An About Face As Biogen Says It Will File Aducanumab in Alzheimer's

No. 3979 November 1, 2019

early 2020. Discussions with regulators in Europe and Japan are in earlier stages. However, it is by no means clear the drug will skate through the FDA approval process, and even if it is approved, and how patients, physicians and payers might weigh the potential cost of the drug against what could be viewed as in- cremental efficacy. Nevertheless, investors were impressed with the revival of aducanumab, sending Biogen’s stock up 26.1% to close at $281.87 after the company’s announcement. Biogen discussed the updated EMERGE and ENGAGE results with the FDA in June and the agency confirmed that the data could support a BLA submission based on those data without the need for any additional studies a day before the company’s earnings call, Samantha Budd Haeberlein, vice presi- An About Face As Biogen Says It Will dent of late-stage clinical development, told Scrip in an interview. File Aducanumab In Alzheimer’s “As of the conversation with the FDA yesterday, they recognized that the data MANDY JACKSON [email protected] set we have was reasonable to go ahead with a filing,” Haeberlein said. “Had they iogen’s unexpected decision to did have an impact on the clinical decline wanted to, they could’ve told us already, pursue US Food and Drug Admin- associated with Alzheimer’s disease in a ‘Now Biogen, we believe you need to do Bistration approval for its previously dose- and time-dependent fashion. another study,’ and they have not done so.” discontinued amyloid-targeting biologic “In retrospect, the result of our fu- aducanumab in Alzheimer’s disease was tility analysis was incorrect. Based on EMERGE DATA SIGNIFICANT met with skepticism given the surprising what we know now, it is clear that the WITH SUPPORT FROM ENGAGE nature of the turnaround. pre-specified futility criteria did not ad- Biogen and Eisai contend that the previ- Biogen and partner Eisai Co. Ltd. said equately anticipate the effect of all the ously failed EMERGE trial is now a success in March that an interim futility analysis variables in these trials,” Biogen CEO with the highest dose of aducanumab showed little chance that the Phase III Michel Vounatsos said during the com- showing a statistically significant improve- EMERGE and ENGAGE clinical trials for pany’s earnings call. ment in the study’s primary endpoint, the aducanumab would meet their primary After working with external experts Clinical Dementia Rating-Sum of Boxes endpoints. However, Biogen executives and consulting with the US FDA it was (CDR-SB). The scale determines the sever- explained on 22 October during the com- determined that the updated data from ity of dementia based on assessments of pany’s third quarter earnings conference EMERGE and ENGAGE as well as results memory, orientation, judgment and prob- call that further analysis of the studies from Phase I/Ib trials justify submission of lem solving, community affairs, home and involving more patients treated at the a biologic license application (BLA), which hobbies, and personal care. highest aducanumab dose show that it Biogen intends to file with the agency in CONTINUED ON PAGE 4

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Zolgensma Quick Off The Blocks BMS Boost Good Week For Vertex Novartis reports healthy early Unexpected early study New triple drug approval sales for the gene therapy (p8) hit for Opdivo/Yervoy (p18) plus an NHS deal (p12-13) IN THIS ISSUE

from the editor [email protected]

We don’t usually celebrate Halloween at Scrip Towers, The company now says the FDA will let it file for approv- but this year a pharma zombie has made it onto our al without doing a new study. Biogen’s explanation that front cover. The dust had appeared to have settled on the futility criteria were wrong and that newer data sup- the disappointing news that Biogen and Eisai had given port an FDA filing left many scratching their heads. We up on their amyloid-beta targeting antibody aducanum- will have to wait until the detailed data presentations at ab. As one of the last in a long line of Abeta failures in the CTAD meeting in San Diego in early December for Alzheimer’s disease from several industry heavyweights, greater clarity. For now, the cloak of skepticism remains few were surprised in March when it was revealed that in place. the product had fallen foul of a Phase III interim futility Meanwhile, bitter negotiations were finally conclud- analysis and would be culled from the pipeline. ed in the UK last week. A stalemate that dated back The surprise came, instead, last week, when the drug to 2016 was breached when Vertex and NHS England lurched back from the grave, less than a month after each made compromises to agree a reimbursement Biogen’s R&D head Michael Ehlers moved onto fresh deal that will give thousands of cystic fibrosis patients pastures, ceding R&D leadership to long-standing chief access to life-changing treatments (see p13). Lessons medical officer and aducanumab enthusiast Al Sandrock. for Brexit, anyone?

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2 | Scrip | November 1, 2019 © Informa UK Ltd 2019 7 Takeda Takes On Celiac Disease Seattle Genetics Poised For Launch AZ Sales Boost

20 11 20

exclusive online content inside: COVER / An About Face As Biogen Says It Will File Alzheimer’s Biomarker Benefit Aducanumab In Alzheimer’s From Failed Janssen BACE Inhibitor? 5 Lilly’s Diabetes Franchise Poised For IAN HAYDOCK [email protected] A Shakeup As Conterno Steps Down

7 AstraZeneca: ‘Firing On All Cylinders’ In Q3

8 Novartis’s Zolgensma Finds Commercial Legs In A First For Gene Therapy

9 Gilead Says Sluggish Yescarta Business Will Continue To Fluctuate

10 Alkermes Restructures, Prioritizing CNS And Oncology And Cutting 160 Employees

11 FTC Closer To Clearing Roche’s Spark Buy: Report

11 Takeda Adds Celiac Disease Candidate To GI Efforts Given the recent and continuing clinical setbacks in the field, Alzheimer’s sufferers and their carers may be encour- 12 Vertex Trikafta Approved As First Triple Combo aged by a new collaboration to help identify biomarkers For Cystic Fibrosis With $311,503 Price Tag for the early detection and monitoring of the disease. 13 Vertex Finally Inks Orkambi Deal In England Janssen Pharmaceutical Cos. and Japanese firm Shion- ogi & Co. Ltd. unveiled during an 18 October summit in 16 AstraZeneca’s Farxiga Approval In Heart Failure Tokyo of the World Dementia Council, an international A First For SGLT2 Inhibitors charity, that they would work with the Alzheimer’s Drug Discovery Foundation (ADDF) to provide broad access to 18 J&J’s Spravato Set For EU Launches Soon clinical samples. The agreement will involve the global provision, free of 18 An Early Surprise Win For BMS’s Opdivo/Yervoy charge, by the two pharma companies and foundation to In Lung Cancer all researchers globally of tissue and blood samples from their now discontinued development program for BACE 20 Seattle Genetics Poised For Big Breast Cancer Launch inhibitors. On Positive Tucatinib Data “Our goal is to fast-track programs to prevent, treat and ultimately cure AD,” ADDF chief science officer Dr Howard 21 Novartis’s Fevipiprant Hit By Phase III Asthma Failure Fillit said. Janssen confirmed in July that it had halted fully the 22 Pipeline Watch clinical development of the BACE inhibitor atabecestat (li- 23 Appointments censed from Shionogi), after elevated liver enzymes were observed in some patients in late-stage studies. Published online 24 October 2019 To read the rest of this story go to: https://bit.ly/2onQBsh @PharmaScrip /scripintelligence

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scrip.pharmaintelligence.informa.com November 1, 2019 | Scrip | 3 HEADLINE NEWS

CONTINUED FROM PAGE 1 Activities of Daily Living Inventory Mild The interim futility analysis conducted Cognitive Impairment Version (ADCS- on 26 December was a pooled analysis of ADL-MCI; 40% versus placebo, p=0.001). data from 1,748 patients enrolled in both Brain imaging of patients enrolled in studies who completed the 18-month EMERGE also showed that low and high treatment period, but the new analysis doses of aducanumab reduced amyloid covers 3,285 patients, including 2,066 plaque deposits in the brain versus pla- who completed 18 months of treatment “We continue to believe cebo at 26 and 78 weeks (p<0.001), which as of 20 March. was supported by biomarker data of tau Patients treated with the highest the devil’s in the details levels in the cerebrospinal fluid (CSF). monthly dose of aducanumab – 10mg/kg and await further clarity ARIA with edema (ARIA-E) and head- – in EMERGE had a statistically significant ache were the most common adverse 23% reduction versus placebo in terms on the full data set.” – events associated with aducanumab of clinical decline from baseline at 18 across both Phase III studies, but most months based on CDR-SB scores (p=0.01). Laura Chico patients with ARIA-E did not experience Patients treated with the highest dose of symptoms and the ARIA-E episodes gen- aducanumab in ENGAGE did not have erally resolved within four to 16 weeks, statistically significant changes in CDR-SB usually without long-term effects. scores versus those who received a place- Haeberlein said that in addition to the bo, but the results “supported the findings high-dose efficacy of aducanumab in of EMERGE,” Biogen said. EMERGE, she is encouraged by the fact William Blair analyst Matt Phipps said that “we have these biomarkers that are in a 22 October note that it is “difficult to enced the side effect and to allow dos- showing us that we are removing the pa- gauge the likelihood of FDA approval” ing up to 10mg/kg in ApoE4 carriers. And thology in the brain and we are slowing for aducanumab, but he pointed out that since ENGAGE began enrolling patients a down the death of neurons as measured “the FDA’s recent track record has allowed month before EMERGE, fewer patients in by the neuronal markers in CSF. I think more subgroup analysis in considering ef- ENGAGE received the high dose for long that data set is a very compelling data set, ficacy, and the unmet need in Alzheimer’s enough to show significant efficacy, the never previously seen for any treatment in disease remains significant.” company explained. Alzheimer’s disease.” Jefferies analyst Michael Yee said in a “With other dose levels not reaching Aducanumab is the first amyloid-tar- same-day note that it makes sense for Bio- significance on cognitive function, and geting agent to get into the brain at high gen to seek approval given all of the work the ENGAGE study failing to meet its pri- enough levels to clear significant amounts and money the company and Eisai have mary endpoint, we continue to believe of amyloid and show dose-dependent ef- put into aducanumab, and based on the the devil’s in the details and await further ficacy in patients, Haeberlein explained. unmet need in Alzheimer’s, but he noted clarity on the full data set,” Wedbush Se- She said Biogen designed its trials, in- that the difference in efficacy for patients curities analyst Laura Chico wrote in a 22 cluding EMERGE and ENGAGE, to enroll receiving the high dose in EMERGE versus October note. patients with confirmed amyloid plaques ENGAGE is troubling. Biogen and Eisai intend to present whose disease hadn’t progressed so much detailed EMERGE and ENGAGE data at that they wouldn’t respond to treatment. STUDY PROTOCOL CHANGES the Clinical Trials in Alzheimer’s Disease BLAMED FOR DATA DIFFERENCES (CTAD) meeting from 4 to 7 December in ANALYSTS REMAIN SKEPTICAL Biogen is attributing the difference in the San Diego. Detailed PRIME results were ABOUT APPROVABILITY two studies to changes in the clinical trial presented at CTAD in December 2016, Nevertheless, Bernstein analyst Ronny Gal protocol for carriers of the ApoE4 gene – also in San Diego. and SVB Leerink’s Geoffrey Porges were a genetic marker that relates to early on- skeptical in separate 22 October notes set and rapid progression of Alzheimer’s MULTIPLE DATA POINTS GIVE that the results of these studies would be disease. These patients originally were BIOGEN, EISAI CONFIDENCE enough to garner FDA approval for adu- treated with aducanumab doses only as The companies did note that other mea- canumab. high as 6mg/kg in EMERGE and ENGAGE, sures of clinical decline also showed “We believe this data will be heavily because ApoE4 carriers treated with the consistent reductions versus placebo scrutinized by the scientific community, drug in the Phase Ib PRIME study were for patients treated with high-dose as it conflicts with the broader set of data more likely to develop amyloid-related aducanumab in EMERGE, including the about the amyloid mechanism so far,” Gal imaging abnormalities (ARIA). Mini-Mental State Examination (MMSE; wrote. “However, it seems Biogen’s argu- However, the EMERGE and ENGAGE 15% versus placebo, p=0.06), the AD As- ment is simply that the dose and duration protocols were changed several months sessment Scale-Cognitive Subscale 13 of therapy were simply not high and long into the studies to allow re-dosing after Items (ADAS-Cog 13; 27% versus placebo, enough to see the change [in the interim ARIA resolved in patients who experi- p=0.01), and the AD Cooperative Study- futility analysis].”

4 | Scrip | November 1, 2019 © Informa UK Ltd 2019 HEADLINE NEWS/Q3 RESULTS

“We do note, however, that Biogen was always very bullish on to a torturous discussion of data, statistics, endpoints, exposure, amyloid-beta, so if we have one concern, is that they may be too treatment effects and safety liabilities. It will probably NOT include optimistic,” he added. a discussion of the massive societal and economic cost of going Indeed, Biogen and Eisai continued to study two additional am- further down this rabbit hole of marginal treatment effects in such yloid-targeting candidates after the Phase III aducanumab studies a widespread and catastrophic disease.” were discontinued. The partners had the last beta amyloid cleav- Biogen will continue to test its new aducanumab hypothesis by ing enzyme (BACE) inhibitor in the clinic after 16 prior failures in reinitiating treatment for patients who were enrolled in the now- the BACE class, until they discontinued the Phase III studies for discontinued Phase III studies and the PRIME long-term extension elenbecestat in September. Phase III studies for the companies’ trial in a re-dosing study. third partnered asset, the anti-amyloid-beta protofibril monoclo- It’s unclear whether the new strategy for aducanumab had nal antibody BAN2401, are ongoing. anything to do with the recent departure of former Biogen execu- Porges noted that the critical question for aducanumab’s future tive vice president for research and development Michael Ehlers, “will be what reassurance the company has received from the but CEO Vounatsos emphasized that “Mike decided to leave the FDA. This could range from ‘the agency has reviewed all the data company on his own.” The CEO expressed his confidence in the with us and has guaranteed approval’ to ‘you can file whatever abilities of chief medical officer Alfred Sandrock, who has taken you want and we’ll review it.’” over the EVP for R&D role in addition to his CMO duties. (Also see “Unfortunately, investors will not be privy to where between “R&D Head Ehlers Bows Out As Confidence In Biogen’s Pipeline Suf- those two extremes the agency-company interactions have fers From Setbacks” - Scrip, 1 Oct, 2019.) been,” he continued. “Regardless, this filing will now come down Published online 22 October 2019 Lilly’s Diabetes Franchise Poised For A Shakeup As Conterno Steps Down

JOSEPH HAAS [email protected]

li Lilly & Co. paired its third quarter of Trulicity (dulaglutide) and Jardiance earnings call with news of a big lead- (empagliflozin), helping to position Lilly Eership change. Longtime diabetes as a sales-volume leader during that time. executive Enrique Conterno will be retir- (Also see “Lilly Rides To Solid First Quarter ing at year’s end, to be succeeded by a fel- On Diabetes, Newer Products” - Scrip, 24 low Lilly veteran, Mike Mason. Apr, 2018.) Serving most recently as president of Ricks listed those two drugs and Basa- Lilly Diabetes, Conterno has had a pivotal glar (insulin glargine injection) as among reporting that sales volume increased 5%, role shaping the company’s diabetes busi- the eight recently launched Lilly drugs but was offset by a 5% revenue decline ness, a key growth-driver for Lilly. Over that drove the firm’s 3% overall sales due to rebates and other sales discounts. his 27-year tenure, the executive worked growth during the third quarter. Along Ex-US revenue exceeded $2.4bn, re- his way up from roles in sales, market- with cancer drugs Verzenio (abemaciclib) flecting 8% growth driven by a 12% uptick ing, finance and business development. and Cyramza (ramucirumab), autoim- in sales volume. This includes $923m in Chairman and CEO David Ricks lauded the mune therapies Taltz (ixekizumab) and EU sales, up 4% year-over-year on 9% vol- work Conterno has done since taking on Olumiant (baricitinib) and chronic mi- ume growth, offset 1% by price and 4% by oversight of the diabetes franchise in the graine drug Emgality (galcanezumab), foreign exchange. Through the first three past decade, saying he is leaving a strong these products yielded 12% year-over- quarters of 2019, Lilly has realized global business for Mason, who has been with year growth and comprised 44% of Lilly’s revenue of $16.2bn, up 2% overall. Of that Lilly for 30 years and serves as senior vice quarterly sales. The pharma also noted increase 7% is due to volume, while pric- president, connected care and insulins. that recently launched nasal glucagon ing issues have cut into revenue by 3% “Enrique has done an outstanding Baqsimi brought in $6m in sales. and foreign exchange by another 2%. job, leading Lilly Diabetes over the past Lilly also repeated a theme from earlier decade, really re-establishing our com- in the year, noting that its performance is SALES PRESSURES CAUSE pany as a leader in diabetes care with the due more to increased volume than price. DISPARITY IN TRULICITY RX, broadest and fastest-growing portfolio of (Also see “Lilly Says Volume Growth Strat- REVENUES medicines in the industry,” Ricks said. He egy, Launches Working Despite Price Pres- Illustrating these trends is the perfor- added that Mason, in leading Lilly’s US sures” - Scrip, 30 Apr, 2019.) US revenue mance of the injectable GLP-1 analog Tru- and Canadian diabetes business in recent was flat year-over-year at nearly $3.1bn, licity, which brought in just over $1bn in years, has overseen successful launches with chief financial officer Joshua Smiley the quarter, with 17% US growth and 50%

scrip.pharmaintelligence.informa.com November 1, 2019 | Scrip | 5 Q3 RESULTS

growth internationally. US prescription “We expect the Q3 negative factors to sword” for competitor Xeris Pharmaceu- growth for the product is outstripping net moderate substantially going forward as ticals Inc.’s recently approved non-inject- sales growth considerably with 39% total impacts from the donut hole diminish in able glucagon Gvoke. (Also see “Xeris Joins prescription growth in the US, but with Q4,” Smiley said. Lilly On Market With Approval Of Easier-To- just 17% net sales growth. This 22% dis- Taltz revenues increased 29% year-over- Use Glucagon “ - Scrip, 10 Sep, 2019.) parity is much higher than the 12% seen year to $340m in the quarter, with US “There clearly appears to be a strong de- in the second quarter and 18% in the first sales up 19% and international sales 68% mand in the market for more convenient quarter, Morgan Stanley analyst David Ris- higher. In the diabetes franchise, Basaglar formulations of glucagon, which is posi- inger pointed out in a 23 October note. sales rose 31% to $263m globally, while tive for Xeris’ Gvoke,” she wrote. “However, Smiley said US pricing pressures, includ- Jardiance saw a 44% uptick to $241m. the quick uptake of Baqsimi also means ing a product mix slanted toward govern- Emgality brought in $48m during the that it is imperative for Xeris to launch ment payers, has exacerbated this dispar- quarter – all but $2m of which was real- its pre-filled syringe version, and more ity in Trulicity performance. Overall, the ized domestically – up 28% from $34m importantly, the autoinjector version of 5% revenue hit it took in the quarter due in the second quarter. Smiley said the mi- Gvoke as soon as possible to participate to US pricing was about three-fifths at- graine drug finished the third quarter with and compete in the switch of patients tributed to rebating and two-fifths to the a 46% US market share of new-to-brand from [glucagon emergency kits (GEKs)] to impact of the Medicare Part D donut hole, prescriptions. the novel glucagon products.” the exec said. The frequency of refills in this market is “We anticipated approximately $200m EMGALITY, BAQSIMI LAUNCHES low, so patient switches should become of impact for the year and our actual results PORTEND CHALLENGES FOR more difficult the longer it takes Xeris to are consistent with this projection,” Smiley COMPETITORS get on the market, she added. continued. “However, we are seeing the do- Credit Suisse analyst Evan Seigerman nut hole impact more concentrated in Q2 said that while this performance posi- MIXED PERFORMANCE and Q3 than prior years and expect a small- tions Emgality as solid competition for IN R&D PIPELINE er impact in Q4. As our largest product, Tru- Amgen Inc.’s first-to-market product Lilly chief scientific officer Daniel Skov- licity, of course, had a significant impact on Aimovig (erenumab), Emgality’s growth ronsky noted that due to the failure of the US portfolio or price decline.” likely means gradual uptake of the CGRP pegilodecakin in metastatic pancreatic “Trulicity’s robust US volume growth of inhibitor class. (Also see “Migraine Market cancer, the company has ended that 42% was consistent with first-half trends Gets Competitive With Second, Third CGRP study. But it continues to advance that and was partially offset by unfavorable Inhibitor Launches” - Scrip, 9 Nov, 2018.) In candidate, acquired in 2018’s buyout of pricing dynamics in the quarter,” he add- a 23 October note, he predicted $88m in Armo BioSciences Inc., in lung and renal ed, explaining that a combination of fac- third quarter sales for Aimovig. cancers, he said. tors resulted in a negative 20% impact on “Although a competitor to Amgen, we This year’s acquisition of Loxo Oncol- the drug’s price during the quarter com- feel that Emgality’s growth may be a posi- ogy Inc. is proving more fruitful, how- pared to a year earlier. tive indication that education and uptake ever, Skovronsky noted while giving an Morgan Stanley’s Risinger noted that for chronic CGRPs is improving after lack- overview of highlights from Lilly’s Phase I the disparity between US prescription luster launches in the CGRP space,” he pipeline. (Also see “Lilly’s Loxo Bet Pays Off growth and net sales is even greater for wrote. “We expect Aimovig to reap the In Thyroid Cancer, A Second Indication For another of Lilly’s growth-driving drugs, benefits of its first-to-market advantage Selpercatinib” - Scrip, 30 Sep, 2019.) Taltz. Indicated to treat psoriasis, psori- and continue to hold a dominant position Along with Phase III RET inhibitor selp- atic arthritis and ankylosing spondylitis, in the chronic migraine market.” ercatinib, that deal brought the pharma the interleukin-17 inhibitor yielded 57% In the easier-to-use glucagon arena, LOXO-305, a next-generation, non-co- total prescription growth during the Baqsimi holds 33% of new-to-brand pre- valent Bruton’s tyrosine kinase inhibitor, third quarter, compared to 19% net sales scription volume in the US and offers the which Lilly has moved to Phase I/II studies growth. (Also see “Lilly’s Taltz Approved For potential to grow the overall glucagon in three types of leukemia. The company AS As New Guidelines Keep TNF Inhibitors market, Smiley said. will present early Phase I dose-escalation In Front Line” - Scrip, 26 Aug, 2019.) That In a 23 October note, SVB Leerink ana- data for LOXO-305 at a medical meeting 38% disparity dwarfs the 7% in the second lyst Ami Fadia asserted that Baqsimi’s later this year, he said. quarter and 22% during the first quarter. launch might represent “a double-edged Published online 23 October 2019

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6 | Scrip | November 1, 2019 © Informa UK Ltd 2019 Q3 RESULTS

AstraZeneca: ‘Firing On All Cylinders’ In Q3

STEN STOVALL [email protected]

straZeneca PLC’s impressive rebound continued in the wealth of our mid-stage pipeline and that we can also be a leader third quarter. The UK firm beat market sales and profit in respiratory disease and in cardiovascular and metabolism,” he Aforecasts, led by its oncology portfolio and marked by a told reporters. heady expansion in emerging markets, with sales in China up 40% But while AstraZeneca aims to be a leading oncology player he at constant exchange rates. stressed that it would not ever seek to become a specialty care pharma that is mainly focused on oncology. “We are diversified with a broad portfolio, which means we are less exposed to something wrong happening with one product or another. And we are also diversified geographically and that should be attractive to our shareholders,” he said, adding: “We will continue allocating resources flexibly across our three therapy areas.”

SLOWING CHINA One cloud on the horizon however is China, where AstraZeneca has long been active. The group had earlier this year forecast a slowdown was coming in China due to the country’s massive centralized “4+7” drug procurement scheme which is being rolled out nationwide, involving some of the largest provincial markets and huge prod- “We have many engines of growth.” – uct volumes. (Also see “What’s At Stake As China Expands ‘4+7’ Pascal Soriot Scheme: An Infographic Snapshot” - Scrip, 19 Sep, 2019.) While growth there remained strong in the third quarter, Soriot said that would now change. “The impact we expected there from VBP, or value-based procurement, has been delayed. The implementation was a little But while the group expects its overall sales to continue ex- slower than we expected. But we can see it is now in full swing … panding in the fourth quarter, it warned that China revenues will and we expect to see the first impact in Q4 this year,” the CEO said. now decelerate, due to market access and pricing reforms there. “We will continue to grow in China, but at a lower rate than we Sales in the third quarter rose 18% from the same year-ago period had been over the last three quarters,” he added. measured at constant exchange rates (CER). That allowed the group He said the reforms being enacted in China reflect market evo- to lift its full-year sales guidance for the second consecutive quarter. lution. “What you must remember is that China is opening to the Product sales are now expected to increase by a low-to-mid-teens world and so opening to innovation,” he explained. percentage at CER; the prior guidance was for a low double-digit “The government in China is looking to give access to new percentage increase. AstraZeneca reiterated its core EPS (earnings medicines and old medicines to more and more patients so they per share) guidance of $3.50 to $3.70 over the full year. are doing two things – they are accelerating approval and reim- “Another strong performance from our new medicines ac- bursement of innovative medicines. They are also trying to reduce companied impressive results in our key markets, most notably the price of all medicines so they can also offer those good but in China, the US and Japan. The performance reinforces our con- older medicines to a broad base population … The impact from fidence in delivering sustainable earnings growth,” Pascal Soriot, this will vary from company to company. But the outlook for China AstraZeneca’s CEO said when updating journalists on the third remains very positive,” he said. quarter results. SORIOT “STAYING” BROAD GROWTH Soriot, who is French-born and has been at the helm of Astra- Soriot said the company was growing across its three main thera- Zeneca for exactly seven years, said he was having too much py areas – oncology, CVRM (cardiovascular, renal and metabolism) fun rebuilding Britain’s second-biggest drug maker to leave any and respiratory. time soon. “We have many engines of growth. It reflects the strategy we “I don’t intend to go anywhere in the near- or mid-term. I’ve got established back in 2014 to focus on three core therapeutic areas. a great team here and we’re doing great work and I’m very excited We may have made progress faster in oncology simply because with all the news flow we’re delivering and the impact that we’re you can get approval for cancer drugs faster than in other fields, making in medicines. So unless the board decides otherwise, I but we are also making tremendous progress in CVRM and re- don’t intend to go anywhere,” he told Scrip. spiratory and I believe over the next couple of years we’ll see the Published online 24 October 2019

scrip.pharmaintelligence.informa.com November 1, 2019 | Scrip | 7 Q3 RESULTS

Novartis’s Zolgensma Finds Commercial Legs In A First For Gene Therapy JESSICA MERRILL [email protected]

ovartis AG’s gene therapy Zolgensma generated $160m in the quarter to $547m. Zolgensma is only approved for a subset of the third quarter, its first full quarter on the market, a strong the patients Spinraza is approved to treat: patients less than two Nlaunch for any new drug in today’s challenging launch en- years old, including patients with SMA types 1-3. Spinraza has a vironment. Zolgensma (onasemnogene abeparvovec) is not the broader label in children and adults. first gene therapy to reach the market in the US or Europe, but it Much of Spinraza’s growth came from sales outside the US, looks like it will be the first to attain commercial traction. though US sales remained stable. Biogen CFO Jeffrey Capello com- Sales of Zolgensma outpaced analyst expectations, which gen- mented during the company’s 22 October call that Zolgensma is erally predicted sales in a range around $100m for the gene ther- having an impact on Spinraza’s performance in the overlapping apy for spinal muscular atrophy. Jefferies analyst Peter Welford, segment in SMA patients under the age of two, but that the com- for example, had forecast sales of $71m, while SVB Leerink analyst peting portion of the market represents only 5% of SMA patients. Mani Forhoohar forecast sales of $120m. Novartis hopes to expand Zolgensma’s label to include SMA One big question for the gene therapy’s launch success has type 2 patients ages two- to five-years old based on the results been market access. Novartis CEO Vas Narasimhan reported dur- of the Phase I, open-label STRONG trial reported in May, but is in ing the company’s third-quarter earnings call on 22 October that discussions with FDA about the data. 90% of commercial patients and 30% of Medicaid patients are Zolgensma was just one of several drugs that powered Novartis’ covered for Zolgensma. third quarter financial performance. Sales of the company’s block- “Importantly, we are now still seeing 99% final approval rates buster psoriasis pill Cosentyx (secukinumab) grew 25% to $937m for patients that are on label after we go through the appropriate in the quarter, despite increasingly competitive dynamics in the appeals process,” he said. category. The heart failure medicine Entresto (sacubitril/valsartan) Zolgensma was approved by the US Food and Drug Administra- grew 59% to $430m. In oncology, the radiopharmaceutical Luta- tion in May for children under two. It launched with a $2.1m price thera grew 113% to $119m, the CDK4/6 inhibitor Kisqali (ribociclib) tag that got a lot of attention and raised questions about how grew 76% to $123m and the first-in-class PI3K inhibitor Piqray (al- payers might respond to the high cost of the one-time treatment. pelisib) generated $43m after being approved by the FDA in May The company didn’t quantify early sales in the second quarter, for HR+, HER2-negative breast cancer with PIK3CA mutations. though Narasimhan assured investors at the time that the launch was going well. The company also faced a big scandal around Zol- MOVING AHEAD WITH ENTRESTO US FILING gensma in August, when FDA reported that early data supporting In another development, Novartis reported that it will file data the approval of the gene therapy had been manipulated and that from the PARAGON-HF trial with the FDA to support a broader use Novartis failed to alert the agency in a timely way. Novartis fired of Entresto for heart failure with preserved ejection fraction. The the AveXis employees who were involved in the data manipula- fate of the regulatory strategy was uncertain after the highly an- tion and doubled down on promises to rebuild trust with society ticipated Phase III study in the patient population narrowly missed after the debacle came to light. the primary endpoint of reducing heart failure hospitalizations During the 22 October call, Novartis outlined its near-term and cardiovascular death versus valsartan alone. However, the growth strategy for Zolgensma, which the company expects company had remained optimistic that Entresto might be able to will come from further penetration in children new to treatment fulfill a need for a subset of the patients. through newborn screening, which is expected to climb from Narasimhan confirmed that Novartis, after discussions with the 30% of newborns to 70% or higher by the end of 2020. Growth FDA, will submit the data to the FDA for inclusion in labeling in will also come from switches from Biogen Inc.’s Spinraza (nusiner- the fourth quarter. Discussions with European and other global sin) to Zolgensma, as well as global expansion. Zolgensma is cur- regulators are continuing. rently under review in Europe. “We are determined to try to find a way to reflect the benefits “We are confident in our longer-term outlook for this medicine,” of Entresto in a broader patient population in an appropriate Narasimhan said. Nonetheless, he guided investors to expect way,” he said. An approval for preserved ejection fraction would fourth-quarter sales of Zolgensma will be in line with the third have doubled the market opportunity for Entresto, which was ap- quarter, because there was a lot of pent-up demand for the treat- proved in 2015 to treat patients with heart failure with reduced ment around the launch. ejection fraction. After a slow initial launch, the drug finally be- came a blockbuster drug for the first time in 2018. BIOGEN’S SPINRAZA HOLDS STEADY Novartis’s consolidated net sales from continuing operations Strong sales of Zolgensma are expected to weigh on Biogen’s rival grew 10% to $12.17bn and net income grew 8% to $2.04bn in the drug Spinraza (nusinersin), a big growth driver for the company, third quarter. but Biogen reported the same day that Spinraza sales grew 17% in Published online 22 October 2019

8 | Scrip | November 1, 2019 © Informa UK Ltd 2019 Q3 RESULTS

Gilead Says Sluggish Yescarta Business Will Continue To Fluctuate JOSEPH HAAS [email protected]

ilead Sciences Inc. expressed con- Gilead also announced that it is bolster- growth to the combination pill Biktarvy fidence in Yescarta’s overall coming its cell therapy manufacturing capabil- (bictegravir/emtricitabine/tenofovir Gmercial trajectory despite a slight ities by opening a new 67,000-square-foot alafenamide (TAF)). (Also see “Biktarvy, downturn in sales from the previous quar- viral vector facility in Oceanside, CA, just PrEP Continue Driving Gilead’s HIV Domi- ter during its third quarter earnings call on north of San Diego. nance” - Scrip, 3 May, 2019.) 24 October. The chimeric antigen receptor O’Day hailed the career of the retiring O’Day noted that the past quarter yield- T-cell (CAR-T) therapy brought in $118m Washington and talked up her recently ed the highest single-quarter total in HIV during the July-through-September pe- appointed successor, Andrew Dickinson, product sales ever for the company. riod, including $32m in the EU; the overall saying during the company’s call that he Worldwide product sales for the quarter total was 2% below the second quarter, “implemented a broader, more strategic declined 2% sequentially, but increased but up 57% year-over-year. deal-making approach” since becoming 1% year-over-year, Washington reported. Departing chief financial officer Robin Gilead’s executive vice president, corpo- US sales came in at $4.2bn, up 4% sequen- Washington pointed out that EU sales rate development and strategy in 2016. tially and 2% year-over-year. In Europe, for Yescarta (axicabtagene ciloleucel) represented a 52% increase sequen- “We anticipate further quarterly sales variations, tially, while US sales of $83m were up 15% year-over-year, but down 13% from but remain very confident in the future trajectory of the prior quarter. She cautioned investors to expect ongoing up-and-down Yescarta.” - Robin Washington performance in the cancer cell therapy space. (Also see “Gilead Maintains Opti- mistic Outlook For Yescarta Despite Slow Washington’s retirement takes effect on 1 sales of $804m represented a 23% down- Growth” - Scrip, 4 Feb, 2019.) November, but she will stay on in an advi- turn sequentially, and an 8% decline year- “It is clear that cell therapy is a validat- sory role through early 2020. over-year. ed platform with hundreds of patients Since agreeing to move over from Jefferies analyst Michael Yee described being treated on a quarterly basis in Roche in December to take the helm the quarter’s performance as “fine but the US,” the exec said. “Yescarta has es- at Gilead, O’Day has reshaped much nothing that necessarily exceeded expec- tablished itself as a differentiated leader of the company’s leadership, a process tations or were a positive upside surprise,” in an increasingly competitive environ- instigated partly by frequent depar- in a same-day note. ment. We will continue to focus our ef- tures by the company’s old guard and Washington hailed continued growth forts on CAR-T education in the com- even newer arrivals. This included hir- for the HIV franchise and predictability munity oncology setting to stimulate ing former Genentech Inc. exec Merdad of decline for its hepatitis C virus (HCV) referrals of appropriate patients to cell Parsey as chief medical officer earlier in portfolio, which brought in $674m during therapy treatment centers.” October. O’Day said on the 24 October the quarter, a 20% decline from the prior “We’ve also observed CAR-T-eligible pa- call that Parsey will lead global develop- quarter and down 25% from $902m a year tients being enrolled in clinical trials at a ment and medical affairs, while Bill Lee earlier. Chief commercial officer Johanna much higher rate relative to commercial will continue to lead Gilead’s research Mercier said sales of Gilead’s authorized patients,” Washington added. “As such … apparatus. (Also see “Gilead’s New O’Day generic versions of its HCV drugs have we anticipate further quarterly sales varia- Regime Has New R&D Structure “ - Scrip, helped stabilize that franchise somewhat tions, but remain very confident in the fu- 10 Oct, 2019.) in the US. (Also see “Gilead Lowering HCV ture trajectory of Yescarta.” Drug List Prices With Authorized Generics “ CEO Daniel O’Day pointed ahead to the OVERALL REVENUES FLAT - Pink Sheet, 25 Sep, 2018.) American Society of Hematology confer- DESPITE HIV FRANCHISE GROWTH In Europe, HCV product sales totaled ence in December, noting that Gilead Overall, Gilead reported a flat quarter $111m for the quarter, a decrease of 60% scientists will present three-year survival for product sales year-over-year, bring- from the second quarter and 45% from data for B-cell lymphoma patients receiving in $5.52bn during the quarter, up the prior year. “Overall, the HCV market ing Yescarta, as well as Phase II data in from $5.46bn a year earlier. This in- continues to see a more predictable de- mantle cell lymphoma for the next CAR- cluded $4.2bn for the HIV franchise, up cline in patient starts and perform in line T candidate out of the Kite Pharma Inc. from $3.7bn in the third quarter of 2018. with our expectations,” Mercier said. pipeline, KTE-X19. The company attributed much of this Published online 24 October 2019

scrip.pharmaintelligence.informa.com November 1, 2019 | Scrip | 9 COMPANIES

Alkermes Restructures, Prioritizing CNS And Oncology And Cutting 160 Employees JESSICA MERRILL [email protected]

Although Alkermes would hope to partner ALKS 4230 if ongoing studies are positive, he said the company has other engineering work underway that could play a role in oncology. “We haven’t been quite as clear on disclosing some of those things but suffice it to say that we have a lot of energy in the labs on areas that we think are proprietary where other people aren’t playing and that we think we can have an impact,” the CEO added. The other core area, CNS, is a space Alkermes has been working in for a long time. The company markets the opioid antagonist Vivitrol (naltrexone), which generated $85.2m in the third quarter, and the long-acting antipsychotic Aristada (aripiprazole) for schizophrenia, which generated $53.6m. Alkermes also receives lkermes PLC has reorganized its business operations to manufacturing and royalty revenues from the sale of several reduce spending and drive profitability, cutting 160 em- drugs developed using its technology, including Johnson & John- Aployees while refining its R&D priorities. The effort is -ex son’s Risperdal Consta, Invega Sustenna and Invega Trinza. pected to yield savings of $150m, the company announced on 23 The company’s latest-stage new drug is ALKS 3831, which the October. company plans to file with the US Food and Drug Administration The restructuring could position Alkermes to improve earnings for the treatment of schizophrenia and bipolar 1 disorder this and will also mark the company’s full transition from a drug deliv- quarter. The drug combines the generically available antipsychot- ery specialist to a drug developer. In R&D, Alkermes will be priori- ic olanzapine with the novel opioid receptor antagonist samidor- tizing two core areas: CNS and oncology. phan, intended to offset some of the propensity for weight gain “Concentration in these focus areas will complete the compa- associated with olanzapine. ny’s transition that has been underway for several years, moving The company expects to capture cost savings through the more away from our legacy of drug delivery and precedented pharma- focused R&D strategy, as well as streamlined SG&A functions. cology to our new molecules and novel mechanisms of action,” “We made certain refinements to the commercial organization, CEO Richard Pops said during the company’s same-day third and we’re recalibrating our marketing investments to focus on the quarter earnings call, announcing the changes. initiatives that are driving the most return on investment,” Pops While Alkermes has had a long-standing presence in CNS disor- added. Alkermes hopes the improved financial efficiency will po- ders, the company’s move into oncology is newer and was more sition the company to achieve sustained non-GAAP profitability fortuitous than by design. and provide more flexibility for business development activities. Oncology may seem like a surprising priority area for a small CNS While Alkermes generated more than $1bn in revenues in 2018, specialist like Alkermes, but the company has an interesting clinical- the company reported a net loss of $139.3m on a GAAP basis and stage asset in development. Alkermes is developing an engineered $97.8m in net income on a non-GAAP basis. Third quarter reve- IL-2 fusion protein (ALKS 4230) as a potential immuno-oncology nues were $255.5m, 2.6% growth versus the prior year; the GAAP candidate, a drug target that has gotten a lot of attention after Bris- net loss was $52.9, or $0.34 per share. tol-Myers Squibb Co. paid Nektar Therapeutics $1.85bn upfront in Evercore ISI analyst Umer Raffat, in an email to investors, said 2018 to partner on a pegylated form of IL-2, NKTR-214, and study the restructuring could enhance Alkermes’ earnings per share tra- in combination with Opdivo (nivolumab) and Yervoy (ipilimumab). jectory, especially given that the company is expected to be re- ALKS 4230 is currently being tested in a Phase I/II study as ceiving a revenue stream from Biogen Inc.’s sales of the multiple monotherapy and in combination with Merck & Co. Inc.’s Keytruda sclerosis drug Vumerity (diroximel fumarate) in 2020. (pembrolizumab) in patients with advanced solid tumors. On 21 “They were always tracking at about break-even on EPS and October, Alkermes also announced a research collaboration with retained the ability to turn the card into positive EPS territory. It Fred Hutchinson Cancer Research Center to study the drug in a seems like they’re doing it now,” Raffat said. Phase II trial in combination with Keytruda in patients with ad- Vumerity was tentatively approved by the FDA in October, but vanced or recurrent head and neck squamous cell cancer. the agency said full approval is pending a patent expiration. The “The oncology focus is a perfect example of how scientific ex- companies have not outlined which patent needs to expire to pave ploration takes you in directions,” Pops said. “The entrée into on- the way for the full approval but did say the timeline for the expira- cology was not a ‘strategic decision’ to get into oncology. It was tion is in October. driven by the cytokine engineering work that we were doing that The restructuring is expected to result in a $15m charge, which first yielded ‘4230.” will be taken in the fourth quarter. Published online 24 Oct 2019

10 | Scrip | November 1, 2019 © Informa UK Ltd 2019 COMPANIES

FTC Closer To Clearing Roche’s Spark Buy: Report

KEVIN GROGAN [email protected]

oche’s insistence that its much-delayed takeover of Spark can be signed off. Following the staff’s recommendation, the FTC Therapeutics Inc. will happen by the end of the year has chairman and four commissioners still have to give their blessing. Rbeen boosted by a report from news and legal analysis com- The deal must also win approval from the UK’s Competition and pany Capitol Forum that US Federal Trade Commission staff have Markets Authority. On 21 October, the agency launched a merger cleared the $4.3bn deal. inquiry and set a deadline of 16 December for a phase 1 decision; The report claimed that FTC staff had recommended that the Roche and Spark will be hoping the deal passes without the need proposed acquisition, announced back in February, be approved to go for a more detailed phase 2 review. without requiring any asset sales. Capitol Forum reported that the During Roche’s third-quarter update on 16 October CEO Sev- staffers had focused on the companies’ hemophilia portfolios, giv- erin Schwan declined to give any specific timelines but said the en that Roche markets Hemlibra (emicizumab), while Spark’s lead Swiss group remained “confident of closing the transaction this clinical asset is SPK-8011, a gene therapy for hemophilia A, which year.” (Also see “Roche Ups Outlook, Sees Spark Buy By Year-End” is expected to start Phase III in 2019 this year; it also is developing - Scrip, 16 Oct, 2019.) SPK-8016 in a Phase I/II trial aimed at addressing the hemophilia A inhibitor population. IMPACT ON OTHER DEALS Spark was the first company to receive US Food and Drug Ad- However it plays out, the Roche/Spark experience has had a con- ministration approval for a gene therapy for a genetic disease siderable impact on the sector. Big pharma buying small biotech in December 2017 when Luxturna (voretigene neparvovec) got was previously a routine and uncomplicated process but that ap- the nod as a one-time treatment for the rare eye disease biallelic pears to have changed and some observers believe the FTC and RPE65 mutation-associated retinal dystrophy. It is currently mar- other antitrust agency’s increased interest in this case has slowed keted in the US by Spark and by Roche rival Novartis AG. down deal making. As well as its hemophilia A efforts, Spark’s other assets include Antitrust issues have been mentioned as possible obstacles to SPK-9001, an investigational gene therapy being developed with the completion of other recently-announced deals. On 10 Octo- Pfizer Inc. for hemophilia B which is in Phase III and SPK-7001 for ber, UCB Group agreed to buy Ra Pharmaceuticals Inc. for $2.1bn choroideremia, currently in Phase I/II trials. The company is also and get access to zilucoplan for the neuromuscular condition developing SPK-3006 for Pompe disease and SPK-1001 for CLN2 myasthenia gravis, a rare disease the Belgian drug maker is also disease – a form of Batten disease – and has additional preclinical targeting with its own FcRN inhibitor rozanolixizumab. (Also see programs for Huntington’s disease and Stargardt disease. (Also “UCB To Buy Ra for $2.1bn And Plays Down Antitrust Fears” - Scrip, see “Roche $4.8bn Buy Sparks Hemophilia Gene Therapy Race “ - 10 Oct, 2019.) Scrip, 25 Feb, 2019.) UCB sees the two investigational products as complementary, The deal has been postponed several times and in June, the FTC although analysts are expecting increased antitrust scrutiny. How- issued a “second request” for information on the deal. Such a move is ever, CEO Jean-Christopheme Tellier said on a conference call that extremely rare in US antitrust law and compelled Roche and Spark to “despite the environment,” the firm was confident it could answer produce even more documentation and appear before regulators. any questions and obtain all the required antitrust approvals be- While the Capitol Forum report provided some good news for fore the end of the first quarter next year. Roche and Spark, there is some way to go before the acquisition Published online 25 October 2019 Takeda Adds Celiac Disease Candidate To GI Efforts JOHN DAVIS [email protected]

our years after first partnering with the US biotech, Cour Pharmaceutical Gluten in wheat FDevelopment Co. Inc., the Osaka, Ja- pan-based multinational, Takeda Pharma- causes difficulties ceutical has acquired an exclusive global license to develop and commercialize for celiac patients Cour’s lead product, CNP-101/TAK-101, for the treatment of celiac disease. The deal is important because there are no treatment options for celiac disease patients other than attempting to control

scrip.pharmaintelligence.informa.com November 1, 2019 | Scrip | 11 COMPANIES/APPROVALS

symptoms by following a gluten-free diet. T-cells which are then either deleted, inac- and were said by Takeda to be the first But there are signs of progress in the de- tivated or converted to T regulatory cells. demonstration of the induction of an velopment of therapies for the condition. As well as validating Cour’s approach to antigen-specific immune tolerance in an In August, Innovate Biopharmaceuticals the treatment of autoimmune diseases, autoimmune disease. Inc. announced it has larazotide acetate exercising its option also underlines Take- In the study, in 34 adult patients with (INN-202), an orally active tight junction da’s drive to maintain its leading position celiac disease, TAK-101 was administered regulator, in Phase III for celiac disease, in the treatment of gastrointestinal diseas- intravenously on days one and eight, and said to be the first Phase III trial to be con- es, with the inflammatory bowel disease a gluten challenge given seven days after ducted in the condition. therapy, Entyvio (vedolizumab), being a the second dose. The challenge involved Immunogenics LLC has an investiga- top-selling product for the firm. 12g of gluten per day for three days fol- tional therapy, latiglutenase (IMGX003), lowed by 6g per day for 11 days. which is being evaluated in a Phase II DEAL TERMS Six patients discontinued the study study for celiac disease, while Provention Takeda signed a partnership with Cour due to gluten-related symptoms, and in Bio Inc. has licensed rights from Amgen back in December 2015 to develop the the 28 remaining patients, the primary Inc. to the anti-IL-15 Mab, PRV015 (for- US biotech’s nanoparticle technology for endpoint was met; the mean change merly AMG 714), which is also in Phase II celiac disease, an abnormal inflammatory from baseline in gamma-interferon spot for the condition. And last month Glaxo- response to the wheat protein, gluten. forming units (SFUs) in an enzyme-linked SmithKline PLC indicated it was to buy The agreement gave Takeda an option immune-assay were 2.10 and 17.57 with celiac disease specialist, Sitari Pharmaceu- on Cour’s wheat protein (gliadin, a com- TAK-101 and placebo, respectively (p= ticals, the first company formed under a ponent of gluten)-containing tolerizing 0.0056). There was also a trend towards 2013 partnership with Avalon Ventures. immune modifying nanoparticles upon protecting the small intestine against Around 1% of the US population has a successful Phase IIa proof-of-concept mucosal damage. The most frequent ad- celiac disease, whose long-term compli- study, and options on three other toler- verse events were nausea, headache, ab- cations include accelerated osteoporosis, izing projects, in return for upfront, mile- dominal pain, and back pain. and reproduction and nervous system re- stone and royalty payments – Cour is Takeda will now start a dose-ranging lated problems. Cour’s nanoparticles are eligible to receive up to $420m in future study of TAK-101 in patients with celiac dis- taken up by mononuclear phagocytes, payments, and royalties on sales of com- ease on a gluten-free diet, while Cour says which then deliver disease-specific anti- mercialized products. it will advance its pipeline in other immune gens or allergens to antigen-presenting Results from just such a Phase IIa disorders, including multiple sclerosis cells in the spleen and liver. APCs then study were presented on 22 October at (CNP-202) and peanut allergy (CNP-201). interact with antigen or allergen-specific the UEG Week 2019 in Barcelona, Spain, Published online 24 October 2019 Vertex Trikafta Approved As First Triple Combo For Cystic Fibrosis With $311,503 Price Tag

JESSICA MERRILL [email protected]

ertex Pharmaceuticals Inc.’s Trikafta The launch of Trikafta is an important Vertex’ three other marketed drugs for (elexacaftor/ivacaftor/tezacaftor) one for Vertex, with the drug expected to cystic fibrosis. Vwas approved by the US Food and address 90% of the cystic fibrosis popu- Trikafta builds on the company’s long Drug Administration in just three months lation, cementing the company’s domi- history in cystic fibrosis. The triple regi- as the first triple combination therapy for nance in the disease. There are approxi- men combines the novel next-generation cystic fibrosis. The FDA cleared the drug mately 2,000 known mutations of the CFTR corrector elexacaftor with the CFTR for patients 12 and older who have at least CFTR gene, but the most common is the corrector tezacaftor and the CFTR poten- one F508del mutation in the cystic fibrosis F508del mutation. tiator ivacaftor. Tezacaftor and ivacaftor transmembrane conductance regulator Vertex said Trikafta provides the first already are marketed by Vertex as the (CFTR) gene. treatment option targeting the underly- dual regimen Symdeko, which launched The news surprised investors, even ing cause of the disease for the roughly in 2018 for cystic fibrosis patients homo- though an approval was expected, be- 6,000 patients 12 years and older who zygous for the F508del mutation or with cause it came five months ahead of the have one mutation of F508del and one one copy of certain mutations that result March 2020 FDA action date. The late-in- minimal function mutation. The medicine, in residual CFTR activity. the-day approval was announced by the however, is also an option for the 12,000 Vertex already markets three drugs for FDA, and Vertex’ stock jumped 4% to close patients with one or two F508del muta- cystic fibrosis, including Symdeko, which the day at $183.98. tions who are already eligible for one of has been a big growth-driver for the

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company, generating $362m in second brought to market for cystic fibrosis. Par- “In the past few years, we have seen quarter sales, edging out Orkambi (luma- ticularly in Europe, Vertex has received remarkable breakthroughs in therapies caftor/ivacaftor) as its top-seller. Orkambi pushback from governments about the to treat cystic fibrosis and improve pa- was approved in 2015 for patients who high cost of treatment. tients’ quality of life, yet many subgroups have two copies of the F508del mutation While discounts and rebates negotiated of cystic fibrosis patients did not have in their CFTR gene. Ivacaftor monothera- with payers may be substantial, the com- approved treatment options,” acting py was the company’s first cystic fibrosis pany still could face criticism for its Trikafta FDA Commissioner Ned Sharpless said drug, which launched in 2012 and is mar- pricing in the US, since Vertex will earn a in a statement. “That’s why we used all keted as Kalydeco. return on its investment in the triple ther- available programs … to help advance The list price for Trikafta will be $311,503 apy at the same price as a drug that treats today’s approval in the most efficient per year, Vertex confirmed. The price is much fewer patients. manner possible.” above analyst expectations and higher Yee pointed out that the new drug’s la- Vertex is running a Phase III study than the $290,000 price tag for Symdeko, bel is broader than expected, since cystic evaluating the triple combination in according to notes from Jefferies analyst fibrosis patients treated with previously children ages 6 to 11, which could fur- Michael Yee. “The price, at $311,000, is a approved Vertex drugs will be eligible for ther expand the number of patients that little above consensus – but we note this treatment with Trikafta. Initial sales perfor- could be treated. is the same price as Kalydeco, with similar mance still may be slow, however, since With the Trikafta approval, the company [forced expiratory volume (FEV)] benefits the drug was approved months ahead of will receive a rare pediatric disease priority and overall as big an efficacy profile as schedule while launch preparations were review voucher, which can be sold or used Kalydeco,” Yee wrote. “The price is around under way, he added. Also, the launch to secure a future priority review. 20% above consensus (upside to earnings will occur close to the Thanksgiving and As Vertex further penetrates the cystic leverage) but not that surprising given Christmas holidays when new prescrip- fibrosis market, the company has reached the profile, in our view.” tions tend to slow. a transition point, where it is looking to The Jefferies analyst noted that Trikafta Vertex confirmed that Trikafta will be build out its pipeline into new areas and is “will now set the pace for Vertex to grow available in US pharmacies in the next changing its leadership. In July, the com- revenues $3bn to $8bn-$9bn and earn- few weeks. pany announced that CEO Jeffrey Leiden ings to triple from $3 to $10 earnings per The company filed for FDA approval will transition into the executive chairman share power over the next few years.” of the triple combination regimen in role in April 2020 and chief medical officer Vertex is one company that has come July. It was granted priority review, Reshma Kewalramani will become presi- under public scrutiny for high drug as well as fast track and breakthrough dent and CEO. prices despite the advancements it has therapy designations. Published online 21 October 2019 Vertex Finally Inks Orkambi Deal In England FRANCESCA BRUCE [email protected]

he stalemate between NHS Eng- tezacaftor/ivacaftor and ivacaftor), to a land and Vertex Pharmaceuticals The deal brings to an “comprehensive NICE appraisal”. T Inc. over the cystic fibrosis drug The agreement also includes a require- Orkambi (lumacaftor/ivacaftor) is finally end the protracted and ment that the company must make equiv- over. The two parties have finally agreed alent terms available to the NHS in Wales a deal that will give the company better controversial wrangling and Northern Ireland. Vertex has already access to the UK, the second biggest mar- announced a separate deal in Scotland. ket for its cystic fibrosis drugs which also that began in 2016. (Also see “RWD Key To Scottish Orkambi include Symkevi (tezacaftor/ivacaftor) and Deal” - Pink Sheet, 12 Sep, 2019.). Kalydeco (ivacaftor). The deal brings to an end the protracted Under the deal announced on 24 Oc- and controversial wrangling that began in tober, patients will have access to Ork- 2016 when the UK health technology ap- ambi and Symkevi in all current and praisal institute, the National Institute for future indications. The agreement also Health and Care Excellence, declined to extends access to Kalydeco, which was recommend Orkambi because its benefits already available for some patients, to did not justify its costs. include all current and future eligible Vertex subsequently tried and failed patient populations. In addition, Vertex to negotiate a “portfolio” deal that would has also agreed to submit its forthcom- have given access to Orkambi, Symkevi ing triple therapy, Trikafta (elexacaftor/ and Kalydeco, plus the company’s pipe-

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line drugs. Its proposal was rejected and ing an “extreme outlier” in its approach to It is unclear what that mechanism is. NHS England came back with a counter pricing at a public hearing held as part of Both NHS England and the company de- offer that it claimed was the biggest fi- a parliamentary inquiry into the lack of ac- clined to reveal whether Vertex would nancial commitment undertaken by cess to Orkambi. He also said that Orkambi lower its price if the NICE appraisal indi- the NHS. That deal was in turn promptly pricing talks had been skewed by a 2012 cated it should. Nevertheless, it is worth rejected by Vertex. And along the way deal that over-priced Kalydeco. Kalydeco noting that NICE would be unlikely to en- there have been parliamentary debates, had not undergone a NICE appraisal. dorse reimbursement of the products if it petitions, a parliamentary inquiry and a Also crucial to an agreement finally be- did not believe there was a good chance public hearing. ing reached was Vertex’s re-engagement the drugs would prove cost-effective. The BioIndustry Association has wel- with the NICE process. The company has In his own letter to Sarah Wollaston, comed the deal, claiming that in light of long claimed that the institute’s standard Vertex CEO Jeff Leiden made it clear it a raft of other agreements struck by NHS technology appraisal process are not suit- still believes there are problems with the England it signals that the UK is receptive able for Orkambi because it is an orphan NICE processes. He welcomed the current to innovation. “This is one of a number of drug as “the science is out pacing the sys- review of NICE’s evaluation methods and deals that the NHS has reached with in- tem.” Vertex also refused to engage with said he hoped they will “be an opportu- dustry to bring life-saving treatments to the NICE process with Symkevi. nity to address the gaps in these methods patients, showing that the UK’s health ser- Simon Stevens, chief executive of NHS for future assessment of medicines in rare, vice is committed to innovation and being England made it clear earlier this week at genetic, life-long conditions.” Leiden add- at the cutting edge of medical products,” a health and social care select committee ed that the select committee would likely said Steve Bates, the association’s CEO. meeting that any deal would depend on play a role in “ensuring they are reviewed Meanwhile, Simon Stevens, chief ex- whether Vertex was willing to re-engage and debated further.” ecutive of NHS England, noted that the with NICE. (Also see “Vertex Strikes Spanish The news came shortly after Vertex told UK had the second highest prevalence Payment-For-Results CF Deal” - Pink Sheet, the Pink Sheet it was hoping a deal would of cystic fibrosis in the world. “That fact 22 Oct, 2019.) be confirmed in the near future. also means that any drug company want- Vertex has agreed to do just that. Its full ing to succeed commercially in this field portfolio, including the triple therapy, will UK WELCOMES INNOVATION? needs to work constructively with the be subject to a comprehensive NICE re- The deal was agreed by NHS England’s NHS,” he said. view, said NHS England. commercial team with collaboration According to NHS England, some 5,000 The appraisal process is expected to from NICE. NHS England pointed to patients could be set to benefit, though conclude by September 2021, said Ste- several other high profile deal negoti- there is no cap on the numbers of patients vens in a letter to Sarah Wollaston, the ated by the team for innovative prod- who could be treated. chair of the health and social care select ucts, including a “first of its kind” agree- committee that has been conducting an ment with Gilead Sciences Inc., AbbVie CONCESSIONS AND inquiry into access to Orkambi. Inc. and MSD to try to eliminate hepati- COMPROMISE The appraisals will be informed by real- tis C in England. There appears to have been movement world evidence gathered over 18 months. Other deals include Biogen Inc.’s Spinra- from both sides in agreeing the deal. “A The UK CF Registry, which is maintained za (nusinersen) for spinal muscular dystro- flexible and collaborative approach by all by the Cystic Fibrosis Trust, will have a key phy and Novartis AG’s Kymriah (tisagen- parties involved in the negotiation,” was role in gathering the evidence. lecleucel) for use in children and young key to striking a deal, Vertex told Scrip’s Nevertheless, a source close to the NHS people with a certain form of leukemia. sister publication, the Pink Sheet. told the Pink Sheet that to secure Vertex’s Vertex has also recently announced a According to NHS England, the deal was participation in the NICE process, some pay for performance deal for Orkambi and possible because Vertex “agreed confi- concessions had to be made. The source Symkevi in Spain. dential commercial terms that constitute pointed to a “flexible contractual mecha- Published online 24 October 2019 good value for British taxpayers.” nism” outlined in Stevens’ letter. This en- Pricing has been a key issue throughout. sures that Kalydeco, Orkambi and Sym- Vertex Versus NHS England: Earlier this year, John Stewart, national kevi will, in all circumstances, “continue to Was The Stand-Off Worth It?: director of specialized commissioning at be available following completion of the https://bit.ly/2PpAwNV NHS England, accused the company of be- NICE appraisal.”

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14 | Scrip | November 1, 2019 © Informa UK Ltd 2019 ScripHEADLINE NEWSAwards Finalists 2019

IQVIA’s Clinical Advance of the Year Award

This Scrip Award seeks to recognize success in a clinical trial of a drug product that is expected to lead to an advance in healthcare. Medidata’s Community Partnership of the Year AKCEA THERAPEUTICS/IONIS PHARMACEUTICALS’ PHASE II STUDY OF AKCEA-APO(A)-LRX IN CARDIOVASCULAR DISEASE This Scrip Award is designed to acknowledge the numerous AKCEA-APO(a)-LRx is an antisense drug designed to inhibit production ways in which pharma and biotech companies give back to of apo(a) protein by targeting apo(a) mRNA in the liver being the wider community. developed in patients with established cardiovascular disease and elevated levels of lipoprotein(a), or Lp(a). Across all dose cohorts in the ASTRAZENECA’S ENERGY CHALLENGE study, AKCEA-APO(a)-LRx significantly reduced Lp(a) levels below the The Energy Challenge is AstraZeneca’s biggest ever STEM Outreach recognized threshold of risk for CVD events (<50 mg/dL), with 98% of programme and is run in partnership with local schools. Created by patients getting below this level in the highest dose group. AstraZeneca scientists from scratch, with the objective of engaging pupils at the critical age of 9-10 years when they are most at risk of ALKERMES’ ENLIGHTEN-2 PHASE III STUDY OF switching off from science, The Energy Challenge schools competition ALKS 3831 FOR SCHIZOPHRENIA has run in 70 primary schools across the Cambridgeshire region. ENLIGHTEN-2 is the second of two Phase III studies in US registration program for ALKS 3831 (olanzapine/samidorphan), a once-daily, oral IQVIA’S LIGHT THE NIGHT CAMPAIGN atypical antipsychotic drug designed to confirm its favorable weight The IQVIA Annual Light The Night Campaign is a series of fundraising profile compared with olanzapine. It met both pre-specified co- campaigns benefiting The Leukemia & Lymphoma Society (LLS)’s primary endpoints, demonstrating a lower mean percent weight gain funding of research to find blood cancer cures and improve the from baseline and a lower proportion of patients who gained >10% of lives of patients. The campaign culminates at the local LLS Light The their baseline body weight at six months compared with olanzapine. Night event in North Carolina, US, which last year hosted nearly 5,000 attendees. Leveraging executive endorsement and grassroots GALAPAGOS’ EQUATOR AND TORTUGA TRIALS fundraising efforts, IQVIA has become a top LLS fundraising partner. OF FILGOTINIB IN PSORIATIC ARTHRITIS AND ANKYLOSING SPONDYLITIS MERCK KGAA’S EMBRACING CARERS INITIATIVE The EQUATOR and TORTUGA trials of filgotinib showed that the Embracing Carers is a global initiative designed to increase selective JAK1 inhibitor has the potential to offer a new treatment awareness, discussion, and action about the overlooked needs of option for psoriatic arthritis (PsA) and ankylosing spondylitis (AS). carers developed in collaboration with the International Alliance of Compared with biologic agents, filgotinib is orally administered, with Carer Organizations. Given that carers often put the needs of others a rapid onset and a sustained response in clinical trials so far. ACR before themselves, Embracing Carers has led to the development and enthesitis scores were encouraging with filgotinib in PsA patients of new resources including the first of its kind Global State of Care in EQUATOR, while spine mobility and function were significantly Report and “Innovative Care Practices”, an evidence-based pathway improved in AS patients in TORTUGA. to implement proven practices.

NATIONAL CANCER INSTITUTE-SPONSORED E1912 REGENERON PHARMACEUTICALS’ SCIENCE TALENT PHASE III STUDY OF IMBRUVICA IN CHRONIC SEARCH LYMPHOCYTIC LEUKEMIA Regeneron has partnered with the Society for Science & the The E1912 study showed Imbruvica plus rituximab significantly Public to become the third title sponsor of the Science Talent Search, prolonged progression-free survival and overall survival versus the oldest and most prestigious science and math competition fludarabine, cyclophosphamide and rituximab (FCR) in previously in the US. Regeneron is investing $3m per year earmarked for untreated patients aged 70 years or younger with chronic lymphocytic outreach and equity programs aimed at bridging opportunity gaps leukemia (CLL) or small lymphocytic lymphoma. FCR has long been for students historically underrepresented in the sciences, while the most commonly used regimen for younger CLL patients, but there equipping educators with the resources to improve the quality of is need for a treatment with an improved safety and efficacy profile. STEM education. These data are evidence that chemotherapy should no longer be the standard of care in many CLL settings. ROCHE/CHUGAI COMMUNICATIONS PARTNERSHIP WITH LADBIBLE FOR THE HAEMOPHILIA SOCIETY NOVARTIS/AVEXIS’ PHASE III STR1VE STUDY OF AND LITTLE BLEEDERS ZOLGENSMA IN SPINAL MUSCULAR ATROPHY Roche/Chugai facilitated a digital-first campaign in partnership with Data presented at the American Academy of Neurology meeting in the world’s biggest social publisher, LADbible, and The Haemophilia May from the ongoing Phase III STR1VE trial of a one-time IV infusion Society and Little Bleeders and developed two Instagram Stories of of Zolgensma in type 1 SMA showed that of 15 patients who that aimed to dispel myths surrounding hemophilia. Roche saw reached 13.6 months of age or discontinued the study prior to 13.6 an opportunity to target the younger generation (18-30 year olds) months of age, 13 (87%) survived without permanent ventilation. who had not been affected by the Contaminated Blood Inquiry and Untreated natural history indicates that only 25% of babies with type 1 create a more positive conversation about hemophilia and empower SMA will survive event-free by the time they reach 13.6 months of age. patients to talk about their condition.

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AstraZeneca’s Farxiga Approval In Heart Failure A First For SGLT2 Inhibitors LEAH SAMUEL [email protected]

arxiga, a sodium-glucose cotrans- definitive moves in the CV space, point- & Co./Boehringer Ingelheim International porter 2 (SGLT2) inhibitor from Astra- ing to the convenience and cost savings GmbH, was the first drug in the class ap- FZeneca PLC, may now be marketed in of a single medication for type 2 diabetes proved to reduce cardiovascular risk in the US to reduce the risk of hospitalization patients who also require treatment for type 2 diabetes based on the EMPA-REG for heart failure (hHF) in patients with type heart failure. outcomes trial in 2017. 2 diabetes, making it the first drug in its While the J&J and Lilly/Boehringer class to win a heart failure indication out- FARXIGA HHF INDICATION drugs have a lead over Farxiga with their side of diabetics with renal co-morbidities. BROADER THAN NEW CV risk reduction indications, Farxiga may The US Food and Drug Administration INVOKANA APPROVAL be the first SGLT2 inhibitor to market as (FDA) approved Farxiga on 21 October as Farxiga’s approval to reduce the risk of hHF a heart failure treatment for patients re- an addition to generic angiotensin-con- in type 2 diabetes patients comes just a few gardless of whether they have diabetes. verting enzyme inhibitors, angiotensin II weeks after the US FDA approved Johnson AstraZeneca has said it will seek a broad receptor blockers and aldosterone antag- & Johnson’s Invokana (canagliflozin) to re- heart failure indication in the first half of onists to reduce the risk of hHF in adults duce the risk of end-stage kidney disease, 2020 based on the DECLARE-TIMI 58 and with type 2 diabetes and established car- doubling of serum creatinine, cardiovascu- DAPA-HF studies. diovascular disease or who have multiple lar death and hospitalization for heart fail- cardiovascular risk factors. ure in adults with both type 2 diabetes and JARDIANCE MAY BEAT AstraZeneca noted that the risk of diabetic nephropathy. FARXIGA TO US TYPE I hospitalization for heart failure “is one of Before adding the hHF indication lim- DIABETES APPROVAL the earliest and most common cardiac ited to diabetics with renal co-morbidities, Lilly and Boehringer’s Jardiance may complications for people living with Invokana was approved last year to re- also have a lead over Farxiga in type 1 type 2 diabetes.” duce the risk of major adverse CV events, diabetes, however. Boehringer is await- The approval is based on results from including heart attack, stroke or CV death, ing a 13 November meeting of the FDA’s the DECLARE-TIMI 58 cardiovascular out- in adults with both cardiovascular disease Endocrinologic and Metabolic Drugs comes trial (CVOT), the largest SGLT2 in- and type 2 diabetes. Advisory Committee, which will evalu- hibitor CVOT conducted to date to evalu- Jardiance (empagliflozin), the well- ate the company’s application for Jard- ate type 2 diabetes patients with multiple established SGLT2 inhibitor from Eli Lilly iance as an adjunct to insulin therapy to CV risk factors or established CV disease. improve glycemic control in adults with It showed that Farxiga significantly re- type 1 diabetes. duced the risk of the primary composite AstraZeneca made similar regulatory fil- endpoint of hHF or CV death versus pla- The risk of ings earlier this year, winning approval in cebo by 17%; this finding was driven by Europe and Japan, but not in the US. The a significant 27% reduction in the risk of hospitalization for European Medicines Agency approved hHF. The treatment benefit was consistent heart failure is one Forxiga (the drug’s name in the EU) on across patient subgroups. the basis of the Phase III DEPICT-1 study, Another study of Farxiga replicated of the earliest and which showed that Forxiga compared to these findings, including in non-diabet- placebo not only required fewer correc- ics. The DAPA-HF randomized trial tested most common cardiac tive insulin doses, but reduced blood sug- whether dapagliflozin would reduce the complications for people ar levels (HbA1c) and helped with weight primary composite outcome of worsen- loss at both the 5mg and 10mg doses. ing heart failure resulting in hospitaliza- living with type 2 The FDA, however, cited concerns about tion, intravenous therapy or cardiovas- the safety of the drug, pointing to the po- cular death in patients with heart failure, diabetes. tential for ketoacidosis, and rejected As- with or without type 2 diabetes. Among traZeneca’s application. the patients who received dapagliflozin, If Jardiance succeeds where Farxiga the frequency of the primary composite failed, it could have a significant market outcome was 26% lower than that among advantage as the first SGLT2 inhibitor ap- the patients who received placebo. proved in the US as a supplemental treat- Biomedtracker analysts have predict- ment for type 1 diabetes. ed that the SGLT2 drug class would make Published online 23 October 2019

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J&J’s Spravato Set For EU Launches Soon

KEVIN GROGAN [email protected]

ohnson & Johnson’s Spravato is within touching distance of lence is scheduled to make a decision on whether to approve the an approval in the EU after the closely watched antidepres- drug for use on the National Health Service in March next year. Jsant derived from ketamine got a positive opinion from Euro- One issue that could impact on access are side effects, the most pean Medicines Agency advisors. common being dizziness, nausea, dissociation, headache, somno- The agency’s Committee for Medicinal Products for Human Use lence and vertigo, the EMA noted. In the US, the approval came (CHMP) has recommended approval for Spravato (esketamine) with a Risk Evaluation and Mitigation Strategy (REMS) program, nasal spray in combination with standard of care drugs – a selec- which requires patients to be monitored at a certified clinic for tive serotonin reuptake inhibitor or serotonin and norepineph- two hours after each weekly dosing and this could be a barrier to rine reuptake inhibitor – for treatment-resistant major depressive Spravato being made widely available in Europe. disorder (MDD). That refers to patients who have had a lack of re- Another issue is sure to be cost. In the US, Spravato’s list price is sponse to at least two different antidepressants. $6,785 for the first month and $3,450 thereafter and the Institute If approved by the European Commission, Spravato, a selective for Clinical and Economic Review released a report on 20 June, NMDA receptor modulator, will offer the first new mechanism concluding the drug’s $32,400 annual list price would require a of action in 30 years to treat MDD. The drug won US approval in 25%-52% discount to reach a “fair” value-priced benchmark. March. At the time, J&J disagreed with the ICER report, maintaining it The market is potentially huge, given that MDD affects about 40 “underestimates the proven short- and long-term benefits that million people across Europe. Allitia DiBernardo, European thera- this treatment, which was granted FDA breakthrough therapy peutic area lead for mood disorders at J&J’s Janssen-Cilag division, designation, brings to TRD patients in need.” (Also see “ICER Faces said “of these people, about one third do not respond to currently New Foe As Patient, Disability Alliance Takes Aims At Reports On available treatments.” Mayzent, Spravato” - Pink Sheet, 22 Jun, 2019.) One of the attractions of Spravato is the rapid response of pa- J&J has said that the US launch has been going well but on its tients to treatment. Existing antidepressants can take several conference call for the third quarter on 15 October, the company weeks to provide relief, whereas the response to Spravato has disappointed some observers by not providing any sales figures. been observed within 24 hours of treatment, which should help Management did say that more than 2,000 sites have been certi- J&J in its discussions with the various European health technology fied under the REMS program for Spravato and that 500 of those assessment bodies. sites are actively treating patients with the drug. The positive opinion in Europe is based on five Phase III trials and Spravato is a key growth driver and earlier this month, J&J filed J&J noted that in one of them, a one-month study, approximately a supplemental new drug application with the US Food and Drug 70 % of all esketamine-treated patients responded to treatment Administration for Spravato for the treatment of patients with with a greater than 50% symptom reduction. Furthermore, “ap- major depressive disorder who have suicidal ideation with intent, proximately half of all treated patients achieved remission, with a very severe patient population that has typically been left out few, if any, symptoms of depression, which is the ultimate treat- of clinical trials. ment goal,” J&J stated. The filing was based on the results of two Phase III clinical tri- J&J is not disclosing any launch plans yet, although in the UK als that focused on the challenging patient population and met Spravato, which as a nasal spray is given in far lower doses than the primary endpoint of reducing depressive symptoms. (Also see the illicit party drug, is initially likely to be made available through “J&J Looks To Expand Spravato Label To Suicidal Ideation” - Scrip, private clinics. The National Institute for Health and Care Excel- 10 Sep, 2019.) Published online 21 October 2019 An Early Surprise Win For BMS’s Opdivo/Yervoy In Lung Cancer

MARY JO LAFFLER [email protected]

ristol-Myers Squibb Co. should be 22 October of an important win in the the Phase III CheckMate-227 trial came able to forestall some investor con- critical first-line lung cancer setting for the out the evening before second-quarter Bcerns about lagging sales of its one- combination of Opdivo plus BMS’s CTLA-4 sales and earnings were released. The ‘227 time leading PD-1 inhibitor Opdivo when inhibitor Yervoy and chemotherapy. data, which support the immuno-oncolo- third quarter results are released on 31 It’s an oddly similar dynamic to the pre- gy combination’s use as a chemo-free op- October with the surprise announcement vious quarter, when positive results from tion for first-line non-small cell lung can-

cer, dominated the earnings call – where ficacy stacks up between the two trials Q2 Yervoy (ipilimumab) sales dropped is uncertain at the moment; predictably, from Q1, although they rose 17% from CM-9LA safety/tolerability will very likely the second quarter of 2018 to $367m. Op- look worse vs KN-189.” divo sales increased 12% year-over-year to There’s more competition coming from $1.82bn for the second quarter of 2019. other IO brands as well. AstraZeneca PLC’s Analysts are anticipating lower sales for POSEIDON trial of Imfinzi (durvalumab) Opdivo and Yervoy for Q3, however. Con- plus its CTLA-4 inhibitor tremelimumab sensus estimates for Opdivo (nivolumab) plus chemo vs. chemo alone in first-line global sales come in at $1.86bn, although The CheckMate-9LA NSCLC is due to report PFS results by year- Morgan Stanley analyst David Risinger results, which weren’t end. AstraZeneca’s trial is quite similar to projects just 1% year-over-year growth to CheckMate-9LA, except chemotherapy is $1.81bn due to “pressure from a shrinking expected until the first dosed continuously rather than the two 2L IO lung cancer market, and growth is cycles used in BMS’s trial. The Imfinzi- driven primarily by adjuvant melanoma half of 2020, are an tremelimumab combination has not and 1L renal cancer.” He also reports to- important win for BMS. yielded great success in previous trials, tal prescriptions for Opdivo are down and recently failed to improve overall sur- 6% year-over-year in recent months. As vival in first-line NSCLC patients with high for Yervoy, Risinger expects global sales tumor mutational burden (TMB) in the of $361m for the third quarter, down 5% NEPTUNE trial. from the same quarter in 2018, while con- A final overall survival readout is sensus is $392m. expected by the end of the year for On 22 October, BMS announced the Roche’s IMpower 132 trial of Tecentriq early termination of the CheckMate-9LA (atezolizumab) plus chemo vs. chemo study after a pre-specified interim analy- alone in non-squamous NSCLC. The sis showed a benefit in overall survival for combination has yet to show a survival Opdivo plus Yervoy and two cycles of che- benefit, however, though it is thought motherapy versus standard chemothera- that may be related to PD-L1 expres- py in first-line treatment of non-small cell sion. (Also see “IMpower132 Casts More lung cancer (NSCLC). cant market share.” Although he and other Doubt On Roche’s Tecentriq In First-Line Wolfe Pharma analyst Tim Anderson analysts agree that “the full presentation NSCLC” - Scrip, 25 Sep, 2018.) saw it as “much-needed positive news” of results and safety will be needed to for BMS as the deal closure with Celgene fully assess the potential of this regimen in WHY TWO CYCLES OF Corp. nears, which will trigger a $7bn ac- the competitive NSCLC landscape,” Phipps CHEMOTHERAPY? celerated share repurchase program. believes the dual datasets should “remove BMS’s Opdivo did not succeed in combi- (Also see “Amgen’s $13.4bn Otezla Buy investor fears regarding the inability of the nation with chemotherapy in a separate Helps Bristol/Celgene Merger Close By company to have clinical success in this arm of CheckMate-227, which was a sur- Year-End” - Scrip, 26 Aug, 2019.) The long- disease setting” and that “investors should prising result because chemotherapy has awaited lung cancer victory should be a have greater confidence in the ability of been a good partner for other IO drugs. nice start as the next couple years will be Opdivo to return to growth given likely The CheckMate-9LA data do provide posi- busy as the “very full” combined Phase III approvals of CheckMate-227 and Check- tive confirmation for an important seg- pipeline progresses. Mate-9LA regimens in first-line NSCLC.” ment of the market. The CheckMate-9LA results, which Immunotherapy benefit, especially for weren’t expected until the first half of BUT WILL IT COMPARE Yervoy, takes time to show, while chemo- 2020, are an important win for BMS. Af- TO MERCK? therapy tends to have quick but not dura- ter a strong start, Opdivo started losing Morgan Stanley’s Risinger, however, “cur- ble effect. “CM-227 proved that the CTLA4 ground in lung cancer and was surpassed rently assume[s] efficacy will be inferior to component offers a durable longer-term as class leader by Merck & Co. Inc.’s Key- MRK’s data cross-trial based upon histori- benefit to patients, but that patients have truda (pembrolizumab). The back-to-back cal analyses.” to wait for some period of time for this to victories in first-line lung cancer should Merck’s dominance has many bases, manifest. It would be better to show both help BMS gain traction in what is the larg- as Keytruda has been shown to offer im- an early and late benefit,” Wolfe Pharma’s est market for immuno-oncology drugs. proved survival as monotherapy and in Anderson commented. “By combining William Blair analyst Matt Phipps com- combination with chemotherapy. “This chemotherapy+Opdivo+Yervoy, BMY mented in a 22 October note that “the will be the benchmark for CM-9LA to may have (finally) found a cocktail of CheckMate-9LA regimen [has] true poten- beat,” Wolfe’s Anderson said in a same- drugs that delivers both near- and longer- tial to move the needle in first-line NSCLC day note. Comparing the trials will have term benefit, leading to an early response and allow Bristol-Myers to garner signifi- to wait for the ‘9LA data, and “how ef- and improved long-term survival.”

scrip.pharmaintelligence.informa.com November 1, 2019 | Scrip | 19 RESEARCH & DEVELOPMENT

Whereas there was no separation of the curves in the first six months of the Check- Seattle Genetics Poised For Big Mate-227 trial, with a trend favoring the chemotherapy arm, using two cycles of chemotherapy has the potential to boost Breast Cancer Launch On Positive the number of initial responders and keep alive patients with aggressive disease – Tucatinib Data helping the survival curves, William Blair’s JESSICA MERRILL [email protected] Phipps explained. “The initial benefit from two cycles of chemotherapy may be most eattle Genetics Inc. appears on track to bring a competitive new drug to market evident in the progression-free survival for advanced or metastatic HER2-positive breast cancer late next year in what is an (PFS) curves, given 30% to 40% of patients Sincreasingly crowded therapeutic area. The company said on 21 October that it ex- treated with Opdivo plus Yervoy have pects to file a new drug application (NDA) with the US Food and Drug Administration disease progression within the first three in the first quarter of 2020 for an oral tyrosine kinase inhibitor that is selective for HER2, months, versus only 20% to 25% for che- tucatinib, which provided notable progression-free survival (PFS) and overall survival (OS) motherapy treated patients,” he added. benefits for patients in an interim look at a pivotal clinical trial. There is a greater safety burden with Due to the positive result, the trial was unblinded and all patients will be given tucatinib the triple combination, but BMS is us- going forward. The positive data triggered a stock rally, with Seattle Genetics closing up ing the lower-dose Yervoy regimen that 15.4% on 21 October at $100.89 per share. was shown to be very tolerable in Check- The Phase II trial – HER2CLIMB – met the primary endpoint of superiority in PFS for Mate-227, with 33% of patients experienc- patients treated with tucatinib plus Roche’s Herceptin (trastuzumab) and capecitabine ing grade 3-4 treatment-related adverse versus trastuzumab and capecitabine alone, with a 46% reduction in the risk of disease events versus 36% of patients treated progression or death. The trial also met the key secondary endpoint of OS, with a 34% with standard-of-care chemotherapy, reduction in the risk of death compared to trastuzumab and capecitabine alone. Phipps reported. “We assume the addition The magnitude of the benefits in terms of months was not disclosed in the top-line of chemotherapy will increase the overall data, but Seattle Genetics plans to present the full data at the San Antonio Breast Cancer adverse event rate in the CheckMate-9LA Symposium on 11 December. trial, but believe it will still be manageable “We believe these outstanding results demonstrate that tucatinib is a differentiated, given the typical lack of overlapping tox- best-in-class, oral HER2 tyrosine kinase inhibitor with a tolerable safety profile that im- icities of the two drug classes. In addition, proves outcomes for patients,” CEO Clay Siegall said during a same-day conference call. treating patients with only two cycles of chemotherapy will reduce the cumula- UNIQUE TRIAL DESIGN SHOWS SUPERIORITY tive platinum toxicity that occurs with in- Demonstrating a significant benefit in combination with Herceptin is a unique develop- creased exposure,” he said. ment and commercial strategy for tucatinib. According to BMS, the safety profile is AstraZeneca PLC and Daiichi Sankyo Co. Ltd., for example, have filed for FDA approval reflective of the known safety profiles of of a trastuzumab-containing antibody drug conjugate (ADC) trastuzumab deruxtecan as the immunotherapy and chemotherapy monotherapy, based on positive data from the DESTINY-Breast01 trial. The open-label trial components in first-line NSCLC. The Op- tested the drug in advanced and/or metastatic patients previously treated with Roche’s divo/Yervoy combination is already es- ADC Kadcyla (trastuzumab emtansine). tablished in melanoma and renal cell car- A biologic license application (BLA) for trastuzumab deruxtecan has been accepted for cinoma, using the lower 3mg/kg regimen priority review by the US FDA with an action date in the second quarter, AstraZeneca and for ipilimumab. Daiichi announced on 17 October. BMS will be pushed on its 31 October The two companies partnered in early 2019, with AstraZeneca agreeing to pay $1.35bn earnings call for details on when the full up front to develop and commercialize trastuzumab deruxtecan jointly. The full data from data will be presented, as the firm only DESTINY-Breast01 have not been disclosed. noted that it will be shared “at an upcom- “You want to choose not the worst of the control arms. You want to choose the best ing congress.” and give yourself a high bar,” Siegall said of the HER2CLIMB clinical trial design. And when As Wolfe’s Anderson concluded, “the pressed on how tucatinib might compare to the AstraZeneca/Daiichi drug in the market, commercial value of CM-9LA will … de- he responded, “I think you will see lots of ways to use tucatinib into the future, alone or in pend on the balance between the clini- combination with many other drugs,” Siegall said. “We think that this oral tablet, relatively cal benefit and the toxicity. It will only well tolerated, [with] impact on brain mets really has a lot of legs.” be once full results are presented that HER2CLIMB enrolled advanced patients, including those with brain metastases, who this risk:benefit assessment will be pos- also showed improvements, with a notable 52% reduction in the risk of disease progres- sible. Additionally, adding a third drug sion or death compared to those who received trastuzumab and capecitabine alone. The into the mix also raises the cost of thera- results included data on the first 480 patients, who had previously been treated with py somewhat.” trastuzumab, pertuzumab (Roche’s Perjeta) and Kadycla; 47% had brain metastases at the Published online 22 October 2019 time of enrollment. HER2CLIMB enrolled a total of 612 patients.

MacroGenics Inc. also is developing a monoclonal antibody targeting HER2, margetuximab, which prolonged PFS in patients with metastatic breast cancer in the SOPHIA trial presented at the Ameri- can Society for Clinical Oncology (ASCO) meeting. Initial overall survival data were underwhelming at ASCO, but more OS details and a BLA filing with the FDA are anticipated in the fourth quarter. (Also see Seattle Genetics hopes to differentiate “Weak SOPHIA OS Signal Dampens Enthu- tucatinib from other HER2-targeting siasm For MacroGenics’ Margetuximab “ - cancer drugs. Scrip, 13 Jun, 2019.) Seattle Genetics acquired tucatinib in 2018 with the purchase of Cascadian “We believe that the benefits on over- DIFFERENTIATION FROM Therapeutics Inc. for $614m in cash. The all survival and in patients with baseline TYKERB AND NERLYNX deal came about after Seattle Genetics’ li- brain mets at the interim analysis are ex- Tucatinib was generally well tolerated, the censing deal with Immunomedics Inc. fell tremely compelling,” SVB Leerink analyst company reported, with a manageable through, as the company sought to ex- Andrew Berens said in a same-day re- safety profile. The most frequent adverse pand its pipeline beyond its internally search note. The benefit seen in patients events were diarrhea, palmar-plantar developed antibody-drug conjugates, with brain metastases could result in tu- erythrodysesthesia syndrome (PPE), nau- including Adcetris (brentuximab vedotin) catinib emerging as a treatment of choice sea, fatigue and vomiting. Adverse events for various CD30+ lymphoma indications. through all lines of therapy in patients leading to discontinuations were infre- The company has initiated a Phase with brain metastases, he said. quent in both the tucatinib arm and con- III trial, HER2CLIMB002, exploring tu- Additionally, Berens applauded the trol arm (5.7% and 3%, respectively). catinib in combination with Kadcyla in company’s decision to study tucatinib in Tucatinib, an oral tyrosine kinase in- locally advanced or metastatic HER2- combination with trastuzumab, which hibitor (TKI), blocks HER2 without sig- positive breast cancer. Seattle Genet- puts the drug in a strong position com- nificant inhibition of EGFR, which has ics is also studying the drug in earlier peting against biosimilar versions of Her- been associated with toxicities like skin lines of breast cancer and other types of ceptin, which have launched in Europe rash and diarrhea. HER2-driven cancer, including colorectal and the US. This difference in selectivity is one cancer. Based on the positive data, man- “Seattle Genetics has strategically cho- thing that separates tucatinib from other agement sounded aggressive about the sen to piggyback on Herceptin’s success,” TKIs, the company said, like Novartis AG’s future development strategy. he said. “While it is an extremely high bar Tykerb (lapatinib) and Puma Biotechnol- “We are going to expand it. It deserves clinically to demonstrate increased effica- ogy Inc.’s Nerlynx (neratinib). Both drugs it,” Siegall said. The company is particularly cy over Herceptin via dual HER2 blockade, are approved for HER2+ advanced or met- interested in studying tucatinib in less ad- we believe this strategy could lead to sig- astatic breast cancer, but use of the drugs vanced patients and the potential impact nificant commercial success, especially as has been constrained by limited efficacy on brain metastases. biosimilar Herceptin emerges.” and high toxicity. Published online 21 October 2019 Novartis’s Fevipiprant Hit By Phase III Asthma Failure ELEANOR MALONE [email protected]

ovartis AG’s asthma hopes have The negative result means the weight receptor-homologous molecule (CRTH2) been dented somewhat by a of expectation increases for another pair receptor, since others in its class have had NPhase III miss for its small mole- of Phase III studies, LUSTER 1 and 2, which mixed results. Citeline’s Trialtrove data- cule candidate QAW039 (fevipiprant). In a are due to read out in the first quarter of base shows that there have been almost note buried in its third-quarter results an- 2020. These are pivotal safety and efficacy as many negative primary outcomes as nouncement, the group revealed that the studies of fevipiprant measuring its effect positive ones in trials of drugs in this class. oral product had failed to reach the prima- on the rate of exacerbations in severe, un- AstraZeneca PLC’s AZD1981, Amgen ry efficacy endpoint of forced expiratory controlled asthma. Inc.’s AMG853, Actelion Pharmaceuticals volume (FEV1) improvement in two Phase Hopes have been somewhat muted Ltd.’s setipiprant and Boehringer Ingel- III trials in patients with moderate asthma. for fevipiprant, an antagonist of oral heim International GmbH’s BI 671800 The safety profile was, however, clean. prostaglandin DP2, or chemo-attractant TURN TO PAGE 23

scrip.pharmaintelligence.informa.com November 1, 2019 | Scrip | 21 PIPELINE WATCH

Scrip’s weekly Pipeline Watch tabulates the most recently reported late-stage clinical trial and regulatory developments from the more Click here for the entire pipeline Pipelinethan 10,000 drug Watch candidates currently- 18-24 under October,active research worldwide. 2019 with added commentary: http://bit.ly/2mx4jY3 Phase III

PIPELINESearch WATCH, 18–24 OCTOBER 2019

Change LOA Event Stage Lead Company Drug Name Indication Comments To LOA (%) (%) Phase III Estelle Updated Mithra Contraception E4 FREEDOM; Effective 0 71 (estetrol/drospirenone) Results Phase III Fortress Biotech, Postsurgical Effective, Well Updated tramadol, intravenous 0 63 Inc. Pain Tolerated Results Phase III Breast Cancer, Updated MacroGenics, Inc. margetuximab SOPHIA; Mixed Results 0 45 HER2-Positive Results Phase III Hepatitis B PROTECT; Met Updated VBI Vaccines Inc. Sci-B-Vac vaccine 0 67 Prevention Endpoints Results Phase III Multiple ASCLEPIOS I, II; Updated Novartis/Genmab ofatumumab 0 58 Sclerosis Positive Results Results Phase III EMERGE, ENGAGE; Alzheimer's Updated Biogen, Inc./Eisai aducanumab Reduced Clinical 44 44 Disease, Early Results Decline Phase II/III Pulmonary Bellerophon Updated INOpulse (nitric oxide) Arterial iNO-PF; Positive Data 0 15 Therapeutics, Inc. Results Hypertension Growth Phase III Top- Lagova (somatrogon), Study 006 (Pediatric); Opko Health/P�zer Hormone 3 57 Line Results long-acting Positive Results De�ciency Tecentriq Phase III Top- Hepatocellular Roche Holding AG (atezolizumab)/Avastin IMbrave150; Improved 7 41 Line Results Cancer (bevacizumab) OS And PFS Phase III Top- Asthma, Novartis AG fevipiprant (QAW039) ZEAL-1,2; Missed Primary -3 65 Line Results Moderate Endpoint Orchard Phase III Top- Metachromatic Therapeutics OTL-200, gene therapy Encouraging Results 0 62 Line Results Leukodystrophy Limited Phase III Top- Aclaris Eskata (hydrogen THWART-1; Met All Common Warts 0 70 Line Results Therapeutics, Inc. peroxide) Endpoints FREEDOM-1; To Kidney Phase III Trial Talaris Therapeutics, Reduce FCR001, cell therapy Transplant 39 59 Initiation Inc. Immunosuppressive Rejection Need Phase III Trial Gilead Psoriatic �lgotinib Versus adalimumab 39 64 Initiation Sciences/Galapagos Arthritis Using ADAM Phase II/III Zosano Pharma C213 (zolmitriptan Cluster Microneedle 0 57 Trial Initiation Corporation patch) Headache Technology Ex. Patients Phase III Trial AB Science S.A. masitinib Mastocytosis w/CutaneousSource: Biomedtracker0 | Informa, 54 2019 Announcement Mastocytosis 22 | Scrip | November 1, 2019 Proliferative © Informa UK Ltd 2019 Phase III Trial CONDOR; Versus Novartis AG Beovu (brolucizumab) Diabetic 51 Announcement a�ibercept Retinopathy

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

CONTINUED FROM PAGE 21 able group of some 1.4 million patients Novartis R&D chief John Tsai indicat- have all failed in asthma. Another CRTH2 aged 12 or over in the US had the treated that winning approval in the severe receptor antagonist, OC000459 (timapip- ment proved successful. asthma indication had always been the rant), was licensed by Oxagen Ltd. to Elev- By comparison, the LUSTER trials are primary goal for fevipiprant, and that the enta for Russia and CIS markets and to studying two doses of fevipiprant com- ZEAL studies in less severe disease were Chiesi Farmaceutici SPA for other markets, pared with placebo over 52 weeks in two done because they were requested of the and has completed a Phase III study in un- separate patient populations: one restrict- company. He noted that the ZEAL results controlled, severe, eosinophilic asthma, ed to patients with severe asthma and were “largely in line with what we saw in but results have not been reported. high eosinophil counts, while the other Phase II” and that he didn’t expect a “read- includes all patients with severe asthma through” from those results to the LUSTER SEVERE ASTHMA TRIAL IS THE regardless of eosinophil status. The pri- results. He added that DP2 activation in- REAL TEST mary efficacy endpoint will be the rate of creases with disease severity, which would Nevertheless, expectations are that the asthma exacerbations, with asthma qual- imply that “as you have more disease you Novartis drug candidate will have a better ity of life score, asthma control score and would likely get more response from DP2s chance of success in severe disease. “If fe- lung function also to be assessed. [like fevipiprant].” vipiprant does work then we think it is more Novartis assumes that should fevipip- Analysts have predicted that Novartis’s likely to work in the LUSTER 1 & 2 studies rant be approved in its base case scenario oral drug could become a blockbuster if in severe asthma patients than in the ZEAL for patients with severe asthma and high approved in asthma. Jefferies analysts put 1 & 2 studies in moderate patients,” com- eosinophils, that would address a US pa- the peak sales forecast at $1.5-2.1bn should mented Jefferies analysts in a 22 October tient population of 1.5 million patients it gain approval, depending on the breadth note, citing an asthma expert who thought aged 12 and over. That would double to 3 of the indication and the pricing strategy. the drug would be adopted but who saw million if it were to be approved also for In fact, the drug could still reach $2bn the evidence for CRTH2 antagonists in mild- patients with low eosinophils. sales even without the moderate asthma moderate asthma as “unconvincing.” “The negative results from these lung indication, they said in a 15 October ZEAL measured lung function change function studies may not bode well for analysis. Nevertheless, their base case over 12 weeks, when fevipiprant was giv- the broader all comers population in the scenario is that it will generate peak sales en on top of inhaled standard of care (i.e., LUSTER studies, evaluating the drug’s ef- of $1.5bn with use predominantly in the inhaled corticosteroid (ICS) with or with- fect on exacerbations, but there is still 10-20% of high eosinophilic severe asth- out a long-acting beta agonist (LABA)). potential for the sub-group of severe ma patients who don’t respond to bio- The trial population had moderate asth- patients with high eosinophils,” com- logics. They pegged the US net price at ma with eosinophils ranging from low to mented Datamonitor Healthcare analyst $7,500 for this scenario. high: this population would yield a treat- Pamela Spicer. Published online 22 October 2019 Company Move APPOINTMENTS Search

To From Effective Executive New Role Previous Role Company Company Date Vice President, Business Beverley Achilles Chief Business O�cer GlaxoSmithKline Development, Immuno- 4-Nov-19 Carr Therapeutics in�ammation Therapy Christopher Cadent Acorda Senior Vice President, Medical Chief Medical O�cer 17-Oct-19 Kenney Therapeutics Therapeutics Affairs Senior Vice President, Greg Noxopharm DZS Clinical Founder and Chief Executive North American 16-Oct-19 Ambra Ltd Services O�cer Operations Nabriva Colin Pulmotect Chief Executive O�cer Therapeutics Chief Executive O�cer 17-Oct-19 Broom Inc plc Tilos Barbara S. Rheos Chief Executive O�cer, Chief Executive O�cer Therapeutics 21-Oct-19 Fox Medicines Founder and Director Inc

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