Spin-Out a Neat Solution for Sanofi's Manufacturing Millstone

No. 3993 February 28, 2020

deteriorate in recent years. (Also see “Sanofi Highlights MS Asset After Solid Q4” - Scrip, 6 Feb, 2020.)

NO MORE PROCRASTINATION Hudson says Sanofi has “procrastinat- ed” on making hard decisions, and the future of its manufacturing base was a major one. The new company’s ranking as the second largest API company globally would be based on sales of approxi- mately €1bn by 2022. The standalone company will com- bine Sanofi’s API commercial and development activities with six of its Europe- an API production sites: Brindisi (Italy), Frankfurt Chemistry (Germany), Haver- hill (UK), St Aubin les Elbeuf (France), Újpest (Hungary) and Vertolaye (France). Sanofi says it intends to establish a long- term customer relationship with the new Spin-Out A Neat Solution For API supplier and to hold a minority stake of around 30% in the new company. It is expected to include 3,100 skilled Sanofi’s Manufacturing Millstone employees and to be headquartered ANDREW MCCONAGHIE [email protected] in France. A planned IPO on Euronext Paris will be weighed up, with a deci- anofi’s new CEO Paul Hudson has Hudson finds solution sion expected by 2022, depending on come up with a neat solution to market conditions. Swhat to do with a string of six out- for legacy sites that have dated manufacturing sites across Europe. MORE STABILITY The company is to spin-out the sites dogged predecessors. Announcing the decision, the com- into a standalone active pharmaceutical pany’s executive vice president, global ingredient (API) manufacturing compa- industrial affairs, Phillipe Luscan, said ny, which would be the second biggest the creation of the company could in the world. the ejection of an earlier chief executive, help bring “greater stability” to medi- Chris Viehbacher in 2014. cines supplies in Europe and the rest of STANDOFFS Hudson took over the top spot in the world. API manufacturing has be- The Paris-headquartered firm was September last year, and has made a come heavily dependent on India and formed by a merger in 2004, but strong series of decisions to move the com- China facilities – the latter accounting unions in France and Germany have re- pany forward since his arrival. This for around 40% of global supplies, but stricted its ability to close its older man- included the decision to abandon fur- its output is currently badly hit by the ufacturing sites – standoffs with unions ther R&D investment in diabetes, after coronavirus outbreak. over job losses being a major factor for having seen its franchise in the field Published online 25 February 2020

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Companies Enter COVID-19 Fightback BMS Joins CAR-T Party Beovu Woes A range of tactics is being tested Liso-cel filing set to change the Novartis’s new AMD therapy hits safety (p16-19) dynamic (p12) concerns (p8) IN THIS ISSUE

from the editor [email protected]

Halicin – the antibiotic candidate recently discovered of Acinetobacter baumannii that is resistant to all known using a machine learning tool developed at Massachu- antibiotics. So far, so exciting. setts Institute of Technology – should be a good news However, the cost and uncertainty associated with story both in the fight against antimicrobial resistance bringing it to eventual approval as a medicine remain and for the improvement of drug discovery through the considerable. use of artificial intelligence. MIT hopes to partner the compound for further devel- The compound was discovered in the Broad Insti- opment. But while big pharma is keen to embrace AI in tute’s open access library of drugs for repurposing drug discovery and beyond, its enthusiasm for novel an- based on its predicted antibacterial activity as identified tibiotics is in short supply, especially when they have yet by a machine learning model that had been trained on to enter human trials (unsurprisingly given that return compounds whose activity against Escherichia coli was al- on investment in this therapeutic area is often negative). ready known. Another machine learning model identi- Let’s hope that soon health systems will come up fied it as likely to have low toxicity in humans. with appropriate commercial incentives to encourage Originally under investigation to treat diabetes, hali- pharma back into the space and enable us to fully profit cin has a novel mechanism of action as an antibiotic, is from such exciting developments in the desperate fight active against many highly resistant bacteria, and in ear- against AMR. ly tests in mice was able to clear infections with a strain

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

2 | Scrip | February 28, 2020 © Informa UK Ltd 2020 Polyphor’s Change Of Focus Vyndaqel Spreads Its Wings

Fighting The 20 5 7 Coronavirus 16

exclusive online content inside: COVER / Spin-Out A Neat Solution For Sanofi’s Manufacturing Pfizer Upjohn’s Ray On Changing The Grave Millstone Trajectory Of NCDs 4 Sobi Reaps Benefits From Acquisitions, Commercial Focus ANJU GHANGURDE [email protected] 5 Merck KGaA Tightens Focus With Allergopharma Sale

5 Job Cuts As Polyphor Focuses On First-In-Class Anticancer

6 Esperion’s Nexletol Reaches The Cholesterol Market Priced To Sell

7 A Runaway Hit In US, Pfizer Gains EU Nod for Vyndaqel In Cardiomyopathy

8 Novartis’s Beovu Launch Clouded By Safety Worries

10 FDA Rejects Keytruda Dosing, Fast Tracks Tecentriq Lung Cancer Review

10 Bluebird Expects Three Filings In 2020, But US Zynteglo Submission Pushed Back Pfizer Upjohn is engaged in a range of activities aimed at moving the needle to improve outcomes and help address 12 With BMS Set To Join, What Next For CAR-T Market? the public health challenge of non-communicable diseases (NCDs), the silent epidemic that is the leading cause of 13 Incyte Ready To Go For Approval premature death globally. Of Topical Ruxolitinib In Atopic Dermatitis In a wide-ranging interview with Scrip, Amrit Ray, Global 14 Genfit Delays NASH Data While It Confers With US FDA President of R&D and Medical at the company, outlines On Methodology how Upjohn’s SNAP (Strategic segmentation for NCD country Action Plans) framework can help establish mar- 16 Coronavirus Pipeline: ket-specific intervention strategies and also lists efforts GSK And Clover Add To Collaborations underway in the Middle East, where the company is sup- porting the United Arab Emirates Healthy Future Study. 18 Flu Vaccine Leader Sanofi Joins Fight Against COVID-19 The long-term study reportedly hopes to enroll about 20,000 participants to determine the causes of chronic dis- 20 Teva’s Austedo Fails In Tourette’s Syndrome eases in Emiratis across the UAE. 21 Stockwatch: Choppy Waters For Teva And Bausch Ray, who comes with extensive experience and a multi- faceted career – including prior roles at Johnson & John- 22 Pipeline Watch son (as global pharmaceuticals Chief Medical Officer) and McKinsey and as a physician in the UK’s National Health 23 Appointments Service – also touched upon the value of embracing digi- tal and artificial intelligence tools. Published online 24 February 2020 To read the rest of this story go to: https://bit.ly/39V5uo2 @PharmaScrip /scripintelligence

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scrip.pharmaintelligence.informa.com February 28, 2020 | Scrip | 3 COMPANIES

Sobi Reaps Benefits From Acquisitions, Commercial Focus JOHN DAVIS [email protected]

ecent strategic product acquisitions (emicizumab). Sobi markets the long-acting With Doptelet, Sobi expects launch of the have strengthened the hematol- Factor VIII product, Elocta (efmoroctocog chronic liver disease indication in the EU in Rogy and immunology businesses alfa), and Factor IX product, Alprolix (eftre- the second half of 2020, and an EU market- of European mid-sized pharma compa- nonacog alfa), in the EU and the middle ing submission for the ITP indication to be ny, Swedish Orphan Biovitrum AB (Sobi), east; partner Sanofi markets them in the US. filed in the first half of 2020. An EU submis- and with several late-stage candidates in Sobi is reaping the benefits of the chang- sion for the use of Kineret (anakinra) for the its pipeline, it expects a “series of launches es: in 2019, total revenues grew by 56% to treatment of familial Mediterranean fever is in the months and years ahead.” reach SEK14.25bn ($1.46bn), and adjusted expected by the end of 2020. “2019 was indeed the year of transfor- EBITA reached SEK6.14bn, up by 72%. How- On the other hand, partner products mation,” said CEO Guido Oelkers. Early in ever, net debt increased to SEK15.40bn by within the specialty care portfolio that the year, Sobi completed the acquisition the end of 2019, compared with net cash of will be discontinued in 2020 will include of US rights to the respiratory syncytial SEK2.99bn on 31 December 2018. Xiapex (collagenase Clostridium histolyti- virus (RSV) therapy, Synagis (palivizumab), During 2019, Synagis performed ex- cum), Ruconest (C1 esterase inhibitor) and from AstraZeneca PLC, and a US commer- tremely well, and Elocta and Alprolix sales Ravicti (glycerol phenylbutyrate). Sales of cialization team. also grew, and the company strengthened Sobi’s leading products are shown in the In June, the Stockholm-headquartered its North American franchise, noted Oelk- table below. firm acquired the hemophagocytic lym- ers. With Elocta, “there is a very substantial Avatrombopag is being investigated phohistiocytosis (HLH) therapy, Gamifant share still out there to convert from the for chemotherapy-induced throm- (emapalumab) from Novimmune SA. short-acting sector,” he noted. bocytopenia in a Phase III study, with More recently, it acquired Dova Pharma- Growth in the 2019 fourth quarter was results expected in the second half ceuticals Inc.., which brought the throm- particularly marked, with revenues up by of 2020. An RSV follow-on product, bopoietin receptor agonist, Doptelet 90% and adjusted EBITA up by 160% com- nirsevimab (MEDI8897), and a candi- (avatrombopag), which is approved in Eu- pared with the 2018 fourth quarter, the date hemophilia A product, BIVV001, rope for chronic liver disease, and market- company reported on 13 February. are in Phase III studies, and a trial of ed in the US for chronic liver disease and In 2020, the company is forecasting an emapalumab for the treatment of chronic immune thrombocytopenia (ITP). increase in revenues to SEK15bn to SEK- secondary HLH has started in adults. These strategic moves are expected to re- 16bn, reflecting double-digit growth in Emapalumab has also been filed for duce Sobi’s reliance on its hemophilia prod- the two core businesses, hematology and approval in the EU for primary HLH. ucts, a therapeutic sector with competitive immunology. EBITA is expected to be flat, new entrants, such as Roche’s Hemlibra in the range SEK5bn to SEK6.3bn. Published online 18 February 2020

Sobi’s 2019 Revenues By Business Area

PRODUCT 2019 SALES (SEKM) 2018 SALES (SEKM) CHANGE CHANGE AT CER

Elocta 4,508 3,261 38% 34% Alprolix 1,463 974 50% 46% Royalties 1,373 1,341 2% -6% Doptelet 34 - N/A N/A Manufacturing revenues 376 436 -14% -14% Total Hematology 7,755 6,012 29% 24% Kineret 1,571 1,320 19% 12% Synagis 2,594 - N/A N/A Gamifant 542 - N/A N/A Total Immunology 4,706 1,320 257% 231% Total Specialty Care 1,787 1,807 -1% -6% Total Revenues 14,248 9,139 56% 48% Source: Sobi

4 | Scrip | February 28, 2020 © Informa UK Ltd 2020 COMPANIES

Merck KGaA Tightens Focus With Allergopharma Sale

JOHN DAVIS [email protected]

he sale of Merck KGaA’s allergy im- But Allergopharma’s development to make inroads into that total. “We are munotherapy unit, Allergopharma, program on an adrenaline (epinephrine) focusing on generating cash and conse- Twill not only improve the focus and autoinjector for anaphylactic reactions, is quently rapidly lowering our debt,” said reduce the debt pile of the big pharma, it not being sold and will remain with Merck. chief financial officer Marcus Kuhnert, in will also add a new international business “By divesting Allergopharma, Merck mid-November 2019. to the acquisitive Munich, Germany-based is further successfully implementing its Dermapharm AG. company strategy, with an even stronger DERMAPHARM EXPANSION The financial terms of the sale, announced focus of its Healthcare business sector on Dermapharm plans to grow through mak- on 19 February, were not disclosed. the development of innovative medicines ing acquisitions, in-house product devel- There has been speculation since the for the unmet medical needs of patients opment and enhancing its presence out- beginning of the year that the family- with difficult-to-treat diseases,” the big side of Germany, Austria and Switzerland. controlled Merck was looking to divest pharma said. The transaction is expected The company manufactures and mar- Allergopharma, whose sales of allergen- to close in the second quarter of 2020. kets off-patent branded medicines, food specific immunotherapies in around At the end of 2018, Merck divested its supplements, and has a parallel import 18 countries is expected to reach €90m consumer health business to Procter & business, axicorp. Group revenues were ($97m) in 2020. Allergopharma’s products Gamble Co. for €3.4bn. But since then €517.6m in the first nine months of 2019. include subcutaneous hypoallergenic it has bought Wilbraham, MA-based The Frankfurt Stock Exchange listed preparations used to desensitize individu- FloDesign Sonic, a cell and gene ther- Dermapharm, which is majority family- als who suffer allergic reactions. apy manufacturer, and the electronic owned via the holding company, The- The allergens therapeutic area has materials supplier, Verum Materials mis Beteiligungs AG, acquired a majority increasingly been out-of-step with Inc, both acquired in October 2019. In stake in the German nutritionals compa- Merck’s aim of developing new chemi- September 2019, Merck acquired the ny, fitvia GmbH in 2019, and also acquired cal entities such as the checkpoint in- semiconductor materials manufacturer, the Spanish herbal extract company, hibitor, Bavencio (avelumab, partnered Intermolecular Inc. Euromed SA. Previously it integrated two with Pfizer Inc.), in various cancer indi- And now with net financial debt at the OTC/generic companies, Strathmann and cations, and the multiple sclerosis ther- end of the third quarter of 2019 amount- Trommsdorff. apy, Mavenclad (cladribine). ing to €7.3bn, Merck executives are keen Published online 20 February 2020 Job Cuts As Polyphor Focuses On First-In-Class Anticancer

JOHN DAVIS [email protected]

fter a Phase III new antibiotic program disappointment last year, AAllschwil, Switzerland-based Poly- phor Ltd. is refocusing its research efforts on a potential first-in-class immuno-oncology compound, while becoming a leaner organization with the loss of around 17 positions. With current funds, Polyphor’s cash runway will last until the end of the first quarter of 2021, executives at the Swiss SIX Exchange-quoted company told an ing evaluated in a Phase III trial, FORTRESS, cally recurrent or metastatic breast cancer, analyst briefing on 20 February. in patients with breast cancer. The pivotal following promising earlier clinical studies. The immuno-oncology product CXCR4 study is evaluating balixafortide combined Around 192 patients have been ran- antagonist, balixafortide, has become Poly- with eribulin (Eisai Co. Ltd.’s Halaven) for the domized to date, ahead of plan; 385 in phor’s lead compound, and is currently be- treatment of patients with HER-negative, lo- total should be randomized by the end of

scrip.pharmaintelligence.informa.com February 28, 2020 | Scrip | 5 COMPANIES/APPROVALS

the third quarter, and first results for the other different combination therapies for But it is aiming to continue development co-primary objective response rate (ORR) balixafortide, and new indications, said of an inhaled formulation of murepavadin endpoint should be available by the end Polyphor’s new CEO, Gökhan Batur. for cystic fibrosis, with a Phase Ia study ex- of the first quarter 2021, Polyphor execu- Batur, who was previously Polyphor’s pected to start in the fourth quarter of 2020. tives said. Data for the progression-free chief commercial officer, was promoted to The preclinical program suggested survival (PFS) co-primary endpoint are ex- CEO in January, following the retirement there was a broader safety margin with the pected in the fourth quarter of 2021. of Giacoma DiNepi. inhaled formulation than with the intra- If approved, balixafortide could be the The Swiss company has discontinued venous formulation, the company noted. first-in-class CXCR4 antagonist to be ap- the clinical development of an intravenous And the data suggested that murepavadin proved for a solid tumor indication. formulation of the candidate antibiotic, could be the first of a new class of Pseudo- Polyphor intends to look beyond recur- murepavadin, because of renal side effects monas aeruginosa-targeted antibiotics. rent metastatic breast cancer to consider reported last year in a Phase III study. Published online 21 February 2020 Esperion’s Nexletol Reaches The Cholesterol Market Priced To Sell

JOSEPH HAAS [email protected]

he approval of Esperion Therapeu- sues gaining traction largely because they tween 4% and 18% of their patients, with tics Inc.’s Nexletol (bempedoic acid) came to market overpriced. Auster estimated 5%-6% market share in T will kick start competition in the “The PCSK9s did $35M in first few quar- the US would lead to blockbuster sales. cholesterol space as the oral drug, which ters but also had lots of pre-auth forms However, a third KOL queried cited a pref- has a new mechanism of action, goes up and poor reimbursement access due to erence for inclisiran or other PCSK9 inhibi- against drugs like the PCSK9 inhibitors the high [wholesale acquisition cost] price tors for incremental LDL-C reduction. currently on the market and Novartis AG’s of $14,000,” Jefferies analyst Michael Yee Esperion said the product will be com- RNA-interference candidate inclisiran, pointed out in a 16 February note look- mercially available on 30 March and noted which is slated for US approval before the ing ahead to the Esperion approval. “At that it is the first oral, non-statin LDL-C- end of 2020. the start, 50%-70% of scripts were getting lowering product approved in the US in Nexletol’s approved indications are rejected by payors and then even when a almost 20 years. The drug’s mechanism of for adjunct to diet and maximally tol- script was OK, another 70% would not get action inhibits the synthesis of cholesterol erated statin therapy in both hetero- filled at the pharmacy due to patient walk- in the liver. Esperion has a second user fee zygous familial hypercholesterolemia ing away from co-pay too high.” date upcoming for a combination of bem- (HeFH) and established atherosclerotic Credit Suisse analyst Martin Auster pedoic acid and ezetimibe (Merck & Co. cardiovascular disease (ASCVD) patients predicted sales greater than $1bn for the Inc.’s Zetia); the action date is 26 February. who require additional lowering of LDL- product based on key opinion leader In an interview ahead of the J.P. Mor- C. Esperion has said it hopes the first-in- opinions – of three doctors surveyed, two gan conference last month, Esperion class, once-daily ATP citrate lyase (ACL) indicated they’d prescribe Nexletol to be- chief commercial officer Mark Glickman inhibitor will obtain preferred formulary said that “In the US, we are not only pre- status in the US and that it plans on an pared, we are excited about launching this access strategy for the product with rea- product on our own.” The firm had already sonable copayments. (Also see “Esperion build its internal team and was in the pro- Expects Preferred Formulary Placement cess of hiring 300 sales representatives, For Oral Cholesterol Drug Bempedoic which it believes is “the right field force to Acid” - Scrip, 29 Oct, 2018.) “In the US, we are not properly educate physicians [and reach] Early reports were that the Ann Arbor, the patients that need bempedoic acid.” MI-based firm would price the product only prepared, we are Outside the US, Esperion is partnered at $9-10 a pill – and in announcing the with Daiichi Sankyo Co. Ltd. for Europe. approval on 21 February, Esperion said excited about launching “We are also at the later stages of discus- eligible patients with commercial health this product on our sion with partners for the rest of the world, insurance might be able to obtain a non-US/non-EU, so that’s Japan and China three-month prescription fill of Nexletol own.” - Mark Glickman etc.,” president and CEO Tim Mayleben for as little as $10. The injectable PCSK9 noted. European approval is expected in inhibitors, initially intended for the most the second quarter. severe section of the market, have had is- Published online 21 February 2020

6 | Scrip | February 28, 2020 © Informa UK Ltd 2020 APPROVALS

A Runaway Hit In US, Pfizer Gains EU Nod for Vyndaqel In Cardiomyopathy ANDREW MCCONAGHIE [email protected]

fizer’s rare disease treatment Vyn- This will only help boost the drug’s rap- daqel (tafadamis) proved to be one id uptake, as will the anticipated launch- Pof the most notable outperformers es in leading European markets, which in new US drug launches in 2019, and the are expected to help it exceed sales of company has now gained approval for the $1bn this year. same use in Europe. The drug’s approval in the US and now Vyndaqel gained US FDA approval in Europe was based on the Phase III ATTR- May last year as a treatment for cardio- ACT study, which demonstrated a signifi- myopathy in adult patients with the rare cant reduction in all-cause mortality and wild-type or hereditary transthyretin amy- frequency of cardiovascular-related hospi- loidosis (ATTR-CM). Priced at $225,000 for a year’s treat- talizations compared to placebo over a 30 This made it the first treatment to hit ment, Vyndaqel has exceeded all sales month period in patients with wild-type the US market for the condition, and is expectations since its launch in the US, or hereditary ATTR-CM. also a first in Europe. achieving $79m in Q3, its first full quarter The European approval helps Pfizer Cardiomyopathy is one of the most on the market. Inc. keep well ahead of its main rival serious complications caused by the It surprised again when it achieved a in the field, Alnylam Pharmaceuticals disease, which is characterized by the remarkable $213m in the final quarter Inc. and its RNAi therapy Onpattro (pati- abnormal build-up of amyloid protein of 2019. A more convenient formulation, siran). This is currently approved to treat in the body, causing organ failure and Vyndamax, was launched in September another subset of patients, those with shortening lifespans. (one daily pill instead of four). TURN TO PAGE 8

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CONTINUED FROM PAGE 7 polyneuropathy caused by the hereditary variant only of trans- The European approval helps Pfizer thyretin (hATTR) amyloidosis. Alnylam wants Onpattro to go head to head with Vyndaqel in keep well ahead of its main rival in the treating cardiomyopathy in both hereditary and wild-type ATTR amyloidosis, and believes its drug will prove itself to have a supe- field, Alnylam. rior clinical performance compared to its rival. Its Apollo B Phase III trial of Onpattro is currently underway, and if the outcome is positive, Alnylam could be ready to file in late 2021 or early 2022. of patients diagnosed is key to expanding treatment. Pfizer Pfizer has the advantage of Vyndaqel being already approved said in a recent analyst call that it had achieved a 9% diag- and well-established in Europe, for the treatment of stage 1 poly- nosis rate in the US, with around 64% diagnosed receiving neuropathy, for which it has been licensed since 2011. treatment. The company says it is investigating numerous Pfizer will now look to gear up negotiations with payers and ways of improving diagnosis rates, including the use of AI. health technology assessment organizations to gain market ac- Vyndaqel is also already approved in Japan, Brazil, the United cess for the drug. England’s cost effectiveness watchdog NICE has Arab Emirates and Canada. its first review meeting of Vyndaqel in its new indication sched- Another company developing a treatment for ATTR cardiomy- uled for March 2019, with guidance expected by June. opathy is Ionis Pharmaceuticals Inc., with its AKCEA-TTR-LRx en- As with most rare diseases, reaching a diagnosis of the tering Phase III trials in January this year. ATTR is often slow, and increasing the speed and numbers Published online 18 February 2020 Novartis’s Beovu Launch Clouded By Safety Worries STEN STOVALL [email protected]

oubts over the safety of Novar- tis AG’s new anti-VEGF eye drug DBeovu (brolucizumab-dbll) have emerged, clouding its current launches in the US and Europe and boosting commercial prospects for other drugs in the anti-VEGF category, notably Bayer AG and Regeneron Pharmaceuticals Inc.’s Eylea (aflibercept). Concerns emerged over the weekend when the American Society of Retinal Specialists (ASRS) warned members in an email of 14 cases of retinal vasculitis in Be- ovu patients, 11 of which were occlusive retinal vasculitis that can lead to vision Beovu safety worries raised by loss, a side effect so far not associated with American Society of Retinal Specialists other human vascular endothelial growth factor (VEGF) inhibitors used in wet age- related macular degeneration (AMD). two fluids which may disrupt the normal Novartis recently outlined to Scrip how The news fanned fresh concerns over retinal structure and cause damage to the it hoped to successfully commercialize its Beovu, given its known increased risk of macula as being a key reason to switch new VEGF inhibitor. inflammation compared with alterna- anti-VEGF products. Also known as RTH258, Beovu was tive treatment options – up until now The Swiss group responded on 25 approved in October by the US Food these had been viewed as reflecting February by announcing the launch of and Drug Administration for treating non-severe events. an external review into the safety of the wet AMD, and brought $35m following Novartis hopes Beovu can become a new drug. It also reiterated its belief in the its launch that same month. The drug replacement for its aging blockbuster Lu- compound. received approval in Europe just weeks centis (ranibizumab), the first VEGF inhibi- But that did little to stop investors sell- ago. Both approvals were based on the tor for wet AMD to reach reach the market. ing Novartis shares into a declining mar- Phase III HAWK and HARRIER clinical tri- It has highlighted its benefits its clinical tri- ket already unnerved by worries over als, in which Beovu demonstrated gains als on intra-retinal and/or sub-retinal fluid, the coronavirus. in best corrected visual acuity that were

8 | Scrip | February 28, 2020 © Informa UK Ltd 2020 APPROVALS

non-inferior to Eylea at week 48. Novar- finally, it will be important to understand tis on 25 February said it stood behind the how these adverse events are related to safety and efficacy of Beovu, which is con- the immunogenicity of Beovu,” Hansen traindicated for patients with active intra- told Scrip. ocular inflammation. Answering those points will take time, “Our clinical development and phar- and work to the advantage of rival prod- macovigilance teams are working with ucts, analysts said. healthcare professionals to quickly obtain “Recent adverse “Recent adverse events that have and evaluate all available information in events that have arisen arisen with Novartis’ Beovu will likely order to classify these events and identify dampen its uptake and minimizes com- potential risk factors.” with Novartis’ Beovu petitive risk to Regeneron’s Eylea fran- The statement continued: “In addi- chise,” analysts at Jefferies said in a 25 tion to our own internal assessment, we will likely dampen its February reaction note. They added: have engaged an external safety review uptake.” – Jefferies “We spoke with two retina doctors who committee to further evaluate these expect Beovu use to significantly de- post-marketing [ASRS-reported] cases. crease in the near term.” We will continue to share details as they Credit Suisse analysts said they were become available.” unsure how material the safety worries Those reviews will have a number of key highlighted by the ASRA would prove points to address, according to Tara Han- to be for Beovu, but acknowledged sen, an analyst with Datamonitor Health- that “with 3,000 retina specialist across care. “First, the review will need to deter- 60 countries, we believe that having mine if there have been any additional ible. Third, the review will need to deter- the safety of Beovu highlighted by this cases other than those already reported,” mine if this issue affects a certain subset organization could have negative im- she said. of patients or if there are any identifiable plications for the short-term uptake of “Second, it will be important to deter- risk factors, in which case those patients the drug.” mine if any of the cases have been revers- could be screened out in the future. And Published online 25 February 2020

Scrip Awards Winner 2019

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Winner: Galapagos’s $345m secondary Galapagos’s win was for its $345m secondary follow-on financing follow-on fi nancing in September 2018, which fulfi lled its fi nancing goal of raising an additional year of R&D spend, following the announcement of fi rst and very positive Phase III results with its lead program fi lgotinib. The transaction was completed in seven hours, at a price 29% higher than the previous fundraising.

JN3134 Scrip Awards 2019 Winner Advert Q.indd 1 2020/02/20 14:55 scrip.pharmaintelligence.informa.com February 28, 2020 | Scrip | 9 REGULATORY

FDA Rejects Keytruda Dosing, Fast Tracks Tecentriq Lung Cancer Review ANDREW MCCONAGHIE [email protected]

erck & Co. Inc. has had its submission for a more conve- $25bn this year, but rising rapidly to around $45bn by 2025. By nient six-week dosing of its blockbuster immunothera- far the most important indication is non-small cell lung cancer Mpy treatment Keytruda refused by the US Food and Drug (NSCLC), which the analysts predict will be worth $17.6bn by 2025. Administration. Keytruda is set to extend its dominance in this field, thanks to its The regulator has issued a complete response letter (CRL) strong data in frontline indications. However Roche is determined to the company, which is seeking to introduce the every-six- to compete in these indications, and the FDA has just granted a weeks administration of a 400mg dose over 30 mins across priority review for Tecentriq as a first-line monotherapy. multiple indications. This use will be for people with advanced non-squamous and The knockback will not come close to derailing the Keytruda squamous NSCLC without EGFR or ALK mutations with high PD- juggernaut, however. The drug pulled in more than $11bn last L1 expression. year, and dominates the PD-1/PD-L1 immunotherapy field across The FDA is expected to make its decision by 19 June. most established tumor types. The submission was based on results from Roche’s Phase III IM- The company says it is reviewing the rejection and will discuss power110 study, which showed that Tecentriq monotherapy im- next steps with the regulator. proved overall survival (OS) by 7.1 months compared with chemo- Keytruda (pembrolizumab) is currently administered once ev- therapy in people with high PD-L1 expression. This is significantly ery three weeks at a dose of 200mg –this is the same schedule behind the near 16 month improvement achieved by Keytruda as Roche’s Tecentriq (atezolizumab), though Bristol-Myers Squibb over chemo in its Keynote-024 study. Co.’s Opdivo (nivolumab) can be given every two week or every four weeks. ADJUVANT SETTINGS THE NEXT BATTLEGROUND As is customary with CRLs, the reasons behind the rejection The big three contenders in the field, Keytruda, Opdivo and Te- have not been spelled out by the company. Merck’s submission centriq, are extending their reach into earlier adjuvant and neo- was based on pharmacokinetic modelling and simulation data, adjuvant settings across a range of tumor types, and a number of and it may be that the FDA considers this insufficiently robust to pivotal readouts are expected in 2020 and 2021. demonstrate that the less frequent dosing retains the clinical ben- Keytruda and Opdivo are already approved in adjuvant set- efits of the standard schedule. tings in melanoma (with Keytruda also approved in renal cell The FDA’s decision contrasts with that of the European Medi- carcinoma) but there remain questions about the efficacy cines Agency, which approved this flexible dosing schedule in of the immunotherapies in other adjuvant and neoadjuvant March 2019, across all monotherapy indications. uses, especially after Tecentriq failed in bladder cancer. (Also The move to more flexible dosing is part of an ongoing compe- see “Tecentriq Disappoints In Post-Surgery Bladder Cancer” - tition between Merck & Co and its rivals in PD-1/PD-L1 immuno- Scrip, 24 Jan, 2020.) therapy, and Keytruda retains a lead in the most lucrative setting, Key readouts expected over the next 12 months or so include non-small cell lung cancer (NSCLC). BMS’s Opdivo in bladder cancer (CheckMate-274) and Merck’s KEYNOTE-522 in triple negative breast cancer (TNBC). TECENTRIQ PURSUES KEYTRUDA IN NSCLC Most notable is Roche and its ImPower010 study targeting ad- The PD-1/PD-L1 immunotherapy market continues to be one juvant treatment of NSCLC, with J.P. Morgan analysts saying this of the strongest growth drivers in the sector, with J.P. Morgan market niche could be worth around $3bn annually. analysts forecasting total market revenues for the drugs to reach Published online 19 February 2020 Bluebird Expects Three Filings In 2020, But US Zynteglo Submission Pushed Back

MANDY JACKSON [email protected]

luebird bio Inc. will have an eventful 2020, including the The company launched its gene therapy Zynteglo (autologous submission of three different products for regulatory ap- CD34+ cells encoding βA-T87Q-globin gene) in the EU, where it bprovals, but at least one milestone will be reached a little was approved for transfusion-dependent beta-thalassemia (TDT) later than previously expected. in June, and will treat its first commercial patient in the first half of

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2020, bluebird said in its fourth quarter and full-year 2019 financial and corporate update, issued after the stock market closed on 18 February. However, the company also said that while it has initiated a roll- ing biologic license application (BLA) submission to the US Food and Drug Administration for Zynteglo as a treatment for TDT, it won’t complete the filing until the second half of 2020 because the submission depends on the availability of certain information, including release assays. That represents a significant delay, since bluebird said last month at the J.P. Morgan Healthcare Conference that the BLA would be filed in the first half of this year. “Europe (particularly Italy) is the most important TDT market given the larger TDT patient base in the Mediterranean basin and so we do not view the [US filing] push out as materially affecting our near-term outlook,” Wedbush analyst David Nierengarten said “We do not view the [US filing] push out in a 19 February note. But bluebird investors didn’t cut the company as much slack af- as materially affecting our near-term ter the delay was announced. The company’s stock closed down outlook.” – David Nierengarten 8.8% at $80.45 per share on 19 February. “In the USA, of course, the real opportunity for LentiGlobin is in sickle cell disease (SCD) and we view the positive data for the HGB-206 trial as presented at ASH as ultimately predicting approval,” Nierengarten wrote. ments over five-year contracts contingent on Zynteglo’s ability to LentiGlobin is bluebird’s gene therapy construct that’s being reduce TDT patients’ needs for blood transfusions. (Also see “Blue- developed for both beta-thalassemia and sickle cell disease, mar- bird Pushes For Zynteglo Pricing Of Five €315K Annual Installments keted under the name Zynteglo for TDT in Europe. The company “ - Scrip, 14 Jun, 2019.) reported positive results from the Phase I/II HGB-206 clinical trial “Although we view the company’s ability to execute on advanc- in SCD at the American Society of Hematology (ASH) meeting in ing its clinical assets toward commercialization positively, we con- December, showing a 99% reduction in painful vaso-occlusive cri- tinue to believe the commercialization of complex cell therapy ses (VOCs) that sickle cell patients experience when red blood cells products will present challenges for the company, which is evi- form a sickle shape due to a mutation in the beta-globin gene. dent by the delays seen in the commercial launch of Zynteglo in Bluebird said in its fourth quarter update that in addition to ini- Europe and the delay in BLA submission in the United States,” Wil- tiating the Phase III HGB-210 clinical trial that will test LentiGlobin liam Blair analyst Raju Prasad said in a 19 February note. in about 40 sickle cell patients with a history of VOCs during the first half of 2020, it also will initiate the Phase III HGB-211 trial this BRISTOL PARTNERSHIP LOWERS COMMERCIAL year to test the gene therapy in 18 SCD patients aged 2-14 who RISK FOR BB2121 have an elevated risk of stroke. Whereas bluebird is on its own with Zynteglo, the company has Chief medical officer David Davidson said during the Q&A session an experienced cancer drug partner for the commercialization following the company’s J.P. Morgan presentation that it will pursue of idecabtagene vicleucel (ide-cel; bb2121), a chimeric antigen approval in sickle cell disease based on interim Phase III results. receptor T-cell (CAR-T) therapy targeting B-cell maturation an- “Our Phase III trial, the HGB-210 trial, mimics [the HGB-206] de- tigen (BCMA) in the treatment of relapsed or refractory mul- sign and that is in the process of being initiated,” Davidson said on tiple myeloma. 14 January. “And what we hope is that by virtue of the strength Ide-cel, which is being developed in partnership with Bristol- of the data we’re seeing in HGB-206, we’d be able to pursue an Myers Squibb Co., is the most advanced BCMA-targeting CAR-T accelerated development strategy whereby interim data from the therapy in development and it will be the first of bluebird’s three HGB-210 trial on top of the HGB-206 data would be sufficient to potential product filings in 2020. support a registration.” Bristol-Myers and bluebird confirmed in their separate fourth However, beta-thalassemia remains the more immediate com- quarter earnings reports that ide-cel is on track for a BLA filing mercial opportunity for LentiGlobin and bluebird noted that it in the US during the first half of 2020. (Also see “BMS Earnings has negotiated reimbursement for Zynteglo in Germany, where it Beat Estimates, But Opdivo Sales Slide Continues” - Scrip, 6 Feb, expects the first commercial patient to be treated during the first 2020.) When Bristol acquired Celgene Corp. for $74bn last year, half of this year. the big pharma agreed to pay Celgene shareholders $9 per Zynteglo’s EU launch has been delayed by both pricing nego- share if ide-cel and two other product candidates are approved tiations with payers in individual countries and by manufacturing in the US within a specific timeframe – a deadline that the BC- challenges. The gene therapy carries a hefty price tag of €1.575m MA-targeting CAR-T therapy appears likely to meet. (Also see in Europe, but bluebird is making the product available in ex- “With Celgene Acquisition Closed, Bristol Faces Major Milestones” change for five annual payments of €315,000 ($356,000) with pay- - Scrip, 21 Nov, 2019.)

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Jefferies analyst Biren Amin said in a 19 February note that the company “has in- With BMS Set To Join, What Next vested in moving bb2121 to earlier lines through ongoing Phase III KarMMa-3 in [third-line (3L) multiple myeloma (MM)], For CAR-T Market? Phase II KarMMa-2 in 2L MM, and Phase ANDREW MCCONAGHIE [email protected] I KarMMa-4 in high-risk [newly diagnosed MM (NDMM)]. The key question he chimeric antigen receptor T cell for bb2121’s path forward will [be] how it (CAR-T) therapies are among the compares to duration versus JNJ/Legend’s Tmost innovative to hit the market ‘4528. Longer follow-up of JNJ-4528’s in recent years, but pioneers Novartis AG’s Phase Ib/II CARTITUDE-1 trial and more Kymriah and Gilead Sciences Inc.’s Yescar- detailed patient baseline information are ta have struggled to meet revenue expec- required to make a comparison.” (Also see tations so far. “J&J Quickly Advances BCMA-Targeting On 13 February, Bristol-Myers Squibb CAR-T As JNJ-4528 Shows 100% Response” Co. filed its contender JCAR017 (lisocabta- - Scrip, 8 Dec, 2019.) gene maraleucel (“liso-cel”)) with the US Regardless of clinical profile, ide-cel still Food and Drug Administration, which will will be the first BCMA-targeting CAR-T challenge Yescarta and Kymriah in the therapy to hit the market, following be- third-line diffuse large B-cell lymphoma hind GlaxoSmithKline’s BCMA-inhibiting (DLBCL) market. ity, with similar issues having already antibody drug conjugate (ADC) belan- The FDA’s PDUFA decision date for liso- held Kymriah back. tamab mafodotin. (Also see “GSK Files Its cel is 17 August, which means it is set to Nadim Ahmed, BMS’s executive vice BCMA Drug In Multiple Myeloma” - Scrip, reach the market nearly three years after president and president of hematology 17 Dec, 2019.) its rivals. Nevertheless, BMS believes its addressed these issues on its Q4 results SVB Leerink analyst Mani Foroohar said therapy can offer more than them. Liso- call with analysts in early February. High- in a 19 February note that he predicts cel, like its established competitors, tar- lighting the superior safety data and op- bluebird will recognize its first commercial gets CD19, but BMS is able to point to trial portunity to grow prescribing via outpa- revenues from ide-cel in 2021, with US, EU data showing it has lower rates of neuro- tient treatment, he also made much of and rest of world revenue and royalties to- toxicity and cytokine release syndrome BMS’s market expertise in hemato-oncol- taling $760m by 2030. than its competitors. ogy, largely thanks to the now-integrated Foroohar also models $2bn in LentiGlo- Whether this will be enough to gain a Celgene. bin sales ($1.16bn for beta-thalassemia great deal of market share is uncertain. “Our footprint out in the community and $853m for SCD) by 2030 as well as If liso-cel can replicate the advantages will really help us to drive those referrals $190m in sales for Lenti-D in the treat- seen in clinical trials in practice, it could into the treatment sites where CAR-Ts ment of cerebral adrenoleukodystrophy gain market share based on allowing will be given as well as expand out into (CALD), which bluebird intends to file in greater CAR-T use in an outpatient set- the community with assets like liso-cel,” the US and EU in the second half of 2020. ting, rather than the intensive hospital- he said. (Also see “Bluebird Lays Some New Eggs, based care often required with the exist- But They’ll Take Time To Hatch” - Scrip, 16 ing competitors. US REIMBURSEMENT May, 2019.) Analysts at Morningstar predict liso-cel One major obstacle to greater uptake of The company had $1.24bn in cash as could reach peak annual sales over $2bn, the existing CAR-T products is US reim- of 31 December compared with $1.89bn even though market leader Yescarta is still bursement. The treatments are currently at the end of 2018, due to increased far off this total after three years. categorized by the Centers for Medicare & operating costs, including research and Gilead saw Yescarta’s revenues climb Medicaid Services (CMS) under the (DRG) development as well as commercial to a respectable $456m for the full year 016 code. This is a fixed-price payment for readiness expenses. Chief financial offi- 2019, however figures from Q4 suggest inpatient-only treatment which poten- cer William Denise Baird said at J.P. Mor- its growth is leveling off, while Novartis’s tially results in hospitals losing money on gan that bluebird’s cash on hand should Kymriah reached only $278m over the every Medicare patient CAR T-cell therapy fund its operations through the second 12 months. based on the list prices of either product half of 2021. Liso-cel is thought to achieve a better in DLBCL at $373,000. Bluebird spent $582.4m on R&D in 2019 safety profile by creating a more “de- However there has been progress on versus $448.6m in 2018 and its selling, fined” ratio of CD4 and CD8 cells. How- this front, with the CMS announcing last general and administrative expenses rose ever this also adds an extra step of com- August that it would fund CAR T-cell ther- to $271.4m last year from $174.1m in the plexity into its manufacturing, which apies for Medicare patients nationwide, prior year. could potentially cause BMS problems and not impose a new Coverage With Published online 19 February 2020 in terms of quality control and scaleabil- Evidence With Development (CED) model,

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which could have further restricted access to the treatments. Incyte Ready To Go For Approval

NEW ENTRANTS IN 2020 AND 2021 Of Topical Ruxolitinib In Atopic The entry of liso-cel is just one of several important developments in the field – Dermatitis with a host of new studies in CAR-Ts as JOSEPH HAAS [email protected] well as other novel biologics. The focus for both the existing CAR-T ncyte Corp. hopes to file the topical formulation of its JAK1/2 inhibitor ruxolitinib for competitors in DLBCL, and all those hop- mild-to-moderate atopic dermatitis by the end of 2020 now that the candidate has met ing to join them, is in moving therapy to Ithe primary endpoint in a pair of Phase III studies. But at least one analyst questions earlier lines of treatment. Gilead is set to whether the drug would be better positioned in such a competitive therapeutic space if unveil its data for Yescarta in DLBCL pa- the company had studied it against topical corticosteroids. tients after a first relapse in the second half of 2020, a use which, if approved, would expand its patient population con- siderably. Gilead’s cell therapy division Kite also has KTE-X19 awaiting an FDA decision for use in mantle cell lymphoma. This could make it the first company to have two CAR-Ts on the market, with an FDA decision expected by 10 August. Novartis has no major filings expected this year, but plans to submit Kymriah to regulators in 2021 for use in the earlier setting after a first relapse in DLBCL, as well in relapse/remitting fol- licular lymphoma. Incyte is preparing to face heavy competition in atopic dermatitis

MULTIPLE MYELOMA Incyte announced in January that topical ruxolitinib met a primary endpoint of inves- Meanwhile, a second wave of CAR-Ts tar- tigator’s global assessment in one Phase III study; the candidate is a different formulation geting BCMA in multiple myeloma pa- of Incyte’s oral Jakafi, which is approved to treat polycythemia vera, myelofibrosis and tients is nearing the market. BMS is ex- acute graft-versus-host disease. The Delaware-based firm revealed on 19 February that pected to file its bb2121 (co-developed ruxolitinib cream met the primary endpoint in the second TRuE-AD pivotal study and pro- with bluebird bio Inc.) in the first half of vided topline efficacy data from both studies. (Also see “Atopic Dermatitis: Ruxolitinib And 2020, potentially becoming the first BC- Baricitinib Spearheading New Therapies” - Scrip, 30 Jan, 2020.) MA-targeting to reach the market. How- Both pivotal trials used a vehicle control – a version of the topical cream without ever it has plenty of late-stage competi- the active pharmaceutical ingredient. Credit Suisse has criticized Incyte’s strategy in tors, including Johnson & Johnson and these studies, saying a demonstration of relative efficacy compared to the current Legend Biotech Corp.’s JNJ-4528, as well standard of care for mild-to-moderate AD, topical corticosteroids, might be more as non-CAR-T rivals, such as GSK’s an- useful for dermatologists. tibody drug conjugate. (Also see “GSK Files Its BCMA Drug In Multiple Myeloma” COMPETING IN AD - Scrip, 17 Dec, 2019.) Atopic dermatitis is becoming a crowded space, dominated currently by Sanofi/Regen- Published online 19 February 2020 eron Pharmaceuticals Inc.’s Dupixent (dupilumab), an injectable interleukin-4 (IL-4)/IL-13 blocker. During its quarterly earnings call on 6 February, Sanofi reported that Dupixent revenues grew 135% year-over-year, to €679m (about $733m) during the fourth quarter of 2019. (Also see “Sanofi Highlights MS Asset After Solid Q4” - Scrip, 6 Feb, 2020.) At the pharma’s capital markets day in December, Sanofi CEO Paul Hudson said Dupix- LET’S GET ent would prevail in the AD competition against a coming wave of oral JAK inhibitors and monoclonal antibodies that block IL-13 or IL-31. (Also see “Sanofi CEO Hudson Delivers An SOCIAL Ambitious Turnaround Agenda” - Scrip, 10 Dec, 2019.) However, topical ruxolitinib is intended to treat a less-severe segment of the AD popu- @PharmaScrip lation. Incyte VP, inflammation & autoimmunity, Jim Lee, said that Dupixent is intended primarily for patients with severe AD and that in clinical trials of Dupixent, patients typi-

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cally had eczema on 50% or more of their representing a sizable expansion mar- variance in vehicle response is not that bodies – compared to 30% or less in the ket for legacy Jakafi API,” Berens wrote unusual in a study of a topical therapy for TRuE-AD studies. Patients with mild-to- in a 19 February note. He predicts a new a dermatologic indication. “From a clini- moderate AD are better suited for topical drug application (NDA) filing with the US cal trial perspective, you do get variabil- therapy, he said. Food and Drug Administration before ity in responses – these are two separate Credit Suisse analyst Evan Seigerman the end of 2020, pending 44-week safety studies that were done, so it could just be called the data positive in a 19 Febru- data from the two studies, and expects a related to the inherent variability often ary note, but said the second Phase III launch in 2021 and peak sales of $1.1bn in observed in clinical trials,” he said, adding study’s good results were largely expect- atopic dermatitis. that Incyte is only starting a deeper dive ed. While topical ruxolitinib is intended into the datasets. for mild-to-moderate AD patients and WHAT THE TRIALS SHOWED “If you take a look at all of the previ- Dupixent is indicated for moderate-to- The Phase III studies enrolled almost 1,250 ous studies done with topical therapies severe patients, he predicted that Incyte patients ages 12 and older who have been in atopic dermatitis, there is a bit of vari- would not make much headway in the diagnosed with AD for at least two years, ability in the vehicle response rate,” Lee overlapping moderate disease patients. are candidates for topical therapy, have continued. “It’s not truly a placebo rate, He expects an indication for AD could an Investigator’s Global Assessment (IGA) this is a skin disease and it can respond bring in $300m for Incyte by 2025, but score of 2 to 3 at baseline and eczema on to emollients. The vehicle is actually the that an ongoing Phase III study of the between 3% and 20% of their body sur- cream without the active drug, so we al- topical formulation in vitiligo is the big- face area, excluding the scalp. ways anticipate some response in that ger market opportunity. Those data are Statistical significance on the IGA treat- arm – it’s a real response. Then, the real expected in 2021. ment success endpoint is defined as an question is what do you get when you “While we could see some overlap in the IGA score of zero (clear) or one (almost add the active drug.” moderate population, we believe [ruxoli- clear) with an additional requirement for Lee said Incyte tested ruxolitinib against tinib and Dupixent] are different (mecha- at least a two-point improvement from vehicle in its Phase III program because nistically and route of administration) and baseline. In TRuE-AD2, first reported in that is what the US FDA prefers to see. are likely to target different populations,” January, the 0.75mg dose of topical rux- Top-line data from the two studies re- Seigerman wrote. A key opinion leader in olitinib met that endpoint in 39% of pa- vealed that both doses of ruxolitinib met dermatology told Credit Suisse she does tients while the 1.5mg dose hit the mark a secondary endpoint of at least a 75% not expect novel entrants in the atopic in 51.3% of patients (p<0.0001 for both improvement from baseline in eczema dermatitis space to provide much chal- doses). For vehicle, 7.6% of patients met severity area index (EASI) score, and dem- lenge to Dupixent in the near-term. the endpoint. onstrated statistical significance for itch Taking a more positive view of the data In TRuE-AD1, 50% of patients getting reduction as measured by Itch Numerical and Incyte’s opportunity in AD is SVB Leer- the 0.75mg dose of ruxolitinib met the Rating Scale. Lee said it is too early to say ink analyst Andrew Berens, who said the primary endpoint, while 53.8% who got whether Incyte will seek labeling claims data “expands [the] revenue opportunity” the 1.5mg dose did so (p<0.0001 for both based on those data in its NDA. He also for the Jakafi franchise. doses). For the vehicle arm, 15.1% met the said it is possible the company could seek “The success in the AD pivotal tri- primary endpoint. approval of both doses tested in Phase III als is a validation of the opportunity for Incyte VP, inflammation & autoimmu- or just one of the doses. topical Jakafi in dermatology indications, nity, Jim Lee said in an interview that the Published online 19 February 2020 Genfit Delays NASH Data While It Confers With US FDA On Methodology

JOSEPH HAAS [email protected]

enfit SA says its decision to push Investors seem to have taken the news and become one of the first drugs ap- back the unblinding of its Phase in stride; the company’s stock closed at proved to treat NASH. Currently the com- GIII RESOLVE-IT study of elafibra- $17.90 on 20 February and fell overnight pany is second in line behind Intercept nor in non-alcoholic steatohepatitis on the news – opening 21 February at Pharmaceuticals Inc., which has obeticho- (NASH) until it receives “insights” from the $17.28. But it ended the day well at $17.86. lic acid pending with a 27 May action date US Food and Drug Administration about The French biopharma is hoping to at the FDA. (Also see “Intercept’s NASH NDA statistical methodology is aimed at put- show that its dual PPAR alpha/delta ago- Positions OCA For May 2020 Approval, Then ting together the best possible new drug nist can resolve NASH by reducing hepato- Launch” - Scrip, 30 Sep, 2019.) application (NDA). cyte ballooning and lobular inflammation, TURN TO PAGE 16

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CONTINUED FROM PAGE 14 The company previously said it would “We’ve been proactive in all this because we see a unveil top-line data from RESOLVE-IT during the first quarter, in time for pre- potential opportunity here.” - Genfit sentation at the 2020 International Liver Congress in London on 15-19 April. The European Association for the Study of the Liver set an abstract submission deadline of 24 February for the meeting. response to news that its data readout is company pushed back the study’s overall However, the data are now more likely being pushed back. “What we’ve noticed timelines due to difficulty enrolling the to surface sometime in April. Genfit told today is that investors seem to have real- trial. (Also see “Genfit’s Enrollment Delay Scrip that it will unblind the RESOLVE-IT ized that this delay is actually not really In NASH May Aid Intercept’s First-To-Market data after getting insight from the FDA material, especially in the big scheme of Goal” - Scrip, 25 Apr, 2017.) on data compilation for its NDA, which things,” Genfit said. “It’s basically consid- RESOLVE-IT is a roughly 2,000 patient, is expected in late March, and should be ered a minor delay, and for good reasons.” placebo-controlled Phase III study testing able to report the pivotal data within days Leerink analyst Thomas Smith said in a an oral 120mg daily dose of elafibranor to weeks. The final patient visit has com- 20 February note that based on his discus- with a primary endpoint of proportion pleted in the trial and the dataset is to be sions with Genfit execs, the delay is based of patients achieving resolution of NASH locked before the end of February. entirely on the FDA’s estimate of when its without worsening of fibrosis at 72 weeks. Genfit’s announcement stressed that feedback will be available. “We believe the It also includes a long-term outcomes por- the deferred unblinding of the study is company may have reluctantly chosen to tion to measure composite all-cause mor- not related to concerns about the efficacy, push back the unblinding of the data to tality, cirrhosis and liver-related outcomes, safety or tolerability of elafibranor, nor maximize the potential benefit claims in with the predetermined number of events does it pertain to corporate, legal, strate- the label in the event of a successful re- expected to take about four years. gic or financial matters at Genfit. sult on the NASH resolution primary end- Secondary endpoints include the pro- “We’ve been proactive in all this because point,” he said. portion of patients achieving improve- we see a potential opportunity here,” the ment in fibrosis score at 72 weeks as well firm stated to Scrip. It noted the advice STUDY’S TIMELINES HAVE BEEN as three comparisons of results at the end will be specific to Genfit and does not per- ADJUSTED MULTIPLE TIMES of 72 weeks and at the end of the out- tain to any change of the endpoints, “but This is not the first time, however, that comes portion of the study: only about statistical methods and ways Genfit has pushed back the approximate ● proportion of patients with liver-relat- to potentially strengthen our NDA dossier readout date of RESOLVE-IT. It previously ed deaths; for elafibranor.” A research note from SVB guided to unveiling data from the first ● proportion of patients achieving im- Leerink notes the company met with the 1,000 or so patients in the study in early provement in liver histology scores; and FDA in late 2019 and discussed key sec- 2019, then third quarter 2019, then fourth ● proportion of patients with improve- ondary endpoints. quarter 2019 and then last September in- ments in cardiometabolic and liver The company also said it was heartened dicated the readout would occur during markers. by what it sees as restrained shareholder the first quarter of 2020. In April 2017, the Published online 24 February 2020 Coronavirus Pipeline: GSK And Clover Add To Collaborations

ANDREW MCCONAGHIE [email protected]

s health officials warn that the coronavirus outbreak could be at a tipping point, after which its development into a Aglobal pandemic may be unstoppable, companies large and small have mobilized in the fight against the disease. Research efforts are now underway to investigate a range of novel and established drug platforms, including repurposed medicines, prophylactic vaccines and therapeutic treatments against SARS-CoV-2. The World Health Organization is leading the charge by working with Chinese researchers to conduct rapid clinical trials of

The Coronavirus Pipeline

COMPANY THERAPEUTIC CLASS ANNOUNCEMENT MADE COLLABORATION

In collaboration with Coalition for Epidemic Moderna Messenger RNA prophylactic vaccine 24 Jan Preparedness Innovations (CEPI) Novavax Prophylactic vaccine 24 Jan Prophylactic vaccine Using its AdVac Johnson & Johnson 24 Jan In collaboration with US govt agency BARDA and PER.C6 technologies RNA interference prophylactics and Sirnaomics 27 Jan therapeutic antivirals Takis Linear DNA prophylactic vaccine 28 Jan Prophylactic vaccine using MVA-VLP GeoVax 28 Jan In collaboration with BravoVax platform Recombinant prophylactic vaccine using In collaboration with GSK (collaboration Clover Biopharmaceuticals 29 Jan its Trimer-Tag technology announced 24 Feb) CureVac Prophylactic mRNA-based vaccine 3 Feb In collaboration with CEPI Vaxart Oral recombinant prophylactic vaccine 3 Feb In collaboration with Beijing Advaccine Inovio DNA immunotherapy vaccine 4 Feb Biotechnology Regeneron Monoclonal antibody antivirals 4 Feb Expanded collaboration with BARDA Beijing CC-Pharming Plant-derived prophylactic vaccine 4 Feb In collaboration with iBio In collaboration with CEPI and University GSK Vaccine adjuvant Immunostimulant 5 Feb of Queensland Recombinant prophylactic vaccine Codagenix/Serum Institute using its proprietary deoptimization 12 Feb of India technology Prophylactic vaccine using proprietary Vaxil BioTherapeutics 13 Feb VaxHit bioinformatics platform Monoclonal antibody antivirals, Vir Biotechnology 13 Feb therapeutic and prophylactic potential Takis Prophylactic linear DNA vaccine 17 Feb In collaboraton with Applied DNA Sciences A DNA based and a live attenuated Zydus Cadila recombinant measles virus vectored 17 Feb vaccine Prophylactic vaccine using recombinant Sanofi 18 Feb In collaboration with BARDA DNA platform Data: Pharmaprojects, Informa existing antiviral treatments to treat pa- emergency therapies by doctors at the epi- SURGE IN NEW CORONAVIRUS tients infected with SARS-CoV-2. center of the outbreak in the city of Wuhan. ENTRANTS CONTINUES As of 23 February, China had reported Meanwhile, more companies and aca- EXISTING ANTIVIRALS 77,042 cases of COVID-19 to WHO, includ- demic research teams continue to an- It announced on 20 February that trials ing 2,445 deaths. nounce research efforts against the have been launched in China to deter- These data shows a decline in the coronavirus, broadly divided into those mine the safety and efficacy of two exist- growth of new confirmed cases in China, investigating new vaccines or antivi- ing antiviral therapies: AbbVie Inc.’s HIV though there are some concerns about rals. The table above lists a number of combination Kaletra (lopinavir and ritona- the Chinese government’s decision to companies and their collaborators, col- vir) and Gilead Sciences Inc.’s nucleotide change how it reports these figures, lated using Informa’s Pharmaprojects analogue remdesivir, already under devel- prompting WHO to warn of compla- database. opment for Ebola. cency. Outside China, there are now China’s own Clover Biopharmaceuticals These trials have been prioritized by the 1,769 cases in 26 countries, with a total has just announced a new research col- WHO as part of its “R&D Blueprint” for ad- of 17 deaths, with outbreaks in countries laboration with GlaxoSmithKline PLC for dressing the outbreak, as the drugs seem to including Italy raising concerns of its its protein-based coronavirus vaccine can- have helped some patients when used as spread around the world. didate (COVID-19 S-Trimer).

scrip.pharmaintelligence.informa.com February 28, 2020 | Scrip | 17 CORONAVIRUS OUTBREAK

GSK is to provide Clover with its pan- grown. Experts say the profile of the dis- ects, even though some of them have not demic adjuvant system for further evalu- ease – less frequently deadly than SARS, yet brought their first products to market. ation of S-Trimer in preclinical studies. but more easily transmitted – suggests it One company which seized this oppor- Clover has one of the largest in-house, could become a permanent background tunity was Moderna Inc., the messenger commercial-scale cGMP biomanufactur- threat similar to seasonal influenza. RNA therapeutics company, which was ing capabilities in China, which it says it Looking at the latest global pipeline one of the first to announced a partner- could potentially rapidly scale up and of agents rushed into preclinical devel- ship with Coalition for Epidemic Prepared- produce large quantities of a new corona- opment in the last few weeks, it is clear ness Innovations (CEPI) to develop a new virus vaccine. that novel or repurposed “off-the-shelf” vaccine on 23 January. Just a few weeks The most significant of new research antivirals could provide a more rapid later the company raised $500m via a new efforts announced last week came from response to the outbreak while the vac- share offer, though this did see its share Sanofi Pasteur, the vaccines division of cines are being developed. Regeneron price decline slightly, signalling that the Paris-based Sanofi. It announced a new Pharmaceuticals Inc. is one of the big markets were not entirely convinced of a research effort being funded by the US biopharma players pursuing the course, business opportunity from the outbreak. agency BARDA, focusing on bringing a expanding on an existing relationship These dynamics have been seen before, new vaccine into in vitro testing within six with BARDA to develop a number of especially when the threat from these ear- months and into initial clinical trials within novel monoclonal antibodies. These lier outbreaks such as Ebola and Zika were 12-18 months. include REGN-EB3, a molecule which downgraded. Gilead Sciences Inc. devel- Despite the rapidity of the response showed promise against the Ebola virus oped remdesivir for Ebola in the 2013- from vaccine companies (most especially a few years ago, but didn’t advance fur- 2016 outbreak, but early trials suggested J&J’s Janssen Pharmaceutical Cos., which ther after that threat subsided. it had limited efficacy against the virus, was the first to declare its intentions), In another pattern now well established with the virus then largely contained. Gil- these 12-18 month timelines will not with the Ebola and Zika viruses in recent ead’s drug could well prove itself useful in see the vaccines distributed on a mass years, a number of biopharma companies treating the coronavirus, and is working scale, which could take at least another have taken the opportunity to raise inves- with Chinese authorities to make it avail- 12 months. By this time, the coronavirus tor interest and capital by answering the able as widely as possible. threat may have receded or, alternatively, call and opening up new research proj- Published online 24 February 2020 Flu Vaccine Leader Sanofi Joins Fight Against COVID-19 ANDREW MCCONAGHIE [email protected]

anofi is joining the race to develop a pledged to make its vaccine adjuvant Sanofi says it has also been in dialogue vaccine against the coronavirus CO- platform available to the Coalition for with BARDA in the last few weeks, and has SVID-19, and says its status as a global Epidemic Preparedness Innovations (CEPI) now confirmed that it will look to develop leader in flu vaccines marks it out from collaborative. its own candidate. other companies who have already com- J&J’s Janssen, which does not have a John Shiver, senior vice president of mitted to the task. large scale flu vaccine platform, was the global vaccine R&D at Sanofi’s vaccines The Paris, France-headquartered firm first to begin research efforts several division Sanofi Pasteur said its candi- has unveiled an alliance with US govern- weeks ago, and as of last week began date could be in in vitro testing within ment agency BARDA to develop a new pooling money and resources with BAR- six months, and in clinical trials within vaccine, and says it can call on the same DA to rapidly develop a safe and effec- 12-18 months. technology used to produce its Flublok flu tive vaccine against COVID-19. Its global These timelines are similar to estimates vaccine, of which 70 million doses were team, which has previously developed put forward by other manufacturers, such supplied to the US market last year. on an Ebola vaccine under similar time as Janssen, who are eager to assist in the COVID-19 is continuing to spread de- pressures is confident it can have a vac- fight against COVID-19, but do not want spite very strict controls on movement cine in initial human studies within a to over-promise, especially as the course and quarantining being enforced in China year. (Also see “Coronavirus: Can Compa- of the disease spread remains uncertain. and other parts of the world, with more nies Achieve Vaccine Ambition? “ - Scrip, Speaking on a media call to announce than 43,000 cases confirmed so far, includ- 28 Jan, 2020.) the launch of its research, Shiver said the ing nearly 400 deaths. Other companies with less proven track efforts of other companies were welcome, Sanofi is one of the big four global vac- records in the field, such as Inovio and but that Sanofi Pasteur would be unique cine companies, alongside GSK, Merck Moderna have also committed to partner- in bringing its experience of producing flu & Co. and Pfizer, however none of these ships with CEPI, and say their novel vac- vaccine in millions of doses to global pa- peers have committed to developing a cine platforms can help them accelerate tient populations. coronavirus vaccine until now. GSK has development timelines. TURN TO PAGE 20

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