Sanofi Plans More Job Cuts, This Time in R&D

No. 3962 July 5, 2019

In France, some research resources will be shifted to immuno-oncology. Sanofi will also reallocate resources towards biologics in France, Germany and the US, with increased investments in gene therapy in France and the US, and in antibody engineering in Germany. The company added that it had “identified areas where it can more efficiently apply its resources” which would include shifting R&D activities among its sites in France. “The transformation of our R&D organization would enable us to focus on the therapeutic areas and platforms where we believe we have the greatest opportunity to make a meaningful difference for patients and to maximize the produc- tivity of our research engine,” said John Reed, Sanofi’s global head of R&D. “We are committed to making these proposed changes responsibly both for colleagues Sanofi Plans More Job Cuts, who will stay and those who may leave the company. We look forward to work- This Time In R&D ing with our Works Council and trade union partners to maintain and enhance ELEANOR MALONE [email protected] our cutting-edge research capabilities in France and Germany.” anofi plans to cut 466 R&D posi- According to French trade union CFE- tions in France and Germany under According to French trade CFDT, the cuts will affect all of its French Sa “voluntary departure program.” R&D sites – Vitry-Sur-Seine, Alfortville and The company said it would “sharpen its union CFE-CFDT, the cuts Chilly-Mazarin near Paris, Montpellier in research focus” in key areas and shift re- the south and Strasbourg in the north- sources to priorities like gene therapy and will affect all of its French east – with the loss of 299 jobs, the closure antibody engineering. R&D sites. of the Alfortville site and the transfer of While oncology, immunology, rare 189 posts between sites. The union con- diseases and vaccines are priority areas, demned what it called “this umpteenth re- the firm will rein in its cardiovascular and structuring plan” and deplored “yet again, diabetes R&D. Although these were once a reorganization carried out without key revenue drivers for the French group, nal partners. Future diabetes research, having taken stock of the previous ones.” they are increasingly challenged by ge- meanwhile, will focus on the discovery Sanofi employs about 25,000 people in neric competition and price pressures. of treatments that treat the underlying France, out of a total of around 104,000 The company said it would limit car- causes of the disease, and the develop- employees worldwide as reported at the diovascular R&D to the development of ment of the current pipeline. The shift in end of 2018. Around 15,000 people glob- its current pipeline and seek to license R&D focus had previously been flagged ally work in R&D. clinical stage programs from exter- up in February. CONTINUED ON PAGE 4

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AbbVie’s Pipeline Plan Legal A Team Bring Them On Allergan merger will fund Bayer brings out the big China releases generics list to combined R&D pot (p5) guns to litigate in US (p9) encourage competition (p19) IN THIS ISSUE

from the executive editor [email protected]

Things tend to get a bit quiet as we approach the US to Allergan’s development portfolio but AbbVie execu- Independence Day holiday but that gives more time to tives say they are looking to the revenues from Allergan digest the broader implications of major news events. – that is Botox, in the main – to fund and expand the The proposed AbbVie takeover of Allergan M&A news new entity’s pipeline. Neuroscience, immunology and is a case in point. Looking to the future, AbbVie says it oncology will remain at the fore. is confident that Allergan’s major product Botox will Meanwhile, fellow US major Bristol-Myers Squibb be rather easier to defend from biosimilar competition is still wrestling with US Federal Trade Commission’s than its own cash cow, Humira. AbbVie CEO Richard concerns in order to effect its takeover of Celgene. BMS Gonzalez says the Botox molecule is technically very dif- needs to find a buyer for Celgene’s blockbuster therapy ficult to copy and that generic competition will be some Otezla to address FTC competitive concerns in psoria- time coming, and may even never materialize. Biosimilar sis, a development that took some investors aback as developers think otherwise. See page 8 for all the details. there is little overlap in the two companies’ immuno- Meanwhile on pages 5-8, Mandy Jackson has taken logical portfolios. As a result, the deal is not now ex- a deep dive into the combined firm’s potential pipe- pected to close until late 2019 or early next year. Jessica line. The proposed deal may have ascribed little value Merrill has all the details on page 4.

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2 | Scrip | July 5, 2019 © Informa UK Ltd 2019 Clovis CEO Interview

BMS’s New Chapter 20 4 Emricasan Final Defeat 13 21

exclusive online content inside: COVER / Sanofi Plans More Job Cuts, This Time In R&D

Lupin Boss On Getting Biosimilar 3 Lupin Boss On Getting Biosimilar Manufacturing Right, Manufacturing Right, Albuterol Outlook Albuterol Outlook ANJU GHANGURDE [email protected] 4 In Merger Plot Twist, BMS Needs A Buyer For Celgene’s Otezla, Raising New Questions

5 AbbVie Will Use Allergan Revenue To Fund Combined Firm’s Large R&D Pipeline

8 Bruised Over Humira Patent Games, AbbVie Sees Smoother Road With Botox

9 Anxious Investors Relieved At Bayer’s Fresh Monsanto Litigation Strategy

10 Doubts Raised Over Regeneron’s Anti-IL 33 REGN3500 At Phase II In Asthma

11 BMS’ Bid For Opdivo In First-Line HCC Stymied

Lupin Ltd. isn’t fretting about not being among the early 12 Cautious Restart To Venetoclax’s CANOVA Trial In movers in the biosimilars space and believes that those Multiple Myeloma who can get the manufacturing of these products right could potentially hold a distinct edge. 13 Conatus Accepts Defeat For Emricasan In NASH In an interview with Scrip, the Indian company’s manag- 14 Genfit Assesses Optimal Elafibranor NASH Combo ing director Nilesh Gupta reiterated that being early in the Therapy Opportunity biosimilars sector “would not have been an advantage,” noting that while products such as granulocyte colony- 16 Dupixent Gets Room To Grow With New Indication In Chronic Rhinosinusitis stimulating factor (G-CSF) became a “nice opportunity” for some, there have also been “casualties” along the way for 16 Pfizer’s Talzenna To Compete With AZ’s Lynparza In pegylated G-CSF. Breast Cancer After EU Okay “I think now is the time to be able to do the right kind/ range of products, be in time for patent expiry as well,” 18 AMAG Must Build Market For Approved Female Libido Drug To Avoid Addyi’s Fate Gupta said. The US biosimilar market for Amgen Inc.’s short-acting 19 Bring Them On: China Releases Generics List To neutropenia drug Neupogen (filgrastim) has seen sig- Encourage Competition nificant uptake for Teva Pharmaceutical Industries Ltd.’s 21 Clovis CEO’s Rough Guide To European Launches Granix (tbo-filgrastim) and Sandoz’s Zarxio (filgrastim-sn- dz), the first biosimilars approved under the new regula- 22 Pipeline Watch tory pathway in the US. In July last year, Mylan NV commenced commercial US 23 Appointments sales of Fulphila (pegfilgrastim-jmdb), the first-to-market biosimilar version of Amgen’s Neulasta, co-developed with Biocon Ltd. Published online 21 June 2019 @PharmaScrip /scripintelligence To read the rest of this story go to: https://bit.ly/2xo9U5C

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CONTINUED FROM PAGE 1 In December 2018 the firm had an- In Merger Plot Twist, BMS Needs A nounced a separate round of cuts in France, with 670 lay-offs in HR, IT and -fi nance to take place by 2020. After finaliz- Buyer For Celgene’s Otezla, Raising ing an agreement on this plan with French labor unions in March 2019, the company New Questions in April unveiled plans to shift support JESSICA MERRILL [email protected] service roles in France in part to external partners and in part to its own platform ristol-Myers Squibb Co. is seeking a some investor challenges, shareholders in Hungary. But after an outcry in France, buyer for Celgene Corp.’s blockbuster in both companies voted in favor of the later that month CEO Olivier Brandicourt Bpsoriasis pill Otezla (apremilast) to merger in April. (Also see “As Expected: told the annual shareholders’ meeting address concerns by the US Federal Trade Shareholders Back Bristol’s $74bn Celgene that the planned relocation of functions Commission around the planned merger Buy” - Scrip, 12 Apr, 2019.) to Hungary would no longer take place. related to competition in psoriasis. The Celgene had already extricated itself The latest organizational restructuring news surprised some investors given that from some existing partnerships in the announcement comes during a period BMS and Celgene don’t currently have a cancer space, including with BeiGene of marked change and upheaval for the significant amount of overlap in the immu- Ltd. and Mereo BioPharma Group PLC, French group. In 2018, Sanofi spent nearly nology space, and while Otezla was not a ahead of the deal closing. (Also see “Deal €13bn on acquiring blood disorder spe- main driver of the merger, it is still a signifi- Watch: Sanofi Further Opts Out Of CNS Tie- cialists Bioverativ and Ablynx. At the end cant revenue-generating growth driver. Up With Voyager” - Scrip, 20 Jun, 2019.) of June 2018, Elias Zerhouni retired after Otezla is approved for the treatment of Otezla is a significantly smaller brand eight years as head of global R&D, to be moderate-to-severe plaque psoriasis and compared to Revlimid, a backbone regi- replaced by John Reed, formerly global psoriatic arthritis and generated $1.61bn men for the treatment of multiple myelo- head of Roche’s pharma research and in 2018, on year-over-year growth of 26%. ma that generated $9.69bn in 2018. But it early development. Then from September BMS has some portfolio overlap in im- is still one of only a handful of marketed 2018 a new CFO was appointed, replac- munology with Orencia (abatacept), drugs Celgene would have brought to ing Jérôme Contamine after his nine years which is approved for rheumatoid arthritis BMS, along with two other cancer medi- in the role. Jean-Baptiste Chasseloup de and psoriatic arthritis, but confirmed that cines, Pomalyst (pomalidomide) and Ab- Chatillon joined from automotive group the FTC’s concerns were related to overlap raxane (paclitaxel protein-bound particles). PSA Group, where he was credited with with a BMS-owned pipeline drug, an oral helping turn around the company. selective tyrosine kinase 2 (TYK2) inhibitor FTC’S CONCERNS RAISE Meanwhile, also in 2018, head of hu- BMS-986165, in late-stage development QUESTIONS FOR THE INDUSTRY man resources Roberto Pucci retired af- for moderate to severe plaque psoriasis. Otezla is also expected to continue to ter nine years, to be replaced by Caroline BMS presumably sees more long-term grow, with some analyst estimates fore- Luscombe, and Bayer’s former head of value in the pipeline asset than in Otezla. casting around $2.5bn in sales of the prod- pharma Dieter Weinand joined Sanofi as The company announced the planned uct in 2023. Another attractive aspect of head of a new primary care business unit divestiture on 24 June and said the merg- the drug is that it would have given BMS a combining diabetes, cardiovascular and er would be delayed several months while foundation in the intensely competitive established products. Earlier in the year, it enters into a consent decree with the psoriasis space ahead of the launch of the Sanofi’s deputy CFO Dominique Carouge FTC. The deal is now expected to close in TYK2 inhibitor. had been appointed executive vice-pres- late 2019 or early 2020 rather than in the The FTC’s concerns raise two big ques- ident head of business transformation. third quarter, BMS said. BMS’ stock opened tions for the industry. First, what drug In February 2019, chief medical officer 4.3% lower at $47.22, although the com- maker that might be interested in buying Ameet Nathwani was given the additional pany also announced disappointing data Otezla could do so without also raising title of chief digital officer. on Opdivo in first-line liver cancer. FTC anti-competitive concerns? Later this year, the group will also get a BMS unveiled plans to buy Celgene for Secondly, does the decision suggest the new CEO, with Paul Hudson, current head $74bn in January as part of a strategy to re- FTC is becoming more stringent when it of Novartis Pharmaceuticals, arriving in duce its dependence on the cancer block- comes to pipeline overlap and could that September to replace Brandicourt. (Also buster Opdivo (nivolumab). But some have implications for other mergers? see “The Challenges Facing Paul Hudson BMS investors were already questioning Roche’s planned acquisition of Spark At the Helm of Sanofi “ - Scrip, 7 Jun, 2019.) the value of the deal with Celgene’s big Therapeutics Inc., for example, has been Brandicourt will leave before the comple- seller Revlimid (lenalidomide) maturing extended twice due to the FTC’s ongoing tion of his five-year 2015-2020 strategic and a limited market exclusivity. (Also see review, without a lot of clarity from Roche road map for the company, laid out after “Bristol Values Celgene’s Hematology, Im- as to why, and with the two companies his appointment in 2015. munology Portfolio At $74bn, But Does It having substantial overlap in hemophilia. Published online 23 June 2019 Price In Risk?” - Scrip, 3 Jan, 2019.) Despite Roche’s $4.8bn acquisition of Spark was

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A BUYER WITHOUT OVERLAP Finding a buyer who can pay that much for a single asset and with commercial synergies in dermatology could prove chal- lenging, however, if the FTC was to subject the transaction to a similar standard as applied to BMS. Big pharmas with a substantial commercial presence in psoriasis like AbbVie Inc., Novartis AG and Johnson & Johnson would presumably also present regulatory concerns, though in the case of BMS, Otezla and BMS-986165 are both oral drugs, which may have raised a A new chapter specific concern. Drug companies that don’t have experience unfolds in the in the fiercely competitive space may be reluctant to take on Bristol/Celgene the commercial challenge, especially if they can’t take advan- merger tage of existing commercial infrastructure. Otezla could be a compelling opportunity for a company with a commercial presence in dermatology, but not specifi- announced in February, with the company originally expecting cally psoriasis. A company like Sanofi could be a possible con- the deal to close in the first half of the year. (Also see “Roche Con- tender, with a presence in dermatology with Dupixent (dupi- fident Spark Therapeutics Acquisition Will Complete In First Half” lumab) for atopic dermatitis, but no late-stage programs or - Scrip, 3 Apr, 2019.) Roche’s tender offer has most recently been marketed drugs for psoriasis. Pfizer Inc. has been building up extended until 31 July. in dermatology, beginning with the launch of Eucrisa (crisab- While the divestiture of Otezla could bring in significant amount orole) in 2017 for atopic dermatitis, but while it doesn’t sell any for BMS – which said the proceeds from the sale would allow the drugs for psoriasis, it does have a TYK2/JAK inhibitor in Phase II company to accelerate its post-closing deleveraging plans – a sale development for psoriasis. by necessity puts the pressure on BMS to unload it quickly. Biotech investors will now be keeping a close eye on any other The value of the drug could be as much as $9.3bn, Credit Suisse signs that the FTC is taking a more aggressive approach to pipe- analyst Vamil Divan speculated in a same-day research note. “The line overlap, and particularly waiting to see what happens next key for Otezla now will be what Bristol can obtain for the asset,” he with the ongoing Roche/Spark review. said. “We believe sellers are often at disadvantage when potential “Bulls say FTC is merely erring on the side of timing caution as buyers know they need to divest a given asset, but there are many they review other healthcare transactions, owing to criticism re- companies with drugs in the dermatology space that may look to lated to lax enforcement and fears that they allow a deal to go bid on the asset.” through that removes a potential disrupter from the market,” Jef- Mizuho Securities analyst Salim Sayed calculated the net pres- feries analyst Michael Yee said. “We continue to be mindful and ent value as much lower, however, pointing out in a same-day are carefully watching to get a better handle on if we are in a more note that the TYK2 launch would be expected to put pressure on aggressive FTC era for biotech.” Otezla long-term, putting the value of the drug in the “high $6bn to low $7bn range.” Published online 24 June 2019 AbbVie Will Use Allergan Revenue To Fund Combined Firm’s Large R&D Pipeline

MANDY JACKSON [email protected]

bbVie Inc. CEO Richard Gonzalez Allergan also markets the dry eye drug maceuticals Inc., and some women’s said repeatedly when describing Restasis (cyclosporine ophthalmic emul- health products, like the birth control pill Athe company’s rationale for buy- sion), which generated $1.26bn in 2018 Lo Loestrin. ing Allergan PLC for $63bn that very little sales, but is poised to face generics this AbbVie executives admitted on 25 value was ascribed to Allergan’s research year, and Lumigan (bimatoprost ophthal- June when the mega-deal was an- and development pipeline. However, the mic solution) to reduce eye intraocular nounced that the company is buying Al- pharmaceutical firms combined have 62 pressure in glaucoma. (Also see “Going lergan to add its nearly $16bn in annual drugs in clinical development – with 38 Generic: Big Brands Poised To Lose Market- sales to AbbVie’s own $33bn in revenue in Phase II and III or awaiting regulatory ing Exclusivity In The US In 2019 “ - Scrip, before its $20bn in Humira (adalimum- approvals, including new indications for 15 Mar, 2019.) Allergan also sells Linzess ab) sales are whittled away by biosimilar marketed products – requiring substantial (linaclotide) for irritable bowel syndrome competitors, which will launch in the US ongoing investment. under a partnership with Ironwood Phar- starting in 2023. However, the executives

scrip.pharmaintelligence.informa.com July 5, 2019 | Scrip | 5 M&A

also noted that revenue from Allergan’s see a lot of added value in the acquired migraines. Ubrogepant, in-licensed from products, including its top-seller Botox pipeline, especially after several high-pro- Merck & Co. Inc., is under review at the US (onabotulinumtoxinA), will help fund file, late-stage R&D setbacks at Allergan. Food and Drug Administration with a de- and expand AbbVie’s pipeline. “In terms of R&D abilities, Allergan has cision expected in late 2019. “This transaction is not a transaction been wanting, and it will bring little to the While “the large majority of the value that’s highly dependent on pipeline,” Gon- table,” Wolfe Research analyst Tim Ander- of this transaction comes from Allergan’s zalez said during AbbVie’s same-day con- son said in a 25 June note. strong portfolio of on-market products,” ference call to discuss the deal with ana- SVB Leerink’s Geoffrey Porges said in AbbVie president and vice chairman Mi- lysts and investors. a 25 June note that “Allergan has been chael Severino said during the company’s He described any successes in Allergan’s dogged by disappointing R&D perfor- conference call, “there are areas in the pipeline after the deal closes in early 2020 mance and unrealistic expectations pipeline that look interesting, such as their as “upside” – value on top of what AbbVie for pipeline programs, and AbbVie has [central nervous system (CNS)] programs.” priced into the acquisition. suffered from some of the same issues,” Severino noted the CGRP inhibitors, “We’re not betting on pipeline,” Gonza- pointing out the disappointing perfor- which include the Phase III drug atoge- lez said. “So, if some of their pipeline assets mance of the cancer drug candidate pant for migraine prevention; the anti- were to work out, there would be an up- Rova-T, which was acquired in the psychotic Vraylar (cariprazine), which won side to our model. We’ve built in very, very $5.8bn purchase of Stemcentrx Inc. in supplemental FDA approval in May for modest assumptions in this.” 2016. (Also see “AbbVie’s Rova-T Disap- bipolar depression; and Botox, which has But while it plans to eliminate $2bn in points As Second-Line SCLC Trial Halted” several cosmetic and therapeutic indica- costs after the companies merge, includ- - Scrip, 6 Dec, 2018.) tions, including chronic migraine prophy- ing $1bn in overlapping R&D expenses, “Diversifying the business is obviously laxis. Vraylar’s sales in its previously ap- AbbVie also believes that combining the important strategically, but we tend to proved indications of schizophrenia and firms’ revenue streams will give it more prefer our companies focusing their busi- bipolar I disorder totaled $487m in 2018 revenue to fund R&D, including additional ness development efforts on filling their and analyst consensus foresees $1.17bn deals to bring in outside assets. pipelines with unique, innovative assets in sales in 2023. “The revenue scale that Allergan brings and that does not seem to be the case When Allergan’s CNS portfolio is to AbbVie will enable enhanced funding here,” Credit Suisse analyst Vamil Divan added to AbbVie’s Duodopa (levodopa/ of our innovative R&D platform and pro- said in a 26 June report. carbidopa) for Parkinson’s disease and vides ample resources for additional pipe- the company’s own pipeline programs, line expansion,” Gonzalez said. NEUROSCIENCE PRESENTS BIG “we see neuroscience as an important While AbbVie already has its sights set ALLERGAN R&D OPPORTUNITIES area for long-term growth potential,” on expanding its R&D programs, despite One of the most highly valued programs Gonzalez said. bringing in 20 Phase II through registra- in Allergan’s pipeline isn’t particularly tional programs from Allergan, it’s not novel – there already are three CGRP in- IMMUNOLOGY, ONCOLOGY alone in discounting the value of the pro- hibitors on the market for migraine head- REMAIN KEY FOR ABBVIE grams it will take on in 2020 when the deal aches – but it could be the first oral drug Allergan’s neuroscience pipeline will add closes. Analysts and investors also don’t and the first on-demand treatment for several programs in areas where AbbVie’s

AbbVie/Allergan CNS Pipelines

ABBVIE’S CNS R&D PROGRAMS ALLERGAN’S CNS R&D PROGRAMS

ABBV-951, a subcutaneous injection of levodopa and carbidopa, is in A new drug application (NDA) is pending at the US FDA for the oral CGRP Phase III for Parkinson’s disease (PD) inhibitor ubrogepant for acute treatment of migraine headaches ABBV-8E12, a monoclonal antibody targeting tau proteins in the brain, is in Phase II for Alzheimer’s disease (AD) and progressive supranuclear The oral CGRP inhibitor atogepant is in Phase III for migraine prevention palsy (PSP) Elezanumab targeting repulsive guidance molecule A (RGMa) is in Phase Vraylar, an oral antipsychotic, is in Phase III for major depressive disorder II for multiple sclerosis (MDD) and Phase I for autism spectrum disorder ABBV-0805, a monoclonal antibody that removes or inactivates alpha- The NMDA receptor modulator AGN-241751 is in Phase II for MDD synuclein, is in Phase I for PD AGN-151607, a neurotoxin, is a next-generation botulinumtoxinA in

Phase I for MDD and Phase II for atrial fibrillation AGN-242626, an oral muscarinic acetylcholine receptor (M4) agonist, is in

Phase I for AD The M1 agonist AGN-242701 also is in Phase I for AD Source: AbbVie, Allergan, Biomedtracker

6 | Scrip | July 5, 2019 © Informa UK Ltd 2019 M&A

not active currently, but immunology and but one exception could be Allergan’s touched and will continue to invest in oncology will remain AbbVie’s bread and IL-23 inhibitor brazikumab (MEDI2070), that unit’s existing assets while adding butter, anchored by Humira until it loses which is in Phase II for UC and Phase II/III new products through R&D and acquisi- patent exclusivity in the US and the he- for CD under a license with AstraZeneca tions. The AbbVie CEO echoed Allergan’s matological cancer therapies Venclexta PLC. Skyrizi is in Phase III for both IBD indi- sentiments about aesthetics still being a (venetoclax) and Imbruvica (ibrutinib). cations and other candidates in AbbVie’s largely untapped market with much room AbbVie and its partners will add more pipeline are being developed for these for growth. indications to the Venclexta and Imbruvica diseases as well. With Allergan’s significant global pres- labels over the next few years, helping to Gastrointestinal disease R&D programs ence in medical aesthetics and its plans to grow the products’ revenues substantially at Allergan also include two drugs for launch several new indications and new by the time Humira goes off-patent. Ana- non-alcoholic steatohepatitis (NASH) – products during the next several years, lyst consensus sees Venclexta sales rising the Phase III CCR2/5 receptor antagonist “we feel highly confident in the competi- from $344m in 2018 to $2.66bn in 2023, cenicriviroc and FXR agonist AGN-242266 tive position of this business,” he said. “In with Imbruvica soaring from $3.59bn last – and the Phase III ghrelin agonist relamo- addition, the medical aesthetics market year to $7.13bn in 2023. relin for diabetic gastroparesis. Allergan remains highly underpenetrated. With in- Allergan does not have any cancer and its Linzess partner Ironwood Pharma- creasing interest and acceptability of aes- drugs, but its gastrointestinal fran- ceuticals Inc. also have a delayed-release thetic procedures and products globally, chise anchored by the irritable bowel version of their drug in Phase II for pain in and increasing utilization within younger syndrome (IBS) products Linzess (lina- IBS with diarrhea. demographics, the medical aesthetics clotide) and Viberzi (eluxadoline) has an market has the potential to double by R&D program that could overlap with in- MEDICAL AESTHETICS: BOTOX 2025, making this franchise extremely at- flammatory bowel disease (IBD) indica- AND BEYOND tractive and durable for AbbVie.” tions – ulcerative colitis (UC) and Crohn’s The most valuable asset in Allergan’s Investors have been somewhat worried disease (CD) – approved for Humira and product portfolio is Botox, which generat- about coming competitors for Botox, in- under investigation for AbbVie’s inter- ed $3.58bn across its therapeutic and cos- cluding a potentially longer-acting neuro- leukin-23 (IL-23) inhibitor Skyrizi (risanki- metic indications. The wrinkle-reducing toxin from Revance Therapeutics Inc., but zumab), which was approved to treat injection is the cornerstone of the com- analysts expect this business to remain psoriasis in April. pany’s market-leading $4.5bn medical fairly stable. (Also see “Another Botox Com- AbbVie does not expect any major aesthetics portfolio and it is a key element petitor: Revance Prepares Longer-Lasting snags in its Allergan acquisition related to of Allergan’s R&D portfolio in aesthetics. RT002 For BLA Submission” - Scrip, 22 anti-competitive concerns that could be Gonzalez said AbbVie will leave the Feb, 2019.) Consensus estimates forecast flagged by the Federal Trade Commission, medical aesthetics business largely un- that Botox Cosmetic sales, which totaled

AbbVie’s Immunology And Oncology Pipelines

ABBVIE’S IMMUNOLOGY PIPELINE ABBVIE’S ONCOLOGY PIPELINE

The BCL2 inhibitor Venclexta, partnered with Roche, is in Phase III for Skyrizi is in Phase III for UC, CD and psoriatic arthritis (PsA); it’s in Phase II multiple myeloma (MM) and mantle cell lymphoma (MCL), Phase II for for atopic dermatitis (AD) and hidradenitis suppurativa myelodysplastic syndrome (MDS) and Phase I for acute lymphoblastic leukemia (ALL) The JAK1 inhibitor upadacitinib is under US FDA review for rheumatoid Imbruvica, a BTK inhibitor partnered with Johnson & Johnson, is in Phase arthritis (RA); it’s in Phase III for PsA, CD, UC, AD and giant cell arteritis, III for first-line follicular lymphoma (FL), relapsed or refractory (R/R) FL or and Phase II for axial spondyloarthritis marginal zone lymphoma (MZL) and first-line MCL. ABBV-599, which combines a Bruton’s tyrosine kinase (BTK) inhibitor and Empliciti (elotuzumab), partnered with Bristol-Myers Squibb Co., targets a JAK1 inhibitor, is in Phase II for RA SLAMF7 and is in Phase III for first-line MM The PARP inhibitor veliparib is in Phase III for non-small cell lung cancer ABBV-323 is a CD40 antagonist in Phase II for UC (NSCLC), BRCA-mutated breast cancer and ovarian cancer Rova-T is in Phase III for first-line treatment of small cell lung cancer ABBV-3373, an anti-TNF and steroid conjugate, is in Phase Ib/IIa for RA (SCLC) The BCL2-targeting navitoclax, also developed with Roche, is in Phase II ABBV-157 targets RORyt and is in Phase I for psoriasis for myelofibrosis Telisotuzumab vedotin, a c-Met-targeting antibody-drug conjugate ABBV-154 is in Phase I for RA (ADC), is in Phase II for solid tumors ABT-165 targeting VEGF and DLL4 is in Phase II for solid tumors Another 14 assets are in Phase I, including Venetoclax for ALL Source: AbbVie, Allergan, Biomedtracker

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$1.55bn in 2018, will be about $1.57bn in Allergan Eye Care Pipeline 2023. Botox Therapeutic sales are expect- ALLERGAN’S EYE CARE R&D PORTFOLIO ed to reach $2.3bn in 2023 versus $2.03bn in 2018. Presbysol is in Phase III for presbyopia Allergan’s aesthetics R&D pipeline in- Bimatoprost SR is an intracameral implant that provides sustained release of Lumigan (bimato- cludes Phase II studies for Botox in reduc- prost) for intraocular pressure (IOP) in glaucoma; it is in Phase III ing jawline and neck wrinkles and a Phase In Phase III for dry eye, Optive Fusion is a multi-dose preservative-free (MDPF) formulation of an I study in improving skin quality. Kybella over-the-counter (OTC) eye drop (deoxycholic acid), approved in the US to Abicipar pegol is a VEGF inhibitor in Phase III for wet AMD and Phase II for diabetic macular reduce the appearance of a double chin, is edema in Phase II for reducing jowl fat. Optive Ultra OTC drops are in Phase II for dry eye A next-generation neurotoxin called nivobotulinumtoxinA – available in a Brimonidine DDS, an implant for sustained release of Combigan (brimonidine), is in Phase II for vial without the need for reconstitution, geographic atrophy (dry AMD) and for glaucoma unlike Botox – is in Phase III for the re- Bimatoprost ring, also in Phase II for glaucoma, is another implant duction of glabellar lines (wrinkles be- Optive Lite MDPF is in Phase I for dry eye tween the eyes) and crow’s feet. And AGN-151597 is a gene therapy in Phase I for retinitis pigmentosa BoNTE (EB-001), the short-acting toxin Source: AbbVie, Allergan, Biomedtracker that Allergan acquired last year with the purchase of Bonti Inc. for $195m up front, is in Phase II for glabellar lines. Phase III asset abicipar pegol could run label limits uptake of the AMD drug. (Also see “Allergan Buys Bonti, Releases into regulatory concerns or commercial “We’ll have to see what the label looks New Data In Defense Of ‘Iconic’ Botox challenges because the potentially lon- like to have a better sense for the oppor- Brand” - Scrip, 14 Sep, 2018.) ger-acting VEGF inhibitor caused a fairly tunity,” he said. “And the tradeoff we’re high rate of ocular inflammation in its looking at is the benefit of the longer- EYE CARE, A PRIORITY AT Phase III wet age-related macular degen- acting nature of this agent compared ALLERGAN, DIVERSIFIES eration (AMD) studies that may limit its to the patients who experience ocular ABBVIE PORTFOLIO use, but Allergan is working on a mid-2019 inflammation, which is on the order of Ophthalmology also has been an im- US FDA submission for the biologic. (Also about 8% to 10% of patients. We’ll have portant therapeutic area for Allergan see “Allergan Improves Safety Of Abicipar, to see what that looks like in the label and will give AbbVie another means for But Not Enough Compared To Lucentis, Ey- and we’ll have to see how that’s viewed diversifying its revenue beyond Humira. lea” - Scrip, 2 Apr, 2019.) by treating physicians.” Allergan’s biggest product in this cat- Since Allergan already has paid for However, Leerink’s Porges said in a egory – Restasis (cyclosporine) for dry and completed the abicipar develop- 26 June note that he expects AbbVie to eye disease – is expected to face gener- ment program, Severino noted during abandon abicipar if the drug receives less ics this year, but the company will main- AbbVie’s call that an approval with a than favorable treatment from regulatory tain a presence in that indication and in favorable label would be added value agencies. glaucoma on top of new ophthalmol- on top of what the company has priced ogy opportunities. into its Allergan acquisition, unless the Published online 24 June 2019 Bruised Over Humira Patent Games, AbbVie Sees Smoother Road With Botox

CATHY KELLY [email protected]

bbVie Inc. believes it will have less Botox marketer Allergan PLC for $63bn in mumab) and entered into a series of pat- trouble protecting market exclu- an effort to reduce its reliance on Humira. ent settlement agreements that delay Asivity for Botox than it has for Hu- Humira has become a poster child for biosimilar competition to the blockbuster mira, which would be a relief to a company detractors of patent gaming aimed at in US until 2023, even while biosimilars whose reputation has taken a beating in blocking lower-priced competition amid launched in Europe in 2018. the public sphere and in Congress over its the ongoing prescription drug pricing de- CEO Richard Gonzalez fielded pointed approach to extending the patent life of bate in the US. questions over the patent estate for Hu- its blockbuster. AbbVie announced on 25 Critics point to the fact that AbbVie has mira at the high-profile Senate hearing June that it has reached a deal to acquire amassed 136 patents on Humira (adali- featuring biopharma executives last Feb-

8 | Scrip | July 5, 2019 © Informa UK Ltd 2019 PRICING/LITIGATION

ruary. The company’s actions spurred in- ALLERGAN’S MOHAWK DEAL terest in bipartisan legislation to reform Allergan has been less effective in extend- the practices of amassing patent “thickets” ing the patent for its second largest drug, and product “hopping,” or effectively ex- the dry eye treatment Restasis (cyclospo- tending the patent life of a product by in- rine), despite the company’s willingness troducing a line extension. Such practices to take unconventional measures. But like may be addressed in a scheduled Senate “It’s highly unlikely AbbVie, Allergan has faced strong public Judiciary Committee markup of several criticism for putting corporate concerns patent legislation proposals. that we would see ahead of lowering prices for patients with AbbVie is not alone in its approach to a biosimilar against its patent extension efforts. extending exclusivity for its blockbuster. “Two Birds of a Feather: AbbVie to Ac- But the facts that it has succeeded in get- Botox for a long, quire Fellow Price-Gouger Allergan,” the ting several additional years of protec- payer-supported Council for Sustainable tion in the US, and that Humira is one of long time, if ever.” – Rx Pricing trumpeted in a statement on the top drugs in terms of Medicare Part D the purchase. “What do AbbVie and Al- spending, has made it a particular target Richard Gonzalez lergan have in common? Both follow the for policymakers. The fact that it is also big pharma playbook of price gouging pa- the top selling drug in the world with tients and consumers while stamping out $19.94bn in revenues in 2018 also makes competition.” Allergan provoked contro- it a target. versy in 2017 with its plan to delay com- Gonzalez predicted that AbbVie won’t if a biosimilar can move into development petition for Restasis by transferring the need to go to the same lengths to protect via the 351k pathway and believe they will patent to the Saint Regis Mohawk tribe, Botox (onabotulinumtoxinA) during a 25 be able to move ahead, according to com- which then claimed sovereign immunity June call on the acquisition. ments by Mylan and Revance executives in to withstand any legal challenges. “As far as it relates to a biosimilar, obvi- earnings calls following the meeting. Under the deal, the tribe received ously that’s an area we know well. And I “Based on the agency’s feedback, the $13.5m up front and was eligible to receive would say when you look at Botox, it’s a companies believe that the 351k path- $15m in annual royalties. In exchange, it very unique molecule,” he said. “And for a way for the development of the bio- agreed to claim sovereign status to get an variety of technical reasons, I would tell similar to Botox is viable and provides inter partes review proceeding dismissed you that it’s highly unlikely that we would the opportunity to develop and com- by the US Patent and Trademark Office’s see a biosimilar against Botox for a long, mercialize the first biosimilar to Botox,” Patent Trial and Appeal Board. long time, if ever.” Mylan President and Executive Director The move put a spotlight on the im- His assurances are interesting given re- Rajiv Malik said during the company’s portance of preserving key assets. Unlike cent comments by prospective biosimilar 26 February call. AbbVie’s patent estate for Humira, Aller- developers Revance Therapeutics Inc. and Gonzalez also noted that Allergan gan’s approach was unsuccessful, and the Mylan NV, which have partnered to work has been successful in deflecting com- resulting decline in Restasis sales was an on developing a follow-on for Botox. petition to Botox from other botulinum important reason for Allergan’s decision to The companies met with the US Food and toxin-based treatments with savvy mar- sell to AbbVie. Drug Administration earlier this year to see keting efforts. Published online 28 June 2019 Anxious Investors Relieved At Bayer’s Fresh Monsanto Litigation Strategy

JO SHORTHOUSE [email protected]

ayer AG’s shares jumped by more which doubled the size of its crop scienc- than 8% to €60.69 on the Frankfurt es division. However, Monsanto’s glypho- Bstock exchange during 27 June as it sate-based weedkillers such as Roundup announced a new strategy to address US have been plagued by allegations that litigation concerning its weedkillers. they cause cancer. The case centers around the seeds firm As of 11 April, lawsuits from approxi- Monsanto, which Bayer bought in June mately 13,400 plaintiffs had been served 2018 for $63bn, the largest acquisition in the US. Dewayne Johnson was the first in the German’s company’s history and to sue Monsanto in 2016 after alleging

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that its products gave him cancer and last the company decisively but prudently ad- in sentiment,” said Morgan Stanley in an August a San Francisco jury awarded him vance the matter,” it said. 27 June note. $289m although that figure was subse- As such, a new supervisory board com- Activist investor Elliott Advisors, which quently reduced. mittee will “intensively monitor” the pro- holds Bayer shares and financial instru- With each court ruling against Bayer cess, consult with the Board of Manage- ments equivalent to €1.1bn ($1.3bn), its shares have been sent tumbling. In ment and make recommendations on the said that it welcomed the steps and was March they fell by 10%, wiping more litigation strategy. It will be equally com- confident it marked a step change in the than €7bn off its value, when second posed of shareholder and employee rep- company’s approach to the legal chal- case was heard before a San Francisco resentatives and made up of eight super- lenges. It said: “Elliott believes that the jury which decided that the weedkiller visory board members, several of whom creation of the special committee will was a significant factor in causing can- have gathered extensive experience with provide a new level of oversight and a cer. In May they fell again, this time by complex litigations. fresh perspective to a litigation strategy 2.3%, when its third court case awarded Bayer has also hired John Beisner, a US in need of a radical overhaul, and help $2bn to a California couple who claimed trial lawyer that represented Merck & Co. guide the company towards a rational, its weedkiller caused their cancer. Inc. during the Vioxx litigation process, fair and swift settlement.” The stock downward spiral has con- and Johnson & Johnson on its DePuy hip Regarding the appointment of Beisner cerned investors who have expressed a replacements case, as an adviser. He is and the special committee formation, wish to see Bayer settle lawsuits, bringing expected to attend the new committee Elliot said that it afforded the company a clarity to the future of the company. meetings and advise on trial tactics and “a valuable platform from which to re- Bayer is now putting together a team mediation. His appointment is “intended solve the uncertainty associated with the to tackle this issue. The company’s super- to add fresh and independent perspec- glyphosate litigation, offering the oppor- visory board met for a full day session on tives to the advice given to the board of tunity for an accelerated settlement with a 26 June to discuss the legal challenges it management,” said Bayer. limited financial cost.” is facing “including those articulated by However, it also said that Bayer could stockholders at the recent Annual Stock- ACTIVIST INVESTORS do more to maximize long-term value holders’ Meeting and in the ongoing Analysts expressed some relief at the for all its stakeholders, adding, “Bayer’s dialogue with investors,” the Leverkusen- development. “We believe the fact that discounted share price today does not based firm said in a statement. Bayer is taking tangible steps towards reflect the significant underlying value “The supervisory board recognizes the bolstering its litigation strategy will of its constituent businesses, or the po- negative effect the litigation uncertainty provide a degree of solace to investors tential value realization opportunity that has had on the stock price and stakehold- but, ultimately, success in the courts is in excess of €30bn.” er perception, and is determined to help will be required to trigger a step change Published online 27 June 2019 Doubts Raised Over Regeneron’s Anti-IL 33 REGN3500 At Phase II In Asthma

STEN STOVALL [email protected]

anofi and Regeneron Pharmaceuticals Inc. released positive did numerically better than REGN3500/SAR440340 across all end- topline results from a Phase II proof-of-concept trial testing points, although the trial was not powered to show differences Stheir monotherapy REGN3500 in asthma, showing it met its between active treatment arms.” targets against placebo. But news that patients treated with Regeneron’s first-in-class “The topline IL-33 results raise questions interleukin-4/IL-13 inhibitor Dupixent – on the market since 2018 – did better than those who received the investigational anti-IL about the role of the class for asthma.” - 33 across all endpoints, fanned doubts among analysts about the role the anti-IL 33 class can play in the respiratory condition. Jefferies In the trial, REGN3500 (also known as SAR440340) monotherapy “significantly reduced loss of asthma control and improved lung function compared to placebo,” the companies said on 21 June. The greatest improvement was observed in patients with blood Combining REGN3500/SAR440340 and Regeneron’s Dupix- eosinophil levels greater than or equal to 300 cells/microliter. ent also did not demonstrate higher benefit compared with When announcing the trial’s topline data the duo also noted Dupixent alone. The Phase II proof-of-concept trial was a random- that “patients treated with Dupixent (dupilumab) monotherapy ized, double-blind, placebo-controlled, 12-week evaluation that

10 | Scrip | July 5, 2019 © Informa UK Ltd 2019 CLINICAL TRIALS

enrolled 296 adult patients with moderate-to-severe asthma who IL-33 binds to IL1R1/ST2 receptor expressed on many immune were not well controlled on LABA and ICS therapy. Patients were cells. IL-33 inhibition could therefore have broader effects than randomized into four treatment groups: REGN3500/SAR440340 current biologics, which only target Th2 cytokines. plus placebo, REGN3500/SAR440340 plus Dupixent, Dupixent GlaxoSmithKline PLC and AnaptysBio Inc. also have anti-IL 33s plus placebo, and placebo. in development for asthma. The primary endpoint was the proportion of patients who expe- Sanofi and Regeneron voiced optimism about the anti-IL 33 rienced loss of asthma control (LOAC) on REGN3500/SAR440340 monotherapy’s prospects. with or without Dupixent, compared with placebo. “This trial suggests that REGN3500 may provide an alterna- More detailed results from the trial will be presented at an up- tive targeted approach for patients suffering from asthma,” said coming, but unidentified medical meeting, the companies said. George Yancopoulos, Regeneron’s chief scientific officer. “We look Analysts at Jefferies in a reaction note the same day said that “de- forward to working with Sanofi to advance REGN3500 through spite monotherapy being superior to placebo, these preliminary re- our asthma clinical trial program, as well as continuing our ongo- sults suggest there may be limited benefit to using an IL-33 instead ing trials in atopic dermatitis and chronic obstructive pulmonary of Dupixent, or from adding REGN3500/SAR440340 to Dupixent.” disease,” he added. Therefore “the topline IL-33 results raise questions about the REGN3500/SAR440340 is being studied in different types of role of the class for asthma,” Jefferies said. asthma (Phase I and Phase II), chronic obstructive pulmonary dis- REGN3500/SAR440340 is a fully-human monoclonal antibody ease (Phase II) and atopic dermatitis (Phase II). that inhibits interleukin-33 (IL-33), a protein that is believed to “We plan to continue studying REGN3500/SAR440340 in these play a key role in type 1 and type 2 inflammation. Preclinical re- diseases and will provide updates as available,” Sanofi said. search has shown REGN3500 blocked several markers of both types of inflammation. Published online 21 June 2019 BMS’ Bid For Opdivo In First-Line HCC Stymied JOSEPH HAAS [email protected]

ristol-Myers Squibb Co. missed in its nificance (p=0.0752). Full results from the “A large Phase III may be needed to effort to show PD-1 inhibitor Op- trial will be presented later at a medical confirm this benefit, particularly in light Bdivo could improve upon standard- meeting, the firm said. Opdivo obtained of this recent setback, but BMS may forge of-care Nexavar in first-line hepatic cell accelerated approval for second-line HCC ahead with another accelerated approval carcinoma (HCC), leaving the pharma from the US Food and Drug Administra- submission in post-Nexavar settings and to look for a combination regimen with tion in September 2017. (Also see “Bristol’s may test the combination in the front-line CTLA-4 inhibitor Yervoy in previously Opdivo Diversifies Options In Liver Cancer” setting,” McLellan added. “For now, we will treated patients, as well as monotherapy - Scrip, 25 Sep, 2017.) have to wait and see.” in adjuvant care. Nexavar stood as the unchallenged On a day of dual surprises for inves- OPDIVO PROSPECTS standard of care in the first-line setting for tors, BMS revealed that CheckMate-459 Datamonitor Healthcare senior analyst roughly a decade, before last summer’s did not demonstrate a statistically sig- Zachary McLellan told Scrip that these re- approval of Eisai Co. Ltd./Merck & Co. Inc.’s nificant benefit on overall survival (OS) sults are “a large blow to [Opdivo’s] pros- Lenvima (lenvatinib). (Also see “First In 10 compared to Bayer AG/Amgen Inc.’s pects” in HCC. He added that a recent deci- Years, But Lenvima’s First-Line Liver Label Nexavar (sorafenib), long the standard in sion to pull a filing for second-line therapy Could Be Challenged Soon” - Scrip, 17 Aug, first-line HCC. Separately, the US pharma in Europe with Opdivo seems “well-found- 2018.) Earlier this year, however, Merck ex- announced that its pending merger with ed” – the European Medicines Agency experienced its own setback in HCC when Celgene Corp. would be delayed while pressed concern that the study used for Keytruda (pembrolizumab) failed the the companies sell off the latter’s psoria- approval in second-line treatment lacked Phase III KEYNOTE-240 study in second- sis blockbuster Otezla (apremilast) in or- a comparator. line HCC. (Also see “Merck’s Keytruda Loss der to address concerns of the US Federal “A path forward in the first-line setting In Liver Cancer Could Be Gain For Rivals” - Trade Commission. (Also see “In Merger where Nexavar remains the standard is Scrip, 19 Feb, 2019.) Plot Twist, BMS Needs A Buyer For Celgene’s now less clear. Combinations may be an In a statement, BMS said it retains confi- Otezla, Raising New Questions” - Scrip, 24 answer, however,” McLellan said. At the re- dence in Opdivo’s potential for HCC treat- Jun, 2019.) cent American Society of Clinical Oncolo- ment and will evaluate insights gained While BMS did not provide full data gy conference, BMS presented data show- from CheckMate-459. More than 1,000 from CheckMate-459, it reported on 24 ing that an Opdivo/Yervoy combination patients were enrolled in the trial, ac- June that Opdivo (nivolumab) showed a regimen yielded better results than Op- cording to Biomedtracker, with treatment positive numerical trend on OS compared divo monotherapy in patients previously continuing until the disease progresses to Nexavar but fell short of statistical sig- treated with Nexavar, the analyst noted. or there is unacceptable toxicity. Beyond

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the primary endpoint of OS, secondary endpoints included overall response rate, Cautious Restart To Venetoclax’s progression-free survival and relationship between patients’ expression of PD-L1 and efficacy – no data for those endpoints CANOVA Trial In Multiple Myeloma were disclosed. JOHN DAVIS [email protected]

OTHER COMBO REGIMENS he lifting of the US FDA’s partial clinical hold on only one clinical study – CANOVA – PENDING of AbbVie Inc./Roche’s bcl-2 inhibitor, Venclexta (venetoclax), in multiple myeloma, While HCC is the most common form of T after changes to its design and while keeping the hold on other studies in multiple liver cancer and fastest-rising cause of myeloma, suggests a cautious approach is being taken to further evaluation of the drug cancer-related mortality in the US, Credit for the additional indication. Suisse analyst Vamil Divan pointed out in Concerns about a higher proportion of deaths seen in the venetoclax arm than the pla- a same-day note that HCC is a relatively cebo arm of another clinical study, the Phase III BELLINI trial, led to the partial clinical hold small market, with about 11,000 patients being put in place in March 2019, with analysts at Biomedtracker suggesting the move in the US and 38,000 worldwide. BMS had might dampen venetoclax’s future commercial growth. seemed well-positioned to gain approval That said, venetoclax met the primary endpoint of progression-free survival in the for the first-line setting based on its ap- BELLINI study, and AbbVie has suggested there may be a potential role for venetoclax in a proval in second-line therapy, he wrote, subset of patients with t(11;14) biomarker-defined myeloma, which accounts for around but its failure to demonstrate an OS bene- 20% of patients with the condition. fit with Opdivo monotherapy now opens The first-in-class bcl-2 inhibitor has been of particular interest for its role in becoming a door for combination regimens being a constituent of chemotherapy-free regimens; venetoclax binds and inhibits the B-cell investigated by competitors including lymphoma-2 protein in cancer cells, which if left unchecked acts to prevent apoptosis of Merck, Roche and AstraZeneca PLC. those cells. William Blair & Co. analyst Matt Phipps This May, AbbVie and Genentech (Roche) gained an additional indication in the US for wrote on 24 June that the failure of Check- the use of venetoclax in a chemotherapy-free, fixed duration combination regimen with Mate-459 places increased importance on the CD20-binding Mab, Gazyva (obinutuzumab) for previously untreated chronic lym- other ongoing BMS trials, notably Check- phocytic leukemia (CLL) in patients with co-existing medical conditions. Mate-9LA, testing Opdivo with Yervoy and two lines of chemotherapy in first-line RISK MITIGATION METHODS lung cancer. That study is expected to re- In the CANOVA (M13-494) study in patients with relapsed/refractory multiple my- port out early in 2020. eloma, venetoclax is being evaluated in combination with dexamethasone and Phipps also slashed his revenue esti- compared with a combination of pomalidomide (Celgene Corp.’s Imnovid) plus mates for Opdivo in HCC based on the dexamethasone in patients with the translocation (11.14) abnormality, said by Ab- trial miss. Blair now projects $212m bVie to be among the most common and routinely tested genetic abnormalities in in 2020, down from $477m; $179m in patients with multiple myeloma. 2021, reduced from $666m; and $146m Changes to CANOVA’s protocol include new risk mitigation measures, protocol-spec- in 2022, rather than the previous esti- ified guidelines and updated futility criteria, and recruitment into the study can now mate of $812m. continue, AbbVie said. All other studies evaluating venetoclax in multiple myeloma BMS noted that it still is testing Op- remain on partial clinical hold while next steps continue to be evaluated with the FDA, divo monotherapy in adjuvant HCC AbbVie added. (CheckMate-9DX) and in combination At last week’s European Hematology Association meeting in Amsterdam, re- with Yervoy (ipilimumab) versus Yervoy searchers reported results from the BELLINI study, which included achieving a pri- monotherapy in previously treated pa- mary endpoint of improved PFS of 22.4 months in patients treated with venetoclax, tients as part of the CheckMate-040 trial. bortezomib (Takeda Pharmaceutical Co. Ltd.’s Velcade) and dexamethasone, com- Biomedtracker lists nine current Phase III pared with 11.5 months in patients treated with bortezomib and dexamethasone programs in HCC, including AstraZeneca’s (hazard ratio = 0.63, p =0.01). The overall response rate was also improved with Phase III HIMALAYA study of anti-PD-L1 venetoclax (82% versus 68%, p<0.01). agent Imfinzi (durvalumab) and CTLA-4 The study involved 291 patients, of which 194 were in the venetoclax arm and 97 in the inhibitor tremelimumab in first-line HCC. placebo arm. Patients had relapsed/refractory multiple myeloma who had received one Data from that study are expected in 2020. to three prior lines of therapy and were sensitive or naive to proteasome inhibitors. Meanwhile, Roche expects data before However, there were 41 deaths (21%) in the venetoclax arm and 11 (12%) in the placebo year’s end from the Phase III IMBrave150 arm of BELLINI, with progressive disease the most common cause (45%). The rates of seri- study combining its anti-PD-L1 Tecentriq ous adverse events (48% vs 50%) and serious infections (28% vs 27%) were comparable (atezolizumab) and chemotherapy agent between the two arms of the study. Avastin (bevacizumab) in first-line HCC.” Published online 24 June 2019 Published online 25 June 2019

12 | Scrip | July 5, 2019 © Informa UK Ltd 2019 NASH

Conatus Accepts Defeat For Emricasan In NASH

JOSEPH HAAS [email protected]

patients with fibrosis, failing to show a one-stage or greater improvement in fibrosis score, compared to placebo, after 72 weeks of treatment. (Also see “Conatus Endures Another NASH Setback With Failure To Hit Fibrosis Endpoint” - Scrip, 21 Mar, 2019.) At the time of the ENCORE-PH failure, Conatus CEO Steven Men- to held out hope that emricasan would prove beneficial in sicker NASH patients, those with decompensated cirrhosis. Those hopes went for naught with the ENCORE-LF outcome revealed on 24 June. In a statement, Mento said the ENCORE studies – designed to show emricasan’s potential benefit in a broad range of chronic liver disease – “provided a fair evaluation of emricasan’s lack of efficacy in these patient populations.” Conatus also announced on 24 June that it is cutting headcount by 40% and suspending development of its other pipeline candidate, preclinical CTS-2090, a caspase inhibitor for inflammasome Conatus’ long struggle with emricasan is at an end disease. Mento said the company hoped to end 2019 with a cash balance of between $10m and $15m. onatus Pharmaceuticals Inc. hung in and talked up the potential of future results as long as it could but finally NOVARTIS DEAL TEMPORARILY MOVED CONATUS Cconceded on 24 June that its pan-caspase inhibitor em- TO THE FRONT ricasan had demonstrated a lack of efficacy in multiple patient At the time Novartis took an option to license emricasan in late types in non-alcoholic steatohepatitis (NASH). The San Diego 2016, the agreement vaulted Conatus near the front of the pack firm said it will wrap up its obligations related to emricasan in an indication with no approved drug therapy and projected an- with partner Novartis AG and consider its strategic alternatives nual global sales of $20bn or greater in the next decade. The deal going forward. brought Conatus $50m up front, a $15m convertible loan and the The last gasp for emricasan – which Conatus hoped would of- potential for a $7m option fee and up to $650m in milestones. Co- fer therapeutic potential from early- to late-stage liver disease – natus also got the right to co-commercialize emricasan with No- came with the drug’s failure in the Phase IIb ENCORE-LF study in vartis if the drug reached market in the US. 217 NASH patients with decompensated cirrhosis. Emricasan did Novartis already was in Phase II with tropifexor (LJN-452) – a not show a benefit compared to placebo for event-free survival – non-bile acid farnesoid X receptor (FXR) agonist – for NASH when an event-driven composite endpoint of all-cause mortality, new the deal was struck. The partners envisioned a combination regi- decompensation events or four points or greater progression on men of emricasan and tropifexor that might offer improvements Model for End-Stage Liver Disease (MELD) score – in a three-arm in both liver function and portal hypertension. study testing 48 weeks of treatment with emricasan 5mg or 25mg Novartis issued its own release about emricasan’s failure in daily. The primary analysis also showed no clear trends of a treat- ENCORE-LF on 24 June, saying it remains “fully committed to ment effect, the company said. pursuing the development of multiple compounds [for NASH] Conatus said it is discontinuing further treatment of patients in collaborations.” The release made no mention of whether the enrolled in ENCORE-LF. It also noted that the 24-week extension partnership with Conatus would be terminated – Novartis global of the ENCORE-PH study in NASH patients with compensated or development unit head-immunology, hepatology and dermatol- early decompensated cirrhosis and severe portal hypertension ogy Eric Hughes told Scrip in March that any such decision likely had shown no statistically significant difference between placebo would have to wait until the end of 2019. (Also see “Novartis’s or three investigational doses of emricasan and no clear trends of NASH Chief: Our Strategy Is Combos With Tropifexor As ‘Backbone’” a treatment effect. Those two setbacks were only the latest in a - Scrip, 12 Apr, 2019.) series for the NASH therapy candidate. By its actions, however, Novartis appeared to be pivoting away This past December, Conatus reported that ENCORE-PH failed from Conatus and emricasan in its NASH strategy in recent years. to meet its primary endpoint – change in hepatic venous pres- In 2017, it partnered with Allergan PLC to test tropifexor with the sure gradient (HVPG) from baseline to week 24. (Also see “In NASH latter’s cenicriviroc – a dual CCR2/5 inhibitor – in NASH. (Also see Race, Bad News For Conatus, Good News For Genfit In PBC” - Scrip, “Could High Profile Combo Be Allergan/Novartis Answer To Late- 10 Dec, 2018.) Emricasan had missed the primary endpoint in a Stage NASH Programs?” - Scrip, 19 Apr, 2017.) Allergan’s drug – ac- Phase II study in liver transplant patients earlier in 2018. quired in a $1.7bn buyout of Tobira Therapeutics Inc. in 2016 – has On 21 March, Conatus reported that emricasan also missed its faced its own clinical setbacks, however, failing to demonstrate a primary endpoint in ENCORE-NF, a 318-patient study of NASH fibrosis-improvement benefit in a two-year data readout in 2017.

scrip.pharmaintelligence.informa.com July 5, 2019 | Scrip | 13 NASH

(Also see “Allergan’s Two-Year NASH Data Fail To Show Fibrosis Ben- During an investor presentation on 23 May, Novartis chief medi- efit” - Scrip, 22 Sep, 2017.) cal officer John Tsai said tropifexor’s efficacy and safety profile Last October, Novartis partnered with big pharma peer Pfizer could position it as a backbone agent in combination therapy for Inc. to test tropifexor with three different oral NASH drug candi- NASH, the field’s longer-term expectation for treating the disease. dates Pfizer has advanced into clinical development: PF-05221404, Novartis plans to read out Phase II data for tropifexor monothera- a Phase II acetyl CoA-carboxylase (ACC) inhibitor; PF-06865571, a py toward the end of 2019, he said, while it has several combina- Phase I diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor; and tion studies that should report data after that. the ketohexokinase (KHK) Inhibitor PF-06835919, now in Phase II At the same event, Novartis’ Pharma CEO at the time, Paul Hud- studies. (Also see “Pfizer/Novartis Collaboration Brings Combined son, called NASH one of the few opportunities where the pharma Strength To NASH Development” - Scrip, 29 Oct, 2018.) might extend itself outside of its focus therapeutic areas. “We can be bold,” he told the audience. “And if our FXR [agonist] reads out TROPIFEXOR MIGHT OFFER SAFETY where it needs to and the combinations [also perform well], that’s ADVANTAGES WITHIN FXR CLASS worth considering a different model.” Hudson has since left Novar- Novartis has touted tropifexor as offering advantages over other tis to become the CEO of Sanofi. FXR agonists in development – including Intercept Pharmaceu- Besides tropifexor, Novartis has two other candidates in ticals Inc.’s obeticholic acid (OCA), widely expected to be the first Phase II in NASH – LIK066, a dual SGLT1/2 inhibitor and LMB763, drug approved to treat NASH in the US – because of its potency also an FXR agonist. (Also see “NASH Pipeline: Racing To The Fin- and its safety profile. Tropifexor is potent enough to be dosed in ish” - Scrip, 21 Mar, 2019.) The pharma also has pointed to its re- micrograms, compared to the 10mg and 25mg strengths Intercept cent acquisition of inflammasome specialist IFM Tre as offering has tested in Phase III, and has not shown the potential to increase the possibility of an immunomodulatory approach to NASH. LDL cholesterol levels in trial participants or cause pruritus, two (Also see “Novartis Dives Into Inflammasome Pool With IFM Tre issues that have plagued OCA. (Also see “Intercept’s OCA Data Bol- Purchase” - Scrip, 1 Apr, 2019.) ster NASH Efficacy, But Pruritus Worries Worsen” - Scrip, 11 Apr, 2019.) Published online 25 June 2019 Genfit Assesses Optimal Elafibranor NASH Combo Therapy Opportunity

JOSEPH HAAS [email protected]

enfit SA is ready to begin combination therapy studies of as AstraZeneca/Bristol-Myers Squibb Co.’s Farxiga (dapagliflozin), its Phase III non-alcoholic steatohepatitis (NASH) candi- Lilly/Boehringer Ingelheim GmbH’s Jardiance (empagliflozin) or Gdate elafibranor with two classes of already marketed dia- Janssen Biotech Inc.’s Invokana (canagliflozin). betes drugs, but that does not mean it has found a partner for a However, Genfit is initiating the POC studies without a part- potential combo regimen. The Lille, France-based company wants nership, which led Bryan Garnier & Co. analyst Jean-Jacques Le to get proof-of-concept data first so that it then can choose the Fur to speculate that the company might want to wait for Vic- partner associated with the greatest opportunity. toza’s patent to expire to create a relatively inexpensive combo Genfit research and development head Dean Hum explained regimen for NASH. that moving into combination trials is part of the launch strategy Separately, Genfit announced on 24 June that it is licensing de- for elafibranor, an agonist of peroxisome proliferator-activated velopment and commercial rights in greater China for elafibranor receptors (PPAR) alpha and delta for which Phase III data are ex- in NASH and primary biliary cholangitis to Terns Pharmaceuticals pected before the end of 2019. The company believes getting Inc., a liver disease- and cancer-focused company based in both combination data for elafibranor with a validated diabetes drug the San Francisco area and Beijing. Genfit gets $35m up front and can improve uptake as the launch progresses. can earn up to $193m in clinical, regulatory and commercial mile- Genfit will be the third company to report Phase III data in stones under an agreement that gives Terns rights to the drug in NASH, following Gilead Sciences Inc.’s unsuccessful trial with ASK1 mainland China, Hong Kong, Macau and Taiwan. inhibitor selonsertib in February and Intercept Pharmaceuticals If elafibranor is launched commercially for NASH in greater Inc.’s success with FXR agonist obeticholic acid (OCA) a week later. China, Genfit also would be eligible for sales royalties in the mid- In May, Genfit announced that it will initiate Phase II proof- teens in Terns’ territories. The companies also will jointly conduct of-concept (POC) studies this summer to assess the potential of liver disease R&D projects, including development of elafibranor combination therapy in NASH for elafibranor plus well-known in tandem with Terns’ proprietary drug candidates. These include diabetes drug mechanisms. The dual PPAR agonist will be tested FXR agonist TERN-101, in-licensed from Lilly in April 2018. Terns with a GLP-1 analog, such as Eli Lilly & Co.’s Trulicity (dulaglutide), initiated a Phase I study of the compound on 13 June. AstraZeneca PLC’s Byetta (exenatide) or Novo Nordisk AS’ Victoza Speaking with Scrip on 20 June, Hum conceded that Intercept’s (liraglutide). It also will be combined with an SGLT2 inhibitor, such OCA will reach market first, but asserted that elafibranor’s efficacy

14 | Scrip | July 5, 2019 © Informa UK Ltd 2019 NASH

and safety profile will position it as both first-line monotherapy CymaBay’s shares finished trading on 20 June down 3.6% to and the backbone of combination therapy in NASH. Intercept will $6.77, as the company struggles to recover from the loss of more seek approval in the US and Europe based on the ability of OCA than half of its valuation following the Phase II data report. Cyma- to reduce fibrosis without worsening of NASH, while Genfit hopes Bay closed at $11.09 a share on 10 June but was down to $5.80 in its Phase III data will confirm earlier trials showing elafibranor can heavy trading on 11 June. resolve NASH by eliminating ballooning of hepatocytes and elimi- Meanwhile, although analysts including Leerink’s Sarraf and nating or reducing inflammation. Garnier’s Le Fur cautioned that there should be no read-through “It’s important for us to get ahead of [the competition] and con- from CymaBay’s poor data to elafibranor, Genfit’s stock has de- sider what kind of combinations make sense,” Hum explained. “If clined from $23.87 on 10 June to $20.14 on 20 June. you consider some of the drugs and who NASH patients are, our understanding is … different combinations will be tried by different “It’s important for us to get ahead of doctors. We think GLP-1 will be a good candidate for combination therapy. We have preclinical data in disease models, in vivo animal [the competition] and consider what models, showing that that combination does provide synergy. And then, the other class of drugs which makes a lot of sense is SGLT2 in- kind of combinations make sense. If you hibitors, and we also have results looking at in vivo animal models.” consider some of the drugs and who Genfit will launch studies of two doublets – elafibranor with a GLP-1 analog and an SGLT2. It has not said yet whether it also NASH patients are, our understanding is plans to investigate triple combination therapy, Hum said. The goal is to demonstrate safety and tolerability with those combina- … different combinations will be tried by tions, while looking for signs of efficacy in both imaging data and circulating markers of liver health. different doctors.” – Dean Hum “This is all a part of our strategy to ensure a successful launch with elafibranor and make sure it has good market uptake,” the exec said. “And this, of course, is all for the benefit of the pa- Hum also said there should be no read-through from CymaBay tients, to make sure that they will be optimally managed by the to Genfit, even though both drugs are in the same class, because different physicians.” Genfit’s drug offers different benefits as a dual PPAR agonist and Genfit’s expectation is that in the early days after NASH drugs because its thesis for Phase III is showing that elafibranor can re- hit the market, patients will be seen more often by general solve NASH by reducing or eliminating liver inflammation and practitioners and endocrinologists than by hepatologists, mak- eliminating ballooning hepatocytes, not by reducing liver fat. ing the availability of data for combination therapy extra important, Hum added. CUTTING FAT VS. REDUCING INFLAMMATION Genfit already is building a commercial team, led by recent hire While quantity of liver fat – CymaBay’s focus – is an upstream Pascal Prigent, most recently VP of marketing for GlaxoSmithKline characteristic of NASH, it can be benign in pre-NASH patients, PLC vaccines and before that a commercial executive with Lilly. Hum noted, pointing out that the thesis that reducing hepatic fat The commercial team will be split between Genfit headquarters can resolve NASH is not proven. Regardless, the liver-fat-reduc- in Lille and its US offices in Boston, Hum said. tion hypothesis is being pursued by several companies, includ- Doing its combination work independently leaves Genfit with ing Madrigal Pharmaceuticals Inc., which recently entered Phase ideal optionality, he asserted. “The objective for us is not to be tied III with thyroid hormone receptor (THR) beta agonist MGL-3196. down to any one drug at this point,” Hum said. “What’s important Elafibranor addresses inflammation through two separate for us is that when the time comes, we can have a drop-in strategy and independent but complementary pathways, Hum ex- for combination … with another drug which has the biggest mar- plained, with agonism of the PPAR alpha receptor targeting in- ket share. That is the long-term view.” flammation in hepatocytes, while PPAR delta agonism targets Kupffer cells, which clear bacteria and help break down red NO READ-THROUGH FROM CYMABAY PPAR blood cells in the liver. AGONIST DATA He added that CymaBay’s interim Phase II data was derived But before Genfit obtains combo therapy data, SVB Leerink analyst from magnetic resonance imaging – proton density fat fraction Pasha Sarraf said in a 19 June note that the company’s upcoming (MRI-PDFF) scans – while elafibranor’s benefits have been demon- Phase III RESOLVE-IT data for elafibranor monotherapy is the most strated with histological data from liver biopsies. significant near-term catalyst in the NASH drug development space. “Elafibranor has shown benefit on resolution of NASH with- However, Genfit’s shares have been trending down slightly out worsening of fibrosis independent of whatever happens on since a competitor reported disappointing interim Phase II data [hepatic] fat,” Hum noted. “It’s going to be the histology that is for a similar drug on 11 June. That’s when CymaBay Therapeutics most important.” Inc. said its PPAR delta agonist did no better than placebo in re- Genfit also has Phase II data indicating that elafibranor can offer ducing hepatic fat in NASH patients. CymaBay has contended that patients additional therapeutic benefit by increasing insulin sensi- its candidate is more potent than Genfit’s elafibranor and offers tivity in the liver and peripheral tissue, the exec said. advantages by only targeting the PPAR delta receptor. Published online 24 June 2019

scrip.pharmaintelligence.informa.com July 5, 2019 | Scrip | 15 APPROVALS

Dupixent Gets Room To Grow With New Indication In Chronic Rhinosinusitis JESSICA MERRILL [email protected]

anofi and Regeneron Pharmaceuti- whose disease is uncontrolled despite sur- results of two Phase III trials. These evaluat- cals Inc. are successfully executing on gery or oral corticosteroid treatment. ed Dupixent 300mg every two weeks with Stheir pipeline-in-a-molecule strategy Dupixent is the first biologic medicine standard of care, mometasone furoate na- for Dupixent (dupilumab), announcing the approved by the FDA to treat CRSwNP, sal spray, compared to placebo plus MFNS. US Food and Drug Administration’s ap- which results in obstructed sinus and Dupixent improved key disease measures proval of a third indication for the IL-4/IL- nasal passages and can lead to difficulty and met all primary and secondary end- 13 blocker on 26 June. The new indication breathing, congestion and reduced sense points, resulting in improved nasal polyp is for chronic rhinosinusitis patients with of smell or taste. Some patients also have size, nasal congestion severity, chronic nasal polyposis (CRSwNP) whose disease severe asthma and can be more difficult to sinus disease and improvements in smell. is not controlled, adding to Dupixent’s ex- treat. The current standard of care is intra- (Also see “Triple Threat: Full Rhinosinusitis isting approvals in atopic dermatitis and nasal or systemic steroids or nasal surgery. Data Place Dupixent Top Of The IL Heap” - moderate to severe asthma. Dupixent generated $374m in the first Scrip, 26 Feb, 2019.) The two partners have expressed big quarter and is well on its way to becom- Treatment also resulted in a reduction ambitions for Dupixent as a treatment ing an important blockbuster franchise. in systemic corticosteroid use. In a pre- for a range of conditions characterized by The first-in-class drug was approved by specified pooled analysis of the two trials type 2 inflammation. Inhibiting IL-4 and IL- the FDA in March 2017 as the first biologic up to 52 weeks, the proportion of patients 13 regulates the type 2 inflammatory re- for moderate-to-severe atopic dermatitis. who required systemic corticosteroids sponse. The companies are continuing to (Also see “Sanofi/Regeneron Choose Access was reduced by 74% with Dupixent ver- explore Dupixent in a range of diseases in- Over Price With Dupixent Launch” - Scrip, sus placebo. Dupixent is priced the same cluding eosinophilic esophagitis, chronic 28 Mar, 2017.) The second indication for for all three indications at a current whole- obstructive pulmonary disease, and food moderate to severe asthma followed in sale acquisition cost of $3,019 per month. and environmental allergies. October 2018, with Dupixent receiving a Novartis AG and Roche also are devel- The approval in CRSwNP expands Du- slightly broader label compared to IL-5 bi- oping the asthma biologic Xolair (omali- pixent’s reach to a new set of patients, al- ologic rivals. (Also see “Dupixent Approved zumab), an immunoglobin E (IgE) blocker, though there is some overlap in patients For Severe Asthma With Broader Label for CRSwNP, and recently announced posi- who also experience asthma. In the US, Than Other Biologics” - Scrip, 21 Oct, 2018.) tive top-line data from two Phase III trials Sanofi estimates there are approximately The FDA approved the newest indica- in the condition. 55,000 to 90,000 adult patients in the US tion under a priority review, based on the Published online 26 June 2019 Pfizer’s Talzenna To Compete With AZ’s Lynparza In Breast Cancer After EU Okay

KEVIN GROGAN [email protected]

aving received the green light in vanced or metastatic breast cancer. The Europe for its PARP inhibitor Tal- approval, which was based on the EMB- Hzenna, Pfizer Inc. is now gearing up RACA Phase III study that showed a 46% to take on AstraZeneca PLC’s class-leading reduction in the risk of disease progres- Lynparza in the BRCA-mutated breast can- sion and a more-than-doubled overall re- cer market. sponse rate compared with chemotherapy After getting a positive opinion from “Lynparza’s built-in (63% versus 27%), comes eight months af- the European Medicines Agency’s Com- physician familiarity ter the US Food and Drug Administration mittee for Medicinal Products for Human approved the therapy in this indication. Use at the end of April, Pfizer has got the remains a strong intra- The nod comes just two months after official thumbs-up to market Talzenna (ta- AstraZeneca and partner Merck & Co. Inc. lazoparib) for germline (inherited) BRCA 1 class revenue driver.” secured European approval for Lynparza and 2-positive, HER2-negative locally ad- TURN TO PAGE 18

16 | Scrip | July 5, 2019 © Informa UK Ltd 2019 HEADLINE NEWS

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CONTINUED FROM PAGE 16 within this class and Talzenna is no excep- 2015 and has been the cornerstone of (olaparib) for germline BRCA-mutated tion. Any differences between medica- the company’s oncology growth plans HER2-negative advanced breast cancer. tions are relatively minor and may impact which will soon be expanded follow- The latter drug is fast becoming a block- prescribing decisions on a per-patient ing last week’s announcement of Pfizer’s buster, with first-quarter sales of $237m basis, but likely won’t impact overall proposed $11.4bn acquisition of Array due mostly to its ovarian cancer revenues. revenues to a significant degree. McLel- BioPharma Inc.. (Also see “Array’s Three Talzenna is only approved for breast lan claimed that “Talzenna’s reduced pill Value Drivers Align With Pfizer’s Three On- cancer and Pfizer and partner Merck burden is negligible and although it may cology Pillars In $11.4bn Deal” - Scrip, 17 KGaA suffered a setback in March when have slightly improved gastrointestinal Jun, 2019.) they discontinued the Phase III JAVELIN side effects compared to Lynparza, other In announcing that deal, Pfizer noted Ovarian PARP 100 study of their PD-L1 in- adverse events like alopecia and higher that one of the main drivers of that deal hibitor Bavencio (avelumab) plus Talzenna anemia rates balance that out,” adding that was to get hold of the BRAF/MEK inhibitor (talazoparib) in previously untreated ad- “Lynparza’s built-in physician familiarity re- combination Braftovi (encorafenib) and vanced ovarian cancer. mains a strong intra-class revenue driver.” Mektovi (binimetinib) which is approved The trial was pulled in part because As is always the case in Europe, price will for melanoma and colorectal cancer. Inter- of the changing treatment landscape in be an issue. Pfizer has not disclosed any estingly, a Phase II trial is underway look- ovarian cancer, and especially following details about the latter or specific launch ing at a combination of Talzenna, Bavencio the approval of Lynparza in the front-line plans but in the US when approval was and Mektovi is underway in adult patients maintenance setting but Pfizer seems obtained, it set a $14,580 per month price with locally advanced or metastatic KRAS- confident it can take on the biggest-sell- tag for Talzenna; Lynparza cost around or NRAS-mutant non-small cell lung cancer ing PARP in the breast cancer indication. $16,200 per month. and pancreatic ductal adenocarcinoma. The US giant pointed out that Talzenna, There are two other approved PARP in- Talzenna is also being evaluated in sev- which was acquired by Pfizer through hibitors for ovarian cancer – GlaxoSmith- eral ongoing clinical trials, including early its $14bn purchase of Medivation Inc. in Kline PLC’s Zejula (niraparib) - which came triple-negative breast cancer and prostate 2016, is the only once-daily PARP inhibitor with its $5.1bn acquisition of Tesaro Inc. - cancer; the drug is in Phase III for the latter approved in Europe for hereditary breast and Clovis Oncology Inc.’s Rubraca (ruca- in combination with Pfizer’s own Xtandi cancer - Lynparza is dosed twice daily. parib). While those PARPs are also being (enzalutamide). However, Datamonitor Healthcare ana- evaluated for breast cancer, the primary The Talzenna green light is also good lyst Zachary McLellan told Scrip that while focus seems to be in other indications [on news for BioMarin Pharmaceutical the approval “broadens Talzenna’s geo- 24 June, GSK announced that its supple- Inc. which will pocket a $15m milestone graphic availability to the EU breast cancer mental new drug application for Zejula for payment from Pfizer that has been trig- market, it will likely remain in Lynparza’s late-stage ovarian cancer has been grant- gered by the European approval. The shadow in the near term. As such, Talzen- ed a priority review by the FDA and has an cash is part of an agreement inked with na is expected to received moderate up- action date of 24 October]. Medivation in August 2015 which in- take in this indication due to need and the Pfizer is no stranger to breast cancer, volved a $410m upfront to Biomarin, and established efficacy of this class in heavily notably with its market-leading CDK4/6 up to an additional $160m in regulatory pre-treated gBRCAm+ patients, but sales inhibitor Ibrance (palbociclib) which is and sales-based milestones, of which will likely still lag behind Lynparza.” approved for hormone receptor-positive, $50m has been earned to date, plus mid- He went on to say that “there seems HER2-negative advanced or metastatic single digit royalties. to be a general consensus of PARP-parity breast cancer. The drug was approved in Published online 24 June 2019 AMAG Must Build Market For Approved Female Libido Drug To Avoid Addyi’s Fate

JO SHORTHOUSE [email protected]

he US Food and Drug Administra- be self-administered as needed in antici- mercial potential of Vylessi remains an tion has approved AMAG Pharma- pation of sexual activity. outstanding debate given its route of Tceuticals Inc.’s Vyleesi (bremela- The product will be commercially administration via injection and risks notide injection), a melanocortin receptor available in September through select around market creation,” in a 23 June agonist, to treat hypoactive sexual desire specialty pharmacies, said the compa- company update note. disorder (HSDD) in premenopausal women. ny, although analysts still retain some Leerink analysts highlight the 6 million The Vyleesi autoinjector is the first treat- skeptism over market potential of the premenopausal women in the US (one in ment for this patient population that can drug. Analysts at Leerink said that “com- 10) with HSDD, of which the clear major-

ity are not on therapy. AMAG’s strategy is has none of these drawbacks. Its method which are associated with the regulation to destigmatize the conversation, create of administration, however, has left some of metabolism, sexual behavior and male an online community and focus on digital doubts in the minds of industry observ- erectile function. channels, much like it did for its vaginal ers. (Also see “US FDA Squashes Sprout’s Vyleesi’s approval is based on two Phase atrophy drug Intrarosa (prasterone). But Attempt To Remove Boxed Warning From III studies, named RECONNECT. The tri- Leerink analysts believe AMAG “will have Addyi Label” - Pink Sheet, 14 Apr, 2019.) als lasted for 24-weeks and enrolled 550 its work cut out to build this market”, as re- Leerink conceded that, while they had patients in each, in which they injected search suggests that 95% of women who been concerned about the subcutane- bremelanotide under the skin of the ab- have HSDD do not know they have a spe- ous method of administration, they were domen or thigh at least 45 minutes before cific medical condition. surprised that physicians at AMAG’s Ana- sexual activity. Twenty five percent of pa- AMAG will work to improve on the lyst Day acknowledged how insignifi- tients had improved sexual desire scores fortunes of its only competitor in the cant this issue was in the clinical trials. compared with placebo patients (17%). market,Sprout Pharmaceuticals Inc.’s Ad- They also noted that nearly 80% of pa- The FDA notes that patients shouldn’t dyi (flibanserin), which was approved tients who completed the Phase III trials use more than one dose a day, or eight in 2015 but has been unable to make elected to remain in the open-label por- doses a month. Patients should stop treat- in-roads in the market, so far peaking at tion of the study. ment at eight weeks if they don’t notice any around $13m sales in 2016. Stephanie Yip, senior analyst at Data- improvement in sexual desire and distress. Addyi has not been the commercial monitor Healthcare, told Scrip, “The fact The most common adverse events success its originators had hoped. Im- that Vyleesi is intended to be taken as found in the trials were nausea, flushing, mediately following its approval, Vale- needed is a key differentiating selling injection site reactions, and headache. In ant Pharmaceuticals International Inc., as point for the brand over its once-daily clinical trials, Vyleesi caused small, tran- was, acquired Sprout for $1bn. However, competitor, Addyi. Although injections sient increases in blood pressure, and is two years later, Valeant sold the subsidiary may not be the preferred route of admin- contraindicated in women with uncon- and Addyi back to its original owners in istration for patients compared to oral trolled high blood pressure or known car- exchange for a 6% royalty on global sales pills, Vyleesi’s longer dosing schedule of- diovascular risk. of the drug. Payers had been questioning fers the benefit of convenience, which AMAG in-licensed Vyleesi from Palatin a price tag in the region of $800 for 30 tab- should drive its uptake.” Technologies Inc. in February 2017. Under lets; the product needs to be taken every Leerink forecasts that Vyleesi can make the terms of the agreement, the approval day. (Also see “Valeant Returns $1bn Female around $90m per year by 2025, and sees of Vyleesi by the FDA triggers a $60m pay- Libido Drug For Free” - Scrip, 7 Nov, 2017.) the potential that Vyleesi can make in- ment obligation to Palatin. Analysts at Jefferies has said in a 22 May roads in this market where Addyi has not, In addition, AMAG will pay Palatin tiered note, based on AMAG’s analyst day, that and “be a much-needed growth driver for royalties on annual net sales of Vyleesi “given the commercial failure of the same AMAG in the medium-to-longer term.” ranging from the high-single digits to the target market drug Addyi… commercial low double-digits. AMAG will also pay challenges remain although one could RECONNECT STUDY Palatin sales milestones based on escalat- argue for difference in products’ profiles.” Bremelanotide is the first of a new class of ing annual net sales thresholds, the first Addyi has a Black Box warning, is contra- drugs developed to treat sexual dysfunc- of which is $25m, triggered at annual net indicated with alcohol, and only available tion, melanocortin agonists. It acts on sales of $250m. through a REMS program, while Vyleesi the MC1 and MC4 receptors, the latter of Published online 24 June 2019 Bring Them On: China Releases Generics List To Encourage Competition

BRIAN YANG & ANJU GHANGURDE

n a bid to encourage generic drug devel- ment, a priority outlined in a plan by Chi- Major cancer drugs on the list include opment, China’s National Health Commis- na’s State Council to support the manu- ixabepilone and fulvestrant for breast can- Ision has listed 34 drugs whose domestic facturing, stable supply and expand the cer and mercaptopurine for leukemia. The patents have expired or are expiring but use of such products. seven orphan disease products include ni- for which there have been no abbreviated Of the 34 products, oncology, anti-infec- tisinone for type 1 hereditary tyrosinemia new drug applications, leading to what it tive and orphan drugs dominate the list, (HT-1) and glatirameracetate, a first-line views as insufficient competition. signaling the government’s strong desire treatment for multiple sclerosis. Developed The list is part of a coordinated effort to promote access to cancer and HIV thera- by Teva Pharmaceutical Industries Ltd., this to encourage generic drug develop- pies, as well as medicines for rare diseases. was ranked 17th in the global list of top-

scrip.pharmaintelligence.informa.com July 5, 2019 | Scrip | 19 GENERICS

selling drugs in 2014, with sales of more NO GENERIC NAME FORMULATION DOSAGE than $4bn. Also listed are two treatments for pul- 1 Nitisinone capsule 20mg monary arterial hypertension, treprosti- 2 Fumatero inhalation 0.02mg/2mL nil and bosentan. The other rare disease 300mg/16.7mL drugs for which insufficient generic ver- 3 Posaconazole injection, tablet (18mg/mL); 100mg sions have been developed in China include icatibant, a treatment for hereditary 4 Ammonia benzene tablet 50mg,100mg vascular edema, and deferasirox, the first 5 Valganciclovir tablet 50mg/mL oral iron chelator approved by the US 6 Rilpivirin tablet 450mg FDA, for patients over six years of age with 7 Abacavir injection 25mg thalassemia iron overload. 8 Ertapenem suspension liquid 1.0g The National Health and Family Planning Commission is now gathering public com- 9 Atovaquone injection 750mg/5mL ments on the list until 25 June 25, via email 10 Ixabepilone injection 15mg, 45mg to [email protected]. 11 Fulvestrant injection 5ml: 0.25g 12 Mercaptopurine tablet 25mg, 50mg INDIA-CHINA MEETING 13 Methotrexate tablet 2.5mg Interestingly, almost alongside the new China initiative to increase generics, the 14 Cyclophosphamide tablet 50mg Indian government machinery is con- 15 Vitamin A acid injection 10mg tinuing to make concerted efforts to 16 Fesoterodine injection 4mg, 8mg engage with the country to push for im- 17 Glatiramer acetate tablet 20mg/ml, 40mg/mL proved market access for Indian drugs, as 18 Azathioprine tablet 50mg, 100mg its Asian neighbor takes definitive steps to open up its market to generic suppli- 19 Raloxifene tablet 60mg ers. India, which prides itself as the phar- 20 Levothyroxine tablet 50μg macy to the world, saw its global exports 21 Eletriptan tablet 20mg, 40mg exceed $17bn in 2017-18 (expected to 22 Pyridostigmine Bromide tablet; suspension release 0.25g (0.2g:0.05g) touch $20bn by 2020), though formula- 23 Levodopa tablet 20mg, 40mg tion exports to China have been minus- 10mg, 25mg, 50mg, cule at just $30m. 24 Brivaracetam injection Markets like the US are important 75mg, 100mg contributors to India’s pharma growth 25 Fosaprepitant dimeglumine injection 150mg - one in every three pills consumed 1mg/mL, 2.5mg/mL, 26 Treprostinil tablet there is estimated to be made by an 5mg/mL, 10mg/mL Indian generics manufacturer – but 27 Bosentan tablet 62.5mg, 125mg China has generally been a tough mar- 28 Colesevelam capsule 625mg ket to crack. 29 Dofetilide injection 0.125mg, 0.25mg, 0.5mg India has been pressing for fast track registration and exports of its medi- 30 Icatibant tablet 30mg/3ml (10mg/ml) cines to China, and sought a clear road 31 Deferasirox eye drops 0.125g, 0.25g, 0.5g map for upping its share of supplies in 32 Alcaftadine eye drops 0.25% China at the India-China Drug Regula- 33 Tafluprost tablet 0.00% tions Meeting on June 21 in Shanghai, 34 Vigabatrin tablet 500mg the first such initiative between the two nations. India’s top ask at the meeting, as indicated by joint secretary of com- China’s regulator, compliance and the ac- ed on the reforms undertaken by China merce Shyamal Misra, continues to be tive pharmaceutical ingredient registration over the past two years and “hoped easing of regulatory hurdles faced by In- process in China. for more engagement on this issue,” a dian firms in China. Indian officials also S Eswara Reddy, India’s drugs con- statement from the the Embassy of In- sought a “more coordinated role” by the troller general, underscored the role of dia in Beijing noted. regulators on both sides. the regulator in facilitating improved Close to 70 pharma firms - 35 Indian The meeting covered, in six sessions, a affordability and accessibility of qual- and 30 Chinese - attended the session, in range of areas including the registration ity medicines, while Xu Jinghe, deputy addition to government delegates from of imported drugs and the procurement commissioner of China’s National Medi- both sides. system in China, overseas inspections by cal Products Administration, elaborat- Published online 24 June 2019

Clovis CEO’s Rough Guide To European Launches

KEVIN GROGAN [email protected]

ith Clovis Oncology Inc. having just launched its PARP inhibitor Rubraca in Germany, the company’s CEO Pat- Wrick Mahaffy has been giving some guidance to fellow US companies who may be looking at setting up operations in Europe themselves. In an interview with Scrip, Mahaffy quipped that his first piece of advice to small-to-medium enterprises looking to make inroads into Europe is that “they shouldn’t try to do it all on their own and they may want to use us as a commercial partner.” On a more serious note, he said it was vital to assemble an experienced leadership team early on, “and you have to be considered local in each of those territories to be competitive to enable a good dialogue with the key opinion leader (KOL) community.” Mahaffy added, “It is kind of obvious but you don’t just send a bunch of Americans over to tell people how to do things. In Ger- many, we hired highly experienced people who know the Euro- pean Medicines Agency and can also manage the reimbursement “You’ve got to be doing clinical trials in process there,” including staff the Clovis chief knew from his spell as CEO at Pharmion Corp., the company Mahaffy founded in 2000 Europe and think about it as a means and sold to Celgene Corp. in 2008. of building experience and a dataset He stressed, “You’ve got to be doing clinical trials in Europe and think about it as a means of building experience and a associated with your drug. Don’t try dataset associated with your drug. Don’t try to come into Europe with US-only and somehow think that’s going to be to come into Europe with US-only enough in Europe.” However, he also cautioned that “it is easy to get ahead of and somehow think that’s going to be yourself in terms of the timing of hiring” when it comes to com- enough in Europe.” – Patrick Mahaffy mercialization. In January this year, the European Commission expanded the label on Rubraca (rucaparib) beyond its initial marketing authorization in Europe for advanced ovarian cancer in selected patients – granted in May 2018 – to include mainte- with access through the Cancer Drugs Fund being an option. Rub- nance treatment for eligible patients regardless of their BRCA- raca is already available for UK patients on the private pay market. mutation status. After that, Clovis is hoping to be in a position to launch in Spain, Rubraca being the first PARP inhibitor to be approved for both France and Italy around the first quarter of 2020, while some treatment and maintenance treatment was the catalyst that led smaller territories such as the Netherlands which have “a more ac- to Clovis launching in Germany and Mahaffy noted that “we only celerated reimbursement negotiation process” may back Rubraca brought on board our German teams at the end of the year and later this year. the first part of this year, because we knew we were going to be The PARP market is a fiercely competitive one, headed by As- launching in March.” He added that “we didn’t bring in a field based traZeneca PLC and Merck & Co. Inc.’s Lynparza (olaparib), while organization in the other European territories with the exception GlaxoSmithKline PLC’s Zejula (niraparib) – which came with its of a relatively small number of medical science liaison (MSL) staff $5.1bn acquisition of Tesaro Inc. is also a rival for Rubraca on the to coordinate and work with KOLs and investigators.” ovarian cancer space. However, Mahaffy is confident that Rubraca The German launch has started well, Mahaffy said, and Clovis can gain market share in Europe, saying that “we have found a has about 25 staff there in varying roles. “We are building good little more willingness to differentiate based on the clinical profile relationships with the KOLs,” he said, pointing out that those re- that’s been established and published for our drug than we see in lationships had begun earlier through an expanded access pro- the US where unfortunately, some say the PARP inhibitors are all gram that made the drug available to eligible patients before the same with the exception of toxic differences.” launch and allowed physicians who had limited experience with Mahaffy pointed to a recent symposium in Germany where at- Rubraca to get more knowledge about the product. tendees were encouraged to review the differences between the As for the rest of the continent, Mahaffy said a launch in the UK various PARPs and “not just asserting that they really are all the same was possible later this year, depending on the outcome of nego- when the data don’t fully support that view. There are differences.” tiations with the National Institute for Health and Care Excellence, TURN TO PAGE 23

scrip.pharmaintelligence.informa.com July 5, 2019 | Scrip | 21 Pipeline Watch - 21-27 June 2019 Phase II

Change Event Lead LOA Drug Name Indication Comments To LOA Stage Company/Partner (%) (%) Phase IIb Novartis NASH, Portal Updated emricasan ENCORE-PH,-LF; Missed -2 8 AG/Conatus Hypertension Results Endpoints Phase IIb linzagolix EDELWEISS; Reduced Updated ObsEva SA Endometriosis 0 67 (OBE2109) Symptoms Results Phase IIa Assembly Updated ABI-H0731 Hepatitis B Encouraging Results 0 25 Biosciences, Inc. Results Phase II Relapsed or Refractory; Updated Epizyme tazemetostat Follicular Lymphoma 0 11 Durable Responses Results Phase II Allena Study 206; Oxalate Levels Updated Pharmaceuticals, reloxaliase Enteric Hyperoxaluria 0 62 Declined Results Inc. Phase II tafasitamab Diffuse Large B-Cell L-MIND (w/lenalidomide); Updated MorphoSys AG 0 39 (MOR208) Lymphoma Promising Activity Results Phase II Primary Biliary GSN000300; Improved Updated GenKyoTex S.A. GKT831 Cholangitis, Hepatic 0 18 Biomarkers Results Fibrosis Phase II Primary Updated OxThera AB Oxabact Hyperoxaluria On Positive Results 0 62 Results Dialysis Phase Ib/IIa G1 Therapeutics, Small Cell Lung w/Tecentriq+Chemotherapy; Updated trilaciclib 0 13 Inc. Cancer Positive Effects Results Phase Ib/IIa Cutaneous T-Cell Investigator Initiated; Updated A�med N.V. AFM13 0 10 Lymphoma Promising Results Results Phase I/II Krystal Biotech, Epidermolysis Updated KB103, gene therapy GEM-1,-2; Positive Results 2 27 Inc. Bullosa Results Phase I/II VB N-01; Immune Updated Vaccibody AS VB10.NEO Solid Tumors 00 Responses Seen Results Phase I/II Catabasis Duchenne Muscular Updated edasalonexent MoveDMD; Clinical Bene�ts 0 57 Pharmaceuticals Dystrophy Results Phase IIb Minerva Top-Line seltorexant Insomnia Positive Results 3 21 Neurosciences Results Phase IIb BPX04 (minocycline) Papulopustular Top-Line BioPharmX, Inc. PRISM; Positive Results 4 28 gel Rosacea Results Phase II REGN3500, (IL-33 Top-Line Regeneron/Sano� Asthma w/dupilumab; -5 13 Ab) Results Positive Results Phase II Oasmia vs. Taxotere; Comparable Top-Line Docecal (docetaxel) Breast Cancer 0 10 Pharmaceutical AB E�cacy Results Phase II Aclaris Top-Line ATI-502 Alopecia Areata Missed Endpoints 0 27 Therapeutics, Inc. Results Phase II Gemphire Familial Partial FPL (PoC); Lowered Top-Line gemcabene 05 Therapeutics, Inc. Lipodystrophy Triglycerides Results Phase II Verrica Top-Line Pharmaceuticals, VP-102 Common Warts COVE-1; Positive Results 5 29 Results Inc. Phase II Atossa Genetics, Top-Line endoxifen Breast Cancer Reduced Breast Density 2 12 Inc. Results Phase I/II Aldeyra Allergic Seasonal; Alleviated Top-Line reproxalap 1 58 Therapeutics, Inc. Conjunctivitis Symptoms Results Phase II Anavex Life ANAVEX2-73-RS-001, An Trial ANAVEX 2-73 Rett Syndrome 0 17 Sciences Corp. Extension Study Initiation Phase II Ascendis Pharma Trial TransCon PTH Hypoparathyroidism PaTH Forward; In Adults 10 26 A/S Initiation Phase II Cara Therapeutics, Korsuva Pruritus In Primary CR845-210401; A 16-Week Trial 0 70 Inc. (CR845/difelikefalin) Biliary Cholangitis Study Initiation Phase II Acceleron Pharma, Pulmonary Arterial Trial sotatercept SPECTRA; Exploratory Study 0 13 Inc. Hypertension Initiation Phase II IL-12 gene Trial Ziopharm Oncology Glioblastoma In The US And Europe 0 10 therapy/cemiplimab Initiation PIPELINE WATCH Phase II Verrica Extennal Genital Trial Pharmaceuticals, VP-102 CARE; A Topical Therapy 0 29 Warts Initiation Inc. Scrip’s weekly Pipeline Watch tabulates the most recently reported Phase Ib/II late-stage clinicalZenith trialCapital and regulatory developments from the more w/talazoparib; In TNBCClick here for the entire pipeline Trial ZEN-3694 Breast Cancer 10 10 than 10,000 drugCorp. candidates currently under active research worldwide.Patients with added commentary: Initiation http://bit.ly/2mx4jY3 Phase III PIPELINE WATCH, 21–27 JUNE 2019 Search

Lead Change To LOA Event Stage Drug Name Indication Comments Company/Partner LOA (%) (%) Phase III veverimer Metabolic Acidosis The Lancet online, 25 Published Tricida, Inc. 0 69 (TRC101) in CKD June, 2019 Results Phase III Skin and Skin- ASSIST-1,2, REVIVE-1,2; Motif Bio plc iclaprim (IV) 0 64 Updated Results Structure Infections Additional Data Actinium Phase III Bone Marrow SIERRA; Engraftment Pharmaceuticals, Iomab-B 0 37 Updated Results Transplant In AML Facilitated Inc. Phase III Top- Poxel, Sumitomo TIMES 3 (Japan); Met imeglimin Diabetes Type 2 0 22 Line Results Dainippon Primary Endpoint Phase III Top- LSK BioPartners, rivoceranib ANGEL; Missed OS Gastric Cancer -5 30 Line Results Inc. (apatinib) Endpoint, Improved PFS Phase III Top- Im�nzi Small Cell Lung CASPIAN; Improved AstraZeneca PLC 0 35 Line Results (durvalumab) Cancer, First-Line Overall Survival Phase III Trial Axsome Major Depressive GEMINI; A Multimodal AXS-05 0 57 Initiation Therapeutics, Inc. Disorder NMDA Antagonist X4 Phase III Trial mavorixafor Pharmaceuticals, WHIM Syndrome 4WHIM; A 52-Week Study 39 59 Initiation (X4P-001) Inc. Phase III Trial Eylea Retinopathy Of Regeneron/Bayer Multi-Country Study 51 Initiation (a�ibercept) Prematurity Phase II/III Trial WAVE Life suvodirsen Duchenne Muscular DYSTANCE 51; A Global 8 24 Initiation Sciences Ltd. (WVE-210201) Dystrophy Study Phase III Trial Laboratoris Sani�t Calciphylaxis In SNF472 In The US And Europe 0 13 Announcement S.L. Dialysis Patients Phase III Trial Ovid Therapeutics, OV101 Angelman Syndrome NEPTUNE; In The US 0 18 Announcement Inc. (gaboxadol) Phase III Trial Catabasis Duchenne Muscular GalaxyDMD; Open Label edasalonexent 0 57 Announcement Pharmaceuticals Dystrophy Extension Approvals Source: Biomedtracker | Informa, 2019

Lead Event Type Drug Name Indication Market Comments Company/Partner ’ We are tweeting, liking and sharing the latest industry news and LETAMAGS GET insights from our globalFemale team Sexual of Arousal editors and analysts,Premenopausal join us! Approval Pharmaceuticals, Vyleesi (bremelanotide) US Disorder Women Inc. SOCIAL @PharmaScrip Approval P�zer Inc. Talzenna (talazoparib) Breast Cancer EU Oral, Once-Daily Alexion In AQP4 Ab Approval for 22 | Scrip | JulyPharmaceuticals, 5, 2019 Soliris (eculizumab) Neuromyelitis Optica US © InformaPositive UK Ltd 2019 sNDA/sBLA Inc. Patients Vertex Approval for Symdeko (tezacaftor/ivacaftor In Children Aged Pharmaceuticals Cystic Fibrosis, Pediatric US sNDA/sBLA and ivacaftor) 6-11 Years Inc. Approval for Somatuline Depot (lanreotide) Neuroendocrine Tumors, A New Syringe Ipsen SA US sNDA/sBLA Pre-Filled Syringe Acromegaly Design Every Two- Approval for Regeneron/Sano� Dupixent (dupilumab) Nasal Polyposis US Weeks SC sNDA/sBLA Injection Dova Approval for Chronic Immune Pharmaceuticals, Doptelet (avatrombopag) US In adults sNDA/sBLA Thrombocytopenia Inc.

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

CONTINUED FROM PAGE 21 He spoke about the hope that physi- nancing until after not only the comple- The GSK purchase of Tesaro once again cians have for a combo that “could po- tion of the trial, but also approval of the put Clovis into the spotlight as a poten- tentially change the shape of the curve expanded label, “ ie, first-line ovarian can- tial takeover target but Mahaffy, who has sufficient to deliver far more long term cer maintenance. plenty of experience in M&A, played a progression free survivors and potentially The next indication that Clovis will hope straight bat. He told Scrip, “At the moment, even increase the number of women who to get a Rubraca approval for is prostate my strong belief is the company needs to are effectively cured in the frontline set- cancer. A filing is planned with the FDA by keep its head down, grind out our clinical ting, who never recur have to go on a sec- the end of 2019 based primarily on data development and drive sales growth both ond or third round of chemo.” presented at ESMO 2018 from the Phase in the US and Europe. Good things will The trial is set to be fully enrolled in the II TRITON2 trial of Rubraca which showed happen if you grind it out, it keeps you fo- middle of next year for the 1,000-patient a 44% confirmed objective response rate cused and could potentially lead to inter- study and “we’re optimistic but it’s always (ORR) in 25 patients with a BRCA 1/2muta- est on the part of somebody else. We don’t fingers crossed when you’re when you’re tion; in April Clovis provided an update to think about it all that much, we just keep engaging in a trial of this size.” A study FDA on 52 patients that showed a similar pushing the ball forward with Rubraca.” this big does not come cheap but Clo- positive trend. One of the ways the ball is being vis signed an innovative financing pact Mahaffy also noted that Clovis was pushed forward is in the Phase III ATHENA with TPG Sixth Street Partners last month about to initiate a basket study that looks trial which is evaluating a combination of whereby the latter is providing a loan up at a handful of different mutations across Rubraca and Bristol-Myers Squibb Co.’s to $175m to cover the ATHENA trial costs tumor types, with the dominant ones be- checkpoint inhibitor Opdivo (nivolum- up to the end of the first half of 2022. ing BRCA 1 and 2 mutations, including ab) in patients with newly diagnosed Mahaffy explained that “necessity is patients with pancreatic cancer. “The goal advanced ovarian cancer. Mahaffy said the mother of invention and we found a is to ultimately get a tumor-agnostic indi- the partners were very pleased with the path that was not dilutive and allowed us cation not unlike Loxo Oncology Inc.’s Vit- pace of enrollment, “which is ahead of our to bring cash in as we needed it to fund rakvi (larotrectinib) and we’ve had a good predictions and I think that speaks to the this trial on a quarterly basis. It extends dialog already with FDA about that trial enthusiasm for the combination of a PD-1 our cash runway pretty significantly and and we’re really enthusiastic about it.” withCo am PARPp ainhibitor.”ny Move there’s no payback expected from this fi- Published online 28 June 2019

APPOINTMENTSSearch

Effective Executive To Company New Role From Company Previous Role Date Arcus Head, Immuno-Oncology Global Eric Hoefer Chief Commercial O�cer AstraZeneca 24-Jun-19 Biosciences Marketing Dicerna David Head, Patient Advocacy Catalyst Vice President, Patient Engagement Pharmaceuticals 13-Jun-19 Caponera and Patient Services Pharmaceuticals and Access Support Inc Dicerna Steven Vice President, Takeda Pharmaceuticals Director, Regulatory Affairs 13-Jun-19 Kates Regulatory Affairs Pharmaceuticals Inc Purnanand Chief Executive O�cer, Chief Executive O�cer, President and Immunome Inc Taris Biomedical 24-Jun-19 Sarma President and Director Director Jean-Paul Chief Executive O�cer MorphoSys AG Syntimmune Chief Executive O�cer and President 1-Sep-19 Kress and President Bon�glio John N. Qrons Inc Chief Operating O�cer Consulting Principal 27-Jun-19 Bon�glio Group Vice President, Corporate Affairs, Matthew Unum Voyager Chief Financial O�cer Communications and Investor 24-Jun-19 Osborne Therapeutics Inc Therapeutics Relations Unum Head, Business and Global Head, Hematology and Mert Aktar Shire plc 13-Jun-19 Therapeutics Inc Corporate Development Immunology Business Development ClickPr hereom for oall tappointments:ion https://bit.ly/2oHWRYn Source: Medtrack | Informa, 2019 scrip.pharmaintelligence.informa.comSearch July 5, 2019 | Scrip | 23

Effective Executive To Company New Role Previous Role Date Adrian Adaptimmune Chief Executive O�cer Chief Financial O�cer 1-Sep-19 Rawcliffe Therapeutics plc Didier Glycostem Chief Medical O�cer Senior Vice President, Clinical Affairs 14-Jun-19 Haguenauer NovaBay Interim Chief Financial O�cer and Jason Raleigh Chief Financial O�cer 17-Jun-19 Pharmaceuticals Inc Treasurer NovaBay Chief Executive O�cer and Interim Chief Executive O�cer and Justin M. Hall 17-Jun-19 Pharmaceuticals Inc President Interim President Chief Medical and Development Frank Weber Polyphor Ltd Director 31-Aug-19 O�cer Roger Vice President, Research and RenovaCare Inc Director, Cell Sciences 6-Jun-19 Esteban Vives Product Development Tetraphase Larry Edwards Chief Executive O�cer Chief Operating O�cer 1-Aug-19 Pharmaceuticals Director

Effective Executive To Company New Role Date Allergy Mary Tavener Non-Executive Director and Member, Audit Committee 19-Jun-19 Therapeutics Keith Schmidt Cerecor Inc Director and Member, Audit Committee and Compensation Committee 12-Jun-19 Entasis David Meek Chairman 24-Jun-19 Therapeutics MiMedx Group K Todd Newton Director 17-Jun-19 Inc Kathleen Behrens MiMedx Group Director 17-Jun-19 Wilsey Inc Director and Member, Regulatory and Compliance Committee and Science Scott Gottlieb P�zer Inc 27-Jun-19 and Technology Committee Regulus Jake Nunn Director and Member, Audit Committee 11-Jun-19 Therapeutics Laurent Fischer Senti Bio Independent Director 12-Jun-19 Heyward R. SI-BONE Inc Director 17-Jun-19 Donigan Mark J. Foley SI-BONE Inc Director 17-Jun-19 Stoke Jennifer Burstein Director and Chairman, Audit Committee 14-Jun-19 Therapeutics STORM John Haurum Independent Non-Executive Director 27-Jun-19 Therapeutics Ltd Sutro Biopharma Connie Matsui Chairman 24-Jun-19 Inc ZIOPHARM Heidi Hagen Director 17-Jun-19 Oncology Inc Advisor

Executive To Company New Role Effective Date Kenneth M. Murphy Harbour BioMed Scienti�c Advisory Board Member 19-Jun-19 Michele Calos Redbiotec AG Scienti�c Advisory Board Member 14-Jun-19 Other

Executive From Company Previous Role Effective Date Move Type Anne Prener Freeline Therapeutics Chief Executive O�cer and Director 13-Jun-19 Resignation Woosok Lee Kolon TissueGene Inc Co-Chief Executive O�cer 7-Jun-19 Resignation Peter Garcia PDL BioPharma Inc Chief Financial O�cer 15-Aug-19 Resignation HEADLINE NEWS

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