In the first case, if you don’t have a One newcomer that VC investors have reliable clonal match, the output is cor- targeted as the leader in low-cost gene rupted and thus useless; in the second, deliverables is Twist Bioscience, a if you can only do the synthesis a few San Francisco-based private start-up times a day, that’s useless too, because launched in 2013. Twist, whose name is the sheer size of the genome means that a play on Watson and Crick’s depiction for any kind of target selection, testing, of the double helix, was founded by and development work you need access Bill Banyai, a pioneering Silicon Valley What we guarantee to these synthetic materials in massive entrepreneur in computer silicon engi- volumes.” Ultimately, it comes down to neering; Bill Peck, a former colleague at Twist is the the productivity of each company’s plat- at the research firm, Complete Genom- form. “What we guarantee at Twist is the ics; and Emily Leproust, a French-born customer will get customer will get a better set of tools for organic and industrial chemist from the its needs – one that will come faster and HP spin-off Agilent Technologies, who a better set of tools at a higher quality and lower cost relative now serves as Twist’s CEO. Over the past to the competition,” she asserts. five years, the company has raised more for its needs – one With this innovative silicon platform, than $259 million from a diverse array of Twist makes its money by offering a range institutional and cross-over investors, that will come faster of synthesized DNA-based materials – including Merieux Developpement, WuXi genes, gene fragments, gene libraries Healthcare Ventures, Russian-Israeli and at a higher and oligonucleotides (short strand DNA software entrepreneur Yuri Milner, the molecules frequently used in sequenc- Pritzker family Tao Investment Fund, quality and lower ing as well as CRISPR gene editing) – to Illumina Ventures, Kangmei Pharmaceu- help companies design, build and test tical Group, Dentsu Ventures, Fidelity cost relative to the complex products in a stable and secure Management and Research Fund, Paladin environment, for eventual use in a wide Capital Group, and Biomatics Capital. competition. range of applications, including drugs, The list is distinctive in displaying Twist’s vaccines and diagnostics. global orientation, with high-profile Eu- ropean and Asian investors represented – Emily Leproust DNA: As You Like It along with some of the bigger names in The mainstay of the business is on US venture capital. CEO, Twist Bioscience demand, custom manufacture of these Of course, Twist is not alone in the synthesized DNA-based products for synthetic biology space. It faces a range companies in many different sectors. of competitors, led by CRO giant Thermo At present, Twist’s entire business is in Fisher Scientific Inc.In an interview with DNA.In 2016, it became the number-one In Vivo, Twist CEO Leproust agrees that producer worldwide of genes for com- synthetic DNA can now be bought from mercial and academic use. Twist relies many places. Nevertheless, she points to on a simple e-commerce, online ordering significant variations in how that DNA is system that ensures delivery of these procured and processed. “Our differenti- clonally perfected gene products to a ating advantage is what we call precision preferred vector in 15 to 20 days or less, at scale. Twist’s proprietary platform is and where proprietary data sensitive to unique in that we took a page from the the customer are protected. The message semiconductor model to synthesize genes to the research community? Here’s an on silicon chips instead of the traditional easy and convenient way to order off the plastic plates, an innovative advance in DNA “menu.”

To help fuel company research efforts, operationalizing the antibody discovery data storage and reducing its cost, both of Twist offers two ready-made tools – the program, Sato will help build out Twist’s which are vital to addressing the relentless genome Custom Capture Kit and the Hu- capabilities in protein engineering and pace of data accumulation. man Core Exome Kit – whereby a physical raise the company’s overall profile in “Our partnership with Microsoft gives separation of various genetic materials the life sciences vertical – a clear sign us a head start in proving that DNA is can be made, based on the materials that Twist sees biopharma as a key to its the transformative next wave in data ar- a client needs to analyze and test in a future growth. chiving and protection,” says Leproust. particular project, and removing those The project will confirm, under real-world deemed extraneous. “The traditional All The World’s Data – conditions, how DNA solves for two key approach has been to simply dump mas- In A Shoebox limitations of existing data storage tech- sive quantities of digitized materials on While synthetic genes, oligo pools and nology: capacity limits due to the low den- the client and expect him to find what’s libraries, combined with the sequencing sity factor; and a short life span – in the relevant. Even though synthesizing is a kits, are Twist’s main offerings to industry, latter case, researchers at the American lot cheaper than it used to be, it’s still management is now moving to establish Chemical Society concluded that using expensive if you don’t know what you are Twist as a leader on the hot topic of using DNA strands instead of legacy electronic looking for. This service helps do that,” DNA to store vast amounts of data. In and magnetic technologies could preserve says CEO Leproust. biopharma, keeping track of the data col- data for 2,000 years with no deterioration. Another product available through lected in developing new and better drugs, Leproust continues, “We’ve been first to Twist is oligonucleotide pools, which before and increasingly after approval, work directly with a major data-reliant consist of large quantities of short strands is a growing operational headache. The enterprise to realize superior storage of DNA (oligos) sold together for a wide volume of information the industry must capabilities combined with measurable variety of applications in the lab. Linking cope with is growing exponentially: cost savings, using our proprietary DNA all these is Twist’s expertise in compil- according to Stanford University, some platform. We expect data storage services ing libraries of DNA that can be used for 153 exabytes (a unit of computer data, to comprise a significant percentage of drug/antibody discovery. expressed mathematically as 1 followed our revenues within the next five years Introduced in February, the Human by 18 zeros) were generated in 2013; since as this technology finds acceptance in Core Exome kit is already topping sales then it has been multiplying at 50% annu- the marketplace, not only in life sciences as the most visible workflow tool in the ally, to a projected 2,300 exabytes in 2020. but in other business segments where we synthetic DNA sector. Adds Leproust, Put simply, the ability to store data – to already have a presence.” “We don’t do ‘me too’ products. The aim preserve it safely, and permanently – is is always to be first-in-class.” not keeping pace with its growth. DNA, Bending To The DNA Future Twist is also looking at ways to marry a format devised by the code of nature Whereas Twist’s existing business its expertise in synthetic DNA production itself, is virtually indestructible against model is transaction-driven, Leproust to specific therapy areas, the most promi- the deterioration of flash drives or digital suggests the company will evolve to a nent of which is the design and target metal tapes and can be accessed through more value-added focus on services that optimization of monoclonal antibodies encoded signals written on endless strings lead to long-term relationships with the against diseases like cancer. Twist has of synthetically engineered DNA. customer. “There are limits to just sell- worked with a license partner, Distribut- The volume of such production is ing DNA to big pharma. We see revenue ed Bio, to create new software that makes significant and, at the current state of potential in moving to help customers it easier for researchers to identify high- technology, quite expensive. But capacity by running some of their experiments quality human antibody therapeutics in improvements are progressing and, with or contributing downstream expertise combination with synthetic DNA. The time, will make the encoding process after they sequence gene fragments us- hope is this combinatorial platform will much cheaper. Significantly, Twist has ing Twist’s DNA software. Adding value reduce the risk in early-stage R&D and established itself as an early leader in the is going to be important as the synthetic create a more efficient bioengineering DNA data storage solution, inking a deal DNA market matures, particularly as model, one through which monoclonal with Microsoft in April 2016 in which the the pricing of DNA replication becomes antibodies can better deliver their pay- Seattle-based company purchased 10 mil- more competitive.” load against gene mutations linked to lion strands of DNA from Twist to use in Twist sees an additional advantage in many serious diseases. encoding data from its own researchers as the breadth of its partnering connections, Twist doubled down on this theme well as from the University of Washington. which includes the ability to conclude with the appointment in June of a new The arrangement led to the successful profitable transactions with companies chief scientific officer and lead executive encoding of a record 200 megabytes of representing the future of gene-based of its pharma business, Aaron Sato, an data on the DNA strands. In April 2017, the industrial and consumer products. One industry veteran who at one point led agreement was renewed and expanded example is the ongoing supply agreement the research team at Sutro Biopharma, a with the purchase from Twist of an ad- Twist has with Boston-based Ginkgo Bio- leader in antibody drug conjugate (ADC) ditional 10 million strands, with the same works, which involves the sale of 1 billion platforms against cancer. In addition to objective of increasing the density of DNA base pairs of synthetic DNA to help drive

22 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com BREAKTHROUGH SCIENCE ❚

Ginkgo’s expansion plans – itself part of ing disrupted itself. Investment analysts tells In Vivo that biopharma, chemicals a collaboration it has with Bayer AG – in interviewed by In Vivo note that, in this and data storage have the biggest poten- developing organic biological products regard, the synthetic biology business tial to contribute to Twists’ bottom line in the field of sustainable agriculture. bears some resemblance to the ruthless, over the next three to five years. The deal is the largest supply agreement technology-induced competitive pres- Finally, as a technology enterprise by volume in the synthetic DNA industry sures visited on the big players in the with outsized ambitions, Twist claims it to date. semiconductor industry over the past also has an ethical mandate to act as an The other asset touted by Twist is a decade. Twist also faces some of the instrument of public trust, in service to global orientation. Early on, Twist formed same trade-secret conflicts common in the public interest. Contends Leproust, a relationship with a cutting-edge Israeli any competitive new technology. “The technology around DNA and genet- start-up company, Genome Compiler, Says Les Funtleyder, health care port- ics is very powerful. It requires that as a which creates software to design and folio manager at E Squared Capital Man- company we take issues like personal simplify access to synthetic DNA. The agement (and an investor in Twist), “In privacy and biosecurity seriously, so that deal resulted in Twist achieving what semiconductors, disruptive technologies a societal consensus allows the benefits investors perceive as one of the most are eroding comparative advantage and from synthetic biology to move forward.” consumer-friendly contracting/purchas- pushing the price of chips steadily lower, In that regard, Leproust takes special ing platforms in the business. In April, which means that being able to deliver pride in her company’s recent contribu- Twist previewed its expansion plans for manufacturing efficiencies at scale is tion to a multilateral effort led by the US Asia with the conclusion of four local dis- now vital to preserving market share. Department of Defense Threat Reduction tribution partners to help build its DNA We see this as an early trend in the syn- Agency and the World Health Organiza- business in Japan, South Korea, India thetic DNA business as well. And Twist tion (WHO) to map the genomic profile of and Hong Kong/Macau. In addition to still has that advantage.” CEO Leproust the human monkeypox virus as part of a its HQ at the Mission Bay campus in San acknowledges that pricing pressures – successful effort to contain an outbreak Francisco, and satellite offices in South induced in part by Twist’s own success of the virus in rural areas of Nigeria last San Francisco and San Diego, Twist in lowering the price of a synthesized year. “Twist did the gene sequencing operates a 30-person research center in gene to an average of nine cents per base, work that led to isolation of the particular Israel. It has a 20-member sales team in with a two-week turnaround time – will viral strain as well as the location of the Europe and another six representatives in require leading-edge companies to offer epicenter of the outbreak, which greatly Asia, with a regional office in Singapore. more than a simple cost advantage to the facilitated contagion control efforts,” All told, the company has just over 300 customer. “It’s driven into the culture of Leproust tells In Vivo. Results of the work employees worldwide. this company an abhorrence to the idea were published online in The Lancet In- The next phase of the Twist global of being average. We are programmed to fectious Disease on January 16 this year. growth plan is China.“The Chinese be disruptive because of our belief that So reputation counts. But might a market is immense and the productivity DNA delivers the power to do good – to good name also be useful in areas be- gain from our products is perfectly timed improve, on a massive scale, the well- yond simple good will – such as a move to what the country requires in moving being of people and our planet.” to become a public company through toward an economy based on efficiency To keep moving to this goal, the com- a well-timed IPO? Leproust is hesitant, and innovation,” Leproust points out. pany will focus on three key strategies: noting how effective the start-up has “China is the centerpiece of our strategy • creating new markets for synthetic been in attracting investors with deep to create a truly globalized customer DNA technologies, the most important pockets.“We have the capital necessary base; we can’t be successful in the long of which is in data storage; to pursue our business mission, but we term without building a presence there, • embracing a more value-added, so- are keeping all options open as we grow. because the life-enhancing potential of lutions-oriented approach to customer Obviously, we want to keep rewarding synthetic biology is registered in nearly needs; and all the stakeholders who’ve supported every domestic industry, from food to • extending the company’s geographic us.”To do that, Twist will have to keep energy to medicine.” Twist is already reach along with a commitment to serve disrupting itself, because its very suc- primed for action in the market, having multiple industries – to go where the cess in lowering costs through scale and recruited as investors several influential market is. efficiency will depend on creating a more local players such as WuXi Health Care Looking ahead, Leproust identifies value-added approach as the business of Ventures and Kangmei Pharmaceuticals. four industries as critical to the com- synthetic DNA matures to becomes a truly pany’s future growth. The list includes, global industry. Keep Disrupting – Or Be Disrupted in addition to biopharma, chemicals bio- IV123562 In Return processing; sustainable agriculture and Everyone in a business that seeks to dis- crop protection; and health, well-being rupt recognizes the importance of being and environmental biological products able to anticipate and adapt to the pace for consumers. A fifth growth segment is Comments: of change – lest the disrupter end up be- the functional realm of data storage. She Email the author: [email protected]

As biopharma’s embrace of real-world evidence (RWE) gathers speed, In Vivo looks at one company that is using a mix of prestigious academic, government and non-profit partners to build a credible foundation for acceptance of this research tool in the wider commercial space.

BY WILLIAM LOONEY he holy grail in medicines evaluation today is reconciling the methodological rigor of the randomized clinical trial (RCT) with value-oriented payment Privately held Aetion Inc., founded in models incorporating diverse data drawn from actual clinical practice. Pow- 2012 by three professionals with erful analytical technologies emerging over the past decade have enabled academic and Silicon Valley number- researchers to access vast amounts of information from non-trial sources, crunching expertise, has launched a Toften compiled for uses unrelated to drug approval or reimbursement. This revolu- novel Evidence Platform. tion in “real-world evidence” (RWE) has failed to dent concerns about its reliability in establishing the benefits and harms of specific drugs – the default research question Early success with Aetion’s technology that the RCT model validates through randomization based on experimental controls has helped mitigate some of the designed around narrow, carefully targeted test populations. biases present in non-randomized “If you don’t randomize, you don’t know” is the rhetorical challenge of RCT tradi- research, outside the familiar domain of the randomized clinical trial. tionalists against RWE. They see this new tool as guesswork on steroids, founded on unstructured observational data that mask hidden biases and can result in dubious conclusions difficult to replicate statistically. Many drug developers interviewed by In So what? Aetion’s platform of carefully curated real-world data from diverse Vivo contend that although better information on the patient experience in the clinic sources can facilitate decision points is welcome and overdue, full confidence in the RWE platform requires more progress relevant to both payers and drugmakers. in meeting four conditions: 1. making part of standard practice a specific, definable It makes strong sense commercially, research question geared to establishing causal links in evidence, longitudinally over given that consensus on defining what time, rather than confirming mere associations;2. seamless integration of the most an outcome is in pay-for-performance appropriate data streams to address the research question, given that RWE relies drug purchasing contracts is critical to heavily on inputs from multiple, disparate sources; 3. solving for study design biases the future of valued-based care. through analytical controls that filter out spurious patterns in data reporting; and4. full disclosure of sources, assumptions and methodology so the evidence behind the research is vetted and understood – transparency is the sine qua non of validation, which for users of RWE is a bankable currency called trust.

24 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com EXPLORING REAL-WORLD EVIDENCE ❚

Battle Of The Acronyms causation or causality), was founded in “My previous work gives me a handle on In other words, the pressure is on for a RWE 2012 by three professionals bridging the what payers expect from the transition standard that bears a stamp of confidence worlds of academia and big data enter- to value-based care,” Magill says in an similar to that of the RCT. What this means prise: Sebastian Schneeweiss, a profes- interview with In Vivo. “It relates to a is finding ways that RWE studies can yield sor of medicine and epidemiology with unique characteristic of Aetion’s mis- outcomes with the rigor and confidence as- joint appointments at Harvard Medical sion, which is to bring payers, providers sociated with a clinical trial. Alternatively, School, the Harvard T.H. Chan School of and manufacturers onto the same page RWE has the potential to compensate for Public Health and Boston’s Brigham and with an evidence platform that inspires long-standing flaws in the RCT, such as lack Women’s Hospital; Jeremy Rassen, also trust and confidence from each party to of generalizability and costs. from the Harvard Medical School faculty a negotiation. Siloed, compartmentalized Here is the good news. There is a grow- but with an additional background in thinking, which is unfortunately all too ing consensus in the research community applications for customer relationship prevalent in today’s health care system, that a more inclusive stance involving both management at Silicon Valley start- is incompatible to getting to goal on ev- approaches to evidence generation will up E.piphany Inc.; and Allon Rauer, a erything from a basic formulary listing to spur efficiencies in drug development, computer science software expert for a risk-sharing outcomes-based contract. raise industry returns on its massive hedge funds and big tech players such Our aim is to break that mind-set by tak- investments in R&D and possibly ease as Hewlett-Packard, who was also one ing uncertainty about evidence out of pressures on drug pricing. Support for of the first hires at E.piphany. the equation.” this includes big league players like the US Of the three co-founders, Rassen cur- Food and Drug Administration (FDA) and rently serves as Aetion’s president and In A Crowded Space, Differentiate the European Medicines Agency (EMA), chief science officer (CSO), while Schnee- Given the growing number of players in the US Congress, PhRMA and other indus- weiss is Aetion’s lead advisor on medicine the RWE space, Aetion knows its vital try groups, and patient advocates, led by and pharmaco-epidemiology.Rauer, who selling point is to be different. A key claim the National Health Council. designed Aetion’s original proprietary is the Aetion Evidence Platform is the The challenge for everyone in the software platform, remains a consultant only RWE tool to have made the transi- pharmaco-evidence generation busi- on technology issues. tion from “casual” (i.e., non-verifiable) ness today is: how? The question The three founders’ combined skill sets to “causal” analytics. The platform is relates squarely to the productivity of – on the analytical drivers of consumer data-agnostic and built-for-purpose, the research enterprise itself. Unfortu- marketing behaviors, the technology not generic; its design seeks to facilitate nately, there is no correlation between behind high-speed financial transac- case-relevant patterns among large, mul- the amount of R&D investment and the tions reporting, and the statistics and tivariate sets of data from diverse sources, number of approved products brought methodological discipline embedded applied longitudinally to track the clini- forward for use in the clinic. The need in health economics and epidemiol- cal experience of patients with similar to bridge this gap between effort, ex- ogy – formed the basic proposition for backgrounds over time. “We start with penditure and results explains why the the new business. The goal is to apply, the premise that the single most useful stakes are so high in generating the kind in a transparent and scalable manner, guide to decision-making in health care of evidence that can predictably account everyday clinical and financial interac- involves understanding what drives these for the many unintended consequences tions in the health care system to deliver timelines – the expressive, individualized involved in developing a complex drug essential evidence about the effectiveness paths that patients take over a single for human use. Everyone may agree the and value of medical treatments. “Our episode of care or the management of goal is to develop evidence that can lift platform takes the mystery out of mak- disease, from diagnosis to treatment to that haze of uncertainty, but the fact is ing sure the data respond to the research cure,” Rassen explains. “It is the time- we are not there yet. question, not the other way around. Too line that establishes causality. Causality At a recent FT Pricing and Value Sum- much of the work today in RWE is flawed is the basis for truth, and truth creates mit, Medicines Co. CEO Clive Meanwell because the data are not relevant to the confidence in affecting outcomes among emphasized the ongoing need for ran- question you are trying to solve, leading other patients with similar conditions.” domization in real-world data studies. to conclusions that take you nowhere,” The starting point for the platform is Rassen tells In Vivo. addressing a foundational question of Aetion: Company With A Cause Crafting that message is the responsi- interest to drugmakers and payers alike: In Vivo has identified one start-up tech bility of the company’s first CEO, Carolyn what does the patient population actually company with a direct mission to tackle Magill, who came on board in September look like in a specified disease area? For this question and build a commercial 2017. With a background at major pro- example, by cross-referencing different proposition proving RWE is no barrier to vider and payer organizations, including data sources the platform can create a generating the hard evidence required Evolent Health and UnitedHealth Group detailed patient profile, including co- in a value-based system of health care. Co., Magill is working to attract investors morbidities such as hypertension, CVD Aetion Inc., whose name originates from and grow the business by promoting the or osteoporosis in a cohort of diabetes the Greek word aetiologia (meaning trademarked Aetion Evidence Platform. patients, then identify where there might

be a mismatch between the prevalence of more than the standard SAS (software Indications of Approved Medicines,” these co-morbidities and the number of as a service) exercise, which is reliant published in JAMA Internal Medicine patients being treated for the condition. on code without context. “We deliver an on November 20, 2017, researchers used Says Rassen, “Realizing the potential of end-to-end product, not a programmer’s the Aetion Evidence Platform to show RWE begins with thoughtful measure- code, with a team of data scientists to that a study using a real-world database ment – who went to the doctor, for what find insights around a highly structured was able to confirm results of an earlier condition, diagnosis and treatment, for research question,” Rassen points out. RCT on a new indication of an existing how long and to what result. From that “The code is there as background but you approved medicine. It concluded that we can frame alternative hypotheses and don’t have to be a coder to understand “such database studies may support direct our analysis toward the best solu- what we deliver,” he continues. “We supplemental effectiveness applications tion to the identified problem.” give you a 200 to 300 page report, writ- for already approved medicines.” And it Such findings can be useful to payers ten in clear English, with an accessible would be much cheaper too. because they expose precisely where visual interface; where the assumptions, A more prominent example is the FDA’s preventive savings can be made by put- methodology and underlying science are decision in May to use the Aetion plat- ting these non-identified patients under documented against the research ques- form to drive a project, based on a man- treatment, while biopharma pursues option, and there is optionality in how you date in the 2016 21st Century Cures Act, portunities with new combination prod- use it – but with guardrails in place so to apply RWE in replicating the results of ucts designed to combat both diabetes that if you claim your drug is 22% more 30 published RCTs, covering four disease and the other underlying disorders. This effective for this group of patients ver- areas (cardiovascular, endocrinology, goal is advanced through the platform’s sus another group, there is a registered musculoskeletal and pulmonary). Of leveraging of networked, rapid-cycle ana- trail of data to validate that assertion. the 30 trial therapies, 23 ended up being lytics that include non-identified records It’s not light reading, but it’s readable, approved by the FDA; the other 7 were incorporating learning from the clinical especially if you are a decision-maker rejected. Scheduled for completion in histories of one of every five Americans. required to choose among alternatives 2020, the project will examine how RWE Using that massive base, Aetion, in a that all appear plausible.” can accelerate timelines to registration typical assignment, constructs a list of Trust also counts, particularly when and deliver evidence to justify supple- measures to be used to identify and de- RWE is tasked to prove that one drug mental indications, both of which will liver verifiable insights on co-morbidity might be better for a defined group of demonstrate added benefit to patients. impacts for specific conditions like dia- patients than another. “Let’s not forget In August, Aetion’s Evidence Platform betes. For that condition alone, a user that payers are also being challenged was selected to power a related initia- can create up to 800 such measures. to justify their existence and must have tive, called REPEAT (Reproducible Evi- The analytical technology behind the confidence that our Evidence Platform is dence: Practices to Enhance and Achieve platform is modeled on the computer reliable – it can’t be a black box calcula- Transparency), sponsored by the Laura software for rapid-fire financial transaction,” says CEO Magill. “The RWE com- and John Arnold Foundation with sup- tions, without the time lag characteristic munity is just at the cusp of brokering port from Harvard Medical School and of other systems in health care. those conversations between payers and Brigham and Women’s Hospital, and with Another point of differentiation is the drug manufacturers, so a commitment to representation from key regulators – the Aetion Evidence Platform’s customer- transparency about the data is necessary FDA, the EMA and the Pharmaceutical friendly profile. While the look and feel of for us to win that seat at the table. We ex- and Medical Devices Agency of Japan the platform is standardized, the options ist to foster trust – it’s the first word I cite – along with medical journals, private available for amassing and analyzing when I get asked about partnering with and commercial health plans, and the data can be customized based on the any stakeholder in health care today.” biopharma industry. The objective is to parameters of a specific research ques- evaluate the current state of transparency tion. Results are profiled in two parts: Selling A Stronger Standard in health databases and research tools, (1) a top-line presentation that relies on Finally, Aetion has made a unique including clarity around exclusion cri- visual presentations of the data; and (2) commitment to help raise standards of teria, approaches to randomization and a customized detailed report that estab- quality and accuracy in applying RWE defining outcomes, to prepare more spe- lishes the bona fidesof the methodologies to today’s world of value-based care. cific guidance in using RWE to improve behind the data, explaining all that was The goal is to burnish the case that RWE health outcomes. Results from this work done in building out the analysis and es- is not inferior but complementary to the are due in late 2019. tablishing a rationale for the recommend- RCT “gold standard.” Aetion is investing Aetion has ventured even further to ed decision points. “This is designed to its own intellectual capital on numerous put its Aetion Evidence Platform to the produce maximum transparency and peer-reviewed studies to demonstrate test in proving its versatility. The com- confidence that the correct methods were how drugs approved through a standard pany aims to show how diverse RWE can used for the questions we’ve been asked RCT can achieve the same result using provide a rationale for repurposing drugs to answer,” Rassen notes. RWE. In one study, “Use of Health Care for treatments that respond to current In that regard, the Aetion platform is Databases to Support Supplemental unmet medical need. It is supporting

26 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com EXPLORING REAL-WORLD EVIDENCE ❚

studies on effectiveness of these drugs big pharma, CROs, insurers, PBMs, teach- Aetion has the financial reserves suffi- in different indications, with particular ing hospitals and academia. cient to meet these objectives – and thus emphasis on uncovering previously un- The quality of Aetion’s research part- the ability to stay private rather than recognized adverse events in patients. nerships is accentuated by a blue-chip pursue an IPO. The payoff will be a repurposed drug for a list of investors. Aetion has raised more What binds the future is Aetion’s new indication that carries an improved than $50 million in the last three years, insistence that all its work be driven by safety profile. mainly from the health tech VC sector. evidence that has impact. Rassen de- In a paper published in Nature Sponsors include Silicon Valley stalwarts clares, “The core of our service platform Communications early this year titled New Enterprise Associates (NEA), Flare is assessing causality – what actions in “Network-based Approach to Prediction Capital Partners, Lakestar and Town the clinical setting had what effect? And and Population-based Validation of in Hall Ventures. Earlier this year, Aetion to what result? On which patient popula- silico Drug Repurposing,” researchers raised $36.4 million in Series B funding tion? It’s an open-ended question. Hence used the Aetion Evidence Platform to pull from the above group, which for the first opportunity rests on our taking RWE insights from two large longitudinal da- time included Amgen Inc.’s in-house VC, to a higher plane, beyond pharmaco- tabases covering more than 220 million Amgen Ventures. According to Magill, epidemiology alone, delivering impact- patient lives. “Repurposing is a practical the company plans to use the money to ful answers to research questions and expression of how our Evidence Platform perform upgrades on its software and to facilitating good decision-making, in the can integrate new, approved indications extend its professional service capabili- broadest possible sense.” Adds Magill, of existing medicines into treatment ties around the structure and execution of “We are now more attuned to understand- protocols,” contends Magill. It’s an risk-based outcomes contracts – the key ing what the ROI is for clients in deciding all-purpose instrument, with relevance growth segment behind RWE. to go with our services. And what’s the to early-stage development, as in ‘I’m What Aetion seeks now is scale. It’s opportunity cost of opting for the status developing this molecule, now where fine to have domain experts but true quo versus what Aetion brings to the should I focus?’; conduct of clinical tri- scale requires collaboration across the market. We cannot thrive just by being a als, by identifying the most appropriate entire organization. Accordingly, Magill substitute – we need to be better.” candidates for enrollment; avoidance of sets as a priority the creation of internal Both Magill and Rassen are optimistic the need to run a new study for a second- processes that will enable decision- about the underlying strengths of the ary indication, saving millions of dollars making to be as fast and efficient as the US health care system. The current frag- on trial administration costs; and getting company’s software. Aetion also plans to mentation in care delivery is giving way a new drug on the market more quickly, make selective enhancements to staffing to precision medicine – a concept whose through uncovering a competitor’s hold beyond the 100 plus professionals now on time has finally come. States Rassen, on patient compliance. Each of these ap- board, who work mainly out of its head- “This transition to precision and value plications carry significant commercial quarters in New York. The company has will strengthen the applicability and benefits to the industry and payers.” additional locations in Boston and Los relevance of RWE because technology Angeles. Beyond its high-grade contacts advances are allowing for the refinement Real World, Real Evidence – with the biggest corporate names in the of such data, from innumerable sources, And Real Impact health care business, Aetion is investing to a level hitherto unimaginable. Diver- The research projects bearing the Aetion to showcase its distinctive approach to sity in data is the future. If you remain a stamp are led by marquee partners with evidence development. “I hired our first business built on siloed information and real policy impact. They illustrate the marketing person here in New York in selective evidence, then it’s a certainty potential to “democratize” the historic June,” Magill relates. “More to come on you will be disrupted.” position of the RCT as the gold standard the people side.” One thing that Aetion does like is diver- of regulatory approval. “The FDA is the Looking ahead, Aetion’s new CEO sees sity. When asked if there are larger trends standard bearer on evidence in medicine customer growth coming from medtech that could end up disrupting Aetion itself, for the entire country, so I believe the firms, smaller pharma and biotech com- Magill and Rassen point not to technol- methodology we hope to develop through panies as well as CROs, as the latter cope ogy but to the control exercised by health these projects will give more certainty and with drugmakers’ insistence on having systems where stakeholders have neither structure to the use of RWE in access deci- data expertise be an integral part of options nor alternatives because one party sions taken not only by the FDA but the the service portfolio. Framing the care owns the whole transactions component, major US commercial players and health pathways sought by professional prac- end to end. Warns Magill, “If you end up plans as well,” Schneeweiss tells In Vivo. tice organizations, other providers and with a market-dominating giant combin- On a more practical level, the relation- patients is another opportunity. From ing Humana and its vast knowledge of ship with important stakeholders helps a geographic perspective, the company the patient-provider experience with the the company stay grounded on the issues is looking toward Asia, and not surpri- ubiquitous retail presence of a Walmart, that matter most to its customers, a com- singly, China, where real-world data then that to me is a threat.” munity that presently includes a major are, at least in theory, an everlastingly Comments: cross-section of public sector institutions, abundant resource. According to Magill, Email the author: [email protected]

There is a unique phenomenon being realized in immuno- oncology deal-making compared with other segments in the life sciences sector – an apparent uncoupling between risk and return on invested capital, as early assets provide similar liquidity to more mature assets.

BY SWARNA MEHROTRA, he biopharma IPO window is rewarding investors with rapid valuation ODED BEN-JOSEPH AND step-ups and a shortened trajectory to an exit (some companies have gone ELLEN BARON public two to three years post-Series A). This path to liquidity is translat- ing into renewed excitement by limited partners who are eager to keep the Unicorn transactions have emerged investment cycle going by supporting larger venture financings at a faster in the IO sector, as well as never seen Tpace. At the halfway point of 2018, the US venture capital market continues to see the before partnerships, financing deals crystallization of a new normal where capital is concentrated into fewer, larger deals. that regularly hit above $200 million, At the same time, the improved access to the IPO market, particularly for immuno- and multibillion-dollar acquisitions and oncology (IO) companies, has been a welcome trend. This, coupled with healthy M&A IPO valuations. activity, results in a lucrative exit landscape. The global IO segment is expected to remain the highest grossing therapy area, exceeding $100 billion by 2024. There is good reason The market is optimizing multiple paths to believe that this market will not turn down anytime soon as big pharma remains to liquidity at all stages of development and experiencing a shortening in time to desperate to boost growth rates and companies are willing to pay up for IO opportunities. exit, which is further propelling investor However, in 2018, there also have been significant, late-stage clinical failures. One of appetite. which, Merck & Co. Inc./Incyte Corp.’s indoleamine 2,3-dioxygenase(IDO) inhibitor trial, created ripples in the market and impacted several other late-stage clinical programs, leav- So what? As IO drugs demonstrate ing a trail of destruction. Bristol-Myers Squibb Co. terminated its late-stage combination robust clinical potential and early trial for its IDO inhibitor (acquired from Flexus Biosciences Inc. for a whopping $1.25 bil- movers reap market rewards, the lion in 2016) and Genentech Inc. terminated its IDO inhibitor partnership with NewLink segment continues to attract significant Genetics Corp., a collaboration that could have generated over $1.15 billion for NewLink. interest from the investor community Although IDO has seen a setback, other immuno-metabolism pathways have received as well as pharma and biotech players, significant investment, including those ofAgios Pharmaceuticals Inc., Kyn Therapeutics, triggering highly competitive behavior IDEAYA Biosciences Inc., Rheos Medicines Inc. and Dracen Pharmaceuticals Inc. There and intense transactional activity. are multiple approaches currently under investigation targeting the metabolism of other

28 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com MARKET INTELLIGENCE ❚

amino acids such as glutamine, arginine in total invested capital. The first half of and particularly adenosine, known to be 2018 saw larger venture investments, with ❚ METHODS harnessed by the tumor microenvironment a 27% increase in average investment size and in inflammatory conditions. compared with the prior year (see Exhibit A broad search was conducted using 1) and a robust VC appetite for early-stage PitchBook to capture the majority of Transaction Trends companies, investing heavily in Series A IO companies; search terms included IO is one of the most promising advances and B (see Exhibit 2). Larger Series A and “oncology” or “cancer” or “tumor” in the treatment of cancer in recent times, B is a key risk mitigation driver, because it or “immuno oncology” or “immune as such it has completely dominated allows CEOs to focus on execution rather therapy” or “immunotherapy” or “tu- biopharma’s transaction landscape in than a continual effort to raise capital. mor microenvironment” for different the past three-and-a-half years. Beyond In addition, access to capital is likely deal types, VC financings, M&As and the impressive number of IO transactions, to increase the probability of meeting IPOs. All companies were screened deal terms have far exceeded the amounts meaningful value-inflection milestones. using company descriptions and an paid for comparable deals in other thera- Undercapitalization continues to plague analysis of their pipeline to deter- peutic areas. Moreover, despite that most the life sciences sector, often leading to mine whether they fall under the IO of the transactions were early-stage, pre- unnecessary failure. category and if they are pure-play or proof of concept, they were able to garner As expected for a rapidly growing seg- have IO as their lead asset. an average up-front payment of roughly ment with a multitude of early-stage com- $150 million and total deal value close panies entering the space, there has been Financing encompassed all VC to $1 billion. To understand the unique a massive increase in clinical trial activity stages with deals above $5 mil- dynamics and transaction trends in the with consequent negative impact on pa- lion included for analysis. Phase IO segment, Outcome Capital tracked a tient enrollment rates. According to Clini- of development was found from total of 244 venture-backed companies calTrials.gov, there are more than 6,200 ClinicalTrials.gov and company (pure-play or lead IO asset) from January industry-sponsored oncology clinical trials press releases. Exit timelines were 1, 2015, through to June 30, 2018. The group ongoing. Due to the massive increase in IO calculated as the time from company analyzed various market parameters clinical activity, trials are taking longer as founding to exit. Deal size was not including invested capital, stage of invest- a result of the fierce competition in patient always available for all companies, ment, path to liquidity, acquisition and recruitment. This represents a challenge for resulting in some exits being ex- partnership transactions, and IPOs. The management teams and is likely to prolong cluded from the analysis. For M&A data gathered also highlight the behavior returns on invested capital for investors. exits, outliers (Juno-Celgene and of individual sub-sectors such as immune Outcome Capital has ranked the top 10 Kite-Gilead) were excluded when modulators and adoptive cell therapy. active investors based on the number of calculating averages. For IPO exit investments in unique IO companies in values, market capitalization at Investor Appetite the last three-and-a-half years (see Exhibit IPO and post-IPO (six months; the The IO segment has attracted significant 3). OrbiMed led the list, with 18 IO invest- typical lock-up) were captured using interest by institutional investors, with ments totaling 19% of its total investments PitchBook and Capital IQ platforms. nearly $1.5 billion in invested capital in the during this time frame. MPM Capital and The list of active investors in IO was first half of 2018 alone. For the first time Atlas Ventures also invested heavily with pulled from PitchBook. in 2018, we saw unicorn deals (greater 35% and 26%, respectively, of their total than $1 billion valuation) with more than investments. Interestingly, New Enterprise $200 million venture investments rounds Associates and Flagship Pioneering, two early assets. Instead, these players are (iMab Pharma, CStone Pharmaceuticals of the largest life sciences venture firms, focusing efforts on clinical trial partner- Co. Ltd., BioNTech AG and Allogene exhibit little presence in the segment. ships (supplying compound but little or Therapeutics Inc.). IO continues to Crossover funds like Cormorant Asset no dollars). This strategy allows them to follow the global venture investing trends Management, Redmile Group and Foresite combine and test their approved drugs where capital invested continues to rise. Capital Management have a dominant with different compounds for enhanced However, a rise in early-stage investing presence in this segment as a result of the efficacy in different modalities in a cost- and early exits, a phenomenon unique to early public liquidity (last money in before contained manner. Meanwhile, CVC the IO segment, has been observed. This IPO). Corporate VCs (CVC) investments group Boehringer-Ingelheim Venture signifies confidence in the underlying show an upward trend with Celgene Corp. Fund doubled its investable capital to science and excitement in the potential investing heavily to maintain its strategic €250 million following recent successes for IO segment growth. focus – with 33% of its total investments in IO, and it currently has five IO compa- The exit timelines have shortened to focused on IO in the last few years. nies in its portfolio. around three to five years in this segment, However, big players, such as Merck, Interestingly, there has been a surge providing comfort to the investors and cre- BMS, AstraZeneca PLC/Medimmune in Chinese venture (6 Dimensions Capi- ating a favorable fund-raising environment. LLC and Roche, already possessing ap- tal, Lilly Asia Ventures, Wuxi Ventures) There was robust year-over-year growth proved IO drugs, are barely investing in investing in US biotechs with IO assets

Exhibit 1 ($9 billion) and Kite Pharma Inc.-Gilead IO Attracts Larger Investments in 1H/18 Sciences Inc. ($11 billion). There were 32 50 acquisitions with an aggregate total capital return of about $15 billion (excluding 45 outliers, Juno-Celgene and Kite-Gilead) 40 with around one third of which ($5.8 billion) were in up-front cash payments. The 35 yearly breakdown of the aggregate and average total and upfront values are shown 30 45 51 52 37 in Exhibit 4. (These are approximate num- 25 bers as some transaction financials were 20 not disclosed and therefore not included in our calculations.) 15 The first half of 2018 continued to Average Invested ($M) 10 demonstrate strong interest in IO assets with a total of seven M&As with higher 5 $33.7 S33.7 $35.8 $45.3 mean transaction and up-front values 0 compared with the previous years. Three 2015 2016 2017 1H/2018 of seven M&A transactions were unicorn Average Invested ($M) No. Of Deals (greater than $1 billion) deals: Janssen Biotech Inc. paid $140 million up front Exhibit 2 for BeneVir Biopharma Inc., with a total Investors Show Appetite For Early-Stage In 1H/18 value of around $1.04 billion, to acquire its preclinical assets and T-stealth plat- 80 form; Eli Lilly & Co. paid $1.53 billion up front to acquire ’s 70 Armo BioSciences Inc. Phase III asset; and Celgene paid a hefty 60 $9 billion to add Juno Therapeutics’ CAR- T platform to its pipeline. 50 These acquisitions suggest a distinct preference for early-stage assets as 40 evidenced by the intense M&A activity 30 around preclinical assets. There seems to be little or no correlation between risk 20 and return on invested capital (ROIC) as early-stage assets provided similar liquid- 10 Average Investment Capital ($M) ity compared with later-stage assets, a 0 phenomenon unique to this segment. Big pharmas that had existing commit- Series A Series B Series C ments in the segment (Merck, BMS) are 2015 2016 2017 1H/2018 buying early assets to extend or diversify their pipelines (Merck-Rigontec GMBH, constituting 20% to 40% of their active clinical research company IQVIA, China’s BMS-IFM Therapeutics) or dramatically portfolio. Thus, Chinese investors ap- pharmaceutical spending will reach $170 expanding their franchises (BMS-Nextar, pear to have become important drivers of billion by 2021, compared with $117 bil- Merck-Eisai Co. Ltd.). Others are in catch- the rush into the IO segment, providing lion in 2016. As China attempts to migrate up mode, paying top dollar to build a biotech companies multibillion-dollar the country’s pharmaceutical sector presence in the segment (Celgene-Juno, valuations. Beijing launched an ambi- beyond low-cost generic medications, Gilead-Kite Pharma, Lilly-Armo, AZ-Com- tious industrial policy in 2015 (Made in this investment wave is likely to continue pugen Ltd., Johnson & Johnson-Benevir). China 2025), making biotech eligible for (unless the current US administration IPOs continue to perform strongly greater government backing. China once levies unsustainable taxes and tariffs). in the first half of 2018 with a total of lagged in drug spending but by allow- eight public debuts raising around $104 ing more investment in US biotech, the Exit Landscape million with a market capitalization of country is now gaining earlier and easier The IO segment demonstrated robust around $538 million, clearly exceeding access to novel therapies and a share in merger and acquisition activity in the time the numbers from the previous years (see the potential high returns. According to period tracked with major headline acqui- Exhibit 5). For the first time, companies health information and technologies and sitions: Juno Therapeutics Inc.-Celgene saw market capitalizations reaching $1

30 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com MARKET INTELLIGENCE ❚

❚ THE EMERGENCE OF IO

The approval of first-generation checkpoint inhibitors, with total values in excess of $1 billion dollars. In early 2018, Merck’s Keytruda and Bristol-Myers Squibb’s Opdivo in the BMS entered a co-development deal with Nektar’s lead IO second half of 2014, catalyzed a wave of deal-making, not program in combination therapies with BMS’ marketed cancer only around other checkpoint inhibitors, but also for mol- immunotherapy Opdivo and Yervoy (ipilimumab), in more than ecules and technologies that could offer synergistic benefits 20 indications for a whopping $3.6 billion-plus, including when used in combination with these drugs. $1.8 billion up front. Merck & Co. partnered with Eisai to co- develop its marketed cancer treatment Lenvima (lenvatinib The underlying rationale of immuno-oncology (IO) therapeutic mesylate) for additional oncology indications, both alone approaches is to take the brakes off the immune system or and in combination with Merck’s Keytruda, a potential $5.77 boost its ability to detect and destroy tumor cells. The ap- billion dollar deal, including $300 million up front. proval of first-generation checkpoint inhibitors, Merck & Co. Inc.’s Keytruda (pembrolizumab) and Bristol-Myers Squibb In 2017, Celgene Corp.entered into a strategic partnership Co.’s Opdivo (nivolumab) in the second half of 2014, catalyzed with BeiGene Ltd. for a total of $1.4 billion ($411 million in a wave of deal-making, not only around other checkpoint in- up-front cash and equity and $980 million in milestones) for hibitors, but also for molecules and technologies that could acquisition of worldwide rights to develop its PD-1 inhibitor offer synergistic benefits when used in combination with BGB-A317. Similarly, Servier SA partnered with Pieris Phar- these drugs. These two checkpoint inhibitors alone generated maceuticals Inc. in a broad co-development deal including a combined $12 billion in sales this year. This has translated Pieris’ preclinical dual-checkpoint inhibitor PRS-332 and up into a patenting frenzy as players seek to stake their claim to seven other IO bispecific drug candidates in a collaboration in this wide commercial landscape and has resulted in large that could generate up to $1.8 billion. pharma and biotech stumbling over each other to acquire or partner with companies developing IO assets. Oncology remained the most competitive area for deal- making in 1H-2018, with IO therapeutics continuing to be Late-comers who were behind the curve in identifying novel the principal driver, as clinical evidence emerges to support drug candidates to augment their pipelines, are now paying next-generation technologies such as chimeric antigen top dollar, thereby further propelling the proliferation of receptor cell therapies (CAR-T), antibody-drug conjugates checkpoint transactions, creating a competitive and crowded and bispecific antibodies. Indeed, one of the largest deals marketplace. Given the impressive overall survival data of of 2018 so far is Celgene’s $9 billion acquisition of the CAR-T some of the combination trials with checkpoint inhibitors, cell company Juno Therapeutics Inc. partnering transactions are gaining significant momentum, IV123568

Exhibit 3 billion at IPO (Aduro BioTech Inc. and OrbiMed Leads On Individual Company Investments NantKwest Inc.), indicating aggressive market uptake of IO assets and comfort to NO. OF NO. OF % OF TOTAL both private and public investors. INVESTORS INVESTMENTS INVESTMENTS INVESTMENTS (IO) (ALL INDUSTRIES) IN IO Phase I assets dominate the public markets with 10 IPOs pulling $968 mil- OrbiMed 18 94 19% lion in value out of the marketplace and Cormorant Asset there seems to be no difference in market 14 45 31% Management capitalization for early- versus late-stage MPM Capital 11 31 35% assets, again, a phenomenon unique to the IO segment. The first half of 2018 saw Google Ventures 11 198 6% shortening of the exit window to about Lilly Asia four years for IPOs and six years for 9 25 36% Ventures M&As with significantly faster ROIC to investors compared with previous years Atlas Venture 9 35 26% (see Exhibit 6). Novo Holdings 9 59 15% Sub-Segment Analysis Celgene 8 24 33% Outcome Capital analyzed the dispo- Redmile Group 8 28 29% sition of capital in different IO sub- Foresite Capital segments. Sub-segments were divided 7 40 18% Management broadly into six classes:

Exhibit 4 • Immune-modifying factors, which Robust Growth In M&A Transactions boost the immune response, including 5000 soluble factors, for example, cytokines, immune-metabolic regulators and 4500 adenosine antagonists to name a few; 4000 • Engineered T cells; 3500 • Checkpoint inhibitors, for example, PD-1, PD-L1, CTLA-4, TIM-3 and IDO; 3000 • Antibody-based therapeutics, for 2500 example, bispecific antibodies and antibody platforms;

Deal Size ($M) 2000 • Innate immunity targeting natural killer 1500 (NK) cells and dendritic cell popula- 1000 tions; and 500 • Cancer vaccines, for example, genetically engineered viruses and vaccines 0 expressing specific antigens. 2015 2016 2017 1H/2018 In the first half of 2018, adoptive cell Upfront Payments ($M) Total Transaction Value ($M) therapy remained the most attractive segment with an average investment of Exhibit 5 $71 million (see Exhibit 7); with two CAR- Phase I Dominates The IPO Exit T US FDA approvals last year (Kymriah [tisagenlecleucel] and Yescarta [axicabta- STAGE GROSS AVERAGE TOTAL AVERAGE TOTAL NO. OF gene ciloleucel]), and large transactions OF LEAD PROCEEDS PROCEEDS MARKET MARKET TRANSACTIONS such as Juno-Celgene and Kite-Gilead, ASSET ($M) ($M) CAP ($M) CAP AT IPO investors are perceiving CAR-T assets as Preclinical 2 85 43 464 232 less risky with greater return on invested capital and greater exit values, with an average market cap of $783 million. Phase I 10 968 97 4887 488 Current exit trends suggest increasing interest in bispecifics and antibody Phase II 8 773 97 2789* 465 platforms and innate immunity assets targeting NK cells, dendritic cells and Phase III 7 582 83 3135 448 CD47-directed therapies with total transaction values of $3.9 billion and *Deleted two deals with market cap >$2 billion (Aduro Biotech and NantKwest) $2.9 billion, respectively (see Exhibit 8). Aduro Biotech, with its lead assets in Exhibit 6 the STING pathway, soared in the public Early Exits Translate Into Faster Returns market with a $1 billion market cap and FortySeven, a clinical stage IO company 12 founded in 2015, with an anti-CD47 antibody as its lead asset, made its public 10 debut in June 2018, raising $113 million with a market cap of $450 million at IPO 8 – a quick return of capital to investors. Additionally, 2017 saw large acquisi- 6 tions in the innate immunity space by some of the established players with approved drugs in IO; Merck’s acquisition 4 Time To Exit (Years) of Rigontec for its Phase I asset targeting the RIG pathway for $554 million with a 2 $137 million up-front value, and BMS’ acquisition of IFM therapeutics for its 0 preclinical STING programs for a total 2015 2016 2017 1H/2018 value of $2.3 billion and a $300 million IPO M&A up-front payment. This suggests an inter- esting trend that big pharmas are looking

32 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com MARKET INTELLIGENCE ❚

to expand their current IO products by Exhibit 7 combining them with some early-stage Stong Investor Interest In Adoptive Cell Therapy In 1H2018 assets in newer sub-segments to create better clinical efficacy and to target dif- 80 ferent modalities (see Exhibit 8). 70 While the approved immune check- points and CAR-T therapies continue to 60 expand their indications, adoptive cell 50 therapy followed by innate immunity and bispecifics as well as other antibody 40 platforms are attracting the most investment activity and are the sub-segments 30 to watch for through 2019. We believe 20 exciting innovations in cancer will Average Deal Size ($M) continue to be found in the IO space, 10 yielding successful clinical results and 0 commercial partnerships and exit op- Immune Adoptive Cell Checkpoint Antibody Vaccines Innate portunities for investors. Modulators Therapy Inhibitors Therapeutics Immunity Key Takeaways 2015 2016 2017 1H/2018 IO may be the perfect storm for venture returns. It represents a radical change Exhibit 8 from traditional cytotoxic drugs, the Antibody Therapeutics, Innate Immunity Top M&A List capital markets are booming, and traditionally slow regulators have catalyzed 4K 8 meaningful new product approvals based on unprecedented clinical data. This is driving VCs flush with cash to engorge 3K 6 new IO market entrants with capital to hit value-inflecting milestones. Coupled with large players jumping at early M&As, 2K 4 biotech companies are enjoying a high probability to exit early. These catalysts are the lifeblood of venture capital returns. 1K 2 In the first half of 2018, the size and Total Number Of Transactions number of venture financings and M&A Average Transaction Value ($M) deals in IO increased to new heights. $2416 $1765 $1605 $1023 $1005 $895 $3940 $823 $2006 $972 $2879 $481 The sector hit new high-water marks 0 0 in IO deal-making: unicorn valuations, Immune Adoptive Cell Checkpoint Antibody Vaccines Innate Modulators Therapy Inhibitors Therapeutics Immunity acquisitions of early assets for multibil- lions of dollars and public debuts with Total Number Of Transactions Total Transaction Value Upfront Value market capitalization of over $1 billion. IO R&D is on an upward surge due to SOURCE FOR ALL EXHIBITS: Outcome Capital massive interest by big pharma and large biotech in clinically effective drug com- played a role in the continued influx of to meaningful improvements in clinical binations. This is creating a voracious China-based capital in US IO companies. outcomes or are we witnessing irrational investor appetite as IO assets are gener- The raising of sizeable war chests from exuberance by investors and strategic ating lucrative and faster returns with venture and corporate investors, the avail- players leading to unduly escalated asset shortening of exit timelines and higher ability of public capital and the exciting values? Time will tell. exit multiples. Notably, unique to this science will propel the next wave of inno- IV123565 segment compared with other segments vation, investor enthusiasm for the space in the life sciences sector is the apparent and early returns on invested capital. READ MORE ONLINE uncoupling between risk and ROIC as Overall, a rather optimistic outlook for the Go online to explore additonal data early-stage assets are providing similar remainder of 2018 and into the near future. and interactive data liquidity to mature assets. The question that remains: are we in visualizations for this article: Buying innovation will not come cheap the midst of a transformational inflec- in this sector and geopolitical forces have tion point in scientific progress leading invivo.pharmaintelligence.informa.com

Stem Cell Research Progress in the US: Where Are We Now? BY NELSON AZOULAY, GREGORY PARKS, VAIBHAV BHATNAGAR AND ROHIT SOOD

he history of stem cell research has been marked by they can be used to regenerate any cell type. However, both a combination of great promise, disappointment and ethical and safety concerns have restricted ESC therapeutic controversy. But progress is being made, with a num- development. While no ESC therapy is currently on the market, ber of stem cell therapies approved and many more several companies have been successful in early-stage clinical in the late-stage pipeline. While the US has lagged trials for the treatment of macular degenerative conditions. behindT other regions in stem cell therapy approvals, recent Other indications where ESCs are being explored include type 1 developments on the regulatory front are intended to provide diabetes, amyotrophic lateral sclerosis (ALS), Parkinson’s disease a clearer path forward and accelerate development. Looking at and spinal cord injury. marketed stem cell therapies and those in development, there Adult stem cells – including mesenchymal stem cells (MSCs) are trends emerging in the US that are influencing stem cell and blood-forming hematopoietic stem cells – are found in R&D and deal-making. While the outlook for stem cell therapies small numbers in some adult tissues, such as bone marrow or is improving, unique commercialization challenges remain that fat. Compared with ESCs, adult stem cells are more limited in developers should consider early in the clinical development their ability to regenerate other cells. Despite this, their use in process if they are to succeed in gaining marketplace access the treatment of disease has been much more successful, as and adoption. exemplified by the widespread use of bone marrow transplants where a patient’s own (autologous) cells or a donor’s (allogenic) Stem Cell Types – Where The Action Is cells are transplanted into the patient to treat diseases such as There are two major groups of stem cells – embryonic and blood cancers. non-embryonic. Embryonic stem cells (ESCs) are derived from The majority of ongoing stem cell trials use MSCs. These three-to-five-day old embryos and hold the most potential as cells can be isolated from bone marrow and other tissues such

34 | In Vivo | October 2018 invivo.pharmamedtechbi.com THOUGHT LEADERSHIP IN ASSOCIATION WITH SYNEOS HEALTH

Exhibit 1: Currently Approved Products in the US

Product Manufacturer Product Description Indication

Allocord SSM Cardinal Glennon Children’s Medical Center

Clevecord Cleveland Cord Blood Center

Hemacord New York Blood Center Unrelated donor transplantation Hematopoietic in patients with disorders affecting Ducord Duke University School of Medicine progenitor cell the hematopoietic system that are from Cord Blood inherited, acquired, or result from Clinimmune Labs, University of Colorado Cord HPC Cord Blood myeloablative treatment Blood Bank

HPC Cord Blood LifeSouth Community Blood Centers, Inc.

HPC Cord Blood Bloodworks

Collection of 40 – 250 ml of Sterile Cord Blood umbilical cord blood from either MacoProductions S.A.S. Collection Unit with vaginal birth or within the sterile Anticoagulant field of a cesarean section

*Includes only stem cell products, not including cell therapy products (e.g., cultured fibroblasts for dermal applications) or gene therapy products

as adipose tissue, umbilical cord tissue, and placental cells. Recent clinical trial successes owe to the advantages associated They are amenable to in vitro expansion and can differenti- with using allogenic products, targeting of indications with high ate into osteoblasts, chondrocytes, and adipocytes. As of 2016, unmet need, and improved clinical trial design and endpoint there were over 490 clinical trials using both allogenic and selection. There has also been significant development in cell autologous MSCs; key disease areas include graft versus host type identification/selection and preparation technologies that disease (GvHD), cardiovascular diseases, bone and cartilage are critical for successful stem cell product development. disorders, immunological conditions, and neurological diseases. However, overall progress in the stem cell field has been slow The world’s first marketed stem cell therapy using MSCs – Pro- due to a number of obstacles, including complex administration chymal (remestemcel-L) developed by Osiris Therapeutics (later and special handling requirements, requirements for “hard” clini- acquired by Mesoblast Ltd) – was approved in Canada in 2012 cal trial endpoints for certain indications, and hurdles to ethics for the treatment of acute GvHD in children, the leading cause committee approval. of transplant-related mortality. Stem cell therapy development in the US faces additional Induced pluripotent stem cells (iPSCs) are generated from challenges. The only FDA approved stem cell therapy products to adult cells by overexpression of certain transcription factors, date are limited to hematopoietic progenitor cells derived from which make the cells similar to embryonic cells at a cellular cord blood (see Exhibit 1). According to a survey of academic level. These cells were once thought to offer great potential for cardiologists/interventional cardiologists, ophthalmologists and therapeutic applications but clinical development has proven rheumatologists conducted by Syneos Health (SERMO Realtime challenging. Despite numerous setbacks, some clinical develop- platform, conducted June 2018), key reasons for the lack of stem ment is ongoing, and international academic and commercial cell product approvals in the US include insufficient government groups have reported encouraging results in age-related macular support and more stringent FDA requirements for trial design degeneration (AMD) and GvHD. and approval compared to other regions. However, recent updates to the regulatory process in the US hold promise for accelerat- US Is Late To Game ing development and commercialization of stem cell therapies Historically, there have been more stem cell products approved going forward. in other geographies compared with the US. Notable products that have been approved outside the US include Holoclar (ap- Regulatory Guidance Catching Up proved in the EU for cornea damage), Neuronata-R inj. (autologous The creation of the breakthrough designation for products MB-MSC; approved in South Korea for ALS) and Alofisel/Cx601 treating serious or life-threatening diseases may allow the US (darvadstrocel; approved in the EU for gastrointestinal fistula). to catch up over time by providing increased FDA guidance and

Exhibit 2: Stem Cell Pipeline in the US

Indication Category Product Company Lead Indication Current Phase

Habeo Cell Therapy Cytori Hand Scleroderma III BLA Filing Immunology MSC-100-IV/remestemcel-L Mesoblast Acute GvHD (Pediatric) Underway MPC-300-IV Mesoblast Chronic inflammatory conditions II

Nuo Therapeutics/ ALD-301 Peripheral Artery Disease II Aldagen

C-Cure Celyad Heart Failure III

Ixmyelocel-T Vericel Dilated Cardiomyopathy II Cardiovascular MyoCell U.S. Stem Cell Heart Failure III

Stemedyne-MSC Stemedica Ischemic Stroke, CHF II * Includes only stem cell products, not including cell therapy products (e.g., cultured fibroblasts for dermal applications) or gene therapy products MPC-150-IM Mesoblast Chronic congestive heart failure III

Diabetic Neuropathy, Diabetic Foot Endocrine PDA-002 Cenplacel Celgene Ulcer With and Without Peripheral II Arterial Disease

ECCO-50 Cytori Osteoarthritis II Musculoskeletal MPC-06-ID/Rexlemestrocel-L Mesoblast Chronic low back pain III

Dry AMD, Stargardt's macular MA09-hRPE Cellular Therapy Astellas II degeneration Sensory Organs ReN003 ReNeuron Retinitis Pigmentosa II

jCell jCyte Retinitis Pigmentosa II

potentially accelerated review for appropriate products. Kite’s has promised to revise their guidance on regenerative medicines CAR-T approval is a recent example of how this program can be sometime in 2018 to keep up with and parallel advances in stem leveraged to accelerate development. cell research technologies and innovation. In addition, the 21st Century Cures Act, enacted in December 2016, provides additional funding for stem cell research and re- Promising Near-Term Pipeline – quires the FDA to facilitate an efficient development program for, And Bump In Deal-Making and expedited review of, new medicines meeting the definition of The near-term pipeline for stem cell therapies in the US looks a regenerative advanced therapy – now referred to as the Regen- promising, with a number of products in Phase II and above, erative Medicine Advanced Therapy (RMAT) designation. RMAT including remestemcel-L (Mesoblast), which is preparing to file designation gives the sponsor of a new drug access to increased a BLA for acute GvHD. Other key areas of focus for stem cell meeting opportunities with the FDA, in a manner comparable to therapies being developed in the US are cardiovascular and those offered to sponsors of breakthrough-designated therapies. immunotherapy indications (see Exhibit 2). The RMAT designation may require a lower clinical evidence There have been 11 acquisition deals completed in the US burden to obtain than the breakthrough therapy designation, over the last few years, with over $1.5 billion in total deal value though this awaits clarification. Furthermore, RMAT designees since 2015. Notable deals in 2017 included Astellas Pharma’s acquire the ability to incorporate real-world evidence (RWE) and acquisition of Universal Cells for up to $102.5 million in upfront potentially other non-traditional approaches into the approval and milestones payments; the acquisition of Calimmune by process. However, it remains to be seen whether this initiative CSL’s CSL Behring unit for $91 million up front and up to $325 will achieve its goal of facilitating faster development while million milestones; and BioTime’s purchase of 21% of Cell Cure maintaining safety and efficacy standards. In addition, the FDA Neurosciences’ shares from Hadasit for $12.4 million. Although

36 | In Vivo | October 2018 invivo.pharmamedtechbi.com THOUGHT LEADERSHIP IN ASSOCIATION WITH SYNEOS HEALTH

ex-US, Takeda’s $628 million acquisition of TiGe- ning for these commercialization considerations nix, which closed in June 2018, is a major event early in the development process. Results from in the stem cell research world, signaling Takeda’s the Syneos Health survey indicate that journals, high level of interest in the stem cell space. Takeda While interest in conferences, and peer-to-peer interactions are hopes to leverage TiGenix’s expertise to accelerate important drivers of product awareness in this development of novel stem cell therapies, includ- and awareness of space. An early focus on physician engagement ing Cx601 for the treatment of complex perianal stem cell and education are likely to be key to driving ac- fistulas in Crohn’s disease. cess and adoption. therapies is high, The development of stem cell therapies in the Preparing For Commercialization US has lagged primarily due to widespread clini- As stem cell therapies start to clear development significant cal failures, limited government investment and and regulatory hurdles in greater numbers, interest barriers exist to a challenging regulatory environment. However, among treating physicians and patients is certain a promising clinical pipeline and an improved to be high but that alone is unlikely to guarantee their successful regulatory landscape are increasing momentum commercial success. Awareness of stem cell prod- in the space. As more stem cell products advance ucts in development is already high in therapeutic commercialization. into late-stage clinical development in the com- areas where stem cell therapies are likely to launch, ing years, researchers and manufacturers would as 78% of ophthalmologists, 56% of cardiologists, be well-advised to anticipate and address early- and 45% of rheumatologists screened in the Syneos on the unique commercialization challenges Health survey reported a high degree of stem cell stem cell therapies present in order to achieve therapy product awareness. successful product launch. While physicians reported a high level While interest in and awareness of stem cell therapies is high, of interest in adopting stem cells (average rating of 6 on a scale of significant barriers exist to their successful commercialization. 1 to 7 where 1: very low interest, 7: very high interest) in a Syneos A report published BMC Biotechnology on challenges facing Health survey, few were able to recall specific products/trials and the commercialization of several cell therapies, including stem most expressed that peer experiences/recommendations along cell therapies, indicated that post-market challenges such as with product efficacy and safety would be most important factors manufacturing costs, storage and distribution, reimbursement in their adoption. A structured and comprehensive go-to-market and convincing providers to change their treatment practices strategy, along with a clear engagement/communication plan, are likely to be key challenges for new entrants. Based on these would ensure that key stakeholders understand the product insights, stem cell product manufacturers should begin plan- value proposition and how it would address current unmet needs.

For more information contact:

Nelson Azoulay Vaibhav Bhatnagar Director, Syneos Health Consulting Senior Engagement Manager, Syneos Health Consulting [email protected] [email protected]

Gregory Parks, PhD Rohit Sood Consultant, Syneos Health Consulting Practice Area Leader, Syneos Health Consulting [email protected] [email protected]

© 2018 by Informa Business Intelligence, Inc., an Informa company. All rights reserved. No part of this publication may be reproduced in any form or incorporated into any information retrieval system without the written permission of the copyright owner.

❚ On the Move Recent executive appointments in the life sciences industry

❚ KATHERINE ATKINSON ❚ TORBJØRN FURUSETH ❚ PETER GOLDSCHMIDT ❚ CHARLES MORRIS

COMPANY CHANGES

EXECUTIVE TO COMPANY NEW ROLE FROM COMPANY PREVIOUS ROLE EFFECTIVE DATE Chris Allurion Chief Financial Boston Heart Chief Financial Officer 12-Sep-18 Tomosivitch Technologies Officer Diagnostics Julie Eastland BioClin Chief Financial Cascadian Chief Financial Officer 18-Sep-18 Therapeutics Inc Officer and Chief Therapeutics and Chief Business Business Officer Officer Pavel Pisa Crescendo Chief Medical Roche Head, Translational 11-Sep-18 Biologics Ltd Officer Medicine Anne Whitaker Dance Biopharm Chief Executive Bausch Health Executive Vice 1-Oct-18 Inc Officer and Director Companies President and Company Group Chairman Katherine Epic Sciences Chief Commercial Edico Genome Vice President, 4-Sep-18 Atkinson Officer Inc Business Development Benjamin Hickey Halozyme Chief Commercial Bristol-Myers General Manager, UK 10-Sep-18 Therapeutics Inc Officer Squibb and Ireland Rene Hoet Imcheck Chief Scientific Bayer AG Vice President, 12-Sep-18 Therapeutics SAS Officer Biologics Research Paul Lepage Intelerad Chief Executive TELUS Health President 25-Sep-18 Medical Systems Officer and and Payment Inc President Solutions Alok Sonig Lupin Ltd Chief Executive Dr. Reddy’s Chief Executive Officer, 18-Sep-18 Officer, US Generics Developed Markets and Global Head, Generics R&D and Biosimilars Thomas Macrolide Chief Scientific Translate Bio Chief Scientific Officer 4-Sep-18 McCauley Pharmaceuticals Officer Inc Timothy P. MOTUS GI Chief Executive ConvaTec Group President, Americas 1-Oct-18 Moran Medical Officer and Director plc Technologies Ltd

38 | In Vivo | October 2018 invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com ON THE MOVE ❚

Take an interactive look at recent executive-level company changes and READ MORE promotions in the biopharma, medical device and diagnostics industries. ONLINE Visit: invivo.pharmaintelligence.informa.com

❚ STEFAN OELRICH ❚ ALOK SONIG ❚ SCOTT SPEARN ❚ GEORG TERSTAPPEN

COMPANY CHANGES

EXECUTIVE TO COMPANY NEW ROLE FROM COMPANY PREVIOUS ROLE EFFECTIVE DATE Adam Keeney NodThera Ltd Chief Executive Sanofi Genzyme Head, Sanofi Genzyme 24-Sep-18 Officer, President Business Development and Director and Licensing

Georg C. Oxstem Ltd Chief Scientific GlaxoSmithKline Head, Platform 10-Sep-18 Terstappen Officer Technologies and Science

James Kupiec ProMIS Chief Medical Pfizer Inc Vice President, Global 13-Sep-18 Neurosciences Officer Clinical Leader, Inc Parkinson’s Disease, and Clinical Head, Neuroscience Research Unit

Charles Morris Radius Health Chief Medical PsiOxus Chief Development 4-Sep-18 Officer Therapeutics Officer Limited

Meredith resTORbio Inc Chief Commercial Shire plc Vice President, Global 18-Sep-18 Manning Officer Product Strategy Lead, Hemophilia

Sanjay Keswani Rheos Chief Executive Roche Senior Vice President 6-Sep-18 Medicines Officer and Global Head, Neuroscience, Ophthalmology and Rare Diseases

Dmitry Sirnaomics Inc Chief Technology Silence Chief Scientific Officer 1-Oct-18 Samarsky Officer Therapeutics

John Hunter SiteOne Chief Scientific Merck & Co. Inc Vice President of 6-Sep-18 Therapeutics Inc Officer Research Science and Head of Discovery Research for the Cardio- Renal Therapeutic Area

October 2018 | In Vivo | 39 ❚ ON THE MOVE

COMPANY CHANGES EXECUTIVE TO COMPANY NEW ROLE FROM COMPANY PREVIOUS ROLE EFFECTIVE DATE

Peter STADA Chief Executive Sandoz US President, and Head, 1-Sep-18 Goldschmidt Arzneimittel AG Officer North America

TorbjØrn Targovax ASA Chief Financial Lytix Biopharma Chief Financial Officer 13-Sep-18 Furuseth Officer

Karima Tillotts Pharma Global Head, AstraZeneca plc Vice President 1-Sep-18 Boubekeur AG Innovation Emerging Portfolio and Search & Evaluation

David Goren Vaxil Bio Ltd Chief Executive AstraZeneca plc President, Israel 6-Sep-18 Officer and Director

Daniel Canafax XW Laboratories Chief Medical Theravance Team Member, Clinical 10-Sep-18 Inc Officer Biopharma Development and Medical Affairs

Joshua Hazelton Z-Medica LLC Chief Medical Cooper Director, Trauma 6-Sep-18 Officer University Health Research System

Anthony Zymeworks Inc Chief Scientific Kite Pharma Inc Interim Chief Scientific 19-Sep-18 Polverino Officer and Officer Executive Vice President, Early Development

PROMOTIONS EXECUTIVE TO COMPANY NEW ROLE PREVIOUS ROLE EFFECTIVE DATE

Manuel C. Aileron Therapeutics Chief Executive Officer Chief Medical Officer, Chief Scientific 6-Sep-18 Aivado Inc and President Officer and Senior Vice President

Stefan Oelrich Bayer AG Head, Pharmaceuticals Executive Committee Member 1-Nov-18 Division

Scott Myers BioClin Therapeutics Chairman and Chief Chairman 18-Sep-18 Inc Executive Officer

Arturo O. Araya Brainstorm Cell Chief Commercial Director 4-Sep-18 Therapeutics Inc Officer and Director

Bjorn Dahlof Cereno Scientific AB Chief Medical Officer Director 13-Sep-18 and Director

James Dentzer Curis Inc Chief Executive Officer, Chief Operating Officer 24-Sep-18 President and Director

Jacqualyn Fouse Dermavant Sciences Executive Chairman Director 4-Sep-18

Trevor Perrior Domainex Ltd Chief Executive Officer Director, Research and Chief 1-Oct-18 Scientific Officer

Goran Ando EyePoint Chairman and Member Director and Member of Science 10-Sep-18 Pharmaceuticals Inc of Science Committee Committee

Tim Hendrickson HLS Therapeutics Inc Chief Financial Officer Vice President, Finance and 6-Sep-18 Administration

40 | In Vivo | October 2018 invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com ON THE MOVE ❚

PROMOTIONS EXECUTIVE TO COMPANY NEW ROLE PREVIOUS ROLE EFFECTIVE DATE Scott Spearn MedX Health Corp Chief Executive Officer President 24-Sep-18 and President

Karim Dabbagh Second Genome Chief Executive Officer, Chief Scientific Officer 26-Sep-18 President and Director

Saqib Islam SpringWorks Chief Executive Officer Chief Financial Officer and Chief 5-Sep-18 Therapeutics Business Officer

Erik Digman Targovax ASA Chief Business Officer Chief Financial Officer 13-Sep-18 Wiklund

Alicia Levey Tempest Therapeutics Chief Business Officer Vice President of Business 4-Sep-18 Development and Strategy

DIRECTORS EXECUTIVE TO COMPANY NEW ROLE EFFECTIVE DATE

Michael F. Giordano Achilles Therapeutics Director 19-Sep-18

Cheryl R. Blanchard Anika Therapeutics Inc Director 5-Sep-18

Julia P. Gregory Cavion Executive Chair 11-Sep-18

Jean-Pierre Bizzari Compugen Ltd Director 5-Sep-18

Frank Torti Dermavant Sciences Chairman 4-Sep-18

Myrtle Potter Dermavant Sciences Director 4-Sep-18

Felicia Williams Meridian Bioscience Inc Director and Member of Audit 20-Sep-18 Committee

Scott Huennekens NuVasive Inc Director 1-Oct-18

Ronald S. Musich Qualigen Inc Director 5-Sep-18

Aoife M. Brennan Ra Pharmaceuticals Inc Director 25-Sep-18

Bernhard Ehmer Symphogen A/S Chairman 3-Sep-18

Mads Krogsgaard Symphogen A/S Director 3-Sep-18 Thomsen

Peter Haahr Symphogen A/S Director 3-Sep-18

Soren Lemonius Symphogen A/S Director 3-Sep-18

Jennifer Jarrett Syndax Pharmaceuticals Inc Director 25-Sep-18

William Meury Syndax Pharmaceuticals Inc Director 25-Sep-18

Karen Zaderej Viveve Medical Inc Director 13-Sep-18

Steve Basta Viveve Medical Inc Director 13-Sep-18

Scott Braunstein ZIOPHARM Oncology Inc Director 18-Sep-18

October 2018 | In Vivo | 41 ❚ DEAL-MAKING

Derived from Strategic Transactions, Informa’s premium source for tracking life sciences deal activity, the Deal-Making column is a ❚ Deal-Making survey of recent health care transactions listed by relevant industry segment – In Vitro Diagnostics, Medical Devices, Pharmaceuticals, and Research, Analytical Equipment and Supplies – and then Covering deals made September 2018 categorized by type – Acquisition, Alliance, or Financing. Strategic Transactions is updated daily with in-depth deal analysis, structural and financial terms, and links to SEC-filed contracts. For information about access please contact Customer Care at 888-670-8900 or [email protected]

❚ IN VITRO DIAGNOSTICS ❚ PHARMACEUTICALS Salix to co-promote Doptelet with Dova Mergers & Acquisitions Mergers & Acquisitions Everest Medicines, VenatoRx team up on combination therapy Quest buys Oxford Immunotec’s US Alexion buys Syntimmune for $400mm lab services biz plus earn-outs Eyevance gets global rights to Focus ’ FreshKote eye drops Allergan acquires neurotoxin start-up Labs Alliances Bonti for $195mm Precision BioSciences and Gilead gets rights to sell ’s Mylan Atomo partner in hep B drug development deal HIV self-test in over 100 countries Amicus buys Celenex for up to worldwide $452mm, acquiring ten rare disease MannKind grants United Therapeutics pipeline programs rights to treprostinil for PAH Financings Novartis divests Sandoz’s US generics Partners Takeda and Molecular files for IPO Guardant Health businesses to Aurobindo for up to $1bn Templates pen new joint development BI exercises option to acquire deal ❚ MEDICAL DEVICES Austrian oncolytic virus company Novo Nordisk, Ossianix ally in Mergers & Acquisitions ViraTherapeutics metabolic conditions pays undisclosed sum for blood AngioDynamics to acquire RadiaDyne Shire Roivant acquires Patara’s sole asset plasma collection firmsanaplasma Boston Scientific shells out $500mm PeptiDream, Santen ally in ophthalmic Supernus acquires epilepsy start-up up front for Augmenix diseases Biscayne Neurotherapeutics for up to BTG buys Novate for $20mm up front $183mm VistaGen gains exclusive license to and up to $130mm in earn-outs Pherin’s PH94B anxiety compound, CTL Medical buys Amedica’s spine Alliances options PH10 for MDD assets OS Therapies enters licensing agreement with Advaxis Lilly pays $50mm up front for rights to Benvenue divests vertebral Chugai’s oral GLP-1 receptor agonist augmentation systems portfolio to Anaeropharma, Astellas to develop anti-tumor therapies United Therapeutics gets NA rights to IZI Medical Samumed’s IPF candidate LeMaitre buys Applied Medical’s Roche licenses IPF candidate to Ark vascular clot management biz Biosciences Financings Adaptimmune nets $99.7mm through pays $1.3bn for remaining Biohaven enters second partnership Medtronic registered direct offering stake in Mazor Robotics with AstraZeneca Public offering nets $18.7mm forAdvaxis Stryker to acquire surgical device Biothera and AZ enter head and neck maker Invuity for $190mm cancer trial collaboration Agenus gets $15mm from Xoma under royalty monetization deal Venus MedTech acquires Keystone BeiGene and SpringWorks enter trial Heart collaboration for solid tumors Allogene files for IPO Novartis invests in, collaborates with Alliances Amicus closes $150mm debt facility to Cellular Biomedicine on CAR-T cancer fund acquisition of Celenex Zai Labs gets rights to Novocure’s immunotherapies Tumor Treating Fields AnaptysBio nets $197.1mm in FOPO CRISPR, ViaCyte ally in cell therapies Public ADS offering nets $284mm for Financings for diabetes argenx FOPO nets $9.4mm for Iridex CSPC gets Chinese rights to Verastem’s Copiktra Xenon buys out milestone and royalty Nuvectra closes $64.9mm FOPO payments owed to Bausch Health for Decibel licenses Phase I hearing loss/ Ra Medical goes public netting XEN1101 balance disorder drug ORC13661 from $61.7mm Oricula Biophytis enters loan agreement with Sensus Healthcare nets $14.1mm Kreos Capital Fosun Pharma subsidiary Ahon through public offering licenses Chinese rights to DiaMedica’s Latest private placement grosses SpineEx seeks to go public DM199 stroke candidate $48.5mm for CASI Pharmaceuticals

42 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com - - - - - ❚

| 43 SpaceOAR DEAL-MAKING In Vivo 2018 | In Vivo October endorectal endorectal /ImmobiLoc IsoLoc vaginal balloon packing system system packing balloon vaginal Alatus The transaction also includes up to up includes also transaction The MEDICAL DEVICES MEDICAL BOSTON SCIENTIFIC SCIENTIFIC CORP. BOSTON INC. AUGMENIX ANGIODYNAMICS INC. ANGIODYNAMICS RADIADYNE ❚ & Acquisitions Mergers , a privately held oncology firm that firm that oncology held , a privately Dyne monitor dose patient sells and develops (Sep.) ing systems. AngioDynamics the acquisition, Through which system, OARtrac RadiaDyne’s gains therapy radiation photon during used is dose, radiation validate and monitor to infor with oncologists radiation providing and plans treatment help adjust to mation also RadiaDyne outcome. patient improve the offers transient remove to designed balloon, motion prostate reduce and gas rectal and cancer, prostate for treatment during the cancer. cervical of treatment during use for AngioDynamics helps The transaction business. oncology its further enhance does also (which month, the company Last pe- and access vascular in the business announced spaces) intervention ripheral tract the Biosentry of seal the acquisition . The Specialties Surgical from system ant the occur reduce to indicated is device CT-guided during pneumothorax of rence Other products procedures. biopsy lung radiofrequency include AngioDynamics by surgical systems, ablation microwave and ports. implantable and tools, resection Deutsche Banks/Advisors: Investment Inc.) (AngioDynamics AG Bank Boston year, this acquisition seventh In its to cash in $500mm paying is Corp. Scientific Augmenix maker device held closely acquire Inc. (Sep.) earn-outs. $100mm in sales-based the developed has Augmenix Ten-year-old FDA-approved and CE-Marked in men who effects side reduce to system prostate for treatment radiation undergo acts and injected is A hydrogel cancer. is acquiring Radia acquiring is Inc. AngioDynamics America Merrill Lynch; Cowen & Co. LLC; LLC; & Co. Cowen Lynch; Merrill America Partners Leerink & Co.; Chase JP Morgan & Co. Blair William LLC;

- - is kits and accessories accessories and kits T-SPOT.TB IN VITRO DIAGNOSTICS IN GUARDANT HEALTH INC. HEALTH GUARDANT ATOMO DIAGNOSTICS ATOMO NV MYLAN QUEST DIAGNOSTICS INC. DIAGNOSTICS QUEST PLC GLOBAL IMMUNOTEC OXFORD Financings Alliances ❚ & Acquisitions Mergers (cancer diagnostics) diagnostics) (cancer Inc. Health Guardant (Sep.) offering. public initial for its filed of Bank Banks/Advisors: Investment Mylan NV Mylan licensed Diagnostics Atomo rapid commercialize to rights exclusive and 100 low- in over HIV for self-tests (Sep.) countries. middle-income in countries to extend rights Mylan’s - the Common East, the Middle Asia, Africa, Latin and States, Independent of wealth diagnostics vitro in The licensed America. themselves screen to individuals enable from taken blood of a drop with HIV for detect can accurately It the fingertip. antibodies, HIV of or absence presence Mylan 15 minutes. in just results providing HIV vitro in the CE-Marked launch to plans tests Point-of-care 2019. in early self-test in low-income important particularly are high. They are rates HIV where territories because areas in those beneficial also are to due reach to difficult often are patients isolated. be socially often can and location is acquiring Oxford acquiring is Inc. Diagnostics Quest laboratory US ’s PLC Global Immunotec (Sep.) business. services the T-SPOT. gains Quest the deal Through for test and Accutix test TB tuberculosis currently are which diseases, tick-borne in laboratories Oxford’s at manufactured Oxford Massachusetts. and Tennessee four just brand the Accutix launched Quest provide will Oxford ago. months the with under a long-term supply agreement. The agreement. supply a long-term under the traditional to an alternative is product latent and active for test skin tuberculin measure to designed is TB and infection Mycobac by activated specifically T-cells T-SPOT.TB antigens. tuberculosis terium QuantiF own Quest’s to complementary services. testing blood ERON tuberculosis

nets $285mm via FOPO via $285mm nets nets $73.5mm via FOPO via $73.5mm nets nets $70mm via IPO via $70mm nets nets $165.2mm via FOPO via $165.2mm nets gets $10mm from Merck $10mm from gets EQUIPMENT SUPPLIES & EQUIPMENT RESEARCH, ANALYTICAL ANALYTICAL RESEARCH, Financings follow-on via $56.4mm nets PacBio ❚ nets $188mm through public public $188mm through nets CRISPR offering FOPO via $94mm nets Dicerna for $189mm nets offering Public Endocyte Entasis in FOPO $75.7mm nets Foamix $195mm nets G1 Therapeutics offering public through Galapagos KalVista for IPO files Sciences Kodiak for $48.8mm nets offering Public Molecular Templates $113.6mm nets Biopharma Principia offering public initial through FOPO via $97.9mm nets ProQR $4mm debt into Q BioMed enters Yorkville with agreement its of $240mm sells Retrophin nets notes; senior convertible $232.8mm $79mm nets IPO ’s Biopharma Sutro Sutro IPO with concurrent PIPE through €50mm in grosses Valneva PIPE oversubscribed Viking Xenon for in $59mm FOPO brings sells and Pharma Soliqua Zealand Royalty to interests royalty Lyxumia $205mm for Pharma company an Informa Inc., Information, Business ©2016 Informa ❚ DEAL-MAKING

as a spacer that pushes the rectum away sets and IP surrounding its silicon nitride and cash acquired. Medtronic already from the prostate to reduce rectal injury biomaterial technology, and will serve as had an 11% equity stake in Mazor under a during radiation. It remains stable during CTL’s exclusive OEM provider of silicon May 2016 deal in which the firms agreed the treatment (for about three months) nitride products for a ten-year period. to co-develop and co-promote in the US and then is gradually absorbed following CTL adds Amedica’s silicon nitride and robotic-based spine systems and applica- radiation therapy. SpaceOAR has poten- metal products to its existing portfolio of tions. The collaboration was expanded in tial for use in other indications including FDA-approved implants and instruments August 2017 when Medtronic became the gynecological and pancreatic cancers. The for spinal surgery. Investment Banks/Ad- exclusive global distributor of the Mazor acquisition further expands BS’s reach visors: Maxim Group LLC (Amedica Corp.) X robotic guidance system. Mazor’s core into the urology space. Earlier this year technology incorporates a precise surgi- BS bought two urology-focused firms- IZI MEDICAL PRODUCTS LLC cal planning suite with 3D analytics and -nVision (April) and NxThera (March). BENVENUE MEDICAL INC. virtual tools; an algorithm-based anatomy Benvenue Medical Inc. has divested its recognition engine; a connection platform BTG PLC vertebral augmentation systems busi- containing biocompatible devices that NOVATE MEDICAL LTD. ness to IZI Medical Products LLC for an securely affix the robotic system to the BTG PLC is acquiring private vascular undisclosed sum. (Sep.) patient’s skeletal anatomy; and a sophis- device maker Novate Medical Ltd. for IZI gains Benvenue’s Kiva vertebral com- ticated registration tool that can analyze $20mm in cash up front and up to $130mm pression fracture (VCF) treatment systems and match images from different modali- in sales-based earn-outs. (Sep.) and Blazer vertebral augmentation devices. ties and body positions. In addition to the Novate’s Sentry is the first available bio- The Kiva line features a flexible implant Mazor X system, Mazor has developed the convertible inferior vena cava filter. It is made from a PEEK-OPTIMA biocompatible Renaissance surgical-guidance system for designed to prevent pulmonary embolism polymer to provide structural support to the minimally invasive spine and stereotactic (PE) in patients at high risk of venous vertebral body and a reservoir to direct and brain procedures. Medtronic looks forward thromboembolic events. Since the device contain bone cement during vertebral aug- to combining Mazor’s robotic-assisted is bioconvertible, it degrades in the body mentation procedures. The Blazer portfolio surgery tool with its own spine implants thus avoiding the need for a second surgi- uses a cannulated curved wire, offering meso it can offer a full and integrated solution cal procedure to remove it. Sentry recently chanical channel creation and accurate ce- for surgeons. Investment Banks/Advisors: received 510(k) clearance in the US and ment deposition across the entire vertebral Goldman Sachs & Co.; Perella Weinberg BTG plans to launch it in H2 of FY2018/19 body. Benvenue’s rationale for the sale is Partners (Medtronic PLC); JP Morgan & Co. using its established vascular sales force. to allow the firm to focus on its Luna 3D in- (Mazor Robotics Ltd.) Twelve-year-old Novate raised nearly terbody fusion system and other minimally $18mm in its first two venture rounds and invasive spinal implants for degenerative STRYKER CORP. is backed by Credit Agricole Private Equity, disc disease. The company’s new Orbit INVUITY INC. Seroba Kernel Life Sciences, ACT Venture discectomy kit can be used with the Luna Stryker Corp. launched a tender offer to Capital, and Seroba Bioventures. implants. Last year IZI acquired four of Cook acquire fellow device maker Invuity Inc. Medical’s vertebroplasty products for use for $7.40 per share in cash (nearly a 50% CTL MEDICAL CORP. in treating vertebral compression fractures premium), representing a total equity AMEDICA CORP. via a minimally invasive surgical procedure. value of $190mm. (Sep.) CTL Medical Corp. is acquiring Amedica Following a successful tender, a sub- Corp.’s commercial spine business for up LEMAITRE VASCULAR INC. sidiary of Stryker will merge with and to $10mm. (Sep.) APPLIED MEDICAL RESOURCES CORP. into Invuity and shares of Invuity will be Financial terms of the agreement are LeMaitre Vascular Inc. is paying $14.2mm- delisted. Invuity’s board of directors has as follows: CTL will assume Amedica’s -$11mm up front and $3.2mm in two later recommended stockholders to tender obligations under its $2.5mm note with installments (of $2mm in 12 months and their shares. Factoring in the company’s North Stadium Investments, but if CTL $1.2m in 24 months)--to acquire Applied debt and cash the enterprise value is doesn’t repay the note in five years it will Medical Resources Corp.’s vascular clot $200.7mm, which effectively values the make monthly payments covering the full management business. (Sep.) transaction at 4.7x TTM sales of $40.8mm. amortization of note, which takes on a new LeMaitre gains the Syntel embolectomy Invuity focuses on developing advanced term of 36 months with a 15% interest rate; and thrombectomy catheters, Python surgical devices for minimal access CTL will issue to Amedica an interest-free over-the-wire embolectomy catheters, surgery through smaller and hidden $6mm promissory note; and the remain- and Latis graft cleaning and irrigation incisions. The company has developed ing $1.5mm is in the form of an earn-out catheters. The vascular clot management the Intelligent Photonics technology for payment should CTL achieves specified biz generated sales of $3.4mm in the last enhanced visualization during surgery sales revenues in the next three years. twelve months. For a one year period, and is focused on women’s health applica- Post-transaction, CTL Medical will change Applied Medical will manufacture the tions including breast reconstruction, and its name to CTL Amedica, and Amedica will acquired products for LeMaitre. gynecology and thyroid related surgeries. re-position and take on a new yet undis- The buyout will augment Stryker’s surgical closed name and will focus on its core bio- MEDTRONIC PLC portfolio, aiding its neurotechnology and materials and OEM business outside the MAZOR ROBOTICS LTD. spine business. Investment Banks/Advi- spine market, such as in the dental and Creating a global leader in the robotics- sors: Moelis & Co. (Invuity Inc.) arthroplasty spaces. CTL gains metal and based spine surgery market, Medtronic PEEK spinal implant products that incorpo- PLC is paying $58.50 per American De- VENUS MEDTECH (HANGZHOU) INC. rate Amedica’s silicon nitride technology, pository Share (each representing two KEYSTONE HEART LTD. including all existing inventory and US ordinary shares; a 19% premium) to ac- Venus MedTech (HangZhou) Inc. is acquir- and OUS regulatory clearances. Specific quire the remaining 89% of Israeli device ing fellow closely held cardiovascular brands that CTL will acquire include the maker Mazor Robotics Ltd. that is doesn’t device maker Keystone Heart Ltd. for an Valeo silicon nitride interbody fusion de- already own. (Sep.) undisclosed sum. (Sep.) vices, and Taurus and Preference pedicle The total purchase price is $1.34bn net Through the deal Venus gains Keystone’s screw systems. Amedica retains all as- of Medtronic’s existing stake in Mazor TriGuard and next-generation TriGUARD

44 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com Scrip Awards 2018

Book your table The 14th Annual Scrip Awards

2018 www.scripawards.com

28 November 2018 | The Hilton on Park Lane, London, UK

Entry and General Enquiries: Natalie Cornwell Tel: +44 (0) 7827 993 776 | Email: [email protected]

Sponsorship and Table Booking Enquiries: Christopher Keeling Tel: +44 (0) 20 3377 3183 | Email: [email protected]

Sponsored by Headline Sponsor

JN1238 Scrip Awards 2018 Book your Table Advert US A4.indd 1 2018/07/02 18:36 ❚ DEAL-MAKING

3 cerebral embolic protection device, NUVECTRA CORP. and pemphigus vulgaris or pemphigus the first designed to provide complete Nuvectra Corp. (neuromodulation devices) foliaceus and has demonstrated positive coverage to all regions of the brain during netted $64.9mm in a public offering of results at rapidly reducing IgG levels. The transcatheter aortic valve replacement 3.2mm shares (including the overallotment) acquisition of Syntimmune and SYNT001 (TAVR) and other cardiac procedures. at $21.25. The company will use the pro- helps Alexion to continue building out and Keystone is enrolling patients in a US ceeds to expand product development and diversifying its pipeline as the firm attempts trial for TriGUARD 3 and anticipates FDA commercialization. Nuvectra is awaiting CE to decrease reliance on marketed terminal review in H1 2019 and expects to get the Mark and PMA approval for its Virtis sacral complement inhibitor Soliris (eculizumab) CE Mark approval by the end of 2018. The nerve stimulation (SNS) device for urinary for diseases including paroxysmal nocturnal companies first partnered back in March incontinence and overactive bladder. In July, hemoglobinuria, atypical hemolytic uremic 2017 to promote Venus’ TAVR system in both EU and US agencies informed Nuvectra syndrome (aHUS), and anti-acetylcholine combination with Keystone’s TriGuard in that additional clinical study data would be receptor antibody-positive generalized my- key Asian markets including China. Just required before recommending approval, asthenia gravis (gMG). Sales of the product four month ago, Venus got exclusive rights but the company still anticipates product accounted for close to 90% of Alexion’s to develop, manufacture, and market Tri- launches by the end of the year (EU) and 2017 revenues, but patents on the drug will Guard 3 and the next-generation cerebral during 1H 2019 (US). (Sep.) expire in the coming years. The purchase embolic protection device in China and of Syntimmune marks the third notable Investment Banks/Advisors: JMP Securities other major Asian markets. Venus now pipeline-expanding deal for Alexion this LLC; Piper Jaffray & Co.; Raymond James & has full access to Keystone’s portfolio and year. In May it offered up $855m to buyWil - Associates Inc.; SunTrust Banks Inc. will sell the products alongside its own son Therapeutics for its rare genetic disease devices, positioning Venus as the leading RA MEDICAL SYSTEMS INC. candidate, and in June, it partnered with Chinese structural heart company. Ra Medical Systems Inc. netted $61.66mm (and took an option to acquire) Complement through its initial public offering of 3.9mm Pharma in a deal focused on development Alliances common shares at $17 on the NYSE. The of a neurodegenerative disease therapy. NOVOCURE LTD. company had planned to sell 3.33mm ALLERGAN PLC ZAI LAB LTD. shares between $14 and $16 each. (Sep.) BONTI INC. Novocure Ltd. granted Zai Lab Ltd. exclusive Investment Banks/Advisors: Cantor Allergan PLC agreed to buy private biotech rights to sell its Tumor Treating Fields cancer Fitzgerald & Co.; Maxim Group LLC; No- Bonti Inc., which is developing botulinum therapy (marketed as Optune) in China, mura Securities International Inc.; Piper neurotoxin serotype E (BoNT/E)-derived Hong Kong, Macau, and Taiwan. (Sep.) Jaffray & Co.; SunTrust Banks Inc. candidates. (Sep.) The Tumor Treating Fields technology ex- SENSUS HEALTHCARE INC. Allergan will pay $195mm up front and ternally applies electrical fields tuned at could also provide undisclosed earn-outs Sensus Healthcare Inc. netted $14.1mm certain frequencies directed at the tumor based on the achievement of certain through the public sale of 2.2mm common site to disrupt cell division and cause commercialization milestones. Bonti was shares at $6.80. The company markets cancer cell death. It is currently marketed founded as Endurance Biotech in 2015 by its SRT-100 and SRT-100 Vision superfi- in the US, EU, Switzerland, Japan, and former Allergan executives and raised an cial radiation therapy (low energy X-ray) other territories to treat glioblastoma aggregate $36.1mm through three rounds, devices to non-invasively treat basal cell multiforme (brain cancer) but is not yet en- most recently a $15.5mm Series C round in carcinoma, squamous cell carcinoma, and dorsed in the Greater China region, where February 2018, through backers including keloids. (Sep.) Zai will pursue regulatory approval. Novo- RBV Capital, City Hill Ventures, Colt Ven- cure gets $15mm up front and is eligible to Investment Banks/Advisors: B. Riley FBR tures, JMCR Partners, and HighLight Capital. receive up to $78mm in total milestones, Inc.; Craig-Hallum Inc.; Maxim Group LLC; The start-up’s pipeline includes two Phase II plus sales royalties from 10% to the mid- Roth Capital Partners BoNT/E programs: EB001A (aesthetic uses teens. The partners will also work together SPINEEX INC. such as wrinkle and scar reduction) and to continue Novocure’s Phase III trials of EB001T (therapeutic uses; ongoing stud- Device firmSpineEx Inc. filed for its initial the system for non-small cell lung cancer ies in post-operative musculoskeletal pain public offering on the Nasdaq. (Sep.) and pancreatic cancer and an upcoming and a trial in wound healing just initiated Phase III study in ovarian cancer. Zai will Investment Banks/Advisors: ThinkEquity this month). Allergan is most interested also undertake studies in China for gastric Partners LLC in EB001A, for which Bonti completed a cancer. Zai is a Chinese biopharma firm first-in-human Phase II trial last year that with a growing pipeline of treatments for confirmed both the safety and efficacy in autoimmune and infectious diseases and ❚ PHARMACEUTICALS a glabellar (skin between the eyebrows cancer. In oncology, the company is work- and above the nose) frown line indication. ing on mid- and late-stage compounds Mergers & Acquisitions During Q1 20918, the company also initiated a Phase IIa trial of EB001A in reducing for ovarian, breast, lung, gastric, and ALEXION PHARMACEUTICALS INC. post-Mohs surgery scarring. EB001 acts liver cancers. Investment Banks/Advisors: SYNTIMMUNE INC. China Renaissance (Novocure Ltd.) within 24 hours of administration and has Alexion Pharmaceuticals Inc. will pay a two- to four-week period of treatment Financings $400mm up front to acquire privately effect, versus the three-seven-day onset held antibody therapeutics developer and three-four-month duration of Botox IRIDEX CORP. Syntimmune Inc. The deal also includes (onabotulinumtoxinA, derived from botu- Ophthalmic device maker Iridex Corp. net- up to $800mm in milestone-dependent linum neurotoxin serotype A, or BoNT/A), ted $9.4mm through a follow-on public of- earn-outs. (Sep.) Allergan’s flagship cosmetic. Allergan fering of 1.67mm common shares at $6. The Five-year-old Syntimmune is targeting the believes EB001’s rapid onset and short company will use some of the proceeds for neonatal Fc receptor (FcRn) to treat rare duration could attract consumers who want potential licensing or acquisitions. (Sep.) IgG-mediated autoimmune diseases. Lead to try an aesthetic neurotoxin without com- Investment Banks/Advisors: Roth Capital candidate SYNT001 is in Phase Ib/IIa trials mitting to its long-term effects. Even though Partners; Stifel Nicolaus & Co. Inc. for warm autoimmune hemolytic anemia more than three-quarters of Botox revenues

46 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com

- - - - ❚

| 47 - an undis for GlaxoSmithKline DEAL-MAKING In Vivo 2018 | In Vivo October which has shown shown has which Imlygic ’s Amgen , the former has has former the GMBH, ViraTherapuetics SHIRE PLC SHIRE AG SANAPLASMA BOEHRINGER INGELHEIM GMBH INGELHEIM BOEHRINGER GMBH VIRATHERAPEUTICS less than stellar sales. stellar than of close the After less a become will ViraTherapeutics deal, the its maintain will BI and of unit research Austria. in Innsbruck, facilities Switzerland- private acquiring is PLC Shire firm sanaplasma based AG (Sep.) sum. closed biopharmaceutical a is Sanaplasma plasma in blood specializing company “the gift as to referred Often collection. starting a necessary is plasma life,” of - immuno of the manufacture for material chronic and rare for therapies globulin Sanaplasma diseases. immunological the in centers donor plasma 14 operates says Shire Hungary. and Republic Czech its increase to it allows the acquisition and term in the longer plasma to access In network. collection European its to add Shire’s strengthens addition, sanaplasma the firm’s in immunology, capabilities $4.4bn generated which business largest 2017. for in sales the Big Pharma’s third large divestiture divestiture large third the Big Pharma’s sold it March In year. this consumer 2014 in the partners’ share its In late- $13bn. for venture joint health Alcon its off spin to decided Novartis June, a separately-traded into division care eye worth up a deal in company independent Aurobindo ago, months two $5bn. Just to generic European ’s Apotex secured itself 200 generics (adding nearly businesses The cur $87mm. for products) 80 OTC and expanding to addition in transaction, rent also will growth, US company’s the Indian gener the second-largest as it position of on number (based in the US player ics the second-biggest and prescriptions) and generic for both firm dermatology US Invest products. dermatology branded Inc. Co. & Jefferies Banks/Advisors: ment Inc.) USA Pharma (Aurobindo - collabo year two an ongoing from Stemming GMBH Ingelheim Boehringer between ration and the acquire option to its exercise to chosen (Sep.) ($245mm). €210mm for latter the around centered had The collaboration oncolytic generation next a of development ViraTherapeutics’ on based platform virus - Stoma (Vesicular VSV-GP candidate lead time the at which glycoprotein) Virus titis - develop in preclinical was signing deal of parties The two cancers. solid for ment with in combination VSV-GP testing were being treatments immunomodulatory “cold” turn to in efforts BI at developed irresponsive are tumors “hot” (cold tumors tumors hot while system, the immune to The only eliminated). and be detected can cur is on the market therapy virus oncolytic rently - - Aurobindo Aurobindo ), and three ), and Fougera NOVARTIS AG NOVARTIS AUROBINDO PHARMA LTD. PHARMA AUROBINDO Sandoz International GMBH International Sandoz ’s Ltd. Pharma Aurobindo certain buy to agreed Inc. USA Pharma GMBH’s International Sandoz portions of and dermatology generic US Sandoz’s US which businesses, solids oral generic US (Sep.) divesting. is AG Novartis parent reviewing was it announced first Novartis Sandoz these for alternatives strategic overall (Sandoz 2017. in November units for sales in US a 16% decline experienced only be the to said Aurobindo, Q2 2018.) bidders, other firm among rumored Indian and $1bn ($900mm in cash to up pay will for $100mm to up of earn-outs potential financing milestones), performance-based - fa debt committed fully a through the deal - com a have businesses selected The cility. rev products--with 300 portfolio of bined Aurobindo Pharma USA Inc. USA Pharma Aurobindo $600mm and year last $1.5bn for of enues EV for 1H 2018 (Sales for reported sales in on $1.2bn based at estimated multiple rate)--which run months six last double $900mm in over generate to expected are closing. after 12 months the first for sales also Aurobindo the transaction, of part As New 750 projects, pipeline additional gains - representa field employees, Jersey-based in (gained brand the PharmaDerm for tives of buy 2012 Sandoz’s in North Carolina facilities manufacturing capabilities specialized with York New and topical lotions, and ointments, in creams, suspensions. and solutions der The US to contributes (which business matology revenues, business’s the acquired 30% of sources) secondary several to according - gyneco antibiotics, topical of up made is antifungals, dermatological and logical analgesics, anesthetic local drugs, acne - a dermatologi and medications, anti-itch oral drug. The generic chemotherapy cal for medicines includes business solids anti-neoplastic diseases, auto-immune The deal therapies. hormonal and drugs, biosimilars on its focus to Sandoz enables and worldwide five markets currently (it other biosimilars several launch to expects biologics immunology and oncology of value-added years), few the next over is This generics. complex and medicines, CLN8 is in preclinical development. The development. in preclinical is CLN8 for candidates include projects additional - Wol C, type Niemann-Pick including LSDs Drs. other disorders. and Sachs, Tay man, support to continue will Meyer and Kaspar - scien as programs these of development existing an With to Amicus. advisors tific the Celenex adds Amicus on LSDs, focus pipeline. disease rare own its to programs (migalastat), drug Galafold first Amicus’ for therapy replacement enzyme an oral last just approved was disease, Fabry’s - Banks/Advi Investment the FDA. month by (Celenex) Markets Capital RBC sors: - (gene therapies for for therapies (gene Celenex AMICUS THERAPEUTICS THERAPEUTICS INC. AMICUS CELENEX Supporting its business strategy to move move to strategy business Supporting its Amicus arena, therapy the gene into pri- acquire to agreed Inc. Therapeutics held vately during Q2 2018 came from therapeutic therapeutic from Q2 2018 came during overactive migraine, (including indications spasticity), and dystonia, cervical bladder, investor a concurrent in disclosed Allergan it 2025 and now between that presentation (to business aesthetics its double to plans direct-to- doubling by sales) in net $7-8bn sales its increasing advertising, consumer in R&D ($1bn more investing also and force, space), in this programs for ear-marked is - prod new one or two launch to a goal with that within year each or indications ucts time period. disorders storage lysosomal neurological pipeline disease rare ten gaining (LSDs)), (Sep.) projects. front up in cash $100mm pay will Amicus shareholders Celenex provide could and ($15mm in earn-outs $352mm to up with milestones, development reaching upon - BLA/MAA submis achieving for $262mm to up and milestones, approval and sion ($500mm/$750mm) sales in tiered $75mm programs. the multiple across milestones) a with the transaction fund will Amicus from facility $150mm debt concurrent fund an investment PLC, Credit BioPharma The Advisors. Pharmakon by managed - Nation of out spun was Celenex stealthy which from (NCH), Hospital Children’s wide therapy gene disease the rare licensed it development. their advance to compounds Brian by developed were The programs at PhD, Meyer, Kathrin and PhD, Kaspar, Arthur Bur collaborator, along with NCH, . All . All State Ohio University of PhD, ghes, intrathecal for intended are candidates validated clinically a using administration, gene vector (AAV) virus adeno-associated has technology AAV This approach. delivery in clinical results successful demonstrated including indications, CNS in rare trials the All (SMA). atrophy muscular spinal in- LSDs, for are therapies gene potential development in clinical-stage two cluding mostthe disease, Batten CLN3 and CLN6 for - neurode fatal, of a group of form common - neuro called disorders genetic generative There (or NCLs). lipofuscinoses ceroid nal disease Batten of subtypes different are genes CLN 13 of one which on depending neuronal to leads that the mutation has demon- candidate The CLN6 dysfunction. and performance motor improved strated well as models in mouse behavior cognitive data in efficacy and safety encouraging as CLN3the while study, I/II Phase ongoing an initiated trial I Phase a in is therapy gene the first treat to expected is which NCH, by months. Additional in the coming patient A third year. next expected is both for data subtype the NCL program disease Batten company an Informa Inc., Information, Business ©2016 Informa ❚ DEAL-MAKING

SUPERNUS PHARMACEUTICALS INC. treatment for the underserved pediatric Phase II beginning in 2019. This is not the BISCAYNE NEUROTHERAPEUTICS INC. cancer osteosarcoma. (Sep.) first time the companies have teamed up. Supernus Pharmaceuticals Inc. agreed OS Therapies pays undisclosed money up Roche also licensed Ark AK0529 in 2014. to acquire epilepsy-focused start-up Bis- front; milestones for development, regula- Now known as ziresovir, the compound is cayne Neurotherapeutics Inc. (BNT) for up tory, and sales achievements; royalties; in Phase II for respiratory syncytial virus to $183mm. (Sep.) and reimbursement for product supply. infection in adults and children. Other dis- Supernus will pay $15mm up front and up OS Therapies will fund all of its studies and eases that Ark focuses on include COPD, to $168mm in earn-outs ($73mm upon plans to evaluate ADXSHER2 in conjunction influenza, and hepatitis B. reaching certain development milestones with The Children’s Oncology Group (part ASTRAZENECA PLC and another $95mm for the achievement of the NCI National Clinical Trials Network) AstraZeneca AB of specified sales goals). BNT was spun for osteosarcoma, a rare cancer that forms BIOHAVEN PHARMACEUTICALS out of predecessor company Biscayne in the bones. Advaxis previously gained HOLDING CO. LTD. approval for the therapy as a canine treat- Pharmaceuticals (which was Insero Health AstraZeneca AB granted Biohaven Phar- prior to that) in January 2017 to take over ment, but it has not yet been developed maceuticals Holding Co. Ltd. exclu- development of BIS001, an anticonvulsant or approved for human patients. Osteo- sive global rights to develop and sell (which Supernus will re-name SPN817) for sarcoma is OS Therapies’ sole focus; the its shelved myeloperoxidase inhibitor Dravet syndrome, a severe form of child- company notes that there have been no AZD3241 (renamed BHV3241) for multiple hood epilepsy. The compound gained new treatment options in 30 years. system atrophy (MSA). (Sep.) orphan drug designation in this indication from the FDA early last year. SPN817 is a ANAEROPHARMA SCIENCE INC. Biohaven made an undisclosed up-front synthetic form of huperzine A (a traditional ASTELLAS PHARMA INC. payment (comprised of cash and equity) Chinese medicine that has demonstrated Anaeropharma Science Inc. and Astellas and will hand over development and sales potential efficacy in multiple models of Pharma Inc. are teaming up to develop milestones, plus up to double-digit royal- CNS conditions), an acetylcholinesterase anti-tumor therapies that incorporate ties. AZ brought the candidate into Phase (AChE) inhibitor that offers high brain Anaeropharma’s in situ delivery and pro- II trials, but discontinued development. penetration. SPN817 is currently in a Phase duction system (i-DPS). (Sep.) It grants Biohaven rights to pursue all indications excluding cardiovascular II proof-of-concept study in adult patients The i-DPS technology is used to improve disease, and further, has agreed to hold with refractory complex partial seizures to drug delivery efficiency by modifying the off for five years on investigating CNS study the safety and pharmacokinetics pro- non-pathogenic anaerobic bacteria known indications for early-stage MPO inhibitors file of an oral extended-release formulation as Bifidobacterium longum, which local- designed to enhance tolerability across it currently has in trials for cardiovascular izes and thrives in the anaerobic environ- conditions. Multiple system atrophy is a various doses. Due to its high potency, ment to produce anticancer proteins, en- initial studies with immediate-release rare neurodegenerative disorder that af- zymes, or other pharmacologically active fects the autonomic nervous system and versions of non-synthetic huperzine A molecules selectively at the tumor site. demonstrated dose-limiting side effects. movement. Biohaven adds BHV3241 to The technology has potential to be more its growing pipeline of projects for neuro Supernus will focus on completing and effective against solid tumors with fewer optimizing the synthesis process of the and psychiatric diseases. The deal is the side effects than traditional anticancer second in two years for the partners; in candidate and developing a novel dos- therapies. Anaeropharma and Astellas will age form for pediatric epilepsy disorders. 2016, AZ off-loaded another discontinued jointly perform research involving specific candidate--lanicemine--which Biohaven Supernus will also pay a maximum royalty substances to develop candidates that use of 12%, which includes a low-single-digit is now developing for Rett syndrome and Bifidobacterium as a drug delivery carrier. other neuropsychiatric conditions. royalty on net sales to BNT as well as any Astellas gets the right of first negotiation applicable royalties to third parties for use to license exclusive commercialization ASTRAZENECA PLC of the intellectual property (surrounding a rights to resulting molecules. Anaero- BIOTHERA PHARMACEUTICALS INC. manufacturing process and huperzine de- pharma has successfully used the i-DPS Biothera Pharmaceuticals Inc. and Astra- rivatives and compositions Insero licensed technology to create its lead program Zeneca PLC teamed up to evaluate the lat- from Yale and Harvard in 2012). Under a APS001F, which is currently in Phase I. ter’s Imfinzi (durvalumab) in combination March 2018 deal, Biscayne licensed Chi- with Biothera’s Imprime PGG to treat pri- nese accelerator Global Drug Development ARK BIOSCIENCES INC. mary untreated locally advanced head and Centre exclusive rights (including IP) to the ROCHE neck cancer before surgical resection. (Sep.) compound in China, Taiwan, Hong Kong, Genentech Inc. and Macau. SPN817 fits in nicely with Su- Imfinzi, an anti-PD-L1 mAb, is marketed for Roche’s Genentech Inc. licensed Ark Bio- bladder and non-small cell lung cancers, pernus’ own CNS disease portfolio, which sciences Inc. exclusive worldwide devel- includes Oxtellar XR (extended-release ox- and is in Phase III trials for head and neck, opment and commercialization rights to small cell lung, and liver cancers, in addi- carbazepine) for epilepsy and Trokendi XR its Phase I idiopathic pulmonary fibrosis (extended-release topiramate) for migraine tional to numerous earlier trials for other (IPF) program AK3280 (GDC3280) plus solid and blood cancers. Imprime PGG is and epilepsy. Supernus also has a neurol- related compounds. (Sep.) ogy and psychiatry pipeline led by SPN812 Biothera’s yeast-derived biologic that acts Ark will pay milestones and sales royal- (Phase II) for attention deficit hyperactivity as a Pathogen Associated Molecular Pat- ties, while Roche retains some preferen- disorder (ADHD) and SPN810 (Phase III) for ter (PAMP) and functions like an ignition tial rights. The Big Pharma got AK3280 impulsive aggression in ADHD. switch in the immune system for innate through its 2014 acquisition of InterMune, and adaptive immune responses. It is in Alliances a pulmonary and fibrotic disease company Phase III trials for colorectal cancer and that brought Roche the IPF drug Esbriet Phase II for breast, head and neck, and ADVAXIS INC. (pirfenidone). The product had 2017 sales non-small cell lung cancers, as well as OS THERAPIES LLC of $882mm, but in 2021 is expected to face melanoma. The partners plan to initiate Advaxis Inc. granted OS Therapies LLC generic competition. AK3280, a second- a Phase II trial with the combination later rights to develop and sell its ADXS31164 generation analogue of Esbriet, is soon this year, with patient enrollment finished (ADXSHER2) Listeria-based vaccine as a expected to enter a Phase Ib trial, with by the end of 2019. Imprime PGG is also

48 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com MTI 100 Rankings Medtech Insight’s Ranking of the Top 10 Most Successful Medtech Companies, and More

Who came out on top in Medtech Insight’s annual roll-call of the 100 most successful global medtech companies? Take a closer look at the top 10 overall players in the market with the Medtech Insight 100 – now available to you as a free download.

Based on Medtech Insight’s deﬁnitive ranking of 100 companies according to their medical device and diagnostics-related sales for the most recent ﬁscal year, Medtech Insight 100 gives you unique insight into the changing landscape facing the power players in the industry.

Discover: • Which companies gained footing over the past ﬁscal year, and which slipped in the rankings • Medtech sales totals for each company for FY 2016 and FY 2015 • A summary of the rankings and the activities that put companies in the top 10 • A look at what lies ahead in 2018 for the movers and shakers on the list

Don’t wait – tap into the depth and breadth of market knowledge that only Medtech Insight provides with your free copy of Medtech Insight 100 Medtech Insight Rankings Pharma intelligence | ❚ DEAL-MAKING

being studied together with Merck’s will also purchase 1.5mm CBMG shares (a Copiktra, a dual inhibitor of PI3K-delta and Keytruda (pembrolizumab) for breast and 9% stake) at $27.43 (a 30% premium) for PI3K-gamma, was recently approved by head and neck cancers. $40mm. Under the other component of the the FDA for adult patients with relapsed or deal, Novartis gains worldwide rights to refractory chronic lymphocytic leukemia/ BEIGENE LTD. certain CBMG CAR-T technology and related small lymphocytic lymphoma who have SPRINGWORKS THERAPEUTICS LLC intellectual property. Novartis’ royalty-free undergone at least two prior therapies. BeiGene Ltd. and SpringWorks Therapeu- license is exclusive with respect to the It also received accelerated approval for tics partnered to evaluate the combination development, manufacture, and commer- follicular lymphoma. CSPC pays $15mm of BeiGene’s lifirafenib (GBG283) with cialization of Kymriah and non-exclusive for up front; $30mm in development mile- SpringWorks’ PD0325901 as a new treat- the development, manufacture, and com- stones; regulatory and commercialization ment regimen for solid tumors. (Sep.) mercialization of other products. CBMG’s milestones of up to $130mm; and double- The collaboration will focus on patients C-CAR011 platform is an anti-CD19 con- digit royalties on sales. CSPC will hold the with RAS and RAF mutations, and other struct engineered and manufactured at a marketing authorization for Copiktra in aberrations of the MAPK pathway. Costs for large scale in the latter’s own Chinese GMP China and will also work with Verastem on the studies will be shared equally; BeiGene facility. Like Kymriah, CMBG’s approach certain other global development and trial will administer the planned Phase Ib trial, also involves engineering autologous im- activities. CSPC adds Copiktra to an oncol- and SpringWorks will oversee development mune cells to recognize and attack tumors. ogy portfolio that includes solid and blood of a fixed-dose formulation. Lifirafenib is C-CAR011 integrates well-studied lenti-viral cancer therapies Keaili (albumin-bound a B-raf kinase inhibitor in Phase I trials vectors and second-generation CAR design paclitaxel for injection; Duomeisu (doxo- for non-small cell lung and endometrial (which represents an advancement over rubicin hydrochloride liposome injection), cancer, melanoma, thyroid, colorectal, and CBMG’s prior CBM-C19.1 construct) as and Jinyouli (PEG-rhGCSF injection), liver cancers. PD0325901, an MEK inhibitor, well as the incorporation of translational DECIBEL THERAPEUTICS was studied by Pfizer for neurofibromato- medicine into each clinical study to aid in ORICULA THERAPEUTICS LLC sis, and SpringWorks is now also evaluat- dose selection, confirm the mechanism of ing it for colorectal, pancreatic, breast, and action and proof of concept, and target the Decibel Therapeutics exclusively licensed non-small cell lung cancer, and melanoma. optimal patient population. CBMG’s CAR-T Oricula Therapeutics LLC’s ORC13661, a The Phase Ib lifirafenib/PD0325901 trial is pipeline includes C-CAR011 programs for Phase I oral drug for the prevention of expected during early 2019. ALL and DLBCL, both in Phase I trials. Other hearing loss and balance disorders fol- candidates based on the platform are in lowing the treatment of severe infections CELLULAR BIOMEDICINE GROUP INC. preclinical development for additional with aminoglycoside antibiotics. (Sep.) NOVARTIS AG cancer indications. ORC13661 is a new chemical entity being Cellular Biomedicine Group Inc. (CBMG) tested for the prevention of ototoxicity that will manufacture and supply Novartis AG’s CRISPR THERAPEUTICS AG works by blocking aminoglycosides from chimeric antigen receptor T-cell (CAR-T) VIACYTE INC. entering into hair cells in the inner ear. therapy Kymriah (tisagenlecleucel) in Chi- CRISPR Therapeutics AG and ViaCyte Inc. Patients at particular risk for ototoxicity in- na. Novartis also invests in the company are teaming up to jointly develop and com- clude those treated for pulmonary exacerba- and gets a worldwide license to CBMG’s mercialize gene-edited allogeneic stem tions from cystic fibrosis, non-tuberculous own CAR-T technology. (Sep.) cell therapies for diabetes. (Sep.) mycobacterial infections, multidrug-resis- CBMG will assist Novartis with the devel- The parties will together create an immune- tant tuberculosis, and endocarditis. The opment of Kymriah in China, but the Big evasive stem cell line. Once a candidate is compound originated from a research agree- Pharma will oversee Chinese regulatory, identified, CRISPR and ViaCyte will jointly ment between the University of Washington commercialization, and distribution tasks. perform further development and eventual and the Fred Hutchinson Cancer Research Once the therapy is approved in China, global commercialization. CRISPR will pay Center and was in-licensed by Oricula in CBMG will take over its manufacturing ViaCyte $15mm in the form of cash or stock. 2013. ORC13661 will be a welcome addition there, receiving a mark-up from Novartis ViaCyte also has the option to receive an- to Boston-based Decibel’s drug discovery, on the manufacturing cost. (Local regula- other $10mm in a convertible promissory development and translational platform for tions require that the specialized drug be note. To the collaboration ViaCyte will con- protecting, repairing and restoring hearing. manufactured in China). Kymriah is an anti- tribute its expertise in creating pancreatic- DIAMEDICA THERAPEUTICS INC. cancer immunotherapy consisting of the lineage cells from stem cells and delivering patient’s own T-cells genetically modified FOSUN INTERNATIONAL LTD. them safely and efficiently to patients. Its Shanghai Fosun Pharmaceutical Group to target CD19 expressed on cancer cells. lead program is clinical-stage PEC-Direct for So far, Novartis has received regulatory Co. Ltd. treating Type I diabetes by administering Jinzhou Ahon Pharmaceutical Co Ltd. clearance in the US, Canada, and Europe stem cell-derived pancreatic progenitor in acute lymphocytic leukemia (ALL) and cells in an implantable device. CRISPR Shanghai Fosun Pharmaceutical Group diffuse large B-cell lymphoma (DLBCL); offers gene editing technologies that can Co. Ltd. subsidiary Jinzhou Ahon Pharma- it also has filed NDAs in Japan for both potentially protect the transplanted cells ceutical Co Ltd. (Ahon) licensed exclusive indications. Kymriah is also in clinical from the patient’s immune system. The development and commercialization trials for other cancers, including chronic firms ultimately seek to combine their IP rights in China, Hong Kong, Macau, and lymphocytic leukemia (Phase III), indolent to produce a beta-cell replacement therapy Taiwan to DiaMedica Therapeutics Inc.’s non-Hodgkin’s lymphoma (Phase II), and for diabetes that doesn’t trigger an immune DM199, a recombinant human tissue of multiple myeloma (Phase I). Under the ten- reaction. the kallikrein 1 (KLK-1) protein, for acute year collaboration (renewable thereafter in ischemic stroke. (Sep.) two-year increments), CBMG gets single- CSPC PHARMACEUTICAL GROUP LTD. Ahon will pay $500k up front; $4.5mm digit escalating percentage collaboration VERASTEM INC. upon regulatory clearance to begin a clini- payments based on net Kymriah product CSPC Pharmaceutical Group Ltd. licensed cal trial in China; $27.5mm in development sales in China, subject to certain caps, for exclusive rights to develop and sell and sales milestones; plus high-single DLBCL and pediatric ALL indications and up Verastem Inc.’s cancer therapy Copiktra to low-double-digit royalties (Strategic to a maximum amount to be agreed upon (duvelisib) in China, Hong Kong, Macau, Transactions assumes 7-29%) on net sales for sales in other indications. Novartis and Taiwan. (Sep.) in the specified regions. Ahon takes over

50 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com

- ❚

| 51 and Molecu and Technosphere DEAL-MAKING In Vivo 2018 | In Vivo October -based therapies could turn into turn could therapies -based ARCUS (insulin) franchise, a blockbuster a blockbuster franchise, (insulin) Afrezza MOLECULAR TEMPLATES INC. TEMPLATES MOLECULAR LTD. CO. PHARMACEUTICAL TAKEDA MANNKIND CORP. MANNKIND THERAPEUTICS CORP. UNITED - a new co-devel penned Inc. Templates lar CD38-targeted surrounding deal opment diseases, for (ETBs) bodies toxin engineered (Sep.) myeloma. multiple including platform has IP protection through 2030. In 2030. through IP protection has platform use will it said MannKind call, a conference grow to the collaboration from the money its - dia II Type and I Type for powder inhalation two sells already Therapeutics United betes. PAH--inhaled for treprostinil of formulations Remodulin. injectable and Tyvaso Ltd. Co. Pharmaceutical Takeda - (cova cccDNA HBV target to designed are cccDNA HBV DNA). circular closed lently for a cure yet not is there the reason is is virus the for treatment once virus; the - replica HBV for allows cccDNA stopped, - nucle ARCUS Precision’s with tion. Studies against results positive shown have ases chronic approved FDA the eight Of cccDNA. as Gilead, belong to three therapies, HBV been shown none have As pills. once-daily that hopes Gilead the disease, eradicate to new for HBV. cure the first - Thera United licensed Corp. MannKind rights worldwide exclusive Corp. peutics a dry- pow commercialize and develop to is which treprostinil, of der formulation arterial pulmonary I for in Phase currently (Sep.) hypertension. - re the rights, MannKind for In exchange $50mm in to up front, up $45mm ceives which of (most milestones development nextthe in achieved be to expected are sales low-double-digit months), and 24 assumes Transactions (Strategic royalties an has also Therapeutics United 10-29%). other include to the license expand option to pulmonary treating for ingredients active hypertension. each of Upon the exercise $40mm to up MannKind pay would option, it milestones, development and in option fees MannKind royalties. low-double-digit plus United provide and manufacture will and supplies clinical with Therapeutics treprostinil, of batches commercial initial manufacture will Therapeutics United and In addi- supplies. commercial long-term on research conduct will tion, MannKind products for Therapeutics United of behalf - agree the licensing of the scope outside based $10mm receive will MannKind ment; treprostinil Inhaled performance. on its technology Technosphere MannKind’s uses portable, small, a via agent the deliver to inhalation, After inhaler. breath-powered the surface at rapidly dissolve the powders the drug at deliver and the deep lung of - circula the arterial into directly high levels providing thus liver the bypassing tion, The exposure. systemic ideal

- - - Zerviate FreshKote is available inFreshKote GILEAD SCIENCES INC. SCIENCES GILEAD INC. BIOSCIENCES PRECISION EYEVANCE PHARMACEUTICALS LLC PHARMACEUTICALS EYEVANCE INC. LABORATORIES FOCUS EVEREST MEDICINES LTD. MEDICINES EVEREST INC. PHARMACEUTICALS VENATORX Precision Bio- Precision and Inc. Sciences Gilead to an agreement penned Inc. Sciences for new treatments develop and discover the latter’s using (HBV) virus B hepatitis (Sep.) editing platform. gene ARCUS formulation perform initial will Precision - can any on studies preclinical and work while the deal, under discovered didates and trials clinical for responsible is Gilead any paying isn’t Gilead commercialization. to up to committed but front up money - royal plus milestones, in total $445mm nucleases ARCUS the mid-teens. to up ties a synthetic nuclease, the ARC from (derived a homing endonuclease) to similar enzyme (cetirizine) ophthalmic solution. Investment Investment solution. ophthalmic (cetirizine) Securities VelocityHealth Banks/Advisors: LLC) Pharmaceuticals (Eyevance Inc. has has LLC Pharmaceuticals Eyevance the to rights global acquired in the aid and evaporation tear combat can is It surface. the ocular of wetting complete contact who wear patients by use for safe US licensed Eyevance ago, year One lenses. ’s Nicox to rights commercialization - patho carbapenem-resistant due to tions ventilator- and hospital-acquired and gens in China, pneumonia bacterial associated (Sep.) Asia. Southeast and South Korea, conduct will Everest and VenatoRx Both for In return III trials. Phase worldwide to up pay will rights, Everest commercial pay milestone and $114mm in up-front VNRX5133 royalties. sales ments, plus inhibitor beta-lactamase an injectable is - ce with in combination being developed - cephalospo a fourth-generation fepime, for on the market already is rin. Cefepime III development Phase infections. various to expected is combination fixed the of has The therapy H2 2018. in commence option be the best-in-class to potential gram-negative resistant multi-drug for - carbape including infections, bacterial and Enterobacteriaceae nem-resistant aeruginosa. Pseudomonas Focus from drops eye lubricant of brand (Sep.) Inc. Laboratories Non-prescription bottles multi-dose preservative-free 10ml eyeThe vials. single-unit 30 of boxes or the integ support to designed are drops to film the tear of layers three all of rity its of Because dry eye. from relief provide blend polymer a patented of combination FreshKote preservative, non-irritating and licensed licensed Inc. Pharmaceuticals VenatoRx to rights exclusive Ltd. Medicines Everest cefepime/ III-ready Phase its commercialize infec tract urinary complicated for VNRX5133 - - - - - ’s Kailikang (alteplase), a tissue tissue a (alteplase), Activase - thrombo the first is Doptelet ’s (rifaximin) for the reduction the reduction for (rifaximin) Xifaxan DOVA PHARMACEUTICALS INC. PHARMACEUTICALS DOVA INC. COMPANIES HEALTH BAUSCH all development, regulatory, sales, mar sales, regulatory, development, all the of form source urine a human (uKLK-1), DiaMedica year, this Earlier protein. KLK-1 and tolerability, II safety, a Phase initiated stroke, ischemic in DM199 for trial efficacy (within infusion an intravenous in which be will onset) symptom stroke of hours 24 21 for injections subcutaneous by followed window therapeutic a possible With days. alter an offers DM199 more, or hours 24 of a encephalopathy, hepatic overt of in risk disease.) liver chronic of result keting, and commercialization activities activities commercialization and keting, licensed its within costs) related (and Capital Hermed its Through territories. 2016 in DiaMedica’s invested Fosun Fund, were proceeds in which placement private trial a pending clinical toward allocated kallikrein- the activates KLK-1 DM199. of - vasodila triggering (KKS), system kinin and repair, cell tion, anti-inflammation, Ib study Phase apoptosis. decreased 2017) in November (announced results phar a demonstrated DM199 revealed to Takeda superior profile macokinetic drug stroke Chinese-approved standard, treatment the current to native Genentech to mid-twenties from ranging centages a $2.5mm make also will and mid-thirties a sales of achievement upon payment milestone. sale for approved agonist receptor poietin in adult thrombocytopenia for in the US who are disease liver chronic with patients Salix a procedure. undergo to scheduled - gastrointes sells and develops primarily considers also but therapies, disease tinal mar (It area. therapy a key disease liver kets plasminogen activator with a 3-4.5-hour a 3-4.5-hour with activator plasminogen is also (DiaMedica window. treatment 2 diabetes Type for DM199 investigating - (preclini injury kidney acute II) and (Phase another option to Ahon gives DM199 cal). Aodejin product lead Ahon’s stroke; treat Injection blood calf a deproteinized is cells of the metabolism increase to (known on the nervous effect a curative have and - cranioce or injury ischemic for system) the captured Ahon In 2017 trauma. rebral the of value sales (70%) by share biggest calf deproteinized for market Chinese extractives. blood Ltd. Pharmaceuticals Salix agreed Ltd. has Pharmaceuticals Salix - Pharma Dova in the US co-promote to drug thrombocytopenia ’s Inc. ceuticals (Sep.) (avatrombopag). Doptelet exclusive the four-year of Under terms 100 sales deploy will Salix partnership, - gastro to the therapy promote to people continue will Dova while enterologists, interven- and hepatologists to it detail to a quarterly pays Dova radiologists. tional per specified at sales) on net (based fee company an Informa Inc., Information, Business ©2016 Informa ❚ DEAL-MAKING

The agreement builds on (but is separate inhaled cromolyn sodium formulation rapid onset of efficacy, excellent safety and from) a prior collaboration through which that’s delivered via a nebulizer to provide tolerability profiles, and greater patient the pair discovered what will now be the high lung deposition and distribution. In a convenience. The addition of Pherin’s lead candidate of the current deal. Takeda Phase IIa trial it demonstrated significant compounds both expands and comple- pays $30mm up front for rights to the reduction in chronic cough in patients with ments VistaGen’s own CNS pipeline, which CD38-targeted ETBs and could hand over idiopathic pulmonary fibrosis. Roivant is led by AV101, an oral, non-opioid, non- up to $632.5mm in milestones ($307.5mm plans to launch a new firm to develop sedating NMDA receptor glycine B (NMDAR related to development and regulatory the asset. According to Patara’s website, GlyB) antagonist in Phase II for MDD (Phase activities and $325mm for sales achieve- PA101 was its only candidate and thus the II)--an indication for which it has FDA fast- ments) plus low-double-digit to low- company has ceased operations. track status as an adjunctive treatment- twenties royalties if Molecular Templates -and Phase I for neuropathic pain, epilepsy, exercises a co-development option on any PEPTIDREAM INC. Parkinson’s disease levodopa-induced of the in-licensed SLT-A fusion proteins SANTEN PHARMACEUTICAL CO. LTD. dyskinesia, and suicidal ideation. after Phase Ia trials. If it chooses not to PeptiDream Inc. and Santen Pharma- exercise the option, Molecular Templates ceutical Co. Ltd. are teaming up in the ROCHE would be eligible for $162.5mm in devel- discovery and development of ophthalmic Chugai Pharmaceutical Co. Ltd. opment/regulatory milestones, $175mm compounds. (Sep.) ELI LILLY & CO. for sale achievements, and high-single- Santen will select various ophthalmic Eli Lilly & Co. licensed exclusive global digit to low-teens royalties. ETBs work disease targets, to which PeptiDream will rights to develop and sell Chugai Phar- through enzymatic and permanent ribo- apply its Peptide Discovery Platform System maceutical Co. Ltd.’s oral glucagon-like some inactivation and are designed to (PDPS) in an effort to identify macrocyclic/ peptide-1 (GLP-1) agonist OWL833 for Type induce internalization into cells against constrained peptides and then optimize any 2 diabetes. (Sep.) poor or non-internalizing targets. The hits. PeptiDream and Santen will conduct Lilly pays $50mm up front and will hand ETBs have been de-immunized, thereby preclinical work, and Santen will solely over undisclosed milestones and royalties. reducing adaptive and innate immune handle clinical trials and gets commer- The Big Pharma is already a big diabetes responses and leading to diminished anti- cialization rights. PeptiDream received an player, with the blockbuster GLP-1 agonist drug antibody response and improved undisclosed up-front payment and will also Trulicity (dulaglutide) in its coffers. The safety. Molecular Templates has its own receive research funding and preclinical, drug brought in $2bn in revenues for Lilly in-house CD38-targeted ETB that it has clinical, and commercialization milestones, last year, but as an injectable peptide ther- been developing aside from the Takeda plus sales royalties. The PDPS platform can apeutic, comes with its own set of draw- collaboration. The second-generation generate hundreds of macrocyclic therapeu- backs. (Peptide drugs tend to carry side de-immunized MT4019 is in preclinical tic peptides against a single target in just effects, including constipation and nausea, multiple myeloma studies. weeks. Last year PeptiDream signed similar and injectable therapies have lower patient agreements with Janssen and Bayer. compliance.) Chugai’s OWL833 is attractive NOVO NORDISK AS to Lilly because it is orally delivered and is OSSIANIX INC. PHERIN PHARMACEUTICALS INC. VISTAGEN THERAPEUTICS INC. also a non-peptide compound, both as- Ossianix Inc. and Novo Nordisk AS are pects which point to the chance for better teaming up in an effort to deliver therapies VistaGen Therapeutics Inc. licensed exclu- outcomes for patients. Preclinical studies for diabetes and other metabolic diseases sive worldwide development and commer- have been completed, and the candidate to the brain across the blood brain barrier cialization rights to Pherin Pharmaceuti- is considered Phase-I ready. (BBB). (Sep.) cals Inc.’s PH94B (aloradine) nasal spray Ossianix will use its patented single- in Phase III for social anxiety disorder UNITED THERAPEUTICS CORP. domain VNAR (Variable parts of IgNAR) (SAD). In addition, VistaGen received an Lung Biotechnology PBC antibodies to deliver a predefined number option to acquire an exclusive worldwide SAMUMED LLC of Novo Nordisk compounds. Novo Nordisk license to develop and sell PH10, Pherin’s Samumed LLC licensed United Therapeu- gets rights to develop and commercialize Phase II nasal spray candidate for major tics Corp. exclusive rights to develop and the therapies and will pay Ossianix an depressive disorder (MDD). (Sep.) commercialize its SM04646 in the US and up-front fee, development and commer- In exchange for the PH94B license, Vista- Canada. (Sep.) cial milestones, R&D funding, and sales Gen issued Pherin a one-time, up-front UT will pay Samumed $10mm up front, up to royalties. Novo Nordisk has a buyout op- payment of $2mm in VistaGen common $340mm in developmental milestones, and tion for each product on pre-agreed yet stock (a total of 1.4mm shares) and will up to low double-digit royalties. SM04646 undisclosed financial terms. Sharks pro- also pay nominal monthly development is a Wnt pathway inhibitor in Phase I for duce IgNAR, which are heavy chain-only support payments for a term of 18 months; idiopathic pulmonary fibrosis (IPF). UT’s antibodies. VNARs are smallest naturally development and regulatory milestones Lung Biotechnology PBC will fund and occurring antibody-derived molecules and (including payments upon approval by perform all development, regulatory, and have high affinity and specificity with the both the FDA and the EMEA); sales mile- commercialization activities in the licensed ability to interact with multiple targets, stones; and future royalties. Under the territories, outside which Samumed retains including those that aren’t accessible concurrent 24-month option agreement all rights. SM04646 has orphan drug status by traditional IgG antibodies. VNAR anti- for PH10, VistaGen issued $250k in stock from the FDA. Earlier this month in a deal bodies can deliver therapies via the BBB (181k shares) up front. Pherin’s intranasal potentially worth $145mm, UT got exclusive utilizing the transferrin receptor. synthetic neuroactive steroid candidates global rights to MannKind’s Phase I dry pow- are derived from compounds known as PATARA PHARMA INC. der formulation of treprostinil for pulmonary pherines, which locally bind to and engage arterial hypertension. ROIVANT SCIENCES GMBH peripheral nasal chemosensory receptors Roivant Sciences GMBH acquired global connected to the hypothalamus and limbic Financings rights to Patara Pharma Inc.’s pulmonary system. This route of administration ren- therapeutic PA101 and related assets. (Sep.) ders a drug rapidly effective in ultra-low ADAPTIMMUNE THERAPEUTICS PLC Roivant has renamed the compound quantities, avoids systemic circulation Adaptimmune Therapeutics LLC netted RVT1601. The acquired compound is an (via the blood-brain barrier), and offers a $99.7mm through a registered direct

52 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com Strategic Transactions Pharma intelligence |

The most trusted source of health care deal intelligence

You can rely on the insight and information in Strategic Transactions to carry out these and many more critical business development activities.

The top pharmaceutical firms and leaders in medical devices, diagnostics, finance and consulting already do.

Available via annual subscription. For more information and to request a complimentary demonstration, visit: www.Pharmamedtechbi.com/STLP ❚ DEAL-MAKING

offering of 10mm American Depositary of anti-IL-33 etokimab (ANB020; Phase II ted $188mm through a public offering of Shares (representing 60mm ordinary for moderate-to-severe atopic dermatitis 4.2mm common shares at $47.50. Funds shares) priced at $10 per ADS. Funds will and severe eosinophilic asthma, and will support continued R&D and platform go towards development of the company’s Phase I for chronic rhinosinusitis with work, including development of lead can- SPEAR T-cell therapies including MAGEA10 nasal polyps) and anti-IL-36R ANB019 didate CTX001 (Phase I/II for sickle cell for melanoma and urothelial, non-small (Phase I for generalized pustular psoriasis disease and beta thalassemia) and CTX110 cell lung, and head and neck cancers; and palmoplantar pustulosis); for manu- (preclinical studies for CD19-positive ma- MAGEA4 for ovarian, urothelial, esopha- facturing costs; and for preclinical and lignancies). (Sep.) geal, and other solid tumors; and AFP for early-stage programs. (Sep.) Investment Banks/Advisors: Barclays hepatocellular carcinoma. (Sep.) Investment Banks/Advisors: Cantor Bank PLC; Goldman Sachs & Co.; Gug- genheim Partners LLC; Needham & Co. ADVAXIS INC. Fitzgerald & Co.; Credit Suisse Group; Guggenheim Partners LLC; JP Morgan & Inc.; Piper Jaffray & Co.; Wells Fargo Se- Advaxis Inc. (listeria-based cancer vac- Co.; Jefferies & Co. Inc.; Wedbush PacGrow curities LLC cines) netted $18.7mm through a public of- Life Sciences fering of 16.7mm common shares at $1.20. DICERNA PHARMACEUTICALS INC. The company also issued six-year warrants ARGENX SE Dicerna Pharmaceuticals Inc. (develops to purchase 14.17mm common at $1.50. Argenx SE (therapeutic antibodies RNAi therapeutics) netted $94mm through Proceeds will support R&D, including work for autoimmune diseases and cancer) a follow-on public offering of 7.68mm com- on ADXSHOT (targets tumor hotspots and netted $284mm through the public mon shares at $13.02. The company plans tumor-associated antigens; NSCLC), ADX- sale of 3.475mm American Depositary to use some of the funds for preclinical SPSA (prostate cancer), ADXSNEO (targets Shares (representing 3.475mm ordinary and clinical studies and ongoing develop- neoantigens; multiple tumors), and axali- shares) at $86.50 per ADS. Proceeds will ment of its technology platform. (Sep.) mogene filolisbac (head and neck and other support corporate and R&D activities, Investment Banks/Advisors: Citigroup HPV-associated cancers). (Sep.) including late-stage development and Inc.; HC Wainwright & Co.; Leerink Part- Investment Banks/Advisors: Cantor launch preparation for efgartigimod for ners LLC; Stifel Nicolaus & Co. Inc.; Sun- Fitzgerald & Co.; Oppenheimer & Co. Inc. myasthenia gravis and immune throm- Trust Banks Inc. bocytopenia. (Sep.) AGENUS INC. ENDOCYTE INC. Investment Banks/Advisors: Cowen & Co. XOMA CORP. (targeted cancer therapies LLC; Evercore Partners; Kempen & Co.; Endocyte Inc. and companion imaging agents) net- Immuno-oncology firmAgenus Inc. closed Morgan Stanley & Co.; Nomura Securities ted $189mm through the public sale of a non-dilutive royalty financing withXoma International Inc.; Piper Jaffray & Co. Corp., which paid $15mm to buy a minority 10.9mm common shares (including the interest in royalties and milestones due to BAUSCH HEALTH COMPANIES INC. overallotment) at $18.50. Proceeds will Agenus under its collaboration with Merck XENON PHARMACEUTICALS INC. support continued pipeline development & Co. Inc. and Incyte Corp. (Sep.) Xenon Pharmaceuticals Inc. is buying and commercial launch preparation for 177Lu-PSMA617, a radioligand therapeutic ALLOGENE THERAPEUTICS INC. out all past, present, and future milestone and royalty payments owed to currently in a Phase III trial for progressive Immuno-oncology firmAllogene Therapeu- Bausch Health Companies Inc. related PSMA-positive metastatic castration- tics Inc. filed for its initial public offering to XEN1101, a Kv7 potassium channel resistant prostate cancer. (Sep.) and plans to trade on the Nasdaq. (Sep.) agonist for epilepsy. (Sep.) Investment Banks/Advisors: Jefferies & Investment Banks/Advisors: Cowen & Co. Co. Inc.; RBC Capital Markets; Wells Fargo LLC; Goldman Sachs & Co.; JP Morgan BIOPHYTIS SA Securities LLC Chase & Co.; Jefferies & Co. Inc. Biophytis SA (therapies for age-related degenerative diseases) entered into a ENTASIS THERAPEUTICS HOLDINGS INC. AMICUS THERAPEUTICS INC. €10mm ($11.6mm) bond financing with Antibiotics developer Entasis Therapeu- Rare disease-focused Amicus Therapeu- Kreos Capital. The 10% senior unsubor- tics Holdings Inc. netted $69.75mm in tics Inc. closed a five-year senior credit dinated loan will be paid in four equal its initial public offering of 5mm common facility (consisting of a $150mm term loan) tranches of €2.5mm--the first two by the shares priced at $15. The company had with BioPharma Credit PLC, an investment end of this month, another by year-end, planned to sell 4.4mm shares between fund managed by Pharmakon Advisors. and the final tranche before June 2019. $16 and $18 each. (Sep.) The loan is interest only for the first four Biophytis will use the proceeds to prepare Investment Banks/Advisors: BMO Financial years, after which interest accrues at a for clinical development of its Duchenne Group; Credit Suisse Group; SunTrust Banks floating rate of LIBOR plus 7.5%, subject myopathy candidate Myoda. (Sep.) Inc.; Wedbush PacGrow Life Sciences to a floor and ceiling. Amicus will use the proceeds to help fund its concurrent CASI PHARMACEUTICALS INC. FOAMIX PHARMACEUTICALS LTD. $452mm buy of private gene therapy com- CASI Pharmaceuticals Inc. grossed Nasdaq-traded Israeli drug delivery pany Celenex and support several years of $48.5mm through the private placement company Foamix Pharmaceuticals Ltd. development costs associated with the ten of 9mm common shares at $5.36 (a 21% (focused on dermatology indications) neurological lysosomal storage disorder discount) to new and returning investors. netted $75.7mm through the public offer- pipeline programs Amicus is getting along The company also issued three-year war- ing of 13.4mm ordinary shares (including with the acquisition. (Sep.) rants to purchase 2.7mm shares at $7.19. the overallotment) at $6. The company Proceeds will support ongoing activities plans to use the proceeds to support both ANAPTYSBIO INC. related to commercialization of the com- an NDA filing with the FDA and commer- AnaptysBio Inc. (antibody candidates for pany’s oncology projects mainly in China cialization costs for FMX101 (4% minocy- inflammation) netted $197.1mm in a fol- and the US. (Sep.) cline), a topical foam for moderate-to-se- low-on public offering of 2.2mm common vere acne, which completed a long-term shares at $94.46. The company plans to CRISPR THERAPEUTICS AG study (part of two Phase III trials) in Janu- use the offering proceeds for R&D of clini- CRISPR Therapeutics AG (CRISPR/Cas-9 ary 2018 demonstrating tolerability and cal programs including for planned trials gene editing-based drug discovery) net- safety. Foamix will also use the money to

54 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com invivo.pharmaintelligence.informa.com - ❚

| 55 DEAL-MAKING In Vivo 2018 | In Vivo October netted netted Inc. Biopharma Sutro SUTRO BIOPHARMA INC. SUTRO BIOPHARMA SUTRO INC. BIOPHARMA SE VALNEVA THERAPEUTICS VIKING INC. The notes covert to common at a rate a rate at common to covert The notes principal $1k per shares 25.7739 of (The per share. $38.80 or about amount, the at $29.27 averaged stock company’s proceeds the of Some sale.) the of time outstanding repurchase to used be will cash, for due 2019 4.5% senior notes will the remainder and interest, including capital and commercial, R&D, towards go (Sep.) expenses. Barclays Banks/Advisors: Investment Leerink Inc.; Co. & Jefferies PLC; Bank Inter Securities Nomura LLC; Partners Inc. national drug disease autoimmune and Cancer developer offering public initial its through $79mm $15. The at shares common 5.67mm of 5mm sell to intended originally company (Sep.) $14-16. of a range at shares & Co. Cowen Banks/Advisors: Investment & Piper Jaffray LLC; JMP Securities LLC; Sciences Life PacGrow Wedbush Co.; and (oncology Inc. Biopharma Sutro development) drug disease autoimmune - place private a through $10mm grossed its of closing the with concurrent ment partner Sutro’s offering. public initial - com 666,666 purchased Inc. & Co. Merck The $15. of the IPO price at mon shares a under together working are companies Sutro which through July in penned deal - conju and synthesis protein its using is drug new discover to platforms gation (Sep.) Merck. for candidates ($58.8mm) €50mm grossed SE Valneva placement private in an oversubscribed €3.75 at shares ordinary 13.33mm of investors to discount) (a slight each MVM and Grimaud Groupe including will The company Partners. Science Life ongoing for the proceeds some of use candidates pipeline its of development and disease Lyme for vaccines including - Securi Guggenheim virus. Chikungunya placement the were Oddo BHF and ties (Sep.) agents. Guggenheim Banks/Advisors: Investment ODDO BHF LLC; Partners (developing Therapeutics Inc. Viking endocrine and metabolic for treatments $165.2mm through netted disorders) common 9.5mm of offering a follow-on the use will The company $18.50. at shares VK5211 of development ongoing for funds VK2809 healing), fracture II for (Phase and hypercholesterolemia for II (Phase - adre for (preclinical VK0214 and NASH), (Sep.) noleukodystrophy). Wainwright HC Banks/Advisors: Investment & James Raymond LLC; Group Maxim & Co.;

- - - - . (Sep.) RETROPHIN INC. MOLECULAR TEMPLATES INC. TEMPLATES MOLECULAR INC. BIOPHARMA PRINCIPIA THERAPEUTICS PROQR BV INC. BIOMED Q (rare disease therapies) therapies) disease (rare Inc. Retrophin of the sale through $232.8mm netted 2.5% its of amount principal $240mm 15, 2025. due September senior notes Molecular Templates Inc. Templates firm Molecular Oncology offer a public through $48.8mm netted and (oncology Inc. Biopharma Principia netted drug discovery) immunology offer public initial its through $113.6mm - (RNA thera NV Therapeutics ProQR netted diseases) genetic rare for pies of public a follow-on through $97.9mm accelerator) (biomedical Q BioMed Inc. deben- $4mm in 5.5% convertible sold $2mm Global; Advisors Yorkville to tures the with tranche in the initial sold was a of the filing pending be received to rest The SEC. the with statement registration $4 or a 7% of the lower at converts debt The a $2 floor. with market to discount for the proceeds use to plans company 89 chloride strontium it’s of the launch palliation; cancer bone for injection USP - fil pre-IND and drug application orphan drug disorder spectrum autism for ings - uttro on data synthesis final QBM001; molecule for and cancer; liver B for side (Sep.) glaucoma. for Man01 selection for PLC; Chardan Capital Markets; Morgan Morgan Markets; Capital Chardan PLC; & Co. Stanley (including shares 9.4mm common ing of The company $5.50. at the overallotment) its on based immunotoxins developing is (ETB) platform, bodies toxin engineered - sup to proceeds offering the use will and diffuse for MT3724 of I/II trials port Phase - pro earlier-stage lymphoma; B-cell large to PD-L1; and and HER2 targeting grams associated expenses development fund CD38-focused announced a recently with Takeda with collaboration & Co. Cowen Banks/Advisors: Investment UBS & Co.; Laidlaw Partners; Evercore LLC; Investment Bank (including shares common 7.2mm ing of (The company $17. at the overallotment) shares 4.69mm sell to planned originally (Sep.) $15-17.) of a range at of Bank Banks/Advisors: Investment Partners Leerink Lynch; Merrill America Fargo Wells Inc.; & Co. Baird W. Robert LLC; LLC Securities (includ shares ordinary 6.61mm of fering at the overallotment) of exercise ing full (Sep.) $15.75. Chardan Banks/Advisors: Investment Evercore Inc.; Citigroup Markets; Capital - Capi RBC & Co.; Wainwright HC Partners; Markets tal

Kodiak Sciences Inc. Sciences Kodiak (therapies for conditions conditions for (therapies KODIAK SCIENCES INC. SCIENCES KODIAK KALVISTA PHARMACEUTICALS INC. PHARMACEUTICALS KALVISTA GALAPAGOS NV GALAPAGOS G1 THERAPEUTICS THERAPEUTICS INC. G1 filed for its initial public offering on the offering public initial for its filed (Sep.) Nasdaq. of Bank Banks/Advisors: Investment Bank Barclays Lynch; Merrill America Ophthalmic-focused Ophthalmic-focused - (develop Inc. Pharmaceuticals KalVista inhibitors) protease ing small-molecule follow-on the through $73.5mm netted shares common 4.6mm of offering public - the overal of exercise full (including will The company each. $17 at lotment) of trials late-stage for the proceeds use (HAE) angioedema hereditary KVD900 for for and submission, the NDA of in support a prophylactic of development ongoing macular diabetic oral and program HAE (Sep.) candidates. edema Cantor Banks/Advisors: Investment Roth Inc.; Co. & Jefferies & Co.; Fitzgerald Inc. Co. & Nicolaus Stifel Partners; Capital Galapagos NV fi- inflammation, fibrosis, cystic including $285mm netted osteoarthritis) and brosis, of in the US offering a public through at Shares Depositary 2.58mm American one new represents ADS Each $116.50. use to plans company The share. ordinary of development ongoing for the proceeds ) Gilead with (partnered filgotinib III Phase colitis, arthritis, ulcerative rheumatoid for III GLPG1690 Phase disease; Crohn’s and - pul idiopathic II GLPG1205 for Phase and II GLPG1972 Phase and fibrosis; monary (Sep.) osteoarthritis. for Citigroup Banks/Advisors: Investment & Stanley Morgan & Co.; Kempen Inc.; Inc.; International Securities Nomura Co.; Inc. & Co. Nicolaus Stifel netted $195mm $195mm netted G1 Therapeutics Inc. - com 3.45mm of sale the public through the overallotment) (including mon shares for drugs develops The company $60. at in clinical projects three has and cancer, - (myelopreserva trilaciclib development: - chemothera during use for tion therapy cancer), lung and (breast lerociclib py), (Sep.) cancer). (breast G1T48 and LLC; BTIG Banks/Advisors: Investment JP & Co.; Wainwright HC LLC; & Co. Cowen Inc.; & Co. Needham & Co.; Chase Morgan Sciences Life PacGrow Wedbush complete two ongoing pivotal Phase III III Phase pivotal ongoing two complete minocycline) (1.5% FMX103 its for trials topical foam for papulopustular rosacea a filing with associated costs fund and pending FMX103 for NDA subsequent (Sep.) results. trial positive of Bank Banks/Advisors: Investment PLC; Bank Barclays Lynch; Merrill America LLC & Co. Cowen & Co.; Fitzgerald Cantor company an Informa Inc., Information, Business ©2016 Informa ❚ DEAL-MAKING

Associates Inc.; Roth Capital Partners; Sun- In Vivo Trust Banks Inc.; William Blair & Co. Pharma intelligence | XENON PHARMACEUTICALS INC. editors editorial advisory board Lucie Ellis Brian Chapman Rare disease biotech Xenon Pharmaceuti- Managing Editor ZS Associates, Partner cals Inc. (neurology-focused ion channel modulators) netted $59.2mm through a William Looney Benjamin Comer Pharma Editor public offering of 4.5mm shares at $14. PwC, Senior Manager Health Research Institute The company will use the proceeds to Ashley Yeo support ongoing development of its epi- Medtech Editor Don Creighton lepsy pipeline, including Kv7 potassium Amanda Micklus ICON channel modulators XEN496 (ezogabine; Principal Analyst Global Head of Pricing & Market Access in Phase II) and XEN1101 (Phase I) and Andrea Charles Sara Jane Demy Nav1.6 sodium channel inhibitor XEN901 Editor Custom Content Demy Colton, CEO (Phase I), as well as Phase I Cav2.1 calcium Regina Paleski Deborah Dunsire, MD channel inhibitor XEN007 (flunarizine) for Contributing Editor XTuit Pharmaceuticals, President & CEO migraine. Xenon concurrently completed a transaction in which it purchased all Barbara Freischem EBE, Executive Director past, present, and future milestone and research manager royalty payments related to XEN1101 Steven Muntner Les Funtleyder owed to Bausch Health, the compound’s E Squared Capital Management originator. (Sep.) deals analysts Health Care Portfolio Manager Beth Detuzzi, Deanna Kamienski Investment Banks/Advisors: Bloom Maureen Riordan Terry Hisey Burton & Co.; Jefferies & Co. Inc.; Stifel Deloitte, Senior Principal, Life Science Nicolaus & Co. Inc. Annlisa Jenkins design supervisor PlaqueTec, CEO ZEALAND PHARMA AS Gayle Rembold Furbert Zealand Pharma AS agreed to sell future Ken Kaitin, PhD royalty streams and $85mm in potential senior designer Tufts Center for the Study of Janet Haniak milestone payments related to its diabetes Drug Development Director drugs Soliqua 100/33/ Suliqua (insulin designers Ellen Licking glargine/lixisenatide) and Lyxumia/Ad- Jean Marie Smith, Paul Wilkinson EY, Senior Analyst lyxin (lixisenatide) to Royalty Pharma for Global Life Sciences $205mm. Sanofi sells the products under Julie Locklear the companies’ 2003 alliance; Zealand will head of editorial ops (pharma) Managing Partner, Genesis Research still be eligible for a $20mm milestone Karen Coleman Roger Longman payment, expected in 2020. Zealand will head of content Real Endpoints, CEO use the proceeds to redeem the remain- Mike Ward der of an outstanding royalty bond and Dan McIntyre to advance development of its in-house advertising Publick House, Partner Christopher Keeling development pipeline. (Sep.) Ranjini Prithviraj Investment Banks/Advisors: Morgan subscriptions DIA Publications Stanley & Co. Dan Simmons, Ewan Ritchie Senior Managing Editor/Associate Director Shinbo Hidenaga Michael Ringel, PhD managing director BCG, Senior Partner and Global Topic Leader ❚ RESEARCH, ANALYTICAL Phil Jarvis Research and Product Development EQUIPMENT & SUPPLIES Kenneth Schultz, MD Halozyme, Vice President of Innovation, Financings editorial office Strategy & Business Development 605 Third Avenue, Floor 20-22 PACIFIC BIOSCIENCES OF New York, NY 10017 Jack Wong CALIFORNIA INC. invivo.pharmaintelligence.informa.com Baxter Healthcare Head of Regulatory Affairs, APAC Genomics firm Pacific Biosciences of (PacBio) netted $56.4mm customer service Nadim Yared California Inc. [email protected] through the follow-on offering of 14.1mm CVRx, President & CEO common shares at $4.25 each. (Sep.) Investment Banks/Advisors: Cantor IN VIVO: [ISSN 2160-9861] is published monthly, except for the combined July/August issue, Fitzgerald & Co.; Cowen & Co. LLC by Informa Business Intelligence, Inc., 605 Third Avenue, Floor 20-22, New York, NY 10017. US Toll-Free: +1 888 670 8900 | US Toll: +1 908 547 2200 | UK & Europe: +44 (20) 337 73737 Australia: +61 2 8705 6907 | Japan: +81 3 6273 4260

Office of publication, The Sheridan Group, 66 Peter Parley Row, Berlin, CT 06037. Postmaster: Send address changes to Informa Business Intelligence, 605 Third Avenue, Floor 20-22, New York, NY 10158.

56 | In Vivo | October 2018 invivo.pharmamedtechbi.com invivo.pharmaintelligence.informa.com