Roche's Pred Leaders on Its Next Generation of Drugs

No. 3982 November 22, 2019

infectious disease, ophthalmology, neuroscience, rare disease and oncology.

ADVANCEMENTS IN PARKINSON’S DISEASE In neuroscience, head of pRED neuroscience and rare diseases Azad Bonni said the company is prioritizing Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, autism spectrum disorders and schizophrenia. “pRED actually has had a large impact on the Roche neuroscience and rare disease portfolio,” he said. The early development group has five molecules in Phase I and Phase II development, and there are six molecules in late-stage development at the Swiss pharma that either came from pRED or that pRED had substantial involvement with, he said. In Parkinson’s disease, a potential disease Roche’s pRED Leaders On Its Next modifying monoclonal antibody prasinezumab is advancing in Phase II. Prasin- Generation Of Drugs ezumab, developed in partnership with Prothena Corp. PLC, could be the first dis- JESSICA MERRILL [email protected] ease modifying treatment for Parkinson’s disease. It targets soluble and insoluble he Roche Pharma Research and to invest in technologies in order to push neurotoxic forms of alpha-synuclein. The Early Development (pRED) unit has the boundaries of what’s possible in terms aim is to prevent the cell-to-cell spreading T helped to shape the development of making drugs.” of pathogenic alpha-synuclein aggregates of drugs like Ocrevus and Hemlibra, fast- Among the newest drugs pRED sci- and prevent the loss of neurons. growing blockbusters that are getting the entists contributed to are satralizumab, Roche is studying prasinezumab in a Swiss pharma through a challenging peri- pending at the US Food and Drug Admin- two-part Phase II study, each portion of od as its older cancer pillars weaken. Now istration for the rare central nervous system which is running 52 weeks, with the first the pharma research group is working disease neuromyelitis optica spectrum dis- data read out expected in 2020. The study to develop the next generation of drugs order, and risdiplam, an oral drug for spinal is enrolling patients with early Parkinson’s that will maintain that momentum for the muscular atrophy that Roche expects to disease who are either treated or untreat- long term. file with the FDA by the end of the year. The ed with monoamine oxidase-B (MAO-B) During an investor event on 11 Novem- pRED group, which employs 2,400 people inhibitors, used to treat symptoms of Par- ber, the group’s leaders, including pRED across seven research sites, is one of three kinson’s disease but not the underlying head William Pao, highlighted some of the independent R&D units within Roche, the cause. The primary endpoint of the ongo- drugs in the early pipeline that they hope, other two being Genentech Early Research ing trial is change in baseline in the Move- years from now, will also be big winners. and Development (gRED) and Chugai. ment Disorders Society Unified Parkin- “We’re not resting on our laurels,” Pao PRED works in several focused thera- son’s Disease Rating Scale (MDS-UPDRS). said. “We realize that we need to continue peutic areas, including immunology, CONTINUED ON PAGE 4

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Vascepa’s Next Steps Buying And Selling NASH Ambitions Amarin set for label wrangling Roche and Merck & Co acquire, AASLD meeting sees Novartis after FDA panel meeting (p15) Lupin and Almirall divest (p5-9) and Pfizer set out their stalls (p20) IN THIS ISSUE

from the editor [email protected]

This week is the World Health Organization’s Antibiotic plicated urinary tract infections in the US in 2018 but Awareness Week. Unfortunately, after many years of sales were so low that the company filed for bankruptcy awareness raising about the issue of antimicrobial less than a year later. resistance, serious structural problems with the Also this year, Tetraphase has had to shut down its market for antibiotics continue to jeopardize R&D. R&D to focus on commercializing its product for se- Awareness is one thing, action is another. rious infections, Xerava (eravacycline), which was Big pharma has mostly withdrawn from antibiotic launched in the US in 2018. R&D. Discovering novel alternatives to existing drugs And just this week, Melinta Therapeutics, which to stay ahead of drug resistance is now left to small launched its MRSA antibiotic Baxdela (delafloxacin) companies. Initiatives like CARB-X, GARD and ND4BB in 2018 and sells other antibiotics acquired from The have helped such firms proliferate in recent years, but Medicines Co, warned investors that it looked likely to their future is under threat. be heading for a Chapter 11 bankruptcy filing. As the BEAM Alliance of European SMEs in the anti- The UK is planning a limited pilot subscription mod- infective field points out, companies that manage to dis- el for access to new antibiotics. Much more like this is cover and develop novel therapies through to approval urgently needed around the world to avoid innovators still risk “failure in the face of success”. Achaogen is a going to the wall and investors vacating the space. case in point: it launched Zemdri (plazomicin) for com-

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EDITORS IN CHIEF Andrea Charles EDITORIAL OFFICE Ian Haydock (Asia) John Davis Blue Fin Building Eleanor Malone (Europe) Kevin Grogan 3rd Floor, 110 Southwark St Denise Peterson (US) Andrew McConaghie London, SE1 0TA Ian Schofield CUSTOMER SERVICES EXECUTIVE EDITORS Vibha Sharma US Toll-Free: +1 888 670 8900 COMMERCIAL Sten Stovall Alexandra Shimmings (Europe) US Toll: +1 908 547 2200 UK & Europe: +44 (20) 337 73737 Mary Jo Laffler (US) US Australia: +61 2 8705 6907 POLICY AND REGULATORY Michael Cipriano Japan: +81 3 6273 4260 Maureen Kenny (Europe) Derrick Gingery Email: clientservices@ Nielsen Hobbs (US) Joseph Haas pharma.informa.com Mandy Jackson ASIA Cathy Kelly Anju Ghangurde Jessica Merrill TO SUBSCRIBE, VISIT scrip.pharmaintelligence.informa.com Vibha Ravi Leah Samuel Jung Won Shin Brenda Sandburg TO ADVERTISE, CONTACT Brian Yang Bridget Silverman [email protected] Sue Sutter EUROPE All stock images in this publication Neena Brizmohun courtesy of www.shutterstock.com Francesca Bruce unless otherwise stated

2 | Scrip | November 22, 2019 © Informa UK Ltd 2019 Roche Buys Promedior Sanofi Pasteur Looks 10 To Future

Bayer’s 20 5 Digital Plans 12

exclusive online content inside: COVER / Roche’s pRED Leaders On Its Next Generation Of Drugs Orphan Drug Access: One-Third Of US 5 Roche Paying $390m Up Front For Coverage Decisions Involve Restrictions, Fibrosis-Fighting Promedior Study Finds CATHY KELLY [email protected] 6 Merck Acquires Novel Neurodegenerative Disease Target With Calporta Buy

7 Lupin Offloads Kyowa Pharma For $525m But Not Exiting Japan

9 No Alarm At Almirall Despite Stake Sale

10 Sanofi Pasteur Head Loew On The Vaccine Unit’s Future Growth Drivers

12 Staying Diversified, Bayer Sees Opportunities In Digital Innovation

15 Amarin Heads Into Vascepa Expansion Labeling Talks The largest US private health plans restrict access to or- After Positive US FDA Panel Review phan drugs in 29% of commercial coverage decisions, according to a study by James Chambers, et al. from the Cen- 17 Double Delight For Novartis At The CHMP ter for the Evaluation of Value and Risk in Health at Tufts Medical Center. 18 European Biotechs Enter The IPO Big League Health plans still cover orphan drugs more generously than non-orphans; the study found plans apply coverage 19 ‘Watch China’ As Its Pharma Butterfly Flaps Its Wings restrictions to non-orphan drugs an average of 41% of the time. However, “the roughly one-third of orphan drug coverage decisions with restrictions are notable and have not 20 Novartis, Pfizer Advance Their NASH Ambitions Separately, As Partners been previously reported,” the authors pointed out. Published in the October issue of the American Jour- nal of Managed Care, the study evaluated 2,268 orphan 22 Pipeline Watch drug coverage decisions by commercial plans operated by 17 of the largest US insurers. The decisions were cur- 23 Clear Path For AstraZeneca’s Roxadustat rent as of March 2018. The data was drawn from the Tufts Medical Center Specialty Drug Evidence and Cov- 23 Appointments erage database, which includes publicly available specialty drug coverage policies. Published online 11 November 2019 To read the rest of this story go to: https://bit.ly/2QwlE0z

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CONTINUED FROM PAGE 1 logical malignancies. Roche decided in as a potentially fundamental therapy in Roche is also pioneering new biomark- May to move the drug forward into late- particular for solid tumors?” he said. ers for Parkinson’s disease, including the stage testing. It’s currently in Phase I test- development of a skin biopsy immuno- ing as a monotherapy, as well as in Phase EYEING IMPROVEMENTS IN histochemistry assay that could diag- Ib in combinations with chemotherapy, OPHTHALMOLOGY nose synucleinopathy in patients, which Roche’s PD-L1 inhibitor Tecentriq (atezoli- In ophthalmology, Roche has had a could establish a new method of diagno- zumab) and the CD20 antibody Gazyva strong commercial presence with Lu- sis for patients. (obinutuzumab). centis (ranibizumab), a VEGF inhibitor for “We’re developing this in the trial, but In heavily pretreated patients with ag- wet age-related macular degeneration. we’re also excited for its use in future trials, gressive non-Hodgkin’s lymphoma who Global Head of pRED ophthalmology Sas- because it should allow us to characterize have exhausted their treatment options, cha Fauser said the company is looking to different groups of patients, as well as in Roche has seen encouraging responses to build on that success in eye disease. determining diagnosis and … responses the treatment. “Our primary focus is on the most preva- of patients to treatments,” Bonni said. “Perhaps going forward most impor- lent retinal diseases, [where] there is still a The group is also working on the devel- tantly is the opportunity to combine this high unmet need and where we can build opment of digital biomarkers that could CD20 therapy,” Rommel said. In combi- on our long experience with anti-VEGF be used to measure a patients’ coordina- nation with Tecentriq in a relapsed/re- and specifically ranibizumab,” he said. tion or walking ability, for example. fractory diffuse large B-cell lymphoma Roche’s core focus is on dry and wet “In neuroscience, we’re actually devel- (DLBCL) patient, he said, the drug has AMD and diabetic complications of the oping this across the board,” he said. “This resulted in “remarkable and rapid deep retina, with drugs that could deliver im- is not just for Parkinson’s disease, but in response in CR.” proved efficacy, longer durability and MS, in Huntington’s disease and spinal Rommel also highlighted another bi- early prevention, but the company is also muscular atrophy.” specific antibody, a FAP-4-1BBL targeted exploring gene therapy, glaucoma and se- Bonni also highlighted gantenerumab co-stimulatory T-cell agonist. It binds to vere dry eye disease. with “brain shuttle” technology in Phase tumor stroma via fibroblast activated When it comes to advances for age-relat- I development for Alzheimer’s disease. protein (FAP) and activates T-cells by the ed macular degeneration and diabetic eye It’s the first Roche monoclonal antibody 4-1BB ligand. The drug could be best-in- diseases, Fauser said the company is study- targeting amyloid beta using the “shut- class, he said, with greater activity and ing combination treatments because while tle” technology to transport it across the less toxicity than some other molecules the introduction of anti-VEGF drugs has blood-brain barrier. The shuttle technol- that have been explored. Clinical testing been transformative, it does not address all ogy could result in a higher concentration began in April 2018 and is continuing in the aspects of the complex diseases. of the antibody reaching the brain. monotherapy and in combination with The company is studying the first bispe- Gantenerumab, partnered with Mor- Tecentriq, he added. cific antibody in ophthalmology, which phosys, is an anti-beta-amyloid mono- In another innovative approach, Rom- binds to VEGF and angiopoetin2 (Ang2), clonal IgG1 antibody that binds aggre- mel pointed to an antibody targeting with the aim of improving vascular sta- gated forms of beta-amyloid and removes CD25 that Roche gained with the 2018 bility and reducing retinal inflammation. plaques from the brain. It is already in acquisition of Tusk Therapeutics Ltd. for The drug, faricimab, has been moved into Phase III development, but without the €70m upfront plus milestones. (Also see Phase III testing based on encouraging shuttle technology. “Just What We Were Looking For: Roche Phase II results. The company expects to Pays €70m For Preclinical Anti-CD25 As- have Phase III data in 2020. IN ONCOLOGY, set “ - Scrip, 28 Sep, 2018.)It targets CD25 “We are now working on the next gen- COMBINATIONS ARE KEY on regulatory T-cells (Tregs) in the tu- eration platform of bispecifics,” Fauser Global Head of pRED Oncology Christian mor microenvironment, but the drug said. These are called DutaFabs and are Rommel highlighted the company’s early is unique, he said, because it does not significantly smaller than Roche’s early pipeline of molecular targeted drugs and block IL-2 signaling. CD25 is strongly bispecific antibodies. The DutaFabs, in cancer immunotherapies, as well as newer expressed on Tregs and less so on effec- preclinical and Phase I clinical develop- approaches for Roche like cell therapy and tor T-cells (Teff). Increasing the Teff:Treg ment, are also compatible with a novel radiotherapy. ratio lowers the threshold for immune port delivery system Roche is developing “There are a number of projects now in response in the tumor. with the aim of increasing the durability of the early stages of clinical development,” Rommel called the early research by ophthalmology drugs. Rommel said. “About a dozen of them are Tusk “brilliant work,” and Roche is now In gene therapy, Roche is planning to positioned to go into the clinic with the planning to move the molecule into the move its first candidate, 4D-110, into the timeframe of the next 12 to 25 months.” clinic early next year. clinic in 2020 for choroideremia, using One drug he highlighted was a bispe- “We basically want to test a so far unan- intravitreal AAV delivery. The company cific antibody that binds to CD20 and CD3 swered important clinical hypothesis: Do is also looking at additional monogenic on T-cells, which recruits T-cells to target Tregs play an important role? Can they be eye diseases. and destroy B-cells, aimed at hemato- targeted? And, if so, what’s their potential Published online 13 November 2019

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Roche Paying $390m Up Front For Fibrosis-Fighting Promedior MANDY JACKSON [email protected]

fter Bristol-Myers Squibb Co. de- resolution process for the prevention and “Through all of that we became more clined to exercise its option to buy reversal of fibrosis in lung, kidney, liver, and more on the radar for big pharma, APromedior Inc. in mid-2018, the bone marrow and eye diseases. Preclinical and Roche – given their deep expertise in small biopharmaceutical company began candidate PRM-167 is being developed the space – was tracking us very closely,” to consider its options for financing Phase for ophthalmology indications. Lettman said. III development of its lead asset PRM-151 “When you look at all of the work we’ve He noted that Promedior was focused in idiopathic pulmonary fibrosis (IPF). Ul- done in the early days preclinically, we’ve on remaining independent after BMS de- timately, Promedior opted to be acquired demonstrated that PRM-151 can both cided not to exercise its option to buy the by another big pharma, announcing on 15 prevent and, probably more importantly, company. By the time Roche began to November that Roche will pay $390m up reverse fibrosis,” Lettman said. “That, for show interest, planning was under way for front and up to $1bn in development, reg- many years, was the holy grail in fibrosis a venture capital crossover round followed ulatory and commercial milestone fees. and still is. There are very few drugs in de- by an initial public offering to fund a Phase III program in IPF and advance PRM-151 in additional indications. The financing plan had “significant interest from the investor community,” according to Lettman. “The fortunate thing with the BMS transaction was that they provided $150m at the time to fund [Phase II] studies non- dilutively and that was a significant capital injection,” he said. Prior to the deal with BMS, Promedior had raised modest venture capital funding, including a $21.5 series D round in 2012. (Also see “ Promedior’s new $21.5M Roche will pay $390m initially and up to $1bn in milestone fees. series D helps advance fibrosis portfolio, including IPF and mylelofibrosis “ - Scrip, 8 Mar, 2012.) Between its VC funding and CEO and Lightstone Ventures general velopment that have been able to do that the large upfront fee from BMS, the com- partner Jason Lettman told Scrip that and we showed in preclinical models an pany maintained a capital-efficient op- Promedior has had an eventful year since ability to do that in the eye, liver, kidney, eration, Lettman explained. Even with a the presentation of Phase II results for bone marrow and, of course, the lungs.” Phase III-ready candidate, it still has just PRM-151 in IPF in May 2018 and the clini- eight full-time employees and several full- cal trial’s publication in the Journal of the EVENTFUL PERIOD GAVE time consultants, he said. American Medical Association (JAMA), all PROMEDIOR FINANCING, of which led to increased investor and DEAL OPTIONS ROCHE WILL USE ITS RESOURCES pharmaceutical partner interest in the In the time since Promedior presented TO ADVANCE PRM-151 company’s lead asset and its pentraxin-2 and published its Phase II results for PRM- Now, with Roche buying Promedior, the platform after Bristol-Myers opted out. 151 in IPF last year, the company also re- Swiss pharma will use its relatively vast Squibb paid $150m up front in August ported positive Phase II results for the can- resources to advance PRM-151 and the 2015 for an option to acquire Promedior didate in myelofibrosis in June of this year small firm’s other anti-fibrosis programs. and access its anti-fibrotic therapies. (Also and unveiled positive long-term results in “What’s great about Roche is the way in see “Bristol’s Fibrotic Game Plan: Prome- IPF in May. which they align with our programs,” Lett- dior Buy Hinges On Phase II Data” - Scrip, Before those disclosures, however, the man said, noting the acquirer’s existing 31 Aug, 2015.) PRM-151 is a recombinant US Food and Drug Administration granted presence in IPF with Esbriet (pirfenidone) form of human pentraxin-2, an endog- a breakthrough therapy designation for – one of just two drugs approved in the enous human protein that is active at PRM-151 in IPF in March, two and a half US for the disease – and its established the site of tissue damage. The therapy months after the agency and the company presence in respiratory diseases and he- and other candidates in Promedior’s pen- agreed on the Phase III clinical trial protocol matology/oncology. The company also traxin-2 platform are designed to initiate a for the biologic in the deadly lung disease. has programs in ophthalmology, which

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should support development of PRM-167. 151 pipeline. The company and the US Beyond IPF, Lettman said Promedior is PRM-151 – with its potential to treat IPF, FDA agreed to a Phase III trial protocol that putting together a clinical protocol for a myelofibrosis and beyond – fits well into is similar to the Phase II study design, with potential registrational clinical trial in my- Roche’s strategy of acquiring molecules improvement in lung function as mea- elofibrosis, which is likely to be a Phase IIb/ that could be considered a pipeline-in-a- sured by forced vital capacity (FVC) as the III study. pill, including in fibrotic diseases where primary endpoint. Other functional gains “We are also pursuing other indica- novel agents may be able to reverse organ will be secondary endpoints, with empha- tions for PRM-151, such as non-alcoholic damage. Global immunology business de- sis on six-minute walk distance (6MWD), steatohepatitis (NASH) or kidney dis- velopment head Patrick Schleck told Scrip which was significantly improved for IPF ease; we’re still in the process of deter- in an interview in June that Roche is look- patients in Phase II. mining what’s the ideal indication,” he ing for opportunities where the company The 6MWD data may prove controver- explained. “But the good news is given and its partners “may be able to go faster, sial as clinicians expressed ongoing skep- how many patients we’ve treated and broader and to multiple indications than ticism regarding the meaningfulness of the fact that we now have patients on perhaps either one of us would have been the endpoint when results for PRM-151 151 beyond five years, we have a nice able to do on our own.” and other IPF candidates were presented quick path to expand the program into However, IPF remains the immediate fo- at the American Thoracic Society meeting other indications.” cus for Promedior’s multi-indication PRM- in May 2018. Published online 15 November 2019 Merck Acquires Novel Neurodegenerative Disease Target With Calporta Buy

MANDY JACKSON [email protected]

valon Ventures managing director Jay Lichter said it was Calporta’s executives “took a bunch of meetings and it just got surprising when Merck & Co. Inc. was one of the first and super-hot, and discussions with multiple parties really began to Amost aggressive pursuers of the venture capital firm’s Cal- accelerate over the summer,” he said, before two acquisition offers porta Therapeutics Inc., which is focused on neurodegenerative and three opportunities to finance the company with blue chip diseases, but the big pharma proved to be the most committed venture funds emerged. partner for the start-up’s lead program. COI Pharmaceuticals, the The two acquisition deals looked similar financially, but Mer- incubator for Avalon’s new life science companies, announced the ck was “much more committed to the target, understood the sale of Calporta to Merck for up to $576m on 13 November. target better, and had a lot more momentum behind them and Four-year-old Calporta was launched as part of Avalon’s part- focus,” Lichter said. Merck tested several of Calporta’s TRPML1- nership with GlaxoSmithKline PLC, which was designed to fund targeting compounds over the summer to confirm that the up to 10 new drug development firms, with an option to buy. The drug candidates were potentially valuable drugs before recent- UK-based pharmaceutical giant opted to purchase only one of the ly closing the acquisition. eight companies the joint venture created – Sitari Pharmaceuti- The parties are not disclosing specifics about the transaction’s cals in September – leaving Avalon and COI (short for Community $576m total value, but the deal includes an upfront payment as of Innovation) to seek out partners, buyers or additional investors well as milestones fees that will be paid upon achievement of cer- for the four remaining active start-ups. tain development and commercialization goals. Calporta is developing selective small molecule agonists of a “Given the early stage of this asset, we’re extremely happy with target called transient receptor potential cation channel, muco- the way the capital lays out,” Lichter said. lipin subfamily (TRPML1). The lysosomal ion channel is a regulator of autophagy, or the process of removing waste from cells. When EARLY-STAGE PROGRAM, TRPML1 stops doing its job, fats and proteins that accumulate in BUT AHEAD OF COMPETITORS cells contribute to neurodegenerative diseases. Even though the Calporta portfolio of compounds is two years Activating the target could reestablish lysosomal processes and or so away from the submission of an investigational new drug restore cellular function with the potential to treat amyotrophic (IND) application to the US Food and Drug Administration, Avalon lateral sclerosis (ALS), Parkinson’s disease, tauopathies – including and COI believe that the company is two or three years ahead of Alzheimer’s disease – and various rare diseases, including lyso- any other companies focusing on the role of lysosome function in somal storage disorders. neurodegenerative diseases and TRPML1 activation. San Diego-based Calporta and its TRPML1 program were “Another reason why Merck was such a great partner was we shopped around at the annual J.P. Morgan Healthcare Conference thought they could get into the clinic quickly and maintain the in January in San Francisco and the company turned out to be a lead that we have against other people who are trying to pros- hot commodity, Lichter told Scrip. ecute this target for similar indications,” Lichter said.

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“Merck was much more committed to Lupin Offloads Kyowa the target.” – Jay Lichter Pharma For $525m But

Calporta has multiple different series of compounds that it has Not Exiting Japan identified since its founding in 2015 and the company has filed for VIBHA RAVI [email protected] patents on two of them. “While we potentially have a clinical candidate in the group that upin Ltd. has finally decided to offload to a local private- eq we’re sending over, Merck will use their own internal abilities to uity group its Japanese subsidiary Kyowa Pharmaceutical In- rank the different series and the compounds within each of those Ldustry Co. Ltd., that had run into troubled waters on account series,” Lichter said. “If we were doing it ourselves, we would be of increasing competition in the local generics segment and the looking at orphan-type diseases like Batten disease, but [because prospect of government-driven price cuts becoming an annual of] the fact that the lysosome loses function and is less efficient at feature in Japan. clearing debris, a variety of diseases come to mind.” The deal is also indicative of private equity’s rising interest in Given the broad scope of diseases with a connection to al- the Japan pharma sector, following on from other major deals tered TRPML1 function, “I think the fellow who figured this out this year. will get the Nobel prize, because it is a really important path- Recovering four and a half times its initial Investment, Lupin way for a bunch of different diseases,” he said. Calporta’s work has sold its 99.82% stake in Kyowa to Plutus, a portfolio com- is based on research licensed from the lab of Haoxing Xu at the pany of Unison Capital Partners IV, LPS and Unison Capital Part- University of Michigan. ners IV (F). L.P., in a deal valuing Kyowa at JPY57.36bn ($525m) Other companies also are looking at lysosome dysfunction or INR37.02bn. Established in 1998, Unison Capital is an inde- and lack of autophagy and their connection to neurodegenera- pendent Japanese private equity firm with operations in Japan, tive diseases, including Lysosomal Therapeutics Inc. and Casma South Korea and Singapore. Therapeutics Inc. The divested business recorded revenues of INR 9.34bn Lysosomal Therapeutics emerged with $20m in series A ven- (JPY14.24bn) in the first half of this fiscal year and INR18.6bn ture capital in 2015 to discover treatments for neurodegenerative (JPY28.33bn) last fiscal year. indications, including Parkinson’s disease. (Also see “G1, Revolu- Lupin indirectly held the stake in Kyowa through its wholly- tion lead $116m in new VC funding “ - Scrip, 5 Feb, 2015.) Casma owned subsidiary Nanomi B.V. in Netherlands. Founded in 1954, launched in mid-2018 with a $58.5m series A round and a focus the Japanese firm develops, manufactures and sells branded and on boosting autophagy in lysosomal storage disorders, liver and generic pharmaceuticals in the Japanese market. muscle diseases, inflammatory disorders and neurodegeneration. Lupin acquired a majority ownership in Kyowa in 2007 and the More recently, Arkuda Therapeutics closed a $44m series A operation is currently the fifth-largest generics player in Japan, ac- round on 7 November to target progranulin as a means for im- cording to IQVIA September data. proving lysosomal function in the treatment of neurodegenera- With the acquisition, Unison gains a diverse product lineup tive diseases. that covers cardiovascular, gastroenterology and other segments with a particularly strong presence in the CNS/neurology space MERCK AS AN IDEAL NEUROSCIENCE PARTNER? where key products are promoted under the AMEL brand. Kyowa At first glance, neurodegeneration may not seem like a natural fit has manufacturing facilities in Sanda and Tottori, and a research for Merck’s portfolio, given its primary commercial focus on the center in Osaka. immuno-oncology blockbuster Keytruda (pembrolizumab). (Also Lupin officials separately said that Unison would retain over 700 see “Merck Confident In Keytruda’s Dominance In Lung Cancer, De- employees at Kyowa. spite Competitors’ Data” - Scrip, 29 Oct, 2019.) However, the company has developed and sold multiple thera- LUPIN CONSIDERS ACQUISITIONS pies in the neuroscience field for several decades – on its own and AS COFFERS SWELL with partners – including Maxalt (rizatriptan) for migraine head- Post this deal, the net debt of Lupin will stand at a reduced aches, Bridion (sugammadex) for the reversal of neuromuscular INR11.3bn, compared to INR43.6bn as of 30 September 2019. blockade induced by anesthesia, and the insomnia medication “This transaction enables us to strengthen our balance sheet Belsomra (suvorexant). It also has early clinical and preclinical as- and provide growth capital for our strategic priorities in markets, sets that it is developing on its own or with partners, including the particularly our growth markets US and India. We are exploring Phase II schizophrenia candidate MK-8189. China…we’re looking at our specialty and complex generics port- Merck also has had some high-profile failures in neurodegenera- folio to see if it makes sense to enter but haven’t determined if it tive diseases, including the BACE inhibitor verubecestat, which like does right now,” said CEO Vinita Gupta. several other late-stage drugs targeting amyloid clearance failed in The company is considering both organic and inorganic in- a Phase II/III clinical trial. vestment opportunities in India, noted managing director Published online 13 November 2019 Nilesh Gupta. While there is currently “no deal flow” domestical-

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ly, the company is interested in multiple PRIVATE EQUITY, therapy areas. OTHER INTEREST “As a company, our big areas are cardio- The new deal signifies continuing interest vasculars, diabetes and inhalation so the from the global private equity sector in intent would be to look for assets in that opportunities in Japan pharma, coming space but we are also building presence in after The Blackstone Group’s major deal India in areas like dermatology, ophthal- “We remain committed earlier this year to acquire private special- mology and urology,” he added. The com- ty group Ayumi Pharmaceutical. Unison pany also intends to focus on the “right to advancing our Capital was a co-owner of Ayumi. (Also see assets” in the US, particularly specialty and “Blackstone Bets On Pharma In First Japan more accretive assets. complex generics, Buy, But Why?” - Scrip, 26 Mar, 2019.) Expanding on the logic for exiting Kyo- biosimilars and specialty In other deal activity, Sandoz Interna- wa, Nilesh Gupta said price cuts in Japan tional GMBH has also just said it will pay put pressure on the company and as a portfolio globally, up to €400m ($441m) to acquire the Japa- pure-play generics player, the manage- nese operations of Aspen Pharmacare ment was faced with a strategic choice including in Japan.” Holdings Ltd.(Also see “Sandoz To Acquire “whether we wanted to differentiate and – Nilesh Gupta Aspen’s Japanese Operations “ - Generics build a different kind of entity in Japan Bulletin, 11 Nov, 2019.) while also trying to build that in the US For major PE groups, the intention is and trying to grow in markets like India – it usually to build up and strengthen the just seemed like a dilution of focus for us.” management of acquired businesses Accounting for nearly 80% of Lupin’s before exiting through divestment to APAC business, revenues from Japan cept, its biosimilar version of Amgen Inc.’s another owner. They apparently see op- were INR5.1bn in the second quarter, Enbrel, in Japan. As the second approved portunities in companies that may be flat over the same period last year and Enbrel biosimilar in Japan after Mochida struggling with the current challenging nearly 9% lower than the first quarter. It Pharmaceutical Co. Ltd. and LG Chem ’s policy and regulatory environment, and contributed nearly 12% to consolidated product, the opportunity from this drug whose owners may be looking to divest sales for the quarter. Company officials seems attractive. and restructure. said they are hopeful of making up for Lupin also has a co-marketing arrange- Blackstone has indicated that it is plan- this reduction in revenue over the course ment with Yoshitomi for Bipresso (que- ning to spend up to JPY500bn across of the next year or so. tiapine fumarate), a specialty drug to treat industries in Japan under a new Asia-fo- bipolar depression, that has been licensed cused fund, marking interest in a market PLANS TO EXPAND MARKETING from Astellas Pharma Inc. where there has traditionally been little PE IN JAPAN investment in pharma. While Lupin is exiting the generic oral KYOWA TO MOVE ‘BEYOND Unison was set up in 1998 by three for- solids business in Japan through the DRUGS’ UNDER UNISON mer employees of Goldman Sachs Japan, Kyowa divestment, it will continue to Tatsuya Hayashi, founding partner of Uni- and supports mid-cap companies across maintain a presence in the country son, said, “We are delighted to welcome multiple sectors formed as spin-offs or through marketing partnerships as well Kyowa into our portfolio and support its through management buy-outs. In 2017, as remaining a supplier to Kyowa even next phase of growth, both in its existing Astellas Pharma Inc. divested a group of after Unison acquires it. business, as Kyowa continues to center older products to LTL Pharma, a new To- “We remain committed to advancing its strategy of strengthening its hybrid kyo-based firm wholly owned by Japan our complex generics, biosimilars and (brand/generics) pharma model in Japan, Established Medicines Corp., an entity set specialty portfolio globally, including in and in expanding its influence in the CNS up under Unison funds. Japan. Between now and closing [the space to beyond drugs.” Jefferies, which acted as sole financial deal] the intent is to close product sup- It also plans to expand the product and adviser to Union Capital, noted that the ply agreements for the products that we service portfolio beyond drugs with sup- Kyowa deal is the largest divestment so far already do from India – we will selectively port from Unison’s healthcare ecosystem by an Indian pharma firm. look at other opportunities apart from of researchers, advisers and strategic part- (With contributions from Ian Haydock in Unison as well and leverage them,” Nilesh ners, including Unison’s own healthcare Tokyo.) Gupta said. portfolio companies. Published online 12 November 2019 Lupin will continue looking for mar- Kyowa will continue its existing R&D keting partnerships in the specialty and manufacturing business ties with Lupin Q2 Hit By drugs as well as complex generics seg- Lupin and will look to further develop US Settlement, Japan ments, he added. business opportunities together in Japan, Injectables Selloff: It has already partnered with Nichi-Iko including “other avenues” in the Japanese https://bit.ly/2XqufUb Pharmaceutical Co. Ltd. to launch etaner- healthcare market, it said.

8 | Scrip | November 22, 2019 © Informa UK Ltd 2019 DEALS

No Alarm At Almirall Despite Stake Sale

KEVIN GROGAN [email protected]

ews that the founding family of Seysara is taking market share off ge- the US in early 2020 and soon after in Almirall SA is selling off a stake nerics and “the utility and effectiveness Europe. The submissions will be based Nin the company has caused the of having an oral antibiotic, approved for on two Phase III studies where complete Spanish firm’s stock to fall 10%, despite a wide age range of patients, continues clearance of actinic keratosis lesions was the company posting a reasonable set of to receive excellent feedback from KOLs observed in 44% and 54% of the patients quarterly results. and patients,” Guenter said. “Our promo- treated with tirbanibulin compared with The markets reacted with concern tional education program has reached 5% and 13% for those on placebo. when it was announced that Grupo Cor- over 2,500 providers, and this positive “We strongly believe that we have a very porativo Landon, a vehicle for the Gallardo feedback is captured in the data with over competitive product,” he stated, claiming family, has sold €167m of shares in Almi- 4,200 dermatologists having prescribed that peak sales potential is over €250m “on rall, which represents a 6.3% stake. The Seysara in the third quarter.” the basis of the profile as it stands today private placement involved the sale of 11 As for psoriasis, the IL-23p19 inhibitor Il- [and] there is potential to further improve million shares priced at €15.25, a discount lumetri achieved sales of €13m during the the profile”. of 10.2% to the company’s closing price first nine months of 2019 and in the third Almirall has also kicked off twin Phase on 12 November. quarter was launched in Austria, Switzer- III trials of lebrikizumab ahead of schedule This still leaves the Gallardo family with land, the Netherlands and Spain. Guenter and 800 patients will be enrolled; top-line a 59.7% stake in the Barcelona-based said he was pleased with the initial uptake results for the 16-week induction period group and the sale was explained as be- of Ilumetri in Germany, where a price has will be expected in first half of 2021. The ing a way of “enhancing the liquidity of been agreed “in line with our expecta- company got hold of the IL-13 antibody the stock and promoting investor visibil- tions” at €12,000 a year. in a licensing deal with Dermira Inc. ear- ity and diversification of the shareholder He added “Our commercial teams have lier this year. (Also see “Almirall Extends base.” Analysts at Sabadell said the news been: very active this quarter, continuing Dermatology Reach With Dermira Lebriki- was a negative, given the level of discount the extensive European rollout campaign. zumab Deal” - Scrip, 12 Feb, 2019.) (Also the shares were offered at, adding that National healthcare systems have pub- see “Dermira’s Lebrikizumab Data Set Up it could lead to doubts mid-term about lished positive comments on the use of Atopic Dermatitis Showdown With Dupix- Almirall’s prospects. the product, including NICE in England ent” - Scrip, 18 Mar, 2019.) However the majority shareholders said and the national Spanish authorities.” they wished to “reiterate their support and Skilarence sales were €24m and Guent- ANALYSTS ENTHUSED confidence in the company and their in- er said the oral formulation was the lead- Analysts at Jefferies issued an investor tention to remain as shareholders.” In May ing product in the dimethyl fumarate note on 11 November saying sales were last year, the Gallardo family increased market in Germany with over 80% mar- line with expectations, while earnings its stake in Almirall to 66.64%, acquiring ket share for the 30 mg initiation pack for before interest, tax, depreciation and the 8.45% holding held by Daniel Bravo, new patients. It is also selling well in the amortization of €236.5m were better than founder of Laboratorios Prodesfarma, Netherlands and rollout is expected to consensus, helped by “continued impres- which merged with Almirall in 1997. continue in Portugal, Poland and Czech sive cost control.” The broker added that The timing of the sale raised eyebrows Republic shortly. feedback from KOLs and a Jefferies US given that Almirall has just unveiled re- R&D chief Bhushan Hardas claimed dermatology survey “underscore our en- sults for the first nine months of 2019 that Almirall made significant progress in thusiasm” for Illumetri and Seysara. which showed healthy sales growth. Rev- its late-stage pipeline during the quarter, Their enthusiasm is such that Jeffer- enues were up 17% to €683m, driven by noting that a cutaneous spray solution ies’ forecasts are higher than Almirall’s its psoriasis franchise of Skilarence (di- of finasteride for androgenic alopecia own, projecting €260m EU peak sales methyl fumarate) and Ilumetri (tildraki- and terbinafine for the topical treatment for Illumetri versus the company’s target zumab), as well as the acne treatment of onychomycosis were filed with the of €200m, and Seysara sales in the US of Seysara (sarecycline). European Medicines Agency. However $200m compared with Almirall’s forecast CEO Peter Guenter said the firm was the company’s hopes are pinned on of $150-$200m. very encouraged by the initial uptake of two late-stage products; tirbanibulin for The analysts are more conservative Seysara, which was launched in the US in actinic keratosis and lebrikizumab for on tirbanibulin, forecasting €135m January 2019 following approval by the atopic dermatitis. peak sales, notably short of Hardas’s Food and Drug Administration in October Hardas said that for tirbanibulin, “we forecast, while they think that lebriki- last year. Sales for the third quarter were have recurrence data which is the last zumab will get to €400m, shy of Almi- €7m, making it the number one branded piece of information we require for the rall’s €450m aim. product in the US oral acne market. regulatory filing,” which is scheduled in Published online 14 November 2019

scrip.pharmaintelligence.informa.com November 22, 2019 | Scrip | 9 COMPANIES

Sanofi Pasteur Head Loew On The Vaccine Unit’s Future Growth Drivers BRENDA SANDBURG [email protected]

anofi’s vaccine unit – Sanofi Pas- teur – is poised to launch new prod- Sanofi Pasteur’s pipeline includes next- ucts that are expected to keep the generation meningococcal vaccine and S monoclonal antibody and vaccine for RSV business growing while the French pharma is in the midst of a business transition, with a new CEO at the helm. A quadrivalent high-dose influenza vaccine Fluzone is launching now, and the company hopes to launch its next-generation meningococcal vaccine MenQuadfi in April. Sanofi Pasteur exec VP David Loew talked to Scrip in an interview in New York about the upcoming launches and the vaccines pipeline candidates that could be future growth drivers. “Vaccines is a thriving business. We have really good growth rates,” Loew said. “It is a Sanofi is in the midst of a big leader- quadrivalent formulation pending at the key strategic lever for the group, and we ship transition; CEO Paul Hudson took the FDA with an action date in February. are well positioned being one of the four helm on 1 September. Hudson hasn’t yet Sanofi has dominated the flu vaccine top vaccine companies in the world.” laid out his growth strategy to investors, market in the older population. In the 2018- Sanofi was the third-ranked vaccines but he is expected to make some changes 2019 influenza season, the firm reported maker based on 2018 vaccines revenues, as the company’s big diabetes business that nearly two-thirds of US adults 65 years behind GlaxoSmithKline PLC and Pfizer comes under pressure. and older who received an influenza vac- Inc. Sanofi Pasteur generated €5.12bn It’s not clear what, if any, changes could cine received Fluzone high-dose. The com- ($5.64bn) in 2018, growth of 2.4%. But the be in store for Sanofi Pasteur, which made pany has also completed Phase II studies of company hasn’t had a breakout block- up about 15% of Sanofi’s 2018 revenues. Fluzone high dose for use in babies. buster vaccines star like GSK has had with Lowe said the business also receives about The company also sells Flublok quad- the shingles vaccines Shingrix, Pfizer has 15% of Sanofi’s R&D budget. rivalent, the only FDA-approved recom- had with Prevnar and Merck & Co. Inc. has binant protein-based influenza vaccine, had with Gardasil. EXPANDING INFLUENZA which it obtained with its 2017 acquisition Sanofi Pasteur’s modest growth has VACCINE PROTECTION of Protein Sciences. been driven by influenza vaccines (Vaxi- The influenza vaccines franchise is the grip, Fluzone, Flublock) and diphtheria/ biggest revenue generator for the unit. In NEXT-GENERATION polio/pertussis/hib vaccines (Hexaxim/ November, the US Food and Drug Admin- MENINGOCOCCAL VACCINE Hexyon, Pentacel, and Pentaxim). Sales istration approved a biologics license ap- Its next near-term vaccine is MenQuadfi, a for the third quarter were down 9.8%, but plication for Fluzone high-dose quadriva- successor to Sanofi’s meningococcal quad- Sanofi attributed the decline to a delay in lent inactivated influenza vaccine for use rivalent vaccine Menactra, which generated influenza vaccine strain selection by the in adults 65 years and older. The trivalent €608m in 2018. Sanofi announced in June World Health Organization and a later formulation containing three influenza that the FDA had accepted the biologics li- shipment of the vaccine. strains had been approved in 2009. The cense application for the vaccine candidate. Loew said the market conditions are ripe new product, available for the 2020-2021 It hopes to receive approval in April 2020. for future vaccines growth as health au- flu season, will contain an additional influ- “Key opinion leaders are very excited thorities around the world acknowledge enza B strain. about this one and we believe it’s going to that vaccines have been under-leveraged. Fluzone was designed specifically for be the best in class,” Loew said. “They realize, when you are in a re- the older population, providing four times He noted that studies have shown im- source-constrained environment, vac- more antigen. Of the nine licensed flu vac- munologically improved responses with cines actually deliver the biggest impact cines in the US, only Fluzone high-dose MenQuadfi versus the currently available in terms of health economics and public and Seqirus’ Fluad, a trivalent formula- quadrivalent options, including Menactra benefit. It’s the most effective intervention tion, were developed for those 65 years and GlaxoSmithKline’s Menveo. after clean water in medicine,” Loew said. and older. Seqirus has an application for a TURN TO PAGE 12

10 | Scrip | November 22, 2019 © Informa UK Ltd 2019 ScripHEADLINE NEWSAwards Finalists 2019

Executive of the Year – Executive of the Year – private and <$1bn market cap >$1bn market cap

This Scrip Award is designed to acknowledge excellence in This Scrip Award is designed to acknowledge the leadership of smaller and private pharmaceutical and excellence in the leadership of larger pharmaceutical biotechnology companies. and biotechnology companies.

RYAN CAWOOD, FOUNDER AND CEO DAVID CHANG, PRESIDENT, CEO AND CO-FOUNDER OF OXFORD GENETICS OF ALLOGENE THERAPEUTICS Ryan Cawood has successfully overseen six new licensing deals David Chang’s achievements include: growing the company to more in the last year for Oxford Genetics’ new scalable gene therapy than 150 employees; taking it public in an IPO that was the second manufacturing technologies, establishing the firm within the biotech largest biotechnology IPO of 2018; expanding the leadership team; industry. The company has enjoyed 300% revenue growth in the and overseeing the creation of a pipeline of CAR T cell therapy 2018/19 financial year, and built an impressive collection of long- candidates. Allogene has now moved its first product candidate into term partners with a business model that allows for scalability and clinical development with the initiation of a Phase I study. licensing platforms that can be used across the industry. JEFF JONAS, CEO OF SAGE THERAPEUTICS JOHN DAWSON, CEO OF OXFORD BIOMEDICA Jeff Jonas has taken Sage from a 30-employee startup to a highly John Dawson has been CEO of Oxford Biomedica since October respected biotech with nearly 800 employees, a first-of-its-kind 2008 and has been instrumental in driving the success of the treatment, and market capitalization approaching $9bn. He has led group’s business model, which is built on the world-leading the formation of Sage’s three central nervous system franchises LentiVector gene delivery platform, and is based on over 20 years of – depression, neurology and neuropsychiatry – with drugs in pioneering science and process development. development aiming to shift in how mental health is thought about and treated. HOSSEIN A GHANBARI, FOUNDER, CHAIRMAN, AND MANAGING DIRECTOR OF ADVANCED RESEARCH FOR SIGGI OLAFSSON, CEO OF HIKMA PHARMACEUTICALS SENSEI BIOTHERAPEUTICS Siggi Olafsson joined Hikma following a challenging 2017, and After a career in which he was involved in the development of committed to restructuring its global R&D function, aligning its Leupron and Survanta and a number of CNS diagnostic tests, resources with the largest market opportunities across the MENA Hossein A. Ghanbari has, at Sensei, developed cell-, tissue-, gene- region, and reinforcing the company’s position as “partner of and serum-based cancer tests for use in precision medicine. He has choice”. Hikma delivered strong results in 2018, with group core conceived and developed anticancer drugs including an antibody, revenue up 7% to $2.76bn, operating profit up 19%, and net debt ADC and CAR-T, as well as a therapeutic cancer vaccine now entering was reduced. Phase II, all targeting ASPH. MENELAS PANGALOS, EVP AND PRESIDENT, KEVIN LEE, CEO OF BICYCLE THERAPEUTICS R&D BIOPHARMACEUTICALS, ASTRAZENECA During the past 12 months, Kevin Lee has accelerated Bicycle’s Mene Pangalos has been instrumental in turning AstraZeneca’s evolution and propelled it into the next level as a newly public, R&D around to a point where new medicines formed a big part in NASDAQ-listed biotech company, a first for a Cambridge, UK- the company’s return to growth in 2018. Pangalos has been a key headquartered company. Bicycle also extended its therapeutic reach driving force behind a near five-fold increase in AstraZeneca’s R&D beyond oncology into neuroscience and anti-infectives, announcing success rate since 2012 by instilling a culture shift that brought a new partnership with Dementia Discovery Fund and securing two back scientific rigor to the forefront of the discovery process and seed grants from Innovate UK and SBRI. implementing the company’s ‘5R Framework’.

AMY SCHULMAN, CO-FOUNDER AND CEO ANDREW PLUMP, PRESIDENT, RESEARCH & OF LYNDRA THERAPEUTICS DEVELOPMENT OF TAKEDA PHARMACEUTICALS During the year, Lyndra released positive data showing the viability Andy Plump led his R&D organization through one of the largest of its ultra-long-acting oral dosage form, announced a Notice of industry transactions of the year when Takeda agreed to acquire Allowance from the United States Patent and Trademark Office and Shire for $62bn. The complementary nature of the two companies’ secured a $60m series B financing round. This progress was made pipelines was central to the agreement, and he has been possible because of Amy Schulman’s expertise in drug development, responsible for reviewing and prioritizing every core R&D project commercialization and her leadership and ability to develop a to identify and accelerate projects with the potential to become thriving startup culture. transformative medicines.

RAMAN SINGH, PRESIDENT AND CEO, MUNDIPHARMA ONNO VAN DE STOLPE, FOUNDER AND CEO ASIA-PACIFIC, LATIN AMERICA, MIDDLE EAST AND AFRICA OF GALAPAGOS Raman Singh has led Mundipharma’s year-on-year growth of 40% Under Onno van de Stolpe’s leadership, in 2018 Galapagos to expand a market reach which now comprises 128 countries. published its first ever Phase III results, for filgotinib in rheumatoid He guided the completion of 40 deals to expand Mundipharma’s arthritis, secured two important business development deals and offering in emerging markets and helped spearhead innovation raised €300m. In the 20 years since its formation, he has built a from its regional headquarters in Singapore. Singh’s profile as company that is now worth over €6bn and, together with partner a healthcare industry thought leader has grown as he has led Gilead, is preparing to bring its first medicine to the market. Mundipharma to be one of the world’s best employers.

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CONTINUED FROM PAGE 10 is developing a monoclonal antibody, Loew noted that while the mAb can Menactra is indicated in the US to prevent nirsevimab or MEDI8897, to prevent RSV provide immediate protection, it takes meningococcal disease caused by Neisseria infection in infants in the first RSV season. time for the immune system to ramp up meningitidis serogroups A, C, Y and W-135 Loew said the company conducted a following vaccination. A vaccine must be in people aged nine months through 55 Phase IIb study in 1,453 babies and was injected directly into the baby or into the years. Menactra does not prevent N men- struck by the results when it was unblind- pregnant mother. Loew noted that there ingitidis serogroup B disease. MenQuadfi ed. Infants had a 70% reduction in getting are still lots of uncertainties when it comes is intended to further expand protection sick and an 80% reduction in hospitaliza- to maternal immunization – a new frontier against A, C, W, and Y serogroups from in- tion. Sanofi expects the results of the in the vaccines space. For one, it’s unclear fants to older adults worldwide. study to be published in the beginning how a mother’s antibodies will be passed In Phase II and III trials, Sanofi said Men- of 2020. onto a delivered baby, and if the baby is Quadfi was shown to be well-tolerated Loew explained that the monoclonal born six months before the RSV season, and demonstrated non-inferior seropro- antibody is intended to be injected at the antibodies may no longer provide tection rates for all four serogroups across birth or before the RSV season starts, typi- protection. age groups when compared to other li- cally in October, to provide protection for censed quadrivalent meningococcal vac- the first six months of the season. A vac- PEDIATRIC 6-IN-1 VACCINE cines. And in individuals two years of age cine could be given two to four months LAUNCH DELAYED and older, it elicited an immune response later for longer term protection against Sanofi has several other vaccine candi- across all four serogroups. the virus. dates in the pipeline, including an HIV vac- In the US, Sanofi is initially seeking an “We believe the antibody is really going cine in Phase II and a herpes simplex virus indication for children two years of age to be the one changing the dogma of how type two therapeutic vaccine in Phase I. and older, adolescents and adults over 55 you protect children,” Loew said. In December 2018, FDA approved years of age. Currently, there is no FDA- Loew noted that 33 million babies Vaxelis, a pediatric hexavalent combina- approved meningococcal vaccine for the around the world get the disease and a tion vaccine to prevent diphtheria, teta- latter age group. Additional Phase III tri- large number are hospitalized. The virus nus, pertussis, poliovirus, hepatitis B and als are being conducted to support an causes bronchiolitis and a build-up of Haemophilus influenzae type b that has expanded indication for infants from six mucus in the lungs that makes breathing not yet launched. The vaccine was devel- weeks of age. difficult. Loew knows from personal expe- oped under a joint venture partnership But meningitis vaccines have not got- rience how frightening the condition can between Merck and Sanofi. Sanofi said ten as much attention as some other new be as his eldest daughter had RSV after they are working to maximize production universally accepted vaccines. There are she was born. of Vaxelis to build a sustainable supply to approximately 350 to 500 cases of inva- There are currently no specific treat- meet anticipated US demand, and there- sive meningococcal disease in the US ev- ments for RSV and no vaccine, though fore the vaccine will not be commercially ery year, which Sanofi said is a dramatic several are in development – including for available prior to 2021. reduction from the thousands of cases both pregnant women and infants – and it The company has another six-in-1 vac- experienced prior to 1995. could be a competitive space. The mono- cine, Shan 6, in Phase III that is to be sold in clonal antibody is on track to be first to emerging markets. That product includes CHANGING RSV PROTECTION market, according to Sanofi. It is in Phase whole cell pertussis vaccine rather than Longer-term, a prophylactic for respirato- III development, while Merck’s RSV mAb is the acellular pertussis in Vaxelis. Loew not- ry syncytial virus (RSV) is moving through in Phase I. Sanofi is also developing an RSV ed that acellular vaccines are better toler- the pipeline. Under a co-development and vaccine, which is in Phase I; others, includ- ated than whole cell vaccines but need to co-commercialization agreement with As- ing Pfizer and GlaxoSmithKline, are further be boosted and are more expensive. traZeneca PLC’s MedImmune unit, Sanofi along with their vaccines. Published online 14 November 2019 Staying Diversified, Bayer Sees Opportunities In Digital Innovation

ANDREW MCCONAGHIE [email protected]

ayer AG has been struggling in recent The purchase of crop science com- claims that Monsanto’s Roundup weed- years, with poor returns to investors pany Monsanto for $62bn in 2018 was killer causes cancer. (Also see “Roundup Band underperforming divisions drag- meant to help revive Bayer’s fortunes, Lawsuits Overshadow Pharma Growth At ging the conglomerate down, with its share but it has found itself fighting thou- Bayer “ - Scrip, 30 Oct, 2019.) price now half what it was five years ago. sands of potentially multi-billion dollar TURN TO PAGE 14

12 | Scrip | November 22, 2019 © Informa UK Ltd 2019 HEADLINE NEWS

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CONTINUED FROM PAGE 12 This is currently the biggest cloud hanging over the company, but its CEO Werner Baumann is determined to turn the business around, and retain its diversified structure. This encompasses crop science, animal health, consumer health and pharmaceuticals. Staying diversified goes against the current trend in the pharma sector, where many companies have already shed animal health and consumer health divisions, Stefan Oelrich, president of Bayer’s such as Novartis AG and Pfizer Inc. or, as in pharma division at the FT conference. GSK’s case, in the process of doing so. Stefan Oelrich, president of Bayer’s pharmaceutical division was in London ing investments – a $250m financing of friendly user interface. We’re going to sup- this week to talk to investors and present Century Therapeutics and the acquisi- port that so the developers can start with at the FT Pharmaceutical and Biotechnol- tion of BlueRock Therapeutics, two com- diabetes and expand from there.” ogy Conference. panies developing next generation cell Bayer’s direct investment in a patient- He took to the stage immediately after therapy technologies. facing tech makes it rare among big phar- GSK’s chief executive Emma Walmsley had Another more unusual investment is in ma companies, but Oelrich says the sector restated her commitment to spinning out One Drop, a digital therapeutic solution has viewed digital as purely a marketing its consumer health division by summer for diabetes and other chronic conditions. tool for too long. He believes patient-facing 2022 –GlaxoSmithKline PLC’s new-found It has become one of the fastest grow- digital services will be a vital component in momentum also making this approach ing diabetes management solutions the disruption of current healthcare silos look most appealing. worldwide, used by nearly 1.5 million peo- and the creation of a new ecosystem - from Bayer remains serious about its diversi- ple in 195 countries, and uses AI and one- which pharma might find itself locked out. fied approach, however. Oelrich pointed to-one coaching to help patients manage This is a field that Oelrich has been ac- to the company’s more than 150 years as their conditions. tive in since before he joined Bayer in Sep- a conglomerate, but also wanted to stress In September, Bayer led a $40m series tember 2018, having pioneered Onduo, a that it was embracing new ways of getting B financing of the company, and entered similar diabetes-focused alliance between ahead in the innovation race. into a licensing deal to use One Drop’s Google and his previous company Sanofi. Bayer’s pharma division needs to re- platform in its global bio-digital efforts He believes pharma should not hold stock its pipeline as its two big earners, in areas such as oncology, cardiovascular back from these new models. wet AMD therapy Eylea (aflibercept) and disease, and women’s health. “If we can reach across through digital blood thinner Xarelto (rivaroxaban) are Oelrich said the cost of managing dia- means increasing transparency, tapping entering their final years, US patents expir- betes and cardiovascular disease was into the lack of efficiency that exists in ing in 2020 and 2024 respectively. enormous – around 20% of US healthcare each of the [healthcare] silos, I think we Oelrich has good news to report on costs – and that it’s logical that healthcare could be a significant player.” that front this year, with the approval of systems will embrace digital health solu- However there are lots of entrants to this two new oncology drugs, ‘tumor agnostic’ tions to these problems. emerging business model, where there are cancer treatment Vitrakvi (larotrectinib) He pointed to Livongo, the digital health sure to be winners and losers. This will be and Nubeqa (daroluramide) for prostate management platform which achieved a decided by how user-friendly consumers cancer co-marketed with Orion. (Also see successful initial public offering (IPO), giv- find these services, and how much they “Bayer’s Vitrakvi Is EU’s First Tumor-Agnos- ing it a $3.4bn market cap. can demonstrate an impact on controlling tic Treatment “ - Scrip, 24 Sep, 2019.) “US healthcare costs [are] roughly $3tn. chronic conditions and healthcare costs. But Bayer has been looking for ways Take 20% of that,” said Oelrich, and it was There is no guarantee that any of these to fast-track its innovation, and perhaps no surprise that Livongo commanded digital platforms will truly take off and not surprisingly for a conglomerate, a few such a huge IPO. change the paradigm. However, for Bayer years ago spawned a new unit solely fo- He said One Drop could compete with it represents a relatively small investment cused on cutting-edge innovation. and go one better than Livongo, provid- and risk compared to the multi-billion Called ‘Leaps’ the division is an attempt ing a consumer-friendly platform and sup- dollar bets it and its peers place in phar- to go one stage further than the traditional plying blood glucose strips and meters via ma R&D – and a field which the German pharma venture arm, by funding innovative a monthly fee. company believes could be a diversifica- technologies across animal health, consum- “It’s very similar to some of the other tion which could help sustain its growth er health, crop science and pharma. products such as Livongo, only I think with in the future. Leaps has already made some promis- cooler devices and a much more patient- Published online 13 November 2019

14 | Scrip | November 22, 2019 © Informa UK Ltd 2019 REGULATORY

Amarin Heads Into Vascepa Expansion Labeling Talks After Positive US FDA Panel Review SUE SUTTER [email protected]

marin Corp. PLC could be facing as 15m US patients, according to compa- label would not say ‘primary’ vs ‘secondary’ extensive labeling negotiations ny estimates. and FDA could work a label that just says Awith the US Food and Drug Ad- Vascepa, a purified ethyl ester of eicosa- established CV disease and let docs use it ministration given that an advisory com- pentaenoic acid derived from fish oil, has in patients deemed relevant based on the mittee’s strong endorsement of a cardio- been approved since July 2012 for the study (although payors might limit it).” vascular risk reduction claim for Vascepa (icosapant ethyl) came with misgivings about the appropriate target population for the triglyceride-lowering drug. On 14 November, the Endocrinologic and Metabolic Drugs Advisory Commit- tee unanimously recommended approval of Vascepa to reduce the risk of CV events based on the results of the 8,179-patient REDUCE-IT outcomes trial. However, the 16-member expert panel A US FDA panel gave a was more divided on the target popula- unanimous thumbs up to expanding Vascepa’s label. tion for the new indication. Ten members favored approval for secondary prevention in patients with exist- narrow indication of reducing triglyceride Yee noted that professional society ing CV disease and primary prevention in levels in adults with severe (≥500mg/dL) guidelines that recommend Vascepa’s use diabetics with additional risk factors for hypertriglyceridemia. for CV risk reduction do not differentiate be- CV disease. This recommendation was The company now is seeking approval tween primary and secondary prevention. based on the overall efficacy results from to reduce the risk of CV death, myocardial SVB Leerink analyst Ami Fadia said that REDUCE-IT, which consisted of patients infarction, stroke, coronary revasculariza- while a vote in favor of approval was likely with established CV disease (70%) and tion, and unstable angina requiring hos- expected following the release of the diabetics with at least one additional risk pitalization as an adjunct to statin ther- agency’s briefing documents two days factor for CV disease (30%). apy in adults with elevated triglyceride earlier, “we also believe the AdCom was However, four panelists strongly op- levels (≥135mg/dL) and other risk factors open minded about an indication for use posed extending the claim to the primary for CV disease. in primary prevention.” prevention setting because they did not “We look forward to anticipated label- “However, the AdCom did not hammer believe efficacy had been demonstrated ing discussions with the FDA, and we con- out many specifics on inclusion criteria for in this lower risk population, while the tinue to prepare for the launch of Vascepa primary prevention, so we believe Ama- remaining two panelists suggested they assuming FDA approval of our sNDA on or rin will be in for a robust discussion with were on the fence. before the target PDUFA date of Decem- the FDA on just how the indication could Even if the approved indication were ber 28,” the company said. read,” she said. to encompass primary prevention, the Analysts were upbeat following the Fadia estimates the sNDA approval panel’s feedback and agency reviewer panel review. In a same-day note, Jeffer- could increase Vascepa’s total market concerns about a disconnect between ies analyst Michael Yee said the 16-0 posi- population from approximately 600,000 the proposed indication and the RE- tive vote for approval “is most important patients to approximately 10m, with DUCE-IT study population mean label- although predictably there was a (mixed) sales potentially exceeding $4bn at peak ing could be more restrictive than Ama- discussion about labeling. Our thesis and in 2028. rin has proposed. valuation are not based on specific ‘de- Jeffries’ Yee estimates 5m-15m patients tails’ of a label as we think docs will use would meet the REDUCE-IT enrollment ON THE BRINK OF MARKET this widely across patients.” criteria and “even just 1m patients on ther- EXPANSION On the panel’s debate over whether the apy would be $2.5bn in sales in USA.” The advisory committee vote puts Amarin primary prevention population should be Vascepa revenues for the first nine on the brink of a huge market expansion included or whether labeling should be months of 2019 were $285.3m, up 89% for its only commercialized drug, poten- limited to secondary prevention only, Yee over the prior year period. Amarin is in the tially opening the door to use by as many said: “This is nuanced because the actual process of doubling the size of its US sales

scrip.pharmaintelligence.informa.com November 22, 2019 | Scrip | 15 REGULATORY

force from approximately 400 to 800 sales dividual components of the composite “As written, the indication for Vascepa professionals in anticipation of adding the endpoint, particularly CV death; and would apply to a group of patients with broader indication. (Also see “Amarin’s ● Breadth of Amarin’s proposed indication. a potentially different benefit/risk consid- Vascepa Momentum Builds Ahead Of Next eration than those studied in REDUCE-IT,” Week’s FDA AdComm” - Scrip, 5 Nov, 2019.) DISTINGUISHING BETWEEN Sharretts said. SECONDARY AND PRIMARY Amarin asserted it took longer for ben- CONCERNS WARRANTING PREVENTION efit to emerge in the primary prevention PUBLIC DISCUSSION The FDA said REDUCE-IT provides strong group, as would be expected. The risk/ The breadth of the indication was a key is- evidence that Vascepa is beneficial in pa- benefit profile for primary prevention is sue heading into the advisory committee tients with established CV disease and most positive in diabetics at highest risk meeting, the scheduling of which came as persistently elevated triglycerides despite of CV events, and a 10-year atherosclerotic a surprise to Amarin and its investors late optimized statin therapy (the so-called CV disease (ASCVD) risk score can be used in the application’s priority review, result- secondary prevention group) and appears to identify these individuals for Vascepa ing in a three-month extension in the user to provide benefit in a subset of patients treatment, Amarin and its experts told the fee date. (Also see “An AdComm After All: with diabetes, additional CV risk factors committee. Amarin’s Vascepa Labeling Update Now and hypertriglyceridemia (the primary Panelists who favored a broad indica- Delayed By FDA “ - Scrip, 8 Aug, 2019.) prevention group). However, “it is argu- tion encompassing primary prevention The FDA review team generally able how broadly this second population did so on the basis of the robust results in agreed with Amarin’s conclusions on should be drawn,” the agency’s briefing the overall trial population, the underlying the major efficacy and safety findings document states. biology of CV disease, and the desire not to from REDUCE-IT. In the Vascepa arm, the effect size for make at-risk patients wait until they have a Compared to placebo, Vascepa reduced the primary endpoint was numerically heart attack before they can get Vascepa. the risk of the primary endpoint – a com- lower for the primary prevention group The panel’s consumer representative, posite of CV death, nonfatal myocardial in- versus the secondary prevention co- Anna McCollister-Slipp, framed the issue farction, nonfatal stroke, unstable angina hort (12% estimated risk reduction vs. as one of access. requiring hospitalization and coronary 27%, respectively), with the benefit in “Given the significant adverse events revascularization – by 25%, a statistically the lower risk group not reaching sta- that you see with statins and the signifi- significant finding in the overall REDUCE- tistical significance. cant need for cardiovascular risk reduc- IT population. Vascepa also reduced the In addition, unlike the REDUCE-IT enroll- tion, and maybe not slam-dunk data but risk of the key secondary endpoint – the ment criteria, Amarin’s proposed indica- pretty good data about potential benefit, three-point composite of CV death, non- tion is not limited by presence or absence my inclination is to let something go onto fatal MI and nonfatal stroke – by 26%, also of CV disease, diabetes in patients without the market that does have demonstrated statistically significant. CV disease, age, LDL-cholesterol or optimi- benefit for which the data may not be per- Amarin’s drug reduced the risk of the zation of statin therapy, the agency said. fect but certainly can be compelling, and individual components of the primary let’s see what happens in the clinical set- endpoint and secondary composite end- ting,” McCollister-Slipp said. points, and all results were statistically sig- “Indications matter in terms of access,” nificant per the prespecified testing plan she continued, referencing open public except for the final endpoint in the hier- hearing testimony from health care pro- archy, all-cause mortality, which trended viders and patients who described their favorably for Vascepa. experience with payers declining to cover Nevertheless, John Sharretts, acting “Predictably there was Vascepa for what currently is an off-label deputy director of the FDA Division of use. “How the agency decides to approve Metabolism and Endocrinology Prod- a (mixed) discussion a medication has real implications on what ucts, said the agency had several con- about labeling. Our patients have access to and what tools are cerns that warranted a public discussion. available to them and their physicians.” These included: thesis and valuation are Marvin Konstam, a cardiologist at Tufts ● Reliance upon a single trial for a first-in- Medical Center, supported extending the class indication; not based on specific indication to the primary prevention set- ● Observed patterns of lipid and inflam- ‘details’ of a label as we ting but said labeling should reflect there matory biomarker changes in the pla- is less benefit in lower risk populations, par- cebo group that suggested a possible think docs will use this ticularly in the context of risks that include interaction between the mineral oil bleeding and atrial fibrillation/flutter. placebo used and statins, which could widely across patients.” “I would at least want to think about make Vascepa look more effective than – Michael Yee working into the labeling the issue of risk/ it really is; benefit as you go to lower risk popula- ● Robustness of the data to support all in- tions, and you’re not lowering the risk of

16 | Scrip | November 22, 2019 © Informa UK Ltd 2019 REGULATORY

bleeding,” Konstam said. “When clinicians are thinking about this, I As for the mineral oil issue, panelists generally agreed with the think they should be thinking that as you go to that low risk popu- agency’s view that while the potential for an interference with lation the risk may be catching up to the benefit.” statins could not be excluded, any impact on the trial’s efficacy Those who opposed a broad indication said they were not con- results would have been small and not enough to invalidate the vinced the drug was effective for primary prevention. otherwise robust efficacy findings. “In the secondary prevention population the data are over- whelming and convincing … but they are wholly unconvincing BLEEDING, A-FIB RISKS in the primary prevention” population, said James De Lemos, a Although there was increased bleeding with Vascepa in REDUCE- cardiologist at UT Southwestern Medical Center. IT, there was no increase in the most worrisome types of bleeding, such as gastrointestinal or central nervous system bleeds, Amarin LABELING LIMITATIONS said. There was a statistically significant increase in atrial fibrilla- Numerous panelists said the indication should more closely tion/flutter, but the risk of more worrisome downstream effects, match the inclusion and exclusion criteria of REDUCE-IT, in- such as MI and stroke, were reduced, the company said. cluding a requirement for either established CV disease or dia- The committee said the risks of bleeding and atrial fibrillation betes with other CV risk factors. Some panelists also favored a did not outweigh the CV benefits seen in REDUCE-IT, and these higher triglyceride threshold and minimum age limit, as well as safety concerns could be addressed in labeling and further stud- language stating that patients should be on maximally toler- ied after approval. ated statin therapy. “I’m not very concerned about the A-fib issue. I don’t think it has Several panelists recommended against a claim for reduction any major impact on the long-term effects in the population,” Kon- of CV death because the magnitude of benefit on that endpoint stam said. “I’m uneasy about the bleeding and … I would consider was not as large or statistically robust as other components in the how do you mitigate that? How does the labeling read? Should five-point composite primary endpoint. there be a warning about that?” Published online 15 Nov 2019 Double Delight For Novartis At The CHMP KEVIN GROGAN [email protected]

he latest meeting of the European an average of 4.3 years versus placebo. As for the UK, the first committee meet- Medicines Agency’s drug evalua- Further EXPAND analyses demonstrated ing of the National Institute for Health and T tion committee, the CHMP, has pro- Mayzent significantly reduced grey mat- Care Excellence (NICE) to discuss the case vided a double boost for Novartis AG with ter volume loss at one and two years, a for reimbursing Mayzent on the National recommendations for its multiple sclero- key driver of disability progression and Health Service will take place in March sis treatment Mayzent and Cushing’s syn- cognitive decline in patients with SPMS. 2020. Initial findings are expected to be drome therapy Isturisa. Earlier this month, the drug got the published at the end of May. The CHMP has adopted a positive opin- green light in Australia and regulatory ion for Mayzent (siponimod) for the treat- filings are currently underway in Swit- MAYZENT SLOW START IN US ment of adults with active secondary pro- zerland, Japan, Canada and China. The daily tablet is an improved version gressive MS, ie, those who have evidence As part of its evaluation for Europe, of Novartis’s older relapsing-remitting of inflammatory activity on an MRI scan the CHMP convened a scientific advisory MS blockbuster Gilenya (fingolimod) and and/or still have relapses. The decision is group (SAG) on neurology that was held is key to its ambitions for growth in the based on the Phase III EXPAND trial which on 7 November to address specific ques- space. However the therapy has not got also formed the basis of the US Food and tions from the regulator. Novartis told off to the best of starts in the US and third Drug Administration’s approval in March, Scrip that the SAG “specifically looked into quarter sales of Mayzent were disappoint- making it the first oral treatment specifi- EXPAND and the clinical relevance of the ing, just $4m compared to consensus fore- cally for that indication. study, as other trials have failed in this pa- casts of $10m. Additional analyses of the EXPAND tient population. In this respect, the CHMP In the Q3 conference call on 22 October, study were presented at this year’s Eu- positive opinion and the indication reflect CEO Vas Narasimhan said, “We are seeing ropean Committee for Treatment and the discussion.” strong interest in the medicine, 90% will- Research in Multiple Sclerosis (ECTRIMS) The European Commission is expected ingness to prescribe, over 2,600 request meeting in Stockholm in September. to give the official thumbs-up within three forms…our key goal now is to enable a That data showed that Mayzent, which months and Novartis said it would work more rapid onboarding of these patients.” selectively binds to the S1P1 and S1P5 closely with all stakeholders to ensure He added that Novartis has seen a 90-day receptors, could delay median time to a Mayzent becomes available as quickly as lag “between initial interest in the medi- score of 7.0 on the expanded disability possible. The firm will initially focus on the cine and actually getting patients fully on status scale (EDSS) – the mark at which usual early launch markets, Germany and board with paid prescriptions. We expect wheelchair-dependence is reached – by some Nordic countries. to work hard to shorten that timeline as

scrip.pharmaintelligence.informa.com November 22, 2019 | Scrip | 17 REGULATORY/BIOTECH FINANCING

well as to work through the backlog of patients.” Novartis pharma head Marie- European Biotechs Enter The IPO France Tschudin said, “We’ve always said that the first 12 months with Mayzent would be about education. Physicians Big League recognize that these patients are progress- WILLIAM MASTERS [email protected] ing. The challenge is that they’re not diag- nosing SPMS and that is because there’ve urope’s biotechnology firms have $5.05bn, setting up a funding stream far been no effective therapies until now. So historically struggled to raise funds bigger than any IPO. this means we need to change habits and Eon a par with US counterparts when that takes time.” going public, often not having the fa- HEADWINDS miliarity with US investors necessary to European biotechs naturally still face the ISTURISA RECORDATI-BOUND achieve a successful flotation. same issues as their US counterparts. The The CHMP has also backed Isturisa (osilo- European biotech firms have tradition- most obvious question firms face after drostat), a cortisol synthesis inhibitor ally gone public on European exchanges having decided to go public is when to for Cushing’s, a rare disorder where the (such as Euronext or the UK’s AIM) where do so. In general firms seek to avoid the body produces too much corticosteroid funds raised have been much lower. How- slow summer period when listing, but hormone. It leads to patients experienc- ever, over the last few years European bio- predicting when the markets will be most ing weight gain, fat build-up on the face techs have increasingly gone public in the receptive to new offerings is challenging. and bruising. US, raising funds on a par with their Ameri- The volatility seen in October illustrated Isturisa works by inhibiting 11-beta-hy- can counterparts. They’ve done this by the potential problems: ADC Therapeutics droxylase, an enzyme responsible for the working hard on the fundamentals: gener- SARL decided to withdraw its IPO offering final step of cortisol biosynthesis in the ating compelling clinical data, drawing up priced at $200m, citing adverse market adrenal gland. However, while Novartis is robust business plans and working hard to conditions, which include the global man- listed on the CHMP’s November meeting meet US investors and win them over. ufacturing slowdown, political uncertain- agenda as being the sponsor of the drug, The graph below shows every US and ty around Brexit and the US-China trade Isturisa was one of three drugs that the European biotech IPO on NASDAQ for war. Markets have been particularly jittery Swiss major sold worldwide rights to in a 2019 as of 12 November listed in date or- since shared work space property firm We- deal with Recordati Industria Chimica & der. Among 43 listings in total, five were Work pulled its IPO following serious con- Farmaceutica SPA inked in July. from European companies. cerns about the company’s governance Under the terms of that deal, the Italian From January to October, European bio- and financials. group paid $390m up front to get hold of techs Genfit SA, BioNTech, Innate Pharma BioNTech SE pushed forward with its Isturisa, Signifor (pasireotide) and its long- SA and Bicycle Therapeutics Ltd. raised IPO on 11 October despite market woes, acting version Signifor LAR. The latter two, similar levels of funding as US firms. Den- and raised $150m – no small sum, but which had sales of $72m in 2018, are ap- mark-based Genmab’s IPO of over half a far below the $250m that was originally proved for Cushing’s and acromegaly in billion dollars, however, was the largest of expected. The German immunotherapy adults for whom surgery is not an option. the year so far, surpassing the next larg- developer may well have done better to Novartis is supplying the products to est IPO by more than $100m. This builds delay its IPO, though an IPO postpone- Recordati for a transitional period and is on a strong showing by ex-US companies ment or withdrawal can generate even eligible to receive milestone payments in 2018, which saw UK-based Autolus more skepticism for companies. (Also see contingent upon the approval and market Ltd. and Orchard Therapeutics Ltd. rais- “Finance Watch: BioNTech, Vir Launch IPOs access of Isturisa, as well as royalties. The ing $150m and $200m respectively, while But Take US Offerings To Market At A Dis- drug is currently under review at the FDA. Germany’s MorphoSys AG bagged $208m. count” - Scrip, 11 Oct, 2019.) The Basel-headquartered firm con- The NASDAQ launches also reflect an A successful IPO isn’t the end of com- firmed to Scrip that once European ap- increasing commitment from European panies’ worries of course. Newly listed proval was granted, Recordati will take biotechs to the US market. It is now cus- companies can see their share prices responsibility for commercialization and tomary to establish an R&D and commer- drop after listing, as they deal with new marketing of Isturisa. cial presence on the other side of the At- higher levels of expectation and scru- Published online 15 November 2019 lantic, most often in and around Boston’s tiny. One notable European example, biotech hub. Autolus, saw its share price fall 63% IPOs only tell part of this story, of year-on-year to November 2019 amid LET’S GET course, with companies raising money concerns of rising costs, manufacturing through private financing rounds and delays for its CAR-T therapies and wor- via licensing deals with big pharma. In ries associated with Neil Woodford - one SOCIAL July, Gilead Sciences Inc.. agreed a huge of Autolus’s investors. (Also see “Autolus @PharmaScrip licensing and equity stake deal with Bel- Faces Life After Woodford With New Czech gian biotech Galapagos NV worth up to Backer” - Scrip, 18 Sep, 2019.)

BiotechBio IPOstec 2019h I P– TheOs Story 20 1So9 Far - The Story So Far 550 500 450 400 350 300 250 200 150 Amount Raised (Million $) 100 50 0

e e or vi ya ail o e a CR re cle ok v eca er ech T ointT cellaone e IGM Gent St tr Ak Aper T Alect Stealth ecision texymeAx BicyIdea Pr A KarunaMirumulcrum Castle Innate Kaleido NGMBio Applied F Genmab Exagenequency Harpoon Pr NextCur ersonalisMorphocAdaptivBridgebio Satsuma r VielaBio BioN CabalettaPhathom Cor Milest P Genomics F urning P Gossamerbio T Springworks 10x Company (In Date Order)

Biotech IPOs on Nasdaq, January-November 2019 Biotech IPOs on Nasdaq, January–November 2019

Autolus is not alone, with fellow European firm Iterum Thera- and Novartis AG’s Arzerra (ofatumumab). But like other stand-outs peutics’ share price falling from $12.85 when it went public in May like MorphoSys and Galapagos, it proves that the region can pro- 2018 to just $2.74 today. duce world-class biotech companies, raising capital to take them Even with that mixed picture, 2019 looks like a turning point for to the next stage of growth. European biotech, thanks to that cluster of IPOs, and the smash Whether or not these emerging commercial-stage companies success of Genmab AS in particular. can resist big pharma buy-outs and maintain expansion is uncer- Of course the Danish firm is an outlier among European firms, tain, but their development has laid a path for other emerging thanks to its existing revenue stream via royalty-generating prod- firms to follow. ucts on the market Johnson & Johnson’s Darzalex (daratumumab) Published online 14 November 2019 ‘Watch China’ As Its Pharma Butterfly Flaps Its Wings STEN STOVALL [email protected]

hina’s increasingly laissez faire ap- Loncar Investments told the conference more are on the way. With the increasing proach to regulation, growing R&D audience. “Even if you’re not involved rivalry, prices for these immuno-oncology Cprowess and huge size will “trans- in making or selling drugs in China, you products are falling. form” the pharmaceuticals sector over the should still be paying attention to this “The fact that a PD-1 drug priced at next decade and likely allow drug prices because over the long-term it is going to $30,000 or less is coming on line some- to fall globally, giving millions of people affect our entire industry, in part by bring- where in the world let alone in an impor- access to medicines that they would oth- ing drug prices down generally,” he added. tant geography such as China with 1.5 bil- erwise be denied. He said the “China Effect” on global drug lion people in it, that will indirectly affect That was one conclusion reached by a prices would be felt both directly and indi- prices in other places,” Loncar said. panel of experts at the FT Global Pharma- rectly, notably through impact on indexed “It won’t cause the price of (Merck & Co. ceutical and Biotechnology Conference, reference pricing. Inc.’s anti-PD-1 agent) Keytruda to crash held in London on 11-12 November. He noted that competition had already overnight from $150K to something much “As an investor, China is the most impor- become much more pronounced in the lower, but overtime indirectly it may affect tant and most fascinating thing happen- PD-1 space in China. Already, five PD-1s the price in other geographies, including ing in our industry,” Brad Loncar, CEO of have been approved and launched and the UK, which may ultimately affect the

scrip.pharmaintelligence.informa.com November 22, 2019 | Scrip | 19 CHINA/AASLD MEETING

prices that we have in the United States,” “Another thing they did was to start re- US and elsewhere. With such a volume the investment told the conference. imbursing innovative medicines, and they of people covering the upfront costs of He noted that US Food and Drug Ad- started clamping down on higher pricing drug development, hopefully the drugs ministration officials have publicly criti- for generics and began to shift that re- can become more affordable and thus cized the way multinational pharma sulting money to innovative medicines. available to people who currently can’t groups have developed and priced their China is now the second biggest market afford them. It presents a paradigm PD-1 therapies in the US. for medicines, and it’s growing like crazy shift,” Oyler said. The agency has also expressed inter- because the innovative drugs are now Another panelist, Nicholas Benedict, est in helping Chinese drug makers ac- nationally reimbursed, which hadn’t hap- who sits on the board of Basel-based celerate access there for their same-class pened before,” the CEO noted. BioValley said the dynamics of China’s products, “with a view to importing their China’s reforming landscape offers the global integration within the life sci- high volume, low-price business model,” chance to accelerate drug development ences sector were being reinforced by he said. globally, he added. Chinese money. “Again, while this will not have an over- “The potential to run a clinical trial that “Chinese capital is increasingly impor- night effect, I do believe China will have might have previously taken three years in tant within Western biotech,” he told the a positive effect (on efficiency and price) just two years – because you can enrol pa- conference. over time, just like it has all other indus- tients more quickly – that’s hugely impact- “It shows that China is actively collabo- tries where China has come online and ful to the whole industry. The complete rating with life science clusters beyond its modernized and become a global com- system still needs to be developed but the borders and what I find particularly inter- petitor, Loncar said. promise is there. It will develop very rap- esting is the type of dynamic that they’re That assessment was echoed by anoth- idly over the next ten years,” Oyler said. trying to build,” he added. er panel member, John Oyler, co-founder He agreed with fellow panelist Lon- “Very often, there’s a sense that Chi- and CEO of BeiGene Ltd., who described car that China’s evolutionary steps nese investment into western biotechs is the changes now going on in China as would re-shape the pharma industry partially about accessing the intellectual “transformational for that country and for in future, and make drugs more afford- property for domestic Chinese rights. And the life sciences industry globally.” able globally, including in the US, Eu- this dynamic speaks to a deeper collabo- He said notable recent changes in China rope and Japan. ration and a lasting collaboration,” Bene- included the removal of barriers there to “It’s already happening in China. dict said. drug reimbursement and the country’s There the price point for average oncol- entry into the clinical trials system. ogy drugs are much lower than in the Published online 13 November 2019 Novartis, Pfizer Advance Their NASH Ambitions Separately, As Partners

JOSEPH HAAS [email protected]

either Novartis AG nor Pfizer Inc. of Intercept Pharmaceuticals Inc., which is Meanwhile, Pfizer believes its ACC in- has entered Phase III in non-alco- expected to be the first company to ob- hibitor PF-05221304 has demonstrated Nholic steatohepatitis (NASH) yet, tain approval for a NASH drug with its FXR it can reduce hepatic fat and fibrosis in but it seems that the smaller companies agonist obeticholic acid (OCA). NASH patients, but concedes that it also ahead in development should be keep- “We believe tropifexor will be the back- has yielded “unacceptable” increases in ing a wary eye on the two big pharmas’ bone therapy in NASH,” Eric Hughes, No- circulating triglycerides. Datamonitor NASH programs, and not just because of vartis global development head for immu- Healthcare analyst Hannah Cohen noted their developing clinical trial partnership nology, hepatology and dermatology, told that Gilead Sciences Inc. has seen similar in the space. Scrip during the meeting. In a late-breaker effects in monotherapy study of its ACC Novartis unveiled new data during the presentation, Novartis reported that in inhibitor firsocostat, and views it as a American Association for the Study of the FLIGHT-FXR Phase IIb study, tropi- slight drag on Pfizer’s drug. Liver Diseases meeting 8-12 November in fexor produced robust, dose-dependent Fortunately, Pfizer has animal model Boston that it thinks could position tropi- reductions in hepatic fat and in the liver data that indicate a combination of ‘1304 fexor (LJN452), a non-bile acid farnesoid enzyme alanine aminotransferase (ALT) at and its DGAT2 inhibitor PF-06865571 X receptor agonist, as best in class. If the 12 weeks compared to placebo. The firm work complementarily, with the latter’s Swiss pharma is right about tropifexor’s expects to report 48-week, biopsy-based mechanism of action countering the overall risk/benefit profile, that would data from the study during the second safety concerns of the ACC inhibitor, Mor- make for a significant shot across the bow quarter of 2020. ris Birnbaum, chief scientific officer for

the company’s internal medicine research comes on top of Novartis’s internal work unit, said in an interview. on NASH R&D, which includes a plan to Those are two of the three compounds advance tropifexor into Phase III soon. – along with Pfizer’s first-in-class keto- Datamonitor’s Cohen, however, noted hexokinase inhibitor PF-06835919 – that that like Intercept’s OCA, tropifexor has are being evaluated for a potential Phase shown some increases in patients’ LDL II combination study with Novartis’s tropi- “We believe tropifexor cholesterol levels in a clinical study, so fexor under an alliance the two pharmas despite the positive efficacy profile and signed in October 2018. will be the backbone strong evidence of a dose-response treatment effect, the concerns over the lipid PRELIMINARY WORK FINISHING therapy in NASH.” – profile call for caution until histological FOR NOVARTIS/PFIZER COMBO data come in. Hughes and Birnbaum both reported pre- Eric Hughes Novartis also is bullish on the SGLT1/2 clinical work investigating each of the po- inhibitor licogliflozin (LIK066), which re- tential combos is complete and that Phase duces glucose and could be a promising I drug/drug interaction studies are nearing combination therapy partner with tropi- completion. The two companies plan to fexor, he said. The company will soon initi- meet at the European Association for the ate the Phase IIb ELIVATE study to try out Study of the Liver next April to plot out the that combination in NASH patients. next steps in the collaboration – a go/no- “We’re all-in on all phases of develop- go decision on whether to move into Phase ment right now,” Hughes said. II, as well as a determination of which Pfizer Novartis remains engaged with part- molecules to pair with tropifexor. presented by PF-1304 in human subjects, ner Allergan PLC in the Phase IIb TANDEM “We’re basically doing all the prelimi- Birnbaum said. The operating theory, he study testing tropifexor with cenicriviroc nary work to put us in a position to move explained, is that ACC inhibition creates a (CVC), a CCR 2/5 antagonist. That study is forward very quickly after safety and the secondary activation of the SREBP1 tran- robustly designed and will read out data tropifexor biopsy study, which I believe scription factor, the master regulator of de based on paired biopsies, Hughes said, will happen at the end of the first quarter novo lipogenesis, while DGAT2 inhibition so it will “get to the essence of what we of 2020,” Birnbaum said. down-regulates the same transcription need to know about these combinations.” Sixteen-week data with PF-‘1304 sug- factor. The company hopes topline data Allergan is also studying CVC as NASH gested the ACC inhibitor had hepatic fat- coming for the combo in the first quarter monotherapy in a Phase III program that and fibrosis-reducing activity that Pfizer of next year will prove the hypothesis. is expected to yield data in late 2021 or is reluctant to walk away from despite the The KHK inhibitor has shown prelimi- early 2022. concern about increasing triglycerides, nary benefit on several metabolic mark- But NASH R&D hasn’t exclusively been the exec said. “We have a lovely clinical ers in both type 2 diabetes and NASH a success for Novartis, which saw its part- result but an unfortunate adverse effect patients, including the ability to improve ner Conatus Pharmaceuticals Inc. shelve which is mechanism-based, so we’re not insulin-sensitivity, so Pfizer is moving to- its Phase II caspase inhibitor emricasan going to get around it,” Birnbaum said. ward a decision whether to continue ad- earlier this year after multiple trial set- In a separate presentation, Pfizer vancing that compound in either combi- backs. (Also see “Conatus Accepts Defeat showed that its DGAT2 inhibitor yields nation or possibly both. For Emricasan In NASH” - Scrip, 25 Jun, roughly 30% liver fat lowering in two 2019.) Hughes said Novartis will apply weeks, which would be clinically mean- NOVARTIS’S FOCUS BOTH things it has learned from that effort to its ingful. The two compounds “really seem INTERNAL AND EXTERNAL future efforts in NASH. Conatus’s studies to be mechanistically antagonistic,” While Pfizer’s NASH focus is mainly inter- focused on later-stage patients, the ones Birnbaum noted. “[But], we ran a study nal now, other than the collaboration with who need a new drug therapy the most, with the combination and found that in Novartis, the Swiss firm has been an active he added. preclinical study with animals, ACC and deal-maker in the space lately; Novartis “They were well-designed studies, they DGAT2 inhibition were more effective paid $310m up front to buy inflamma- were looking at the right endpoints; un- than either alone for fat and more crucial- some-focused IFM Tre in April, then paid fortunately the compound didn’t work,” ly for NASH progression, but even more $80m for the right to license a preclini- the exec said. “The learnings from those impressively, the DGAT2 suppressed com- cal integrin inhibitor discovered by Pliant studies are very important – defining how pletely the increase in circulating triglyc- Therapeutics Inc. on 23 October. (Also see to monitor those patients and how to set erides by ACC inhibition.” “Novartis Adds To NASH Pipeline By Licens- endpoints and work with the FDA and Pfizer has preliminary data indicat- ing Pliant’s Integrin Inhibitor” - Scrip, 23 other authorities was very important, and ing the two drugs are safe together and Oct, 2019.) I think that there’s a lot to be proud of in now hopes to prove their synergy and Hughes sees the recent deals as “partic- that program.” PF-5571’s ability to offset the safety issues ularly exciting,” and noted that the activity Published online 15 November 2019

scrip.pharmaintelligence.informa.com November 22, 2019 | Scrip | 21 PIPELINE WATCH

Scrip’sPipeline weekly Pipeline Watch Watch - tabulates 8-14 the November most recently reported 2019 late-stage clinical trial and regulatory developments from the more Click here for the entire pipeline than 10,000 drug candidates currently under active research worldwide. with added commentary: http://bit.ly/2mx4jY3 Phase III

PIPELINESearch WATCH, 8–14 NOVEMBER 2019

Change LOA Event Type Lead Company/Partner Drug Name Indication Comments To LOA (%) (%) Phase III Systemic Lupus TULIP; The Lancet Published AstraZeneca PLC anifrolumab 0 57 Erythematosus Rheumatology, 11 Results Nov, 2019 Phase III Korsuva KALM-1; NEJM, Published Cara Therapeutics Pruritus 0 70 (difelikefalin) 8 Nov, 2019 Results Phase III GUARD; JAMA Bekinda Published RedHill Biopharma Ltd. Gastroenteritis Netw Open, 8 0 68 (ondansetron) Results Nov, 2019 Anemia Due to Phase III Chronic Renal ALPS, ANDES, Updated FibroGen/AstraZeneca/Astellas roxadustat 0 74 Failure, Dialysis- OLYMPUS; Results Independent Pooled Analyses Phase III APeX-2; Hereditary Updated BioCryst Pharmaceuticals, Inc. BCX7353 Reduced Attack 0 62 Angioedema Results Rates Anemia Due to HIMALAYAS, Phase III Chronic Renal ROCKIES, Updated FibroGen/AstraZeneca/Astellas roxadustat 0 73 Failure, Dialysis- SIERRAS; Pooled Results Dependent Analyses Anemia Due to Phase III Chronic Renal J01 (Japan); Updated Akebia/Mitsubishi Tanabe vadadustat 0 61 Failure, Dialysis- Positive Data Results Independent Phase III Rheumatoid FINCH 1, 2, 3; Updated Gilead/Galapagos �lgotinib 0 72 Arthritis Pooled Analyses Results Phase III CONFIRM; Met Hepatorenal Updated Mallinckrodt plc terlipressin Primary 0 65 Syndrome Type 1 Results Endpoint Phase II/III bardoxolone Updated Reata Pharmaceuticals, Inc. Alport Syndrome CARDINAL; 1 64 methyl Results Positive Data Phase II/III SELECT Axis 1; Rinvoq Axial Updated AbbVie Inc. Promising 4 63 (upadacitinib) Spondyloarthritis Results Results Phase II/III ASLAN Pharmaceuticals Pte TreeTopp: Top-Line varlitinib -5 30 Ltd Biliary Tract Cancer Results Mixed Results Juvenile A3921104 Phase III Top- Xeljanz P�zer Inc. Rheumatoid (Pediatric); 5 64 Line Results (tofacitinib) Arthritis Positive Data Phase III Top- Nucala Hypereosinophilic GlaxoSmithKline plc 8 43 Line Results (mepolizumab) Syndrome Positive Results ILLUMINATE-C; Phase III Trial Alnylam Pharmaceuticals, Inc. lumasiran Hyperoxaluria An RNAiSource: Biomedtracker0 | Informa, 62 2019 Initiation Therapeutic Phase III Trial Jardiance In Hospitalized 22 | Scrip | NovembBoehringerer 22, 2019Ingelheim/Lilly Acute Heart Failure © Informa0 UK Ltd 47 2019 Initiation (empagli�ozin) Patients Zimura Dry Age-Related Phase III Trial Second Pivotal Iveric Bio (avacincaptad Macular 0 24 Announcement Study pegol) Degeneration

Source = Biomedtracker; LOA = Biomedtracker's opinion on likelihood of approval. Use the scroll bars to move up and down and across in the tables. ASN MEETING

Clear Path For AstraZeneca’s Roxadustat

ANDREW MCCONAGHIE [email protected]

straZeneca PLC and FibroGen Inc. vascular (CV) safety analyses from the John Houghton, AstraZeneca’s global will be confident of US approval pivotal Phase III programme assessing medicine leader said the companies were Afor roxadustat after unveiling reas- roxadustat for the treatment of patients pleased with the results, and confirmed suring cardiovascular safety data for their with anemia from CKD. The data present- that they remained on track to submit the new anemia treatment. ed at the American Society of Nephrology drug to the FDA by the end of 2019. Roxadustat is the front runner in a new (ASN) Kidney Week 2019 in Washington, He said that AstraZeneca and Fibrogen class of oral HIF-PH inhibitors used to treat DC, US, covered three different CKD sub- were the only companies in the field to anemia, and needed to show superiority groups: non-dialysis dependent, dialysis undertake a comparison with a placebo, in safety compared to existing standard dependent, and incident dialysis patients. helping it to strengthen its lead over its treatment, erythropoiesis-stimulating In the latter two studies roxadustat rivals. GlaxoSmithKline PLC and Kyowa Ki- agents (ESAs), on top of already-released was compared with epoetin alfa and was rin’s daprodustat has been filed in Japan, efficacy data. found to have a lower risk of major ad- with US Phase III data due in 2020. ESAs, such as Amgen Inc.’s Epogen verse cardiovascular event MACE+ (CV Another alliance is Akebia Therapeutics (epoetin alpha), are well-established death, non-fatal MI, non-fatal stroke or Inc./Mitsubishi Tanabe Pharma Corp./Ot- treatments for several classes of anemia, hospitalisation from unstable angina) and suka Holdings Co. Ltd., whose vadadustat but the injectable drugs are linked with no increased risk of MACE or all-cause has also been filed in Japan, and will also thromboses and cardiovascular events. mortality in both groups. produce US Phase III data next year. The new data confirm the potential of In the first group, non-dialysis dependent The results were good news for Fibro- roxadustat in replacing these older treat- patients, the risk of MACE, MACE+ and all- Gen, which saw its shares close 10% up ments in patients with anemia caused by cause mortality was comparable to placebo. following the data release.There had chronic kidney disease (CKD) on dialysis. Roxadustat was discovered by FibroGen, been major concerns about the drug’s Even more encouraging are the postive which has a co-marketing deal with Astra- safety profile after FibroGen had with- results in CKD patients not (yet) receiving Zeneca covering the US and China, where held details of earlier safety readouts. dialysis, as this could expand the drug’s the drug is already approved in CKD, re- Approval from the FDA in 2020 would market significantly. gardless of whether they require dialysis. open up a large market for AstraZeneca This should help it fulfill analyst fore- FibroGen is co-marketing with Astellas and Fibrogen-in both replacing ESAs, casts of $1.4bn in revenues by 2024. Pharma Inc. in Japan, where the drug is also but also expanding to those patients On Friday 8 November, the companies already approved, as well as the EU, CIS and who do not receive dialysis. presentedComp pooledany Mefficacyove and cardio- Middle East, where it is not yet filed. Published online 11 November 2019

APPOINTMENTSSearch

Effective Executive To Company New Role From Company Previous Role Date Chief Executive Managing Director and Vice Klaus Aeterna Aeterna Zentaris Ocer, President and President, Quality and 4-Oct-19 Paulini Zentaris Inc GmbH Director Regulatory Jean- Chief Commercial Vice President and Global Bavarian GlaxoSmithKline Christophe Ocer and Executive Vaccines Commercialization 31-Mar-20 Nordic AS plc May Vice President Leader Paul A. Ideaya Vice President and 5AM Ventures Executive in Residence 5-Nov-19 Barsanti Biosciences Inc Head, Drug Discovery Executive Vice Senior Vice President, Chief Howard President and Head, Shire Medical Ocer and Head, Ipsen Group 1-Dec-19 Mayer Research and Pharmaceuticals Research and Development, Development Neuroscience Jim Johnson & Chief Information Chief Information Ocer, Bayer AG 3-Oct-19 Swanson Johnson Ocer Crop Science Teva Chief Financial Ocer Senior Vice President, ClickEli hereKalif for all appointments:Pharmaceutical https://bit.ly/2oHWRYn and Executive Vice Flex Ltd Source: Medtrack |8-No Informa,v-19 2019 Finance Industries Ltd President scrip.pharmaintelligence.informa.com November 22, 2019 | Scrip | 23 HEADLINE NEWS

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