Shire Could Reclaim HAE Prophylaxis Market from CSL Behring

31 August 2018 No. 3920

Scripscrip.pharmaintelligence.informa.com Pharma intelligence | informa were earning and bring currently untreated patients into the fold due to its convenience of administration. “Today’s approval should position Shire to not only maintain but also significantly grow its dominant HAE franchise,” Jefferies analyst David Steinberg wrote. He predicted that the product will be launched in the fourth quarter of 2018 and eventually achieve peak global sales of approximately $1.8bn. Privately held CSL Behring does not di- vulge sales for individual products, but on Aug. 15 reported that sales of its specialty drugs, including Haegarda, totaled $1.49bn for the 12 months that ended June 30. It also claimed the product had taken roughly a 50% market share in the US for HAE prevention since its launch in 2017.

BROAD ADOPTION EXPECTED Shire has not yet announced a launch date Shire Could Reclaim HAE Prophylaxis or pricing for Takhzyro. Shire Chief Medical Officer Howard Mayer asserted in an interview that the product may achieve “broad Market From CSL Behring adoption given its product profile, certainly JOSEPH HAAS [email protected] in patients with HAE who have considered prophylaxis in the past, but also patients S FDA approval for Shire PLC’s zyme that is chronically uncontrolled in who are receiving on-demand therapy.” Takhzyro as a subcutaneous pro- HAE patients. In the 125-patient, Phase III HELP trial – Uphylactic for attacks of hereditary Shire’s Kalbitor (ecallantide), approved in the largest study conducted to date in HAE angioedema should position the company 2009, also is a kallikrein-inhibitor, but it is the prevention, according to Shire – a 300 mg to begin winning back market share lost to lowest-selling of the firm’s three HAE drugs. dose given every two weeks resulted in a CSL Behring’s prophylactic agent Haegar- US sales totaled $48.3m in 2017, compared mean monthly 87% reduction in attacks da. Analysts predict rapidly ramping sales to $427.3m for Cinryze, a C1 esterase inhibi- compared to placebo. The drug also met all for Takhzyro, reaching blockbuster totals in tor approved for prophylaxis, and $229.7m secondary endpoints with no treatment-re- just a few years. for Firazyr (icatibant), a bradykinin B2 receptor lated serious adverse events. Of the patients Unlike Haegarda, which inhibits HAE inhibitor approved to treat acute HAE attacks. receiving study drug who completed HELP, patients’ C1 esterase levels, Takhzyro The specialty pharma has conceded that 97% continued into an open-label exten- (lanadelumab-flyo) is a kallikrein-inhib- following launch the antibody product sion trial to evaluate long-term safety and efficacy of Takhzyro, Shire noted. iting monoclonal antibody. It is the first might cannibalize its existing HAE port- The secondary endpoints further under- antibody product approved for HAE – folio. Analysts said in notes following the line the product’s efficacy, Mayer said. At thought to affect roughly 40,000 patients Aug. 23 Takhzyro approval that while this the end of six months, participants who globally – and the first prophylactic might happen, the drug’s sales may even- agent that addresses kallikrein, an en- tually exceed what the other HAE therapies CONTINUED ON PAGE 10

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Hudson In India Scrip Infographic ESC Conference Novartis Pharma’s CEO discusses Japan’s patent loss challenge (p6-7) Munich meeting hears products and pricing (p8-10) mixed data (p17-21) IN THIS ISSUE

from the executive editor [email protected]

It’s unfortunately trite to say that cardiovascular drug scope and ambition. They are looking to add another development takes a lot of heart, but it does require an 10 indications/label expansions to the six already ap- amazing amount of dedication and consistency – not proved in the US, and seek to deliver on that with the to mention resources. The recent European Society of MARINER data presented at ESC. Cardiology annual meeting underscored the long-term As the article on p17 explores, while the COMMAND- commitment required in this field. ER HF study will not support a filing in heart failure, Johnson & Johnson and Bayer’s partnership on the companies believe they can seek approval in certain Xarelto is a prime example. Following up on the origi- acutely medically ill patients based on the MARINER nal pivotal trials, they set off on an ambitious plan to trial, in combination with the older MAGELLAN trial. expand the novel oral anticoagulant’s use with the EX- The path forward shows the value of foresight and ex- PLORER trial program, with a target of over 100,000 tensive data collection out of such a broad program. patients across five trials. This was later expanded in Other highlights out of the ESC meeting include Pfiz- high-risk populations with another 11 trials covering er’s ATTR-ACT trial for tafamidis (p20). And check on- more than 275,000 patients – which the companies line for coverage of the CAMELLIA trial for Eisai/Arena’s note is “unmatched” by any other NOAC in its size, obesity drug Belviq – which leaves lingering questions.

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EDITORS IN CHIEF Andrea Charles EDITORIAL OFFICE Ian Haydock (Asia) John Davis Christchurch Court Eleanor Malone (Europe) Kevin Grogan 10-15 Newgate Street Denise Peterson (US) Ian Schofield London, EC1A 7AZ Vibha Sharma CUSTOMER SERVICES Joanne Shorthouse EXECUTIVE EDITORS US Toll-Free: +1 888 670 8900 COMMERCIAL Sten Stovall US Toll: +1 908 547 2200 Alexandra Shimmings (Europe) UK & Europe: +44 (20) 337 73737 Mary Jo Laffler (US) US Australia: +61 2 8705 6907 Michael Cipriano POLICY AND REGULATORY Japan: +81 3 6273 4260 Derrick Gingery Maureen Kenny (Europe) Email: clientservices@ Joseph Haas Nielsen Hobbs (US) pharma.informa.com Emily Hayes ASIA Mandy Jackson Cathy Kelly TO SUBSCRIBE, VISIT Anju Ghangurde scrip.pharmaintelligence.informa.com Jung Won Shin Jessica Merrill TO ADVERTISE, CONTACT Brian Yang Brenda Sandburg Bridget Silverman [email protected] Sue Sutter EUROPE All stock images in this publication Neena Brizmohun courtesy of www.shutterstock.com Francesca Bruce unless otherwise stated

2 | Scrip | 31 August 2018 © Informa UK Ltd 2018 GBT’s Bargain Buy Deal Logic

Ambitious Argenx

20 11 13 12

exclusive online content inside: Q&A: Merck KGaA Global Head Of Medical Affairs On COVER / Shire Could Reclaim HAE Prophylaxis Market From Pipeline Persistence CSL Behring https://bit.ly/2wu8cyZ 4 China Vs. Cancer: Seven Companies Given Price Cuts, Maria Rivas has been in post as Merck KGaA’s global head of Roche Gets New Approval medical affairs for just over a month. She talks to Scrip about her immediate priorities, and the Darmstadt-based company’s potential in immunotherapies and oncology. 5 Portfolio Streamlining At GSK India But Long Term Commitment Intact Anoro Comparisons Trip Up AZ’s Bevespi In Latest COPD Study 8 Novartis Pharma CEO On Star Products, Pricing And Rebates https://bit.ly/2wlOi9N AstraZeneca has failed to show that its LAMA/LABA combo 11 GBT Picks Up Inclacumab From Roche’s Bargain Bin Bevespi Aerosphere is better than GSK’s Anoro Ellipta in a Phase IIIb study, a result “inconsistent” with previous data, but not surprising according to experts. 12 Future Looks Bright For Ambitious Argenx

13 Evotec’s CEO Explains Logic Behind Drug Discovery Pact Chindia Generics: A Dream or Reality? With Novo Nordisk https://bit.ly/2MyjQn4 Meeting and greeting is necessary, as is the right form of 14 Dravet Syndrome: Now With Two Approved Treatments partnership and getting everyone on board. But as Indian drug makers learn the ropes of entering the complex Chinese 15 Allergan’s Ulipristal Gets An FDA Rejection market, the seemingly natural fit may still have a long way to go. 15 Lynparza Blazes PARP Trail In China Novo Nordisk Adds Momentum To Oral Semaglutide With Good PIONEER 5 Data 16 Japan Approval Another Boost For Tagrisso in 1L NSCLC https://bit.ly/2wo4XcS Novo Nordisk announced another set of positive PIONEER trial 17 J&J Sees A Path Forward For Xarelto In Post-Hospital VTE data backing its oral GLP-1 receptor agonist semaglutide, this Despite MARINER Failure time showing superior reduction of blood sugar levels and weight in adults with type 2 diabetes compared with placebo. 20 Pfizer Has Tafamidis Data In Hand, But Market Development Still A Challenge Pfizer, Astellas Accelerate Xtandi’s Timeline In Early Prostate Cancer 21 Novartis’ SOLAR-1 Shines on Alpelisib In Breast Cancer https://bit.ly/2BK9Y4Q Protocol changes for the Phase III ARCHES and EMBARK trials will 22 Pipeline Watch deliver results in hormone-sensitive prostate cancer a year and a half earlier than expected. Xtandi may then gain a valuable new 23 MC2 Plots Course For Topical Psoriasis Drug Launch indication sooner than anticipated, but generics for competitor Zytiga could launch before then. 23 Appointments Deal Watch: Harbour Expands Horizons Beyond China https://bit.ly/2BTxcFO Antibody developer Harbour Biomed signs its first deal for rights outside China in cancer pact with Kelun. Portage buys SalvaRx to increase its immuno-oncology capabilities, while Paragon spinout Emalex will take over Psyadon’s pediatric Tourette @PharmaScrip /scripintelligence syndrome program. /scripintelligence /scripintelligence

scrip.pharmaintelligence.informa.com 31 August 2018 | Scrip | 3 EMERGING MARKETS

China Vs. Cancer: Seven Companies Given Price Cuts, Roche Gets New Approval BRIAN YANG [email protected]

hina’s newly established Medical In- 21 x 125mg tablets. Roche backed out of vial, a reduction of 20%, the reasoning being surance and Support Administration that round, but voluntarily cut its prices for that China’s medical insurance scheme cov- C(MISA) has thrown its first punch, Tarceva later. ers a wide population. lowering the prices of 14 widely prescribed Since the wide success in China of the For cancer drugs that face generic com- cancer drugs. blockbuster movie Dying to Survive, which petition in China, the prices may be cut The majority of the products affected are is about the problems of cancer drug access more deeply. On August 3, the newly estab- from multinationals, which accounted for and has shed a harsh light on prices, the is- lished MISA noted a new effort to cut levels seven out of the nine companies hit by the sue has become a national hot button topic. for both originator drugs and generics. new cuts. During bidding discussions, MISA is said The reductions ranged from 3% to 7.8%, The new price reductions to have proposed using the lowest bidding with an average cut of 4.8%, and were reflect an increasing price as the reference for both originator based on new import tariffs and reduc- and generics drugs that have passed bio- tions in value-added tax (VAT). Since May, pressure on makers to equivalence testing. the Chinese government has reduced import tariffs for cancer drugs from 3-6% to lower prices, even for some ALECENSA’S FAST APPROVAL zero, and lowered the effective VAT rate products still under patent Parallel to the new price reductions, Chi- from 17% to 3%. na meanwhile has been accelerating new The affected products includeJohnson protection cancer drug approvals. The latest such & Johnson’s Velcade (bortezomib) and clearance has been granted to Roche’s Zytiga (abiraterone); Bayer AG’s Nexevar non-small cell lung cancer therapy Al- (sorafenib), AstraZeneca PLC’s Iressa (ge- ecensa (alectinib). Developed by Chugai Chinese Premier Li Keqiang has repeat- fitinib) and Faslodex (fulvestrant); Novartis Pharmaceutical Co. Ltd. , this is indicat- edly requested a lowering of oncology AG’s Afinitor (everolimus); Celgene Corp.’s ed for anaplastic lymphoma kinase (ALK)- drug pricing, and the pressure is building Revlimid (lenalidomide); GlaxoSmithKline positive NSCLC patients. for access to products that have not been PLC’s Tykerb (lapatinib) and Roche’s Mab- Lung cancer is the most prevalent form covered by the National Drug Reimburse- Thera (rituximab), Herceptin (trastuzumab), of malignancy in China, with 80-85% of all ment List (NDRL). Dedicated price nego- Tarceva (erlotinib) and Avastin (bevacizum- patients having NSCLC; ALK-positive disease tiations will start soon to further lower the ab). (Celgene has since licensed Revlimid to is a rare but fast-progressing type. burden to patients, noted the medical in- Alecensa gained US approval last No- BeiGene Ltd. in China.) surance agency. Drugs from domestic makers hit by the vember, and EU approval one month later. move include Betta Pharmaceuticals Co. OTHER DRUGS In March, the China FDA granted it a pri- Ltd.’s Conmana (icotinib) and Jiangsu Hen- The new price reductions reflect an increas- ority review and an official approval five grui Medicine Co. Ltd.’s Aitan (apatinib), ing pressure on makers to lower prices, even months later. which are also on the price reduction list. for some products still under patent protec- To accelerate new oncology products Based on its new policies, MISA has initi- tion and for which there is no generic com- to the market, China is using the prior- ated new negotiations with cancer drug petition in China. ity review mechanism to shorten approv- makers, requiring them to comply with re- One tactic is volume in return for price re- als to as little as six months, from 18-24 calculated prices based on the new tariff/ duction, under which manufacturers agree months previously. tax rate. to cuts to ensure inclusion into the national In a rare and bold move, the country also medical insurance coverage scheme and recently released a list of 48 drugs from PREVIOUS CUTS the expected large volume uptake this multinationals qualified for such fast-track Some of the cancer drugs had already should bring. reviews. (Also see “China Calling: Dozens Of seen deep price cuts in a previous round Novartis’s Lucentis (ranibizumab), for Drug Firms Handpicked For Fast Track Re- of price negotiations, such as Iressa, Con- one, was priced at CNY7,125 per 10mg/ views” - Pink Sheet, 12 Aug, 2018.) mana and Tarceva. The first two were hit by ml, 0.2ml vial in the first round of price Alecensa is the third drug from Roche the 2016 price negotiations, with Iressa cut negotiations to ensure inclusion in the to treat NSCLC in China, after Tarceva and by 55%, to CNY2,358 ($343.80) for a box of NDRL in 2017, when the list was updated Avastin. 10 x 250mg tablets, and Conmana suffered after an eight-year hiatus. After the nego- Published on 21 Aug 2018 a 54% reduction to CNY1,399 per box of tiations, Lucentis was cut to CNY5,700 per From the editors of PharmAsia News.

4 | Scrip | 31 August 2018 © Informa UK Ltd 2018 EMERGING MARKETS

Portfolio Streamlining At GSK India But Long Term Commitment Intact ANJU GHANGURDE [email protected]

laxoSmithKline PLC expects to prune the number of Much of the streamlining in India appears geared towards ac- products it will focus on in India as the UK-based multina- celerating sustained profitable growth to create “enduring value” Gtional tweaks its emerging markets business model with for shareholders. an eye on improved competitiveness and profitability. The effec- “We will be driving this performance with fewer but more focused tive roll out of innovative products on the Indian market will re- priorities,” Annaswamy Vaidheesh, GlaxoSmithKline Pharmaceuticals’ main a thrust area. vice president South Asia and managing director India, said in the GSK India will now focus on 20 key brands to drive growth in company’s latest annual report. identified therapy areas over the next 18 months or so, down from He maintained this will help the company become “more com- around 70 brands currently. The firm is said to have, over the past, petitive, win in the market”, and serve patients, while the approach already pared the number of brands from about 130 to 70. is also strongly aligned with the long-term priorities – Innovation, Fewer brands would help simplify operations and also allow the Performance and Trust – as laid out by GSK’s CEO Emma Walmsley. company to “put our energy where it matters”, GSK India was report- Last year, Walmsley had, among other aspects, emphasized the need ed as saying in the local media. The streamlining effort could also po- to be more competitive in emerging markets, where returns in some tentially see some brands being sold or discontinued, though there cases had been impacted by competition and evolving regulations. is no official word on this as yet. “We need a model that can competitively drive what is today GlaxoSmithKline Pharmaceuticals Ltd., the Indian arm of a largely classic branded product business with brands like Aug- the multinational, is evolving its commercial operating model mentin (amoxicillin/clavulanate), but also one that can success- in India to invest resources in key products and patients/con- fully launch more new innovations such as the Ellipta portfolio sumers to drive growth. Identified therapies will also be sup- or Nucala. To do this we are going to create a new, single, dedi- ported by an “incremental field force” during the course of the cated, end-to-end operating model for emerging markets span- year, the Indian arm said at the time of its first quarter results ning commercial, supply and R&D for life-cycle management,” on July 24. Walmsley said at the time. The group was expected to develop its own dedicated gover- COMMITTED TO INDIA nance model and the “right commercial structure” for each market, But no major pull back of sorts appears on the cards in India, and GSK whether this be a standalone business, a cluster of similar markets, emphasized to Scrip that the country is a “very important” market in or a distributor-led model. Each market will be resourced accordingly which it has a “strong heritage and ambitious plans” for patient ac- and the company remains very committed to access to its medi- cess to its world-leading medicines and vaccines. cines, Walmsley said at the time. “We are focusing on key brands to drive growth in identified therapy areas where there is significant unmet patient need. We INDIA MARKET PRESSURES are also increasing our field force by a third, and are committed GSK’s tweaked avatar in India, though part of a broader emerging to India and its patients for the long-term,” the company added. markets revamp at the company, also comes against the backdrop of The main focus therapy areas will be anti-infectives, dermatology multiple market pressures in the country, including sustained efforts and vaccines – segments where GSK already has a leadership posi- to cap prices of essential medicines, a push towards generic name tion in India – and also the respiratory space. GSK is the number one prescriptions, and evolving clinical trial regulations. (Also see “OPPI company in the vaccines self-pay segment in India with around a Chief Vaidheesh On Burning Industry Issues In India” - , 4 Dec, 2017.) 28% market share in value terms. Once the top ranked company in India, GSK is currently at ninth The self-pay vaccines market in India is estimated at INR19.92bn position in the country as per July 2018 MAT data from AIOCD ($285m) as per IMS MAT (moving annual total) data for March 2018, AWACS, a market research agency that tracks retail sales. The British and growing at around 16%. Seven of GSK’s products figure in the multinational has, however, already been fine-tuning its operations top 20 list of vaccines in the self-pay market, the data show. in the country to propel growth. GSK also expects to introduce in India innovative products In 2016, GSK India boss Vaidheesh told Scrip how the firm was from its global pipeline, especially in the anti-infectives and re- deploying a host of measures including cross functional “excellence spiratory segment. teams”, a multi-channel approach to reduce “information asymmetry” Scrip recently reported that novel respiratory products like Nu- for customers, calibrating prices to improve access, and penetrating cala (mepolizumab) and Relvar Ellipta (fluticasone/vilanterol), deeper into middle and rural India as part of efforts to create, deliver known as Breo Ellipta in the US, were among the new products and capture value. headed to India from the global portfolio. (Also see “Nucala It is not immediately clear if some of these plans may have been Among Flurry Of New Respiratory Products On Indian Horizon” - further tweaked under the emerging markets remodeling effort. Scrip, 7 Aug, 2018.) Published online 23 August 2018

scrip.pharmaintelligence.informa.com 31 August 2018 | Scrip | 5 JAPAN’S PHARMACEUTICAL INDUSTRY

Although 10 of Japan’s largest pharma companies look set to add $11bn in PATENT LOSSES CHARACTERIZE JAPAN’S revenues over the next nine years, a CAGR of only 1% reﬂects an expected $4.8bn in CHALLENGING PHARMA FUTURE patent expiries, leaving Japanese pharma heads relying on innovation for the next phase of the region’s major wins.

GENERIC COMPETITION $4.4bn COMPANY GROWTH wiped from core and WINNERS LOSERS THERAPEUTIC GROWTH expiry portfolios BY 2027 By 2022, Otsuka will LOSSES lead growth with portfolio of psychiatry drugs 32% $69.5bn Oncology Total predicted of US sales -29.3% -26.2% -46.3% -22.5% will be a revenues by 2027 will come Astellas Daiichi Kyowa Sumitomo -$802m from marketed $17bn Sankyo Hakko Kirin Dainippon Daiichi Sankyo losses market oncology drugs marketed current current Eisai will add portfolio drugs marketed marketed from patent expiries portfolio portfolio portfolio $1.54bn values values to the top line 25% $11.4bn OPERATING ENVIRONMENT -1.2% CAGR Revenues from new drugs CNS will be a Population $2.6bn Kyowa Hakko Kirin will come added by just 10 companies $1.54bn peaked in 2009... 33% revenues weighed down from CNS of population Present by 2027 $14bn by heavy exposure to market was over 60 generics. in 2015 Astellas is expected to 2018: 48.8% Target generic launch 8 new products M&A 2027: 46.3% volume share ...and fell by 42.4% of 80% of $16bn Share of the native will be aged 1 million substitutable revenues by 2027 market drops due to during 2010–15 over 60 in 2050 market presence of foreign A merger between Eisai and companies More drug -600 jobs Otsuka would have multiple price cuts will Astellas reorganizes with beneﬁts and fast-track their come in 2020 competition for Micardis mutual growth. and Vesicare looming

Source for all data: Datamonitor Healthcare’s Pharmavitae

6 | Scrip | 31 August 2018 © Informa UK Ltd 2018 JAPAN’S PHARMACEUTICAL INDUSTRY

Source for all data: Datamonitor Healthcare’s Pharmavitae

scrip.pharmaintelligence.informa.com 31 August 2018 | Scrip | 7 EXECUTIVE INTERVIEW

Novartis Pharma CEO On Star Products, Pricing And Rebates ANJU GHANGURDE [email protected]

aul Hudson, CEO of Novartis Phar- veloped strong competency for demon- changes or suggested changes. We believe ma AG, discusses pricing, and ex- strating our value to payers and patients we have less exposure than other organiza- Ppectations and dynamics around and health systems. tions in those environments. the company’s star products including Clearly changing times in the US for sure. how Cosentyx (secukinumab) is sitting We worked tirelessly to be leaders of out- AG: But, in general is the pricing debate a pretty in the rheumatology and psoriasis comes-based contracting – does our medi- bit too skewed against pharma in the US? space, despite competition. Heart fail- cine do what we say it will do. We worked PH: Like many things, if you only talk price, ure drug Entresto (sacubitril/valsartan), very hard to make sure we price responsibly. then you don’t fully understand value. which is well on its way internationally, Our group CEO Vas Narasimhan reconfirmed Whatever the price be, if it’s only the stick- could potentially emerge as one of the that we won’t take any price rise for the re- er you are talking about then we would most successful medicines ever launched mainder of the year. That’s more to guide strongly encourage people to fully appre- by Novartis in India. for stability. Whilst we will maintain prices ciate the value that we bring to patients, In an exclusive interview with Scrip at as they are, the pharmacy benefit manag- society and health systems. That said, we Novartis India’s sprawling office in Hyder- ers [PBMs] will continue to ask for increasing welcome further transparency on the role abad, Hudson also indicated that while rebates but that’s the nature of where we of the PBM, the role of the wholesaler and there is a global “lack of understanding” of live. We launched Aimovig (erenumab) very specialty pharmacy. Net rebates in the US pricing of “cures” like gene therapies, the recently in the US and launched it below are close to 40% for the industry. That’s a outlook of payers towards such products the cost effectiveness standard. And we did big premium that’s being passed on in the has been encouraging. that because we realized the sheer scale of middle between the innovator and the The Swiss multinational also appears to the unmet need. We didn’t want patient/the patient for managing a formulary and for be keeping a close eye on potential op- health system affordability to affect this. distributing medicines. I don’t underesti- portunities around India’s massive National Wherever you go in the world innova- mate they play an important role but the Health Protection Scheme, expected to be tion is still rewarded; innovation still has transparency on the scale of that rebate is rolled out next month. Dubbed “Modicare”, its place. And fundamental to any pricing overdue. Before President Trump came in akin to Obamacare in the US, the govern- discussion, I have to ask myself are we do- to begin his term, he raised many ques- ment-sponsored insurance aims to cover ing something better than standard of care tions and I think since then the debate has around 40% of India’s population. – are we treating a disease that’s an unmet opened up much more for people to un- need ; are we bringing value in a sustain- derstand who are all the players and frank- ANJU GHANGURDE: It’s probably tough able way to health systems? And I’m proud ly it’s not just pharma in that equation. times to be a CEO of pharma, what with of the decisions from innovation to pricing escalating pricing pressures across key that the company has taken. In Japan, we AG: Cosentyx had a great Q2 with sales of markets – the US, Japan and the goings are putting our gene therapy [AVXS-101] $701m and total number of prescriptions on in China. What’s your take on the ongo- through the approval process. The PMDA (TRx) in the US up by over 80%. (Also see ing action and how is Novartis balancing has awarded it a “Sakigake” designation “Cosentyx Carries Novartis Sales But Kym- value and volumes given that science is -breakthrough. There’s still a great desire for riah Manufacturing Gives Cause For Con- currently probably at its exciting best with innovation to be rewarded. In China, the cern” - Scrip, 18 Jul, 2018.) Do you expect immunotherapies, gene therapy etc? change in the rules where major medicines emerging competition from the IL-23 class PAUL HUDSON: It’s a great time to be are going to be approved in China without to slow things down a bit – J&J’s Tremfya a pharma CEO, not least the underlying additional studies because of the huge un- (guselkumab) has a head-to-head trial performance of our business is healthy met need, and we are positioned well we with Cosentyx – or is Consentyx on course and strong. We are growing volumes sig- think in the Chinese market, growing sig- to take over from Humira? nificantly – meaning we are helping treat nificantly. The quality of our medicines and PH: Cosentyx’s $701m in Q2 was a real unmet need. There is of course, never indeed the quality of our generic medicines statement of our ability to execute global- more so a desire for us to show the value means that we have less exposure than ly, not just the US. Here in India, our aspira- that we bring to health systems across the many of the competition in terms of the tion is to be the number one monoclonal world. People don’t often mention Europe new standards that the China government antibody in the branded market for these but we’ve been living with price controls has set. In the US, the new administration patients over time. So, it’s a worldwide and cost-effectiveness in Europe for two is looking for opportunities to influence or performance, and a worldwide expecta- decades and we are one of the most suc- change the pricing environment; they are tion. We tend to focus a little bit on the cessful organizations there. We have de- not all list price some are Part B or Part D US because there is a net price debate –

8 | Scrip | 31 August 2018 © Informa UK Ltd 2018 EXECUTIVE INTERVIEW

what do you have to rebate for a position PH: We guided at the half year, there is be even faster. We have a co-marketing in a competitive market. We chose in Q1 a good chance Entresto will be a block- arrangement with Lupin Ltd. and Cipla to offer some additional rebate to make buster this year, which is a significant step Ltd. for the product. sure that we had the opportunity to be in what was a slow launch. We learnt a lot used in biologic-naïve patients. In the US, from that launch which will help us longer AG: Novartis hasn’t really shied away from the IL-17 class is more effective in psoriasis term. The growth of Entresto now means bringing in its latest products to India, but than anti-TNF. But when Humira (adalim- that we are well on our way and we will be would pricing dynamics mean that prod- umab) is the anti-TNF, the rebating posi- margin-accretive from the first day of 2019 ucts like Luxturna (voretigene neparvovec) tion means that you are used after Humira. and that is fantastic given the length of – Spark launched the product at the list Whilst that’s ok, when you have aspirations patent and the lack of competition – that’s price of $425,000 per eye, or $850,000 for to be a $4-5bn medicine, and frankly you going to be a very important contributor most patients in the US - or Aimovig aren’t just expect patients do better on Cosentyx to our success. What we are seeing in the likely to be India-bound anytime soon? than they do on anti-TNF, it’s important to real world is that the real world effective- PH: In the US we, priced Aimovig with our make sure you have access in earlier line. ness of Entresto is being demonstrated as partner Amgen, lower than cost effective- So we rebated, to make sure that we did perhaps even stronger than we saw in the ness, meaning we are outperforming the not have to step through the competition. clinical work, which of course is designed contribution back to society and we’ve Where that led us is frankly we are a mar- mainly for approval. The symptom benefit seen that reflected in the uptake. We will ket leader on new patients in psoriasis - we is so significant that we know that patients launch Aimovig in India in Q1 2020 and are ahead of all of the new launch compe- are feeling different and able to do more. we haven’t reached the decision on pric- tition and we are also the market leader in A study in the US that’s just been pub- ing but we know that the market in terms rheumatology. Perhaps, what is not as well lished shows that for a major US healthcare of value is very small. But we think that’s understood is that the patient population system if you use Entresto, you reduce the because of a lack of understanding. So, in rheumatology is as large as the patient cost of treating a heart failure patient by as the market leader currently, it will be population in psoriasis. almost 30%. That’s total cost – so you add our responsibility to work locally to de- IL-23s - that’s really competition in pso- in Entresto and total cost goes down 30% cide how to price and demonstrate value, riasis; it is not competition in rheumatology including drug. That’s where we should depending on unmet need and opportu- because Stelara (ustekinumab), and now the be because it allows health systems to be nity. Importantly for places like India, price IL-23s are showing themselves to be not as sustainable and patients to get innovation. is sometimes just slightly less important effective in rheumatology indications. You Entresto is perhaps one of the best-ever than affordability. There is no point seek- will have seen risankizumab decided not to launches in cardiovascular in India in recent ing a great price and then patients are un- pursue studies in ankylosing spondylitis for history. Not only that, it’s possible Entresto able to, from an out of pocket perspective, example. So, we know that in rheumatology could go on to be one of the most success- get access to the medicine. Most of the there are only two players – us and there’s ful medicines that our Indian organization two days I’ve spent here has been how Eli Lilly & Co. with Taltz (ixekizumab). We’ve has ever launched. And that just shows you do you help somebody make a choice seen in clinical practice we are able to pre- the early physician and patient feedback in between a medicine, which we think has serve a sustained response for multi-years. India. I had the opportunity to meet cardi- a low price, and perhaps cell phone data We think we are unique. In psoriasis, we are ologists from Hyderabad who reconfirmed and other things that they would spend the only medicine with five-year data. For to me that we need to partner on helping their money on. similar reasons and that 90% of patients can remote patients; we need to partner on For Luxturna and gene therapies there retreat and capture response with Cosentyx, demonstrating our value and providing is global lack of understanding of what which is significantly higher than any of the services and education but they were very cures should be priced at. Gene therapies, competition because we are fully human optimistic about the future of Entresto (sold particularly for monogenic diseases, is [monoclonal antibody]. So, we think we are as Vymada in India). So, overall the future of going to be a new science for many pay- well differentiated in rheumatology, well Entresto looks incredibly bright. The growth ers and regulators alike. We didn’t price differentiated in psoriasis but we accept of Entresto and Cosentyx in our organiza- Luxturna in the US, when we are ready we psoriasis is more competitive. We’ve recon- tion since 2015 has now given us a chance will have those – we’ve started those con- firmed our commitment to consensus this to demonstrate we know how to launch versations in Europe with reimbursement year globally and so we’ll be a multi-mega medicines.And with 11 launches over the authorities. For Luxturna and indeed even blockbuster by the end of this year. next three years, that’s very important. more so for AVXS-101, our gene therapy MILAN PALEJA, COUNTRY PRESI- in spinal muscle atrophy (SMA), payers AG: Both Cosentyx and Entresto are avail- DENT AND COUNTRY HEAD (PHAR- have been very open to conversations. able in India – how have they fared and are MACEUTICALS) NOVARTIS INDIA: En- What you may think is a high price, they TRx growth levels significant? What about tresto India growth numbers are almost do recognize the investment needed to the prospects of using real world data from in line with global growth numbers and get the science to become a reality. And these products in India/China? (Also see the number of heart failure patients in they also do recognize it’s a very small “Real World Data Helping To Drive Rise Of the country are so huge that we see, in number of patients. So, if you look at SMA Novartis’ Entresto” - Scrip, 29 May, 2018.) the ‘outer years’, maybe our growth could CONTINUED ON PAGE 10 scrip.pharmaintelligence.informa.com 31 August 2018 | Scrip | 9 EXECUTIVE INTERVIEW/HEADLINE NEWS there are about 700 babies born world- son conversation that will be needed across see a significantly expanded role for India wide a year that suffer from SMA Type 1. the country. We talked to cardiologists about in the data and digital part going forward, 90% of those babies will die before their running heart failure clinics in 600 villages given the IT prowess here and also India’s second birthday, so if you can cure them in remoter parts of this region. And they tell ambition to be the “AI Garage for 40% of what does that mean. And payers are, we you how difficult it is even for out-of-pocket the world”? (Also see “India’s Big AI ‘Garage’ found, very collaborative in trying to find and even for patients who understand but Ambition – Can It Get The Mechanics Run- ways to appropriately bring those to mar- can’t get to see the right physician or need ning ?” - Scrip, 25 Jun, 2018.) ket. For emerging markets, there is anoth- to be convinced to take a medicine. We PH: It’s not one garage. Remember we have er level of complexity because there is of- think Modicare is a commitment to those the largest number of patients in a longitu- ten a basic level of healthcare investment most vulnerable probably, but the industry dinal data set out of any other pharma com- required before scientific breakthrough as a whole is going to have to work in part- pany or healthcare institution; we have close and innovation. nership to try and make sure that volume is to two million patients’ data that we can anal- accessed appropriately. And where patients yse for trends, themes, signals, drug hunting AG: How is Novartis looking at the ambi- are still suffering, they get access to more in- opportunities and there are different centers tious Modicare plan - India’s massive Na- novative medicines after that. of excellence to do that type of work and tional Health Protection Scheme (NHPS), MP: If you look at the current announce- different companies, who are growing from which expects to cover 100 million poor ment of Modicare, it does not cover NCDs start-ups to become serious businesses to and vulnerable families with health cover [non-communicable diseases] and out- analyse that data in India and globally. When for secondary and tertiary care hospital- patient expenses, and if you look at some we get to the big data analytics and manag- ization? What kind of potential partner- of the current biggest health issues in the ing, on a worldwide scale, then it’s most likely ship opportunities could it open up? country, it includes NCDs. What would be here in Hyderabad. Hyderabad has become PH: Any policy that tries to get access for important for us as a company and an in- a worldwide center of excellence for data, for patients that have no access and no cover- dustry is to work with the government to digital, for analysis. It’s pretty extraordinary. I age is to be applauded. It is a hard thing to see how they can expand the coverage don’t think any other company has made the execute universal insurance. Even in markets and further it is opened to even innova- commitment we’ve made here in India. I go like the US we’ve seen that has been difficult tive medicines, which can be very helpful to other parts of the world and they talk with to do. With the people that I’ve met, I feel and where we are very keen to partner. pride about how they are being supported that we need to and we are offering our- from Hyderabad. That’s quite an interesting selves as a partner in that provision of health. AG: Novartis’ stated long-term strategy sort of ‘export’ that comes from here that It is one thing providing access but there is a is to emerge as a leading medicines com- shouldn’t be missed. great deal of education and person to per- pany powered by data and digital. Do you Published online 24 August 2018

received Takhzyro experienced 83% fewer on the product is BTIG analyst Timothy that number, the analyst predicted. While moderate-to-severe attacks and 87% few- Chiang, whose Aug. 24 note on the ap- Takhzyro may cannibalize Shire’s existing er attacks that needed on-demand treat- proval predicts peak sales of $1.4bn- HAE portfolio, Jefferies’ Steinberg noted, ment. After reaching steady state with $1.5bn within five years of launch. Fur- he thinks the new product will produce therapy, 77% were attack-free at the end ther, Chiang expects Takhzyro to catalyze significantly higher sales margins than of six months. continued growth for Shire’s larger im- Cinryze or Firazyr. As a franchise, he an- Labeling recommends a 300 mg dose ev- munology portfolio. ticipates the Takhzyro/Cinryze prophylaxis ery two weeks, but says for some patients, “We believe the upcoming launch of business will eventually top $2bn in an- monthly dosing can be considered after Takhzyro could provide more visibility for nual worldwide sales. steady state is reached. By contrast, while the company’s immunology segment, The portfolio of four HAE therapies also Haegarda showed similar efficacy in a Phase which we estimate will generate around could benefit Shire in terms of US market III study (median reductions in monthly at- $4.75bn in 2018 and around $5.04bn in access, the analyst said, because it could po- tacks ranging from 89%-95% compared to 2019,” he said. “We think the approval of la- sition products with different price points placebo), it is dosed at a much higher vol- nadelumab will strengthen Shire’s leading and modalities “that could cater to different ume than Takhzyro, 60 iU/kg based on the position in the HAE treatment market, with patient’s weight. the potential for additional sales gains over segments of the market.” Jefferies’ Steinberg pointed out that the next two to three years.” Shire’s Mayer told Scrip he thinks Phase Takhzyro’s dose is much lower in vol- Dosing convenience with Takhzyro also III data showing that patients were able ume, with less frequent dosing than the could net Shire a great number of patients to self-administer Takhzyro in less than CSL Behring product. “Haegarda’s twice- than currently receive prophylactic ther- one minute might be its greatest selling weekly injections are arguably far less apy, Chiang said. Current estimates have point. “I think that creates a significant ad- convenient than either the expected 3,000-4,000 US HAE patients on prophy- vantage compared to what is already out once-monthly or twice-monthly Takhzy- laxis. Takhzyro’s efficacy and safety profiles there,” he said. ro dosing,” the analyst said. Also bullish and dosing convenience could double Published online 24 August 2018

10 | Scrip | 31 August 2018 © Informa UK Ltd 2018 DEALS

GBT Picks Up Inclacumab From Roche’s Bargain Bin KEVIN GROGAN [email protected]

oche has become the latest pharmaceutical major this week, file of inclacumab are well characterized based upon Roche’s prior after Gilead Sciences Inc., to unload what was once seen as clinical studies, which enrolled more than 500 patients.” It added Ra promising asset, handing inclacumab over to Global Blood that P-selectin inhibition “is a clinically validated target in SCD, Therapeutics Inc. for just $2m upfront. known to reduce the incidence of VOCs,” and it has already begun The Swiss major has licensed inclacumab, a monoclonal antibody the process of technology transfer from Roche to a contract manu- against P-selectin, to GBT, which plans to develop it for vaso-occlusive facturing organization. crises (VOC) in patients with sickle cell disease (SCD). Roche was previously evaluating the drug as a treatment for coronary artery disease but SHIFT TO SICKLE CELL DISEASE its silence on the compound has been deafening for over five years. Approximately half of individuals with SCD, a lifelong inherited blood disorder caused by a genetic mutation in the beta-chain of hemoglobin, experience VOC. The pain can affect any body part but often involves the abdomen, bones, joints and soft tissue, causing a decrease in quality of life and an increase in the risk of death. The deal makes sense for GBT given that voxelotor, its lead investigational drug which is an oral, once-daily therapy, is in Phase III trials for SCD. CEO Ted Love said in a statement that the firm had been “working diligently to diversify our product pipeline through both internal research and external business development efforts” to become “the preeminent SCD company,” and inclacumab was “an ideal complement to voxelotor.” In June, GTB noted that having held talks with the FDA, it was pursuing accelerated approval for voxelotor based on positive top-line data from part A from the Phase III HOPE study. On the primary endpoint, 58% of patients on voxelotor dosed with 1500 mg at week 12 achieved a greater than 1 g/dL increase in hemoglobin versus 9% on placebo. Mark Breidenbach, an analyst at Oppenheimer, issued a note saying that inclacumab “could help fill a clinical benefit gap for -pa tients receiving voxelotor,” adding that available data suggest the latter “rapidly and sustainably reduces hemolytic anemia but may require extended dosing before a tangible VOC benefit develops. Sickle cell disease is an area of high Inclacumab could provide an immediate VOC benefit,” he added, unmet need writing that he sees the drug as “a complementary and logical addition” to GBT’s pipeline. SCD is an area of high unmet need. The generic chemotherapeutic In March 2013, Roche presented data at the American College of hydroxurea has been the main approved treatment, but is associated Cardiology meeting which showed that inclacumab, which came with some severe toxicities that make it hard to use. Emmaus Life out of a collaboration with Genmab AS, reduced heart tissue dam- Sciences Inc.’s Endari (L-glutamine oral powder) got FDA approval age in patients with acute coronary syndromes who were dosed last year as the first new drug approved for the disease in the US in with the P-selectin antagonist prior to angioplasty in a Phase II trial. almost 20 years. (Also see “Emmaus Plans Modest Pricing In 4Q Rollout At the time, the study’s lead investigator Jean-Claude Tardif from the Of Sickle Cell Drug Endari” - Scrip, 9 Jul, 2017.) University of Montreal, stated that the clinical benefit after a single As for inclacumab, it will not be getting to the market any time injection of the antibody was “exciting,” but needed to be replicated soon as GBT said it did not anticipate submitting an investigational in larger studies. New Drug Application to the FDA until 2021. Potentially much closer Given the lack of news concerning inclacumab after that ACC to approval is Novartis AG’s crizanlizumab, which is also a P-selectin meeting, it appears that Roche was not prepared to conduct those targeted antibody obtained through the November 2016 acquisition larger trials in a compound that Tardiff had claimed “could become of Selexys Pharmaceuticals Corp, and is scheduled to be filed in the part of the therapeutic armamentarium in modern cardiology.” For US by the end of 2018. whatever reason, Roche discontinued the inclacumab program fol- Roche’s decision to divest inclacumab came a day after Gilead lowing the aforementioned Phase II trials and now GBT has got hold handed over the stalled Phase III Janus kinase 1/2 and activin recep- it for a token upfront, although Roche is eligible to receive up to tor type 1 inhibitor momelotinib to Sierra Oncology Inc. for just $125m in development and commercialization milestone payments $3m upfront. (Also see “Sierra Believes It Can Do Better Than Gilead for the sickle cell disease indication, plus tiered royalties. With JAK Inhibitor Momelotinib” - Scrip, 23 Aug, 2018.) GBT noted that “the pharmacokinetic, safety and tolerability pro- Published online 24 August 2018

scrip.pharmaintelligence.informa.com 31 August 2018 | Scrip | 11 DEALS

Future Looks Bright For Ambitious Argenx KEVIN GROGAN [email protected]

ith AbbVie Inc. licensing a pre- Primary results from a Phase II trial for ef- clinical immuno-oncology drug, gartigimod in idiopathic thrombocytic pur- Wand strong data backing its lead pura are expected next month, with a more candidate efgartigimod, argenx SE of Bel- detailed set of data set to be presented at gium’s antibody technology platform has the American Society of Hematology meet- been validated. ing in San Diego in December. The compa- The AbbVie deal, announced Aug. 22, We continue to seek ny already has positive Phase II results from saw the US major has exercised an option it the drug in another indication, myasthenia took out in April 2016 to develop and com- out cutting-edge gravis, and a Phase III trial is being prepared mercialize ARGX-115, an antibody targeting research and targets with 150 patients expected to be enrolled; it glycoprotein A repetitions predominant is also being tested in mid-stage studies for (GARP) which plays a key role in the regu- while advancing pemphigus vulgaris. lation of production and release of active The argenx spokesperson told Scrip that transforming growth factor beta. our current the firm was looking to take efgartigimod ARGX-115 is believed to selectively limit collaborations, all into Phase III on its own and sees it as a the immunosuppressive activity of activated pipeline-in-a-product opportunity. Argenx regulatory T-cells (Tregs), thereby stimulating with the potential to is focusing on the drug in rare diseases but the immune system to attack cancer cells. the potential in bigger indications such as The premise is that ARGX-115 could prove broaden our pipeline lupus and multiple sclerosis could make for useful as monotherapy or in combination and demonstrate partnering possibilities. with anti-PD1/L1 and/or anti-CTLA4 agents, As for the rest of the pipeline, ARGX-110 or with cancer vaccines, to improve the ac- our discipline as a is in a Phase II study for cutaneous T-cell tivity and safety of those immunotherapies. lymphoma and in a Phase I/II trial in acute An argenx spokesperson told Scrip that strategic partner myeloid leukemia and myelodysplastic in the two years since AbbVie took out the syndrome. Argenx also has a collaboration option, a lot of preclinical work had been with Leo Pharma AS signed in May 2015 for done and the partners hoped to enrol the rent collaborations, all with the potential to ARGX-112 for inflammatory skin disorders. first patient in clinical trials next year. The broaden our pipeline and demonstrate our In addition to an upfront and other pay- company banked $40m when the deal was discipline as a strategic partner.” ments, argenx could pocket up to approxi- announced and received $20m more. It is Two additional IAP programs have started mately €100m as well as royalties on net eligible to receive milestone payments of to bear fruit. One is ARGX-116, discovered in sales of any product from the deal with the up to $625m, as well as tiered royalties, if all collaboration with disease biology experts Danish company – a third preclinical mile- goes well in the clinic. from Staten Biotechnology, which special- stone was banked in April this year following Argenx, which has bases in Ghent, Bel- izes in the field of dyslipidemia and the the approval of the clinical trial application gium and Breda in the Netherlands, has other is a pact with Broteio Pharma of the (CTA) filing for ARGX-112. It also received a also secured co-promotion rights for ARGX- Netherlands to develop therapies for severe payment from Shire PLC triggered by the 115-based products in the EU and Switzer- autoimmune diseases. latter exercising its option to in-license an land. AbbVie seems convinced of the candi- The deal went down well with investors, antibody. No details about the indication date’s potential and Tom Hudson, its head of as argenx shares went up 4.7%, while ana- specifically being pursued have been dis- oncology early discovery and development, lysts at JMP Securities issued a note saying closed but argenx rather vaguely notes on noted in a statement that “our collaboration that the AbbVie collaboration “further sup- its website that it might be a therapy to treat with argenx over the past two years has been ports our view that the company’s tech- a rare disease such as Hunter syndrome or productive and we look forward to continue nologies are differentiated and important in Fabry disease, or for a specialist condition working together to fuel scientific progress.” the development of novel biologics to ad- such as ADHD or ulcerative colitis. CEO Tim Van Hauwermeiren said the deal dress unmet medical needs.” Cashwise, argenx is in good shape after highlighted the important of argenx’s Inno- While getting AbbVie fully onboard is a raising approximately $100m through a Nas- vative Access Program (IAP) as ARGX-115 is validation of argenx’ Simple Antibody tech- daq listing in May 2017 – its shares are also the result of research initially carried out by nology, which employs llama immunization, traded on Euronext Brussels. As of June 30, the de Duve Institute/ Université Catholique the more immediate focus is on efgartigimod. cash and equivalents amounted to €338.9m de Louvain in Belgium. He added that the The latter is a first-in-class antibody fragment and the spokesperson noted that the firm IAP “remains a strategic priority for us [and] designed for the treatment of patients with has enough money to fund operations for at we continue to seek out cutting-edge re- severe autoimmune diseases and the compa- least the next couple of years. search and targets while advancing our cur- ny is developing the drug in three indications. Published online 23 August 2018

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Evotec’s CEO Explains Logic Behind Drug Discovery Pact With Novo Nordisk STEN STOVALL [email protected]

votec AG hopes its just-inked strategic diseases, while in October 2012. Evotec pact with Novo Nordisk AS will move and Bayer AG entered an ongoing part- Esteadily from its preclinical stages nership in the disease area of endome- – based on IP held by the Danish group – to triosis. “I see this agreement with Novo a long-term drug discovery and develop- Nordisk as a starting point,” Lanthaler said. ment alliance in which the duo jointly own “Novo Nordisk will initially give us one or the assets. two projects to work on and if they are That’s the view expressed to Scrip by the satisfied we would hope it would lead to biotech’s Austrian CEO, Werner Lanthaler. a broader collaboration, in similar ways to Under the alliance announced Aug. 22, our partnerships with Bayer and Celgene. Werner Evotec AG Novo Nordisk aims to use Evotec’s tech- Lanthaler I’d hope that Evotec and Novo Nordisk nology to advance potential proprietary could at some point then build joint IP on small-molecule candidates from pre- which to work together.” clinical development to regulatory filing He said Evotec’s R&D arrangement with quickly for treating co-morbidities associ- ‘Novo Nordisk will initially the Danish diabetes specialist is funda- ated with diabetes and obesity, such as mentally different from its alliance with diabetic kidney disease, non-alcoholic give us one or two projects France-based Sanofi, and that the two steatohepatitis (NASH) and cardiovascu- collaborations would be ring-fenced and lar diseases. to work on and if they are kept separate. It will use Evotec’s INDiGO platform, satisfied we would hope which integrates operations and acceler- WORKING ON CELL THERAPY ates early drug candidates into the clinic it would lead to a broader “With Sanofi we’re working predominant- using strategies designed specifically for collaboration, in similar ly on cell therapy using joint IP but based the molecule, therapeutic area and stra- IP we generated, therefore that partner- tegic needs. ways to our partnerships ship is being conducted within our In- In an interview with Scrip, Lanthaler novate segment,” the CEO said. “With said, “This reflects the fact that Novo Nor- with Bayer and Celgene. I’d our Novo Nordisk alliance, the IP is 100% disk, which is world leading in insulin, hope that Evotec and Novo owned by them, and so it falls under our world leading in antibodies, hasn’t built Execute operations.” a small molecule presence; they were Nordisk could at some point He added, “We will keep the two opera- looking for a strategic partner and after then build joint IP on which tions separate – that between us and Sanofi studying the landscape, chose Evotec to and us and Novo Nordisk – and ensure that provide that small molecule platform. to work together’ there is no overlap between the two.” And, as is typical of Novo Nordisk, they With the Sanofi operations, R&D activi- are starting off on this quest with a very ties will be using Evotec’s sites in Germany long-term view, an approach which is as well as in Sanofi’s locations in Toulouse, very attractive to us.” France while with the Novo Nordisk collabo- ties are built on partners’ intellectual prop- ration “we’ll be doing the R&D in the Evotec EVOTEC EXECUTE VS EVOTEC erty and use the Austrian group’s integrated labs in Oxford, UK and in Verona, Italy, to INNOVATE drug discovery and development tools and make sure there is no overlap or conflict be- The intellectual property for the partner- in-house know-how. tween the two,” he explained. ship comes from Novo Nordisk. “They have Evotec is already working with French Lanthaler said that one of the key mes- generated a very interesting piece of chem- drug maker Sanofi to research new diabe- sages from Evotec’s pact with Novo Nordisk istry for this alliance, and so this partnership tes medicines, having launched its strategic was that the Danish group is “re-opening falls into what we call ‘Evotec Execute’, as alliance, TargetBCD, three years ago. its portfolio of options and pursuing those opposed to ‘Evotec Innovate’ where the IP In late 2016, Evotec and Celgene again in small molecules, such as NASH and comes from us. Corp. entered into a strategic drug dis- the obesity space which they are already The Evotec Innovate segment focuses covery and development collaboration to pursuing with other therapeutic modalities. on investing and developing Evotec propri- identify disease-modifying therapeutics We will help them do this.” etary assets while its Evotec Execute activi- for a broad range of neurodegenerative Published online 23 August 2018

scrip.pharmaintelligence.informa.com 31 August 2018 | Scrip | 13 APPROVALS

Dravet Syndrome: Now With Two Approved Treatments MANDY JACKSON [email protected]

ravet syndrome begins in early childhood, but following FDA cebo on top of stiripentol and other epilepsy medicines in 87 two- to approval of Diacomit (stiripentol) from Biocodex two drugs 19-year-olds for 15 weeks. Results reported in July showed a 54.7% Dhave been cleared this year to treat the disease in the US reduction in the number of monthly seizures for ZX008-treated pa- and, with multiple other treatment options in the pipeline, one more tients versus those given a placebo. The median decline in monthly could be approved in 2019. seizures was 62.7% for ZX008 and 1.2% for placebo. Gentilly, France-based Biocodex announced on Aug. 23 that FDA Biomedtracker notes that the Danish firm Lundbeck Inc. drug Onfi approved Diacomit for seizures associated with Dravet syndrome in (clobazam) was in Phase III development as an adjunctive therapy for patients aged 2 and older when already being treated with clobazam. Dravet, based on the March 2015 initiation of the placebo-controlled The agency’s Aug. 20 decision follows the approval in June of GW Phar- CLOVER I study. However, the sponsor withdrew the study in Septem- maceuticals PLC’s Epidiolex (cannabidiol) – a marijuana plant-based ber 2015 due to recruitment challenges, according to clinicaltrials.gov, medicine that will launch after scheduling by the US Drug Enforcement and Lundbeck no longer includes the program in its late-stage pipeline. Administration – and precedes a new drug application (NDA) filing Onfi was approved for Lennox-Gastaut in 2011. It was Lundbeck’s planned for Zogenix Inc.’s ZX008 in the fourth quarter of this year. top-selling drug in the first half of 2018 with DKK1.76bn ($274.6m) Dravet is also known as severe myoclonic epilepsy in infancy in sales, but FDA recently approved the first generic version of Onfi, (SMEI), because of its early onset, severity and potential for ataxia and which is set to lose patent exclusivity in October. psychomotor retardation and affects about 2,000 to 8,000 patients in EpyGenix Therapeutics says it has three drugs in clinical devel- the US. Seizures begin in most cases during the first year of life, with opment for Dravet, including the Phase I drug EPX-100, an antihis- a high frequency of status epilepticus that contributes to mortality tamine with antiepileptic activity via the serotonin (5HT) signaling among the young patients. Diacomit will be available to treat the pathways. The company also has two serotonin (5HT) modulators in disease in US pharmacies in January. Phase II – EPX-200, an FDA-approved weight loss drug, and EPX-300, Diacomit, approved in the US as capsules and a powder for oral an FDA-approved antidepressant and insomnia drug. suspension, is not a new drug outside of the US; it’s been approved The Paramus, N.J.-based company is entirely focused on rare ge- in Europe since 2007 and in Canada and Japan since 2012. Biocodex netic epilepsies and says all three of its candidates have been grant- described the possible mechanisms of action for the anticonvulsant’s ed orphan drug designations in the US, though no studies are listed effects as being mediated through the GABA-A receptor with po- on clinicaltrials.gov. tential inhibition of cytochrome P450 activity, which increases blood PTC Therapeutics Inc. in South Plainfield, N.J., is recruiting patients levels of the benzodiazepine clobazam and its active metabolite. for a Phase II clinical trial testing Translarna it initiated in 2016 to test The 65-year-old private French firm’s drug was approved in the its RNA-targeting drug in epilepsy patients with a nonsense muta- US based on two studies in Europe, STICLO France and STICLO Italy, tion in CDKL5 or Dravet syndrome. New York University School of in which the primary endpoint was the responder rate, defined as Medicine is the study sponsor and PTC is listed as a collaborator. the percentage of patients with a greater than 50% decrease in the Xenon Pharmaceuticals Inc. presented interim Phase I safety re- frequency of generalized clonic or tonic-clonic seizures in a 30-day sults in May and intends to report final Phase I data from healthy vol- period compared with a four-week baseline period. unteers in the second half of 2018 for XEN901, a Nav1.6 sodium chan- The responder rate in STICLO France was 71% for patients treated nel inhibitor. Phase II studies are planned based on the final Phase I with Diacomit versus 5% in the placebo group. The responder rate in results in adult focal seizures and rare pediatric epilepsies. STICLO Italy was 67% versus 9.1%, respectively. Biscayne Neurotherapeutics Inc., Opko Health Inc. and Ovid The most common adverse reactions to Diacomit across the trials Therapeutics Inc. each have preclinical programs in Dravet syn- were somnolence (67%), decreased appetite (45%), agitation (27%), drome, according to Biomedtracker. Opko’s OPK88001 is an oligo- ataxia (27%), weight loss (27%), hypotonia (24%), nausea (15%), trem- nucleotide that’s designed to increase production of the sodium or (15%), dysarthria (12%) and insomnia (12%). One patient discon- channel protein SCN1A and it is expected to move into the clinic tinued treatment after experiencing status epilepticus and another this year. Biscayne’s BIS-001 inhibits acetylcholinesterase to increase discontinued due to drowsiness, impaired balance and sialorrhea. GABA levels that activate anti-excitatory pathways; it’s in Phase II for GW Pharma’s cannabinoid receptor-targeting drug Epidiolex was the treatment of focal seizures in adults. approved on June 25 for the treatment of Dravet and the larger rare Ovid’s TAK-935 is the cholesterol 24-hydroxylase (CH24H) inhibitor seizure disorder Lennox-Gastaut syndrome. In a Phase III study in 120 TAK-935 (OV935) that’s being developed in partnership with Takeda children and young adults with Dravet syndrome and drug-resistant Pharmaceutical Co. Ltd. with a Phase Ib/IIa study under way in seizures who were receiving standard-of-care epilepsy drugs, includ- adults with developmental and epileptic encephalopathies. ing clobazam and valproate, the number of convulsive seizures dur- The companies expanded their partnership to additional adult and ing a 14-week treatment period dropped from 12.4 to 5.9 for in the pediatric rare epilepsies in July. Among three new Phase II studies Epidiolex arm versus a dip from 14.9 to 14.1 in the placebo arm. expected to begin in the third quarter of this year is ELEKTRA, which Zogenix will seek approval for its ZX008 (low-dose fenfluramine) in will evaluate TAK-935 versus placebo in 125 patients with Dravet and Dravet syndrome later this year based on the results of two Phase III Lennox-Gastaut syndromes. studies, including Study 1504, which evaluated the drug versus pla- Published online 24 August 2018

14 | Scrip | 31 August 2018 © Informa UK Ltd 2018 APPROVALS

Allergan’s Ulipristal Gets An FDA Rejection JESSICA MERRILL [email protected]

US FDA complete response letter ease businesses as it braces for the impact a selective progesterone receptor modula- (CRL) for Allergan PLC’s ulipristal ac- of generics, but bids for the women’s health tor (SPRM), was based on the results of two Aetate in the treatment of abnormal business have been constrained by the un- Phase III trials in the US and four EU regis- uterine bleeding in women with uterine certainty around Esmya, management re- tration studies. Allergan markets ulipristal in fibroids removes an overhang on the com- cently reported. Canada under the name Fibristal. pany’s effort to sell its women’s health unit, Trouble for Esmya began brewing late last “Allergan continues to believe in the but it will also negatively impact any poten- year after reports of liver injury surfaced in need for novel treatment options for wom- tial valuation of the business. Europe. The European Medicines Agency’s en who are looking for a non-surgical treat- The company announced the receipt of a Pharmacovigilance Risk Assessment Com- ment for uterine fibroids,” the company CRL in response to a new drug application mittee initiated a review, and the European said in a statement. (NDA) for ulipristal Aug. 21, which was not Commission eventually adopted recom- Those interventions could be on the ho- a surprising development but a disappoint- mendations in June that include regular rizon, but marketed by other drug makers. ing one for Allergan nevertheless. The pros- liver testing for women taking the medicine AbbVie Inc. and Neurocrine Biosciences pects of the drug reaching the US market and restrictions on the drug’s use to women Inc. are on track to file a supplemental NDA were diminished after reports of serious liver ineligible for surgery to treat uterine fibroids. for the gonadotropin-releasing hormone injury and hepatic failure in women taking Gedeon reported dramatically lower sales (GnRH) receptor antagonist Orilissa (elago- the product came to light in Europe, where of the drug in the first half of the year. The lix) in 2019, having already announced data the drug is marketed by Gedeon Richter European review led FDA to push back the from two positive Phase III trials. The compa- PLC as Esmya. PDUFA date for Allergan’s NDA for ulipristal nies announced more data Aug. 22 from a Allergan pumped up investors on the earlier this year to August. Phase III extension study that was in line with commercial potential of Esmya in 2017, Allergan didn’t specifically say FDA was the results seen in the prior studies. Orilissa promoting it as one of “six stars” that would concerned about liver toxicity, but said the was approved by FDA in June for the treat- help see the company through a loom- agency requested additional information, ment of pain associated with endometriosis. ing patent cliff for the dry eye blockbuster citing safety concerns regarding Esmya Myovant Sciences Ltd. is developing a Restasis (cyclosporine). post-marketing reports outside of the US. similar GnRH receptor antagonist, relugolix, More recently, Allergan announced plans The company said it plans to meet with FDA which is in Phase III with data expected in to sell its women’s health and infectious dis- to assess next steps. The NDA for ulipristal, 2019. Published online 23 August 2018

Lynparza Blazes PARP Trail In China IAN HAYDOCK [email protected]

ollowing a priority review, AstraZen- parza for the additional indication of breast The approval for Lynparza means the eca PLC and Merck & Co. Inc.’s Lyn- cancer is among a group of products re- drug is now available in 61 countries for Fparza (olaparib) has received approval cently granted a review under the regulato- various indications; the product was first ap- from the China National Drug Administra- ry authorities’ expanding fast-track system. proved for ovarian cancer in the US and EU tion (CNDA), for the maintenance treatment The new approval in the group of initial in- in December 2014. of adult patients with recurrent epithelial dications was granted based on two pivotal It is estimated that 22,500 women in Chi- ovarian, fallopian tube or primary peritoneal studies – the Phase III international SOLO-2 na die every year from ovarian cancer and cancer who are in a complete or partial re- trial in BRCA-mutated, relapsed ovarian can- there are over 52,000 new diagnoses record- sponse to platinum-based chemotherapy. cer, and the Phase II Study 19 trial as a main- ed annually. Platinum-based chemotherapy The clearance makes Lynparza the first tenance monotherapy in platinum-sensitive has so far been the only treatment option ever PARP inhibitor to be approved in the relapsed ovarian cancer. in the country for women with platinum- country, which has been taking steps over The first of these showed improved pro- sensitive recurrent ovarian cancer, and no this year to accelerate the availability of gression-free survival of 19.1 months ver- new medicines for this patient population novel cancer drugs through priority and sus 5.5 months for placebo, while Study 19 had been approved in the last decade. fast-track reviews, in tandem with price cuts showed an overall survival of 29.8 months Competition in China’s nascent PARP sector to improve affordability for patients. for the drug versus 27.7 months for placebo. is looming however, with potential class rivals Roche’s ALK inhibitor Alecensa (alectinib) China is increasingly accepting foreign moving ahead across various indications. has also just been approved in China for clinical data to support approvals, particu- Published online 23 August 2018 ALK+ non-small cell lung cancer, while Lyn- larly in high medical need areas. From the editors of PharmAsia News.

scrip.pharmaintelligence.informa.com 31 August 2018 | Scrip | 15 APPROVALS

Japan Approval Another Boost For Tagrisso in 1L NSCLC IAN HAYDOCK [email protected]

new approval from Japan’s Minis- company’s top-selling oncology product. phoma (CTCL), a rare form of non-Hodgkin’s try of Health, Labour and Welfare Among its potential EGFR-targeting global T-cell lymphoma. CCR4 is frequently ex- Amoves AstraZeneca PLC’s Tagrisso rivals in Japan, Pfizer Inc. filed for the lo- pressed on leukemic cells. A requirement (osimertinib) into the first-line setting in this cal approval of dacomitinib in NSCLC this for pre-treatment diagnostic testing of potentially large market for the treatment May. However, some analysts see a limited CCR4 expression has now been removed, of inoperable or recurrent EGFR mutation- threat from the molecule given tolerability and dosage and administration changed. positive non-small cell lung cancer (NSCLC), questions and comparative data from the The modifications are based on results adding to the epidermal growth factor re- FLAURA trial showing progression-free sur- from MAVORIC, the largest global Phase ceptor tyrosine kinase inhibitor’s class lead vival (PFS) advantages for osimertinib. III randomized trial of systemic therapy in this indication. FLAURA assessed the efficacy and safety in CTCL, in which identification of CCR4- As elsewhere, the approval was based of 80mg orally once daily versus standard- positive cells before enrollment was not re- on results from the global Phase III FLAURA of-care first-line EGFR TKIs (either erlotinib quired. The 372-patient trial compared the trial, which included Japanese patients, and (Tarceva) 150mg orally once daily or ge- therapy with vorinostat in patients failing at it came after a priority review granted by fitinib (Iressa) 250mg orally once daily) in least one prior systemic treatment. the ministry this February given the medi- previously-untreated patients with locally- The dosing regimen – which is now ap- cal need for new effective therapies in the advanced or metastatic EGFRm NSCLC. proved in Japan – involved weekly intrave- first-line setting. The double-blind, randomised trial in- nous administration of 1mg/kg for the first Tagrisso was first approved in Japan in cluded 556 patients across 29 countries, and 28-day cycle, then on days one and 15 of March 2016, again following a priority re- incorporated sites in Japan. subsequent cycles. view, as a first-in-class therapy for the treat- Osimertinib demonstrated superior PFS Poteligeo was first approved in Japan if re- ment of patients with EGFR T790M muta- of 18.9 months compared with 10.2 months lapsed/refractory CCR4-positive adult T-cell tion-positive inoperable or recurrent NSCLC for the comparator arm, and this benefit lymphoma in 2012, and subsequently for resistant to existing first-line EGFR-inhibitors. was consistent across all subgroups includ- relapsed/refractory CCR4-positive periph- Dave Fredrickson, head of AZ’s Oncol- ing in patients with or without CNS metas- eral T-cell lymphoma and cutaneous T-cell ogy Business Unit, said the new clearance tases, an important consideration in lung lymphoma, and chemotherapy-naive CCR4- would help in “replacing older medicines… cancer patients. positive adult T-cell leukemia/lymphoma. given the high prevalence of the EGFR mu- Tagrisso 40mg and 80mg once-daily oral The antibody was also approved in the US tation in Japan.” tablets have now received approval in 39 in August 2018 for adult relapsed/refractory markets, including the US and Europe, for mycosis fungoides of Sezary syndrome (the HIGHER MUTATION RATE first-line EGFRm advanced NSCLC, and more most common type of CTCL) after at least While only around 10-15% of NSCLC patients than 75 markets, including the US, Japan, one prior systemic therapy, and is under re- in the US and Europe have EGFRm NSCLC, China and Europe, for second-line use in pa- view in the EU for CTCL. this proportion rises to 30-40% in Asia, and tients with EGFR T790M mutation-positive the secondary EGFR T780M resistance mu- advanced NSCLC. LINZESS FOR CONSTIPATION tation – against which osimertinib is also The drug is also being developed in the The other line extensions approved by the active – causes resistance to standard EGFR adjuvant setting in the ADAURA trial and in ministry included Astellas Pharma Inc.’s inhibitors in around two-thirds of these. locally-advanced unresectable NSCLC in the Linzess 0.25 mg tablets (linaclotide; licensed Such patients are particularly sensitive LAURA program, and in combination with from Ironwood Pharmaceuticals Inc.) for to treatment with EGFR-TKIs, which act to other treatments. the additional indication of chronic con- block the cell signalling pathways that drive AstraZeneca is planning to launch at least stipation, other than constipation associ- tumor growth. In addition, about 25% of six new medicines in the oncology space ated with organic disorders (defined as that patients with EGFRm NSCLC also have brain between 2014 and 2020, and Tagrisso and caused by anatomical/pathological chang- metastases at diagnosis (increasing to ap- its expanded use are seen as key growth es or abnormalities in the visceral, organic, proximately 40% within two years of diag- drivers within this sector. nervous, or other tissues, detectable by radi- nosis), which can reduce median survival to The company’s PD-L-targeting antibody ography and endoscopy). less than eight months, AstraZeneca noted. Imfinzi (durvalumab) was approved in Japan The guanylate cyclase-C receptor agonist Osimertinib has shown clinical activity for maintenance use in locally advanced was first approved in Japan in December against CNS metastases, which in addition to NSCLC in July. 2016 (launched in March 2017) as the first its improved tolerability compared with ear- Among the other new indications and prescription treatment in the country for lier generation EGFR inhibitors, is expected to revised uses newly approved by the MHLW adults with irritable bowel syndrome with help the drug’s competitive and commercial was Kyowa Hakko Kirin Co. Ltd.’s anti- constipation (IBS-C). position. First-quarter sales of Tagrisso were CCR4 antibody Poteligeo (mogamulizumab) Published online 21 August 2018 $338m globally, making it the UK-based for relapsed/refractory cutaneous T-cell lym- From the editors of PharmAsia News.

16 | Scrip | 31 August 2018 © Informa UK Ltd 2018 ESC MEETING

J&J Sees A Path Forward For Xarelto In Post-Hospital VTE Despite MARINER Failure MANDY JACKSON [email protected]

Xarelto is a Factor Xa inhibitor developed and commercialized under a partnership between Janssen and Bayer AG. Janssen markets the drug in the US, while Bayer sells it in the rest of the world. Xarelto is indicated in the US for multiple VTE-related indications including for the prevention of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients under- going knee or hip replacement surgeries; to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the treatment of DVT and PE; and to reduce the risk of recurrence of DVT and PE following six months of treatment for DVT and/or PE. Janssen sponsored the MARINER and COMMANDER HF studies as part of Janssen and Bayer’s EXPLORER program that includes several lengthy trials aimed at seeking additional indications for Xarelto or expanding the novel oral anticoagulant’s label.

ohnson & Johnson’s Janssen Pharmaceutical Cos. said on MARINER RESULTS MIXED, BUT INDICATE Aug. 27 that its oral anticoagulant Xarelto (rivaroxaban) is ap- VTE BENEFIT Jpropriate for the prevention of venous thromboembolic events MARINER was a placebo-controlled pivotal study that enrolled (VTE) in certain acute medically ill patients following discharge from 12,019 acute medically ill patients upon discharge from a three- to the hospital even though the Phase III MARINER trial in this popula- 10-day hospital stay for a variety of reasons, which may have in- tion did not meet the primary efficacy endpoint. cluded heart failure, infectious diseases, stroke, chronic obstructive Janssen believes that the MARINER data combined with results pulmonary disease (COPD) or inflammatory diseases – a popula- from the MAGELLAN study completed in 2011 show that Xarelto tion with an increased risk of VTE for up to three months after leav- can reduce VTE in patients after they’ve been hospitalized for sev- ing the hospital. eral days if administered to individuals who are not believed to MARINER participants had to be at least 40 years old (mean was be at high risk for bleeding events. The J&J subsidiary intends to 69.7) with an assessed risk of VTE. They were treated from the time discuss the cumulative data with the US FDA, but it will not pur- of hospital discharge for 45 days with Xarelto or placebo. Individuals sue approval for the prevention of heart attack, stroke and death receiving Xarelto were given a 10 mg once-daily dose if they had in heart failure patients based on results from the Phase III COM- mild or normal renal function or 7.5 mg once daily if they had mild MANDER HF study. renal impairment. MARINER and COMMANDER HF were presented at the European The primary efficacy endpoint was the composite of VTE and VTE- Society of Cardiology (ESC) meeting in Munich, Germany and pub- related death, which occurred at a rate of 0.83% for Xarelto versus lished in the New England Journal of Medicine on Aug. 26 and 27. 1.1% for placebo – a 24% reduction, but that was not statistically sig- “Combination of these [MARINER] results with those of the MA- nificant (HR=0.76; 95% CI, 0.52-1.09; p=0.136). GELLAN trial tell a more complete story about rivaroxaban’s role of List noted that “there was little difference between the study arms preventing VTE in appropriately selected patients with acute medi- with respect to deaths adjudicated as related to VTE,” but the rate of cal illness,” Janssen Research and Development LLC Global Thera- VTE alone for Xarelto versus placebo was significant at 0.18% versus peutic Area Head-Cardiovascular and Metabolism James List said 0.42% (HR=0.44; 95% CI, 0.22-0.89; p=0.023). during an Aug. 27 analyst call. “We see a filing pathway toward ap- Indeed, Alex Spyropoulos of Lenox Hill Hospital in New York City proval with these combined findings and look forward to discuss- and his co-authors wrote in the NEJM that “appropriate selection of ing them with the FDA.” medically ill patients may reduce the health burden of nonfatal ve- List said the effects of Xarelto on VTE was consistent across both nous thromboembolism in this population.” studies, so results in this population from 20,000 patients enrolled Despite the primary endpoint result, however, List also noted in MARINER and MAGELLAN should be enough data for physicians that when deaths from any cause, not just from VTE, were included to determine who can be appropriately treated with the drug fol- in an exploratory secondary composite endpoint of symptomatic lowing a lengthy hospital stay. He said the findings also should VTE and all-cause mortality the result was statistically significant at inform a discussion between Janssen and the FDA about a label a rate of 1.3% for Xarelto versus 1.78% for placebo – a 27% reduction allowing for the treatment of acute medically ill patients with a (HR=0.73; 95% CI, 0.54-0.97; p=0.033). high VTE risk, but lower bleeding risk. CONTINUED ON PAGE 18 scrip.pharmaintelligence.informa.com 31 August 2018 | Scrip | 17 ESC MEETING

SAFETY BETTER IN MARINER THAN IN MAGELLAN anteeing an approval for Xarelto for the same indication that was ap- The primary safety endpoint was major bleeding according to Inter- proved for Bevyxxa, but he also does not expect the MARINER results national Society on Thrombosis and Haemostasis (ISTH) bleeding cri- to reduce the pressure on Portola in marketing its drug. teria. Janssen said major bleeding was infrequent and the difference “Although we believe the removal of potential competition is a between Xarelto and placebo – 0.28% versus 0.15%, respectively positive for Portola, we note significant work is still needed to gain (HR=1.88; 95% CI, 0.84-4.23; p=0.124) – was not significant. Non- adoption of Bevyxxa in the United States, and therefore the MARI- major clinically relevant bleeding was higher with Xarelto at a rate of NER results do not significantly alter the near-term headwinds for 1.42% versus 0.85% for placebo (HR=1.66; 95% CI, 1.17-2.35; p=0.004). Bevyxxa, in our view,” he wrote in an Aug. 27 note to Portola investors. Bleeding “is a side effect associated with any anticoagulant medi- cation, but the mixed results and failure to meet the primary end- HEART FAILURE STUDY IS A WASH point may lead physicians to question whether the modest benefit The result of COMMANDER HF, however, clearly showed that Xarelto of Xarelto use outweighs the potential deleterious effects seen with did not make an impact in this indication. The study looked at wheth- major bleeding and the statistically significant increase in risk of clini- er Xarelto could reduce the risk of heart attack, stroke and death in cally relevant non-major bleeding,” Biomedtracker said in an Aug. 27 5,022 patients who experienced a recent episode of acute decom- report on the MARINER results. pensated heart failure (ADHF) and had symptomatic heart failure for Nevertheless, the Biomedtracker analysts noted that Janssen’s “op- at least three months. timism regarding the possibility of indication expansion may not be The primary efficacy endpoint was a composite of heart attack, misplaced,” since Portola Pharmaceuticals Inc.’s newer Factor Xa stroke and all-cause death and the result was not significant with a inhibitor Bevyxxa (betrixaban) was approved in 2017 to prevent VTE 25% rate of those events for Xarelto plus the standard of care ver- in the same acute medically ill population even though the drug did sus 26.2% for the standard of care alone, which was at the treating not meet its primary endpoint with in the pivotal APEX trial. physicians’ discretion, but could include aspirin or dual antiplatelet “However, the APEX trial results were unique in that Bevyxxa failed therapy (HR=0.94; 95% CI, 0.84-1.05; p=0.270). to reach significance in a specific patient population (patients with There were numerically fewer heart attacks for Xarelto versus the an elevated D-dimer level), but did reach statistical significance standard of care, occurring at a rate of 3.9% versus 4.7%, respectively within the larger at-risk population. This is not the case in the MARI- (HR=0.83; 95% CI, 0.63-1.08; p=0.165), and fewer strokes (2% versus NER trial,” Biomedtracker noted. “The APEX trial compared the use of 3%; HR=0.66; 95% CI, 0.47-0.95; p=0.023). However, Janssen noted Bevyxxa both within the hospital and after hospital discharge to the that the lack of a difference in the rate of deaths, which comprised use of [Sanofi’s Lovenox (enoxaparin)].” about 80% of the primary endpoint in both groups, suggested that Treatment with Xarelto in MARINER did not begin until after pa- the high death rate in these patients is driven by poor heart function tients were discharged from the hospital, but MAGELLAN did include rather than thrombotic events. treatment in the hospital and out of the hospital. That was one of a List noted that secondary endpoints in COMMANDER HF also did handful of changes from MAGELLAN that Janssen instituted in MARI- not show a benefit for Xarelto therapy in heart failure patients, including rehospitalizations. NER to improve safety findings, since MAGELLAN succeeded on effi- Published online 27 August 2018 cacy, but had a bleeding rate that was deemed unacceptable. Other changes in MARINER included the lower 7.5 mg dose for patients with moderate renal impairment and exclusion of patients deemed to have a higher bleeding risk. “Despite the mixed [MARINER] results, it is possible that Xarelto sees an approval for this indication without reaching its primary endpoint. However, even if the indication is approved, it is unclear how the LET’S GET mixed results of this study will impact the actual use and uptake since the VTE prophylaxis space is fairly new,” Biomedtracker’s analysts said. SOCIAL DISAGREEMENT ON APPROVABILITY, IMPACT ON BEVYXXA “Bevyxxa was the first novel oral anticoagulant (NOAC) approved for We are tweeting, liking and sharing the latest the indication and has experienced slow uptake,” they continued. “It industry news and insights from our global will be interesting to see if uptake of Bevyxxa is slow because of ex- team of editors and analysts, join us! ternal issues such as unfamiliarity with the drug, reimbursement concerns and availability of the drug, or whether there is a lack of need within the indication itself. If the former is true, Xarelto may benefit from broad familiarity regardless of disappointing trial results.” It may be difficult to compare across the MARINER and MAGELLAN studies for Xarelto and the APEX trial for Bevyxxa, however, because Portola’s study enrolled older patients who spent more days in the @PharmaScrip hospital than those in the Janssen trials, according to William Blair analyst Matt Phipps. Phipps did not see the MARINER results as guar-

18 | Scrip | 31 August 2018 © Informa UK Ltd 2018 HEADLINE NEWS

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Pfizer Has Tafamidis Data In Hand, But Market Development Still A Challenge JOSEPH HAAS [email protected]

hase III data showing tafamidis can “The disease is often initially misidenti- results, combined with a benign safety pro- reduce all-cause mortality and car- fied as more common types of heart failure, file, suggest an important role for tafamidis Pdiovascular-related hospitalization but the symptoms persist and patients may in the treatment of transthyretin amyloid has Pfizer Inc. anticipating a potential rare consult with several cardiologists over time,” cardiomyopathy,” Cristina Quarta, Univer- disease blockbuster, but it conceded Aug. said John Young, group president of Pfizer sity College London, and Scott Solomon, 27 that first it will have to make substantial Innovative Health. “Unfortunately, once Brigham & Women’s Hospital, said in an edi- efforts to build the market in transthyretin patients receive the accurate diagnosis of torial on the study data. cardiomyopathy (ATTR-CM). ATTR-CM, the median life expectancy in The editorial notes that the study re- Analysts swooned at the data showing untreated patients is reported to be only sults do raise questions about tafamidis’ a 30% reduction in all-cause mortality and 2.5 years in those with the hereditary form mechanism of action, the time course of 32% decrease in cardiovascular-related hos- and 3.6 years for the those with the wild- benefit and timing of treatment over a pa- pitalization at 30 months compared with type form. We have a large task in front of tient’s course of disease. Quarta and Solo- placebo, projecting a future blockbuster for us: the first and foremost, help cardiologists mon note the drug – which binds to and Pfizer in an indication with no current thera- to better understand this disease; and drive stabilizes the structure of transthyretin – peutic option beyond heart or liver trans- patients to centers of excellence.” only showed reductions in hospitalization plantation. Developing the market in ATTR-CM must after nine months and a mortality benefit But first Pfizer will have to leverage the start with increasing diagnosis of the disor- at 18 months. Phase III ATTR-ACT data, presented at the der, Pfizer’s Global President-Rare Disease “Moreover, a subgroup analysis showing European Society on Cardiology Congress Paul Levesque told the call. He estimates greater benefit in patients with less severe Aug. 27 in Munich, and push diagnosis, to that there are about 50 centers of excel- heart failure suggests that treatment might establish a market for the cardiac form of lence in the US, and noted that availability of best be initiated at an early stage of disease, transthyretin-mediated amyloidosis. scintigraphy at these centers is more wide- when the underlying pathology may be “Management noted that increasing spread than Pfizer anticipated. more easily reversed as compared with later awareness of the disease and diagnosis rates “Improving diagnosis rates will rely on stages,” the authors state. “It is possible that will require significant market development, several factors, including expanding the by slowing or halting amyloid deposition, and that the company is well positioned number of centers of excellence and driv- tafamidis may allow the activation of local for this given its experience in cardiology,” ing patients in those centers, use of scin- recovery processes that progressively result Deutsche Bank analyst Gregg Gilbert said in tigraphy,” he said, adding that the lack of in a remodeling of the amyloid deposits, a an Aug. 27 note. He predicts a US approval a drug therapy probably is among the reduction in the strain on the cardiac walls, and launch in 2020 for tafamidis and peak reasons for the low diagnosis rate. “Pfizer and ultimately in a clinical benefit. Once sales of $1bn or greater. will continue to remain active in educat- amyloid has caused irreversible organ dam- A widely underdiagnosed or misdiag- ing cardiologists and collaborate with key age, disease-modifying treatments may be nosed form of heart failure, ATTR-CM affects stakeholders in organizations to support less likely to be effective.” an estimated 400,000-500,000 people in the awareness, training, tools to accelerate and US and Europe, according to Pfizer, but less expand diagnosis ahead of the potential SIZING UP THE COMPETITION than 1% of them likely are diagnosed pres- launch of tafamidis.” Earlier in August, RNA-interference pio- ently. Between 15% and 25% of the world- neer Alnylam Pharmaceuticals Inc. ob- wide disease population is thought to be in RESEARCHERS QUESTION tained its first regulatory approval, getting the US. TIMING OF THERAPY a US FDA nod in hereditary transthyretin- Diagnosis may improve, however, now The ATTR-ACT data confirm the op- mediated amyloidosis (hATTR) with On- that the old standard of biopsy can be re- timism Pfizer previously hinted at in pattro (patisiran), but the indication was placed with the nuclear imaging test scin- March, when top-line data for tafamidis narrower than the biotech had hoped tigraphy and the pharma also anticipates suggested new promise for a drug that and the label included no data on cardio- significant clinician enthusiasm for tafami- had been stalled since an FDA complete vascular endpoints. ATTR-CM is a sub-in- dis, an oral, daily tablet, as it could offer the response letter in 2012. dication of hATTR and Pfizer noted that its first therapeutic option for ATTR-CM be- Simultaneous with the ESC presentation, ATTR-ACT study was the first Phase III trial yond heart or liver transplantation. the ATTR-ACT data were published online in testing a drug therapy in ATTR-CM. To build a market in ATTR-CM, Pfizer must the New England Journal of Medicine. Besides Onpattro and tafamidis, the address several factors, execs told a same- “Given the dearth of acceptable treat- only other advanced drug candidate in day investor call. ments for this disorder, these robust efficacy this therapeutic area is Ionis Pharma-

ceuticals Inc.’s Tegsedi (inotersen), an 441-patient ATTR-ACT study go beyond ment arms, which tested daily 20 mg and antisense therapeutic awaiting FDA ap- efficacy levels many analysts have said 80 mg doses of the oral tablet, respectively. proval for hATTR, with a regulatory deci- would indicate significance, ISI Evercore BMO Capital Markets analyst Alex Arfaei sion expected in October. That candidate analyst Umer Raffat said that a longer trial said in an Aug. 27 note that as the diagnosis also is in Phase II for ATTR-CM. Tegsedi likely would have shown an even greater rate for ATTR-CM improves over time, Pfizer obtained a recommendation for approval mortality benefit compared to placebo. should gain a significant share of the market from the European Medicines Agency On the investor call, Brenda Cooperstone, if tafamidis gets FDA approval. He predicted (EMA) in June, while tafamidis is ap- Pfizer’s chief development officer for rare ex-US business will comprise about half of proved in Europe under the brand name diseases, said an ongoing extension proto- the drug’s peak revenues, which he pegs at Vyndaqel for related indication of familial col may reveal a greater benefit long-term. $1.3bn in 2027. amyloid polyneuropathy (FAP). “It is certainly possible that with further A key remaining question will be whether However, there is additional activity earli- follow-up, we will see further separation in Pfizer seeks and/or obtains approval of ta- er in the pipeline. Start-up Eidos Therapeu- terms of the mortality and therefore an in- famidis at the 20 mg or 80 mg dose. The tics Inc. is trying to ride the wave of amy- creasing survival benefit, and we do have an ATTR-ACT study used a 2:1:2 randomiza- loidosis drugs with its own small molecule ongoing open-label extension, which will tion protocol, meaning that twice as many for ATTR. give us further information with regard to patients received the 80 mg dose as the Young noted that tafamidis’ two poten- the mortality in the longer term,” she noted. 20 mg, and that the control group was the tial competitors have only been studied in Pfizer reported that the trial showed a same size roughly as the 80 mg group. Ap- polyneuropathy and have not been stud- consistent directional mortality benefit proval of the larger dose in the US probably ied in wild-type patients. “I certainly don’t across all patient subgroups. Secondary would mean a higher price – Levesque said want to speak for competitors and their endpoints demonstrated a reduced decline the average annual price per patient in the data, but I think the likelihood is that … our in six-minute walk test distance and reduced EU and Japan for Vyndaqel is about $75,000. data set will set a very high bar for others decline in a quality of life assessment as well. The BMO blockbuster sales estimate for to be able to demonstrate their effective- Meanwhile, the drug showed an observed tafamidis is based partly on an expecta- ness in this [ATTR-CM] patient population,” safety profile similar to placebo. The discon- tion for US pricing of about $250,000, Ar- he told the call. The mortality and hospi- tinuation rate in the study was higher in the faei said. talization benefits demonstrated In the placebo group than in either of the treat- Published online 27 August 2018

Novartis’ SOLAR-1 Shines on Alpelisib In Breast Cancer JOHN DAVIS [email protected]

ovartis AG’s PI3K inhibitor, alpelisib clinical benefit rate, efficacy in the PIK3CA Alpelisib has shown promise when used (BYL719), has met the primary end- non-mutated cohort, and safety and efficacy. for PROS (PIK3CA-related overgrowth Npoint in the global Phase III SOLAR-1 According to analysts at Datamonitor spectrum) in a group of French patients, trial, showing an improvement in progres- Healthcare, the development of PI3K in- and Novartis is exploring options to eval- sion-free survival (PFS) in patients with PIK- hibitors in this indication has been difficult uate alpelisib in a clinical study, the com- 3CA-mutated HR+/HER2- breast cancer. due to limited efficacy and adverse events, pany told Scrip. And buparlisib (BKM120), The Basel, Switzerland-based multina- and Novartis is hoping the alpha isoform- has just been out-licensed to the Hang- tional says the results will lead to the start of specific inhibition of alpelisib will lead to zhou, China-based company, Adlai Nor- discussions on marketing submissions with higher selectivity and a better tolerability tye. Buparlisib has shown activity in com- regulatory authorities worldwide. profile than those reported with its pan- bination with paclitaxel in patients with Adverse events observed in SOLAR-1 PI3K inhibitor buparlisib, which failed in the head and neck squamous cell carcinoma, when alpelisib was combined with the mar- Phase III BELLE-3 trial. and Adlai Nortye presented a thoughtful keted estrogen receptor modulator, fulves- clinical plan for its future development, trant, were generally consistent with those OTHER COMPANIES Novartis said. observed in previous studies with alpelisib Roche’s alpha-specific PI3K inhibitor taselisib Pfizer Inc. also has a dual inhibitor of PI3K and fulvestrant, the company said in its Aug. also recently failed in the clinic, the analysts and mTOR, gedatolisib in Phase I in solid tu- 23 announcement. note. In the Phase III SANDPIPER trial, taselis- mors, and Eli Lilly & Co. is also studying a However, further details on the efficacy ib’s two-month PFS improvement was sta- dual PI3K/mTOR inhibitor. In a brief reaction and tolerability of alpelisib were not given, tistically, but not clinically, significant, and note to the SOLAR-1 data, Jefferies analysts with the company saying further results the tolerability profile was again suboptimal estimated peak annual sales of alpelisib would be presented at a forthcoming medi- and did not reflect an improvement over could reach $1.5bn annually. There are no cal conference. Of interest will be the candi- pan-PI3K inhibition. As such, the full SO- approved PI3K inhibitors for HR+ advanced date drug’s effects on secondary endpoints LAR-1 dataset is needed to determine the breast cancer. such as overall survival, overall response rate, potential of alpelisib in this indication. Published online 23 August 2018

scrip.pharmaintelligence.informa.com 31 August 2018 | 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: http://bit.ly/2mx4jY3

Selected clinical trial developments for the week 17–23 August 2018

LEAD COMPANY/PARTNER COMPOUND INDICATION COMMENTS PHASE III INTERIM/TOP-LINE RESULTS Novartis AG alpelisib breast cancer SOLAR-1; met primary endpoint. type 2 diabetes and Novo Nordisk semaglutide, oral PIONEER 5; met primary endpoint, well tolerated. renal impairment MC2-01 (calcipotriene and Superior to Taclonex topical suspension, MC2 Therapeutics A/S psoriasis betamethasone) cream well tolerated. Bevespi Aerosphere (glycopyr- chronic obstructive AstraZeneca AERISTO; mixed effects, well tolerated. ronium/ formoterol) pulmonary disease AbbVie Inc. Orilissa (elagolix) uterine fibroids ELARIS-UF EXTEND; reduced menstrual bleeding. UPDATED PHASE III RESULTS Neurocrine Biosciences Inc. Ongentys (opicapone) Parkinson’s disease BIPARK I; reduced off-time. Neurocrine Biosciences Inc. Ingrezza (valbenazine) tardive dyskinesia KINECT 4; clinical improvements. PHASE III INITIATED Bristol-Myers Squibb & Co. BMS-986165 psoriasis POETYK-PSO-1; in moderate to severe disease. INP-104 (intranasal dihydro- Impel Neuropharma Inc. migraine STOP-301; long-term intermittent use. ergotamine mesylate) Can-Fite BioPharma Ltd. piclidenosan psoriasis Comfort; in moderate to severe disease. PHASE III ANNOUNCED Cabometyx/Cometriq Ono/Takeda (cabozantinib) renal cell cancer CheckMate 9ER; in Japan. and nivolumab PHASE II INTERIM/TOP-LINE RESULTS Kyowa Hakko Kirin Co. Ltd. KW-6356 Parkinson’s disease Well tolerated and effective. VR647 (budesonide) asthma in infant and Vectura Group PLC Reduced delivery time and ease of use shown. nebulizer pediatric patients Taiwan Liposome Co. Ltd. TLC599 osteoarthritis pain Met endpoints. UPDATED PHASE II RESULTS BELIEVE-PV; well tolerated, lowered Principia biopharma Inc. PRN1008 pemphigus vulgaris auto-antibody levels. CLR 131, radio- iodinated Cellectar Biosciencies Inc. phospho-lipid drug multiple myeloma Signs of clinical benefit, well tolerated. conjugate PHASE II INITIATED A C Immune, Ltd. ACI-24, anti-Abeta vaccine Alzheimer’s disease ACI-24-1801; in mild disease. MediciNova Inc. MN-166 (ibudilast) alcohol use disorder NIAAA RO1; in treatment-seeking patients. supinoxin with Rexahn Pharmaceuticals, Inc. breast cancer In metastatic disease. pembrolizumab Sihuan Pharma Holdings Group Ltd. KBP3571 (anaprazole) duodenal ulcer In China. Source: Biomedtracker | Informa, 2018

MC2 Plots Course For Topical Psoriasis Drug Launch JESSICA MERRILL [email protected]

he private Danish company MC2 Therapeutics is preparing A formulation that is easier to apply could improve compliance for the launch of its first drug, a topical cream MC2-01 (cal- and thus efficacy. Some research has shown as many as 73% of pa- T cipotriene/betamethasone) for psoriasis based on its propri- tients on topical drugs for psoriasis do not comply with their treat- etary PAD technology, now that the drug has shown superiority in ment, according to the company. a Phase III trial over Leo Pharma AS’s Taclonex, a commonly used MC2-01 represents the first time the vitamin D analogue calci- first-line therapy. MC2 said it will file a new drug application (NDA) potriene has been combined with the steroid betamethasone in an with the US FDA for MC2-01 in the first half of 2019. aqueous solution, MC2 noted. Taclonex combines the same active On Aug. 21, the company announced the positive Phase III data ingredients in a topical suspension. Leo Pharma is an experienced showing MC2-01 demonstrated superiority to Taclonex based on a dermatology player that generated DKK3.59bn ($600m) from psoria- decrease in the Physician Global Assessment (PGA score) of 40.1% sis products in 2017. But the company reported that sales of Taclonex versus 24% after eight weeks, and meeting the primary endpoint of declined 24% in the US in 2017, with the topical psoriasis market non-inferiority of MC2-01 to Taclonex. The study met key secondary dominated by generics. Leo Pharma has turned its marketing focus endpoints as well, including superiority to Taclonex on the percent to Enstilar, a topical foam containing the same two active ingredients. reduction in mPASI score from baseline at Week 8 (64.8% versus MC2 is a small company, just 16 employees, but would consider 52.3%) and patient convenience. The trial enrolled 796 patients. launching the product independently if it is approved by the FDA. Launching a new drug in the highly competitive market for topi- It has not ruled out working with a larger commercialization partner cals for psoriasis won’t be easy, as the category is also dominated by either, Lange said. “The goal of MC2 Therapeutics is to build a new generics. But MC2 believes MC2-01 offers an important advantage pharmaceutical company based on this [PAD] technology,” Lange when it comes to the convenient formulation. said. The company, which started in 2010, is studying other topical “There are two things patients need. One is very effective relief of and ophthalmology formulations with the technology, including a symptoms and fast, and they need a product that is doable for them, formulation of cyclosporine, the active ingredient in Allergan PLC’s very convenient to use and absorbs quickly into the skin,” President Restasis, in Phase II development for dry eye. Jesper Lange told Scrip. “Traditional solutions have only focused on ef- “We aren’t ignorant to the cost involved in building a US sales force,” ficacy and fast onset, but they are Vaseline-like ointments, which are Lange said. But he said the company’s two investors, two Danish fami- veryCo goodmp at adrivingny moleculesMove into the skin to target tissue, but they lies, are aware of the potential investment and commercial opportunity. leave the skin very greasy and are not very good for putting on clothes.” Published online 21 August 2018 Search

Effective Executive To Company New Role From Company Previous Role Date Achillion Vice President, Clinical Synergy Laura Barrow Pharmaceuticals Operations and Head of Lead, Program 21-Aug-18 Pharmaceuticals Inc Project Management Achillion Steven Chief Medical Officer and Pharmaceuticals UniQure Chief Medical Officer 21-Aug-18 Zelenkofske Executive Vice President Inc AIVITA Vice President, Business Senior Director of Kevin Green Allergan 16-Aug-18 Biomedical Development Business Development AIVITA Scott Burell Chief Financial Officer CombiMatrix Corporation Chief Financial Officer 16-Aug-18 Biomedical AVM Iain Duncan Chief Operating Officer 6-Aug-18 Biotechnology Patrick Regional President, Bayer Lockwood- Consumer Health, North The Oneida Group Chief Executive officer 13-Aug-18 Corporation Taylor America Executive Director Senior Vice President of Michael T. Merck Research Translational Biomarker Indi Molecular Strategy and Technical 22-Aug-18 Klimas Laboratories Immuno-oncology and Business Development Cardiometabolic Lead Senior Vice President, Late Source: Biomedtracker | Informa, 2018 Suresh Intra-Cellular Lead, Clinical Stage Clinical Development Allergan plc 20-Aug-18 Durgam Therapies Inc Development and Medical Affairs scrip.pharmaintelligence.informa.com 31 August 2018 | Scrip | 23 Gjest Lytix Biopharma Auditor and Consultant, Chief Financial Officer PricewaterhouseCoopers 20-Aug-18 Breistein ASA Capital Markets Vice President, Lead, GE Healthcare’s Dale Wolf NuVasive Inc General Electric 16-Aug-18 Manufacturing Florence Anders Oncopeptides Chief Financial Officer Wilson Therapeutics AB Chief Financial Officer 1-Nov-18 Martin-Lof AB Vice President, Sensei Inovio Pharmaceuticals Ildiko Csiki Chief Medical Officer ImmunoOncology 21-Aug-18 Biotherapeutics Inc Clinical Development Peter P. Sucampo UroGen Pharma Chief Financial Officer Chief Financial Officer 20-Aug-18 Pfreundschuh Pharmaceuticals, Inc Senior Medical Director, Jonathan Vericel Chief Medical Officer Ferring Pharmaceuticals Orthopedic Clinical 20-Aug-18 Hopper Corporation Development Verrica Neetu Vice President, Business Pharmaceuticals PBM Capital Group 15-Aug-18 Dhaliwal Development Inc Promotion

Effective Executive To Company New Role Previous Role Date Achillion Vice President of Clinical Development Marc Uknis Pharmaceuticals Vice President 21-Aug-18 and Head of Nephrology Therapeutics Inc Allegro Hampar Chief Executive Officer, Co-Founder Ophthalmics Executive Chairman and Co-Founder 21-Aug-18 Karageozian and Director LLC Allegro Vicken Chief Executive Officer, Co-Founder, Co-Founder, President, Chief Medical Ophthalmics 21-Aug-18 Karageozian President and Director Officer and Director LLC Astellas Pharma National Vice President, Key Account David Abbott Director, Key Account Management 16-Aug-18 US Inc Management Director, Corporate Development and Randoll Sze Athenex Chief Financial Officer 20-Aug-18 Investor Relations, Asia Pacific Susana Director, Innovation and International Rodriguez Cantabria Labs Chief Executive Officer 3-Jul-18 Business Development Navarro

Rui Avelar Evolus Inc Chief Medical Officer and Head, R&D Chief Medical Officer 15-Aug-18 Merz Pharma President and Chief Executive Officer, Bob Rhatigan Chief Executive Officer, Americas 1-Sep-18 GmbH & Co North America Antoinette Executive Vice President, Global Terumo BCT Inc Chief Executive Officer 1-Apr-19 Gawin Commercial Director

Executive To Company New Role Effective Date

Carol Ashe Aptose Biosciences Inc Director 15-Aug-18 Jeb Keiper Cardurion Pharmaceuticals Indepndent Director 16-Aug-18 Dan Mendelson Centrexion Therapeutics Corporation Director 15-Aug-18 Cynthia Smith Dicerna Pharmaceuticals Inc Director 16-Aug-18 J. Kevin Buchi Dicerna Pharmaceuticals Inc Director 16-Aug-18 Steve E. Krognes Gritstone Oncology Inc Director 9-Aug-18 Julie Hambleton IGM Biosciences Inc Director 15-Aug-18 Jeffrey Chodakewitz resTORbio Inc Director 15-Aug-18 Jonathan Bates Spring Bank Pharmaceuticals Inc Director 16-Aug-18 Scott Smith Spring Bank Pharmaceuticals Inc Independent Director 16-Aug-18 Advisor

Executive To Company New Role Effective Date

Pietro Lio Bactevo Ltd Scientific Advisory Board Member 14-Aug-18 Jason B. Fleming Bio-Path Holdings Inc Scientific Advisory Board Member 16-Aug-18 Robin Franklin Frequency Therapeutics Scientific Advisory Board Member 14-Aug-18 Sheng Ding Frequency Therapeutics Scientific Advisory Board Member 14-Aug-18 Maries van den Broek Redbiotec AG Scientific Advisory Board Member 20-Jul-18 Other

Effective Move Executive From Company Previous Role Date Type Aralez Rob Harris Pharmaceuticals Director and Member of Transaction Committee 10-Aug-18 Resignation Inc Aralez Seth A. Director, Chairperson of Nominating and Governance Committee and Pharmaceuticals 10-Aug-18 Resignation Rudnick Member of Audit and Compensation Committee Inc

Juan Matji Cantabria Labs Chief Executive Officer 3-Jul-18 Resignation Chris Evolus Inc Founder and Chief Operating Officer 15-Aug-18 Resignation Marmo Torbjorn Lytix Biopharma Chief Financial Officer 20-Aug-18 Resignation Furuseth ASA Non-Executive Director, Chairman of Remuneration Committee and Ian Gilham Vernalis plc 16-Aug-18 Resignation Member of Audit, Nomination and Corporate Governance Committee Partnerships in PCT: LET’S Clinical Trials GET CLINICAL Europe Learn from the leaders. 27-29 November 2018 Connect with all the key stakeholders. CCIB Barcelona, Spain Build your next partnership and watch the sparks fly.

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