5 January 2018 No. 3886

Scripscrip.pharmaintelligence.informa.com Pharma intelligence | informa bination in indications beyond – including AstraZeneca PLC’s study of Imfinzi (durvalumab) with tremelimub in non-small cell lung cancer, and Bristol- Myers Squibb Co.’s study of Opdivo () with Yervoy (), also in NSCLC. Patel is also keeping an eye on combinations involving PD-1/PD-L1 inhibitors and IDO inhibitors, including the Phase III ECHO 301 trial of Merck & Co. Inc.’s Keytruda () in combination with epacadostat, which is expected to be reported in the first half of the year. Beyond the hotly anticipated IO+IO combinations there will be other areas of progress in combination treatment of cancer: Wood highlights immune cell- Shutterstock: Zeynep Demir Zeynep Shutterstock: targeted and tumor-cell targeted thera- pies as a promising pairing. “I expect par- ticularly effective results when the tumor What Does 2018 Hold For The cell-targeted therapy can stimulate im- munogenic cell death and enhance tu- mor antigen priming. The SMAC mimetics Pharma Industry? are good case in point,” he commented. ELEANOR MALONE [email protected] Boehringer Ingelheim is developing a SMAC mimetic, including in combination rescription drug pricing, technol- ing up the approval indications and count- with PD-1 inhibition. ogy, business model innovation, M&A, less trials of combination therapies under Roche UK’s medical director Rav Seerut- Pgene therapies and immuno-oncolo- way, 2018 will bring many more advances, hun has no fear that there are too many gy will be key issues of concern in 2018, ac- and maybe the odd setback. players developing investigational cancer cording to a survey of industry stakeholders Boehringer Ingelheim GMBH’s head immunotherapy treatments, despite the and experts. While oncology – and immu- of discovery research, Clive Wood, antici- ongoing proliferation of trials. “My view is no-oncology in particular – is certain to con- pates “more clinical results that guide us that it’s going to lead to more personalized tinue as the therapeutic area of most activity to where and how we should use immu- therapies, and all the drugs and combina- and progress, other therapeutic categories notherapy in cancer, in particular how to tions will find a place in different treatment were also singled out as offering particular select combinations with checkpoint in- pathways,” he told Scrip. interest in 2018. These included migraine, hibitors.” He is also prepared for “surprises As for CAR-T therapies, DMHC’s Patel ex- HIV, NASH and obesity. about how different combinations work pects to see recently approved Yescarta with different tumor types.” (axicabtagene ciloleucel) and Kymriah (ti- IO’S ONWARD MARCH Datamonitor Healthcare oncology lead sagenlecleucel) expand their markets both geographically and in terms of therapeutic After another year of significant progress analyst Hardik Patel will be watching for indication. (Also see “Gilead/Kite Pricing For in immuno-oncology, with checkpoint in- top-line data from trials of PD-1/PD-L1 hibitors from a handful of companies rack- inhibitors and CTLA-4 inhibitors in com- CONTINUED ON PAGE 6

BROUGHT TO YOU BY THE EDITORS OF PHARMASIA NEWS, START-UP AND SCRIP INTELLIGENCE

AstraZeneca’s Pipeline Riches Hits and Misses Year to Remember Could AZ become a victim of its 2017’s clinical trial successes Vintage crop of new US drug own success? (p22-24) and failures (p13-15) approvals in 2017 (p10) IN THIS ISSUE

from the editor [email protected]

Welcome to our bumper New Year issue. It’s packed many loss-making minnows that nonetheless keep the with insights on what to expect for 2018, as well as industry’s lifeblood of innovation circulating. round-ups of drugs approved and trials that went On the Scrip 100 site, our subscribers can access in- right – and wrong – in 2017. On top of that, some teractive charts offering a range of metrics for the com- hardy pharma souls continued doing business in the panies in our Scrip 100 universe, and also download dying moments of last year; if you missed the final Excel versions of the charts. Beyond the data tables, you flurry of M&A, approvals and trial read-outs, then will find feature articles diving into topics as diverse as look no further. gene editing, international reference pricing, and how We were pretty busy ourselves at Scrip last month, to future-proof talent. There are interviews aplenty with launching our famed annual Scrip 100 Review. The a range of industry executives, and insights into thera- print version will be out next week, but you can access peutic areas from depression to cancer. all the content online right now, at www.scrip100.com. Last year’s haul of new drug approvals (see p10) re- The review includes financial data on more than 650 flected the great advances that our industry has made in companies, from the big 20 that generated the vast ma- recent years. With immuno-oncology, gene therapy and jority of the industry’s total 2016 profit of $137bn and artificial intelligence offering so much promise, expect employed half of its workforce of 2.3 million, to the another action-packed year.

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Scrip is published by Informa UK Limited. ©Informa UK Ltd 2018: All rights reserved. ISSN 0143 7690.

2 | Scrip | 5 January 2018 © Informa UK Ltd 2018 Christmas Bonus 20 Stables And Drones

Sales Force 20 4 Return 32

exclusive online content inside: Mitsubishi Seeks To Revoke Kolon Gene Therapy Deal COVER / What Does 2018 Hold For The Pharma Industry? But Damage Limited? 4 Roche Ramps Up Cancer Portfolio With $1.7bn http://bit.ly/2lK6sNc Ignyta Buy Mitsubishi Tanabe has sought to cancel the license agreement for Kolon Life Science’s Invossa, clouding the South Korean firm’s 5 Mallinckrodt Reduces Acthar Reliance With $1.2bn global ambitions for the allogeneic cell mediated gene therapy. Sucampo Buy However, analysts don’t anticipate a big hit for Kolon even if the 9 Roche Digs In To Early Breast Cancer With Perjeta deal falls through given that the cancellation demand is not linked to Invossa’s efficacy. 10 A Year To Remember For US Drug Launches

Genexine Seals I-O Licensing Deal With I-Mab, 12 ICER Views Kymriah, Yescarta As Cost Effective Builds Momentum 13 The Year’s Clinical Trials In Review: Big Hits In 2017 http://bit.ly/2CJMnhB Genexine has reached a critical point in developing its immuno- 14 The Year’s Clinical Trials In Review: Big Misses In 2017 oncology pipeline, firming up a $548m-plus licensing out pact 20 The Return Of The US Pharma Sales Force for an asset with the Shanghai-based I-Mab Biopharma. The South Korean firm expects the deal to serve as a yardstick of 21 Millendo Gets European Foothold With Alizé Acquisition ‘value determination’ in its future global transactions. 21 Summit Completes 2017 With Discuva Buy Interview: Orchard’s Gene Therapies Bear Fruit With 22 AstraZeneca’s Pipeline Reaps Rewards Of Return $110m Financing To Science http://bit.ly/2kPsNYr The UK firm has attracted more top-tier investors who are clearly 25 AbbVie’s Upadacitinib Aces Another Arthritis Trial, impressed with its gene therapy for bubble baby syndrome and But Safety Concerns Linger a high-quality pipeline in other very rare diseases. 26 The Next Challenge: Improving And Predicting Responses Charting The Slow-Growing Psoriatic Arthritis Market As CAR-T Therapies Advance http://bit.ly/2lJlfrx 28 Unlocking Market Access For Novel Drugs In China Despite the availability of anti-TNF biosimilars, the global market for drugs for psoriatic arthritis will grow to $4.1bn in 2025 due 29 Pharma-BAT Digital Health Tango In China: to the entry of new branded drugs at high prices in the US, Will It Pay Off? according to a new Datamonitor Healthcare forecast report. 30 China API Juggernaut Rolls On But Can India Recoup? Deal Watch: Boehringer’s Busy End Of Year Includes 31 Bumpy Ride Awaits Indian Firms In 2018 Deals With Roche, Autifony (And Then There’s Amazon) http://bit.ly/2EGu0KJ 32 Profile: Novartis’ Gildea On Stable Girl Grit And Drones The German pharma options potassium channel modulator technology from Autifony and partners with Roche on 34 Pipeline Watch immunological approaches to irritable bowel syndrome. Roche unveils discovery pacts with Confo and DiCE. 35 Appointments

Finance Watch: Happy Holidays For Flagship With A New $618m Fund http://bit.ly/2EDJBe5 Private Company Edition: Flagship ends 2017 with its biggest life science fund yet totaling $618m. Also, December sees a year-end surge in VC deals, including a $100m Series B round @PharmaScrip /scripintelligence for Allakos. /scripintelligence /scripintelligence

scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 3 DEALS

Roche Ramps Up Cancer Portfolio With $1.7bn Ignyta Buy KEVIN GROGAN [email protected]

he holiday season was a very happy one for Ignyta Inc. fol- If approved, and Ignyta is hoping for a tissue-agnostic label, entrec- lowing the news that Roche is paying $1.7bn to acquire the tinib would compete with Pfizer Inc.’s Xalkori (), which is T San Diego-based rare cancer specialist. approved for ROS1+ NSCLC but has poor CNS penetration. Another Under the terms of the deal, which has been agreed unanimously product, Pfizer’s , which is an ALK and ROS1 inhibitor with by the boards at both companies, the Swiss major is paying $27 per CNS activity, is in Phase II. share which represents a premium of 74% on Ignyta’s closing price Another potential rival that will have watched the link-up with on Dec. 21 and 89% over its average stock price over the past 90 days. Roche with great interest will be another company looking at tissue- In return, Roche is getting its hands on , which Ignyta has agnostic cancer therapies, Loxo Oncology Inc. Last month, the firm claimed could be a best-in-class therapy for non-small cell lung can- signed an agreement with Bayer AG, including a hefty $400m up- cer (NSCLC) patients. front fee, to develop and commercialize its NTRK inhibitor larotrec- tinib – this week (Dec. 20), Loxo initiated a rolling submission of its NDA for the latter to the US FDA for the treatment of TRK fusion can- cers. (Also see “Loxo’s Requires Paradigm-Change In Clini- cal Practice” - Scrip, 5 Jun, 2017.) Ignyta, which raised $160m after issuing 10m shares in a public offering in October, says it has an ‘Rx/Dx approach’ to development, combining precision therapeutics and in-house molecular diag- nostics. Its pipeline includes taladegib, a small-molecule hedgehog pathway inhibitor which is in Phase Ib trials for ovarian cancer, RXDX- 105, a RET inhibitor also in Phase Ib in patients with advanced lung cancer and other solid tumors, and RXDX-106, a pseudo-irreversible inhibitor of the TAM (TYRO3, AXL, and MER) family of receptor tyro- sine kinases which is currently in late-stage preclinical development. As for Roche, its pharmaceuticals chief Dan O’Day said in a state- ment that “cancer is a highly complex disease and many patients Shutterstock: Vera Petruk Vera Shutterstock: suffer from mutations which are difficult to detect and treat.” He -add ed that the Ignyta acquisition “builds on Roche’s strategy of fitting Entrectinib is a inhibitor being developed for treatments to patients” and will allow the company “to broaden and tumors that harbor NTRK or ROS1 fusions – the latter occur in strengthen its oncology portfolio globally.” about 2% of all NSCLC cases. In October, interim data presented The deal comes at a time when Roche is preparing for a battering at the World Conference on Lung Cancer in Yokohama from the from biosimilar competition to some of its big-selling cancer thera- Phase II STARTRK-2 trial in patients with ROS1 fusion-positive pies. MabThera/Rituxan () is already suffering market share advanced NSCLC revealed that entrectinib demonstrated a 78% erosion in Europe and rivals to Herceptin () and Avastin (25 out of 32) and 69% (22 out of 32) confirmed objective re- () are lining up. (Also see “New Drugs Shine But Biosimi- sponse rate (ORR). lars Blunt Roche Revenue Rise” - Scrip, 19 Oct, 2017.) The drug also showed a median duration of response of 28.6 Datamonitor Healthcare analyst Ali Al-Bazergan told Scrip that with months and median progression free survival (PFS) of 29.6 months in the deal, Roche continues to focus on its bolt-on strategy to comple- this population, with 53% of patients remaining on the study. Impor- ment its oncology portfolio. He added that entrectinib “brings in tantly, in terms of activity in the central nervous system, entrectinib an extremely promising multi-targeted NTRK/ROS1/ALK inhibitor” showed 83% (five out of six) confirmed intracranial ORR in patients which is on track for dual NDA submissions in both the NTRK tissue- with measurable brain metastases. agnostic and the ROS1-positive NSCLC indications in 2018. With over 200 patients treated at the recommended Phase II Al-Bazergan added that Bayer’s partnership with Loxo for laratrenc- dose, most adverse events were Grade 1-2 and reversible, and tinib “strengthens the market opportunity for entrectinib” and also only 3% of patients discontinued from the study due to treat- “paves the way towards a best-in-class profile owing to strong results ment-related . With its duration of response, PFS data in the Phase II STARTRK-2 study with potential long-term differentia- times and its ability to cross the blood-brain barrier, Ignyta be- tion coming from PFS and CNS activity.” lieves entrectinib, which has PRIME designation from the EMA Another company full of Christmas cheer following the Roche deal and breakthrough therapy designation from the US FDA, has the is Nerviano Medical Sciences SRL which licensed entrectinib to Ig- potential to be used as a first-line targeted therapy for patients nyta in 2013. The Italian firm is eligible for royalties on the drug. with ROS1-positive NSCLC. Published online 22 December 2017

4 | Scrip | 5 January 2018 © Informa UK Ltd 2018 DEALS

Mallinckrodt Reduces Acthar Reliance With $1.2bn Sucampo Buy ELEANOR MALONE [email protected]

allinckrodt PLC has agreed to Meanwhile, Mallinckrodt is also suffering Sucampo has settled with Par for the acquire Sucampo Pharmaceu- from the broader challenges affecting spe- launch of an authorized generic version of Mticals Inc. for $1.2bn, including cialty medicines and generics firms, particu- the drug in the US in 2021. the assumption of the latter’s debt. The deal larly in the US. Sucampo’s other marketed product is the most notably brings one significant mar- Investor reaction to the Sucampo deal ocular pressure-lowering drug Rescula (un- keted asset, and two late-stage candidates announcement was marginally positive: oprostone), which is sold in Japan and gener- for rare diseases which are projected to gen- Mallinckrodt’s shares closed up 0.7% at ates less than 5% of the company’s revenues. erate up to $450m in peak sales between $23.48 following the announcement on Sucampo has projected it will book total them, if approved. Dec. 26, 2017. The small boost is none- 2017 revenues of $250-255m and adjusted The deal helps US-listed, UK-headquartered theless dwarfed by the 55% decline the net income of $63-68m. Mallinckrodt reduce its revenue reliance on stock has suffered since the start of 2017. controversial specialty medicine H.P.Acthar Mallinckrodt’s market capitalization stands PIPELINE BOOST gel (repository corticotropin injection), which at $2.2bn, down from $5.0bn at the begin- The acquired company will flesh out is used in a range of autoimmune, inflamma- ning of the year. Mallinckrodt’s later stage pipeline with VTS- tory and other conditions including lupus, While analysts at Morgan Stanley in a Dec. 270 for the rare and fatal neurodegenerative multiple sclerosis and infantile spasms. 26 note described the deal as “a marginal disease Niemann-Pick type C and CPP-1X/ Acthar has attracted negative attention positive because it diversifies [Mallinckrodt] sulindac for familial adenomatous polyposis from investors, regulators and politicians away from Acthar,” Moody’s ratings agency (FAP), both in Phase III trials. because of its high price. Mallinckrodt ac- warned that it was considering downgrad- VTS-270, which has the potential to treat quired the product from Questcor in 2014, ing Mallinckrodt’s ratings because of added a large majority of all Niemann-Pick patients, but it was originally approved in 1952; its debt the company plans to take on to fund is slated for FDA submission in 2018, with an price has increased from $1,650 to $34,034 the acquisition. Moody’s noted that the approval decision expected in 2019. a vial since 2001, with much of the increase transaction would increase Mallinckrodt’s Mallinckrodt will have global rights to the arising before Mallinckrodt took ownership. gross debt/EBITDA (earnings before interest, product, and expects to receive a priority re- In January 2017 Mallinckrodt paid a fine tax, depreciation and amortization) ratio on view voucher should it be approved. It proj- under a settlement with the US Federal a pro forma basis from 4.4 to 4.9, reducing its ects total peak sales of $150m. Trade Commission in a case in which Quest- financial flexibility. Sucampo acquired the product through cor was alleged to have acquired a compet- “Mallinckrodt also faces earnings pressure the purchase of Vtesse Inc. earlier in 2017. ing product to keep it off the market. (Also in its specialty generics segment and sales (Also see “Sucampo Looks To Add Heft With see “Mallinckrodt’s FTC Settlement Seems A growth headwinds in 2018 on its largest Vtesse Acquisition” - Scrip, 3 Apr, 2017.) Blip For Acthar Blockbuster” - Scrip, 19 Jan, drug, Acthar,” it stated. “That said, the ac- CPP-1X/sulindac is expected to complete 2017.) There have also been allegations of quisition of Sucampo provides incremental Phase III at the end of 2018. Sucampo is de- price fixing against Mallinckrodt and United earnings diversification for a few years and veloping it in partnership with Cancer Pre- BioSource, a subsidiary of US pharmacy ben- improves its pipeline of late-stage drugs.” vention Pharmaceuticals (CPP), from which efit management group Express Scripts that Mallinckrodt says it would anticipate acquir- describes itself as providing pharmaceutical AMITIZA REVENUE STREAM ing North American rights to the product for and patient support services. Express Scripts Sucampo’s main commercial product is a nominal fee, should the trial succeed. announced in November 2017 that it was Amitiza (lubiprostone), a treatment for vari- The drug is expected to be filed and po- selling United BioSource to private equity ous constipation indications, which is also tentially approved in 2019. Peak US sales firm Avista Capital Partners. awaiting a US approval decision (expected of more than $300m are anticipated by Acthar accounted for 34% of Mallinck- in January 2018) to treat pediatric functional Mallinckrodt, which would share some of rodt’s net sales in 2016, but the product’s constipation in children aged six to 17. The the profits with CPP. sales fell by 5.6% in the third quarter of 2017, product is partnered with Takeda in the US, The Sucampo acquisition is just the latest bringing the whole company’s sales and UK and Switzerland and with Mylan in Ja- in a string of transactions by Mallinckrodt, earnings down. The company noted that in- pan, and brought in total net sales of $456m which is looking to divest under-performing creasing numbers of prescriptions were go- in 2016, although more than half of that businesses while purchasing more promising ing unfilled, possibly because insurers were goes to Sucampo’s commercial partners. activities in bolt-on deals. (Also see “Mallinck- putting up more hurdles to reimbursement. Sucampo itself booked revenues of $201m rodt’s InfaCare Buy Leaves Room For Further Di- Mallinckrodt warned that a further decline in combined product sales and royalty pay- versifying M&A” - Scrip, 7 Aug, 2017.) was foreseen in the fourth quarter. ments, up 45% on the prior year. Published online 27 December 2017

scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 5 2018 PREVIEW

CONTINUED FROM COVER be in the details, with close attention ex- Yescarta Undercuts Novartis’s CAR-T Kymriah” pected to how the product labels are dif- - Scrip, 18 Oct, 2017.) ferentiated, and how that affects pricing Brian Atwood, MD of Versant Ventures and and reimbursement. “Success in clinical co-founder and CEO of Cell Design Labs trials for drugs for new classes has not al- Inc., believes that ASCO 2018 “could be a ways recently translated into immediate very important meeting after a quiet 2017.” commercial success, so this additional hurdle should not be taken for granted,” ADVANCED THERAPIES he cautioned. The approval of Spark Therapeutics Inc.’ vi- Addressing earlier candidates in the R&D sion loss gene therapy Luxturna (voretigene pipeline, Sanofi’s head of neuroscience re- neparvovec-rzyl) in December was high- search, Rita Balice-Gordon, expects 2018 lighted by Boehringer’s Wood as one of the to bring “new breakthroughs in how toxic “flashes of success” achieved by gene thera- proteins aggregate to cause neural dysfunc- pies in 2017. “These are still heading to their Rita Balice-Gordon tion, plus links between brain function and coming of age,” he said. “Further progress in bluebird bio Inc. or Spark” and lots of deal diabetes/obesity.” a positive direction is likely in 2018.” making both in terms of partnerships and Boehringer’s Wood meanwhile believes Eduardo Bravo, CEO of allogeneic stem “maybe more full-company acquisitions that metabolic disease research “will see a cell therapy developer Tigenix, con- than we’ve seen in past years.” new emphasis on clinical testing of com- curred. “There has been a number of binations of drug candidates in obesity.” He developments in regulatory processes NEUROSCIENCE AND MORE thinks the combinations will “take advan- around the world aimed at speeding Others highlighted therapeutic advances tage of synergistic/additive efficacy at more up market access of these treatments,” in CNS, metabolic disorders and infectious favourable exposure levels” and expects a he said. “And with more products either diseases. similar trend in non-alcoholic steatohepati- close to or gaining approval, advanced Roche’s Seeruthun expects breakthroughs tis (NASH). therapies are closer than ever to deliver- in neurodegenerative disease R&D, and For Michael Haydock, Datamonitor ing on their potential.” highlighted Roche’s ongoing Phase III Al- Healthcare lead analyst for cardiovascular On the regulatory front, Informa Pharma zheimer’s programs with amyloid-targeting and metabolic and infectious diseases, News principal analyst Amanda Micklus and as well as the biggest event in the infectious dis- expects the FDA “to continue in 2018 to the Swiss group’s recently licensed candi- ease landscape in 2018 will be the ex- fulfill provisions laid out in the 21st Century date for Huntington’s disease, IONIS-HTTRx: pected US approval of Gilead Sciences’ Cures Act to develop a regulatory frame- Roche and partner Ionis will present data HIV combination bictegravir/emtric- work around regenerative medicines. FDA on the latter drug at medical conferences itabine/tenofovir alafenamide (B/F/TAF) commissioner Scott Gottlieb has already in 2018. (Also see “Roche’s Neuroscience in February, followed by EU approval in announced a series of regulatory guidances, Franchise Gets Lift From Huntington’s Break- the third quarter. “It will be Gilead’s flag- including two final and two draft docu- through” - Scrip, 12 Dec, 2017.) “We are hop- ship single-tablet regimen to replace ments, and I believe there are more in the ing to move in both diseases beyond slow- Genvoya, which is already a blockbuster,” pipeline, including disease-specific guid- ing progression to modifying the disease,” he said. “ViiV Healthcare’s dolutegravir- ances on gene therapy (the first of which is he said. Nonetheless, Datamonitor Health- based products have been stealing mar- to be in hemophilia).” care lead analyst Dan Chancellor, who spe- ket share away from Gilead in recent Micklus believes the appointment of cializes in CNS, said “2018 should actually be years, so B/F/TAF is expected to reverse Scott Gottlieb was a “big win” for the cell a relatively quiet year for pivotal trial read- the tide and recoup some of Gilead’s mar- and gene therapy industry in 2017: “He has outs” in Alzheimer’s. ket share.” DMHC predicts the product been a champion for this market and under- Instead, he is “looking towards the will reach peak sales of $5.7bn in 2022, stands that the FDA needs to modernize its first approvals of the exciting anti-CGRP helping to drive growth for Gilead as its processes when it comes to evaluating cell antibody class for migraine prevention.” HCV franchise continues to hemorrhage and gene therapies, including the use of Added Dan Digaudio, drug analyst with sales in the face of pricing competition adaptive clinical trial design and early and Informa Pharma Intelligence’s Phar- and falling patient numbers. frequent communications with sponsors.” maprojects, “Will Eli Lilly & Co.’s galca- She expects the momentum generated nezumab, Novartis AG’ or PERSONALIZED MEDICINE around cell and gene therapies in 2017 Teva Pharmaceutical Industries Ltd.’s For Robert Tansley, investment director at with the approval of CAR-T therapies, posi- be the first approved? Cambridge Innovation Capital, 2018 will tive clinical data read-outs, Gilead Sciences The winner will have a clear advantage by see significant advances in personalized Inc.’s acquisition of Kite Pharma Inc. and being the first to deliver a breakthrough medicine, with ongoing improvements other developments will continue into therapy to patients imprisoned by severe in cost-effectiveness and sensitivity of ge- 2018, with “possibly accelerated filings for and chronic migraine attacks.” Nonethe- nomic analysis meaning “a wide range of hemophilia gene therapy candidates from less, Chancellor warned that the devil will tests are beginning to emerge.” He believes

6 | Scrip | 5 January 2018 © Informa UK Ltd 2018 2018 PREVIEW

the personalization of medicine “will grow and growing oncology market “will drive a chain, said Salil Kallianpur, former executive substantially in 2018 and beyond, improv- shift in how pharma engages with stake- of GlaxoSmithKline India and co-founder ing response rates dramatically and making holders. Technology will play a key role in and partner of The Digital Transformation treatments much more effective and effi- driving personalized customer experiences Lab. He speculated that Amazon could cient than those seen in the past.” to meet the unique needs of the oncology “use its scale to become the single largest “We’ll truly see personalized treatments space,” he predicted. buyer and distributor of generic medicines coming into play in 2018,” agreed Roche’s Meanwhile, Veeva’s vice president Vault and use its vast global shipping network to Seeruthun, who added “we’re coming to EDC, Richard Young, thinks “risk-based get medicines from ‘factory to formulary’ in see genomic profiling become a standard of monitoring (RBM) will be replaced this a matter of hours,” with cost savings passed care. The challenge is how to use genomic year by risk-based everything (RBX), a new on to patients. profiling and aggregate datasets and use al- approach where each data point can be Mehta Partners’ Viren Mehta, a regular gorithms to personalize treatments, both in analyzed to help companies make better Scrip columnist, agrees that disruptors from drug development and patient care.” decisions.” Modern data systems will help outside the industry will leave big pharma manage the increasing volume and diver- in particular facing the challenge of defin- DATA, DIGITAL TECHNOLOGY sity of data sources, he added. ing “what is their critical value proposition” AND ARTIFICIAL INTELLIGENCE Medidata Solutions Inc. is another firm in 2018. Many of those Scrip spoke to highlighted using a cloud-based platform to provide so- Data technology is undoubtedly a key digital technology in one form or another as lutions to the pharma industry. Glen de Vries, component across the healthcare and bio- an area of likely progress in 2018. president and co-founder, thinks “2018 will pharma universe, and looks set to revolu- “It is clear that companies that have be a year that we look back on as the inflec- tionize it in many ways, with cost pressures strong data driven cultures are the big win- tion point around collaboration that results acting as a major impetus for change. ners in driving value. It is no longer about in sustainable improved outcomes, both for “Worldwide cost pressures will lead big, thick, small and other adjectives to patients and for the business of life sciences. to continued disruption in healthcare. describe data but it’s about using the best Without restrictive categorizations like “pre- To achieve greater efficiency, innovation approaches to drive better decision mak- competitive,” and with broader impact than throughout the entire system, from new ing,” declared Milind Kamkolkar, chief data the handful of platform trials run to date, we healthcare delivery models to novel R&D officer at Sanofi, which is embarking on an will see a proliferation of adaptive designs, strategies will be key to progress in 2018,” enterprise information management (EIM) comparator arms based on shared patient commented Elias Zerhouni, executive vice- capability “that will lead our business into an data pools and real-world data, and con- president, global R&D at Sanofi, summing evolved way of building value.” sistent acceleration of evidence generation up the thoughts expressed by many others. Kamkolkar believes that “AI will reach -- all leading to access to the best possible critical mass as an enterprise capability therapies for patients in need.” PRICING with its first major win in Natural Lan- One downside of the increasingly digi- Mehta points out that people today live guage Intelligence.” This will enable the tized world is the rising threat of cyber- longer “only to face more maladies of ag- extraction and analysis of data currently crime. Viktors Engelbrehts, director of threat ing.” He believes that whereas “the debate held captive in studies, publications and intelligence at cybersecurity firm eSentire, about the cost of medicine to date has documents and the like to “create new in- warned that 2017 saw an increasing num- been focused on each episode [of illness], sights we never had access to and better ber of attacks carried out against biotech- soon a global or lifetime budget will an- chor such discussions, within which each address unmet needs of our customers.” nology and other healthcare industry tar- individual treatment will need to find its He also highlighted blockchain as “a new gets. With a 90% increase in alerts sent on own rightful place.” He believes the de- way of managing and engaging with data hostile traffic, biotechnology is mostly tar- bate will tighten in 2018, with a shift from in a secure and permission based way” geted for its intellectual property. “To cyber- the concept of quality adjusted life years that is worth watching in pharma in 2018: criminals, biotech organizations are in a mix (QALY) per treatment to an overall quality for example, Sanofi will be running some of being a source of information or IP theft, adjusted life (QAL) valuation of medicine pilots to use it to give customers better and also are a potentially easy target for tra- throughout a person’s lifetime. access to their data in trials. ditional, financially motivated cybercrime,” More immediately accessible to action, Cloud computing firm Veeva is focused said Engelbrehts. Biopharma companies in Kallianpur expects lifting barriers to generic on pharma and life science industry ap- 2018 should step up their defenses as these drug competition will be a priority of the US plications. Its general manager CRM, Arno attacks are not going away. government and FDA, with more focus in Sosna, agrees about the rise of AI. “In 2018, Another threat for pharma comes from 2018 on speeding up approval of complex companies will significantly scale their use non-traditional firms entering the fray, and generics and biosimilars “to bring much of artificial intelligence for a wider range of digital experts like Amazon should be close- needed choice and competition” to reduce commercial applications. With greater scale, ly watched in 2018. Although Amazon has the prices in categories that account for the applications such as predictive customer yet to throw its hat in the ring, it is a “master” most expensive medicines. Meanwhile, as engagement will become more ubiquitous,” at getting products from manufacturers to regards high-priced branded medicines, he said. His colleague Kilian Weiss, general consumers and this mastery is desperately manager KOL solutions, notes that the huge needed in “a very inefficient” pharma supply CONTINUED ON PAGE 8 scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 7 2018 PREVIEW

CONTINUED FROM PAGE 7 in 2018 on the back of the clarification and sellers. “In the US at least, small to mid- Edison director-analyst Andy Smith thinks of some uncertainties including pricing cap biotech have market caps that start “commercial payers will continue to flex legislation and tax reform. The ability to at at least $1bn. Either price expectations their muscles in 2018.” repatriate ex-US cash at a one-time tax have to rise at the acquiring companies, or DMHC’s Chancellor wondered whether rate of 10% and clarification of corpo- more likely, prices will come down. I was the promises that some pharma compa- rate tax will allow biopharma to allocate told by an investor the other week that nies made in 2017 to limit annual drug price capital towards higher-risk deal making. generalist investors are still overweight increases were isolated events. He pointed That said, companies will continue to use healthcare and continue to sell those hold- out that “two high-profile drug launches – disciplined M&A as a vehicle to sharpen ings down (hence the fairly ugly 2017 tax Ocrevus and Dupixent – notably undercut strategic focus into therapeutic areas that loss selling season for biotech). This may the list prices of the competition” in 2018. have critical mass, paving the way for a continue in 2018 until prices get cheap His colleague at Datamonitor Health- few larger deals.” enough to catalyze a new wave of M&A.” care, Tijana Ignjatovic, noted that in the US Results Healthcarepartner Kevin Bottom- eyes will be on the work of the Institute ley agreed: “Assuming that the latest corpo- BREXIT for Clinical and Economic Review (ICER), rate tax reforms are enacted in the US, this Last, but by no means least, Brexit was which “has been increasingly active and will unlock large pharma M&A, which has flagged as an important topic for 2018. is now timing the release of its reports so been quiet for the last 15 months. Expect “UK pharma companies will continue to they could be referenced by payers when large pharma companies to be targets and hedge against a ‘hard’ Brexit by investing in making their coverage decisions… Its for example, Pfizer Inc., to be active. All operations in the EU. Inward investment in partnership with the VA (Department of large pharma are seeking scale economies UK pharma research will be strong; recruit- Veterans Affairs) indicates that the direc- and pipeline.” ing and retaining EU talent will be an ongo- tion of travel is heading towards greater So did Leo Gribben, UK TAS Life Sciences ing challenge,” said Bottomley. influence, with the next step potentially Leader at EY: “Overall, the prospects for the Roche’s Seeruthun acknowledged that working with the CMS.” However, an im- transaction market look good. If recent “there are a lot of unknowns” but pointed pact on publicly funded Medicare cover- press commentary is anything to go by, out “the current UK government’s interest is age is unlikely in 2018, she believes, since with upcoming sales in OTC, consumer to maintain regulatory alignment.” He sees it would require a legal change. health and generics expected during the Brexit as offering an opportunity for the UK Ignjatovic will also be watching for “any course of the next financial year, there could medicines regulator MHRA to work along- new pricing or reimbursement mecha- be a lot of assets coming to the market with side the European Medicines Agency and nisms specifically for oncology combi- no shortage of willing buyers. to take a leadership role and help ensure UK nations” since a burgeoning number of “The question that everyone is posing is patients get earlier access to medicines. “But such treatments are coming through whether private capital could play a bigger we need to maintain a very close relation- the pipeline and promise significant part in these asset auctions than we have ship with the EMA.” Seeruthun also said the improvements in outcomes for patients previously seen, both for those that will industry needed “clarity relatively quickly” on – which poses a challenge for payers, come with infrastructure and for those who the rules governing medicines entering the especially where the elements of a com- have built the platforms to acquire brands UK from the EU, both for clinical trials and bination are manufactured by different with no infrastructure. Equally, throw into prescribing. companies. “We expect that in multiple the mix some of the bigger players, who Clive Wood expressed concern about countries there are efforts to develop have the ability to be creative and swap as- the prospects for the wider European re- new policies to allow payers to negotiate sets, and it could help unlock some of the search effort. “Much has been said about a reduced price for such combinations.” transactions. the important topic of harmonization of Such proposals are being considered in “The US tax reform could also allow some drug regulation post-Brexit. I hope that as Germany although political factors may the US majors to release their trapped off- clarity emerges in the coming year, we can stymie legal reform. shore firepower. Some estimate that this also focus on preserving the strength and Meanwhile, she notes that the UK will could release funds worth over $150bn.” integrity of scientific research cooperation likely experience tough negotiations as the But Andy Smith was not so sure. “Typically across Europe,” he said. “Europe is a criti- current Pharmaceutical Price Regulation biotech stocks jump when investors think cal link in the global engine of innovation Scheme expires at the end of 2018 while of repatriated cash as they seem to assume for patients. To allow it to slip in any way, the NHS struggles with serious financial that if will fuel M&A. I don’t think that this would be at our peril.” pressures. will be the case and irrespective of where “The uncertain fallout of Brexit will contin- cash in the last few years has been derived ue to present a challenge for us all in 2018 M&A – retained earnings, debt or repatriation – it and beyond. This means the final deal must There were mixed views among those more often gets spent on share buy-backs. have pragmatic solutions so that patients consulted on merger and acquisition Expect that to rate higher than M&A in C- can have secure access to the medicines trends for the coming year. Ali Al-Bazer- suites,” he predicted. they need once the UK is out of the EU,” said gan, Datamonitor Healthcare lead analyst, He also thinks that there is still a discon- Lars Bruening, CEO of Bayer UK & Ireland. is “anticipating bolstered M&A traction nect in price expectations between buyers Published online 29 December 2017

8 | Scrip | 5 January 2018 © Informa UK Ltd 2018 APPROVALS

Roche Digs In To Early Breast Cancer With Perjeta EMILY HAYES [email protected]

enentech Inc./Roche has strengthened its foothold in early Perjeta was just approved for adjuvant use, but guidelines from breast cancer with a new supplementary US FDA approval the National Comprehensive Cancer Network (NCCN) already rec- Gfor the rising HER2 franchise star Perjeta covering use in the ommended use for high-risk HER2-positive patients in the adjuvant adjuvant (after surgery) setting and full approval in the neoadjuvant setting who did not receive the drug prior to surgery. (before surgery) line of therapy. Genentech’s Perez explained that there has been debate in the FDA approved Perjeta () on Dec. 20 for use with Ge- breast cancer community, with some feeling that patients deserved nentech’s HER2 franchise grandfather Herceptin (trastuzumab) and access to Perjeta in the adjuvant setting as well as neoadjuvant use, chemotherapy for adjuvant use in HER2-positive early breast cancer but the company has not been promoting it in this line of therapy as at high risk of recurrence. Per the label, the regimen should be given that would have been an off-label indication before now. for one year – up to 18 cycles. With the launch of Perjeta in 2012 and the antibody drug con- The filing had priority review, based on the Phase III APHINITY results, jugate Kadcyla (ado-trastuzumab) in 2013, “Roche is in a strong and approval came more than a month earlier than the user fee date of position to continue expanding its breast cancer franchise beyond Jan. 28. The APHINITY study included 4,805 patients and with a median Herceptin, regardless of biosimilars (which we expect in late 2017 of 45.4 months of follow-up the combination of Perjeta with Herceptin in Europe and 2019 in the US),” Morningstar analyst Karen Anderson and chemotherapy reduced the risk of breast cancer recurrence or said in a Dec. 20 note. death by 18% versus Herceptin and chemotherapy alone (p=0.047). “Patents on newly approved drugs Perjeta and Kadcyla run to 2025 “High risk” wasn’t precisely defined in labeling and may be subjec- and 2023, extending the profitability of the firm’s Herceptin-based tive, depending on the patient. The company will be helping physi- breast cancer franchise,” Anderson noted. cians understand what they think it means, Edith Perez, vice president and head of Genentech’s US BioOncology Medical Unit, told Scrip. APHINITY UNDERWHELMED The definition of “high risk” was broader than expected, “giving on- The new approvals represent an important step in staking a claim in cologists the freedom to treat any patients for whom they are par- the treatment of early cancer, a goal for many oncologic therapies ticularly concerned about the possibility of recurrence, either based across tumor types, even though results of the study underwhelmed on their clinical features or their personal circumstances,” Jefferies investors at the time of release at the American Society of Clinical analyst Jeffrey Holford observed in a Dec. 21 note. Oncology meeting in June. The agency has now also granted full approval of the Perjeta/Her- Overall, the absolute difference between the two study arms (Per- ceptin/chemotherapy combination in the neoadjuvant setting for jeta/Herceptin/chemo versus Herceptin/chemo) was only 0.9% (94.1 HER2-positive, locally advanced inflammatory or early-stage breast vs. 93.2%). cancer. The Dosage and Administration section of revised labeling Results were better in certain subgroups and analysts speculated for this indication now says that treatment should continue for one that use would be confined to those at highest risk. year, up to 18 cycles, whereas it had not previously been specified. At the time, Jefferies analysts said that the data were at the bottom The accelerated approval in neoadjuvant breast cancer, grant- end of expectations and that they expected use would be prioritized ed in September 2013, was supported by the Phase II NeoSphere in the 34% of patients in the highest-risk subgroup, who got the study, which used the emerging surrogate endpoint of pathological greatest benefit (a 23% improvement in disease-free survival). complete response (pCR). In that trial, 40% of those in the Perjeta/ But with the better-than-expected labeling and approval timing, Herceptin/chemo arm had a pCR versus 21.5% for Herceptin with along with input from physicians, Jefferies revised its expectations. chemo. Approval marked the first and still only use of the FDA’s ac- A recent proprietary survey of US breast oncologists suggests phy- celerated pathway for neoadjuvant breast cancer drugs. sicians already have extensive experience using Perjeta in metastatic “After speaking with Roche, we estimate that the updated label for and neoadjuvant breast cancer patients already, Holford said in his neoadjuvant use, which now specifies patients should receive up to post-approval note Dec. 21. US oncologists expect to use Perjeta in 18 cycles [per] year of post-operative dosing, could add over $1bn of about 44% of adjuvant patients who are now treated with Herceptin additional sales potential in this setting on top of current estimates. and Jefferies believes this equates to a CHF4.3bn revenue opportunity. In terms of the adjuvant indication, we see the definition of ‘high risk’ “Across all indications, we currently forecast risk-adjusted sales by as being broader than expected,” Holford said. 2021 of CHF6bn vs. consensus of just CHF4bn,” Holford said. Perjeta initially was approved in mid-2012 for first-line metastatic Meanwhile, Roche also is positioning Kadcyla and other drugs for HER2-positive breast cancer. a role in early breast cancer. The drug has become an important contributor to Roche group The Phase III KATHERINE study tests Kadcyla in HER-2 positive early sales, bringing in CHF1.6bn ($1.6bn) in the first nine months of 2017, breast cancer and residual invasive disease following neoadjuvant ther- up by 17% from the year-ago period. The company declined to break apy. Results are expected in 2018. The Phase III KAITLIN adjuvant study out sales by indication. tests Kadcyla with anthracyclines, followed by taxanes combined with Execs have emphasized the importance of APHINITY in earnings Herceptin plus Perjeta, versus treatment with anthracyclines followed calls, noting that Perjeta sales already are above CHF2bn on an an- by Kadcyla plus Perjeta. Results are expected in 2019. nualized basis. Published online 21 December 2017

scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 9 2017 IN REVIEW

A Year To Remember For US Drug Launches JESSICA MERRILL [email protected]

he year 2017 was bountiful for US zumab) for bladder cancer and Eli Lilly & Dupixent, meanwhile, also launched in drug launches, and several new en- Co.’s Talz (ixekizumab) for psoriasis. April as the first systemic therapy for the T trants represent significant medical The record-breaking number of approvals treatment of atopic dermatitis, a painful advances in cancer and other therapeu- in 2017 returns the industry to a level of pro- skin condition. (Also see “Sanofi/Regeneron tic areas of high unmet medical need. The ductivity more consistent with recent prior Choose Access Over Price With Dupixent launch of the first CAR-T therapies, Novartis years. The 22 novel approvals coming out of Launch” - Scrip, 28 Mar, 2017.) It generated AG’s Kymriah and Gilead Sciences Inc.’s CDER last year was the lowest annual total $118m through the third quarter, suggest- Yescarta – potential cures for some cancer for the center since 2010. ing it is on a blockbuster trajectory. patients – are notable enough to call 2017 a Achieving $200m in first-year sales is groundbreaking year for new drugs. NOVELTY generally viewed within the industry as an Commercial success is the real test for Among some of the most novel new drugs indicator that a new drug is headed toward new drugs, at least for investors. The winners approved in 2017 were the CAR-T therapies blockbuster status, though launch timelines and losers on that front will be sorted out Kymriah and Yescarta and Spark Thera- have lengthened across the industry in re- over the course of 2018, but several drugs peutics Inc.’s Luxturna (voretigene nepar- cent years as reimbursement and market are already poised to become blockbusters, vovec-rzyl). Luxturna is viewed by many as access have become more challenging. including Roche’s Ocrevus (ocrelizumab) the first true gene therapy approved in the Another notable launch was Biogen Inc.’s for multiple sclerosis, Sanofi/Regeneron US, though the CAR-T treatments have also Spinraza (nusinersen), yet another ground- Pharmaceuticals Inc.’s Dupixent (dupilum- been designated as gene therapies. Kymriah breaking technology and the first medicine ab) for atopic dermatitis and GlaxoSmith- was approved in August for pediatric acute approved for the rare neurodegenerative Kline PLC’s shingles vaccine Shingrix. lymphocytic leukemia (ALL), while Yescarta disease spinal muscular atrophy (SMA); it “It’s almost like there has been a slow re- was approved in October for a larger indi- is an antisense oligonucleotide drug that tooling of the entire pharma sector and we cation in adults with relapsed or refractory manipulates the RNA to produce proteins are starting to see the results of that hap- large B-cell lymphoma after two or more needed for proper muscle function. pening now,” Bain & Co. partner Michael Ret- lines of systemic therapy. Luxturna was one Spinraza was approved by FDA in late De- terath told Scrip. “What we saw is pharma re- of the last approvals of 2017, the first treat- cember 2016 but is included here because tooling and moving into new technologies ment for an inherited blindness that affects the launch occurred primarily in 2017. Bio- like gene therapy and CAR-Ts.” only a few thousand patients in the US. gen priced the drug higher than expected, ZS Associates Managing Principal Maria Despite enthusiasm for the pioneering $750,000 for the first year of treatment and Whitman agreed. “2017 has been a story on therapeutics, the commercial potential of $375,000 in subsequent years due to the the innovation side,” she said. “One of them the drugs remains uncertain; they target lower dosing schedule, and initial sales ex- is the CAR-T story, and we can add into it the niche patient populations and are ultra ceeded expectations. Spinraza generated gene therapy story. What this tells us is we high-priced, which could lead to reimburse- $521m in the first nine months of 2017, are at the tip of an era of therapies that pres- ment challenges that are expected to slow though sales appeared to be plateauing ent new opportunities and also new chal- the launch trajectory. in the third quarter. Analysts still expect lenges on the system.” Whether or not these innovative technol- Spinraza to become a blockbuster, despite ogies turn into big revenue generators will some unsteadiness as some patients begin A YEAR OF FIRSTS be a key test for industry. switching to the lower maintenance dosing. FDA approved a record 46 novel new drugs Drugs like Roche’s Ocrevus and Sanofi/ in 2017, including four just in the week lead- Regeneron’s Dupixent, which debuted MANY FAST FOLLOWERS ing up to Christmas, breaking the previous in the first half of 2017 and target larger While the level of innovation was notable in record of 45 approvals in 2015. patient populations, already appear on 2017 in some instances, many of the NMEs The year far outpaced 2016 when it their way to achieving the industry’s cov- that launched were fast followers, the sec- comes to the number of new launches, and eted blockbuster status. Ocrevus is one ond- or third-to-market drugs, or even the it appears poised to exceed 2016 on the early standout when it comes to revenues. fourth or fifth. metric of commercial successes too. Only Ocrevus generated CHF497m ($503.6m) “The negative trend was in first-in-class 22 new molecular entities were approved after launching in April, driven by strong medicine approvals,” Whitman said. In on- in 2016, and last year’s early winners were efficacy data and a monopoly in a chal- cology, she pointed out that only 42% of the new combination pills in hepatitis C, the lenging patient population. Ocrevus is the NMEs approved represented novel mecha- quick but short-lived blockbusters Epclusa first and only disease modifying therapy nisms of action. from Gilead and Zepatier from Merck & Co. for primary progressive multiple sclerosis The fast followers were particularly evi- Inc. The 2016 class included several drugs (PPMS), one of the most disabling forms dent in the PD-1/L1 category, where Merck that were the second or third to market like of MS, and is also approved for relapsing KGAA/Pfizer Inc.’s Bavencio (avelumab) Roche’s PD-L1 inhibitor Tecentriq (atezoli- forms of the disease. and AstraZeneca PLC’s Imfinzi (durvalum-

10 | Scrip | 5 January 2018 © Informa UK Ltd 2018 2017 IN REVIEW ab) were the fourth and fifth PD-1/L1 in- A Snapshot Of The Drugs That Launched In 2017 hibitors to market, respectively, following US APPROVAL MANUFACTURER & DRUG INDICATION Merck’s Keytruda (pembrolizumab), Bristol- (THROUGH OCTOBER) Myers Squibb Co.’s Opdivo (nivolumab) and Roche’s Tecentriq (). Biogen Spinraza Spinal muscular atrophy December 2016 How the PD-1/L1 market will shake out Synergy Trulance Chronic idiopathic constipation January over the long-term is still the big question; Valeant Siliq Psoriasis February the market is expected to become even HR+/HER2- metastatic or advanced breast Novartis Kisqali March more oversaturated as additional drugs are cancer approved. The early entrants – Keytruda and Pfizer/Merck KGAA Merkel cell carcinoma March Opdivo – are dominating the market, while Bavencio cancer leader Roche’s Tecentriq has turned Zejula Recurrent ovarian cancer March in a solid early performance in bladder can- Primary progressive and relapsing multiple cer and lung cancer. Roche Ocrevus March sclerosis Pfizer did not break out sales of Bavencio Sanofi/Regeneron in 2017, generally a sign the revenues are Atopic dermatitis March Dupixent not material to the company’s financials. Bavencio was approved by FDA in March Neurocrine Ingrezza Tardive dyskinesia April Acute myeloid leukemia, systemic mastocytosis for Merkel cell carcinoma, a rare skin cancer, Novartis Rydapt April and gained a bladder cancer indication in and mast cell leukemia May. Imfinizi was approved by FDA in May Teva Austedo Chorea associated with Huntington’s disease April for bladder cancer and had not yet gener- AstraZeneca Imfinzi Urothelial cancer May ated material sales as of AstraZeneca’s third Sanofi/Regeneron Rheumatoid arthritis May quarter financial results. Kevzara A similar dynamic unfolded in breast can- Portola Bevyxxa Anticoagulant for VTE June cer, where Novartis and Lilly are fast followers J&J Tremfya Plaque psoriasis July behind Pfizer’s first-to-market CDK4/6 inhibi- tor Ibrance (palbociclib), which launched in Puma Nerlynx Early-stage HER2 over-expressed breast cancer July 2015 and has become a pillar of Pfizer’s on- Gilead Vosevi Fixed-dosed combination for hepatitis C July cology portfolio. Ibrance generated $2.41bn Celgene Idhifa AML with an IDH2 mutation August in the first nine months of 2017 and Novartis AbbVie Mavyret Fixed-dose combination for hepatitis C August and Lilly are hoping to capture a piece of the Relapsed/refractory B-cell precursor acute action with Kisqali and Verzenio, respec- Pfizer Besponsa August lymphoblastic leukemia tively. Kisqali was approved by FDA in March, The Medicines though Novartis said the full US launch be- Antibiotic for complicated urinary tract infection August Company Vabomere gan in earnest in August. Verzenio was ap- proved in October. It’s too early still to say Novartis Kymriah Pediatric acute lymphoblastic leukemia August whether the new entries are impacting sales Eli Lilly & Co Verzenio HR+/HER2- breast cancer September of Ibrance (Kisqali only generated $26m in Bayer Aliqopa Relapsed/refractory follicular lymphoma September the third quarter, according to Novartis), but AstraZeneca Relapsed/refractory mantle cell lymphoma October competition could put more pressure on Calquence price in the category. Gilead/Kite Yescarta Certain types of B-cell lymphoma October Followers weren’t just in oncology, how- GlaxoSmithKline ever. Sanofi/Regeneron’s Kevzara (sarilum- Shingles vaccine October Shingrix ab) was approved in May as the second Source: Pink Sheet Performance Tracker (not inclusive of every FDA approval) IL-6 inhibitor for rheumatoid arthritis, which will compete against Roche’s entrenched Actemra (tocilizumab). Johnson & John- commonplace, putting more pressure on over and over again,” said Bain’s Retterath. son’s Tremfya (guselkumab) is a first-in-class drug companies to execute quickly on their “When a company launches, the follow up IL-23 blocker approved in July for psoriasis launch, even as new drugs often face more product that is launching behind is often six but it will compete in a crowded category market access challenges that lengthen the months out, and the one after that is anoth- for psoriasis drugs, which includes J&J’s own launch trajectory. er six to 12 months. You have a very small IL-12/IL-23 blocker Stelara (ustekinumab). “The first mover advantage is more diffi- window while the competitive dynamic is Valeant Pharmaceuticals International cult to play than it used to be, particularly in changing in the market.” Inc. launched a third-to-market IL-17 block- oncology,” Whitman said. The competitive and commercial dynam- er Siliq (brodalumab) for psoriasis. Fast fol- “There is an increased focus of companies ics remain as difficult as ever. lowers in pharma are becoming far more pursuing the same disease areas. We see it Published online 29 December 2017 scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 11 REIMBURSEMENT

ICER Views Kymriah, Yescarta As Cost Effective MANDY JACKSON [email protected]

he Institute for Clinical and Economic Review (ICER) said in a didn’t exceed the threshold of $50,000 per QALY, $100,000 per QALY draft report issued on Dec. 21 that the recently approved chi- or $150,000 per QALY. However, Yescarta’s costs did exceed that line T meric antigen receptor T cell (CAR-T) therapies from Novartis at $100,000 and $150,000 per QALY, but not at $50,000 per QALY. AG and the Gilead Sciences Inc. subsidiary Kite Pharma Inc. are ICER noted several limitations for its assessment, including the cost effective at current prices. fact that both Kymriah and Yescarta have only been studied in small, This is the first formal critique of the list prices for Novartis’s Kym- single-arm clinical trials, while most standard-of-care therapies have riah (tisagenlecleucel) and Gilead/Kite’s Yescarta (axicabtagene cilo- been tested against comparators in large randomized trials. Also, leucel), the first two treatments approved in the US in which T cells approvals have been granted based on response rates rather than are removed from a patient and genetically reengineered to target a progression-free or overall survival endpoints. specific antigen on cancer cells – CD19 in the case of both products. And in terms of how the treatments will be paid for, there are still a Kymriah and Yescarta each appear to be generally cost effective in lot of unknowns about contracts with payers and health care provid- their approved indications at costs that in many cases won’t break ers, including the handling of adverse events, such as severe cytokine the health care system’s bank. release syndrome (CRS) and neurotoxicity. Both are common side ef- Kymriah was approved on Aug. 30 for the treatment of pediatric fects for CAR-T therapies that can be severe in the immediate weeks and young adult patients (up to age 25) with B-cell precursor acute following infusion with the reengineered cells, requiring hospitaliza- lymphoblastic leukemia (ALL) that is refractory or has relapsed after tion in some cases until symptoms subside. at least two prior lines of therapy and Novartis set its price in that The ICER report noted the impressive efficacy of CAR-T therapies indication at $475,000 before discounts. The company also negoti- to date, which have given patients and parents a lot of hope where ated an outcomes-based contract with the Centers for Medicare and there was none before for relapsed and refractory patients. However, Medicaid Services (CMS) under which CMS will not pay for Kymriah if the same patient groups also noted a fear of the unknown, includ- patients don’t respond within the first month of treatment. ing long-term safety and the duration of responses over years rather The wholesale acquisition cost (WAC) for Gilead/Kite’s Yescarta, ap- than months. Aside from the medicines’ costs, there also was a con- proved on Oct. 18 for the treatment of relapsed or refractory large cern about the costs of travel to certified treatment centers and time B-cell lymphoma after two or more lines of systemic therapy, is off from work while patients are monitored for side effects. $373,000. However, the ICER report notes that the cost of leukapher- esis to extract patients’ T cells is included in the cost of Kymriah, but A B+ FOR HEALTH BENEFITS not in the price for Yescarta. With efficacy, safety and cost in mind, ICER gave Kymriah and Yes- Cost effectiveness was outlined by ICER as $150,000 or less per carta a B+ rating, meaning that there is high certainty of a small net quality-adjusted life year (QALY) gained and Kymriah came in below health benefit. this threshold 99% of the time when compared to chemotherapy ICER estimated that 68% of Kymriah-treated patients and 30% of with clofarabine in the product’s approved indication. By the same clofaradine-treated patients would be alive and responding to treat- measure, Yescarta judged against chemotherapy was cost effective ment at one month. The numbers dropped to 43% and 11%, respec- 68% of the time. The therapies were analyzed in multiple scenarios tively, at one year and remained stable at 42% and 11% at five years. and models, including short- and long-term cost effectiveness, and CRS and neurological toxicities were the main safety concerns for societal versus health care costs. Kymriah as well as hypogammaglobulinemia due to B-cell aplasia However, the analysis of Kymriah took into account the outcomes- in some patients, requiring ongoing intravenous immunoglobulin based agreement that Novartis has with CMS and potentially other (IVIG) treatment, and the unknown potential in the longer term for payers, while Yescarta was evaluated by its announced WAC price mutagenesis by the chimeric gene inserted into the patients’ T cells. alone, since Gilead has not disclosed any outcomes-based agree- As with Kymriah in pediatric ALL, Yescarta and Kymriah provided re- ments. If such contracts were in place, ICER acknowledged that mission for greater percentages of patients than salvage chemothera- Yescarta’s cost effectiveness would be more favorable under agree- py in these adult patients with relapsed or refractory B cell lymphoma. ments that give discounts and provide for cost-forgiveness when ICER said there was not enough data from the JULIET study of patients don’t respond to treatment. Kymriah in non-Hodgkin’s lymphoma to forecast survival for Kymri- The costs of the medicines also are not expected to be overly bur- ah-treated patients, but the analysis of data from the ZUMA-1 study densome for the health care system. ICER estimates that the cost of of Yescarta showed a big survival benefit. Novartis is seeking approv- any biopharmaceutical product would have to be renegotiated if its als in the US and EU for diffuse large B cell lymphoma (DLBCL), but annual budget impact exceeds $915,000 per patient. ICER’s cost-effectiveness analysis did not look at Kymriah in the future Looking at a five-year time horizon, Kymriah’s annual budget impact indication, only pediatric and young adult ALL. was estimated at $198,000 if payers cover only patients that respond ICER estimated at one month that 76% of Kymriah-treated pa- within the first month post-infusion. Yescarta’s annual budget impact tients and 26% of chemotherapy-treated patients would be alive in terms of a five-year horizon was forecast to be $209,000 per patient. and responding to treatment. CRS and neurological toxicities also Kymriah did not exceed the $915,000 annual budget line when were the major safety concerns for Yescarta as well as the unknown its price, including ancillary costs at treatment centers and hospitals, potential mutagenesis. Published online 21 December 2017

12 | Scrip | 5 January 2018 © Informa UK Ltd 2018 2017 IN REVIEW

The Year’s Clinical Trials In Review: Big Hits In 2017 EMILY HAYES [email protected]

hen it comes to pharmaceuti- with the release of full data from the piv- over competing PD-1/L1 inhibitors for this cal drug development the wins otal SWORD studies for ViiV Healthcare’s indication. Success in this line of therapy W can be few and far between, but Tivicay (dolutegravir) and Janssen Phar- took some of the edge off of the failure when a new drug performs well in a mid- to maceuticals Inc.’s Edurant (rilpivirine) in of the company’s Imfinzi/tremelimumab late-stage clinical trial, the rewards can be rich February. (Viiv is majority owned by Glaxo- combination to demonstrate a significant – for patients and investors. Here are some of SmithKline PLC.) The US FDA approved the improvement in progression-free survival the notable clinical trial successes in 2017. regimen in November for patients with HIV in the MYSTIC study of first-line metastatic type 1 whose virus has been suppressed for lung cancer. CV OUTCOMES STUDIES GALORE at least six months, after a speedy review AstraZeneca announced in October that The long-awaited release of full results for thanks to a priority review voucher, and FDA has accepted a filing to cover earlier Amgen Inc.’s FOURIER cardiovascular (CV) the fixed combination pill is now branded use, based on PACIFIC data. Imfinzi was ap- outcomes study of the cholesterol-lowering as Juluca. Analysts say the introduction of proved in May for treatment of second-line PCSK9 inhibitor Repatha () fi- a two-drug regimen is groundbreaking for bladder cancer, a space crowded with oth- nally came in March 2017, at the American the HIV market, though it may take time to ers in the same class. AstraZeneca reported College of Cardiology meeting. The drug introduce such a big change. sales of only $1m in the third quarter of demonstrated a statistically significant re- 2017 and said that it was more focused on duction in the number of events included A GOOD YEAR IN HEMOPHILIA launching in lung cancer. in the primary composite endpoint, though The year closed out with gene therapy com- Roche’s PD-L1 inhibitor Tecentriq (at- the magnitude of the benefit (15%) was ing into its own, with the approval of Spark ezolizumab) looks well positioned fol- lower than expected. Repatha now has a CV Therapeutics Inc.’s Luxturna and hemo- lowing the release of positive results in outcomes claim based on the data. philia gene therapies drawing attention at December for the drug in combination How this will translate into reimburse- the American Society of Hematology (ASH) with the company’s VEGF inhibitor Avastin ment access and sales remains to be seen, annual meeting in December. Early data for (bevacizumab) and chemotherapy in the but the drug already started to outperform Spark’s hemophilia B candidate SPK-9001, IMpower150 study in first-line NSCLC. The Sanofi/Regeneron Pharmaceuticals Inc.’s partnered with Pfizer Inc., and BioMarin same month, the company reported that competing PCSK9 inhibitor Praluent (ali- Pharmaceutical Inc.’s valoctocogene roxa- the combination worked well in first-line rocumab) in the fourth quarter of 2016. Re- parvovec in hemophilia A both received kidney cancer in the IMmotion151 study. sults from the ODYSSEY CV outcomes study glowing reviews in the New England Journal The drug had faced a setback, however, of Praluent are due in early 2018. of Medicine – editorials suggested that a cure earlier in the year with the failure of Tecen- Merck & Co. Inc. announced in June that for the devastating disease is now in sight. triq to demonstrate a significant benefit its cholesterol-lowering anacetrapib sig- The hemophilia treatment space has also for progression-free survival in a Phase III nificantly reduced major coronary events in recently undergone a big change with the confirmatory study in bladder cancer, the the REVEAL CV outcomes study, a surprising approval of Roche’s Hemlibra (emicizumab), drug’s first approved indication. outcome in light of failures of other drugs a bispecific that binds in the CETP inhibitor class. However, due to both Factor IXa and X, for hemophilia A ROAD PAVED FOR CANNABINOIDS to the commercial challenges of launching with inhibitors. Publication of full Phase III results for GW this kind of candidate, Merck opted not to The company also announced positive Pharmaceuticals PLC’s Epidiolex (cannabi- pursue regulatory approval. results from the HAVEN 3 study of patients diol) for Dravet syndrome, a severe type of Other CV outcomes successes include with hemophilia and no inhibitors, data that pediatric epilepsy, in the New England Jour- positive results for Johnson & Johnson’s could see the drug used in a much bigger nal of Medicine in May marked an important SGLT2 inhibitor/diabetes drug Invokana population, and HAVEN 4, which tested a step for advancing pharmaceutical-grade (canaglifozin) in the CANVAS outcomes more convenient monthly dosing schedule. cannabinoids as a therapeutic option. The study and Novartis AG’s IL-1β inhibitor an- Updated data from older studies presented drug is one of over 50 cannabinoids in any tibody canakinumab (ACZ885) in the CAN- at the ASH meeting support the drug’s safe- stage of development, in a field that is heav- TOS atherosclerosis study. ty profile and durable efficacy. ily focused on neurological conditions. GW These positive data contrasted with nega- filed the drug for approval in the US at the tive results for AstraZeneca PLC’s diabetes AZ’S IMFINZI & ROCHE’S end of October and has been raising funds drug Bydureon (long-acting exenatide) in TECENTRIQ GAIN GROUND in order to prepare for commercial launch. the Phase IIIb/IV EXSCEL outcomes study. Positive data for AstraZeneca PLC’s PD-L1 On Dec. 28, the company announced that inhibitor Imfinzi (durvalumab) in the PA- the FDA accepted the filing and granted it VIIV’S TWO-DRUG HIV COMBO CIFIC study set the drug up for an interest- priority review status; the user fee date is The possibility of a two-drug regimen for ing market opportunity in treating stage III June 27, 2018. HIV maintenance therapy became a reality non-small cell lung cancer, with a head start Published online 28 December 2017 scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 13 2017 IN REVIEW

The Year’s Clinical Trials In Review: Big Misses In 2017 LUCIE ELLIS [email protected]

n the high-risk, high-reward field of pharmaceuticals, the clinical tri- and in combination with chemotherapy. A successful trial in combi- al disappointments come as frequently as the misses. The year 2017 nation with tremelimumab in first-line metastatic NSCLC was how Iincluded some exceptional advances and some big flops as well. AstraZeneca hoped to jump ahead of rivals in the highly competitive Topping the list of clinical trial disappointments would have to immuno-oncology space. The company also concluded that Imfinzi be Axovant Sciences’ intepirdine for Alzheimer’s disease. Sure, int- alone, although not formally tested, would not have met a pre-spec- epirdine is in a therapeutic category filled with landmines and inves- ified threshold of PFS benefit over standard of care in the NSCLC trial. tors have all but come to expect failure in Alzheimer’s disease, but The news was a hit for AstraZeneca, which responded by partner- somehow Axovant’s parent company Roivant Sciences GMBH and ing its PARP inhibitor Lynparza (olaparib) with Merck & Co. Inc. the its CEO Vivek Ramaswamy had investors hoping for a win. Axovant same day in exchange for $1.6bn upfront. All hope is not lost for Astra- debuted on the public markets in 2015 with the biggest IPO ever for Zeneca. MYSTIC is ongoing, assessing overall survival (OS) endpoints a biotech – a sign of the enthusiasm. for Imfinzi monotherapy and the Imfinzi plus tremelimumab combi- But the excitement was tamped down in September when the nation, with data expected in the first half of 2018. selective 5-HT6 receptor antagonist failed to show a benefit in “MYSTIC technically still has a few more chances to succeed,” mild-to-moderate Alzheimer’s patients in the Phase III MINDSET Biomedtracker analysts said at the time. “However, even a successful clinical trial. In the end, the bigger surprise was that Axovant OS outcome would likely have a minimal real-world impact with the managed to convince investors a drug GlaxoSmithKline PLC availability of Keytruda which showed both a PFS and OS benefit,” sold for $5m had such big potential. The company’s stock fell they noted. 74% on the news while investors wait to see if intepirdine per- And, Imfinizi did show a benefit in a different Phase III trial, PACIFIC, forms better in patients with dementia with Lewy bodies, where in patients with unresectable stage III NSCLC after standard chemo- a Phase IIb trial is underway. Hopefully, better news is in store for radiation treatment. Data from PACIFC, which were presented at the Axovant in 2018. European Society of Medical Oncology meeting in September 2017, Just months after Axovant’s Alzheimer’s dreams crashed and showed that the drug improved progression-free survival by just burned, Celgene Corp. had to watch its own dream to lead in Crohn’s over 11 months – 16.8 months in the Imfinzi arm compared to 5.6 disease go up in smoke. The company announced in October that it months with placebo – with a hazard ratio of 0.52. was terminating two Phase III clinical trials testing mongersen after a Research has been focused on later stages of lung cancer, particularly data safety and monitoring committee overseeing the REVOLVE trial patients with metastatic stage IV disease. The latter setting makes up determined the study was futile. The disappointment was palpable, about 50% of lung cancer patients, but this still leaves the other 50% given that mongersen was one of Celgene’s highest profile late- with stages I, II and III – which represents a sizeable market opportunity. stage development programs, and the setback shook investors. The AstraZeneca believes it is ahead of competitors in this earlier company’s stock fell 8.4% on the news, with investors questioning NSCLC setting. Trials of other anti-PD-1/L1 agents, such as Merck’s the company’s ambitions to expand in inflammation & immunology. Keytruda and Bristol-Myers Squibb Co.’s Opdivo (nivolumab), Celgene also paid handsomely to acquire mongersen, an oligonu- launched in 2017. cleotide that decreases a protein called Smad7. The firm paid $710m AstraZeneca filed a supplemental biologics license application to buy privately held Nogra Pharma Ltd. to get its hands on the (sBLA) for Imfinzi in stage III NSCLC to the US FDA in Oct. asset in 2014. IMVIGOR211 SURPRISE MYSTIC’S MISS Roche’s PD-L1 inhibitor Tecentriq (atezolizumab) stumbled in May While programmed cell death protein 1 (PD-1) and program death- this year when the company’s confirmatory Phase III IMvigor211 ligand 1 (PD-L1) inhibitors are the apple of the immuno-oncology study in bladder cancer did not meet its primary endpoint. The drug sector’s eye, representing huge breakthroughs in the use of the im- failed to show a survival benefit in patients with previously-treated mune system to battle cancer, the development space is not all suc- metastatic urothelial cancer when compared with chemotherapy. cess stories. The result was a surprise as the drug had been granted accelerated AstraZeneca PLC took a frontal blow in July when its PD-L1 drug approval by the FDA in 2016 for bladder cancer patients who had or Imfinzi (durvalumab) failed to meet primary progression free survival were being treated with platinum-based chemotherapy, based on (PFS) endpoints in the Phase III MYSTIC trial in non-small cell lung data from the IMvigor210 trial. cancer (NSCLC). IMvigor211 is the first randomized Phase III study of Tecentriq com- Top-line data showed that Imfinzi in combination with the pared with chemotherapy in people with advanced bladder cancer CTLA-4 inhibitor tremelimumab failed to significantly improve PFS who were previously treated with a platinum-based chemotherapy. compared to platinum-based standard of care chemotherapy in The study evaluated the efficacy and safety of Tecentriq compared previously untreated patients with metastatic NSCLC, a potentially with chemotherapy (vinflunine, paclitaxel or docetaxel) administered lucrative indication. every three weeks in 931 people with previously-treated metastatic Merck’s Keytruda (pembrolizumab) is the only PD-1 inhibitor ap- urothelial cancer who progressed during or following a platinum- proved for first-line NSCLC, with indications for use as a monotherapy based regimen.

14 | Scrip | 5 January 2018 © Informa UK Ltd 2018 2017 IN REVIEW

Roche said at the time of the IMvigor211 failure that “while these stone-based or royalty payments and Janssen will not bear the future results are not what we had expected, we believe that Tecentriq will costs of developing and commercializing the HCV portfolio. Achillion continue to play an important role in the treatment of people with currently has no plans to advance the HCV program on its own. advanced bladder cancer.” The combination had previously reported promising Phase II data Tecentriq has a second confirmatory study, IMvigor130, ongo- indicating potential for a six-week duration of treatment. But Janssen ing to complete conditional approval of the drug for first-line blad- is moving away from HCV drug development due to the efficacy of der cancer patients who are ineligible for cisplatin chemotherapy. what’s already available to patients – particularly Gilead Sciences’ Topline results from the IMvogor130 trial are expected in 2019. sofosbuvir-driven portfolio. Gilead is effectively the only HCV com- The drug won approval in Europe in 2017 for locally advanced or pany with a nucleoside polymerase inhibitor in its portfolio now metastatic bladder cancer after prior platinum-containing chemo- that J&J and Merck have stepped back from the space; its sofosbuvir therapy or for patients who are considered cisplatin ineligible. But product is marketed as Sovaldi as a monotherapy and is the back- the bladder cancer market is more competitive now than ever before of the combination treatments Harvoni, Epclusa and Vosevi. and Tecentriq’s limited effect in the IMvigor211 trial will set it back Janssen and Achillion joined up in May 2015 to develop JNJ-4178 compared to other approved PD-1/PD-L1 therapies. as part of a worldwide license and collaboration arrangement. Under Bavencio, Merck KGAA/Pfizer Inc.’s PD-L1 inhibitor, was grant- the original deal, Achillion received $225m equity investment from J&J’s ed US accelerated approval in second-line advanced or metastatic venture arm, Johnson & Johnson Innovation - JJDC Inc. Achillion was urothelial cancer on May 9, 2017, shortly after AstraZeneca’s Imfinzi also eligible for up to $900m in milestones and double-digit royalties. gained its first approval, for the same indication on May 1, again in Meanwhile, Merck announced in Sept. that it was ending develop- the US. Keytruda was approved on May 18 in the US for first-line pa- ment efforts for its HCV pipeline, which was driven by nucleoside poly- tients who are ineligible for cisplatin-containing therapy, and (with merase inhibitor MK-3682 (uprifosbuvir); the centerpiece of the New a breakthrough designation) patients with disease progression on Jersey pharma’s $3.9bn buyout of Idenix Pharmaceuticals Inc. in 2014. or after platinum-containing chemotherapy. Keytruda also won ex- Eliav Barr, Merck senior VP for global clinical development for infec- panded approval for the same indications in Europe this year. tious diseases and vaccines, said at the time that the number of treat- ment options available for HCV, along with a review of clinical data KEYTRUDA STUMBLE for Merck’s two-drug and three-drug next-generation combinations, Furthermore, in July this year, Merck’s Keytruda suffered a setback resulted in the pharma determining it would not continue investing when it failed to show a survival benefit in the KEYNOTE-040 study in development of further regimens. of head and neck cancer. This trial was meant to produce confir- This decision ended work on the two-drug MK-3682B regimen, matory data for Keytruda, which had already received accelerated which included uprifosbuvir and ruzasvir (a follow-on to Merck’s approval in the US as a second-line treatment for patients with NS5A inhibitor elbasvir), as well as a three-drug regimen including head and neck cancer. those two compounds and Merck’s protease inhibitor grazoprevir. Despite the endpoint miss in KEYNOTE-040, Merck does not ex- pect a label change for Keytruda in the US because median overall A ROUGH YEAR FOR CANCER VACCINES survival (OS) for the anti-PD-1 drug in the study of recurrent or meta- The year of 2017 was not kind to cancer vaccines, a very tough de- static head and neck cancer was still better than investigator’s choice velopment space. Studies of Argos Therapeutics Inc.’s pivotal trial of chemotherapy. of the dendritic vaccine rocapuldencel-T in metastatic kidney cancer However, similar to Roche’s predicament in bladder cancer, Keytruda and Agenus Inc.’s Prophage G-200 in a National Cancer Institute- is competing against BMS’s Opdivo in head and neck cancer, which al- funded Phase II study of glioblastoma were both recommended for ready has full FDA approval in the same second-line patient population. early termination in February, due to the unlikelihood of improving overall survival. Argos, however, decided to press on with its study, END OF ROAD FOR TWO HCV COMBOS called ADAPT. September brought news that Bavarian Nordic AS’ This year also saw Johnson & Johnson and Merck discontinue their e Phase III PROSPECT study of the prostate cancer vaccine Prostvac interferon-free regimens for chronic hepatitis C (AL-335/odalasvir/ (rilimogene galvacirepvec) in metastatic castration-resistant prostate simeprevir and uprifosbuvir/ruzasvir/grazoprevir, respectively) be- cancer, was recommended for early termination due to futility, send- cause of a lack of clinical differentiation from currently available op- ing the firm’s share price down more than 48%. tions and rapid contraction of the HCV market. Dropping these treatment regimens stung for both pharmas as QUESTIONING REGENERON they previously invested in multi-billion-dollar deals to acquire viable Regeneron Pharmaceuticals Inc.’s announced in November that it combinations. was scrapping its ophthalmic combination of nesvacumab and Eylea J&J company Janssen suspended development of its triple com- () after data showed no improvement over Eylea alone in bination therapy, known as JNJ-4178, in Sept., also ending its devel- two Phase II studies, one in diabetic macular edema and the other in opment partnership with Achillion Pharmaceuticals Inc. for the wet age-related macular degeneration. The news caused investor to combination treatment. question the company’s long-term growth potential beyond Eylea. The companies said at the time that ongoing Phase II studies with The next key catalyst is the release of results from the Phase III PAN- JNJ-4178 would be completed as planned, but there would be no ORAMA study of Eylea in diabetic retinopathy, which are due in the additional developments thereafter. As a result of the termination first half of 2018. of the Janssen agreement, Achillion will not receive any future mile- Published online 28 December 2017 scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 15 HEADLINE NEWS THOUGHT LEADERSHIP IN ASSOCIATION WITH ICON THOUGHT LEADERSHIP IN ASSOCIATION WITH ICON

pared the effectiveness of fluorate/vilanterol to and noted that there were 123 post-marketing safety Tackling RWE Challenges To maintenance therapy in treating patients with chronic events – 59 safety communications, 61 boxed warnings obstructive pulmonary disease (COPD). Published in the and three outright product withdrawals – impacting 71 New England Journal of Medicine in September 2016, new therapeutics. Demonstrate Healthcare Value the study found that the rate of moderate or severe COPD Regulators and policymakers are starting to look at exacerbations was significantly lower by 8.4% with the how to incorporate RWE in product assessments. The US 21st Century Cures Act requires the FDA to develop guidance for using RWE to support approvals of new Large scale computational power indications for existing drugs and post-approval study requirements. In the US, the FDA published final guid- to apply against RWD is becoming ance on the use of RWE for regulatory decision making for medical devices in August 2017 and has announced increasingly affordable and accessible plans to publish draft guidance on the use of RWE for the assessment of safety and effectiveness in regulatory to all stakeholders. submissions before the end of 2021. Similarly, the European Medicines Agency (EMA) adaptive pathways program, in principle, embraces therapy than with standard care. greater use of RWE to support conditional approval Other trials that have an RWE component are already and/or expansion of indications once a product is ini- in the works. Sanofi, the French pharma major, is spon- tially approved in a narrower population. soring ACHIEVE CONTROL, an observational study Indeed, in a bid to provide patients access to innovative enrolling 3,324 patients and due for completion in July but often expensive medicines – usually cancer drugs – a 2018. The study is designed to assess the clinical and number of European countries have introduced man- health outcomes of Toujeo ( glargine) compared aged entry agreements. These can take many different to commercially available basal for initiation forms although finance-based schemes are more preva- of therapy in insulin-naïve patients with uncontrolled lent than performance-based ones. Finance-based MEAs Type 2 diabetes. The key metric will be the proportion range from simple discounts to more nuanced price and of patients with individualized HbA1x target attainment volume caps. Performance-related MEAs, most frequent- at six months without documented hypoglycemia. ly used by Italy, are designed to determine refunds for Novartis, the Swiss pharma, is sponsoring PANGEA non-responders and involve patient registries managed 2.0 an observational study involving 1,500 patients by the Italian Medicines Agency (AIFA) to allow shar- that is due to complete in March 2020. The study ing other clinical information and safety data between has been designed to examine the long term benefit regulators, clinicians and pharmacists. of switching multiple sclerosis patients with disease activity, following treatment with currently available Real World Examples eal world evidence (RWE) is expected to ments. It also includes epidemiological data, registry drugs, to Gilenya (fingolimod). Therapeutic efficacy Several drugs have been approved with real world have a significant impact on how health- data, health survey data, plus a host of new forms of of the switch will be evaluated by modified Rio score, data. Amgen used RWE to supplement a clinical trial care technologies will be developed and information such as social media data, wearables-de- NEDA-4 and 2D focussed disability score. PANGEA of Blincyto (), its drug which received consumed and on biopharmaceuticals, in rived data, sensor and behavioural data. 2.0 will also assess new forms of data acquisition and accelerated approval from the FDA in December 2014 particular. The major challenge to RWE Large scale computational power to apply against the predictive power of proposed treatment using the for treatment of acute lymphoblastic leukemia. Amgen becomingR truly embedded in the healthcare continuum RWD is becoming increasingly affordable and acces- MSDS 3D patient management system. submitted a single study as well as a historical compar- is that there is still not common ground about what sible to all stakeholders. As such, this creates greater RWE is being used in different forms by regulatory ator arm of patients who received standard of care as counts as relevant data. opportunities for real world insights into patient be- authorities. Pharmacovigilance is a mandatory require- the control arm. The company reported a significant Much of the debate across the healthcare continuum haviours, treatment costs and drug performance. ment from several regulatory authorities and that, in treatment response in the Phase II single arm study continues to focus on value and value frameworks in The US Food and Drug Administration defines RWE most cases, is based on real world data. Regulators are and two years later, when publishing its Phase III the US and health technology assessments in a regu- as evidence generated from real world data in a highly increasingly asking for commitments from drug devel- randomized, open-label TOWER study, obtained the latory context and reimbursement content, ex-US. Dif- pragmatic way. One of the main arguments in favour of opers for post-marketing safety studies as a condition same median overall survival of 7.7 months for Blin- ferent stakeholders – whether producers, payers or using real world data is that clinical trials are often to product registration and approval. Indeed, the FDA cyto versus 4 months for standard of care. patients – may pick and choose which real world data too narrow, excluding too many people and are not has made progress on using RWE within rare disease points they wish to emphasise and then convert into pragmatic enough. Consequently, trials have been drug development and post-market safety surveillance. Similarly, Alexion Pharmaceuticals Inc managed RWE. Fortunately, there is a growing body of evidence conducted that do not represent how the drug might It has been used, for example, to support the approval to secure an extension to the label from the Euro- highlighting how companies are overcoming these perform in a real world setting. of New Drug Application (NDA) submissions for rare pean authorities when investigators used a disease challenges and embracing RWE. The Salford Lung Study is a much cited example of diseases or in small population settings. registry to obtain a comparator group to measure Real world data (RWD), the underlying data sup- a real world effectiveness trial in that it demonstrated A study published in the Journal of the American the efficacy of Soliris (eculizumab) as a treatment porting the generation of RWE, encompasses all infor- a higher magnitude of effect in the real world than had Medical Association (JAMA) 9 May 2017, highlights of paroxysmal nocturnal hemoglobinuria (PNH) to mation generated in routine medical practice such as been seen in a randomized controlled trial. Conducted the importance of post-approval surveillance of safety reduce hemolysis. Initially, the drug’s use had been electronic health and medical records (EHR), claims in 75 general practices in and around Manchester in the issues. The study examined 222 novel drugs and bio- restricted to patients with a certain disease severity. data, pharmacy data, and clinical outcomes assess- UK, and sponsored by UK pharma GSK, the study com- logics approved by the FDA between 2001 and 2010 16 | Scrip | 5 January 2018 © Informa UK Ltd 2018 THOUGHT LEADERSHIP IN ASSOCIATION WITH ICON HEADLINE NEWS THOUGHT LEADERSHIP IN ASSOCIATION WITH ICON

pared the effectiveness of fluticasone fluorate/vilanterol to and noted that there were 123 post-marketing safety Tackling RWE Challenges To maintenance therapy in treating patients with chronic events – 59 safety communications, 61 boxed warnings obstructive pulmonary disease (COPD). Published in the and three outright product withdrawals – impacting 71 New England Journal of Medicine in September 2016, new therapeutics. Demonstrate Healthcare Value the study found that the rate of moderate or severe COPD Regulators and policymakers are starting to look at exacerbations was significantly lower by 8.4% with the how to incorporate RWE in product assessments. The US 21st Century Cures Act requires the FDA to develop guidance for using RWE to support approvals of new Large scale computational power indications for existing drugs and post-approval study requirements. In the US, the FDA published final guid- to apply against RWD is becoming ance on the use of RWE for regulatory decision making for medical devices in August 2017 and has announced increasingly affordable and accessible plans to publish draft guidance on the use of RWE for the assessment of safety and effectiveness in regulatory to all stakeholders. submissions before the end of 2021. Similarly, the European Medicines Agency (EMA) adaptive pathways program, in principle, embraces therapy than with standard care. greater use of RWE to support conditional approval Other trials that have an RWE component are already and/or expansion of indications once a product is ini- in the works. Sanofi, the French pharma major, is spon- tially approved in a narrower population. soring ACHIEVE CONTROL, an observational study Indeed, in a bid to provide patients access to innovative enrolling 3,324 patients and due for completion in July but often expensive medicines – usually cancer drugs – a 2018. The study is designed to assess the clinical and number of European countries have introduced man- health outcomes of Toujeo (insulin glargine) compared aged entry agreements. These can take many different to commercially available basal insulins for initiation forms although finance-based schemes are more preva- of therapy in insulin-naïve patients with uncontrolled lent than performance-based ones. Finance-based MEAs Type 2 diabetes. The key metric will be the proportion range from simple discounts to more nuanced price and of patients with individualized HbA1x target attainment volume caps. Performance-related MEAs, most frequent- at six months without documented hypoglycemia. ly used by Italy, are designed to determine refunds for Novartis, the Swiss pharma, is sponsoring PANGEA non-responders and involve patient registries managed 2.0 an observational study involving 1,500 patients by the Italian Medicines Agency (AIFA) to allow shar- that is due to complete in March 2020. The study ing other clinical information and safety data between has been designed to examine the long term benefit regulators, clinicians and pharmacists. of switching multiple sclerosis patients with disease activity, following treatment with currently available Real World Examples eal world evidence (RWE) is expected to ments. It also includes epidemiological data, registry drugs, to Gilenya (fingolimod). Therapeutic efficacy Several drugs have been approved with real world have a significant impact on how health- data, health survey data, plus a host of new forms of of the switch will be evaluated by modified Rio score, data. Amgen used RWE to supplement a clinical trial care technologies will be developed and information such as social media data, wearables-de- NEDA-4 and 2D focussed disability score. PANGEA of Blincyto (blinatumomab), its drug which received consumed and on biopharmaceuticals, in rived data, sensor and behavioural data. 2.0 will also assess new forms of data acquisition and accelerated approval from the FDA in December 2014 particular. The major challenge to RWE Large scale computational power to apply against the predictive power of proposed treatment using the for treatment of acute lymphoblastic leukemia. Amgen becomingR truly embedded in the healthcare continuum RWD is becoming increasingly affordable and acces- MSDS 3D patient management system. submitted a single study as well as a historical compar- is that there is still not common ground about what sible to all stakeholders. As such, this creates greater RWE is being used in different forms by regulatory ator arm of patients who received standard of care as counts as relevant data. opportunities for real world insights into patient be- authorities. Pharmacovigilance is a mandatory require- the control arm. The company reported a significant Much of the debate across the healthcare continuum haviours, treatment costs and drug performance. ment from several regulatory authorities and that, in treatment response in the Phase II single arm study continues to focus on value and value frameworks in The US Food and Drug Administration defines RWE most cases, is based on real world data. Regulators are and two years later, when publishing its Phase III the US and health technology assessments in a regu- as evidence generated from real world data in a highly increasingly asking for commitments from drug devel- randomized, open-label TOWER study, obtained the latory context and reimbursement content, ex-US. Dif- pragmatic way. One of the main arguments in favour of opers for post-marketing safety studies as a condition same median overall survival of 7.7 months for Blin- ferent stakeholders – whether producers, payers or using real world data is that clinical trials are often to product registration and approval. Indeed, the FDA cyto versus 4 months for standard of care. patients – may pick and choose which real world data too narrow, excluding too many people and are not has made progress on using RWE within rare disease points they wish to emphasise and then convert into pragmatic enough. Consequently, trials have been drug development and post-market safety surveillance. Similarly, Alexion Pharmaceuticals Inc managed RWE. Fortunately, there is a growing body of evidence conducted that do not represent how the drug might It has been used, for example, to support the approval to secure an extension to the label from the Euro- highlighting how companies are overcoming these perform in a real world setting. of New Drug Application (NDA) submissions for rare pean authorities when investigators used a disease challenges and embracing RWE. The Salford Lung Study is a much cited example of diseases or in small population settings. registry to obtain a comparator group to measure Real world data (RWD), the underlying data sup- a real world effectiveness trial in that it demonstrated A study published in the Journal of the American the efficacy of Soliris (eculizumab) as a treatment porting the generation of RWE, encompasses all infor- a higher magnitude of effect in the real world than had Medical Association (JAMA) 9 May 2017, highlights of paroxysmal nocturnal hemoglobinuria (PNH) to mation generated in routine medical practice such as been seen in a randomized controlled trial. Conducted the importance of post-approval surveillance of safety reduce hemolysis. Initially, the drug’s use had been electronic health and medical records (EHR), claims in 75 general practices in and around Manchester in the issues. The study examined 222 novel drugs and bio- restricted to patients with a certain disease severity. data, pharmacy data, and clinical outcomes assess- UK, and sponsored by UK pharma GSK, the study com- logics approved by the FDA between 2001 and 2010 scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 17 HEADLINE NEWS THOUGHT LEADERSHIP IN ASSOCIATION WITH ICON THOUGHT LEADERSHIP IN ASSOCIATION WITH ICON

Defending Optimal Pricing eration of anticoagulants. The company has enrolled within unstructured clinical notes within EHR. Novo Nordisk is investing significant effort in While RWE does not guarantee access, it is clearly 34,500 patients in the GLORIA-AF study and plans Moreover, as most sources of real world data are not generating RWE to support its diabetes franchise. having an impact on the thinking of payers. Indeed, to include a total of 56,000 in the registry. So far, the actually collected for research purposes, data quality RWE from a post-marketing study conducted by but RWE originating from, for example, patient registries, company has been running observational studies but is is an issue. EHRs, for example, are primarily intend- requested by the French authorities for the GLP-1 EHRs, claims data or cohort studies, is likely to become considering ways of doing prospective pragmatic trials ed for patient management, rather than for research, agonist Victoza helped broaden the product’s label an increasingly important means of supporting inno- in the future. Possibilities, as the field evolves, include and there is a clamour for more alignment across all to an additional patient subgroup in Quebec. More- over, the Danish pharma believes two RWE-generat- vative pricing and outcomes-based contracting strate- running real world trials to support supplemental in- stakeholders to develop consistent data structure and ing studies around the long acting insulin Tresiba, gies, proving the value of medicines to payers, potentially dication filings with the FDA. gathering methods. Indeed, transitioning from an ad launched in Europe in 2013 and in 2016 in the improving the probability of winning reimbursement. Pfizer, the world’s largest pharma company, is leading hoc to an industrial approach to curating RWE will US, both highly competitive and price-sensitive Following a health technology assessment (HTA), the use RWE at almost every stage of a medication’s life require collaboration and investment from all stake- markets, will strengthen the company’s positon in NICE, the National Institute for Health and Care Excel- cycle. The company conducts a significant amount of holders. Regulators, in collaboration with the pharma pricing negotiations, beef up its marketing commu- lence, who is responsible for assessing that the National non-interventional research. For retrospective studies it industry and payers, still need to formulate robust nications and enhance its value dossier in markets Health Service of England and Wales is getting value for uses de-identified secondary data sources such as insur- standards for RWD collection from a variety of sources. where the product has yet to launch. its money, changed its mind and decided to recommend ance claims and EHRs to evaluate epidemiology, treat- Motivating this are are manufacturers, payers and Johnson & Johnson’s Zytiga (albiraterone acetate) for ment patterns, clinical outcomes, healthcare resource third parties, who are looking beyond their own walls to While much of the focus is on using RWE to get chemotherapy-naïve metastatic castration-resistant use and costs associated with a treatment of disease. establish the true value of medicines. Most value-based regulatory approval of drug applications, it can also prostate cancer patients after the company presented Moreover, patient data generated by wearables, apps or contracts to date have been bilateral and payer popula- be used for clinical practice guidelines to decide how RWE from US insurance claims data. even tapping into social media will become an important tion-specific, where the manufacturer and the payer share to best manage patients, for payers deciding whether Many managed entry agreements or risk sharing deals source for understanding patient needs and behaviours. data. An alternative option would be to include broader to pay for a drug, and for comparative effectiveness. in Europe rely on gathering real world data. France Typically, the company will provide RWE on epidemi- sets of relevant RWD – including data generated by third agreed to reimburse Celgene Corp.’s Pomylast (pomalido- ology and unmet needs through analysis of secondary parties – into the parties’ value-contract adjudication Highlighting The Value Proposition mide) for multiple myeloma under a risk-sharing scheme. data sources and collecting information from patients, calculations. This would have stakeholders seeking out The company will have to repay the cost of the drug if a physicians and payers. Real world data is also often in- additional appropriate sources of data to analyse, not patient does not respond to the treatment. Risk-sharing Eli Lilly & Co used real world data to size the cluded in economic models, while supplemental infor- necessarily just a specific payer’s population, but an even single-use vials for its recently launched IV cancer schemes are also in place elsewhere in Europe, while mation, such as healthcare resource use, productivity larger representative real world population set in order drug Lartruvo () in an effort to reduce a recent evaluation of NICE submissions has revealed loss and out of pocket expenses, is collected during the to reduce administration costs and potential conflicts. potential waste and cost of treatment. An analy- that RWE drives HTA approval in 86% of submissions. running of clinical trials. Following launch, compa- While such data sharing for value-based contract sis of population-based weight and body surface Regulators are increasingly using RWE to monitor nies may conduct comparative effectiveness research administration purposes is not commonplace, industry data, from more than 240,000 oncology patients, any post-approval safety concerns. This has been par- to either identify and understand sub-populations or has long been quite content to use third-party generated informed the decision to develop a 190mg vial ticularly useful when looking at novel anticoagulants provide value differentiating evidence. data to administer prescription market share-based alongside the original 500mg Lartruvo vial. The especially when compared with industry mainstay While there is an expectation that all pharma com- contract. Indeed, reliable and independent third party company reckons the trade-off is a cost reduction warfarin. In recent years, more than 100 observation- panies will need to have RWE strategies in place, one data can be important in subsequent value-based con- of $1,132 per patient per administration. al studies have been published on real world use of of the biggest roadblocks in using RWE for regulatory tract negotiations. anticoagulants. In the US, these have typically used purposes is the inadequate data in electronic healthcare RWE clearly has huge potential to inform healthcare claims databases from Medicare and Medicaid, while records (EHR). This is because the traditional outcome stakeholders – whether manufacturers, regulators, cli- the European studies have relied upon national data- measures that are used in conventional drug develop- nicians, patients or payers. While there are still multiple Japan’s Takeda says RWE has confirmed the benefits bases. Importantly, it appears that the anticoagulants ment are not generally found in EHRs. The challenge challenges with RWE becoming a consistent mainstay of its best-selling inflammatory bowel disease ther- behave in the real world as they did in clinical trials. is that much of the needed clinical information is stuck of the healthcare regulatory oversight and commercial apy Entyvio (vedolizumab) in US medical practice. One huge potential source of data is the FDA’s Senti- in the doctor’s notes as unstructured data. Advances in performance insight, it is clear that there is an appetite RWE collected in the US conformed the efficacy nel program which houses electronic health care data machine learning and natural language processing are among all stakeholders to resolve them. Big data capabil- of the drug, first launched in the US in 2014, as for more than 223 million individuals – about half the expected to provide some resolution to this challenge ities and linkage of data sources will drive an increased a treatment of ulcerative colitis (UC) and Crohn’s US population -- from health plans, health care systems and enable practitioners to mine the gold buried deep development and application of real world evidence. disease. The company believes the Entyvio RWE and academic medical centers. Moreover, the number will help the IBD community decide on the drug’s of individuals in the network will increase in the com- role in their medical practices. ing years with the addition of data from the Centers for Michael Pace, Senior Principal, Pricing Jim Carroll, Vice President, Real World Evidence, Medicare and Medicaid Services. Indeed, the large and and Market Access, Commercialisation and Commercialisation and Outcomes, ICON plc. Indeed, the VICTORY (vedolizumab for health out- Outcomes, ICON plc. comes in inflammatory bowel diseases) consortium growing number of patients covered by the US FDA’s Jim Carroll leads ICON’s Real World Evidence Strategy & of ten IBD medical centers reported on a cohort Sentinel electronic data network offers drug sponsors Mike has over 20 years of executive experience with global Analytics group, which develops real world data (RWD) and technology based solutions to support sponsors who of 180 patients with moderate to severe active UC, looking to satisfy post-market safety requirements biopharmaceutical firms and digital health start-up ven- using real world data an extensive data set. Having tures, leading commercial strategy, payer and specialty are seeking to expand labelling and market access, while who were treated for 12 months in routine practice, staying ahead of the growing demand for evidentiary participated in a pilot program, Pfizer also noted the pharmacy account management, market access contract- and followed through electronic medical record ing and operations, sales, sales training and leadership requirements. Jim has over 20 years’ CRO and pharma- searches, review of clinical records or by questions potential to look beyond post-approval safety signals. development functions. At EMD Serono, he instituted the ceutical experience. He joined ICON from inVentiv Health, addressed to the centers. Some 77% of patients The company noted that Sentinel could also be used outcomes-based contracting effort that led to the first out- where he led the formation of a new business unit focused achieved mucosal healing, defined as having a Mayo to conduct drug utilization studies to look at off-label comes-based agreement on a specialty medication with a on providing novel RWD-driven services. endoscopic subscore of zero or one, while 51% of uses as well as questions around appropriate use. health plan, followed by the first outcomes-based agreement patients had a clinical remission and 41% had a Not surprisingly, Boehringer Ingelheim has used with a pharmacy benefit manager in the United States. steroid-free remission. real world data to build its case for its direct thrombin inhibitor Pradaxa (dabigatran), the first of the new gen- 18 | Scrip | 5 January 2018 © Informa UK Ltd 2018 THOUGHT LEADERSHIP IN ASSOCIATION WITH ICON HEADLINE NEWS THOUGHT LEADERSHIP IN ASSOCIATION WITH ICON

Defending Optimal Pricing eration of anticoagulants. The company has enrolled within unstructured clinical notes within EHR. Novo Nordisk is investing significant effort in While RWE does not guarantee access, it is clearly 34,500 patients in the GLORIA-AF study and plans Moreover, as most sources of real world data are not generating RWE to support its diabetes franchise. having an impact on the thinking of payers. Indeed, to include a total of 56,000 in the registry. So far, the actually collected for research purposes, data quality RWE from a post-marketing study conducted by but RWE originating from, for example, patient registries, company has been running observational studies but is is an issue. EHRs, for example, are primarily intend- requested by the French authorities for the GLP-1 EHRs, claims data or cohort studies, is likely to become considering ways of doing prospective pragmatic trials ed for patient management, rather than for research, agonist Victoza helped broaden the product’s label an increasingly important means of supporting inno- in the future. Possibilities, as the field evolves, include and there is a clamour for more alignment across all to an additional patient subgroup in Quebec. More- over, the Danish pharma believes two RWE-generat- vative pricing and outcomes-based contracting strate- running real world trials to support supplemental in- stakeholders to develop consistent data structure and ing studies around the long acting insulin Tresiba, gies, proving the value of medicines to payers, potentially dication filings with the FDA. gathering methods. Indeed, transitioning from an ad launched in Europe in 2013 and in 2016 in the improving the probability of winning reimbursement. Pfizer, the world’s largest pharma company, is leading hoc to an industrial approach to curating RWE will US, both highly competitive and price-sensitive Following a health technology assessment (HTA), the use RWE at almost every stage of a medication’s life require collaboration and investment from all stake- markets, will strengthen the company’s positon in NICE, the National Institute for Health and Care Excel- cycle. The company conducts a significant amount of holders. Regulators, in collaboration with the pharma pricing negotiations, beef up its marketing commu- lence, who is responsible for assessing that the National non-interventional research. For retrospective studies it industry and payers, still need to formulate robust nications and enhance its value dossier in markets Health Service of England and Wales is getting value for uses de-identified secondary data sources such as insur- standards for RWD collection from a variety of sources. where the product has yet to launch. its money, changed its mind and decided to recommend ance claims and EHRs to evaluate epidemiology, treat- Motivating this are are manufacturers, payers and Johnson & Johnson’s Zytiga (albiraterone acetate) for ment patterns, clinical outcomes, healthcare resource third parties, who are looking beyond their own walls to While much of the focus is on using RWE to get chemotherapy-naïve metastatic castration-resistant use and costs associated with a treatment of disease. establish the true value of medicines. Most value-based regulatory approval of drug applications, it can also prostate cancer patients after the company presented Moreover, patient data generated by wearables, apps or contracts to date have been bilateral and payer popula- be used for clinical practice guidelines to decide how RWE from US insurance claims data. even tapping into social media will become an important tion-specific, where the manufacturer and the payer share to best manage patients, for payers deciding whether Many managed entry agreements or risk sharing deals source for understanding patient needs and behaviours. data. An alternative option would be to include broader to pay for a drug, and for comparative effectiveness. in Europe rely on gathering real world data. France Typically, the company will provide RWE on epidemi- sets of relevant RWD – including data generated by third agreed to reimburse Celgene Corp.’s Pomylast (pomalido- ology and unmet needs through analysis of secondary parties – into the parties’ value-contract adjudication Highlighting The Value Proposition mide) for multiple myeloma under a risk-sharing scheme. data sources and collecting information from patients, calculations. This would have stakeholders seeking out The company will have to repay the cost of the drug if a physicians and payers. Real world data is also often in- additional appropriate sources of data to analyse, not patient does not respond to the treatment. Risk-sharing Eli Lilly & Co used real world data to size the cluded in economic models, while supplemental infor- necessarily just a specific payer’s population, but an even single-use vials for its recently launched IV cancer schemes are also in place elsewhere in Europe, while mation, such as healthcare resource use, productivity larger representative real world population set in order drug Lartruvo (olaratumab) in an effort to reduce a recent evaluation of NICE submissions has revealed loss and out of pocket expenses, is collected during the to reduce administration costs and potential conflicts. potential waste and cost of treatment. An analy- that RWE drives HTA approval in 86% of submissions. running of clinical trials. Following launch, compa- While such data sharing for value-based contract sis of population-based weight and body surface Regulators are increasingly using RWE to monitor nies may conduct comparative effectiveness research administration purposes is not commonplace, industry data, from more than 240,000 oncology patients, any post-approval safety concerns. This has been par- to either identify and understand sub-populations or has long been quite content to use third-party generated informed the decision to develop a 190mg vial ticularly useful when looking at novel anticoagulants provide value differentiating evidence. data to administer prescription market share-based alongside the original 500mg Lartruvo vial. The especially when compared with industry mainstay While there is an expectation that all pharma com- contract. Indeed, reliable and independent third party company reckons the trade-off is a cost reduction warfarin. In recent years, more than 100 observation- panies will need to have RWE strategies in place, one data can be important in subsequent value-based con- of $1,132 per patient per administration. al studies have been published on real world use of of the biggest roadblocks in using RWE for regulatory tract negotiations. anticoagulants. In the US, these have typically used purposes is the inadequate data in electronic healthcare RWE clearly has huge potential to inform healthcare claims databases from Medicare and Medicaid, while records (EHR). This is because the traditional outcome stakeholders – whether manufacturers, regulators, cli- the European studies have relied upon national data- measures that are used in conventional drug develop- nicians, patients or payers. While there are still multiple Japan’s Takeda says RWE has confirmed the benefits bases. Importantly, it appears that the anticoagulants ment are not generally found in EHRs. The challenge challenges with RWE becoming a consistent mainstay of its best-selling inflammatory bowel disease ther- behave in the real world as they did in clinical trials. is that much of the needed clinical information is stuck of the healthcare regulatory oversight and commercial apy Entyvio (vedolizumab) in US medical practice. One huge potential source of data is the FDA’s Senti- in the doctor’s notes as unstructured data. Advances in performance insight, it is clear that there is an appetite RWE collected in the US conformed the efficacy nel program which houses electronic health care data machine learning and natural language processing are among all stakeholders to resolve them. Big data capabil- of the drug, first launched in the US in 2014, as for more than 223 million individuals – about half the expected to provide some resolution to this challenge ities and linkage of data sources will drive an increased a treatment of ulcerative colitis (UC) and Crohn’s US population -- from health plans, health care systems and enable practitioners to mine the gold buried deep development and application of real world evidence. disease. The company believes the Entyvio RWE and academic medical centers. Moreover, the number will help the IBD community decide on the drug’s of individuals in the network will increase in the com- role in their medical practices. ing years with the addition of data from the Centers for Michael Pace, Senior Principal, Pricing Jim Carroll, Vice President, Real World Evidence, Medicare and Medicaid Services. Indeed, the large and and Market Access, Commercialisation and Commercialisation and Outcomes, ICON plc. Indeed, the VICTORY (vedolizumab for health out- Outcomes, ICON plc. comes in inflammatory bowel diseases) consortium growing number of patients covered by the US FDA’s Jim Carroll leads ICON’s Real World Evidence Strategy & of ten IBD medical centers reported on a cohort Sentinel electronic data network offers drug sponsors Mike has over 20 years of executive experience with global Analytics group, which develops real world data (RWD) and technology based solutions to support sponsors who of 180 patients with moderate to severe active UC, looking to satisfy post-market safety requirements biopharmaceutical firms and digital health start-up ven- using real world data an extensive data set. Having tures, leading commercial strategy, payer and specialty are seeking to expand labelling and market access, while who were treated for 12 months in routine practice, staying ahead of the growing demand for evidentiary participated in a pilot program, Pfizer also noted the pharmacy account management, market access contract- and followed through electronic medical record ing and operations, sales, sales training and leadership requirements. Jim has over 20 years’ CRO and pharma- searches, review of clinical records or by questions potential to look beyond post-approval safety signals. development functions. At EMD Serono, he instituted the ceutical experience. He joined ICON from inVentiv Health, addressed to the centers. Some 77% of patients The company noted that Sentinel could also be used outcomes-based contracting effort that led to the first out- where he led the formation of a new business unit focused achieved mucosal healing, defined as having a Mayo to conduct drug utilization studies to look at off-label comes-based agreement on a specialty medication with a on providing novel RWD-driven services. endoscopic subscore of zero or one, while 51% of uses as well as questions around appropriate use. health plan, followed by the first outcomes-based agreement patients had a clinical remission and 41% had a Not surprisingly, Boehringer Ingelheim has used with a pharmacy benefit manager in the United States. steroid-free remission. real world data to build its case for its direct thrombin inhibitor Pradaxa (dabigatran), the first of the new gen- scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 19 SALES AND MARKETING

The Return Of The US Pharma Sales Force JESSICA MERRILL [email protected]

he steady US sales force decline that began a decade ago is revers- T ing, driven by growth in oncology, although the number of sales reps in the US remains well below the peak level of the primary care blockbuster era. Data from the consulting firm ZS Associ- ates and PharmaForce Deployment Analyz- er show the number of pharma sales reps in the US grew significantly in 2016 year-over- year and held steady in the first part of 2017. There were more than 70,000 pharma sales reps in the US in 2016 for the first time since 2011, the year Pfizer Inc.’s crown jewel Lipi- tor (atorvastatin) went generic. In the first half of 2011, there were more than 75,000 sales reps in the US, but the number declined to 65,000 by the end of that year; the decline continued until 2014, Shutterstock: Ollyy Shutterstock: when there were around 55,000 pharma sales reps in the US, according to the ZS/ PharmaForce data. Pharma companies be- Only 46% of physicians are considered accessible gan cutting their promotional spending, particularly the size of their commercial to sales reps in 2017; the numbers are even more sales teams, in 2012 as the commercial mix striking when it comes to oncology, where only of products changed and as companies turned more focus to programs like copay 24% of physicians were considered accessible in assistance and market access strategies. By the end of 2014, the number of reps in 2017 compared to 80% in 2009 the US had begun edging up again to about 61,000 reps, and the momentum continued. 2012. The numbers are even more striking Data shows that oncologists are more “It almost sounds like back to the world when it comes to oncology, where only 24% willing to speak to sales reps when a new of Lipitor and Plavix,” joked ZS Managing of physicians were considered accessible in drug is approved. The steepest access de- Partner Pratap Khedkar in an interview. But 2017 compared to 80% in 2009. clines in the last six years correspond with of course, it’s not the world of Lipitor and “Oncologist access is down to 25%, which gaps in new launches. Plavix. It is the world of Opdivo and Keytruda. means 75% of the time the rep can’t get in Another age-tested pharma promotional Thus, it’s not too surprising that the number when they want to,” Khedhar said. vehicle is also on the rise – direct-to-con- of sales reps in the US is still 31% lower than In oncology, drug makers tend to orga- sumer advertising. Spending by pharma- in the peak of 2005, when there were more nize their sales force around a product, or ceutical companies on DTC advertising has than 100,000 US pharmaceutical sales reps. in some cases even by indication. But as rebounded to levels not seen since 2006. The challenges for commercial teams are companies add new cancer drugs or as the But pharma companies are also explor- also different today, as the growth is coming products add new indications it could put ing ways to reach consumers beyond their largely from oncology, not primary care, and more pressure on access, according to ZS. living room and at the point of care in phy- while access to physicians is generally chal- “There are only 12,000 oncologists in the sicians’ offices. Pharma is investing about lenging, it is particularly difficult to reach US,” Khedhar said, “so all of those sales forces $800m in point-of care promotions in doc- oncologists. have to talk to the same doctors.” tors’ offices and hospitals, according to ZS. Access to physicians has declined consid- Consider that in the PD-1/L1 space alone “The point is if you are sitting on your erably since 2009, according to ZS’ Access- there are currently five approved drugs and couch watching TV, the odds are you aren’t Monitor, which evaluates data from thou- another 20 in development, and it is clear even going to see a doctor for months, but sands of physicians. Only 46% of physicians the promotional market is going to become here it is actually hitting you when you are are considered accessible to sales reps in saturated. “Oncologists are going to say no in that healthcare mode,” Khedhar said. 2017 compared to 51% in 2014 and 65% in way,” Khedkar said. Published online 27 December 2017

20 | Scrip | 5 January 2018 © Informa UK Ltd 2018 DEALS

Millendo Gets European Foothold With Alizé Acquisition KEVIN GROGAN [email protected]

fter pulling the plug on one investigational endocrine disor- uled to begin next year for classic congenital adrenal hyperplasia and der therapy last month, Millendo Therapeutics Inc. of the the treatment, a selective inhibitor of acyl-CoA:cholesterol acyltrans- AUS has got hold of another one – for unrelenting hunger – ferase 1 which is codenamed ATR-101, is also in Phase II for Cushing’s through its acquisition of France’s Alizé Pharma SAS. syndrome and Phase I for adrenocortical carcinoma. In the all-stock deal, Millendo has gained Alizé’s livoletide, which Now, with the acquisition of Alizé, Millendo has “two first-in-class, demonstrated positive Phase II results last year in reducing hyper- late-stage clinical assets and a presence in both the US and Europe,” phagia, or insatiable hunger, in patients suffering from the rare ge- CEO Julia Owens told Scrip. She noted that the plan was to build a netic disease Prader-Willi Syndrome (PWS). Livoletide is an analog of fully integrated company in endocrinology and she feels that “we unacylated ghrelin, commonly known as the ‘hunger hormone’ and can create significant value by ultimately marketing our products, at the companies claim it has the potential to be a first-in-class treat- least in the US and potentially Europe. Our focus on endocrine dis- ment for PWS, the most common form of genetic obesity, which has eases is appropriate for that as a modest-sized sales force can cover an estimated prevalence of one to nine per 100,000. the necessary physician population effectively.” Livoletide has been granted orphan drug designation in PWS, That said, Owens added that, “We will remain open to partnering which is caused by the lack of expression of several genes on chro- as a core function for the company, though more likely for other ter- mosome 15, by the FDA and has received a positive opinion from the ritories when it comes to commercial rights to our programs. We also European Medicines Agency for orphan drug status. remain active in seeking new partnerships for programs that can be Livoletide will help fill the gap in Millendo’s pipeline left by the re- added to our pipeline.” cent decision, made with almost no fanfare, to cull MLE4901, a drug She went on to say that based on the intent to be a fully integrated acquired from AstraZeneca PLC in January 2016 for polycystic ovary company, “having a European presence was a natural step and one syndrome (PCOS). Earlier this year, Millendo presented positive Phase we would have taken anyways in the next few years.” Owens pointed II data on the therapy for the treatment of menopausal hot flashes out that “we have been conducting clinical trials in Europe for years but the firm said last month that it had decided to discontinue de- and have worked closely with groups like the European Network for velopment of MLE4901 “after assessment of the clinical risks and ben- the Study of Adrenal Tumors. Extending that to having a R&D team in efits of the program.” Europe will facilitate those activities and set us up for further expan- The axing of MLE4901 meant that Millendo just had one product sion of our work in Europe.” in development, nevanimibe. A Phase IIb study of the drug is sched- Published online 21 December 2017 Summit Completes 2017 With Discuva Buy JOHN DAVIS [email protected]

he Nasdaq and AIM-listed UK biotech Summit Therapeu- agreement with the big pharma company, Roche. The Swiss multi- tics PLC announced the day before Christmas Eve that it was national had an agreement with Discuva under which it would pay Tacquiring fellow UK company, Discuva Ltd., and that com- development, commercialization and sales milestone payments on pany’s antibiotics discovery platform for finding novel mechanisms any compound developed using the Discuva technology that is, or of action. has been, optioned by Roche. The agreement involved the develop- Privately-held Discuva was bought for a mix of cash and shares, ment of new antibiotics to treat life-threatening infections caused £5m ($6.7m) in cash and £5m in new ordinary shares of Summit, by multi-drug resistant Gram-negative bacteria using Discuva’s pro- which is unlikely to unduly stretch Summit’s finances. Following the prietary Selective Antibiotic Target IdentificatioN (SATIN) technology. acquisition, the University of Oxford spin-out says its cash runway re- The acquisition of Discuva underlines a renewed sense of confi- mains at just over 12 months, with its cash and cash equivalents able dence at Summit Therapeutics, which secured a US BARDA contract to fund the company’s activities through to Dec. 31, 2018. worth up to $62m in the third quarter of 2017 to support, in part, Discuva has a proprietary bacterial genetics-based platform that the Phase III development of one of its two lead products, the “pre- facilitates the discovery and development of novel differentiated an- cision antibiotic” candidate, ridinilazole. Summit also raised £14.9m tibiotics, combining transposon technology with bioinformatics to ($20.1m) in a follow-on public offering of American Depositary Shares create a platform for discovering new antibiotics. The company was in September 2017, and announced it had licensed Latin American targeting the ESKAPE (Enterococcus faecium, Staphylococcus aureus, rights to ridinilazole to Brazil’s Eurofarma Laboratorios SA on Dec. Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas ae- 21, 2017, for $2.5m up front and up to $25m in milestones. ruginosa and Enterobacter sp.) pathogens that represent the leading The initiation of a Phase III clinical program for ridinilazole, involv- cause of multi-drug resistance and hospital-acquired infections. ing two clinical studies, is expected in the first half of 2018. The acquisition also brings with it Discuva’s 2014 development Published online 27 December 2017 scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 21 RESEARCH & DEVELOPMENT

AstraZeneca’s Pipeline Reaps Rewards Of Return To Science ALEX SHIMMINGS [email protected]

year of “unprecedented” activity and All this is resting on increased success cancer, following the overall survival results a Phase III pipeline brimming over rates in early stage development, he added, in H1 – although little further was said about Awith products allowed AstraZen- and this “underpins our confidence that the it during the R&D day. eca PLC to claim at an R&D day on Dec. 14 productive pipeline is sustainable for years Some analysts believe this reticence that its focus on science in the five years to come.” AZ has nearly tripled the number told its own story. Analysts at Bernstein since CEO Pascal Soriot arrived has changed of its scientific publications since 2010 and pointed out that the company’s refusal to the culture of its business. “the number of high-impact publications be drawn on whether a separation could Sean Bohen, chief medical officer and continues to grow.” be seen in the PFS curves even without EVP of global medicines development told Indeed, the brisk pipeline pace set in 2017 a significant difference bodes ill. “Bristol- analysts that the sheer number of posi- is set to continue next year when the com- Myers Squibb Co. was willing to disclose tive results announced during 2017 “really pany is hoping to return to sales growth, PFS data on its ‘214, ahead of having OS outweighed the number of unfavorable mainly driven by its oncology portfolio. Fur- data, so why not AstraZeneca? A logical outcomes”, namely MYSTIC’s PFS results for ther out, observers say, earnings are also set inference would be that there was no PD-L1 inhibitor Imfinzi (durvalumab), the to gain momentum. “On a revenue basis, curve separation,” they said. complete response letter for hyperkalemia 2017 should be the trough, but EPS may not Natixis analysts were a little more optimis- treatment ZS-1 and the Phase III failure of begin to grow until 2019,” said Tim Ander- tic. “We still think these results could be posi- asthma product tralokinumab. son at Bernstein in a Dec. 14 research note, tive. That said, we may be more cautious on High points of the year were the FLAU- adding that in the longer term, EPS growth the addressable patient population,” they RA trial of Tagrisso (), Imfinzi’s should be among the very best of the nine said. “Indeed, based on recent develop- PACIFIC study and the launch of Fasenra major EU/US pharmaceutical companies ments in immuno-oncology (IO) we think (benralizumab). Looking forward to 2018, the analysts cover. that while IO+chemo combinations show the company is expecting data readouts But this also means the firm should be efficacy in all patients (PD-L1 positive and for Farxiga (dapagliflozin; the DECLARE out- wary. “If industry consolidation occurs, be- negative), this is less sure for IO+IO combi- comes study), roxadustat (Phase III), PT010 tween AstraZeneca’s full Phase III pipeline, nations like Imfinzi + tremelimumab tested (Phase III) and anifrolumab (Phase III), while its superior growth and its comparatively in MYSTIC.” it also continues to advance its oncology smaller size, it could be a take-out candi- This means, they added, that there is a lifecycle programs for Lynparza (olaparib), date,” he added. possibility that these final results will show Tagrisso, Imfinzi andCalquence (acalabruti- Natixis analysts also see 2018 as a transi- efficacy in patients with a PD-L1>25%, nib). See table on page 24 for AstraZeneca’s tion year, owing to the impact of Crestor ge- which would limit the number of target pa- expected late-stage pipeline news flow nerics and the fact that new replacements tients to 40% of the addressable population, next year and into 2019. Imfinzi and Tagrisso are “just ramping up”. i.e. close to 125,000 patients, or peak sales of “Developing medicines for patients is They also said in a Dec. 15 research note that around $2bn. high risk, high reward, and occasionally you they do not expect to see any real uptick in For PACIFIC however, AstraZeneca ex- will encounter disappointment. However, EPS until 2019, when they expect it to rise pects a regulatory decision in the US in the this year, we were rewarded with an ex- by 14%. first half, followed by the EU and Japan in tensive list of successes across all the main the second for Imfinzi in locally advanced therapy areas following the science that’s ONCOLOGY RICHES or Stage 3 unresectable non-small cell truly rewarded AstraZeneca this year, and Overall, oncology will remain the key fo- lung cancer following standard chemora- we hope to continue our success in 2018 cus of AstraZeneca’s three major therapy diation therapy. and beyond,” Bohen told analysts. “This is a areas, which also include cardiovascular/ AstraZeneca says there are an estimated clear illustration of the improvement in As- metabolic and respiratory, but Bohen also 105,000 patients in Stage 3 lung cancer, of traZeneca’s R&D productivity and just how highlighted interesting candidates for Al- which about 76,000 are unresectable. “This the culture of our business has focused on zheimer’s disease (lanabecestat) and lupus is a meaningful opportunity and one that science in the last five years.” (anifrolumab). “Pipeline opportunities that matters a lot for patients and their caregiv- In support of his premise, Bohen pointed often get overlooked.” ers,” Bohen said. “We continue to see the PA- to the number of US FDA breakthrough Within oncology, the anti-PD-L1 immuno- CIFIC trial two years to three years ahead of therapy designations granted in 2016 and oncology product Imfinzi will stay front and competition in the Stage 3 setting.” 2017 – five in total. “We rank well compared center. The company is sanguine, in public Further clinical readouts for Imfinzi in to the rest of the industry when we look at a least, about MYSTIC’s ultimate prospects – other indications, such as bladder, liver and our three main therapy areas.” slating a second-half filing in first-line lung head and neck cancers, but these markets

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are much smaller than for lung cancer. The nounced in the first half of next year. In Oc- inspection of the dedicated facility for ZS-9 product is also being tested in combina- tober, AstraZeneca gained a US approval of in Texas.” For its potential first-in-class treat- tion with and IDO1 inhibitor epacadostat, its BTK inhibitor Calquence, in a “reasonably ment for anemia and chronic kidney disease and other lifecycle opportunities are being small indication”, namely previously-treated and end-stage renal disease roxadustat, As- evaluated. mantle cell lymphoma (MCL). The com- traZeneca expects data from the Phase III Following the success of FLAURA of the pany estimated that around 3,000 patients OLYMPUS trial next year in chronic kidney next-generation EGFR inhibitor Tagrisso in are diagnosed with mantle cell lymphoma disease patients who are not receiving dialy- NSCLC the company is looking forward to each year in the US. It has just presented the sis. The primary endpoint is to demonstrate regulatory decisions on the expansion of its MCL data at the American Society of He- a superior hemoglobin increase with a non- indication to include the first-line EGFR-mu- matology Meeting, “along with a couple of inferior MACE incidence over placebo. This tated NSCLC setting. Filings have recently chronic lymphocytic leukemia trial updates is one of a number of HIF prolyl hydroxylase been made in the EU and Japan, with the in monotherapy and in combination with inhibitors approaching the market. US expected soon. Overall survival data are GA101, or , where Calquence A Chinese rolling regulatory submission is still awaited from this study, however, but demonstrated early efficacy signals along completed, and a US regulatory submission it is difficult to give guidance as events are with good tolerability”. The major Phase III is due in 2H 18. slow to accrue and patient crossover is oc- data for its use in the larger chronic lympho- curring, Bohen told analysts. cytic leukemia indication study are not due RESPIRATORY Tagrisso is currently on the market for use until 2019. The US approval of Fasenra in severe eo- in second-line T790M-mutated NSCLC pa- sinophilic asthma was another high point tients and performed strongly in the third ‘If industry consolidation in 2017. Based on the results of the WIND- quarter. WARD program, the IL-5α receptor inhibitor AstraZeneca’s PARP inhibitor Lynparza occurs, between is under regulatory review in the EU, Japan features heavily in its pipeline plans. The and several other countries with decisions company presented data from the Phase II AstraZeneca’s full Phase III anticipated in first half of next year. basket trial MEDIOLA at the World Congress pipeline, its superior growth Next steps are to develop an autoinjec- on Lung Cancer meeting in October. tor in the GRECO trial for which a readout is The data from the small cell lung cancer and its comparatively expected in the second half of 2018. Then population showed that the Lynparza plus smaller size, it could be a there is the Phase III VOYAGER program Imfinzi combination was well-tolerated looking at Fasenra in patients with severe compared with historical data on topote- take-out candidate’ COPD. For those patients who have an exac- can, the current standard of care for the erbation history, “it’s pretty well established second-line setting. Furthermore, the dura- that there’s an inflammatory component tion of response and overall survival data underlying those exacerbations. And we’re exceeded those previously reported with CARDIOVASCULAR looking at benralizumab as a potent agent topotecan. “All responses occurred prior to In the cardiovascular/metabolic arena, to reduce that hyperreactivity and inflam- the addition of Imfinzi, suggesting that the AstraZeneca says it is “taking a holistic ap- mation and reduce that risk of exacerbation,” initiation of these responses was driven by proach”. Foremost here are the plans for the said Bohen. Lynparza. Interestingly, the median overall SGLT2 inhibitor for diabetes Farxiga and its Its other great hope in respiratory area is survival data suggest that Imfinzi, or the cardiovascular outcomes study DECLARE tezepelumab, particularly since the failure of combination, may have long-term efficacy due in the second half of next year. tralokinumab. The anti-thymic stromal lym- potential, even in patients who lack an ob- Added to which is the DPAP-HF study phopoietin biologic is the first epithelium- jective response,” Bohen said. in heart failure due in 2019 (although the targeting medicine with potential differenti- Further MEDIOLA data reported at the company wouldn’t be drawn on whether ated efficacy in patients with moderate to San Antonio Breast Cancer Symposium an interim analysis would be forthcoming in severe asthma. showed Lynparza and Imfinzi were well 2018) and the DAPA-CKD in renal patients in In September, along with partner Amgen tolerated in the germline BRCA-mutated 2020. “We want to stop disease and regener- Inc., AstraZeneca presented the PATHWAY metastatic breast cancer population. “The ate organs,” Bohen said. Phase IIb data for tezepelumab at the Euro- objective response rate was 52% and a little Glossing over the CRL in May for ZS-9 in pean Respiratory Society Congress in Milan, lower than what we observed in the Olym- hyperkalemia, Bohen said: “I want to take which indicated what AZ believes is poten- piAD trial. But this may have been due to this opportunity to remind you of the po- tial best-in-disease efficacy. First Phase III later line of therapy and smaller sample size,” tential for providing a best-in-class treat- trial NAVIGATOR has initiated with a patient said Bohen. ment for hyperkalemia, once approved.” enrolled. “We will need to see the final Phase AstraZeneca sees significant opportu- It has already had the positive CHMP III profile, but at this stage, tezepelumab has nity to expand Lynparza through its col- opinion in the EU and more news in the US the potential to be one of the broadest and laboration with Merck & Co. Inc. and the will be reported in due course. “We have most promising biologic medicines for the two companies have agreed development made significant progress in addressing treatment of respiratory diseases.” plans and more trials are expected to be an- the deficiencies identified during the FDA CONTINUED ON PAGE 24 scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 23 RESEARCH & DEVELOPMENT

CONTINUED FROM PAGE 23 AZ’s Late-Stage Pipeline News Flow In 2018 and 2019 Progress should also come next year for AstraZeneca’s third major respiratory prod- H1 2018 H2 2018 2019 uct, the triple combo PT010 (budesonide/ Regulatory decision glycopyrronium/formoterol), which is being Lynparza - ovarian cancer 2L Lynparza - breast cancer (JP) pursued for both COPD and asthma. (EU, JP)-breast cancer (US) There is a significant unmet need in COPD Tagrisso - lung cancer (US) Tagrisso - lung cancer (EU,JP) patients that is well established, with around 40% to 50% of patients treated with inhaled Imfinzi - lung cancer Imfinzi - lung cancer (PACIFIC) (PACIFIC) (US) (EU, JP) corticosteroid and long-acting beta agonist, receiving an add-on medicine in the form of Bydureon BCise - type-2 diabetes (EU) a long-acting muscarinic antagonist. Fasenra - severe, uncontrolled “The differentiating factor for PT010 will be Bevespi - COPD (EU) the pressurized metered-dose inhaler plus asthma (EU,JP) the fast onset of action and the inclusion of Regulatory submission budesonide,” said Bohen. The data readout is Lynparza expected to start in the first half of next year, Lynparza - breast cancer (EU) Lynparza - ovarian cancer 1L - pancreatic cancer 1L followed by regulatory submissions. - ovarian cancer 3L Imfinzi+ treme - lung cancer BEST OF THE REST 1L (NEPTUNE) Outside its core therapy areas, AstraZeneca Imfinzi+/-treme Imfinzi+/-treme sees much promise in its lupus therapy ani- Imfinzi+/-treme - lung cancer 1L (MYSTIC) - lung cancer 1L (POSEIDON) - lung cancer 3L (ARCTIC) - head & neck cancer 1L, 2L frolumab and its Alzheimer’s disease thera- - bladder cancer 1L (DANUBE) py lanabecestat, a BACE inhibitor. (KESTREL, EAGLE) - Based on promising Phase II data, the ani- - thyroid cancer frolumab development program includes hairy cell leukaemia 3L Brilinta - CAD2/type-2 an additional precision medicine strategy Roxadustat - anaemia (US) to best identify which patients will respond diabetes CVOT better to anifrolumab based on an inter- Farxiga - type-2 diabetes feron gene signature test. The product dif- CVOT (DECLARE) fers from its competition in that it blocks the PT010 - COPD Fasenra - COPD interferon receptor rather than targeting in- Anifrolumab - lupus terferon itself, thereby providing more com- Key Phase III data readouts plete isoform blockade. Lynparza - ovarian cancer 1L Lynparza-pancreatic cancer 1L Lynparza-ovarian cancer 3L Both its Phase III trials, TULIP 1 and TULIP 2, are fully recruited with primary Imfinzi-lung cancer (PACIFIC) endpoints at 48 weeks, and readout ex- (final OS) pected in the second half of next year. Imfinzi+/-treme Regulatory submissions are due in 2019. - lung cancer 3L (ARCTIC) Imfinzi+/-treme - lung cancer 1L (MYSTIC) Imfinzi+treme - lung cancer 1L (POSEIDON) Looking forward, AstraZeneca has an on- (final OS) - lung cancer 1L (NEPTUNE) - bladder cancer 1L (DANUBE) going Phase II trial with subcutaneous - head & neck cancer 1L, 2L - liver cancer 1L (HIMALAYA) administration, plus an ongoing Phase II (KESTREL, EAGLE) trial in lupus nephritis. Brilinta-CAD/type-2 diabetes But the Natixis analysts said they thought CVOT “the group may be tempted to sell this Farxiga-type-2 diabetes Farxiga-HF product to a third party, as it does not fit ful- CVOT1(DECLARE) ly with the therapeutic areas it wants to fo- PT010 - COPD Fasenra - COPD cus on”. They estimate anifrolumab to bring lanabecestat-Alzheimer’s in close to $500m in peak sales. Anifrolumab - lupus disease And with Eli Lilly & Co., AstraZeneca is hoping to buck the trend in Alzheimer’s with Source: AstraZeneca Late-Stage Pipeline Webcast Dec. 14, 2017 lanabecestat. While acting on BACE, it takes a different approach from other candidates action than that of the anti-amyloid beta an- second Phase III trial, DAYBREAK, for mild Al- in this field by depleting amyloid beta in ce- tibodies and is a mechanism underpinned zheimer’s disease, is still recruiting. rebral spinal fluid. “We have seen several set- by strong genetic evidence.” The product has a fast track designation backs with other medicines in this disease,” The Phase II/III AMARANTH trial for early and the first Phase III data are expected in said Bohen. “This is a different mechanism of Alzheimer’s disease is now fully recruited. A 2019. Published online 22 December 2017

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AbbVie’s Upadacitinib Aces Another Arthritis Trial, But Safety Concerns Linger EMILY HAYES [email protected]

bbVie Inc.’s JAK1 inhibitor upadacitinib succeeded in another Pulmonary embolism also was a concern in the SELECT-BE- Phase III rheumatoid arthritis study – this time as a monother- YOND study – two cases were reported and one was fatal. Car- Aapy – but concerns persist about cardiovascular safety due to diovascular safety has been a factor holding back Eli Lilly & Co./ a small number of cases of pulmonary embolism, one fatal, as well Incyte Corp.’s competing JAK1/2 inhibitor baricitinib, which is as competitive positioning relative to other drugs in the same class. due to be refiled with the US FDA in January, following a com- AbbVie reported Dec. 20 that upadacitinib (ABT-494) met the plete response letter in April that asked for additional safety data. co-primary endpoint in the Phase III SELECT-MONOTHERAPY study, (Also see “AbbVie’s New Generation JAK inhibitor Looks Good But CV which tested the candidate in patients with moderate-to-severe Specter Looms” - Scrip, 12 Sep, 2017.) rheumatoid arthritis (RA) who did not adequately respond to treat- Pfizer Inc.’s Xeljanz (tofacitinib), a JAK1/2/3 inhibitor, is the first and ment with methotrexate. only in the class approved for rheumatoid arthritis, available on the Two different once-daily doses were tested – 15 mg and 30 mg US market since 2012, and has not been associated with these kinds – against methotrexate. Both doses hit the mark on the co-primary of cardiovascular events, though it does have a boxed warning for endpoint measure at 14 weeks, which included the ACR20 score, serious and life-threatening infections. meaning a 20% improvement on the American College of Rheuma- BMO Capital Markets analyst Alex Arfaei said in a Dec. 20 note that tology disease scale, reflecting improvements in tender and swollen the monotherapy data for upadacitinib appear modestly better than joint counts, and low disease activity. baricitinib in the RA-BEGIN study in terms of efficacy and did not -al The two doses also demonstrated significant improvements on all leviate cardiovascular safety concerns. secondary endpoints, including ACR50 and ACR70, meaning a 50% “We believe these concerns should result in increased regulatory and 70% improvement, respectively. scrutiny, and tempered physician uptake. Moreover, we do not be- Upadacitinib is an important drug for AbbVie in preparing for the lieve [upadactinitib] can significantly displace the well-entrenched future beyond its TNF blocker Humira (adalimumab). The company Xeljanz, which does not have these safety concerns,” Arfaei said. has touted upadacitinib and the IL-23 inhibitor risankizumab as Arfaei also noted the impact of anti-TNF biosimilars after 2018 in highly differentiated, best-in-class agents across a range of immune- the EU and 2022 in the US and the patent expiry of Xeljanz in 2025 mediated conditions, marking AbbVie’s progress from one drug to a as competitive factors that will put pressure on new JAK inhibitors in portfolio of therapies for immune disorders. rheumatoid arthritis. The Phase III SELECT program for upadacitinib includes six studies The analyst is forecasting risk-adjusted sales for upadacitinib of evaluating the drug in more than 4,000 patients with moderate-to- about $2bn (20%-40% below consensus) by 2023. severe rheumatoid arthritis in various treatment scenarios. In addition Biomedtracker’s David Dahan told Scrip that the death due to a to SELECT-MONOTHERAPY, two other studies have been positive. hemorrhagic stroke and the pulmonary embolism event appear SELECT-BEYOND and SELECT-NEXT tested upadacitinib in mod- concerning, especially since two cases of PE were reported in SE- erate-to-severe rheumatoid arthritis patients who did not respond LECT-BEYOND. to or were intolerant of biological disease-modifying anti-rheumatic “The company notes that the overall incidence of deep vein drugs. In addition to rheumatoid arthritis, upadacitinib also is in de- thrombosis and pulmonary embolism remains consistent with the velopment for a range of other related conditions, including psoriatic background rate for the rheumatoid arthritis population suggest- arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis and ing that these cardiovascular events should not derail approval of atopic dermatitis. upadacitinib. However, as results from additional Phase III trials are On the safety front, AbbVie reported that results in the SELECT- disclosed any additional cardiovascular adverse events will be moni- MONOTHERAPY study were in line with previously reported studies tored carefully,” Dahan said. and that no new safety signals were detected. The rate of serious ad- Leerink Swann analyst Geoffrey Porges, however, found the latest verse events was 5% for the 15 mg dose, 3% for the 30 mg dose and safety results to be reassuring. 3% for methotrexate. Porges views the single fatal hemorrhagic stroke as unlikely to However, in the test drug arms, the company also reported two have been drug-related and said that one case of PE “does not seem concerning cases in patients with pre-existing cardiovascular risk fac- unusual given the size of the trial, the background rate in this popula- tors. One patient on the 15 mg dose died after a hemorrhagic stroke tion and AbbVie’s disclosure that the patient had pre-existing cardio- caused by a ruptured aneurysm. Another on the 15 mg dose had a vascular risk factors.” pulmonary embolism (PE). “We continue to believe AbbVie’s upadacitinib program, which is “Across the SELECT rheumatoid arthritis program, including both enrolling over 4,500 patients, is sufficiently large to report multiple the placebo-controlled and extension periods, the rate of deep vein pulmonary emboli without risking the approvability of the drug,” thrombosis and PE remains consistent with the background rate for Porges said. the RA patient population,” AbbVie said in a statement about the data. Published online 21 December 2017 scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 25 RESEARCH & DEVELOPMENT

The Next Challenge: Improving And Predicting Responses As CAR-T Therapies Advance MANDY JACKSON [email protected]

ow that investigators have shown Longo and Walter Urba wrote in a Dec. 10 so that patients are getting the promised promising efficacy for chimeric -an New England Journal of Medicine (NEJM) dose – not too few or too many CAR-T cells. Ntigen receptor T cell (CAR-T) thera- editorial published on the same day as ar- “We’ve done a lot of science and a lot of pies in patients who’ve run out of options, ticles about Kymriah and Yescarta studies. work to get that right,” Juno’s President of researchers and biopharmaceutical com- Tran is an assistant member of the T Cell Research and Development Sunil Agarwal panies are trying to understand why some Response Laboratory, part of the Earle A. told Scrip. patients stop responding while others don’t Chiles Research Institute within the Provi- Agarwal noted that investigators who respond at all. dence Cancer Center in Portland, Ore. Lon- have tested multiple CAR-T therapies in CAR-T cell persistence, loss of the target- go is an oncologist at Dana-Farber Cancer clinical trials see JCAR017 as a potentially ef- ed antigen and emergence of treatment- Institute in Boston and a professor at Har- fective, yet safer treatment option. resistant mechanisms are areas of interest. vard Medical School. Urba is an oncologist “One of the fundamental concepts that Combining CAR-T therapies with other and director of research at the Providence existed even just a year ago was that all drugs and developing bispecific CAR-T can- Cancer Center. CARs are the same and in order to get a ben- didates are among the approaches that are efit to the patients you have to have toxic- being explored to increase response rates JUNO HOPES FOR SAFETY, ity,” Agarwal said. “People view JCAR017 as a and extend survival. These were hot topics EFFICACY GAINS second-generation CAR, and they say that during the American Society of Hematolo- Juno Therapeutics Inc. was neck-and- you can have efficacy without toxicity. It’s a gy (ASH) meeting In December, where data neck with Novartis and Kite in the race to fundamental shift from a year ago to today.” for the first two CAR-T therapies approved bring a CD19-targeting CAR-T therapy to In the Phase I study TRANSCEND, which in the US and several CAR-T hopefuls were market, but safety issues for its first candi- is enrolling patients with relapsed or refrac- presented between Dec. 9 and 12. date JCAR015 put the company two years tory aggressive B cell non-Hodgkin lympho- Surprising efficacy in relapsed and refrac- behind its main competitors. ma (NHL), the overall response rate (ORR) tory leukemia and lymphoma patients who Juno believes that its follow-on candi- was 74% at three months among 19 diffuse previously were treated with multiple lines date JCAR017 (lisocabtagene maraleucel), large B cell lymphoma (DLBCL) patients of therapy led to US FDA approval in August which has a 4-1BB co-stimulatory domain treated with JCAR017 and the complete re- for Novartis AG’s Kymriah (tisagenlecleucel) rather than CD28, is not only a better prod- sponse (CR) rate was 68%. and in October for Gilead Sciences Inc.’s uct than JCAR015, but could be a best-in- By comparison, an analysis presented at Yescarta (axicabtagene ciloleucel), devel- class product based on emerging safety ASH of 81 DLBCL patients enrolled in the oped by the recently acquired subsidiary and efficacy data. pivotal Phase II JULIET study for Kymriah Kite Pharma Inc. “Recent studies have shown intrinsic dif- showed three-month ORR of 38% and CR Both CAR-T therapies involve the remov- ferences in CAR-T cells that use CD28 rather of 32% stabilizing at six months with ORR of al of patients’ T cells, which are genetically than other co-stimulatory molecules, such 37% and CR of 30%. In terms of safety, 58% reengineered to target CD19 on cancer as 4-1BB, but it remains unclear whether of patients experienced cytokine release cells before being infused back into the either co-stimulatory domain will confer dif- syndrome (CRS) – 15% Grade 3 and 8% patients. But while Kymriah, Yescarta and ferences in activity or persistence in patients Grade 4 – and 21% had neurotoxicity (12% other CAR-T therapies have shown un- and whether such responses are dependent Grade 3 or 4). Both side effects are common precedented efficacy, there still are many on the tumor type. Therefore, optimization in patients treated with CAR-T therapies and patients whose cancer doesn’t respond of CAR constructs and manufacturing as frequently are severe. and some whose disease stops respond- well as combination strategies with immu- For JCAR017, CRS and neurotoxicity – a ing after a few months. nomodulatory agents are being explored,” deadly side effect for five patients treated “Despite the impressive clinical results, University of Texas MD Anderson Cancer with predecessor JCAR015 – were experi- approximately half the patients with re- Center Professor Sattva Neelapu, a lead in- enced by 36% and 21% of the 67 patients fractory or relapsed large B-cell lympho- vestigator for the ZUMA-1 clinical trial that enrolled in TRANSCEND’s core group. Only mas will not have a durable response supported approval for Gilead/Kite’s Yescar- 1% experienced severe CRS while 15% had after anti-CD19 CAR-T-cell therapy. The ta, and colleagues wrote in a Dec. 10 NEJM severe neurotoxicity. reasons for this variation in response are article about the study’s latest results. Some DLBCL patients in both TRAN- not completely understood, but a num- Juno developed JCAR017 with its defined SCEND and JULIET were treated on an ber of strategies are being investigated to composition platform under which it manu- outpatient basis, staying close to their treat- enhance the therapeutic efficacy of CAR- factures T cells in very specific amounts to ment centers so they could return quickly if T cells against lymphoma,” Eric Tran, Dan produce a defined dose of engineered cells, severe CRS or neurotoxicity were suspected.

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Enrollment in TRANSCEND’s pivotal cohort COMBINATION THERAPY Increased cell surface BCMA may increase is ongoing and Juno expects that cohort to OPTIONS potency of a BCMA-directed CAR-T therapy.” generate the necessary data to support a Juno and Celgene are enrolling patients Celgene Corporate Vice President-Transla- biologic license application (BLA) in time for a with DLBCL in a study that tests JCAR017 tional Development, Kristen Hege said dur- BLA submission to the FDA in the second half in combination with AstraZeneca PLC’s ing the company’s Dec. 10 investor event of 2018 with approval anticipated in the latter PD-L1 inhibitor Imfinzi (durvalumab). An- during ASH that one of the things Celgene part of 2019. Juno’s partner Celgene Corp., other study will be initiated in 2018 to test is trying in order to boost CAR-T cell per- which plans to start a global trial for JCAR017 JCAR017 in combination with a Bruton ty- sistence is to test its partnered therapies – in DLBCL in 2018, has rights to the CD19 pro- rosine kinase (BTK) inhibitor in chronic lym- both BCMA-targeted bb2121 and JCAR017 gram outside of North America and China. phocytic leukemia (CLL). against CD19 – in combination studies. Celgene and its other CAR-T partner Agarwal noted that the CAR-T field still is Hege noted that product modifications are bluebird bio Inc. could have the fourth trying to figure out the best staging of the cell under consideration as well. CAR-T therapy on the US market with their therapies and targeted or immuno-oncology “We also have another program that candidate bb2121, which targets B cell mat- agents. He said Imfinzi will be administered we have partnered with bluebird which uration antigen (BCMA) for the treatment of three or four weeks after JCAR017 infusion, is skewing the product – the BCMA CAR-T multiple myeloma. The companies antici- because there is some concern that with a product – toward a stem cell memory phe- pate FDA approval in 2020. checkpoint inhibitor in the bloodstream at notype that at least in animals has been the time of CAR-T administration the reen- shown to be associated with more durable SHORT-LIVED RESPONSES gineered cells could expand too quickly, in- persistence,” Hege said. But even with complete response rates that creasing the incidence of severe toxicities. are far superior to standard-of-care chemo- Safety is a crucial question in regard to MORE PREDICTIVE DATA therapy, many patients in the clinical trials combination therapy given the severe ARE NEEDED conducted to date are not responding or initial CRS and neurological side effects However, she also noted that there is not stop responding after the first few months observed within the first few weeks or enough data available yet from clinical trials of treatment. months of treatment. “that really hone in on what the predictors MD Anderson’s Neelapu said in an inter- The Tran, Longo and Urba NEJM editorial of the deeper or less-deep responses are, view with Scrip that at least a third of patients noted that “combining anti-CD19 CAR T-cell even predictors of resistance,” but research who don’t respond to CAR-T therapy or who therapy with other agents, such as Bruton in that area is ongoing. eventually stop responding no longer ex- tyrosine kinase inhibitors and inhibitors of Bluebird President and CEO Nick Leschly press CD19, which is at least one mechanism immune checkpoint pathways (e.g., pro- also noted during his company’s Dec. 9 ASH for CAR-T resistance along with the emer- grammed death 1 [PD-1] protein or its ligand investor event that there have been no spe- gence of immune checkpoints, such as PD- [PD-L1]), may also increase therapeutic effi- cific indicators to date to explain why pa- L1. He said the answer may be combination cacy. However, because the mechanisms of tients didn’t respond or stopped respond- therapy with PD-L1 inhibitors or treatment the toxic effects associated with this therapy ing to treatment with bb2121. with bispecific CAR-T therapies, which in- are not completely understood, strategies “There were patients that did have a de- volve T cells reengineered to seek out two that enhance the potency of these products crease in BCMA expression, some of them targets on cancer cells instead of one. run the risk of inadvertently worsening the did not; patients that had ongoing T-cell ex- Juno presented findings during the ASH already daunting toxic effects.” pansion and some that had decreased, so it’s meeting from its assessments of JCAR017 Juno is not deterred by the safety ques- still unclear what’s causing the potential re- infiltration into tumor tissue to explore po- tion in its pursuit of agents that could be sistance or escape at this point,” Leschly said. tential mechanisms of treatment resistance added to CAR-T treatment to improve the What is clear is that a lot more research and patient relapse. CAR-T cell infiltration efficacy of the therapies. The company is needed not only to test new CAR-T can- was higher in patients who responded to recently announced a license agreement didates, but to improve responses to the treatment, but in most patients with dis- with Eli Lilly & Co. for the gamma secre- therapies. ease progression CAR-T cells were rare or tase inhibitor (GSI) LY3039478 to test in Novartis Senior Vice President David absent in tumor tissue even though CD19 combination with its BCMA-targeting Lebwohl, Franchise Global Program Head was present and CAR-T cells were detected CAR-T therapy JCARH125 in 2018. (Also for CAR-T therapies, said during the com- in peripheral blood. see “Deal Watch: Vertex Selects First Candi- pany’s Nov. 11 investor event to discuss The company noted that “there does not date Under CRISPR Gene-Editing Collabora- data presented at ASH that “we do not yet yet appear to be a singular resistance path- tion” - Scrip, 13 Dec, 2017.) know how to predict which patients are way upregulated in the tumor at the time Juno said in Dec. 6 announcement about going to respond. However, we do have a of progression, but well-known pathways the deal that “gamma secretase is an en- very extensive analytic program looking at such as PD-L1 and IDO were upregulated in zyme that cleaves a set of transmembrane immuno-phenotyping of cells as well as different patients. These data suggest that proteins, including BCMA. Multiple publica- the patients’ tumors, and we obviously will combinations with other immunotherapies tions have shown that treatment with GSIs keep looking to try to find something that may be beneficial to further improve out- can increase surface expression of BCMA can predict response.” comes with JCAR017 therapy.” on tumors, particularly multiple myeloma. Published online 29 December 2017 scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 27 EMERGING MARKETS

Unlocking Market Access For Novel Drugs In China BRIAN YANG [email protected]

fter an eight-year hiatus, China’s public payer, the Ministry of drug price negotiations to be completed within three months to six Human Resources and Social Security (MHRSS) updated its months evaluation, while in China there is no such requirement, al- Anational reimbursement drug list (NRDL) in 2017. though the MHRSS has talked about updating the list on a rolling basis. That translates into a novel drug waiting an average of six years to In China, when a novel drug from certain makers is not selected for gain national reimbursement in China. national drug negotiation or the maker chooses not to participate, The lack of coverage has meant low uptake of innovative thera- the best way forward is to negotiate with local authorities, recom- pies upon market launch in China, according to a recent report by mended the report. industry associations, led by R&D based Pharmaceutical Association “A drug maker should consider the flexibility to negotiate solely Committee (RDPAC), and written by McKinsey. with provincial government, in a bid to get their drugs reimbursed, Among six therapies launched on the market, Merck & Co. Inc.’s rather through the national negotiations,” said the report. Januvia (sitagliptin), Roche’s Avastin (bevacizumab), Bayer AG’s Makers should set their product’s ex-factory prices to reflect China’s Xarelto (rivaroxaban), Pfizer Inc.’s Enbrel (etanercept), Novartis AG’s market conditions, no matter whether the product is included in the list Lucentis () and Roche’s Tarceva (), sales in China or not because of a price monitoring system, emphasized the report. are only 16% of their respective sales in Japan, despite China having Because several provincial governments endeavor to cover indi- a much larger population. vidual drugs ahead of the national coverage, drug makers should ac- Apart from a higher GDP (Japan’s $39,000 vs. $8,100 in China) and tively seek local coverage. One example is Eastern Zhejiang province, larger healthcare expenditure (10.2% vs. 6.2%), Japan’s timely reim- which recently extended coverage to 36 drugs, mainly anticancers, bursement (within 3 months of launch) also contributes to the large treatment for severe mental disorders, hemophilia, diabetes and car- difference, noted the report. diovascular conditions. A timelier reimbursement is thus vital to ensure market access for novel drugs in China. SEPARATE FUNDING To that end, policy makers should actively listen to input from the As increasing numbers of innovative drugs are heading to the mar- industry and align closely with each other, proposed the report, enti- ket, China should consider setting up a separate fund to provide cov- tled Improve Market Access to Novel Drugs and Ensure Healthier China, erage for such drugs, said the report. released on Dec.13 in Beijing. Such funding would allow hospitals to start using them, and pa- Unlike the National Health Service in UK and the US Ministry of tients could access upon their market launches. Health, Labor and Welfare, China lacks a central agency to coordinate The low market share of commercial insurance also deters market among state agencies, and between the central government and lo- access for such treatment. Private health insurance accounts for 10% cal authorities in making reimbursement policies. of the total health insurance market, owing to a lack of electronic A cross-agency leading payer is necessary to oversee the policy health records (EHR) and little influence over hospital prescription making process, noted the report. decisions, as well as low public awareness. Additionally, policy makers need to regularly listen to industry in- China’s single pay-for-service method doesn’t help either. Other put, and seek comments from stakeholders. In the past, agencies in countries such as Australia, UK and France use more sophisticated China generally released drafts and asked the industry to comment methods combining several treatment-based methods. within two weeks, which left insufficient time to have the comments To cure the market access condition, China should take a combi- reflected in the final regulations. nation of measures, suggested the report. One is that MHRSS should Other stakeholders, including physicians, patient groups should take a leadership role, supported by the National Health and Family also be included in the comments gathering process, the report Planning Commission (NHFPC). Others include: recommended. • Allow makers to submit reimbursement applications and conduct China needs to employ transparent and evidence-based stan- regular negotiations; dards when it considers what drugs to be included for reimburse- • Local authorities shouldn’t further adjust the reimbursement level ment, it proposed. once it has been set by the central government; Although China has started its national drug negotiation mecha- • Hospitals shouldn’t further negotiate drug prices after the NRDL nism, mainly relying on expert comments, there is a need for a reim- listing; bursement framework based on a drug’s clinical evidence. • Link quantity with pricing; Recent reports exposed so-called “magic drugs (Shenyao)”, such as • Exclude innovative new drugs from limitations of “one drug, two Shapuaisi (bendazac lysine) eye drops, sales of which reach CNY750m products” allowed in each hospital; ($115m) a year, despite a lack of clear clinical benefits. • Improve Pharmaceutical Affairs Committee inside hospitals. “The clinical evidence should be evaluated by an independent The lack of reimbursement poses the biggest challenge to drug mak- third-party committee,” said McKinsey’s partner, Zhou Gaobo, who ers, now that the national medicines agency China FDA has made ma- presented the report. jor improvements to the new drug approval process, said Jean-Chris- Timely updating of the NRDL is another measure to encourage drug tophe Pointeau, Sanofi China GM and deputy chairman of RDPAC, who innovation in China. Several countries require clinical evaluation and presented at the launch event.. Published online 29 December 2017

28 | Scrip | 5 January 2018 © Informa UK Ltd 2018 EMERGING MARKETS

Pharma-BAT Digital Health Tango In China: Will It Pay Off? BRIAN YANG [email protected]

017 has been marked by active deal- cal information and diseases management. The Tencent system can screen for the making between drug makers and Based on Alibaba’s code-based product cancer with 90% accuracy, and 95% for 2internet giants in China. From Glaxo- traceability tool, it will be integrated with sarcoidosis on lungs. The plan is to work SmithKline PLC to Sanofi, pharma compa- information on chronic ailments such as with medical institutions and expand to nies eagerly embraced a new environment cardiovascular disease and diabetes. more cancer types. in which patients turn to their smartphones Sanofi also rolled out itsMC2 project, a for health solutions. multi-channel platform providing physi- MEDICAL INSURANCE PLUS From disease management to commercial cians with information and customized Facing challenges of limited or no coverage model innovation, digital tools have become feedback through online tools ranging from for innovative new drugs, companies are more important in a country with the world’s telephone, email, Chinese social network looking for new ways to expand the access. largest mobile phone and internet users. WeChat and web conference. And technology could aid these efforts. China has surpassed the US as the larg- One such tech startup is CareVoice, est mobile pay market, and among Chinese ONCOLOGY AND AI which developed a ‘Yelp’ review app for physicians, 71% of them prefer internet and Digital health’s latest battlefield is artificial healthcare services in China in which users mobile devices to get medical information intelligence, driven by China’s policy push can get personalized health care options, and mobile phones and internet are two to become a world power in AI and led by based on reviews and recommendations. most used tools, noted a survey conducted companies both large and small. Initially targeting mid-to-high income in 2014 by the international public relations On Dec.14, the government released a consumers in Shanghai, CareVoice has firm Ruder Finn. national Three-Year Plan in artificial intel- partnered with health insurers AXA and An integrated approach that combines ligence. The plan calls for several priorities pharmacy operators 1Yaowang to provide traditional face-to-face interaction with mo- including medical imaging assistance plat- expats and Chinese users with health man- bile and digital information provision is thus form, video and imaging identification sys- agement and medical need. vital to win the battle for attention of the tems and service robotic devices. The partnership will allow the insurer physician and patient. Alibaba has already invested $227m in the know more about their customers and pro- Hong Kong-based startup SenseTime that vide more customized services. ONLINE TO OFFLINE focuses on artificial intelligence research CareVoice founder Sébastien Gaudin So far, the biggest role for digital health ap- and has multiple advanced technologies previously worked at Sanofi. Some of the parently is medical information offering and for facial recognition, machine learning and startup’s recent partnerships include one disease management. Many drug makers smart city systems. with Johnson&Johnson to expand edu- look at smartphone apps and code-based Meanwhile, the Hangzhou-based Alibaba cation on contact lenses in China, and technology centered on chronic diseases is developing machine-learning to get au- the Saas (software as a service) InsurTech and vaccines as a fast and cost-effective way tomated diagnosis of sarcoidosis, an inflam- platform to improve health and insurance to reach tens of millions of users in China. matory condition forming on organs includ- experiences. GSK, for one, inked a deal with Alibaba ing the lungs. “Pharma companies have market access to reach out to millions of healthy Chinese Additionally, Alibaba is partnering with challenges to get innovative drugs covered adults who browse online regularly but Intel and the Beijing-based oncology diag- by social insurance and are seeking new ways haven’t thought about getting shots to nosis and big data firmLinkDoc to conduct to reduce pay-out for patients and/or gener- protect them from illness. The innovative a competition to help scout for talent, find ate new sources of revenues beyond drugs,” service platform uses Alibaba’s online com- appropriate algorithms, and analyze com- Gaudin told Scrip in a written response. merce site Taobao to feature information on puter tomography lung images to precisely Increasing the awareness for commercial GSK vaccines, starting with Cervarix. Users diagnose sarcoidosis. insurance products is vital in China, said the can get vaccination consultation and book But the real leader in AI could be the entrepreneur. an appointment, all done via a smartphone Shenzhen-based Tencent, which is build- He also underscored the importance of or website. ing a national platform for an AI-based leveraging resources from insurance and The tie-up with Alibaba came days after medical imaging diagnosis system. In Au- pharma companies so that beneficiaries GSK nixed its neurosciences research unit in gust, Tencent launched Miying (Seek Im- can be diagnosed earlier and benefit from Shanghai, as a part of an R&D restructuring aging), the first AI-based esophageal can- easier access to relevant medical providers after new CEO Emma Walmsley took over. cer diagnosis system. Esophageal cancer and treatment, while lowering cost for all Similarly, French drug maker Sanofi has is among the most prevalent cancer types stakeholders. signed a deal with Alibaba to provide medi- in China, especially among rural residents. Published online 28 December 2017

scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 29 EMERGING MARKETS

China API Juggernaut Rolls On But Can India Recoup? ANJU GHANGURDE [email protected]

ndia could be staring at a national health shortages of essential drugs in India,” he said. has increased over the years, productivity crisis in the backdrop of its continuing The KPMG-CII report identifies a string of also has improved, aided by factors such as Imassive reliance on Chinese active phar- measures as part of a structured approach superior quality infrastructure and produc- maceutical ingredients (APIs), including to help India achieve self-sufficiency in the tion techniques. China’s labor productivity those used in drugs for high-burden dis- API segment. Short-term recommendations is estimated to be nearly 1.5-times higher eases such as diabetes and cardiovascular include using existing capacities, focusing than that of India. ailments, according to a report by the pro- on quality, identifying critical APIs and se- fessional services firm KPMG and the Con- curing the supply chain. Mid-term efforts CHINA REFORMS federation of Indian Industry (CII). need to be geared toward, among other Meanwhile, some industry experts men- India accounts for 20% of the global things, nurturing entrepreneurship in the tioned how ongoing reform in China could disease burden and in addition to com- bulk-drug industry and establishing a con- work in India’s favor in the API segment, if municable diseases such as malaria and ducive ecosystem of policies, regulations only the industry and government could tuberculosis, the growing numbers for non- and financial incentives. operate in tandem to seize the opportunity. communicable diseases (NCDs) pose addi- Industry experts, however, lamented that Dilip Shah, secretary general of the In- tional health care challenges. NCDs account although there has been long-running dis- dian Pharmaceutical Alliance (IPA), told Scrip for about 60% of all deaths in India. cussion around the dire situation in the Indian that with the China Food and Drug Admin- The KPMG-CII report, released Dec. 20, API segment, not much real on-ground impe- istration (CFDA) joining the International notes India’s heavy reliance in 2016 on Chi- tus has been provided by the government. Council for Harmonization (ICH) as a new nese imports for both APIs as well as key in- India’s 2017 draft pharmaceutical policy regulatory member, and the Pharmaceuti- termediates such as 6APA (100%), penicillin outlines measures to encourage end-to- cal Inspection Co-operation Scheme (PIC/S) (98.5%) and ciprofloxacin (99%) in the anti- end indigenous drug manufacturing, in- as a new observer, it will mean greater en- biotics segment. Dependency on Chinese cluding that of APIs and their precursor forcement and compliance requirements in API imports was also as high as 98% and intermediates, though some experts told China. This, in turn, will add to costs for some 100% for drugs such as and losartan, Scrip that quite a few of these measures are players and force others to shut down. respectively, in the cardiovascular segment “not really workable.” Shah said that this could “disturb” the tradi- with similar high reliance for metformin and In 2015, an Indian expert committee tional Chinese advantage, providing oppor- glimepiride (diabetes) and isoniazid and headed by V. M. Katoch, a former director tunities for Indian manufacturers to make streptomycin (tuberculosis). India had an es- general of the Indian Council of Medical Re- APIs from the basic stage and look at alterna- timated 64m cases of cardiovascular disease search and secretary, department of health tive sources. “It may be a blessing in disguise,” and around 69m cases of diabetes in 2015. research, had recommended a raft of mea- Shah said, but emphasized that the Indian Public health emergencies may require sures to revive and promote the production government should look into the issue of large quantities of specific drugs to be made of APIs in the country, including the “judi- APIs on “mission mode” and also ensure the available in a short timeframe and the report cious and liberal” use of anti-dumping du- commercial viability of any plans. India had cautions that a foreign supplier of APIs “may ties and safeguards. earlier joined ICH as an observer. not be as responsive” to immediate public However, India’s Department of Pharma- China’s joining ICH was in the spotlight health demands as local producers. “The in- ceuticals (DOP) viewed the implementation earlier this year. Theresa Mullin, director of US ability to procure certain medicines could of the Katoch committee recommendations FDA’s Office of Strategic Programs in the Cen- lead to a national health crisis,” it notes. in a fixed timeframe as untenable, accord- ter for Drug Evaluation and Research, noted India imported nearly 272m kg of bulk ing to local media reports in June. The gov- in an August blog post that discussions with drugs and intermediates valued at nearly ernment at that time indicated that it was the CFDA revealed that it faces many of the $2.8bn in 2016. China alone is said to account looking into the issue of duty structure, as- same challenges that other ICH partners and for around 70% of such imports by value. Cut- sistance to bulk-drug parks and interest-rate the FDA do. China needs to ensure that pa- price imports from China have led to a gradu- support to the industry, and trying to obtain tients have access to innovative products, al erosion of India’s bulk drug manufacturing necessary approvals for providing funds. An and that pharmaceuticals are safe and held capacity, with several sites closing. umbrella scheme was being prepared, with- to a consistent quality standard, she added. Ravind Mithe, partner, strategy and opera- in which assistance to the bulk-drug indus- The blog post also pointed out that new tions, management consulting, KPMG in In- try for common facilitation would be a sub- ICH members are required to, among other dia, called for “urgent interventions” from the scheme, the DOP is reported to have said. criteria, implement a basic set of regulatory government as well as industry given the The Chinese industry, on the other hand, requirements for the manufacture of phar- strategic nature of India’s dependence on is known to be backed by strong policy sup- maceuticals, for the conduct of clinical trials its Asian neighbor. “Such high dependency port and other incentives from the govern- and for stability testing of pharmaceutical means that any disruption in the supply ment to set up mega API clusters that create products. of APIs can potentially result in significant economies of scale. While China’s labor cost Published online 22 December 2017

30 | Scrip | 5 January 2018 © Informa UK Ltd 2018 EMERGING MARKETS

Bumpy Ride Awaits Indian Firms In 2018 (And Then There’s Amazon) ANJU GHANGURDE [email protected]

otential turbulence on home turf and an uptick in the inten- Kaul believes that the impact of price-capping will be more on sity of competition on the US market could make 2018 quite healthcare services companies rather than pharmaceutical firms. Pa tough year for Indian firms to navigate – at least that’s the However, even the services firms, he says, will “adjust” prices by charg- general forecast of key industry experts. ing more for the service versus the product (most hospitals have al- Compounding the challenge is the Amazon factor that could ready tweaked their pricing, he points out) so that a ceiling price on mean widespread disruption in the US market, a key contributor to a device does not hamper their profitability. revenues for several frontline Indian firms, although the online retail 2017 witnessed the contentious capping of prices of stents and giant has not publicly confirmed its intent to enter the US prescrip- then knee implants in India, which set off a chain of events including tion drug arena yet. the US medical device lobby group AdvaMed seeking the interven- Dilip Shah, secretary general of the Indian Pharmaceutical Alliance tion of the US Trade Representative. (IPA), which represents leading domestic firms, said that the “single Kaul also predicts the rise in AYUSH [ayurveda, yoga and naturopa- minded pursuit” of “access at affordable prices” by the Indian govern- thy, unani, siddha and homoeopathy], nutraceuticals and cosmeceu- ment and “complete disregard” for promotion, development and ticals in the Indian market. “While the pharma market stabilizes post growth of the industry could have “major adverse impact” on the GST [Goods and Service Tax] trade disruptions, the biggest growth growth and sustainability of the Indian pharmaceutical industry in 2018. will come from ayurvedic, nutraceutical and cosmeceutical products “These pursuits include generic prescribing, drug substitution, the thanks to the rising middle class and increasing GDP per capita.” GST pricing regulator’s activism and amendments to India’s Drug Prices was implemented with effect from July 2017 and has been dubbed Control Order (DPCO), 2013,” Shah told Scrip. as the biggest tax reform since India’s independence. GST replaces There has been significant debate in 2017 around the govern- most indirect taxes currently in place and eliminates a multiplicity of ment’s plans to consider a potential legal frame under which phy- taxes and their cascading effect in the country. sicians in India will have to prescribe medicines by their generic Danssen Consulting’s Dangi, a former president and executive di- names only. (Also see “India Premier Pushes For Generic Prescriptions rector of Johnson and Johnson India, also said that India’s draft phar- But Hurdles Loom” - Pink Sheet, 4 May, 2017.) Dr Ajit Dangi, president ma policy 2017, which proposes to rein in contract manufacturing, and CEO of Danssen Consulting, noted that the generics-only diktat if implemented, would be a “major blow” to both Indian as well as is a “worrisome development” for companies that have successfully multinational companies. built strong brands in spite of intense competition in a market “clut- “There is substantial spare manufacturing capacity in the industry tered with hundreds of me-too brands.” and if this recommendation goes through, it will significantly increase Besides, a poll-bound India could mean that “political expediency manufacturing cost and also affect SMEs [small and medium-sized will dictate populist measures,” IPA’s Shah said. India heads into gen- enterprises] which form the bulk of contract manufacturers,” Dangi eral elections in 2019. maintained. (Also see “OPPI Chief Vaidheesh On Burning Industry Issues A top executive of a leading multinational concurred that health In India” - Scrip, 4 Dec, 2017.) is part of the political agenda, but maintained that was also “good,” since health will be accorded the much-needed importance it de- US REFORM, FDA ACTION But it’s probably the US market – in the backdrop of reform propelled serves. He noted that while patient-centric policies and announce- by the FDA – that could potentially tip the growth scales one way or ments are welcome, there are several research studies, including the the other for Indian firms. IMS Study in 2013 on Healthcare Access in India, that shows that the IPA’s Shah says that US protectionist policy, as manifested in tax real barrier to access is the inability to pay out-of-pocket and the lack reforms and ‘Make in America’ efforts, could have a powerful impact of insurance cover. on industry. In addition, FDA reforms, he indicates, could be a mixed bag. “They PRICE CAPS, CONTRACT MANUFACTURING would on one hand benefit the generic industry by more action in Unsurprisingly, pricing is expected to stay a prominent theme in area like REMS [Risk Evaluation and Mitigation Strategy], but also hurt 2018, though it remains to be seen if things could be as acrimoni- on the other by quicker approval of ANDAs bringing in intense com- ous as in 2017. (Also see “India’s Pricing Tussle Escalates After Regulator petition,” Shah maintained. The FDA has been keen to deal with REMS Names “Overcharging” Firms” - Pink Sheet, 12 Apr, 2017.) abuses that block generic entry. Sanjiv Kaul, partner at the private equity firm, ChrysCapital, told Kaul too anticipates an increase in competition in the US Scrip that while price-capping is “here to stay” as it is the “only ef- through quicker ANDA approvals; smaller players will not stop fective policy” that the government can implement in the short filing ANDAs as they have already invested in manufacturing term, such fixing of prices will only be for drugs and devices that are plants and R&D, he says. The FDA has been working to prune the deemed essential, such as in the oncology, nephrology and cardio- vascular segments. CONTINUED ON PAGE 32

scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 31 HEADLINE NEWS/EXECUTIVE INTERVIEW

CONTINUED FROM PAGE 31 number of review cycles necessary for an ANDA approval. He also sees a shift in Profile: Novartis’ Gildea On Stable focus from revenues to EBITDA [earnings before interest, taxes, depreciation and Girl Grit And Drones amortization] for larger generics players. ANJU GHANGURDE [email protected] “Teva has already announced major cuts in expenses and in the tail-end products. Ex- Deborah Gildea pect other large generics [firms], including Indian peers, to follow suit,” Kaul declared.

AMAZON EFFECT Significantly, all the expertsScrip reached out to recognize the disruption that a po- tential entry of Amazon in the US prescrip- tion drugs space could bring. Shah suggests that an Amazon entry may appear beneficial in the short term, but could turn “painful” as the online retail giant acquires “muscle power” to negotiate bulk purchases. Dangi underscores that major disruption and competition in the pharmaceutical in- dustry is not going to come from other drug firms but from the “Googles and Amazons of the world.” “These companies will depend more and more on technology and digitization to dis- eborah Gildea’s early days as a stable DEBORAH GILDEA: I worked as a stable rupt the market not only affecting the logis- girl probably provided some useful girl from when I was 12 until I went to uni- tics and supply chain but also diagnosis and Dgrounding on compassion and the versity. On Sundays, I would be in sole charge cure by bringing healthcare to one’s door- significance of money. Some of that expo- of the horses and I needed to cycle several step,” he said. sure also perhaps helps her navigate the miles to get there come rain, snow or wind. Kaul believes that Amazon, and perhaps tightrope between social and commercial This gave me a strong sense of responsibil- more importantly, CVS-Aetna, will re-define metrics as head (APAC) of Novartis’ Social ity and the pocket money I earned provided the pharma supply chain in the US. This, he Business. increased independence. notes, will have a larger impact on brand- In an interview with Scrip, Gildea com- ed/patented products as innovators will mends GlaxoSmithKline PLC ‘s former AG: Who was your biggest influence, and not be able to command the market and chief executive for his role why? distributors will push for more and faster in changing the access to medicines para- DG: The woman I worked for [as a genericization (already 75% by volume, he digm in the pharmaceutical industry. She youngster at the stable] was super or- estimates). (Also see “CVS/Aetna To Merge In supported the development of GSK’s ac- ganized and I guess this rubbed off. She Defensive Play To Reshape Health-Care Deliv- cess to medicines strategy in 2010 and also taught me that in life you always ery” - Medtech Insight, 4 Dec, 2017.) moved to Asia to lead its implementation have a choice in any situation. Always “It would be really interesting if Ama- across emerging markets. The soft-spoken recognizing the choice, no matter how zon also vertically integrates to acquire (or but firm Gildea was GSK’s general manag- unpalatable, puts you in the driving seat partner with) a manufacturer – that would er, developing countries Asia (Cambodia, no matter what the twists and turns of change the entire ball game,” Kaul said. Laos, Myanmar and Papua New Guinea) life may bring you. The MNC executive quoted previously, prior to joining Novartis in 2017. however, offers a word of caution. He speci- Gildea, who was in India recently as AG: Who do you admire in the industry, fies that while no sector seems “safe” as Am- Novartis’ for-profit social business initia- and why? azon explores unchartered territory, those tive, Arogya Parivar, completed a decade DG: The person I most admire in the in- expecting Amazon to rush into healthcare of operation, also discussed how digital dustry is Sir Andrew Witty. The drive and may need to press a pause button as the platforms and drones could help improve commitment that he has given to access online retail giant will have to watch out for access to healthcare. to medicines has changed and challenged regulatory risks so that it does not “taint its everyone in the industry to think different- reputation” in any way. ANJU GHANGURDE: What are the key ly, focusing attention on the 5 billion who Published online 28 December 2017 things that shaped you when growing up? still struggle to access good healthcare.

32 | Scrip | 5 January 2018 © Informa UK Ltd 2018 EXECUTIVE INTERVIEW

AG: The more challenging role of the two: DG: I would follow my parents’ example DG: I would like to see the social busi- being APAC head of Novartis’ social busi- and run a small business of my own, al- ness become a sizable part of Novartis in ness or mother? though my business idea keeps changing! all low- and middle-income countries. My DG: Both roles have their moments! How- ambition is also to create a talent pipeline AG: What has your proudest moment ever, becoming a mother has been the for the wider business. This is an extremely been in corporate life? best personal development investment complex and challenging area to work in that I have ever made. It has made me DG: Having two of my team selected for which provides rapid development op- more self-confident, patient and unruffled a prestigious 18-month global develop- portunities for people with the right mind when things don’t go smoothly. Parent- ment program [in GSK]. There were only set and energy. As we become even more successful I hood is also a wonderful bridge to con- 10 places available across the whole of would expect other players to enter this nect with the many people that I get to Africa and Asia. I would love to make a space. This is very healthy for us and it will meet in the course of my work. When you similar impact on my team’s develop- stop us from becoming complacent. sit and talk together, you soon come to ment in Novartis. realize that every parent wants the same AG: One change you effected in your com- AG: Non-traditional players like Google, things for their children - for them to be pany (in GSK or Novartis) that you believe is Apple and Amazon could potentially re- safe, healthy and able to access education. important/invaluable? shape various aspects in the phama sec- I feel very fortunate to have been born in a DG: I was fortunate enough to be part tor including areas like social business. country where it is easier to provide these of the three-person team that developed Do you expect to harness some of this for my child. the Access to Medicines strategy for GSK potential? AG: One on-ground learning in markets soon after Andrew Witty became CEO. I DG: I believe that social media has tre- like Cambodia, Laos, Myanmar, Papua then got the opportunity to implement mendous potential to provide patients New Guinea, India and across your numer- the strategy at a regional level and to set with essential information and to link ous career roles that has always stayed up a country from scratch. them to qualified HCPs. We are already with you? experimenting with a new approach in AG: The term social business, some may the Philippines that has a digital platform DG: The barriers to accessing medicines say, is a bit of an oxymoron. What are three as its backbone. The data that has been are consistent across all the markets that key essentials you believe are sacrosanct to gathered so far is providing new insights I have worked in. The questions that you ensure a balance between doing good for into patients’ needs at a community lev- need to ask are: Do patients understand community and for the company? el. This helps us to provide very targeted that they have a disease than can be DG: We always start by providing health health education. The next phase will be treated (if it is acute) or managed (if it is education first. As we learn about com- to find novel ways to make medicines a chronic condition)? Do the medicines munity’s needs we then look to find ways available to communities who tradition- that the patient needs fit within the pa- to make our activities self-sustaining. ally have little/no supply. We are looking tient’s lifestyle, beliefs and the healthcare Separating health education from our at numerous options including e-pre- system that is available? Are the medi- commercial activities ensures that our scriptions and the use of drones. cines available in the community where health educators and the doctors who the patient lives? Is the medicine afford- AG: One myth about the pharma industry volunteer at our health camps are free to able for the patient? And is the patient and top women executives in the corpo- focus on the needs of patients. At a coun- able and willing to take the medicine for rate world that you’d like to set straight? try head/area level we focus on a mixture as long he/she needs? The relative impor- of social and commercial metrics. To be DG: The belief that price is the only tance of each barrier can vary from mar- successful, both sets of metrics need to barrier to patients being able to access ket to market but you need to address be achieved. medicines. We need to address the full them all if you want to improve access to ecosystem if patients are to be able to medicines for patients. AG: Where and how do you see Novartis’ access healthcare no matter where they social business in five years…a bigger can- live in the world. AG: How do you step back and get per- vas, more players or more challenges? Published online 27 December 2017 spective? DG: This is very humbling work. Each time I go and sit with some patients I am reminded how fortunate I am and how much more there is to do. As a team, we LET’S GET SOCIAL focus on making small sustainable differ- We are tweeting, liking and sharing the latest industry news and ences rather than pretending that there is a magic bullet solution. insights from our global team of editors and analysts, join us!

AG: If you weren’t a pharma executive, @PharmaScrip what would you be? scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 33 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 two weeks 15–28 December 2017

LEAD COMPANY/PARTNER COMPOUND INDICATION COMMENTS Phase III Results Published skin and skin structure Motif Bio PLC iclaprim (iv) REVIVE-1; Clinical Infectious Diseases, Dec. 21, 2017. infections Simplify 2; The Lancet Haematology, Gilead Sciences Inc. momelotinib myelofibrosis Dec. 20, 2017. Roche Tecentriq (atezolizumab) bladder cancer IMvigor211; The Lancet, Dec. 18, 2017. Avycaz (ceftazidime plus hospital acquired Allergan PLC REPROVE; The Lancet, Dec. 15, 2017. avibactam) pneumonia FOCUS4-D; The Lancet Gastroenterology & AstraZeneca PLC AZD8931 colorectal cancer Hepatology, Dec. 15, 2017.

Phase III Interim/Top-line Results Revlimid (lenalidomide) indolent non-Hodgkin’s RELEVANCE; not superior to chemotherapy Celgene Corp. plus rituximab lymphoma regimen. upadacitinib, an oral JAK1 AbbVie Inc. rheumatoid arthritis SELECT-MONOTHERAPY; met all endpoints. selective inhibitor Gedeon Richter PLC/Allergan PLC Vraylar (cariprazine) bipolar I depression RGH-MD-54; positive results. gastric cancer as Merck & Co. Inc. Keytruda (pembrolizumab) KEYNOTE-061; missed primary endpoint. second-line therapy Hunter syndrome and SHP609 (idursulfase) by Missed endpoints; no impact on iv use in current Shire PLC cognitive impairment in intrathecal administration Hunter syndrome indications. children

Phase III Initiated CONTESSA; an oral taxane for locally advanced Odonate Therapeutics LLC tesetaxel breast cancer or metastatic disease. anemia due to chronic Bayer AG molidustat, oral MIYABI ND-C and ND-M; non-dialysis patients. renal failure Poxel SA/Sumitomo Dainippon imeglimin diabetes, type 2 TIMES 1; in Japan. Pharma Co. Ltd. Diffusion Pharmaceuticals Inc. trans sodium crocetinate glioblastoma INTACT; in newly diagnosed inoperable disease. ofranergene obadenovec VBL Therapeutics (VB-111), anticancer gene ovarian cancer OVAL; in platinum- resistant disease. therapy mobilizing stem cells in GENESIS; in addition to G-CSF in transplant BioLineRx Ltd. BL-8040 multiple myeloma patients. Biohaven Pharmaceuticals Holding obsessive-compulsive trigriluzole At 35 sites in the US. Co. Ltd. disorder Minerva Neurosciences Inc. MIN-101 schizophrenia For negative symptoms. Incyte Corp. epacadostat renal cell cancer KEYNOTE-679/ECHO-302; as first line therapy. Novo Nordisk AS Tresiba (insulin degludec) type 1 diabetes EXPECT; in pregnant women.

34 | Scrip | 5 January 2018 © Informa UK Ltd 2018 PIPELINE WATCH

VBI Vaccines Inc. Sci-B-Vac vaccine hepatitis B PROTECT, CONSTANT; a third-generation product.

Phase III Announced Verrica Pharmaceuticals Inc. VP-102 molluscum contagiosum A double-blind study. Associated with age-related macular Apellis Pharmaceuticals Inc. APL-2 geographic atrophy degeneration. phenylephrine plus Eyenovia Inc. mydriasis MicroStat; to dilate pupils. tropicamide Eyenovia Inc. MicroProst (Gla203) glaucoma a micro-formulation of a prostaglandin.

Updated Phase II Results Abivax ABX464 HIV/AIDS ABX464-005; HIV reservoir reduction observed. ASN-002, interferon- nodular basal cell Ascend Biopharmaceuticals Ltd. Clinical responses seen. gamma gene therapy carcinoma

Phase II Completed RXI-109, a self-delivering RXi Pharmaceuticals Corp. wound healing Improved scar appearance, well tolerated. RNAi

Phase II Interim/Top-line Results Kevetrin (thioreido- Innovation Pharmaceuticals Inc. ovarian cancer Modulates p53 protein, anticancer effects seen. butyroanitrile) UCB SA bimekizumab psoriatic arthritis BE ACTIVE; skin and joint symptoms improved. GC4419, a dismutase severe oral mucositis in Galera Therapeutics Inc. Reduced symptoms. mimetic head and neck cancer Source: Biomedtracker

APPOINTMENTS

Neurotrope Inc. has appointed Charles Ryan CEO, effective Feb. wholly-owned CDMO subsidiary, Avid Bioservices. Before that, Liais 15, 2018, following the resignation of Susanne Wilke. Ryan served was executive director, head of global biologics business develop- as senior vice president and chief intellectual property counsel at ment at Allergan PLC. Lias succeeds Steven King, who has resigned Forest Laboratories for more than 10 years, and is currently presi- as president and CEO to pursue other professional interests. dent and CEO of Orthobond Corp. Neurotrope is evaluating bry- ostatin-1 in a Phase II study for advanced Alzheimer’s disease, and is Allergan PLC has promoted Wayne Swanton to executive vice conducting preclinical studies of bryostatin for Fragile X syndrome, president, global operations following notification thatRob Stew- Niemann-Pick type C disease, and Rett syndrome. art, executive vice president and COO, was leaving. Swanton will join Allergan’s leadership team and will maintain responsibility for Concert Pharmaceuticals Inc., the US biopharma company cre- global manufacturing, quality, supply chain, procurement, pharma- ating a pipeline of deuterated new medicines, has appointed Marc ceutical technology, operational excellence, engineering, environ- Becker as CFO, effective Jan. 4, 2018. Before joining Concert, Becker mental health and safety, and security. was senior vice president and CFO at CRISPR Therapeutics, and be- fore that was CFO and senior vice president of r4EVO Biologics. Following his departure from Allergan, Rob Stewart is joining the US generics company, Amneal Pharmaceuticals LLC, as president, Timothy Crew has been named CEO of the Philadelphia-head- and will become President and CEO of Amneal Pharmaceuticals Inc. quartered generics firm, Lannett Co. Inc., effective Jan. 2, 2018, when the merger of Amneal and Impax Laboratories Inc. is com- succeeding Arthur Bedrosian. Crew was most recently CEO of Cipla pleted. Paul Bisaro, the president and CEO of Impax, will become North America, and before that he was senior vice president and executive chairman. Amneal’s co-CEOs and co-founders, Chirag and commercial operating officer at the North American generics divi- Chintu Patel, will serve as co-chairmen of the combined company’s sion of Teva Pharmaceuticals. board of directors.

Tustin, California-based Peregrine Pharmaceuticals Inc., which is Acticor Biotech, the 2013 spin-off from France’s governmental transitioning from an R&D-focused business to a pure-play contract research institute, Inserm, which is developing a monoclonal an- development and manufacturing organization (CDMO), has ap- tibody fragment for the acute treatment of ischemic stroke, has pointed Roger Lias as president and CEO; Lias is currently a board named Yannick Plétan chief medical officer. Plétan was formerly director of Peregrine, and since Sept. 2017 has been president of its head of the medical division at Roche in France. scrip.pharmaintelligence.informa.com 5 January 2018 | Scrip | 35 February 12-13, 2018 CE NVESTOR New York Marriott Marquis CONFERENCE

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