Pfizer's Bourla

No. 3985 December 13, 2019

line success and business development. “In the next two years, we need to see how the pipeline is delivering,” he said. Bourla has been outspoken that when it comes to business development, he doesn’t see a mega-merger on the hori- zon. Instead, he said he is looking to bring in mid-stage clinical development assets to complement the internal pipeline. It sounds like investors can expect the company to be active on the business development front within those guard- rails. “I want to double it,” he said of the pipeline, which includes 92 projects right now. “And, we are going to double it by bringing in a lot of innovation to complement what we distribute.” The company is focusing business development on six core therapeutic areas Pfizer’s Bourla: “I Think We Forgot as well, but Bourla indicated the company will be actively building out those areas both through internal investment and What It Looks Like To Grow” external collaboration. “We’re going to be JESSICA MERRILL [email protected] active because Pfizer is a very big plane and it cannot fly with one engine,” he said. fizer Inc. CEO Albert Bourla took in July it will merge the Upjohn business Bourla highlighted Pfizer’s recent acqui- over the top leadership spot from with Mylan NV to form a new generic drug sition of the cancer specialist Array Bio- PIan Read a year ago, but has quickly company to be called Viatris GMBH. Pharma for $11.4bn as an example of the executed on big changes poised to make The resulting Pfizer will be significantly kinds of deals the company will be pursu- Pfizer significantly smaller and faster smaller, with a 2020 annual revenue base ing. “When I saw the royalties they are col- growing. The chief exec looked back at of around $40bn from a 2018 base of lecting from 10 different companies, I real- his first year of leadership, and the state of $53.65bn, but growing at about 6%. ized this is a company that has produced. the company, from the stage of the Forbes Bourla said he is confident the company Why don’t we get them?” Healthcare Summit in New York City. will maintain a 6% growth rate through While Pfizer is executing on business de- “I think we forgot what it looks like to 2025 at least because the company isn’t velopment, Bourla said another big prior- grow,” Bourla told attendees during a pre- facing big patent losses during that time- ity for him in the near-term is changing the sentation on 5 December. “Growth culture frame. Right now, Pfizer is cycling through culture at Pfizer, a common refrain among is a very different culture [versus] when the loss of the blockbuster Lyrica, which is the industry’s new big pharma leaders. you need to just control costs.” weighing on 2019 revenues. Bourla said he is striving to create a youth- Pfizer is being reshaped through the “We have a unique window of opportu- ful, patient-centric, risk-taking environment spinout of its consumer health care and nity to get it right,” Bourla said. That time- at Pfizer, so that the employees feel it is a Upjohn established products business, line is about six or seven years because af- “company that thinks big, that has courage.” balanced with small to mid-sized deals ter that, more patent losses will be coming. But he said he is only building on the to add to the innovative pharmaceuti- His primary goal, he said, is to sustain the groundwork laid by former CEO Read. cal pipeline. The company announced solid growth beyond 2027, relying on pipe- Published online 6 December 2019

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Through The AI Maze ASH Meeting R&D Woes In CNS Pharma’s adventures in J&J gives chase to BMS/bluebird Sage suffers depression setback artifical intelligence (p10) in BCMA-targeting CAR-T (p14) while Biogen still needs to convince with aducanumab (p16 & 19) IN THIS ISSUE

from the editor [email protected]

For the last issue of the year, I’d like to highlight just Her work contributed to the development of the PARP two of the many inspiring people who are making a dif- inhibitor Rubraca, which was approved for ovarian can- ference to human health through drug development. cer in the US in 2016 and in the EU in 2018. Jane Osbourn OBE was announced last week as the Not content with saving the lives of women with ovar- winner of the 2019 Scrip Lifetime Achievement Award. ian cancer, Curtin decided that it was “wrong for me to Her career in antibody engineering has spanned aca- benefit from this financially,” and with her share of the demia and industry and contributed to the develop- royalties from the drug she set up the Curtin PARP (Pas- ment of Humira and Benlysta. In her moving accept- sionate About Realising your Potential) Fund, donating ance speech, Osbourn talked about how a sense of £865,000 to help disadvantaged people overcome bar- responsibility towards patients drove her and her team riers to employment or education. “I’m proud that this on, and also about the importance of team work, diver- research will change lives, and I have everything I need sity, risk taking and openness. But her best advice was in life,” she explained. “be generous” – with ideas, time and support for others. Both Curtin and Osbourn are shining examples in One person who has been incredibly generous is our industry, which has the great privilege of helping Nicola Curtin, a professor at Newcastle University, UK. humanity and making money in the process.

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2 | Scrip | December 13, 2019 © Informa UK Ltd 2019 SEASON’S GREETINGS Wishing our readers a joyful holiday season and all the best for 2020.

The next issue will be on January 10, 2020. For online access please contact [email protected]

exclusive online content inside: COVER / Pfizer’s Bourla: “I Think We Forgot What It Looks Interview: Double Delight For Like To Grow”

ImmuPharma’s Dimitriou 4 Astellas To Pay $3bn For Gene Therapy Company Audentes KEVIN GROGAN [email protected] 4 Novartis Enters ‘Transformational’ Cloud Computing Pact With Amazon

5 Sanofi Bets Big On IO With Synthorx Buy

6 Neurocrine Adds Epilepsy Assets From Xenon

8 Lilly Taps Loxo Execs To Bring Back That Biotech Feeling

9 What Lies Beneath China’s Steep Price Cuts For New Drugs

10 Pharma Finds Its Way in AI

ImmuPharma PLC CEO Dimitri Dimitriou had an excellent 14 J&J Quickly Advances BCMA-Targeting CAR-T day on 28 November as his daughter got married and the As JNJ-4528 Shows 100% Response UK biotech signed a deal for Lupuzor with the US’s Avion Pharmaceuticals LLC that has breathed new life into the prospects for the investigational lupus drug. 16 Biogen’s Big Day Arrives, But Aducanumab Results The pact will see Avion pay for a new Phase III trial up Don’t Answer Key Question to $25m for Lupuzor (forigerimod), ImmuPharma’s first-in class autophagy immunomodulator which has been on a 18 Early Assets Excite At Novartis R&D Day less than smooth development path. That path got particularly bumpy In April last year when late-stage data showed 19 Sage Still Sees Approval Path After Depression Drug Fails that while Lupuzor plus standard of care (SOC), such as In Phase III Trial steroids, anti-malarials and methotrexate, was more effective than placebo plus SOC (52.5% versus 44.6%), the high 21 Acadia’s Nuplazid Shows Nearly Three-Fold Reduction response rate in the latter group meant the primary end- In Psychosis Relapse point of statistical significance was not reached. Dimitriou said it was important to point out that it was 22 Pipeline Watch probably the SOC effect rather than placebo that led to the higher than expected response rate and missing 23 More Top Level Pharma Exits In India As Cipla COO Departs statistical significance. He added that in hindsight, setting that endpoint and not targeting only patients in the active state of the disease was unfortunate “and while 23 Appointments we took a big hit, we knew that in the right patients, the drug worked.” Published online 6 December 2019 @PharmaScrip /scripintelligence To read the rest of this story go to: https://bit.ly/36fhjnh

/scripintelligence /scripintelligence

scrip.pharmaintelligence.informa.com December 13, 2019 | Scrip | 3 DEALS

Astellas To Pay $3bn For Gene Therapy Company Audentes

ANDREW MCCONAGHIE [email protected]

stellas Pharma Inc. is to acquire Au- Its lead candidate is AT132, a gene our existing pipeline, including its lead dentes Therapeutics for $3bn, in a therapy being developed to treat XLMTM, program AT132 for the treatment of X- Atransaction that confirms the abid- a serious, life-threatening, rare neuro- Linked Myotubular Myopathy (XLMTM). ing attraction of gene therapy companies muscular disease which causes extreme By joining together with Audentes’ tal- for big pharma companies looking to up- muscle weakness. The inherited condition ented team, we are establishing a leading date their pipelines. affects male infants and results in respira- position in the field of gene therapy with The Japanese big pharma company tory failure and early death. The therapy the goal of addressing the unmet needs of has agreed with the San Francisco- has shown promise in interim results from patients living with serious, rare diseases.” based company’s board to pay $60.00 a Phase I/II trial. The value of the acquisition comes per share in cash to acquire it in full, rep- Analysts at Jefferies were positive on close to the $4.3bn Roche has offered resenting more than double its closing the move, but noted that only 40 boys are for another gene therapy company, market capitalisation. likely to be born with XLMTM every year Spark Therapeutics. The high price Astellas has paid will in the US, and calculated therefore that US One key difference between that trans- undoubtedly raise eyebrows among an- annual revenues might reach just $80m. action (still awaiting regulatory sign off) alysts and investors, who over the course On that basis, Astellas will be looking and this latest deal is that Spark already of 2019 have grown more skeptical to the potential of Audentes’ work across had its first gene therapy on the market about the long term commercial value three modalities – gene replacement, vec- at the time of the acquisition, rare eye dis- of these first generation cell and gene torized exon skipping, and vectorized RNA ease gene therapy Luxturna. therapy platforms. knockdown – to provide much broader The deal isn’t Astellas’ first foray into However this has helped to drive down opportunities. Programs already in Au- gene therapy, Last year it spent $109m the value of gene therapy companies in dentes’ preclinical and discovery pipeline to buy out UK ophthalmic gene therapy 2019, Audentes included, which has seen include Pompe disease, Duchenne mus- company Quethera, and also has a licens- its share price fall 30% since August. cular dystrophy and Mytonic dystrophy. ing deal with fellow Japanese firm Clino in This means Astellas has been able to “Recent scientific and technological retinitis pigmentosa, and a research alli- bag itself a bargain relative to valuations advances in genetic medicine have ad- ance with Harvard Medical School. earlier this year, and must now show vanced the potential to deliver unprec- Other notable transactions in the field how it can help develop and commer- edented and sustained value to patients, include Novartis AG’ $8.7bn acquisiton of cialise Audentes Therapeutics Inc.’ plat- and even to curing diseases with a single AveXis in 2018, which brought with it the form and pipeline. intervention,” said Kenji Yasukawa, presi- now-launched Zolgensma, and the much Audentes is focused on developing dent and CEO, Astellas. smaller $800m buy-out of UK-based gene treatments for serious rare neuromuscular He added: “Audentes has developed therapy company Nightstar by Biogen in diseases using its AAV gene therapy tech- a robust pipeline of promising product March 2019. nology platform. candidates which are complementary to Published online 4 December 2019 Novartis Enters ‘Transformational’ Cloud Computing Pact With Amazon

STEN STOVALL [email protected]

ovartis AG has turned to Amazon’s Cloud comput- for custom, cloud-based solutions that enhance agility ing expertise to hone the Swiss drug maker’s and cost efficiencies across the drug maker’s business Npharmaceutical manufacturing, supply processes and systems. The partnership will see the chain, and delivery operations by making them creation of command “Insight Centers” to provide more efficient and real-time. Shahram real-time visibility across Novartis’s global manu- Ebadollahi The head of data science and AI at Novartis facturing operations and distribution centers, told Scrip the multiyear collaboration with Ama- Shahram Ebadollahi said. zon Web Services (AWS), announced on 4 Decem- “This collaboration is in line with our digital trans- ber, will build an enterprise-wide, global data and formation,” he said. “It is very solutions oriented but analytics platform designed to form the foundation TURN TO PAGE 6

4 | Scrip | December 13, 2019 © Informa UK Ltd 2019 DEALS

Sanofi Bets Big On IO With Synthorx Buy

KEVIN GROGAN [email protected]

ith the acquisition of US biotech Synthorx Inc. for $2.5bn, Sanofi’s Reed said that Synthorx’s pipeline of engineered lym- Sanofi’s new CEO Paul Hudson has confirmed immuno- phokines also known as Synthorins, had “great promise not only Woncology (IO) as a key focus for the French drugmaker. for oncology but also for addressing many autoimmune and in- Sanofi will pay $68 a share in cash for Synthorx, which repre- flammatory diseases.” Based on the observation that low doses of sents a 172% premium on its closing price on Friday (6 Decem- IL-2 can dampen immune-cell activation, Synthorx has been eval- ber). The attraction of Synthorx lies in its lead IO candidate THOR- uating possible opportunities in chronic graft versus host disease, 707, a variant of recombinant interleukin-2 (IL-2), which is in Phase atopic dermatitis and Crohn’s disease. I/II development in multiple tumor types as a single agent and will CEO Hudson added that this acquisition “fits perfectly with our be investigated in combination with checkpoint inhibitors. strategy to build a portfolio of high-quality assets and to lead with The combo approach is of particular interest to Sanofi which has innovation,” on which more will be addressed at Sanofi’s capital an approved checkpoint inhibitor of its own. Libtayo (cemiplim- markets day tomorrow (10 December). He claimed the Synthorx ab), a PD-1 inhibitor developed with Regeneron Pharmaceuticals purchase was “aligned with our goal to build our oncology fran- Inc., is currently marketed for adults with advanced cutaneous chise with potentially practice-changing medicines and novel squamous cell carcinoma who cannot have surgery or radiation combinations. treatment and is also in trials for a variety of cancers, notably cervi- The deal represents quite a windfall for Synthorx which was cal and non-small cell lung. (Also see “Sanofi’s Libtayo Lands In EU founded in 2014 with a platform discovered at The Scripps Re- With Skin Cancer Nod” - Scrip, 2 Jul, 2019.) search Institute. The La Jolla, CA-headquartered group listed on As well as Libtayo, Sanofi will be looking at “multiple combina- the NASDAQ almost a year ago to the day, raising $131m from the tion opportunities” with THOR-707 and other oncology assets, in- sale of 11.9m shares at $11 each. cluding its anti-CD38 monoclonal antibody isatuximab, which is currently under review at the US Food and Drug Administration ANALYSTS VIEW and European Medicines Agency for the treatment of relapsed/re- Bryan Garnier analyst Jean-Jacques Le Fur issued a note on 9 De- fractory multiple myeloma. (Also see “Sanofi Myeloma Drug Shines cember saying that “regarding THOR-707 we estimate that a lot But Darzalex Dominates Still “ - Scrip, 3 Jun, 2019.) remains to prove especially the interest of having a pegylated IL-2 Sanofi R&D chief John Reed claimed: “Synthorx’s exceptionally compared to a traditional one and to show higher efficacy. There- novel discovery platform has already produced a molecule that fore, the price paid could appear high.” has the potential to become a foundation of the next generation Analysts at Jefferies described the deal as “an unexpected of I-O combination therapies.” By selectively expanding the num- move,” saying “it’s clear Sanofi believes that IL-2 will be a backbone bers of effector T-cells and natural killer cells in the body, THOR- of IO therapy.” The broker said it does not anticipate any other bids 707 “can be combined with our current oncology medicines and to come in for Synthorx nor does it expect any issues with the US our emerging pipeline of immuno-modulatory agents for treating Federal Trade Commission. cancer,” he added. There has recently been increased antitrust scrutiny in the US In preclinical studies, because THOR-707 is designed to be a on a number of M&A deals involving overlapping therapeutic ar- “not-alpha” IL-2, it did not cause the potentially deadly side ef- eas, notably Celgene Corp. being forced to sell its psoriasis drug fect of vascular leak syndrome (VLS) seen with recombinant IL-2 Otezla (apremilast) to Amgen Inc. for $13.4bn to win US Federal in the past. Synthorx noted that Proleukin (aldesleukin), an IL-2 Trade Commission approval for its merger with Bristol-Myers therapeutic approved by the FDA over 25 years ago and now Squibb Co.. Roche’s proposed acquisition of Spark Therapeutics marketed by the UK’s Clinigen Group PLC for renal cell carcinoma Inc. has been repeatedly delayed and the Swiss major has just an- and melanoma, has produced “durable clinical responses – and in nounced yet another extension to close the deal to 16 December. some cases cures” but its widespread use has been limited by tox- (Also see “FTC Closer To Clearing Roche’s Spark Buy: Report” - Scrip, icities, which include VLS as well as by its short half-life, requiring 25 Oct, 2019.) IV dosing every eight hours for up to five days. (Also see “US Rights More details on the Synthorx acquisition will be given during Deal Will Make Proleukin Clinigen’s Biggest Product “ - Scrip, 13 Feb, the capital markets day and Bryan Garnier’s Le Fur wrote that 2019.) (Also see “Novartis, Zurich University Spin-out Anaveon Tack- Hudson may not provide financial guidance having only been les IL-2 Challenges With Fresh Funds” - Scrip, 1 Mar, 2019.) at Sanofi for four months. “We think he will highlight his strategy The San Diego-based firm said that THOR-707 was designed to roadmap from a more general perspective. His challenge … will have key advantages over current IL-2 therapies, “such as improved be to convince investors that they can have confidence in a return selectivity, increased therapeutic index, ease of use and reduced risk to sustainable earnings per share growth,” he said, adding that the for anti-drug antibodies.” It added in combination with checkpoint focus will probably be on R&D and the strategy to replenish the inhibitors may have greater anti-tumor effects than PD-1 inhibitors pipeline. (Also see “The Challenges Facing Paul Hudson At the Helm alone, without the VLS observed with aldesleukin. (Also see “Scrip’s of Sanofi “ - Scrip, 7 Jun, 2019.). Rough Guide To IL-2: Mother Of All Cytokines” - Scrip, 26 Mar, 2018.) Published online 10 December 2019

scrip.pharmaintelligence.informa.com December 13, 2019 | Scrip | 5 DEALS

CONTINUED FROM PAGE 4 anchored in machine learning and AI to create these Insight cen- Neurocrine Adds Epilepsy ters for monitoring real time with analytics to help make better business decisions and to increase efficiency in our manufacturing and supply chain.” Assets From Xenon Novartis CEO Vas Narasimhan has regularly emphasized that JOSEPH HAAS [email protected] automation and culture change is needed at Novartis to improve its overall performance. (Also see “Strategy At Novartis: Culture eurocrine Biosciences Inc. is continuing to bring in assets Change As The ‘How’ Behind The ‘What’” - In Vivo, 19 Nov, 2018.) through a new partnership with Xenon Pharmaceuticals “This new platform will enable Novartis to transform the NInc. that adds epilepsy candidates to its pipeline and funds way it manufactures and delivers medicines, meaning new an R&D collaboration with the smaller firm, which enables Xenon treatments can be made available to patients faster,” Ebadol- to focus more on a pair of Phase II epilepsy candidates it wants to lahi summarized. take to market on its own. The collaboration with Amazon Web Services should enable Neurocrine announced 2 December that it will pay $50m up manufacturing and planning teams at Novartis to better forecast front – divided between cash and equity – to obtain worldwide and track production lines, detect potential bottlenecks, and per- rights to Phase II-ready XEN901, a selective Nav1.6 sodium chan- form predictive maintenance of machines, and have adjustments nel inhibitor. The agreement also gives Neurocrine rights to pre- made automatically to enhance accuracy. clinical Nav1.6 and dual Nav1.2/1.6 inhibitors and funds a multi- Novartis plans to use Amazon’s AWS IoT (Internet of Things) ser- year collaboration with Xenon to discover and develop additional vices to visualize data that can then be assessed using computer compounds in those classes. vision algorithms that monitor for risks to manufacturing produc- It’s Neurocrine’s second deal of the year, following a late January tion. These include unplanned downtime, out of stock inventory, tie-up with Voyager on gene therapy candidates for Parkinson’s or delayed orders. disease and Friedreich’s ataxia with a $165m upfront payment, “When this is up and running with this real-time data, Novar- including $115m in cash and $50m in equity. (Also see “Voyager tis will be able to automatically take corrective action to ensure Nabs Neurocrine As Partner In CNS Gene Therapy” - Scrip, 29 Jan, that medicines are more efficiently produced and distributed to 2019.) San Diego-based Neurocrine markets Ingrezza (valbena- almost 1 billion patients in 155 countries around the world,” Eba- zine) for tardive dyskinesia, a product showing steady growth dollahi said. with sales of $515m through the first three quarters of 2019, after “This collaboration begins immediately and hopefully we’ll see banking $410m in 2018. some good results from it by mid-2020. It promises to be transfor- Both the Voyager and Xenon transactions outlines up to $1.7bn mational for us,” he added. in development, regulatory and commercial milestone fees for No financial or investment details were given. Neurocrine’s partner. “Our CEO Vas Narasimhan has often said that transforming On a same-day investor call, Xenon CEO Simon Pimstone the company is a key objective, through the importing of, the said the costly effort to develop XEN901 fits better in the hands collaborating around, and the development of technology,” of the wealthier Neurocrine, while his company adds to its fi- Ebadollahi explained. nancial runway and can put full focus into Phase II epilepsy The collaboration with Amazon is consistent with Novartis’s candidates XEN496 and XEN1101. The former, a Kv7 potassium SENSE operations center in Basel which monitors hundreds of channel modulator, could enter Phase III early in 2020, the exec clinical trials worldwide. (Also see “How Novartis Is Making SENSE said, while the latter is expected to produce Phase II data by Of Clinical Data In Digital Age” - Scrip, 6 Feb, 2019.) the end of 2020. “This collaboration is different but will build on the success of A Kv7 potassium channel opener, XEN1101 could be an “only- our SENSE operations center.” in-class” therapy for focal seizures, Pimstone asserted, offering dif- “The Insight centers that we are going to build for our technical ferentiation from current anti-seizure medications. operations will be used both at the local level within at individual “Recognizing the opportunity for multiple indications, and manufacturing sites, and also employed globally.” therefore the need for significant investment in XEN901 and next- “This alliance will span multiple years. It’s not just for one proj- generation sodium channel candidates,” Pimstone said, “we made ect. One thing I’m really excited about is learning from the likes the strategic decision to seek a partnership to allow us to more of AWS and by extension Amazon about new ways of working,” comprehensively develop the sodium channel assets, while also Ebadollahi said. investing more heavily in our retained assets, which we believe “The physical transformation this will bring is not just about offer a very significant promise.” tools and technology – although that’s an important ingredient – but also the way of working, acquiring the mindset needed for DEAL TERMS BRING XENON developing these kinds of solutions and digital expertise, and do- MULTIPLE OPPORTUNITIES ing so through a collaboration like this.” The upfront payment from Neurocrine to Xenon includes a $20m “This will contribute to the data science - and the culture of data equity stake, priced at $14.20 per share, which Xenon president science - at Novartis,” he concluded. Ian Mortimer called a significant premium to the biotech’s aver- Published online 5 December 2019 age trading price in recent months. Xenon also can earn a near-

6 | Scrip | December 13, 2019 © Informa UK Ltd 2019 DEALS

than Nav channel drugs that aren’t selective inhibitors, he added. “We believe targeting the Nav1.6 sodium channel makes sense as there is ample scientific literature and human genetic evidence indicating that mutations of the SCN8A gene impact this sodium channel’s behavior and function,” Goodman wrote. “Current anti-epileptic drugs such as phe- nytoin, carbamazepine and lacosamide target Nav channels more broadly, which can serve as directional proof-of-concept in epilepsy, but XEN901 is differentiated as it is designed to specifically target the Nav1.6 channel, which is the most highly expressed sodium channel in the excitato- ry pathways in the central nervous system.” In addition to VY-AADC, a Phase II can- term milestone of $25m upon Neuro- didate obtained in the Voyager partner- crine filing an investigational new drug Neurocrine thinks ship, Neurocrine’s pipeline also includes (IND) application with the US Food and XEN901 offers potential Phase II NBI-74788 in congenital adrenal Drug Administration to advance XEN901 hyperplasia, North American rights to into a placebo-controlled Phase II study in multiple epilepsy Bial-Portela & CA SA’s Phase III Parkin- in SCN8A developmental and epileptic son’s candidate opicapone (FDA action encephalopathy (SCN8A-DEE). Fifty-five indications. date 26 April 2020) and a Phase III label- percent of that milestone fee would be a expansion effort for valbenazine in Hun- further equity investment by Neurocrine tington’s chorea. at a 15% premium to Xenon’s volume- Pimstone said his company’s expertise weighted average share price over the DEVELOPING SPECIALTY FOR in neuroscience and ion channel modula- prior 30 days. NEUROCRINE tion should be complementary with Neu- Mortimer told the investor call he thinks Credit Suisse analyst Evan Seigerman rocrine’s clinical development and com- this is the largest deal around a pre-Phase applauded the deal from Neurocrine’s mercial experience in neurology. III epilepsy candidate to date. “We have perspective in a same-day note, saying it “We believe we have strong rationale secured excellent terms for a pre-efficacy strengthens the company’s “pipeline op- for specifically inhibiting the Nav1.6 and asset, and we believe we have struck the tionality” and adds an encouraging op- Nav1.2/1.6 channels as a therapeutic right balance between near-term cash portunity in epilepsy. strategy for diseases of hyperexcitability, through the upfront payment, near-term SVB Leerink analyst Marc Goodman including epilepsy,” the Xenon CEO said. milestone opportunities and collabora- took a similar view on 2 December, say- “However, this therapeutic approach has tion funding with longer-term value cre- ing investors will be intrigued by the not been tested clinically and will likely ation opportunities through significant opportunity the collaboration brings to require intense and broad development. development milestones and participa- Neurocrine as new mechanisms of ac- That is why we think that Neurocrine’s tion in commercial success,” he said, add- tion are showing potential in epilepsy. investment into XEN901 and related pre- ing that the deal likely extends Xenon’s Specifically, he cited the recent approv- clinical assets provides us the greatest cash runway from 2021 into 2022. als of Zogenix Inc.’s Fintepla (low-dose probability of success to test our thesis In addition to the up to $1.7bn for fenfluramine) and GW Pharmaceuticals broadly with numerous compounds hav- milestones and tiered sales royalties tied PLC’s Epidiolex (cannabidiol) for rare ing different properties and profiles in dif- to XEN901 and the other Nav1.6 and forms of epilepsy, such as Dravet syn- ferent indications.” Nav1.2/1.6 inhibitors covered by the deal, drome. (Also see “Zogenix’ ZX008 Emerg- Published online 2 December 2019 Neurocrine funds all development costs es As Strong Contender In Rare Epilepsy” for these programs along with a research - Scrip, 12 Jul, 2018.) collaboration of up to three years (speci- Goodman pointed out that Neuro- fied at a minimum of 10 full-time equiva- crine plans to target both SCN8A-DEE LET’S GET lent personnel). Xenon also holds an op- – an ultra-orphan indication thought tion to fund 50% of the US development to have well under 1,000 patients – and SOCIAL costs of XEN901 or another candidate in the broader indication of focal epilepsy @PharmaScrip exchange for increased royalties up to in adults. XEN901’s mechanism of ac- 20% of US sales. tion may offer a better therapeutic index

scrip.pharmaintelligence.informa.com December 13, 2019 | Scrip | 7 COMPANIES

Lilly Taps Loxo Execs To Bring Back That Biotech Feeling

JOSEPH HAAS [email protected]

li Lilly & Co.’s turnaround in oncology has been a long time Hyman, currently the head of early drug development at Memo- coming. It’s been a historic focus for the Indianapolis-based rial Sloan Kettering Cancer Center, will join the team in January as Ebiopharma, and the company has made some sizeable addi- its chief medical officer. The unit will report to Lilly chief scientific tions in recent years to build out its oncology business. Now the officer Daniel Skovronsky. company is leveraging its acquisition of Loxo Oncology Inc. to es- When Lilly acquired Loxo in January, it placed a significant bet tablish a new cancer R&D unit led by former Loxo execs and incor- on that company’s tumor-agnostic, genetic approach to selecting porating personnel from Lilly Research Laboratories. patients and treating cancer. (Also see “Lift-Off For Lilly In Cancer Big pharmas have a history of trying to replicate the nimbleness Genetics With Loxo Buy” - Scrip, 7 Jan, 2019.) The $8bn price tag and efficiency of a biotech company within their larger organiza- factored out to $235 a share, a 68% premium over Loxo’s closing tion. And companies often try to maintain the success of an ac- stock price the day before the transaction was announced. But quired company by letting it operate somewhat independently the deal has yielded results already, when RET (rearranged during of the parent corporation – such as Gilead Sciences Inc.’s decision transfection) kinase inhibitor selpercatinib showed high response with Kite Pharma Inc. earlier this year. rates in thyroid cancer in September, after Lilly already announced Roche offers a close parallel to Lilly’s new move, as it has kept it would file the drug for US approval in RET fusion-positive non- Genentech Inc. as a separate entity in many ways since the 2009 small cell lung cancer. (Also see “Lilly’s Loxo Bet Pays Off In Thyroid buyout, with its own governance, budget partnering teams and Cancer, A Second Indication For Selpercatinib” - Scrip, 30 Sep, 2019.) portfolio. (Also see “Genentech’s Early Cancer Technology Scout On Partnering, Roche Setup & BD Challenges” - Scrip, 30 Mar, 2017.) Its GETTING PAST SOME SETBACKS Genentech Early Research and Development (gRED) unit is an in- That early success offered a contrast to the Phase III failure of dependent, autonomous R&D unit within Roche, driving much of Lilly’s immuno-oncology candidate pegilodecakin in metastatic the pharma’s oncology drug development. pancreatic cancer in October. (Also see “Lilly’s Pegilodecakin Fails With the early successes Loxo has brought to Lilly, the company Pancreatic Cancer Test” - Scrip, 17 Oct, 2019.) Lilly still holds out is hoping that the biotech’s old management team can offer an hope for the compound – the basis for the $1.6bn buyout of Armo insightful approach to oncology discovery and R&D, including BioSciences Inc. in 2018 – as a combination agent with checkpoint through deal-making. Announcing the new structure, Lilly said inhibitors in NSCLC, however. the unit will “curate a balanced pipeline of medicines – whether Shortly after the Loxo deal was announced, Lilly sustained an- internally or externally discovered” to help gain Lilly a leadership other major cancer R&D setback when its Lartruvo (olaratumab) position in oncology. failed to show an overall survival benefit in soft-tissue sarcoma in In addition to adding to the pipeline via business development, a Phase III confirmatory trial supporting its accelerated approval, the unit, to be called Loxo Oncology at Lilly, will oversee cancer R&D based on a Phase II study. (Also see “Lartruvo Phase III Fail Rocks regardless of the therapeutic modality and also oversee clinical de- Lilly Oncology Plans” - Scrip, 21 Jan, 2019.) velopment and regulatory affairs. Once a drug candidate approach- In addition to selpercatinib, Lilly said its near-term focus will be on es commercialization, it will be turned over to the Lilly Oncology another Loxo candidate, the selective, non-covalent BTK inhibitor Business Unit headed by senior vice president/Lilly Oncology presi- LOXO-305 and a pair of internally discovered candidates – LY3499446, dent Anne White, the company announced 5 December. a selective covalent KRAS GC12 inhibitor; and LY3484356, a selective Leading the new unit will be former Loxo CEO Josh Bilenker, estrogen receptor degrader. Lilly did not specify the development who recently became the pharma’s acting oncology chief when stage or cancer type for either of the latter two molecules. former senior VP-oncology R&D Levi Garraway departed after Lilly is scheduled to present data on LOXO-305, however, at the three years to become Roche’s chief medical officer and head of American Society of Hematology annual meeting 7-10 December global product development. (Also see “Roche’s New Chief Medi- in Orlando, including interim Phase I data from a Phase I/II study cal Officer Levi Garraway Brings Deep Cancer Genomics Expertise” in B-cell malignancies. Also at ASH, the pharma will present pre- - Scrip, 19 Aug, 2019.) It was only July 2017 when Garraway and clinical data activity in Imbruvica (ibrutinib)-resistant chronic lym- then Lilly Oncology president Susan Mahony laid out a revised phocytic leukemia (CLL) and a poster on the drug’s activity against cancer strategy that would center on foundational therapies that various BTK substitution mutations. “inhibit a key dependency within the tumor.” (Also see “Lilly Hopes The Loxo Oncology team will also be charged with adding to To Revitalize Its Cancer Brand With ‘Foundational’ Agents” - Scrip, the pipeline through acquisition and in-licensing opportunities, 25 Jul, 2017.) with Skovronsky saying Lilly hopes to incorporate the Loxo dis- The January 2019 acquisition of Loxo was a major move in covery and development philosophy “at a much larger scale.” Lilly that direction. also stated several early-stage clinical oncology candidates will Joining Bilenker in the leadership of Loxo Oncology at Lilly will be “wound down and terminated,” with disclosure of which can- be former Loxo chief operating officer Jake Van Naarden and for- didates slated for the pharma’s fourth quarter 2019 earnings call mer chief development officer Nisha Nanda. In addition, David in early 2020.

8 | Scrip | December 13, 2019 © Informa UK Ltd 2019 COMPANIES/CHINA

Currently, Lilly’s pipeline lists more efforts in type 2 diabetes and Alzheimer’s regimen,” he said. “So, for me, the question than a dozen clinical candidates for disease, the exec said Lilly is hopeful that is how much space, first of all, can we dif- oncology, including label-expansion data from the Cypress 1 study of pegilo- ferentiate and then how big is the gap? efforts for Verzenio (abemaciclib) into decakin in first-line lung cancer, expected Because I think if we go on to registration- adjuvant and HER2-positive metastatic during the first half of 2020, will yield type trials, we’ll need to have a significant breast cancer and Cyramza (ramucirum- better results than the previous study in improvement over monotherapy or have ab) in NSCLC. pancreatic cancer. He asserted that there a different comparator there. In addition to the Verzenio supple- should be little read-through from the “But also, we’ll be able to read through mental indications and olaratumab, pe- drug’s results in pancreatic cancer to its from that trial to the activity of the agent gilodecakin and selpercatinib, the Phase potential efficacy in lung cancer. in general, which could inform subse- II pipeline includes LY3200882, a TGF beta “When we acquired Armo and acquired quent investigations,” Skovronsky contin- receptor 1 kinase inhibitor being studied pegilodecakin, we commented that this ued. “So, for example, IO failures could be for undisclosed cancer indications. The is something that we see as a high-risk/ an interesting population. Another inter- Phase I pipeline lists seven assets, includ- high-reward opportunity,” Skovronsky esting population is RCC, renal cell carci- ing three immune-oncology candidates noted. “I think the risk profile is differ- noma patients, where there was some ac- targeting IDO1, PD-1/PD-L1 and TIM-3, ent in different indications for sure. And tivity in the Phase I study from Armo.” but details on those candidates are scant. probably, we saw pancreatic cancer as The exec also said he’s confident that Lilly’s recent cancer efforts also include a the highest-risk trial. Armo had started selpercatinib holds a best-in-class profile partnership signed in October 2017 with that Phase III when we acquired the com- among RET inhibitors. “Patients haven’t Germany’s CureVac AG to investigate po- pany and the asset, and so we weren’t in been on this drug that long, but the du- tential next-generation cancer vaccines. a position to stop the trial.” rability data continues to be very impres- (Also see “Lilly’s Billion-Dollar Deal With In NSCLC, the study is investigating the sive,” he said. “I think it has set a very high CureVac For ‘Next Generation’ Immuno- combination of pegilodecakin with Merck bar for any follow-on competitors.” therapies” - Scrip, 19 Oct, 2017.) & Co. Inc.’s Keytruda (pembrolizumab) ver- “We also have all of the attributes we sus Keytruda monotherapy. wanted,” Skovronsky added. “We have ex- SKOVRONSKY TALKS “The hope, if this drug is active in this traordinary intracranial activity, which is UP PIPELINE population, is that we’ll see a pretty wide very important. We have activity against Speaking at the Evercore ISI HealthCONx margin in efficacy. I think it would have to gatekeeper mutations, which we fully ex- conference 4 December, Skovronsky be- be given the fact that there are alterna- pected and saw. And we have a specificity trayed no hints that a major reshuffling of tives to patients that IO monotherapy can profile. That means we don’t have any off- Lilly’s cancer R&D engine was imminent. be surpassed with, for example, a KEY- target safety issues.” While also discussing the pharma’s R&D NOTE-189 [Keytruda plus chemotherapy] Published online 5 December 2019 What Lies Beneath China’s Steep Price Cuts For New Drugs BRIAN YANG [email protected]

he dust may have settled but the debate is just starting. Steep Price Cuts In Exchange For Coverage May Not Be Worth As soon as the 2019 version of the China National Reim- Celebrating, One Insider Says T bursement Drug List (NRDL) was out, there was a rush of celebration among companies whose products were included in the list. Some companies even seemed to have already prepared their press statements, releasing them just after the 28 November official announcement. Several multinational drug makers including Merck & Co. Inc., Novartis AG, Sanofi and Roche put out releases close on the heels of the announcement released by the National Health Security Administration. Novartis, in a post on the popular Chinese social portal WeChat, hailed that seven of its products had been included in the list, including Entresto (sacubitril/valsartan), Lucentis (ranibizumab), Afinitor (everolimus). The Swiss drug maker also noted that 20 drugs have been covered since 2017 when the last NRDL was updated. French firm Sanofi also put a WeChat statement announc- US drug maker Gilead Sciences Inc. is among those that have ing three product inclusions: Aubagio (teriflunomide), Renagel seen one of the deepest price cuts; two of its direct acting (sevelamer) and Lyxumia (lixisenatide). agent hepatitis C drugs, Epclusa (sofosbuvir and velpatasvir)

scrip.pharmaintelligence.informa.com December 13, 2019 | Scrip | 9 CHINA/ARTIFICIAL INTELLIGENCE

and Harvoni (ledipasvir and sofosbuvir) were among three HCV (nivolumab) from BMS and Keytruda (pembrolizumab) from Merck treatments that have seen on average 85% price cuts. Gilead & Co, and three domestic antibodies, plus one more coming. In or- executive expect the coverage to expand access to the drugs der to compete in the crowd, makers are elbowing out each other in China. to get coverage with lowered prices, but still, only one PD-1, Tyvyt “It’s unprecedented that four new products can get reimburse- (sintilimab) from Innovent Bio received NRDL coverage. ment just after around one year of launch,” noted Roger Luo, Gil- ead China GM via a LinkedIn post. “It’s a new milestone for Gilead SELECTION PROCESS STIRS UP China after we got seven new products approved in the last two COMPETITIVENESS years…in 2019, there will be 60,000-plus patients who can benefit The largest revamp to the national medical coverage list, the 2019 from our innovative products.” NDRL and price negotiation is a competitive process, especially In an interview with China state broadcaster CCTV, Luo said for widely prescribed drugs such as direct acting agent (DAA) hep- the prices will “allow common Chinese people benefit from these atitis C drugs that will treat millions of patients in China. drugs with slashed prices, and benefit from value brought by the The process starts from the selection of candidates to be in- latest innovation and technologies.” cluded in the list by an extremely large pool of physicians, 10,000 The excitement about expansion of access was echoed by oth- in total, and only the drugs selected by them are subject to price ers. Sanofi said the inclusion will allow timely access to new treat- negotiations and inclusion consideration. ments, increasing patients access and reducing disease burden. The sheer number of experts not only present uncertainties but the selection process alone makes the process challenging LOW PARTICIPATION, STEEP CUTS, to predict. The competitiveness is more pronounced in the case UNPREDICTABLE OUTCOME of hepatitis C drugs. Unlike for other drugs, government negotia- However, one industry insider told Scrip that the decision to tors used an intensely competitive bidding process for HCV drugs, slash prices this deep in exchange for the coverage is much citing that large patient population and high treatment costs as- more complex. sociated with them. For one, out of 119 newly approved drugs that qualified for the The process only allowed two makers to compete for one class reimbursement coverage, 70 drugs were eventually included, of the treatment, noted Xianjun Xiong, director of the National leaving 49 (or over 40% of drugs) not included in the list. Not only Health Security Administration. “The process is not price negotia- products from multinational drug makers, four of 12 Chinese do- tion but a price bidding,” the insider maintained, adding that it’s a mestically developed novel new drugs were not included as there diversion of the original design of the process. was no agreement on the pricing. China has one of the world’s largest HCV carriers, with an es- Secondly, the average prices were slashed by 60.7% across the timated 10m people infected, and over 50% of them belong to board, a 65% cut for cancer drugs and antidiabetes therapies genotype 1b, according to Gilead. and 85% discount for hepatitis C treatments. “Many globally well- Another US drug maker Merck & Co whose Zepatier (elbasvir known and high-priced drugs are now at prices that are afford- and grazoprevir) was included in the final coverage list, said the able to common people, nearly all important drugs are now of- competitive process shows the importance the government is fered at global low prices,” hailed the government in a statement placing on HCV treatment. 28 November. “There were only two DAA agents for hepatitis genotype 1b But the industry insider noted that “participation is low, the included in the list, showing that the government places a high price cuts are steep, and the outcome is still hard to tell”. importance to such agents to fight HCV,” said Merck China GM First, competition had made the decision to get the coverage Joseph Romanelli in a 28 November statement via the company more urgent than two years ago when the price negotiation mech- Wechat platform. anism was first introduced to be part of the reimbursement process. Still, it’s too early and hard to predict outcomes of the steep price The competitiveness is evident among high-priced novel prod- cuts, the insider stressed, but a right pricing strategy will be top pri- ucts including immune-oncology drugs. Already, there are five ority for any drug maker eyeing coverage in such negotiations. PD-1 drugs approved and launched in China, including Opdivo Published online 5 December 2019 Pharma Finds Its Way in AI LEAH SAMUEL [email protected]

harma has been slower than other “You’re taking people who have deep ex- from quickly analyzing numerous medical industries in fully embracing artificial pertise in lots of areas and all of a sudden images and research papers to sorting drug Pintelligence technology, Peter Hen- you’re saying there’s this new thing that can candidates and potential patients. stock, head of AI and machine learning at solve all your problems across the board. “All the literature, all the intelligence, Pfizer Inc., toldScrip at a recent conference And they’ve heard that before,” he said. can go through AI,” he said. “It’s going help on artificial intelligence and biopharma. AI has taken root in drug discovery, but it you figure out which patients are going to He cited a certain wariness in the industry. has a lot more to offer in drug development, benefit, which patients should be studied,

10 | Scrip | December 13, 2019 © Informa UK Ltd 2019 ARTIFICIAL INTELLIGENCE

which patients might be the first to drop detected around 40 projects that didn’t out of study, which clinics are the right get [past] the pilot project barrier, which ones, which biomarkers to target, and Pharma is watching, means they didn’t go into production. The which compounds to test. AI is going to and making definitive, question is why?” change everything in drug development After a closer look at some of the stalled from start to finish.” if careful, moves into projects, Sanofi realized its initial mistake. Pharma is watching, and making de- “It started with us relying on the vendors finitive, if careful, moves into the space. the space. to put together all the machine learning ”There’s more buy-in this year than last and the AI components,” Cornejo said. It year,” Henstock said. turned out that some vendors Sanofi had Some pharma executives suggest that chosen simply didn’t have experience with AI and pharma have just started getting large-scale or specialized projects. to know each other. That process was the “You need to have some baseline before focus of the sessions on pharma at the AI you start building on top of that; if you World conference in Boston, where drug don’t have that, pretty much the vendor is makers shared their experiences introduc- learning AI with us.” ing AI to their companies, offering advice Cornejo advises testing a vendor’s capa- for others who want to do the same. bilities before signing a contract. “My first They emphasized that investing in AI question is, if I send you this PDF are you should be based on determinations of willing to run it through your tool or your what’s possible, what’s necessary and cost if we followed a traditional approach. If engine – first, to see if it works, and then to what’s valuable. we use these methods, and if we used the give me an outcome?” tools that we based on these methods, then Cornejo also noted that Sanofi’s past MAKE THE CASE EARLY & OFTEN this is how much money we’ll save you.” vendors often didn’t know enough about “We are going through big field of change,” It’s not enough to just promise such health care or pharma to recognize what said Angeli Moeller, AI lead at Bayer AG. value, Moeller said. Once the work is un- would work, or not work, for Sanofi. “And Calling the technology a “radical transfor- derway, there needs to be a way to look in [pharma] vendors are supposed to have a mation” for pharma, she added that suc- on the process. Regularly checking in with health care background.” cessfully bringing AI into a drug company updates should start as soon as there is That’s a tougher problem, Pfizer’s Hen- starts with building the case for investment. agreement to fund the AI project. stock agreed, suggesting that, ideally, “[Any company would] want to invest “It’s not ‘This has my approval and I will pharma would have its own AI specialists. in something that gives a top-line and never look at it again,’” Moeller said. “It’s “But it’s difficult to get talent,” he said. “If bottom-line impact,” Moeller said. “But AI that he will track whether or not we de- you are an expert at AI, would you want is just a tool. it’s just a method. It’s just the liver on it. Our CFO needs to know what to work in pharma, which only sometimes way you’re getting there.” impact we’re going to have on our phar- does AI, or a place like Google, which is Moeller talked about a data project at ma bottom line and top line and he tracks running it? In pharma, you need people Bayer. “They began by really building out it. We’re there, at the executive committee with the AI skills, but who also have the the data lake that they need to store the and our board of management on a regu- science. And that’s a harder fit.” electronic medical records, to intercon- lar basis presenting our results.” For its part, Sanofi turned its struggles nect them with the clinical data,” she said into a set of guidelines for AI teams going “But our CFO kept saying, ‘No, you’ve got BUILD THE RIGHT TEAM forward. As early adopters demonstrate to start with the value case. Build the data Presentable results come from having a both the potential for AI and machine architecture after you’ve shown the value knowledgeable AI team from the start, said learning to improve drug discovery and de- case works, after you’ve shown me the Eduardo Cornejo, AI lead at Sanofi. He add- velopment, more companies will learn from return on investment. Then I’ll give you ed that his company learned that lesson the their experiences. That should pave the way money to build data architecture.’ hard way, after various AI projects failed. forward for the more wholesale embrace of “So you’ve got to start with the value “What we have done in almost two these new technologies that Pfizer’s Hen- case,” she said. “To your CFO, you can say, years is to collect all the information about stock and others are hoping to see. for example, this is what your Phase III study AI projects in the company,” he said. “We Published online 2 December 2019

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We would like to thank everyone who attended the MEDIDATA’S COMMUNITY PARTNERSHIP th OF THE YEAR AWARD 15 Annual Scrip Awards, held on 4 December at AstraZeneca’s Energy Challenge the Hilton on Park Lane, London. MSD’S INNOVATION AWARD Mogrify’s direct cellular conversion technology EXECUTIVE OF THE YEAR – FOR SMALL The evening, hosted by broadcaster Fiona Bruce, CAP & PRIVATE COMPANIES Highly Commended: Ryan Cawood, Founder and CEO of OXGENE was a celebration of excellence across all parts of Lyndra Therapeutics Inc.’s ultra-long acting pill the pharmaceutical, biotech and allied industries BEST CONTRACT RESEARCH ORGANIZATION IQVIA’S CLINICAL ADVANCE OF THE YEAR AWARD – FULL-SERVICE PROVIDERS and recognized both corporate and individual Novartis/AveXis’ Phase III STR1VE study of Zolgensma ICON achievement. in spinal muscular atrophy Highly Commended: PPD FINANCING DEAL OF THE YEAR SAVE THE DATE: Scrip Awards 2020 Galapagos’s $345m secondary follow-on financing BEST CONTRACT RESEARCH ORGANIZATION – SPECIALIST PROVIDERS Wednesday 2 December WORLDWIDE CLINICAL TRIALS’ LICENSING DEAL OF Quanticate Hilton on Park Lane, London THE YEAR AWARD Innate Pharma and AstraZeneca’s five-part deal WUXI APP TEC’S BIOTECH COMPANY including monalizumab in immuno-oncology OF THE YEAR AWARD Galapagos www.scripawards.com BEST PARTNERSHIP ALLIANCE Cancer Research UK, LifeArc and Ono Pharmaceutical SYNEOS HEALTH’S BEST NEW DRUG AWARD Cancer Immunotherapy Alliance Alnylam Pharmaceuticals’ Onpattro (patisiran) for polyneuropathy of hereditary transthyretin- BUSINESS DEVELOPMENT TEAM OF THE YEAR mediated amyloidosis Procter & Gamble’s Business Development Team PHARMA COMPANY OF THE YEAR EXECUTIVE OF THE YEAR – FOR LARGE & MEDIUM Takeda Pharmaceutical Co Ltd CAP COMPANIES Menelas Pangalos, EVP and President, R&D SCRIP’S LIFETIME ACHIEVEMENT AWARD BioPharmaceuticals, AstraZeneca Jane K Osbourn OBE

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J&J Quickly Advances BCMA-Targeting CAR-T As JNJ-4528 Shows 100% Response MANDY JACKSON [email protected]

evelopment of Janssen Pharma- However, Janssen’s JNJ-4528 also is de- ential expansion of CD8-positive T-cells, ceutical Cos.’ JNJ-4528 is sev- livering impressive results, with a 100% which “suggest that the high anti-myelo- Deral months behind the most ORR at six months for 29 patients with ma activity of JNJ-4528 seen at a relatively advanced B-cell maturation antigen fourth-line-plus multiple myeloma treat- low T-cell dose is potentially related to its (BCMA)-targeting chimeric antigen reed with a median dose of 730,000 cells per preferential and consistent in vivo expan- ceptor T-cell (CAR-T) therapy, but the kilogram, up from a 91% ORR in the ASH sion of CD8-positive CAR-T cells,” the com- Johnson & Johnson subsidiary is running abstract released in November when just pany said. at full speed to generate pivotal trial re- 21 patients had been assessed. Janssen’s partner on JNJ-4528, China’s sults and move into earlier lines of multi- Among the responses observed in Legend Biotech Corp., also reported up- ple myeloma treatment based on strong CARTITUDE-1, 69% of patients achieved dated data at ASH from the LEGEND-2 Phase Ib responses. a CR in the Phase Ib portion of the study, study conducted in China with LCAR- Even so, Bristol-Myers Squibb Co. and including 66% with stringent CRs. Alto- B38M, which uses the same CAR-T con- its partner bluebird bio Inc. are working gether, 86% of JNJ-4528-treated patients struct as the treatment being tested in hard to maintain the likely first-to-market achieved a very good partial response CARTITUDE-1. The overall response rate advantage for their BCMA-targeting CAR- (VGPR) or better while the other 14% had in the new LEGEND-2 data was 88% with T therapy idecabtagene vicleucel (ide-cel; a partial response (PR). All of the evalu- a CR rate of 46%; 64% of MRD-negative bb2121). They defended that position by able patients achieved minimal residual patients who achieved a CR remain pro- reporting top-line results from the Phase II disease (MRD)-negative status at 28 days gression-free. Median progression-free KarMMa pivotal trial on 6 December – less post-infusion. At six months, 27 of the 29 survival (PFS) was 20 months, but me- than 24 hours before Janssen revealed re- patients were progression-free. dian PFS for MRD-negative patients was sults from the Phase Ib portion of its CAR- “We’re seeing a very rapid time to re- 28 months. TITUDE-1 clinical trial at a press briefing sponse – the mean time to response is The updated LEGEND-2 results show at the American Society of Hematology about a month,” Janssen’s Craig Tendler that many patients remain in response a (ASH) annual meeting in Orlando, FL. told Scrip. Tendler is vice president of late- year later compared with the 88% ORR in Bristol recently acquired its share of stage development and global medical 57 patients that Legend reported at ASH bb2121 in the nearly $76bn acquisition of affairs for oncology, hematology and sup- in December 2018, including a 74% CR Celgene Corp.; the big pharma and blue- portive care. rate. (Also see “Poseida, Legend/Janssen bird intend to submit the CAR-T therapy Look To Snag Celgene/Bluebird’s BCMA for approval by the US Food and Drug DURABILITY IS KEY Crown” - Scrip, 4 Dec, 2018.) Administration and other regulators in the The ability to maintain response is a key first half of 2020. (Also see “With Celgene issue for CAR-T therapies, with durabil- SAFETY RESULTS COMPARABLE Acquisition Closed, Bristol Faces Major ity of response dependent on continued FOR BB2121 AND JNJ-4528 Milestones” - Scrip, 21 Nov, 2019.) Janssen expansion and persistence of the reengi- In terms of safety, bb2121 and JNJ-4528 is attempting to quickly catch up, having neered T-cells. In the case of autologous look fairly similar to date with low rates of fully enrolled the Phase II portion of CAR- treatments like bb2121 and JNJ-4528, severe cytokine release syndrome (CRS) TITUDE-1, which is intended to serve as a patient’s own T-cells are removed, ge- and neurotoxicity, which can rapidly esca- a pivotal trial. The J&J subsidiary has also netically reengineered to target a specific late in CAR-T-treated patients. moved JNJ-4528 into Phase II and III stud- cancer antigen, then infused back into Bristol and bluebird reported that 83.6% ies testing the CAR-T therapy in patients the patient. (107/128) of patients treated with bb2121 who failed fewer lines of therapy than the Bristol and bluebird reported median experienced CRS and 18% (23/128) had patients enrolled in CARTITUDE-1. duration of response across all three neurotoxicity. However, grade 3 or higher Bristol and bluebird reported a 73.4% bb2121 doses tested in KarMMa was 10.6 CRS was observed in only seven patients objective response rate (ORR) and 31.3% months with median progression-free (5.5%), including one patient who died, complete response (CR) rate for bb2121 survival of 8.6 months. and only four patients (3.1%) had grade 3 in 128 relapsed and refractory multiple It remains to be seen if JNJ-4528 will or higher neurotoxicity events, but there myeloma patients, who all received at meet or beat bb2121’s duration of re- were no grade 4 or 5 events. least three prior treatment regimens, sponse, but Janssen also was set to report Janssen reported that the most com- with a median of 11.3 months of follow- technical data for JNJ-4528 at ASH on 9 mon adverse events observed with JNJ- up in the KarMMa study, setting a high December that show expansion of CD8 4528 in CARTITUDE-1 were CRS (93%), bar for competitors. and CD8-positive CAR-T cells with prefer- neutropenia (93%, all grade 3), anemia

14 | Scrip | December 13, 2019 © Informa UK Ltd 2019 ASH MEETING

(86%, 55% grade 3) and thrombocytope- tients in the JNJ-4528 cohort will receive patients with extramedullary tumors had nia (86%, 69% grade 3). Of the CRS events, one or two courses of PVd or DPd plus a undetectable tumors. The 17 patients in 86% were grade 1 or 2, with one grade 3 short course of immune system-condi- remission at seven months had a 28.8- event and one patient who died of com- tioning chemotherapy before infusion week median duration of response. Cel- plications from grade 5 CRS at day 99. with the CAR-T cells. lyan is planning a larger Phase II trial for its There were three cases of neurotoxicity “We’re very much modeling this after BM38 cells in the US and China. (10%), but only one of those was a grade what we did for Darzalex, in that when Multiple bispecific antibodies target- 3 neurotoxic event that occurred together you see very compelling single-agent ac- ing BCMA and CD3 are in development as with CRS. tivity in very, very refractory patient popu- well, including REGN5458 from Regener- “The safety profile is also very consis- lations we are all-in in terms of broaden- on Pharmaceuticals Inc., which presented tent with what was reported previously ing the program and focusing on certain safety and early clinical activity at ASH in in the LEGEND study from China with the patient segments that are at high risk and a poster on 8 December. Three patients same CAR-T construct … with the major- trying to intervene earlier, where the pa- were treated as of the 12 July abstract ity of patients experiencing mild to mod- tient’s immune system may actually be at cutoff date, including one patient who erate cytokine release syndrome, usually a higher functioning level and therefore achieved a VGPR, one with progressive coming on at about seven days and re- you may be able to see better results with disease and one with stable disease. solving over the next few days,” Tendler the BCMA CAR-T,” Tendler said. Off-the-shelf products, like ADCs and said. “The neurotoxicity, which is a very “The CAR-T function and their ability to bispecific antibodies, are less complicat- important concern, was very, very infre- kill tumor cells is very much dependent ed, more convenient and likely less expen- quently observed.” upon the potency and the strength of the sive than autologous cell therapies, but “All of that is so far a very good profile CAR-T, so perhaps if we start with patients whether or not they are more effective that we think bodes well for a BCMA CAR-T with more functional immune systems and/or safer than CAR-T therapies is still that is differentiated and hopefully should and more robust T-cells … they may actu- an unanswered question. even look better when it’s brought into ally be stronger, more effective and in fact Nevertheless, Janssen is exploring other earlier-stage disease,” he added. hopefully deliver better anti-myeloma ac- BCMA-targeting modalities besides the tivity,” he continued. CAR-T construct used for JNJ-4528 and MORE STUDIES COMING other multiple myeloma drug targets. The The Phase II portion of CARTITUDE-1 is COMPETITORS COMING IN company has two bispecific antibodies – fully enrolled and Janssen has initiated BCMA CLASS OUTSIDE CAR-TS one targeting BCMA and CD3 and another two new studies in less advanced pa- While Janssen is moving quickly to catch targeting GPRC5D and CD3 – in Phase I. tients. The Phase II CARTITUDE-2 trials up with Bristol and bluebird, CAR-T thera- Those antibodies simultaneously target is enrolling multiple cohorts of multiple pies are one of multiple modalities being an antigen on cancer cells and a protein myeloma patients, including individuals used to target BCMA in multiple myeloma. on T-cells to recruit the patient’s own T- who are relapsed or refractory after one GlaxoSmithKline PLC may be first to mar- cells to the myeloma cells. to three prior lines of therapy, including ket with a BCMA-targeting product – the “They are not CAR-Ts; they are meant autologous stem cell transplant; patients antibody-drug conjugate (ADC) belan- to have the same ultimate purpose at the who progressed quickly after front-line tamab mafodotin (GSK2857916) – which end in terms of activating T-cells to de- therapy; and patients who received a prior the company plans to submit for regula- stroy myeloma cells, but they are off-the- BCMA-directed therapy. tory approvals before the end of this year. shelf,” Tendler said. The Phase III CARTITUDE-4, a random- (Also see “DREAMM-2 Put GSK’s BCMA Drug “It’s very much in line with our overall ized trial of JNJ-4528, has not yet begun In Pole Position In Multiple Myeloma “ - mission and strategy in myeloma to utilize to enroll patients. This study will evaluate Scrip, 23 Aug, 2019.) all of the agents in our armamentarium the CAR-T therapy in multiple myeloma Bispecific therapies also are emerg- and our pipeline and to develop those patients who are relapsed or refractory ing as competitive options in the BCMA combination regimens that can really after treatment with Bristol/Celgene’s class, including a CAR-T candidate devel- move the science forward and eliminate Revlimid (lenalidomide) against two other oped by China’s Cellyan Therapeutics Co. disease, ultimately to cure some subsets regimens that frequently are used in this Ltd. and known as BM38 cells, targeting of patients,” he continued. “We now actu- population. BCMA and CD38. In Phase I results slated ally have some of the best opportunities in The Phase III study’s three arms will for a 9 December presentation at ASH our pipeline to move that science forward test JNJ-4528 versus Bristol/Celgene’s in 22 fourth-line or greater multiple my- and really try to eliminate the disease.” immunomodulatory agent Pomalyst eloma patients, including nine with ex- Published online 8 December 2019 (pomalidomide) and Takeda Pharmaceuti- tramedullary tumors, 18 patients (90.9%) cal Co. Ltd.’s proteasome inhibitor Velcade treated with BM38 cells had MRD-neg- UniQure Aiming To Be (bortezomib) plus dexamethasone (PVd) ative disease after a median of 36 weeks First With Hemophilia B and versus the combination of J&J’s CD38 of follow-up. Twelve patients had a strin- Gene Therapy: inhibitor Darzalex (daratumumab) plus gent CR (54.5%) and seven had a good or https://bit.ly/2LDxjrd Pomalyst and dexamethasone (DPd). Pa- very good PR (31.8%). Eight of the nine

scrip.pharmaintelligence.informa.com December 13, 2019 | Scrip | 15 CTAD MEETING

Biogen’s Big Day Arrives, But Aducanumab Results Don’t Answer Key Question MANDY JACKSON [email protected]

iogen’s closely watched Phase III cebo as assessed by CDR-SB, which was results for its amyloid-targeting statistically significant (p=0.01), while Btherapy aducanumab in the treat- high-dose aducanumab showed an im- ment of patients with early Alzheimer’s provement versus placebo in ENGAGE, disease, presented on 5 December at but the difference was not significant. the Clinical Trials in Alzheimer’s Dis- The company said at the time that the ease (CTAD) meeting in San Diego, did difference between the results of the two not answer a big outstanding question: Phase III studies was explained by clinical Can the drug win US Food and Drug trial protocol changes that allowed for Administration approval? patients with the ApoE4 gene, which is The company presented a complex associated with early diagnosis and rapid dataset, including results only for pa- progression of Alzheimer’s disease, to be tients treated with the highest dose of retreated after experiencing the poten- aducanumab based on a fourth and final tially serious side effect of amyloid-related clinical trial protocol change that allowed Unanswered: Is FDA imaging abnormalities (ARIA) and to be ti- for patients with the ApoE4 gene to be ti- approval of aducanumab trated up to the higher aducanumab dose. trated up to the highest dose. This cut of Since ENGAGE began enrolling pa- the data showed statistically significant re- possible? tients before EMERGE, more patients sults for the primary endpoint of change in EMERGE were exposed to the higher from baseline at 18 months in cognitive dose – 10mg/kg administered intrave- decline as assessed by the Clinical Demen- nously once monthly – for longer periods tia Rating-Sum of Boxes (CDR-SB) in both of time. Haeberlein indicated in her CTAD the EMERGE and ENGAGE studies, where- GAGE trials short in March after an interim presentation of the Phase III data that as in the intent-to-treat analysis with twice futility analysis found the studies were the median cumulative dose exposure in as many patients only the EMERGE results not likely to be successful. (Also see “Why EMERGE (n=1,643) and ENGAGE (n=1,663) for the highest aducanumab dose were Biogen/Eisai’s Aducanumab Failure Is Not was 116mg/kg before the fourth proto- statistically significant. The End Of Amyloid Hypothesis” - Scrip, 21 col amendment was implemented and The conflicting datasets could pose Mar, 2019.) The companies then reversed 153mg/kg after. challenges at the FDA, since Biogen and course in October when they said further With that in mind, Haeberlein presented its partner Eisai Co. Ltd. will seek approval analysis of the data supports a BLA, which the EMERGE and ENGAGE results sepa- to treat a disease with several million pa- the FDA agreed would be appropriate to rately, but then directed attention to the tients. The Alzheimer’s Association esti- submit. post-protocol version 4 results for patients mates that 5.8 million people in the US With few detailed data points, analysts treated with 14 monthly infusions of adu- have Alzheimer’s disease and the number have spent the last two months debat- canumab at 10mg/kg. will grow to 14 million by 2050. ing whether Biogen and Eisai have the In EMERGE, CDR-SB scores declined Biogen has said that the FDA gave the right data to not only win FDA approval, by 0.53 points in the high-dose group, green light for a biologic license applica- but to convince doctors to prescribe the which was a 30% difference from the tion (BLA) filing based on the EMERGE and drug and payers to reimburse its poten- change in the placebo group at 18 ENGAGE results, and the company said it tially high cost. There’s no doubt, however, months (n=288) in the post-protocol will complete the BLA submission early that millions of patients and their caregiv- version 4 subgroup. In ENGAGE, CDR-SB next year, but that doesn’t mean approval ers are clamoring for a disease-modifying scores declined 0.48 points in the high- in the US or elsewhere is guaranteed. Sa- drug. Aducanumab would be the first-ev- dose group (n=261), which was a 27% mantha Budd Haeberlein, Biogen’s vice er Alzheimer’s therapy to treat the under- difference from the placebo group. Both president of late-stage clinical develop- lying cause of the disease. were statistically significant. ment, confirmed during a same-day in- In the larger intent-to-treat dataset, vestor call that the company is preparing DATA CONTROVERSY ONGOING however, only the EMERGE result was global submissions for aducanumab. Biogen claimed in October that patients statistically significant at the highest adu- Biogen and Eisai are facing skepticism treated with the higher of two aducanum- canumab dose (n=547), with a 0.40-point about their filing plans because the com- ab doses in the EMERGE study had a 23% decline in CDR-SB scores, representing panies cut the Phase III EMERGE and EN- reduction in cognitive decline versus pla- a 23% reduction versus placebo. In EN-

GAGE, CDR-SB scores increased by 0.03 call for FDA to approve based on the tients on the drug during the clinical trials, points for patients treated with the high- data and it would be political pressure indicating that they expect those patients est dose of aducanumab (n=555), which that forces the hand.” to enthusiastically resume treatment. was only a 2% difference versus placebo. Yee said in a 5 December note that the Stephen Salloway, a neurology profes- question of whether the agency is likely to sor at Brown University, said that “every SKEPTICISM CONTINUES AS approve aducanumab based on the cur- patient and family is very enthusiastic NEW QUESTIONS EMERGE rent dataset remains unanswered, along about returning and being part of that … Many were skeptical of Biogen’s explana- with several other questions, such as how we’ve had many studies that have termi- tion for the differences in the EMERGE and many ApoE4 patients were in the protocol nated early recently and we haven’t had ENGAGE results in October when Biogen 4 subgroup, why response curves for adu- that response with any other treatment.” and Eisai announced their plan to seek ap- canumab improved steeply from week 50 Similarly, Sharon Cohen, medical direc- proval early next year based on two Phase to week 78, what geographical differences tor at the Toronto Memory Program in III studies that were stopped for futility there were in the results, whether the re- Canada, said “this is exactly the case in just seven months earlier – skepticism that sults may be impacted by unblinding the Toronto at our site as well,” despite the does not seem to have changed with the studies to investigators and patients, and inconvenience of going to the clinic for a new details and subgroup analysis pre- if stopping and then restarting treatment monthly infusion. sented at CTAD. affected the data readouts. Salloway, Cohen and Paul Aisen, direc- “As many had anticipated, the magni- In response to a question about pa- tor of the Alzheimer’s Therapeutic Re- tude of effect on cognitive endpoints was tients experiencing ARIA and whether this search Institute at the University of South- small,” Datamonitor Healthcare analyst Pa- impacted data assessments for those pa- ern California, hailed the EMERGE results mela Spicer wrote on 5 December. “Look- tients, Haeberlein noted during Biogen’s in particular as representing a major ad- ing at just the final data, which will serve investor call that patients with ARIA are vance for Alzheimer’s treatment. as the basis for the FDA filing, ENGAGE aware of what’s going on because they “The data is complex. I think that the failed to demonstrate a statistical ben- may need more imaging or a dose inter- futility decision was highly unfortunate efit on ADAS-Cog (Alzheimer’s Disease As- ruption, but the raters who assessed the and puts us in the situation of inter- sessment Scale-Cognitive Subscale), CDR- EMERGE and ENGAGE patients were blind- preting complex data, but clearly the SB (Clinical Dementia Rating Scale Sum ed to whether or not patients had been di- EMERGE final analysis is positive,” Aisen of Boxes), and MMSE (Mini-Mental State agnosed with ARIA. said. “When we consider the difference Exam), with the latter endpoints showing In terms of whether ARIA will be a in the timing of enrollment into ENGAGE numerical worsening.” problem for prescribers in the real world, relative to the protocol version change “In contrast, EMERGE showed miniscule, if aducanumab is approved, Haeberlein and the resulting reduced exposure to but significant, improvement on all of said, “we in our studies and other sponsors the effective high dose of aducanumab, I these endpoints, achieving less than half have learned a lot about ARIA in the last think the data from ENGAGE and EMERGE of what has been reported to be minimally five years. The vast majority of ARIA does can be considered consistent.” clinically important differences on these not seem to be problematic.” In most cas- “Most patients and providers are likely outcomes,” Spicer continued. “Looking at es, patients safely resumed treatment with to endorse this [protocol 4] subset analy- the graphs depicting longitudinal changes their prior aducanumab dose, she noted. sis, despite its questionable statistical from baseline seems to show a lack of dose “We would never want to dismiss safety, basis, and for that reason, we expect response on CDR-SB and no separation however we would not have implemented ‘aducanumab excitement’ to get even from low dose on ADAS-Cog at weeks 26 these protocol amendments if we had not higher,” SVB Leerink analyst Geoffrey and 50 in the EMERGE study. Further, the gotten more comfortable with ARIA, its Porges said in a post-presentation note. 78-week results only represent around 50% risks and how to manage it,” Biogen execu- “We continue to believe that aducanum- of the patients in each arm, whereas the 50- tive vice president of R&D and chief medi- ab is likely to be approved.” week results depict closer to 80% per arm cal officer Alfred Sandrock told the com- However, most analysts indicated that (about 290 versus 430 patients per arm).” pany’s investor call. Biogen intends to run the data presented at CTAD provided Biomedtracker lowered the likelihood a re-dosing study, which will give EMERGE more details, but raised more questions, of approval for aducanumab by 6% to and ENGAGE trial participants a chance to including Wedbush Securities analyst 38%, which is 14% below average for get back on aducanumab treatment – or Laura Chico, who said in a 5 December Phase III Alzheimer’s drugs. start therapy for the first time if they re- report that “overall, we continue to hold a Commenting on a recent Lancet publi- ceived a placebo previously. cautious view.” cation critical of the strategy to seek ap- Chico noted that “while there is likely proval for aducanumab, Jefferies analyst DOCTORS – PARTICULARLY to be continued and extensive cuts of the Michael Yee said in a 4 December note: ADUCANUMAB INVESTIGATORS data that emerge, we think the bigger “At end of the day the fundamental call – CHEER RESULTS question is the clinical meaningfulness is the totality of data we see likely do not Doctors asked to comment on the adu- of these results. Panelists, which included stack up to FDA rigor typical of approval canumab data were enthusiastic about the investigators from the ENGAGE/EMERGE … so this would be an unprecedented results, including physicians who had pa- studies, indicated they see the results as

scrip.pharmaintelligence.informa.com December 13, 2019 | Scrip | 17 CTAD MEETING/RESEARCH & DEVELOPMENT

clinically meaningful; however, there is in development. He said more research are expected in 2022. An additional study still the issue of the failed study.” in drug development outside of amyloid for aducanumab likely would deliver data Likewise, Credit Suisse’s Evan Seiger- and on biomarkers of Alzheimer’s drug ef- after the gantenerumab results. man said in a same-day note that “we ficacy are needed to advance the field. Biogen’s Phase I/Ib PRIME study for adu- await further discussion and commentary canumab, which immediately preceded from KOLs (not just those who believe in ANOTHER TRIAL TO CLEAR UP the Phase III program, gave the company the a-beta hypothesis) to better under- DATA CONTROVERSY? its initial confidence in the drug because stand if aducanumab can in fact win ap- Sandrock and Haeberlein declined to proof the reduction in amyloid plaques seen proval from FDA. While the comparison vide additional details about the EMERGE in the brains of Alzheimer’s patients and between the ITT and Post-PV4 data is in- and ENGAGE studies during Biogen’s in- improved cognition, as presented at CTAD teresting, we need more context to better vestor call beyond the data presented at in 2016. understand what could be driving the ef- CTAD. “There’s a time and a place for ev- However, the company has since had fect seen on CDR-SB.” erything. We will soon be under review, so reason to question the amyloid hypothe- Alzheimer’s Drug Discovery Founda- we’re sensitive to what we present now,” sis – the notion that clearing amyloid-beta tion founding executive director and chief Sandrock said. from the brain slows Alzheimer’s disease scientific officer Howard Fillit had a more Pressed about why the company be- progression and potentially improves measured response to Biogen’s CTAD pre- lieves it has data necessary to support ap- cognition. There have been years of Phase sentation, noting that while aducanumab proval, he noted that, “we don’t file willy- III failures for other amyloid-targeting appears to have an effect on Alzheimer’s nilly. We only go to filing when we believe therapies; most recently Biogen and Eisai disease at higher doses in a percentage there’s a benefit/risk argument based on discontinued development of their beta of the EMERGE and ENGAGE populations, the science and based on the data.” amyloid cleaving enzyme (BACE) inhibi- more data will be needed to show the While a new trial could clear up the dis- tor elenbecestat – the last BACE inhibitor drug has a meaningful clinical effect for crepancy between EMERGE and ENGAGE, in clinical development – in September. patients. Biogen and Eisai may be compelled to Published online 5 December 2019 Fillit called the studies’ results “an incre- push aducanumab toward FDA approval mental step” in advancing the science and now given competitive dynamics, since GemVax’s Novel Peptide For potentially getting a disease-modifying Phase III data for Roche’s amyloid-target- Alzheimer’s Set To Advance drug to patients, but suggested that adu- ing biologic gantenerumab – delivered After Positive Phase II: canumab’s efficacy may be enhanced by by subcutaneous injection versus adu- https://bit.ly/354QiCT combining it with other types of therapies canumab’s intravenous administration – Early Assets Excite At Novartis R&D Day KEVIN GROGAN [email protected]

ovartis AG has presented a de- “The stars are aligned ... because our ability to invest in tailed look into both early and Nlate-stage assets which it believes R&D is directly correlated to the financial performance could produce 25 potential blockbusters. At an investor R&D event in London on of the company.” – Jay Bradner 5 December, the Swiss major highlighted 60 projects in Phase II, of which at least ten are expected to advance into Phase III each year in 2020 and 2021. Over 90% optimism and enthusiasm and the pro- Novartis announced an agreement are projected to be first-in-class or first- ductivity is really remarkable.” in July with Mirati its KRAS G12C inhibi- in-indication. Head of the part of Novartis that discov- tor to test MRTX849 in combination with Speaking to a small group of journal- ers drugs and typically takes them up to TNO155. It also made a recent investment ists hours before the investor event, Phase IIa, Bradner highlighted the firm’s in KRAS inhibition for its own portfolio, Jay Bradner, president of the Novar- portfolio of early-stage molecular “glues” partnering with Cancer Research UK. tis Institutes for BioMedical Research led by TNO155, a first-in-class SHP2 in- Bradner talked about intermolecular (NIBR), said “the stars are aligned... hibitor. He said this “could be a really big glues, which stick two proteins together. because our ability to invest in R&D deal” to treat solid tumors and based on A good example of those are protein de- is directly correlated to the financial preclinical data, has proved to be “power- graders, molecules “that take a target pro- performance of the company. These fully synergistic” with KRAS inhibitors that tein that’s maybe even undruggable and have really been the salad days so in are being developed for G12C-mutated, they glue it to the disposal system of the the labs right now, there’s quite a lot of non-small cell lung carcinoma. cell to take out the trash and destroy that

protein.” This is the scientific program he der to increase resourcing,” with 430 potential to become a foundational runs when not on NIBR leadership duty, drug discovery projects bring trimmed therapy across myeloid diseases. It is and one protein degrader has just entered to about 325. currently in a pivotal Phase II program in the clinic, “with a very strong pipeline be- The R&D day also saw Novartis high- myelodysplastic syndrome, with Phase hind it.” light projects that should be advancing I data to be presented at the imminent He said, “We’ve put a huge emphasis into pivotal trials in the coming years. First American Society of Hematology (ASH) on first in class. It may seem obvious but up was iscalimab, a monoclonal antibody meeting in Orlando. most of biopharmaceutical research is (mAb) against the CD40 receptor which Another asset that will be moving fast-follower research. This illusion of best the firm believes has the potential to be- into late-stage trials next year is TQJ230, in class, which I regard as a surrogate for come the standard of care in transplant. It an antisense oligonucleotide to reduce not first in class, is pervasive in our ecosys- has also demonstrated positive proof-of- lipoprotein(a) a currently untreatable tem and you may know the term ‘the best concept in Sjögren’s syndrome, and trials risk factor for cardiovascular disease. A source of new drugs is old drugs.’ We reject are being initiated in six separate indica- CV outcomes trial of over 7,500 patients that hypothesis.” tions. (Also see “Can Novartis Reclaim Pio- evaluating the RNA-targeting lipid-low- neering Role In Transplantation? “ - In Vivo, ering candidates recently licensed from HIGHEST HANGING FRUIT 2 Oct, 2019.) Ionis Pharmaceuticals Inc. affiliate -Ak Saying that Novartis’s strategy is “to reach Also causing excitement was LNP023, cea Therapeutics Inc. is planned to start for the highest hanging fruit,” Bradner said an oral factor B inhibitor which targets in 2020. that “the core of our research engine is the alternative complement pathway. The drug is key to Novartis’s CV efforts now fully rebuilt.” This required a change Novartis claimed that early Phase II which have just received a boost with its on cultural expectations and manage- data support advancing the drug as a proposed $9.7bn acquisition of The Medi- ment teams “and most importantly, pri- first-line treatment for the rare blood cines Company and the latter’s closely- oritization of our portfolio – research and disorder paroxysmal nocturnal hemo- watched siRNA drug inclisiran. (Also see “It development were regrettably at quite a globinuria (PNH). Has Been A Long Farewell To The Medicines distance before.” Full Phase IIa/IIb readouts are expected Company” - Scrip, 26 Nov, 2019.) The portfolio has been overhauled next year and 20021 for LNP023. It is in de- Published online 6 December 2019 “to engender rapid transit from the labs velopment for three rare renal diseases – into the clinics and into the marketplace, IgA nephropathy, membranous nephrop- through clarified and uniform strategies athy and C3 glomerulopathy. Novartis Targets Ten like you would expect from a vertically- In immuno-oncology, the Basel-based Indications For Cosentyx: integrated organization,” he said. “We’ve group touted MBG453 as a first-in-class https://bit.ly/2PG1yzh also markedly reduced the scope in or- anti-TIM-3 mAb which it thinks has the Sage Still Sees Approval Path After Depression Drug Fails In Phase III Trial

LEAH SAMUEL [email protected]

age Therapeutics Inc. executives are The Phase III MOUNTAIN trial missed the primary endpoint positioning the failed MOUNTAIN Strial of its antidepressant SAGE-217 as more of a molehill and suggesting that the data could still be supportive of a new drug submission to the US Food & Drug Administration. The firm announced SAGE-217 had missed the primary endpoint in the Phase III trial in acute treatment of major depressive disorder. However, the company’s review of the data indicates that there was a problem with compliance, as many patients had no detectable level of drug in their blood, and that there was a high number of patients with less severe de-

scrip.pharmaintelligence.informa.com December 13, 2019 | Scrip | 19 RESEARCH & DEVELOPMENT

pression. Reanalysis of patients with more timepoints through and including Day 15 “We view this study as … strongly severe MDD showed a significant effect (-13.0 for 30mg vs. -11.2 for placebo at Day supportive of a generalized MDD filing,” for SAGE-217. 15, p<0.048). Jonas told the call. “Even if you just look Sage chief medical officer Stephen Jonas also said that the MOUNTAIN at the data we presented, if you look at Kanes told a 5 December investor call that study enrolled more patients with a mild- forest plots, it’s all in the right direction the company is currently thinking “about er severity of symptoms (less than 24 on in terms of drug activity. So I think at this how we can use the data at hand, includ- the HAM-D scale) than had been enrolled point, our plans are going to remain the ing the results from this study which we in previous studies of SAGE-217. “Patients same. We have other studies that will referred to as supportive, to put together with milder symptoms are more hetero- really completely inform how this drug a filing,” noting that Sage is in “ongoing geneous, have a more variable response, ought to be used. We’re encouraged by talks with the FDA.” and of course, statistically, there is numeri- the maintenance data we’ve seen here. Sage is banking on the appeal of a new cally less room for improvement,” he said. So I think our intent right now is, based treatment paradigm unlike that of other When including only patients with a on the data from this study, is that the oral antidepressants, which require daily HAM-D of at least 24 (n=124 for SAGE-217 pathway to MDD and PPD combined re- maintenance doses to control the condi- 30mg), a post-hoc analysis demonstrated mains open for us.” tion. SAGE-217, a next-generation positive statistical significance at all timepoints Jonas did say that MOUNTAIN’s re- allosteric modulator optimized for selec- through and including Day 15 (-13.7 for sults suggest that Sage rethink study tivity to synaptic and extrasynaptic GABA- 30mg vs. -11.4 for placebo at Day 15, methodology. A receptors, is taken for only two weeks p<0.032). Analyses utilizing a HAM-D cut- “Ultimately, what we’ll do is we’ll look and then stopped. The drug is seen as an off of 25 or 26 were also statistically signifi- at the procedures, not the data but the oral successor to Sage’s postpartum de- cant, the company reported. procedures that are going on in the ongo- pression drug Zulresso. (Also see “Sage’s The company noted that there was ing studies and see if there’s anything we Zulresso Launch Is Off, But Not Running “ rapid onset, with effect showing at Day need to amend,” he said. - Scrip, 6 Aug, 2019.) 3, and that improvements in depressive symptoms were sustained in all treatment ANALYSTS HOPE FOR REANALYSIS SHOWS SUCCESS groups through Day 42 of the double- ANOTHER TRIAL In the MOUNTAIN trial, 581 randomized blind portion of the study. Long-term Jeffries analyst Andrew Tsai comment- patients received nightly doses of 20mg, follow-up data will be collected at six ed that the company’s next steps were 30mg, or a placebo for two weeks. The months. “murky” and suggested that Sage’s op- 30mg dose was associated with a mean Secondary endpoints included the tions might become clearer as it releases reduction of 12.6 in the Hamilton Rat- change from baseline in the Montgomery- SAGE-217 trial results from the other ing Scale for Depression (HAM-D) total Åsberg Depression Rating Scale (MADRS) major depression studies. “Our base case score after two weeks, compared to 11.2 and the Hamilton Anxiety Rating Scale assumption is for Sage to ‘wait’ until 2-3 for placebo (p=0.115). The 20mg dose (HAM-A) total score, among others, but of the MDD expansion studies readout, of SAGE-217 did not show a difference Sage is not releasing secondary endpoint since company believes at least one of from placebo. results at this time. those could serve as a ‘backup’ pivotal,” he CEO Jeff Jonas told the call that there said in a 5 December note. were two factors potentially affecting FILING PLANNED, BUT Meanwhile, analyst Tim Lugo of Wil- trial results. For one thing Sage’s post UNCLEAR liam Blair found some encouragement hoc analysis of the patient blood-level Sage management attempted to assure in the post-hoc data. “We do not view measurements found that 9% of the investors and analysts that the totality it as a complete failure for the program 30mg group had no measurable drug of the data will support FDA approval given the continued rapid effect of concentration. of SAGE-217, declining to provide clar- SAGE-217.” “This is a long half-life drug and the ity about its regulatory plans or address Lugo also noted Sage’s “strong pipe- assay is sensitive down literally to the whether it would conduct another study. line” of neurological and psychiatric nanogram level. So they had undetect- The drug has already succeeded in one drugs, said, “We still see potential for able drug,” he said. Patients were as- Phase III trial in MDD, and two more – SAGE-217 in several depressive disor- sessed at day 8 and day 15, and “given SHORELINE (retreatment) and RAINFOR- ders. There is a precedent for approval the pharmacokinetics of the drug and EST (comorbid MDD and insomnia) – with [Johnson & Johnson’s] Spravato, the sensitivity of the assay and the time will report out in 2020. In addition, the which was approved based on a posi- point that we sampled, they weren’t tak- drug has succeeded in a Phase III trial in tive Phase II study and a positive Phase ing drug. There’s just no other explana- postpartum depression. (Also see “Sage III relapse prevention study after failing tion for it. So that’s it. So they just didn’t Impresses With Second Postpartum De- a prior Phase III study.” take drug.” pression Therapy” - Scrip, 8 Jan, 2019.) Ex- The company’s stock fell 50.7% on the After excluding these patients from the ecs also noted that SAGE-217 has break- news, closing at $60.18. analysis, the company found there was a through designation, so the firm is in statistically significant improvement at all close consultation with the FDA. Published online 5 December 2019

Acadia’s Nuplazid Shows Nearly Three-Fold Reduction In Psychosis Relapse MANDY JACKSON [email protected]

he market for Acadia Pharmaceuti- of the cause of the dementia – Alzheimer’s Adverse event rates in the randomized cals Inc.’s Nuplazid (pimavanserin) disease or otherwise. portion of HARMONY were 41% for pi- T could grow to 10 times its current “It’s encouraging to me that as a clinician mavanserin and 36.6% for placebo, while Parkinson’s disease psychosis population that if I prescribe this drug there’s a pretty serious adverse event rates were 4.8% for if it is approved to treat dementia-related good chance the patient is going to re- pimavanserin and 3.6% for placebo. The psychosis based on the results of a Phase spond,” he commented on the investor call. most common side effects were headache III study presented on 4 December at (9.5% for pimavanserin versus 4.5% for the Clinical Trials on Alzheimer’s Disease PIMAVANSERIN CUT DRP placebo) and urinary tract infections (6.7% (CTAD) conference in San Diego. RISK SIGNIFICANTLY versus 3.6%). Despite higher rates of ad- Acadia stopped the Phase III HARMONY All 392 DRP patients enrolled in the HAR- verse events for Acadia’s drug, treatment trial early in September based on positive MONY study were treated with 34mg of discontinuation rates were lower for pima- interim efficacy, and in data presented at pimavanserin once-daily in a 12-week vanserin at 2.9% versus 3.6% for placebo. CTAD the company showed that demen- open-label period; while dosing could be There was one death during the open- tia patients treated with pimavanserin reduced as needed to 20mg during the label portion of the trial and another were 2.8 times less likely to have a psy- first four weeks, 90% of the trial partici- death in the pimavanserin arm of the ran- chotic relapse than those who received a pants remained on the 34mg dose. domized portion, but HARMONY investi- placebo during the randomized portion Individuals who responded to the drug gators determined than neither death was of the study. San Diego-based Acadia will based on assessments at weeks eight and related to the study drug. submit a supplemental new drug applica- 12 moved into the study’s randomized Safety concerns had been raised in 2018 tion (sNDA) for pimavanserin in the treat- portion, where they were treated with pi- based on adverse event reports since Nu- ment of dementia-related psychosis (DRP) mavanserin (n=105) or placebo (n=112) plazid’s first approval in 2016, but the FDA to the US Food and Drug Administration for 26 weeks (six months) or until relapse. determined that the severe side effects in 2020 based on these results. Relapse was defined as hospitalization and deaths reported were consistent with CEO Steve Davis told Scrip that the due to DRP, significant deterioration of the drug’s label and its elderly Parkinson’s drug’s efficacy and safety make it an attrac- dementia-related symptoms on clinical disease population. tive alternative to atypical antipsychotics scales, withdrawal from the study or use Davis said there are three important currently used off-label to treat DRP – an of another antipsychotic drug to manage takeaways from the HARMONY results. indication with no approved therapies. In hallucinations and delusions. “The first is in the open-label portion fact, no new drugs have been approved to Acadia reported that 61.8% of the pa- of the study we saw that pimavanserin treat dementia in 15 years, he noted. tients enrolled in the open-label portion showed a meaningful reduction and stabi- “These are patients that carry high dis- of HARMONY responded to treatment. lization of the symptoms of psychosis over ease burden to start with and when you Psychosis symptoms as measured by the five clinically dosed subtypes [of DRP]; be- layer psychosis on top of the cognitive Scale for the Assessment of Positive Symp- ing able to stabilize these patients during deficits that they have, the burden of de- toms-Hallucinations and Delusions (SAPS- that 12-week open-label period was a very mentia is really a lot to carry,” Davis said. H+D) improved by 75.2% from baseline to meaningful finding [and] it’s consistent “So, if we can help them by treating the week 12 (73.1%-83.3% depending on the with what we’ve seen in previous studies,” psychosis symptoms, I think you have a dementia subtype). he noted. very high impact on people.” Pimavanserin met the primary endpoint “Second, in the double-blind period pa- University of California, Los Angeles of time to relapse in the randomized por- tients on placebo were almost three times psychiatry, behavioral sciences and aging tion of HARMONY by reducing the risk of more likely to experience a psychotic re- professor Gary Small, who also is director psychotic exacerbation by 63% versus pla- lapse compared to pimavanserin,” Davis of the UCLA Longevity Center and the cebo (HR=0.353, p=0.0023), which means continued. “Third, in this study, as we ex- geriatric psychiatry division at the Semel that pimavanserin prevented relapse at pected based on previous studies, pima- Institute for Neuroscience & Human Be- a rate 2.8 times that seen in the placebo vanserin was very well tolerated.” havior, noted during Acadia’s 4 December group. On a secondary endpoint related In terms of safety and tolerability, he investor event that not only are there no to the risk of treatment discontinuation said that what was most important in approved drugs for DRP, but the treat- for any reason, pimavanserin-treated pa- this elderly population with multiple co- ments that are used do not work well. tients saw a 55% risk reduction versus morbidities is that there was no negative Small said based on the HARMONY data, those who received a placebo (HR=0.452, impact on cognition. pimavanserin is a good option regardless p=0.0024) – a 2.2-fold difference. Published online 5 December 2019

scrip.pharmaintelligence.informa.com December 13, 2019 | Scrip | 21 PIPELINE WATCH

Scrip’s weekly Pipeline Watch tabulates the most recently reported 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: Pipeline Watch - 29 November-5 December 2019http://bit.ly/2mx4jY3 Phase III

PIPELINESearch WATCH, 29 NOVEMBER–5 DECEMBER 2019

Change Lead LOA Event Type Drug Name Indication Comments To LOA Company/Partner (%) (%) Phase III AVEO TIVO-3; The Lancet Published Pharmaceuticals, tivozanib Renal Cell Cancer Oncology, 3 Dec, 0 27 Results Inc. 2019 Phase III AB07015; Updated AB Science S.A. masitinib Asthma Encouraging 0 68 Results Results Phase III Acadia Nuplazid Dementia In Updated Pharmaceuticals, HARMONY; Met 0 60 (pimavanserin) Alzheimer's Disease Results Inc. Primary Endpoint Phase III EMERGE, ENGAGE; Updated Biogen, Inc. aducanumab Alzheimer's Disease -6 38 Results Mixed Results Phase IIb/III Amphora (pH Chlamydia, Evofem Top-Line regulating Gonorrhea In AMPREVENCE; 4 65 Biosciences, Inc. Results salts) Women Positive Results Phase III Top- Ardelyx Inc. tenapanor Hyperphosphatemia PHREEDOM; Met 2 71 Line Results Primary Endpoint Phase III Top- Aldeyra reproxalap Dry Eye Disease 55 Line Results Therapeutics, Inc. RENEW; Mixed Results 0 Aurinia Phase III Top- Pharmaceuticals voclosporin Lupus Nephritis AURORA; Met 0 62 Line Results Inc. Endpoints Phase III Top- Sage Therapeutics, Major Depressive SAGE-217 MOUNTAIN; -13 48 Line Results Inc. Disorder Mixed Results PHALCON-EE; A Phase III Trial Phathom vonoprazan Potassium Erosive Esophagitis 59 59 Initiation Pharmaceuticals (Takecab) Competitive Acid Blocker Immune Phase III Trial Argenx efgartigimod Thrombocytopenic Double-Blind Study 39 62 Initiation NV/Halozyme Purpura Phase II/III Zealand Pharma Congenital In Pediatric dasiglucagon 0 68 Trial Initiation A/S Hyperinsulinism Patients Phase III Trial Galectin Non-Alcoholic NASH-RX; Adaptive belapectin 0 13 Announcement Therapeutics, Inc. Steatohepatitis Design

Source = Biomedtracker; LOA = Biomedtracker's opinion on likelihood of approval.

Source: Biomedtracker | Informa, 2019

More Top Level Pharma Exits In India As Cipla COO Departs

ANJU GHANGURDE [email protected]

t has been a year of high-profile pharma with any organization, our workforce business and member of the manage- exits in India. And after the recent depar- continues to evolve to meet their per- ment council at Dr. Reddy’s Laboratories Iture of Roche’s India managing director, sonal and professional aspirations,” Cipla Ltd. in a previous stint. He has also held se- it’s now Cipla Ltd.’s global chief operating said, adding that it valued both the “time nior management positions at the Piramal officer, R Ananthanarayanan, who is mov- Ananth spent” with the company as well group’s pharma operations. ing on. as “his contribution.” Ananthanarayanan, who holds a PhD Ananthanarayanan (Ananth to his close Cipla did not, however, immediately in pharmaceutical technology from Uni- peers) took charge as COO in August 2018, clarify the specifics around the COO’s exit versity of Mumbai, had been working on coming with a broad remit covering sev- or if a replacement had been identified, a string of new initiatives at Cipla in key eral key operational areas. His role included whether from within the ranks or external areas such as manufacturing. In a previ- overseeing R&D, manufacturing, supply talent. Pharma in India has seen a number ous interview with Scrip, the executive chain, the active pharmaceutical ingredi- of recent top-level exits: Roche India man- outlined how Cipla was rethinking and ents (API) business and the key geographies aging director Lara Bezerra, Eisai Pharma- refining its manufacturing operations in of North America, Europe and emerging ceuticals India Pvt. Ltd. head Sanjit Singh the backdrop of an intensely competitive markets. He had been tasked to help lever- Lamba and Janssen India chief Sanjiv Na- environment and evolving customer and age and grow Cipla’s generics portfolio and vangul are among those who moved on regulatory requirements. competencies in these markets. this year. Cipla, he said at the time, was priori- Cipla confirmed to Scrip that Anan- tizing several initiatives to ensure that thanarayanan had decided to “pursue in- RETHINKING MANUFACTURING its manufacturing keeps pace with the terests beyond the company,” noting that Cipla’s Ananthanarayanan came with ex- changing environment and demands in the executive had been a key member of tensive industry experience; he was presi- the sector, including looking at time to the company’s leadership team. dent and CEO of Teva API and Biologics turn around a product and a continued “Our rich legacy of care and our hu- from December 2014 to July 2018 and had focus on security and assurance of supply, manitarian approach to business has also been president of the Pharmaceuti- among other areas. made Cipla an employer of choice. As cal Services and Active Ingredients (PSAI) Published online 4 December 2019 Company Move

APPOINTMENTSSearch

Effective Executive To Company New Role From Company Previous Role Date Agios Bristol-Myers Interim Head, Drug Bruce Car Chief Scienti�c O�cer 6-Jan-20 Pharmaceuticals Squibb Discovery Executive Vice Jonathan Agios Chief Legal O�cer Celgene Corp President, General 3-Dec-19 Biller Pharmaceuticals Counsel Vice President and Malin Alligator Ferring Chief Operating O�cer Head, Translational 29-Nov-19 Carlsson Bioscience AB Pharmaceuticals Medicine Curtis L. Amphivena Chief Executive O�cer, Parvus Chief Executive O�cer 2-Dec-19 Ruegg Therapeutics Inc President and Director Therapeutics Inc and President John Nektar Chief Commercial O�cer Chief Commercial Pharmacyclics 3-Dec-19 Northcott Therapeutics and Senior Vice President O�cer Dennis Executive Vice President, Havas Health & Orexo AB Chief Digital O�cer 2-Dec-19 Urbaniak Digital Health You Andy Relay Chief People O�cer and Broad Institute Chief People O�cer 5-Nov-19 Porter Therapeutics Executive Vice President

Click here for all appointments: https://bit.ly/2oHWRYn Source: Medtrack | Informa, 2019

scrip.pharmaintelligence.informa.com December 13, 2019 | Scrip | 23 HEADLINE NEWS