No. 3963 July 12, 2019

(over 200mg) and a lowering of sperm counts. Following the discussions, the 52- week data from the trial, expected later this year, will be sufficient for Gilead to file the NDA. In an interview with Scrip at the Europe- an League Against Rheumatism congress in Madrid last month, where the full re- sults from FINCH 1 and 3 were presented, chief medical officer Walid Abi-Saab spoke about the MANTA study. He noted that “in Europe and Japan, and Japan usually tends to be very conservative, they’re OK with this. Of course they’re interested to see the results of MANTA in humans but they’re not putting a lot of emphasis on it. The FDA took a little bit more of a more conservative position.” Abi-Saab said, “At the end of the day, it’s a risk/benefit discussion. Now that we have the full data set from FINCH, we can Gilead To File Filgotinib For RA in say, ‘Guys, this is the efficacy of this com- pound, this is the safety of the compound 2019, Earlier Than Forecast and we’re very pleased with our safety profile.’” He stressed that “we don’t want to KEVIN GROGAN [email protected] get into an acrimonious relationship with the FDA and we need to demonstrate to he US filing for rheumatoid arthri- verely active ulcerative colitis or Crohn’s them that we genuinely want to do that tis (RA) of Gilead Sciences Inc. and disease, and whether the agency wanted study as fast as possible,” although he ad- T Galapagos NV’s closely watched to see the full MANTA data set before ac- mitted enrolment has been slow. filgotinib is now expected by the end cepting a submission. (Also see “Galapa- Abi-Saab added, “We are very keen to of this year, allaying fears that the drug gos Flies As Filgotinib Soars In FINCH Stud- figure this out and put it behind us be- would be at a competitive disadvantage ies” - Scrip, 31 Mar, 2019.) cause if you ask me honestly, I think the to AbbVie Inc.’s already-submitted rival If that were to have been the case, the likelihood that we’re going to be dem- JAK inhibitor upadacitinib. filgotinib filing would have been pushed onstrating that filgotinib has any issues Gilead has announced that it has held a back to 2021 when MANTA is due to be is extremely low.” He went on to say that pre-submission meeting with the US Food completed. However it seems that the FDA he understood the agency’s stance as and Drug Administration to provide an talks went well, as Gilead said in a state- “they worry that once they give you ap- update about filgotinib, an oral, selective ment that “as a result of this discussion, a proval, then the cat is out of the bag and JAK1 inhibitor, and discussed the positive path forward has been established to sub- then they don’t have much more power to Phase III FINCH program. Significantly, the mit the new drug application (NDA) for fil- impose post-approval studies other than talks with the FDA also focused on the gotinib as a treatment for RA in 2019.” public shaming.” ongoing Phase II MANTA safety study as- The FDA wanted the MANTA trial to be The response to the news from ana- sessing semen parameters with filgotinib conducted after animal studies found a lysts was positive. Credit Suisse issued an treatment in men with moderately to se- link between the high doses of filgotinib CONTINUED ON PAGE 4

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Versant’s Century Aims Hanmi Downs Approvals And Launches Off-the-shelf cell therapies Another licensee returns New nods for Xpovio, Ultomiris, in its sights (p19) product rights (p5) Libtayo and Dupixent (p7, 10-12) IN THIS ISSUE

from the editor [email protected]

The effectiveness of the UK government might be in tidal wave that has seen so many other issues swept out freefall these days, but it hasn’t always been that way. of the public eye. In one area in particular, it has been a world leader. The One of the major contributions to progress in the efforts of the outgoing chief medical officer Dame Sally field was the O’Neill Review’s itemization of specific Davies and others, including Lord (Jim) O’Neill, helped measures that could be adopted to correct the unfa- galvanize global efforts to tackle the crisis of antimicro- vorable economics of antibacterial drug development bial resistance in recent years. It is therefore especially and commercialization, which have strangled R&D in bleak to read O’Neill’s assessment of the treatment of the field and left us to rely on old drugs to which in- the issue at last month’s G20 summit in Japan (see p21). fections are becoming increasingly resistant. The fact is O’Neill was commissioned by former UK Prime Min- that the G20 statement in 2019 failed to reflect advanc- ister David Cameron to conduct a review on antimicro- es over the past few years and made no hard commit- bial resistance in July 2014. The work was completed ment despite work already undertaken by the O’Neill in May 2016, just a month before the country voted in Review and others in the field. What a shame if Brexit favor of Brexit, prompting Cameron’s departure and has reduced the UK’s policy heft where it could really effectively launching a long-lasting political and social be of benefit.

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

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2 | Scrip | July 12, 2019 © Informa UK Ltd 2019 Libtayo Comes Into Land

Sarepta Share Bounce

G20 Paltry On AMR 20 11 18 21

exclusive online content inside: COVER / Gilead To File Filgotinib For RA in 2019, UK Committee Attacks Pharma Over Earlier Than Forecast Lack Of Medicinal Cannabis Research 3 UK Committee Attacks Pharma Over Lack Of Medicinal Cannabis Research IAN SCHOFIELD [email protected] 4 GSK’s Otilimab Goes Head-To-Head To Crack Rheumatoid Arthritis

5 Hanmi Faces Another Licensee U-Turn, This Time Janssen On Obesity/Diabetes Drug

6 Boehringer Adds Yuhan’s First-In-Class Dual Agonist To NASH Portfolio

7 Karyopharm’s Xpovio In Multiple Myeloma Priced At $22,000 Per Four-Week Cycle

9 Amarin Will Double Vascepa Sales Team In Big Bet On Supplemental Approval

10 EU Ultomiris Approval Rounds Off A Good Week For Alexion’s Complement Franchise A UK parliamentary committee has criticized the pharma- ceutical industry for not putting medicinal cannabis prod- 11 Sanofi’s Libtayo Lands In EU With Skin Cancer Nod ucts into clinical trials, saying that companies that fail to do 12 CHMP Delivers More Good News For Sanofi’s Dupixent so should be “named and shamed.” “It is concerning that that some pharmaceutical compa- 13 LSKB Still Upbeat On Rivoceranib Despite ANGEL Failure nies are still resistant to making their products available for In Late-Line Gastric Cancer research,” says the House of Commons’ health select commit- 15 AstraZeneca Gets Imfinzi Boost From CASPIAN tee. Without a robust evidence base allowing patients and Lung Cancer Trial clinicians to weigh up any risks and benefits of medicinal cannabis products, they “will remain unlicensed for the many 16 Dainippon’s Lead Boston Asset Hits Wall In Pancreatic Cancer areas where patients wish to know if they could be effective.” In a report published on 3 July, the committee urges the 18 Sarepta Shares Bounce As Pfizer’s DMD Gene Therapy Sparks Safety Concerns Department of Health and Social Care to investigate cases where companies are not providing their products, and to 19 Versant’s Century Aims For Off-The-Shelf Cancer Cell Therapies “set out a plan to incentivize industry to take a more active role in research itself.” 20 Korea Eases Stock Rules To Help Bioventures Stay Listed, Focus On R&D It also says that even though medicinal cannabis products were reclassified as Schedule 2 controlled drugs last year, 21 UK’s O’Neill ‘Frustrated’ By G20’s ‘Paltry’ AMR Message allowing them to be prescribed by specialist doctors under specific conditions, “very few prescriptions have been issued 22 Pipeline Watch for such products,” because most of them do not have a UK 23 Appointments or EU marketing authorization, nor have they been OKd by the health technology assessment (HTA) body, NICE. Published online 5 July 2019 @PharmaScrip /scripintelligence To read the rest of this story go to: https://bit.ly/2JtVkPD

/scripintelligence /scripintelligence

scrip.pharmaintelligence.informa.com July 12, 2019 | Scrip | 3 HEADLINE NEWS/RESEARCH & DEVELOPMENT

CONTINUED FROM PAGE 1 investor note on 2 July that referred to comments by new Gil- GSK’s Otilimab Goes Head- ead CEO Daniel O’Day on the company’s first quarter earnings call indicating that it would be able to file for approval without the full data from MANTA, so “we see this as a positive sign for To-Head To Crack O’Day’s tenure in that he is able to execute against his word and is focused on pipeline execution.” Rheumatoid Arthritis The broker noted the market’s fears that with the absence of clear JOHN DAVIS [email protected] timelines from MANTA trial, the launch of filgotinib could have been delayed to at least 2022, potentially placing the drug a long way he Phase III clinical trial program for GlaxoSmithKline PLC’s behind AbbVie’s JAK inhibitor upadacitinib. The FDA is expected to novel mechanism-of-action rheumatoid arthritis candi- give its decision on the drug for RA in the third quarter after AbbVie T date, otilimab (GSK3196165), will include head-to-head used a priority review voucher to speed up evaluation. comparisons with marketed RA therapies including Pfizer Inc.’s oral JAK inhibitor, Xeljanz (tofacitinib), and Sanofi/Regeneron “They worry that once they give you Pharmaceuticals Inc.’s injectable anti-interleukin-6 Mab, Kevzara (sarilumab), the UK big pharma announced on 3 July. approval, then the cat is out of the bag...” The breadth of the program is one of the clearest signs yet of the effort GSK is continuing to put into developing the in- – Walid Abi-Saab vestigational rheumatoid arthritis therapy, which, as an anti- granulocyte macrophage colony stimulating factor (GM-CSF) monoclonal antibody, has a mechanism of action that would be novel for an antirheumatic. Analysts at Morgan Stanley agreed that timing for a US launch GSK has previously signaled a strong interest in immune-in- had been a key investor focus given filgotinib is likely to get to flammation, and its drive to extend its activities in the sector be- market after upadacitinib and “we believe a 2019 filing plan is a yond the marketed lupus product, Benlysta (belimumab). Howev- bull case scenario and clearly indicates that the FDA is comfort- er competition in this field is strong, with new products like Gilead able with interim safety data from the MANTA studies being in- Sciences Inc./Galapagos NV’s JAK inhibitor filgotinib and AbbVie cluded in a filing.” However, in a 2 July note, the broker wrote that Inc.’s upadacitinib nearing the market. “one lingering concern” investors may have “is whether a more All development and commercialization rights for otilimab rapid path to filing may come at the expense of a more restric- (then MOR-103) were licensed from MorphoSys AG in 2013, in a tive label [but] overall, we believe this news is a clear positive for deal that included a €22.5m upfront, up to €423m in milestones, Gilead and Galapagos, as a 2019 NDA filing sets up filgotinib for a and royalties on sales. US RA launch in 2021, one year ahead of consensus expectations.” The Phase III program for otilimab was designed in collabo- Jefferies analysts described the announcement as “an incremen- ration with regulators, explained GSK chief scientific officer tal positive surprise” but claimed that “an outstanding question is Hal Barron, and has now started in patients with moderate-to- whether Gilead has a priority review voucher handy and thus can severe rheumatoid arthritis who have had an inadequate re- keep the timing tight.” If MANTA comes out clean, they said that “we sponse to disease modifying antirheumatic drugs (DMARDs) or would certainly argue everything would be very good and Gilead targeted therapies. The program, called ContRAst, is the first would be very competitive if not best-in-class compared to AbbVie.” in RA to include head-to-head comparisons with current treat- If the data were negative and filgotinib did cause a reduction in ments in all three pivotal studies. The primary endpoint will be sperm count, “this scenario wouldn’t appear to block Gilead’s abil- the proportion of patients achieving the American College of ity to file. Rather, it would be an issue in the label, which isn’t too Rheumatology criteria (ACR20) at week 12 with otilimab versus commercially relevant in our opinion given that these indications placebo. Otilimab is being given as 90mg or 150mg subcutane- comprise of mostly females,” Jefferies concluded. ous weekly injections. At SVB Leerink, analysts issued a note on 2 July saying that “we The cytokine, GM-CSF, is believed to play a central role in im- were wrong [as] we viewed the testicular toxicity signal story as a mune-mediated diseases, acting on macrophages and other im- big and bounded uncertainty for filgotinib.” Still, it remains to be mune cells to cause inflammation, joint damage and pain. Otil- seen how well it can compete with upadacitinib, which Leerink imab is believed to block the interaction of GM-CSF with its cell stated will have “the full might of AbbVie’s pharma commercial surface receptor. machine behind it.” In a Phase II dose-ranging study, BAROQUE, reported at the Oc- The analysts concluded by noting that after attending EULAR, tober 2018 meeting of the American College of Rheumatology, they were “struck by one simple reality: the RA problem remains otilimab added to methotrexate therapy in 222 patients with an unsolved. Only less than 10% of patients achieve drug-free remis- inadequate clinical response to methotrexate, was associated sions despite being heavily bombarded by biologics. While the with an encouraging rapid onset in reducing pain and tender joint antibodies will not be disappearing anytime soon, it may be time counts. Although the primary endpoint of the study was missed, to reconsider new modalities more broadly, increasing the oppor- secondary endpoints produced statistically significant improve- tunity for great oral drugs.” Published online 2 July 2019 ments, Biomedtracker analysts noted.

4 | Scrip | July 12, 2019 © Informa UK Ltd 2019 RESEARCH & DEVELOPMENT/DEALS

Preclinical data suggests otilimab may targeted therapies, only around 30% of native (non-TNF) mechanisms of action to have a broader range of therapeutic activ- patients treated with marketed therapies increase from just under £7bn in 2019 to ities than conventional biologics, includ- achieve remission, and daily pain is a key around £9bn in 2024. Few other companies ing a specific effect on pain, and although driver of switching between biological are developing anti-GM-CSF antibodies for the treatment of rheumatoid arthritis has and oral therapies. rheumatoid arthritis; UK biotech Izana Bio- benefited from the development of TNF While the worldwide RA market for anti- science is preparing to conduct a Phase II inhibitors and other biologic therapies, TNFs has been slowly declining since 2016- trial in ankylosing spondylitis with its anti- there is still an unmet need for effective 17 because of the launch of biosimilars, GSK GM-CSF Mab, IZN-101. therapies. GSK noted that with multiple expects the market for RA drugs with alter- Published online 2 July 2019 Hanmi Faces Another Licensee U-Turn, This Time Janssen On Obesity/Diabetes Drug

JUNG WON SHIN [email protected]

anssen Pharmaceutical Cos. has re- desired endpoints. “Metabolism remains Despite the rising prevalence of obese turned the rights to obesity/diabe- a critical part of the Cardiovascular & Me- individuals globally, the area has been chal- Jtes therapy HM12525A (JNJ-5111), a tabolism therapeutic area at Janssen, and lenging for pharmaceutical therapies, as pa- long-acting GLP/GCG analog to origina- our strategy to advance new therapies for tients generally want more weight loss than tor Hanmi Pharmaceutical Co. Ltd., after metabolic disease states, including obe- medications are able to provide and safety Phase II studies achieved their weight sity, has not changed,” it stressed. is so critical, Peter Chang, principal scientific reduction targets, the primary evaluation analyst at Biomedtracker, told Scrip. indicator, but not their glycemic control OBESITY/DIABETES A Obese diabetics are an important seg- goals for obese diabetics. CHALLENGING SPACE ment, along with drugs that treat both The South Korean firm was upbeat how- Even so, this is disappointing news the diabetes and cause weight loss, as ever. “Through the results of Phase II trials for Janssen. While the cardiovascular/ they are more apt to be treated medically. Janssen has conducted, the compound metabolic area is core, with blockbust- Novo Nordisk AS has started to be more has sufficiently proven its efficacy as an ers such as blood thinner Xarelto (rivar- successful with Saxenda (liraglutide, a obesity drug,” it declared. “This has prov- oxaban) and Invokana (canagliflozin) for higher dose version of Victoza) for obesity, en the glycemic control needs for obese diabetes, it has only a limited pipeline in though it is still used in only a limited num- diabetics, so we will reflect this need and diabetes/obesity. ber of patients, of which an estimated 20- determine future development directions 30% are diabetics, the analyst explained. of the compound after an internal review.” Another challenge for competitors is The company will be able to retain the that other new drugs such as Novo’s GLP- upfront payment of $105m that its US 1 agonist Ozempic (semaglutide) and its partner paid under the license deal. oral formulation, as well as Eli Lilly & Co.’s HM12525A is a novel ultra-long-acting GLP-1/GIP co-agonist tirzepatide, are rais- dual agonist comprising a chemically syn- Despite the rising ing the bar on weight loss and glycemic thesized GLP-1/GCG peptide conjugated control. Novo is hoping that combination with a human IgG Fc fragment via a flexi- prevalence of obese use of Ozempic and the amylin analogue ble PEG linker. The once-weekly product is individuals globally, AM833 could lead to weight loss of 20%- site-specifically conjugated using Hanmi’s plus, Chang said. proprietary LAPSCOVERY technology for the area has been “So if HM12525a fell short on glycemic sustained duration of activity. control, it is not too surprising that Jans- Under the agreement signed in 2015, challenging for sen dropped it. That issue has been a ma- Janssen gained exclusive worldwide pharmaceutical therapies, jor limitation of combined GLP-1/gluca- rights to the therapy excluding in South gon agonists, because glucagon agonism Korea and China. Hanmi was also eligible as patients generally increases blood glucose. Companies have for a total of up to $810m in milestone been trying to find combinations where payments plus double-digit sales royalties want more weight loss the added weight loss leads to enough after commercialization. than medications are improvement in glycemic control that it Janssen told Scrip that it had decided overcomes the negative effects of gluca- to end the program because the results of able to provide. gon agonism, and apparently that was not the Phase II studies did not meet all of the seen here,” he said.

scrip.pharmaintelligence.informa.com July 12, 2019 | Scrip | 5 DEALS

Janssen does have earlier stage candi- In January this year, Eli Lilly & Co. re- In Seoul, shares in Hanmi fell more than dates in Phase I and preclinical studies, turned rights to the novel Bruton’s 20% in early trading on 4 July on disap- which could be interesting, but there is tyrosine kinase inhibitor LY3337641 pointment over the news, which the firm still significant uncertainty about their (HM71224) it had licensed in from Han- disclosed to the stock market late on 3 prospects. In a recent R&D call for the CV/ mi in 2015, after the US giant decided July. Hanmi reassured investors that the metabolic space, they instead highlighted to halt its Phase II program in 2018 due return of the rights frequently occurs in retinal disease and a collaboration on Fac- to what it saw as weak data. (Also see the process of new drug development. tor XIa inhibition, where the candidates “Hanmi To Step Up Global Drug Develop- “Although it is a difficult road ahead to de- are more advanced, Chang commented. ment As Lilly Returns BTK Rights” - Scrip, velop global new drugs, its challenges will 23 Jan, 2019.) not stop us,” it said. HANMI HIT AS FOURTH In 2018, Hanmi decided to stop all fur- The South Korean firm said it is pro- COMPOUND RETURNED ther development of its third generation gressing nearly 30 new drugs in its pipe- Meanwhile for Hanmi, this is the fourth EGFR inhibitor Olita (olmutinib) following line and still has collaborations with vari- time to face a return of licensed-out com- Zai Lab Ltd.’s return of rights in the China ous other big pharma partners such as pounds following a series of massive li- region to the drug and Boehringer Ingel- Sanofi, Spectrum Pharmaceuticals Inc. censing deals with global pharmas over heim GmbH’s cancellation of an earlier li- and Genentech Inc. the past few years. censing deal. Published online 4 July 2019 Boehringer Adds Yuhan’s First-In-Class Dual Agonist To NASH Portfolio

JUNG WON SHIN [email protected]

outh Korea’s Yuhan Corp. and Boehringer Ingelheim GmbH Yuhan Inks Second NASH have inked a collaboration and license agreement for the License-Out Agreement Sglobal development of a first-in-class GLP-1/FGF21 dual agonist for the treatment of non-alcoholic steatohepatitis (NASH) and related liver diseases, in a deal worth as much as $870m, in- cluding $40m in upfront and near-term payments, plus royalties. The worldwide deal, excluding South Korea, marks the sec- ond NASH license-out deal for Yuhan following that with Gil- ead Sciences Inc. in January, validating its competitiveness in the therapy space and reflecting the strong global interest in the yet unconquered area. (Also see “Asia Deal Watch: Boost For Esperion’s Cholesterol Candidate As Daiichi Brought On Board” - Scrip, 8 Jan, 2019.) The leading South Korean pharma’s main therapeutic focus is on cancer as well as metabolic diseases such as NASH and diabe- tes, and its efforts to transform into an R&D innovator now appear to be recognized globally after a series of deals since last year with global firms including Janssen Biotech Inc. manufacturing capability, and in the cardiometabolic disease sec- tor already sells the DPP-4 inhibitor Trajenta (linagliptin) and SGLT- LANDMARK DEAL 2 inhibitor Jardiance (empagliflozin). It is also progressing clinical The new collaboration brings together Yuhan’s expertise in FGF21 trials of a GLP-1R/GCGR dual agonist, and so is a suitable partner biology, obesity and NASH with Boehringer’s global experience for Yuhan, the brokerage said. and commitment to bringing innovative medicines to patients Hana Financial Investment said that the deal also derived from with cardiometabolic diseases, said Yuhan. Yuhan’s collaboration with a domestic biotech partner, and point- The deal also marks Yuhan’s first external partnership for a bio- ed to Yuhan’s pipeline immuno-oncology drug YH24931, which it logic and is the first licensing out of a biologic targeting NASH by brought in from its joint venture with Sorrento Therapeutics Inc., a Korean firm, noted Jung Hee Lee, CEO and president of Yuhan. as another asset worth keeping an eye on. In a research note on the alliance, Mirae Asset Daewoo pointed The compound licensed to Boehringer is a fusion protein utiliz- to the large deal value and upfront payment, even though it is ing the long-acting hybrid (HyFc) technology of Korean venture for a still preclinical-stage molecule that hasn’t completed toxicity Genexine, and was developed in-house by Yuhan. Preclinical evi- tests. Boehringer is considered as a good partner with biologics dence suggested high efficacy when combining the gut-derived

6 | Scrip | July 12, 2019 © Informa UK Ltd 2019 DEALS/APPROVALS

hormone GLP-1 with FGF21. As Yuhan applied Genexine’s tech- with a focus on innovative drugs for the treatment of the conse- nology, it has to pay 5% of the license deal value, excluding sales quences of diabetes and contributing factors like obesity. royalties, to Genexine. Yuhan has already been a commercial partner for Boehringer’s The dual GLP1R/FGF21R agonist approach is expected to re- diabetes products in South Korea for many years, providing an ex- duce liver cell damage and hepatic inflammation by resolution isting link for the new alliance. of steatohepatitis, as well as having direct antifibrotic effects. The addition will complement Boehringer’s existing R&D portfolio in NASH NEEDS NASH, adding another potential first-in-class opportunity. NASH is generally caused by the accumulation of fat in the liver, giving rise to inflammation and finally leading in many patients DEAL BUOYS BI’S PRESENCE IN to liver fibrosis and cirrhosis. It has an especially high prevalence CARDIOMETABOLIC DISEASE among obese and diabetic patients and remains an area of high- For the private German group, the addition of Yuhan’s preclini- unmet medical need with no currently approved treatments. cal molecule will further beef up its R&D expertise in cardiomet- According to Informa’s Datamonitor Healthcare, NASH is con- abolic diseases, including NASH. The deal is also in line with its sidered to be an ongoing burden to society with the number of deal-making strategy to focus on early-stage collaborations to prevalent cases projected to increase by over 13% from 2016 to bolster its therapeutic focus in selected areas including cardio- 2035. The possible progression of patients to cirrhosis and hepa- metabolic diseases. tocellular carcinoma in particular will result in an increased bur- In late May, BI inked a second obesity deal with Danish biotech den on overall healthcare systems. Gubra ApS to develop poly-agonist peptides for obesity and con- Several diabetes and other drugs such as pioglitazone, rosigli- comitant diseases. (Also see “BI Inks Second Obesity Pact With Den- tazone, losartan and metformin are used off-label to treat non- mark’s Gubra” - Scrip, 31 May, 2019.) alcoholic fatty liver and NASH patients, as various new dedicated Boehringer believes that in many cases approaches targeting therapies progress globally through development. one of the features of NASH will not be able to achieve the de- Genfit SA, for one, is ready to begin combination therapy stud- sired outcomes in patients with advanced stages of the disease. ies of its Phase III candidate elafibranor with two classes of already Thus the company has built a comprehensive program to develop marketed diabetes drugs. (Also see “Genfit Assesses Optimal Elafi- next-generation therapy approaches targeting all three key driv- branor NASH Combo Therapy Opportunity” - Scrip, 24 Jun, 2019.) ers of the condition - steatosis, inflammation and fibrosis. After multiple Phase IIb trial failures, Conatus Pharmaceuticals Boehringer has a long history of R&D for cardiometabolic dis- Inc. said in June it will wrap up its obligations related to its pan- ease and has established a broad portfolio of marketed products caspase inhibitor emricasan with partner Novartis AG and con- for thromboembolic disorders, type 2 diabetes, acute myocardial sider its strategic alternatives going forward. (Also see “Conatus infarction, hypertension and cardio-renal risk reduction. The pipe- Accepts Defeat For Emricasan In NASH” - Scrip, 25 Jun, 2019.) line also extends beyond type 2 diabetes and anticoagulation Published online 2 July 2019 Karyopharm’s Xpovio In Multiple Myeloma Priced At $22,000 Per Four-Week Cycle

JOSEPH HAAS [email protected]

aryopharm Therapeutics Inc. obtained approval for Xpovio effective 5 July. Vice president of sales Perry Monaco was promot- (selinexor) to treat penta-refractory multiple myeloma pa- ed to a senior VP position to oversee Xpovio’s launch. Ktients on 3 July, with a full approval hinged on the ongoing Executives said during a same-day investor call that the drug Phase III BOSTON trial, despite safety concerns and other issues should be available to patients by 10 July, noting that a consid- overhanging the drug. erable amount of Xpovio already has been manufactured. Karyo- Pessimism reigned regarding the chances for the first-in-class pharm set the drug’s wholesale acquisition cost at $22,000 per nuclear export inhibitor to gain accelerated approval following four-week dosing cycle, which will be the same for all four ap- a US FDA advisory committee review in February, but investors proved dosing regimens. turned optimistic as the agency’s decision was announced. “We wanted to make sure that cost was not going to be a fac- In fact, Karyopharm’s stock surged 36% to $11.09 per share tor in determining the optimal dose for a patient,” CEO Michael even before trading of the company’s stock was halted just after Kauffman told Scrip. “It would be absolutely the wrong thing to do 11 a.m. Eastern – a few hours before Xpovio’s approval was an- medically. The price itself was basically placed at the higher end of nounced. The stock resumed trading and was up another 6% in what’s currently done in myeloma now with Pomalyst (pomalido- the after-hours market. mide) and with Darzalex (daratumumab), particularly in the late Karyopharm’s 3 July news also included an announcement that stage, and it’s a bit lower than some of the other drugs in hemato- chief commercial officer Anand Varadan will depart the company logic malignancies for these patients who unfortunately have ex-

scrip.pharmaintelligence.informa.com July 12, 2019 | Scrip | 7 APPROVALS

hausted all available options. But what we didn’t want to do was However, there is language regarding monitoring instructions, provide an incentive to get the wrong dose.” recommended concomitant therapy, and warnings and precau- Celgene Corp.’s Revlimid (lenalidomide) is the top-selling mul- tions about thrombocytopenia, neutropenia, gastrointestinal tox- tiple myeloma drug globally, but it is expected to face generic icity, hyponatremia, infections, neurological toxicity and embryo- competition in 2022. That means the Xpovio launch will occur fetal toxicity. Prescriptions will be accompanied by a medication in an indication with significant branded drug competition and guide, Karyopharm noted. expectations of increased genericization, adding to the potential Addressing the safety and tolerability language in the label, challenges posed by the departure of Karyopharm’s CCO. Kauffman pointed out that penta-refractory myeloma patients are The company did not comment on why Varadan is leaving the very sick, with an average life expectancy of three-to-five months, company, but Kaufmann wished the outgoing executive well dur- [so adverse events when introducing a new medicine isn’t unex- ing the investor call and noted that Varadan “played an integral pected]. [He noted that while] Xpovio has side effects, including role in our commercial preparedness.” numerically more incidents of nausea and anorexia than seen with other myeloma therapies like Pomalyst and Kyprolis (carfil- OUTLOOK WAS BLEAK AFTER ADVISORY COMMITTEE zomib), [they aren’t of a magnitude of concern to doctors Karyo- Commercialization of Xpovio appeared uncertain after a 26 Feb- pharm has spoken with]. ruary meeting of the FDA’s Oncologic Drugs Advisory Committee “What we didn’t have was major organ toxicities or major (ODAC), during which the panel voted 8-5 that approval of se- adverse reactions,” Kauffman said. “We did have a number linexor should wait until the Phase III BOSTON data were available. of serious adverse events, but the percentage was similar to At that point, chances for accelerated approval did not look good, Pomalyst and Kyprolis and the nature of those serious adverse Kauffman admitted. But near-immediate dialogue between the events were really what happens to people who have three- company and the agency addressed issues of concern, he noted, to-five months to live. I think FDA’s safety group understood enabling the accelerated approval to go forward. (Also see “Keep- early on that there was nothing that was going to be of suf- ing Track: Poteligeo, Onpattro, Galafold And Annovera Approved; ficient magnitude or concern to a physician that they would Selinexor Submitted” - Pink Sheet, 12 Aug, 2018.) need a black box.” FDA officials told Karyopharm that despite the vote recom- mending against accelerated approval, they also took note of A 70-PERSON TEAM TO CALL ON MYELOMA DOCTORS other commentary in favor of the approval, including those by On Karyopharm’s call, Monaco outlined a launch strategy in the one multiple myeloma expert on ODAC. “They also listened which 70 sales reps and nurse liaisons will call on 1,300 key very carefully to the patients and the doctors who spoke during physicians, including about 400 who treat more than 50% of the public session,” Kauffman said. “There was a definite sense the projected patient base. Karyopharm said an estimated at FDA that the ODAC vote, which was reasonably close, maybe 69,000 myeloma patients currently are on drug therapy and didn’t quite reflect the reality” of the drug’s risk-benefit profile in a about 6,000 of those individuals fall into the penta-refracto- patient population with very limited options. ry group. Xpovio represents the first approval against a new The discussions also identified additional data that the agency myeloma target since 2015, the company pointed out, since wanted to see, which Karyopharm provided, the exec said, and Bristol-Myers Squibb Co.’s anti-SLAMF7 therapy Empliciti (elo- clarified that the company, which had no commercial products, tuzumab). (Also see “BMS/AbbVie Empliciti Leaps Ahead, Wins was not able to offer patients an expanded access program while Fast FDA Nod” - Scrip, 30 Nov, 2015.) approval was pending. The FDA had indicated that Karyopharm While it awaits data from the BOSTON trial, an event-driven was capable of doing such a program, which may have swayed study that could read out later this year or early in 2020, Kauff- the votes of some ODAC panel members, Kauffman said. man said the study offers the potential to quickly advance Xpovio Going into the advisory committee, briefing documents men- to second-line myeloma therapy. The drug is a good candidate tioned concerns about drug toxicity and also questioned how for earlier lines of therapy, he asserted, because it offers a new clear the benefit of selinexor was in a combination regimen mechanism of action, is oral and combines well with other agents. with dexamethasone. (Also see “Karyopharm’s Selinexor: US FDA Karyopharm also has studies underway investigating first-line my- Unconvinced By Efficacy In Single-Arm Trial” - Pink Sheet, 22 Feb, eloma therapy with Xpovio, he said. 2019.) The new drug application (NDA) was backed by the Phase Datamonitor Healthcare analyst David Dahan suggested that IIb STORM study, which showed a 25.3% overall response rate in a early uptake of Xpovio will be limited. subgroup of 83 patients. However, those responses included one “Since doublet regimens are typically reserved for heavily pre- stringent complete response, no other complete responses, four treated patients who are not fit enough for more rigorous triplet very good partial responses and 16 partial responses. therapies, it is likely that selinexor’s initial target patient popula- tion will be limited,” Dahan told Scrip. “However, Xpovio is also WARNINGS AND PRECAUTIONS, BUT NO BLACK BOX being evaluated in the Phase III BOSTON trial as part of a triple The accelerated approval – for combination therapy with dexa- combination with Velcade (bortezomib; Takeda Pharmaceutical methasone in multiple myeloma patients who have received at Co. Ltd./Johnson & Johnson) and dexamethasone in the second- least four prior therapies and whose disease is refractory to at least to fourth-line settings, which will help the drug increase its com- two proteasome inhibitors, two immunomodulators and anti-CD38 mercial potential.” antibody therapy – includes a label with no black box warning. Published online 3 July 2019

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Amarin Will Double Vascepa Sales Team In Big Bet On Supplemental Approval JOSEPH HAAS [email protected]

marin Corp. PLC previewed its sec- ond quarter sales performance on A2 July, pointing to a sizeable in- crease for Vascepa ahead of an anticipated US approval that would increase the puri- fied fish oil pill’s market exponentially, and revealed plans to double its sales force for the product. Ireland-headquartered Amarin said sales of Vascepa (icosapent ethyl), approved by the US Food and Drug Administration in 2012 to reduce very high triglyceride levels, totaled $97m-$101m during the second quarter and $170m-$174m in the first half of 2019. The company anticipates major growth in the product’s indicated population following FDA approval ex- pected this fall; the label expansion would The company’s record quarter with label expansion,” he said. be based on cardiovascular outcomes data “The $420m high end suggests healthy in patients with high triglycerides, includ- revenue during the quarter-over-quarter increases from the ing less severe triglyceride levels than out- second quarter.” lined in Vascepa’s current label. first two quarters was In REDUCE-IT, an 8,179-patient study in The company’s record revenue during attributed to increased statin-treated patients with elevated car- the first two quarters of this year was at- diovascular risk, Vascepa as an adjunct to tributed to increased demand for Vascepa, demand for Vascepa. dietary changes yielded a 25% reduction approved in the US to reduce triglyceride in relative risk of cardiovascular outcomes, levels in patients whose levels are 500mg/ including a 20% decrease in risk of cardio- dL or greater. Still subject to auditor re- vascular disease-related mortality. (Also view, estimated sales of the proprietary study results unveiled in September, see “Amarin’s REDUCE-IT Data For Vascepa formulation of the omega-3 eicosapen- which showed an ability to reduce car- May Be Game-Changing, But Not Without taenoic acid (EPA) rose 84-92% year-over- diovascular risk by 25% on top of statins. Controversy” - Scrip, 12 Nov, 2018.) In a key year during the second quarter and by 76- (Also see “’That’s Huge, Folks’: Amarin’s secondary endpoint assessing first cardio- 80% during the first six months of 2019. Vascepa Cuts CV Risk By 25% On Top Of vascular death plus non-fatal heart attacks Vascepa has a 28 September action Statins” - Scrip, 24 Sep, 2018.) The project- and/or strokes, the trial also demonstrated date at the US FDA for a supplemental ed second quarter sales of Vascepa indi- a 26% relative risk reduction. new drug application (sNDA) that if ap- cate “robust demand” with dollar figures These reductions were greater than proved would make it the first drug with “well above even bullish expectations, so what was seen in CVOT trials for PCSK9 an indication to reduce residual cardio- this is a strong result,” the analyst added. inhibitors such as Amgen Inc.’s Repatha vascular risk in patients who are managed (evelocumab) and Sanofi/Regeneron for LDL cholesterol on statin therapy, but SALES GUIDANCE INCREASED Pharmaceuticals Inc.’s Praluent (alirocum- need treatment for persistently elevated TO $380M-$420M ab), although Amarin points out that Vas- triglycerides. (Also see “Keeping Track: A Amarin increased its full-year sales guid- cepa does not compete directly with the Busy Week For Regenerative Medicine, A ance to a range of $380m-$420m from PCSK9 class of drugs. Surprise Priority Review For Vascepa, And a previous $350m projection, which Yee In an email exchange, Amarin CEO John Tazemetostat Aims For Accelerated Ap- called conservative based on current Thero declined to say whether the compa- proval” - Pink Sheet, 1 Jun, 2019.) trends for the product. “We see [the] lower ny is seeking a labeling update that would Jefferies analyst Michael Yee wrote opti- end of new guidance as conservative as include the key secondary endpoint from mistically in a 2 July note about Vascepa’s math shows even minor increases in the REDUCE-IT. “It is premature to discuss label chances for the expanded label based on second half would get to $380m and sales details,” the exec said. “We are pursuing the REDUCE-IT cardiovascular outcomes should pick up big, especially in the fourth FDA approval of an expanded indication

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for Vascepa for cardiovascular risk reduc- submit to the FDA’s Office of Prescription the company’s stock closed up 16% at tion in patients with elevated triglyceride Drug Promotion by October. The compa- $22.37 per share. levels, despite statin therapy.” ny hopes to be able to roll out DTC adver- Amarin also stated that it remains on While the outcome of FDA’s review of tising by the second quarter of 2020. track to file Vascepa for approval in the the sNDA filing is uncertain, Amarin is Thero told Scrip that most physicians EU by the end of 2019. The company is moving forward with a confident outlook. “have limited or no awareness of Vascepa.” not partnered on development or com- Although previously it planned to build “Our focus in educating physicians and mercialization of the product in Europe at up incrementally to a headcount between other health care professionals regarding present, and Thero indicated that poten- 600 and 800 sales representatives, it now Vascepa after label expansion will begin tial partnering in Europe is not a priority is working to double the team to 800 by with reminding them that cardiovascular right now. October. The decision is based partly on disease is an enormous and growing health “While Amarin has been approached positive feedback from doctors about the care burden; that existing standard-of-care by various companies which seek to REDUCE-IT data, Amarin noted, along with therapy is important but insufficient (e.g. promote Vascepa in the EU, the timing a need to reach doctors not yet informed cholesterol lowering lowers cardiovascular and specifics of Vascepa commercial- about the drug as well as data suggesting risk by 25%-35% but this leaves 65%-75% ization in the EU is under review and, the potential benefits of calling on target- remaining risk); that other products seek- although important, a lower priority at ed physicians more frequently. ing to address this residual cardiovascular this time than ensuring [expanded] ap- The company also benefited from risk have failed; and that Vascepa provides proval and successful launch of Vascepa American Diabetes Association treatment a new cost-effective treatment options for in the US and preparing for the EU sub- guidelines issued in March that recom- such patients,” he said. mission,” he said. mend Vascepa therapy for diabetes pa- Amarin’s board of directors is fully sup- Amarin has lined up partners for Vas- tients with high triglycerides. (Also see portive of the plan for a quick ramp-up of cepa in Canada, China and the Middle “Amarin’s Vascepa Gets ADA Recommen- the commercial team, he noted, and the East; in addition to the US, the drug also dation For Patients With Diabetes And High expense of adding that much staff should is approved in Lebanon and the United Triglycerides” - Scrip, 28 Mar, 2019.) benefit investors quickly if the label ex- Arab Emirates. Eddingpharm Interna- pansion is approved and sales grow as tional Holdings Ltd. paid $15m up front, PHYSICIAN EDUCATION, anticipated based on the expanded label, with the potential for $154m in mile- DTC CAMPAIGN PLANNED FOR Thero said. Getting the sNDA approved stones as well as sales royalties in 2015 EXPANDED LABEL would add “millions of patients in the for rights to market the product in Chi- Key parts of Amarin’s planned commercial United States, alone” as potential custom- na, Hong Kong, Macau and Taiwan. HLS ramp-up are physician education efforts ers for Vascepa, he noted. Therapeutics Inc. obtained Canadian as well as a direct-to-consumer (DTC) ad- Investors responded positively to rights to Vascepa in 2017. vertising campaign the company plans to Amarin’s announcements on 2 July, as Published online 2 July 2019 EU Ultomiris Approval Rounds Off A Good Week For Alexion’s Complement Franchise

ALEX SHIMMINGS [email protected]

he European Commission has approved Alexion Phar- Ultomiris is a longer-acting C5 complement inhibitor than maceuticals Inc.’s Soliris successor, Ultomiris, for its first Soliris (eculizumab), being dosed every eight weeks rather than Tindication, paroxysmal nocturnal hemoglobinuria, just every two weeks (following a weekly induction period for four days after the US Food and Drug Administration approved weeks), and the company is hoping it will become the new stan- Soliris for its fourth indication, neuromyelitis optica spectrum dard of care for patients with paroxysmal nocturnal hemoglo- disorder (NMOSD). binuria (PNH). In April, the EMA’s Committee for Medicinal Products for Hu- Alexion has previously said that the first EU launch of Ultomiris man Use recommended approval of Ultomiris (ravulizumab) for was expected in Germany around mid-year. The new product was the treatment of adult patients with PNH with hemolysis and clini- first approved in the US in December 2018, and its first quarter cal symptoms indicative of high disease activity, and also for adult sales performance was promising, showing a good conversion patients who are clinically stable after having been treated with rate. Combined Q1 revenues from Soliris/Ultomiris were up by Soliris for at least the previous six months. (Also see “ViiV’s Poten- 23% year-on-year to $987m, with Soliris contributing $962m (ver- tial HIV Blockbuster Among Latest Drugs To Win EMA Nod “ - Pink sus $977m in 4Q18) and Ultomiris $25m. Sheet, 29 Apr, 2019.) Ultomiris has EU orphan drug designation. It The C5 franchise accounts for around 87% of Alexion’s revenues was also approved in Japan last month. and the company is relying on its combined growth ahead of

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first competition from generic versions of patients who are anti-aquaporin-4 (AQP4) cy was broader than they had expected. Soliris expected from 2021. Alexion said antibody positive, ie, about 73% of In the pivotal trial, Soliris was given to pa- during its Q1 earnings call that Ultomiris NMOSD patients following an expedited tients who had prior immunosuppressive was well on its way to achieve the com- six-month priority review. (Also see “Keep- therapies and had multiple relapses over pany’s guidance of >70% switching of US ing Track: US FDA Closes Out First Half Of the previous one to two years, but the ap- PNH patients by the end of 2020. 2019 With CRL For Edsivo, But A Burst Of proved indication has no restrictions by Alexion has already filed Ultomiris in Supplemental Approvals” - Pink Sheet, 29 prior treatment, they noted in a 27 June the US for use in Soliris’s second indica- Jun, 2019.) research note. tion, atypical hemolytic uremic syndrome NMOSD is a rare, severe autoimmune “Despite the label, we don’t think (aHUS), and will further submit it for the disease that can cause progressive and Soliris will capture significant use in front expanded indication in the EU and Japan irreversible damage to the brain, optic line treatment given Rituxan’s favorable later this year. Positive Phase III data in this nerve and spinal cord, which may lead to cost-benefit profile (~70% disease con- setting were released in January. (Also see long-term disability. Complement activa- trol under Rituxan and ~$60K first year “Alexion Looks To Broaden Complement tion due to anti-AQP4 antibodies is one cost compared ~$700K first year cost for Inhibitor Market With Next-Generation Ul- of the primary underlying causes of the Soliris),” they said. “We expect most insur- tomiris” - Scrip, 29 Jan, 2019.) destruction in these patients, Alexion says. ance payers to require evidence of Rituxan Soliris meanwhile has been shoring up The expanded approval was based on failure before reimbursing for Soliris in this its sales with its new indications, particu- the results of the Phase III PREVENT trial disease but do expect relatively open ac- larly generalized myasthenia gravis (gMG), recently published in the New England cess to Soliris for relapsed patients in late a label it got in the US in late 2017. Journal of Medicine. In the 143-patient line treatment.” Jefferies analysts reckoned that Q1 study, “treatment with Soliris reduced the Analysts at Wedbush said in a 28 June Soliris sales for the gMG indication were number of NMOSD relapses by 94% over research note that their estimates as- roughly $150m. “Assuming steady new the 48-week course of the trial” compared sumed around 4,000 NMOSD address- gMG patient adds (~200/quarter), we es- with placebo, the FDA summarized. “Soliris able patients in the US, based on the timate Soliris sales in gMG could reach also reduced the need for hospitalizations anti-AQP4 status. They forecast FY19-FY22 ~$700m in FY19 (~17% of Soliris/Ultomiris and the need for treatment of acute attacks NMOSD revenue of $9m, $41m, $75m and sales),” they said in a Q1 earnings notes in with corticosteroids and plasma exchange.” $179m, respectively. “With additional ap- late April. The product is currently under review provals anticipated in other geographies for the same indication in the EU and Ja- (e.g. EU, Japan), our furthest out year esti- NMOSD MAKES FOUR pan; it has orphan drug status for NMOSD mate (FY26), projects NMOSD revenue will Now, Soliris can exploit its fourth indica- in all three markets. reach $1.3bn.” tion, NMOSD, in the US. The FDA has ap- Analysts at SVBLeerink commented that proved Soliris for use in adult NMOSD the latest indication given by the US agen- Published online 5 July 2019 Sanofi’s Libtayo Lands In EU With Skin Cancer Nod JO SHORTHOUSE [email protected]

egeneron Pharmaceuticals Inc. and adults with advanced cutaneous squa- on data from the pivotal EMPOWER-CSCC-1 Sanofi’s PD-1 inhibitor Libtayo (ce- mous cell carcinoma (CSCC) who cannot trial, which along with two advanced CSCC Rmiplimab) has been given the nod have surgery or radiation treatment. expansion cohorts from a Phase I trial, pro- by the European Commission, making it Already approved in the US since Sep- vide the largest prospective clinical data the first treatment available in Europe for tember 2018, the EU approval was based set to date to evaluate a systemic therapy in patients with advanced CSCC. Libtayo’s runway has been cleared for landing The conditional approval recognizes the extreme unmet need in advanced CSCC. As part of the conditional approv- al, Sanofi and Regeneron will add a new patient group to EMPOWER-CSCC-1 to further support the benefit-risk profile of Libtayo, and report the results to the EMA. The EMA will review any new information at least every year and update product la- belling as necessary. Libtayo’s current recommended dose is 350mg IV infusion every three weeks.

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Treatment may be continued until disease progression or unac- “Although there is significant uncertainty around the evidence for ceptable toxicity. cemiplimab, the committee noted that the overall response rates Although CSCC is the second most common form of skin cancer, reported in the trials are very promising,” NICE said in a statement. accounting for about 20% of all skin cancer cases, the therapy ap- John Stewart, NHS England’s director of specialized commis- provals in the US and EU are for patients who are not candidates sioning, said: “NHS England has worked closely with Sanofi and for curative surgery or radiation. Approximately 95% of CSCC pa- NICE to reach a deal to make this hugely promising innovative tients are effectively managed with surgery, greatly reducing the drug available, meaning NHS patients in England will be among number of treatable patients. the first in Europe to benefit.” “With no competition in this indication, Libtayo has shown a strong initial launch in the US, with $27m in sales in Q1 2019,” OTHER INDICATIONS said Michael Ramirez, analyst at Datamonior Healthcare. “[Leerink Libtayo is also in Phase III trials for cervical and non-small cell lung analyst Geoffrey] Porges has estimated global sales of $1.4bn in cancer, in Phase II trials for basal cell carcinoma, brain and prostate 2021, with $600m of that total coming from US sales,” he said. In cancer, and Phase I trials for hematologic cancer, melanoma, renal addition to the US and EU, Libtayo is also currently approved in cell cancer and solid tumors. Canada and Brazil. “While approvals for use in NSCLC and cervical cancer certainly Advanced CSCC includes both patients with locally advanced have the potential to drive growth for the drug, Libtayo will be disease, where the cancer cannot be cured by surgery and/or met with significant competition in these areas,” said Ramirez. radiation, and patients with metastatic disease. Patients with ad- Merck & Co. Inc.’s Keytruda (pembrolizumab) has been approved vanced CSCC have a life expectancy of approximately one year. for second-line use in cervical cancer for over a year and enjoys substantial physician familiarity in multiple indications. UK PRICING Four PD-1/PD-L1 inhibitors are currently approved for NSCLC. The UK’s The National Institute for Health and Care Excellence However, Ramirez told Scrip that if positive results were ob- (NICE) has recommended cemiplimab to be available within the tained for the three ongoing Phase III trials, particularly the trial Cancer Drugs Fund. comparing Libtayo combinations to Keytruda monotherapy in In the UK, it is estimated that around 560 people per year with first-line NSCLC patients with PD-L1 expression ≥ 50%, the drug locally advanced or metastatic cutaneous squamous cell carcino- could compete despite its late market entry. This trial is among ma in adults, where curative surgery or curative radiotherapy is the first head-to-head trials between PD-1/PD-L1 inhibitors. not appropriate, are eligible for treatment with cemiplimab. “Jorge Insuasty of Sanofi has previously disclosed that he be- The list price of cemiplimab is £4,650 per 350mg vial (1 treat- lieves Libtayo has the opportunity to be positioned third among ment cycle). The list price for one year of treatment with cemiplim- the PD-1/PD-L1 inhibitors in NSCLC, behind Keytruda and Op- ab is £80,877. divo,” Ramirez concluded. Published online 2 July 2019 CHMP Delivers More Good News For Sanofi’s Dupixent KEVIN GROGAN [email protected]

he opinions issued at the latest monthly meeting (24-27 skin with Dupixent compared with placebo (24% versus 2%). 37% June) of the European Medicines Agency’s drug evaluation of patients on drug achieved a clinically meaningful improvement T committee revealed more good news for Sanofi’s Dupix- in itch compared with 5% with placebo. ent, its Regeneron Pharmaceuticals Inc.-partnered therapy which Sanofi will be hoping that getting the expanded label for Dupix- is expected to comfortably pass the €1bn sales barrier this year. ent, which is currently approved in the EU for use in adults with The Committee for Medicinal Products for Human Use (CHMP) moderate-to-severe AD and for adults and adolescents as an add- has adopted a positive opinion for Dupixent (dupilumab) recom- on maintenance treatment for severe asthma with type 2 inflam- mending extending its approval to also include adolescents aged mation, will boost sales of what is becoming its flagship product. 12 to 17 years of age with moderate-to-severe atopic dermatitis First-quarter revenues from the drug were €329m (+186.9%), with (AD) who are candidates for systemic therapy. If approved, and the US making up €266m of that, driven by a successful asthma the European Commission’s formal thumbs-up should come in launch – it became commercially available for adolescent AD in the next few months, it would be the first biologic approved to mid-March in the US. treat these patients. Sanofi and Regeneron also have an ongoing Phase III trial in The expanded approval is based on data from the LIBERTY AD children with AD aged six to 11. They are also running a pediatric program, including a pivotal Phase III trial which showed that Du- AD study in children aged six months to five years old which is in pixent significantly improved skin lesions, reduced itching, and Phase II/III. helped clear the skin of adolescent patients. Specifically, at 16 In an investor note issued 1 July, analysts at Morgan Stan- weeks, the average improvement in the Eczema Area and Severity ley gave some insight into a discussion with Bill Sibold, head of Index (EASI) from baseline was 66% compared to 24% for placebo Sanofi’s Genzyme unit from an investor roadshow in Paris about and more than 10 times as many patients had clear or almost clear Dupixent. He stressed that the company was “at the beginning of

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building a broad presence across multiple nusitis is “a nice addition for Dupixent, but indications and across physician groups,” won’t move the needle,” noting that while according to the broker, but is “not overly CRSwNP is not a significant indication, “it concerned by emerging competition in does broaden Dupixent’s usage in differ- AD,” notably from oral JAK inhibitors. ent therapeutic areas and demonstrates Although there are no JAK inhibitors the product’s growing portfolio of indica- approved yet for AD patients, there are Although there are no tions.” He added that he expected insur- a number vying to be first to market, no- JAK inhibitors approved ance companies “to have a very high bar for tably Eli Lilly & Co.’s Olumiant (baricitinib) paying for maintenance treatment with a and Pfizer Inc.’s abrocitinib, which have yet for atopic dermatitis high-priced injectable medicine when low posted promising Phase III data, with Ab- priced generic intranasal steroids and one- bVie Inc.’s upadacitinib and Incyte Corp.’s patients, there are a time surgical options are widely available.” topical version of Jakafi (ruxolitinib) fur- number vying to be first Porges went on to say that “ultimately ther back. However there are lingering the sweet spot for Dupixent in this indica- safety concerns about JAK inhibitors and to market. tion is most likely to be for patients who the Morgan Stanley report cited Sibold have other allergic symptoms, such as as stressing Sanofi’s belief those fears and asthma or AD, in which case the sinusitis the clinical data seen so far for emerging improvement is likely to be viewed as fur- injectibles “do not suggest significant dif- ther justification” for using the drug. ferentiation to Dupixent which has set a While asthma and AD will continue to very high efficacy/safety bar and estab- drive the commercial prospects for Dupix- lished real-world experience (50,000 pa- (CRSwNP). The green light, granted on 26 ent, it is being studied for an additional four tients treated).” June, expands Dupixent’s reach to a new indications, namely eosinophilic esophagi- The AD expansion in Europe came a set of patients, making it the first biologic tis (Phase III), chronic obstructive pulmo- couple of days after Sanofi and Regeneron approved by the FDA to treat CRSwNP, al- nary disease (Phase II), grass allergy (Phase received the US Food and Drug Adminis- though there is some overlap in patients II) and peanut allergy (Phase II). Consensus tration’s approval for a third indication who also experience asthma. estimates for global Dupixent sales are for the IL-4/IL-13 blocker, chronic rhino- SVB Leerink analyst Geoffrey Porges $5.1bn by 2023 and $5.8bn by 2025. sinusitis patients with nasal polyposis wrote in a 26 June investor note that si- Published online 2 July 2019 LSKB Still Upbeat On Rivoceranib Despite ANGEL Failure In Late-Line Gastric Cancer

JUNG WON SHIN [email protected]

fter preliminary top line results showed that a Phase III study for Arivoceranib (also known as apa- tinib) in later line gastric cancer failed to meet its primary endpoint, US-based LSK BioPharma Inc. (LSKB) is planning to seek an alternative development path, but still believes it can gain the US FDA’s approval of the VEGFR-2 inhibitor. “Although the trial didn’t meet the overall survival endpoint, it doesn’t mean we be- lieve that the technology or rivoceranib has failed. It has already successfully been used for a number of years in China,” said Arlo McGinn, managing director of business and product development at LSKB, which is a subsidiary of South Korea’s HLB Co. Ltd. provide the data we need to file for the create for LSBK is that it delays filing for “We are disappointed that the study approval based on a single study at this the first market approval outside China,” missed the primary endpoint and didn’t time, but the biggest challenge this will he added.

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McGinn’s video clip was posted on bination treatment, and in colorectal can- ANGEL study and this will help us identify a the website of HLB after shares of HLB cer and hepatocellular carcinoma. path for filing an NDA in the third- or fourth- plunged in the wake of the announce- McGinn said the main impact from line gastric cancer indication,” he said. LSKB ment of the top line data from the ANGEL missing the primary endpoint is the like- also feels that the ANGEL data will be ex- study. LSKB intends to publish the full re- ly delay in a US NDA filing. “We need to tremely helpful and will inform the design port within the next few months. take a step back and work on a plan that of clinical studies in other indications such Rivoceranib is a vascular endothelial is most efficient way to get the required as the planned second-line gastric cancer growth factor receptor 2 (VEGFR2)-targeted data for filing in the gastric cancer as a use and for colorectal cancer as well. small molecule inhibitor under develop- third-, fourth-line indication.” ment for third-line treatment of advanced “One option for strategy would be to le- LIKELIHOOD OF APPROVAL or metastatic gastric cancer, in which it acts verage the positive data that we do see in LOWERED to inhibit angiogenesis, a critical process in the ANGEL study and conduct a confirma- Even so, Informa’s Biomedtracker said the cancer growth and proliferation. tory study. We believe it could be a smaller, news is “highly disappointing” for LSKB. Al- LSKB holds the global rights, excluding faster clinical study. We will be working though rivoceranib trended toward an OS China, and has partnered for develop- internally in the coming weeks to develop improvement and significantly improved ment and marketing in South Korea. The the whole plan for the possible confirma- PFS, missing the primary endpoint will likely molecule was approved in third-line gas- tory study,” he said. HLB said it expects an delay regulatory submission, it noted. LSKB tric cancer in China in 2014 through Jiang- additional one-year period will be required had hoped to file by late 2019, but without su Hengrui Medicine Co. Ltd. to conduct such an additional smaller trial. further data it is difficult to determine the It pointed to the fact that some other like full impact of the poor outcome in an area ADDITIONAL ANALYSES, STUDY Cyramza (ramucirumab) had been ap- of unmet need within gastric cancer. TO DETERMINE APPROVAL PATH proved after additional studies were con- Given LSKB’s signals that it would still LSKB has completed the unblinding and ducted after failing in a Phase III program. continue to discuss rivoceranib’s potential preliminary review of the top line data in this indication with regulatory agen- from ANGEL, which enrolled 460 advanced ONGOING FAITH IN MOLECULE cies, Biomedtracker said it is not suspend- or metastatic gastric cancer patients. The South Korean firm reassured investors ing the drug in this indication but lowered While the rivoceranib arm did achieve that it doesn’t expect to face any financ- the likelihood of approval by 5 percentage better median overall survival (OS) com- ing issues from the failure, as LSKB had points to 30% versus the average of 35%. pared with placebo, and a result com- already prepared funding of KRW48bn In its gastric cancer pipeline report pub- parable to other approved drugs in this ($41m) for clinical trials and HLB has also lished in December 2017, Datamonitor indication, the result against this primary secured more than KRW30bn in financing. Healthcare predicted that the uptake of endpoint was not statistically significant. A planned merger between HLB and LSKB the drug would likely be low due to the However, the drug did demonstrate a is expected to go ahead. relatively small eligible patient popula- highly significant improvement in median LSKB still believes rivoceranib is an ac- tion in the third-line setting. The buildup progression-free survival (PFS), a second- tive cancer drug because the vast body of toxicity may also preclude heavily pre- ary endpoint, and was also generally well of data it has acquired from Hengrui’s de- treated patients from further drug thera- tolerated, and safety results were consis- velopment in China indicates this is the py, and as a result, many patients who fail tent with prior studies. case. Because of the positive signals from multiple therapies are often treated with LSKB will conduct further analyses as the ANGEL study, McGinn said the issue best supportive care only, it noted. additional data become available, such of overall survival may actually be related Furthermore, rivoceranib will likely face as overall response rate (ORR) and time to to the changing way that gastric cancer is significant competition from established progression, will follow surviving patients, being treated. Even over the short period targeted therapies such as ramucirumab, and will keep an open dialog with regula- of time for the trial, the standards of care pembrolizumab and nivolumab. None- tory agencies to determine the appropri- for the disease have changed significantly. theless, the lack of effective options in ate path to approval for rivoceranib in the “We still believe the ANGEL study was later line settings continues to make this gastric cancer monotherapy indication. designed correctly, but considering the an area of limited competition and high The company also plans to continue on- changes in gastric cancer treatments, the unmet need, and the drug could find a going clinical development programs in ANGEL study didn’t fully provide the data role in patients who fail to respond to im- other indications including earlier lines of necessary to file for the approval. I believe munotherapies, Datamonitor said. therapy for gastric cancer as part of com- we will get a lot of good data out of the Published online 5 July 2019

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AstraZeneca Gets Imfinzi Boost From CASPIAN Lung Cancer Trial ELEANOR MALONE [email protected]

straZeneca PLC’s Phase III CASPIAN study of Imfinzi (dur- with the disappointing results from Opdivo in later lines of treat- valumab) in patients with first-line extensive-stage small- ment, suggesting “the benefit [of the PD-1/PD-L1 class] may be Acell lung cancer has met its primary endpoint. more pronounced when used as an upfront therapy.” They raised An interim analysis showed a significant and clinically mean- their estimated likelihood of approval for Imfinzi in the indication ingful positive overall survival benefit for patients treated with from 35% to 39%. Imfinzi in combination with standard-of-care etoposide and The Credit Suisse analysts cautioned against comparing Tecen- platinum-based chemotherapy options versus chemotherapy triq and Imfinzi in the extensive SCLC setting because of differ- alone. “We see this as a positive surprise for a study that has re- ences between CASPIAN and Roche’s IMpower133 study, notably ceived very little investor attention,” commented Credit Suisse the fact that patients in the CASPIAN control arm received more analysts in a 27 June note. They believe the checkpoint inhibi- intensive therapy and IMpower133 included relapsed less-ad- tor could achieve peak annual sales of $500m in this indication vanced stage patients, unlike CASPIAN. should it be approved. The trial is also studying Imfinzi in combination with AstraZen- INTEREST REVITALIZED IN INFIMZI STUDIES eca’s CTLA-4 inhibitor tremelimumab and chemotherapy but re- They view the CASPIAN results as having a broader benefit be- sults for this arm are not yet available. yond its specific setting, “revitalising interest in the long tail of Full data are expected to be presented at a scientific meeting IMFINZI Phase III studies.” AstraZeneca’s checkpoint inhibitor had later in 2019, such as World Conference on Lung Cancer or the suffered a blow when it failed in the key MYSTIC study in first-line European Society for Medical Oncology (ESMO) annual congress, Stage IV metastatic NSCLC, even though it succeeded in gaining both of which are being held in Barcelona in September. approval for Stage III unresectable lung cancer on the basis of its Small-cell lung cancer (SCLC) accounts for only about 15% of PACIFIC study. (Also see “Mystic Miss Not Make Or Break For Im- all lung cancer deaths but is an area of significant unmet need as finzi” - Scrip, 16 Nov, 2018.) the prognosis is poor: only 6% of all SCLC patients will be alive Credit Suisse points out that the company has “a rich catalyst five years after diagnosis. About two thirds of SCLC patients are stream of other Phase III studies” with results due over the next 18 diagnosed with extensive-stage disease. months, both as a monotherapy and in combination with treme- Imfinzi was approved by the US Food and Drug Administra- limumab and/or chemotherapy, many of which are focused on tion for previously treated metastatic bladder cancer in May 2017 first-line therapy. and for unresectable Stage III non-small cell lung cancer that has Among imminent Imfinzi mono- and combination therapy not progressed following chemoradiation in May 2018. It was ap- Phase III trial read-outs based on which - if positive ­- AstraZeneca proved for the same NSCLC indication in Europe in September anticipates filing for approval extensions in the US, EU and Japan 2018 and is also approved in several other countries including Ja- by the end of 2019 are: pan. Sales of the product amounted to $633m in 2018 and $295m ● KESTREL, studying Imfinzi and tremelimumab in first-line in the first quarter of 2019. head and neck squamous cell carcinoma, for which Credit Suisse predicts peak annual sales of $1bn and a 25% prob- PLAYING CATCH-UP ability of success; In advanced SCLC it is playing catch-up to Roche’s rival PD-L1 in- ● DANUBE, combining Imfinzi and tremelimumab for first- hibitor Tecentriq (atezolizumab), which gained US FDA approval line bladder cancer; Credit Suisse forecasts a 50% probabil- for first-line treatment along with etoposide and carboplatin ity of success and $400m peak sales; in March 2019. Merck & Co. Inc.’s Keytruda (pembrolizumab), a ● NEPTUNE, also combining Imfinzi and tremelimumab, this PD-1 inhibitor, is also being studied in this indication, in the Key- time in first-line non-small cell lung cancer, with a 10% note-604 study, due to read out in December 2019. probability of success according to Credit Suisse and the But Bristol-Myers Squibb Co.’s Phase III CheckMate-451 trial of potential for $1bn in peak annual sales; and PD-1 inhibitor Opdivo (nivolumab) in combination with CTLA-4 ● POSEIDON, combining Imfinzi and chemotherapy with or inhibitor Yervoy (ipilimumab) failed to meet its primary endpoint without tremelimumab in first-line non-small cell lung can- of overall survival in November 2018. (Also see “BMS SCLC Chances cer, which Credit Suisse assigns a 10% probability of suc- Dive After Opdivo, Yervoy Combo Flunks Checkmate-451” - Scrip, 27 cess and up to $500m in annual sales. Nov, 2018.) However, the FDA had already granted Opdivo accel- Imfinzi is also being studied following concurrent chemo- erated approval in third-line or later metastatic SCLC settings in radiation therapy in limited-stage SCLC in the Phase III ADRI- August 2018. ATIC trial. Analysts at Biomedtracker commented that the positive results shown by Tecentriq and Imfinzi as first-line therapy contrasted Published online 2 July 2019

scrip.pharmaintelligence.informa.com July 12, 2019 | Scrip | 15 RESEARCH & DEVELOPMENT

Dainippon’s Lead Boston Asset Hits Wall In Pancreatic Cancer IAN HAYDOCK [email protected]

umitomo Dainippon Pharma Co. ing reached – and determined “futility”, The company’s share price dipped im- Ltd.’s (SDP) novel oral investiga- which usually means that statistical signif- mediately after the announcement but Stional cancer agent napabucasin icance and the primary endpoint were un- has since recovered ground, perhaps giv- has failed in a Phase III study in one its likely to be met. Neither SDP or Boston are en that napabucasin remains in a Phase III main lead indications, after the futility of providing any further details at this stage. US/Japan trial for its potentially larger in- continuing the trial was determined in The open-label trial was assessing napa- dication of colorectal cancer, and is in ear- an interim analysis. bucasin in combination with weekly nab- lier clinical development for various other The development marks a major set- paclitaxel and gemcitabine, versus the indications, all as part of combination back for the Japanese company in its latter two drugs alone, for the first-line therapy. These include hepatocellular car- effort to build out a cancer pipeline treatment of patients with metastatic pan- cinoma (HCC), gastrointestinal cancer and and business against the background creatic adenocarcinoma. solid tumors (all in Phase I/II in the US). of the looming loss of US exclusivity SDP said it had “accepted the recom- The colorectal study is looking at com- in early 2023 for its current top seller mendation and has decided to discontin- bination use with Folfiri (folinic acid, flu- globally, the atypical antipsychotic ue the study,” and noted that no new safe- orouracil and irinotecan) with or with- Latuda (lurasidone). ty concerns were raised by the board. The out Avastin (bevacizumab), an approach Sales of this product in North America, company added it is “currently evaluating adopted after an earlier monotherapy its main market, were $1.66bn (+3%) in the impact that this matter will have on its trial was stopped on monitoring board the fiscal year ended 31 March, and SDP consolidated financial results” for the cur- advice after it stumbled on efficacy at an is bidding to become a “global specialized rent fiscal year ending next 31 March. interim analysis. player”, helped by planned M&A activity, SDP noted recently that an interim in its defined core area of psychiatry and analysis by the trial board had allowed the neurology, as well as oncology. study to continue. The failure is also a strategic miss for Napabucasin (BBI608) acts an an oral SDP’s past acquisition strategy given that cancer stemness inhibitor and is bioacti- napabucasin was originated by Boston vated by the cancer cell enzyme NQO1, Biomedical, acquired for $2.63bn in 2012 The failure is also a which generates reactive oxygen species in a bid to strengthen the Japanese firm’s to inhibit cancer stemness and tumor oncology pipeline. strategic miss for progression-related pathways including SDP had until recently been anticipating STAT3, resulting in cancer cell death. a US launch in pancreatic cancer in fiscal SDP’s past acquisition In the colorectal indication, Datamoni- 2021, saying it expected napabucasin “to tor Healthcare is forecasting global sales become a blockbuster at peak revenue” in strategy given that of $72.7m in 2025, constrained by expect- total across all indications, while stopping napabucasin was ed initial approval only in the second-line short of providing detailed forecasts. or later setting. Part of its US business development originated by Boston plans for the product included building MORE DEALS TO FILL PIPELINE? a specialist sales and marketing organiza- Biomedical, acquired Pancreatic cancer is a particularly tough tion, and it looks likely that these will be in 2012 to strengthen oncology target with a low disease sur- affected by the setback. vival rate, although promising results for the Japanese firm’s AstraZeneca PLC/Merck & Co. Inc.’s PARP FUTILITY FINDING inhibitor Lynparza (olaparib) in metastatic The company’s wholly owned US subsid- oncology pipeline. patients with germline BRCA mutations iary Boston Biomedical received a recom- were reported at ASCO this year. (Also mendation on 1 July from the indepen- see “AZ/Merck & Co’s Lynparza POLO Study dent data and safety monitoring board ‘Practice Changing’ For Pancreatic Cancer for the CanStem111P study with napabu- Subgroup “ - Scrip, 3 Jun, 2019.) casin to discontinue the Phase III trial in For SDP, there are no other late-stage pancreatic cancer. projects in its oncology pipeline, while the This came after an interim analysis – company’s core neurology and psychiatry conducted upon 50% of total events be- TURN TO PAGE 18

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CONTINUED FROM PAGE 16 cer stemness kinase inhibitor in US Phase It is not yet clear whether napabu- pipeline is dominated by line extensions. I/II trials for HCC and solid tumors (the lat- casin’s failure in pancreatic cancer will One bright spot is imeglimin (licensed ter including as monotherapy). affect SDP’s strategic mid-term plan to from Poxel SA), an antidiabetic for which SDP’s share price has already come un- spend JPY300-600bn ($2.68-5.36bn) on positive results have been reported this der sustained pressure this year, falling M&A over the next five years, in terms of year. (Also see “Positive Phase III Data Set by around 40% and hit particularly hard revenue generation to support this, or a Stage For Japan Imeglimin Filing” - Scrip, in late January after Japanese bioventure harder focus on new deals to fill the on- 10 Apr, 2019.) partner SanBio Co. Ltd. unveiled disap- cology pipeline. The other main ex-Boston asset is am- pointing results for a novel cell therapy in casertib (BBI503), a first-in-class oral can- ischemic stroke. Published online 4 July 2019 Sarepta Shares Bounce As Pfizer’s DMD Gene Therapy Sparks Safety Concerns

JO SHORTHOUSE [email protected]

fizer Inc. has allowed a peek into its Phase Ib clinical data on 17%. It is in Phase II development with its micro-dystrophin gene PF-06939926, its investigational gene therapy for Duchenne therapy program for AAVrh74.MHCK7.micro-Dystrophin, other- Pmuscular dystrophy (DMD), and while it does show some wise known as SRP-9001. signs of efficacy, safety is a concern. “We believe Sarepta remains in the driver’s seat with its AAVrh74 The primary endpoint of the ongoing Phase Ib study is to assess micro-dystrophin gene therapy, with its 24-patient placebo-con- the safety and tolerability of the gene therapy, and one of the six trolled study almost fully enrolled (23 patients now enrolled), and boys participating had a severe immune reaction to the therapy; its confirmatory study (with commercial supply) targeted to begin even so Pfizer is continuing its plans for a Phase III trial. by year end,” said BTIG analysts in a 28 June note. The patient in question developed a rapid antibody response with activation of the complement system associated with acute kidney injury, hemolysis and reduced platelet count. This partici- pant was promptly admitted to a pediatric intensive care unit and received intermittent hemodialysis, as well as two intravenous doses of Alexion Pharmaceuticals Inc.’s complement inhibitor Soliris (eculizimab). The boy spent 11 days in hospital and his renal function returned to normal within 15 days. No other participants will be dosed until the specific additional safety monitoring, which has been endorsed by the external data monitoring committee, has obtained all appropriate approvals at the clinical research sites. Other side effects seen in the trial included nausea, vomiting and fever in four out of the six patients. To complete the Phase Ib study Pfizer aims to enrol approxi- Sarepta bounces on Pfizer data but will it win the game? mately 12 boys with DMD who are ambulatory and aged from five to 12. To date, six study participants ranging in age from six to 12 years have received the one-time intravenous dose of “We believe Sarepta could be the first company to enter the US PF-06939926 at either 1E14 vector genomes/kilogram (vg/kg) market with its gene therapy for treating DMD in 2021. We esti- or 3E14 vg/kg. mate Sarepta to generate annual sales of around $2bn from its gene therapy segment by 2024.” COMPETITORS PTC’s non-gene therapies Emflaza (deflazacort), and Sarepta’s Pfizer is not the only party to have had safety wobbles with its Exondy 51 (eteplirsen) are the only products approved in the US, DMD gene therapy. In May, Solid Biosciences Inc. announced that while PTC Therapeutics Inc.’s Translarna (ataluren) is the only ap- a patient had experienced a serious adverse event while in a trial proved therapy in the EU. for its lead DMD product SGT-001, and had been reported to the FDA. (Also see “Solid Biosciences’ DMD Gene Therapy Undermined EFFICACY DATA By Safety Wobbles “ - Scrip, 15 May, 2019.) Secondary endpoints of the clinical study include measurement And while the news of Pfizer’s so-so results were being digested of expression of mini-dystrophin distribution within muscle fibers by the markets, the shares in Sarepta Therapeutics Inc. soared by by immunofluorescence and concentration by liquid chromatog-

18 | Scrip | July 12, 2019 © Informa UK Ltd 2019 RESEARCH & DEVELOPMENT/COMPANIES

raphy mass spectrometry (LCMS). There was efficacy in muscle ministration, concomitant medications, participant selection and fiber distribution and mini-dystrophin concentration demonstrat- safety monitoring. ed. Preliminary results from open muscle biopsies of the biceps PF-06939926 is a rhAAV vector that delivers a shortened, but taken two months after dosing show detectable mini-dystrophin functional copy of the dystrophin gene, called mini-dystrophin. immunofluorescence signals with a mean of 38% and 69% posi- Pfizer on-boarded the therapy as part of a 2016 deal with Bamboo tive fibers taken from participants who received PF-06939926 at Therapeutics. (Also see “Pfizer Advances Duchenne Drug As It Pri- 1E14 vg/kg and 3E14 vg/kg, respectively. oritizes Gene Therapy” - Scrip, 12 Apr, 2018.) Biomedtracker analysts said: “Initial data from multiple sites Pfizer will present these data at the 25th Annual Parent Project on muscle fiber distribution, minidystrophin concentration, Muscular Dystrophy (PPMD) Connect Conference in Orlando, FL. and signs of potential clinical benefit are encouraging but war- rant further investigation, and the safety profile of the investi- GOTTLIEB JOINS BOARD gational therapy is acceptable for continued development. In other news, Pfizer announced 27 June that the ex-Food and “As the safety concerns may well be manageable, we are in- Drug Administration commissioner Scott Gottlieb would be join- creasing our likelihood of approval, but with the small number ing its board, effective immediately. He was also appointed to the of patients treated, limiting that to 1%,” said Biomedtracker. “The regulatory and compliance committee and the science and tech- safety issues could place the drug at a competitive disadvantage, nology committee of Pfizer’s Board. though, depending on how relative efficacy turns out and wheth- Prior to serving as commissioner, Gottlieb held several roles er similar issues turn up with competitors.” in the public and private sectors, including serving as the Pfizer is continuing to collect data from this ongoing open-label FDA’s deputy commissioner for medical and scientific affairs study in boys with DMD, and is also in the planning stages for a and as a senior adviser to the administrator of the centers global, randomized, placebo-controlled Phase III study, expected for Medicare and Medicaid services, where he helped imple- to begin in the first half of 2020 with commercial-scale manufac- ment the Medicare drug benefit, advance policies to improve turing processes using multiple 2000-liter bioreactors. healthcare quality and promote the effective use of new medi- The study will use the lessons from the ongoing Phase Ib study cal technologies. to make decisions about the optimal dose, assay, method of ad- Published online 2 July 2019 Versant’s Century Aims For Off-The-Shelf Cancer Cell Therapies

JOSEPH HAAS [email protected]

entury Therapeutics debuted on 1 Century CEO Lalo Flores noted the reached the same conclusion that I want- July with $250m in backing for its previous history between Versant and ed to be in cell therapy and with a com- Cstrategy to develop off-the-shelf Bayer, which together launched Blu- pany that can distinguish itself from all of cell therapies for cancer using induced eRock Therapeutics with $225m in series the other players,” he said. pluripotent stem cells (iPSCs), an approach A funding in late 2015 to develop stem The versatility if iPSCs should prove it says will give it technological advan- cell therapies for cardiovascular and ideal for cell therapy, the exec explained, tages over much of the cell therapy field. neurodegenerative disease. Flores, who because of their “self-renewing” capac- Bayer AG’s venture capital arm – provided was hired to helm the new company last ity and the fact that they can go through $215m in funding, with Versant Ventures year, has his own history with Versant. multiple rounds of cellular engineering. and technology partner Fujifilm Cellular The VC firm was among the investors This process can yield master cell banks of Dynamics Inc. kicking in the remainder. in hepatitis B-focused biotech Novira modified cells that then can be expanded Versant founded the company with Therapeutics Inc. where Flores was the and differentiated into immune effector seed funding in 2018, followed shortly CEO when it was bought out by Johnson cells – such as T-cells or natural killer (NK) thereafter by a deal with Fujifilm that & Johnson in 2015. cells – that can become allogeneic thera- gives Century exclusive access to im- Versant was pondering the game- peutics, he asserted. mune effector cell-differentiation pro- changing potential of cell therapy in can- “The main power of these cells is that tocols and intellectual property that will cer and “quickly came to the conclusion they offer unlimited replication capac- enable it to manufacture its cell thera- that to make a difference, we need to de- ity, they can propagate indefinitely in cell pies at commercial scale. Specifics of velop off-the-shelf products,” Flores told culture,” Flores said. “The cells themselves the partnership with Fujifilm were not Scrip. The venture firm also determined don’t have drug-like utility; their utility is detailed, but the Japanese firm will be that iPSCs were an ideal platform for such that we can take advantage of this indefi- the primary manufacturer of Century’s products, he added. “They recruited me to nite replication capacity ex vivo to incor- therapeutic products. join as CEO in the summer of 2018; I had porate multiple different types of genetics

scrip.pharmaintelligence.informa.com July 12, 2019 | Scrip | 19 COMPANIES

or engineering that the ultimate effector cells of interest will have in their genome.” “The main power of these cells is that they offer Other cell therapy companies, working from donor-derived primary cells, get one unlimited replication capacity, they can propagate shot at engineering the cells to have the indefinitely in cell culture.” - Lalo Flores desired characteristics, he noted, because they need to work at a high efficiency to produce enough cells to have a therapeu- tic end product. With rejection being a gene-editing processes its scientists have immune cell products that emerge from primary issue with using cell therapies in developed, Flores said. The company still Century’s pipeline. He did not elaborate patients with solid tumors, Flores and his needs to determine which of those meth- further on those rights. team believe the multiple rounds of engi- ods will work best, but as of now, it won’t Bayer previously entered the gene- neering they’ll be able to do will allow the need to license CRISPR-Cas9 access to do editing and cellular therapy space in production of cells that won’t be rejected its gene-editing. 2015 via a joint venture with CRISPR by a patient’s immune system. “Because we’re working with iPSCs, we Therapeutics AG. That resulted in the “That why CAR-Ts haven’t worked very can use methods that are not possible for inception of Casebia Therapeutics, fo- well in solid tumors, because the field be- cell products that rely on primary cells,” cused on hemophilia, blindness and lieves that all these other molecules that the exec explained, “because they don’t congenital heart disease. (Also see “Bay- tumors secrete inhibit the activity of these replicate effectively. So, we have access to er And CRISPR Form Cutting Edge Gene cells,” he added. other gene-editing approaches that work Editing JV” - Scrip, 22 Dec, 2015.) Flores declined to offer timelines for quite well with iPSCs and that’s why, for At an Alliance for Regenerative Medi- Century’s work or be specific about which the moment, we’re not licensing CRISPR- cine conference last fall, Casebia report- types of cancer it wants to target. How- Cas9.” ed that it will be selecting candidates ever, the firm does plan to work first to Despite Bayer’s significant invest- for advancement to clinical develop- obtain proof-of-concept in hematologic ment in Century, Flores stressed that his ment this year, with a goal of filing an cancers, where cell therapies have a bet- firm is independent and free to develop investigational new drug (IND) applica- ter track record of success. The company wholly owned candidates and partner tion in 2020. (Also see “Early-Stage Cell hopes that will de-risk its approach before with whomever it can attract. He ex- And Gene Therapy Progress: Updates moving on to solid tumors. pects that Century will collaborate with From Casebia, BlueRock, Athersys, Cy- academic institutions, other biotechs nata” - Scrip, 11 Oct, 2018.) At the same APPROACH INCLUDES and possibly big pharma companies meeting, Bayer- and Versant-backed PROPRIETARY GENE-EDITING “that can complement our technology BlueRock highlighted its preclinical TECHNOLOGY and add value beyond what we have stem cell program to reverse motor def- In addition to Fujifilm’s iPSC capabilities, with our existing platform.” icits in Parkinson’s disease. Century will employ some proprietary Flores conceded, however, that Bayer technology of its own, including multiple does hold some limited rights to innate Published online 2 July 2019 Korea Eases Stock Rules To Help Bioventures Stay Listed, Focus On R&D

JUNG WON SHIN [email protected]

outh Korea has revised initial public panies that don’t meet standard profit- nesses such as beauty or functional health offering and stock listing manage- ability requirements to list if they met foods, rather than their core new drug de- Sment rules to lower the barriers for technology parameters, or allow compa- velopment activities, in order to raise sales. innovative companies, including bioven- nies with strong growth potential to float Under the new rules unveiled by the tures, seeking to go public. The changes upon a recommendation from IPO lead Financial Services Commission (FSC), are designed to enable such firms to re- managers, must meet an annual KRW3bn companies won’t be placed under the main listed and focus on R&D and con- ($2.6m) revenue requirement five years exchange’s supervision even if they don’t tinued growth without having to worry after listing. If they don’t, their stocks will meet the annual KRW3bn revenue re- about meeting revenue requirements. be placed under the supervision of the ex- quirement, if their combined sales in the At present, biotech firms which de- change and face possible delisting. last three years exceed KRW9bn. buted on the Kosdaq market under the To meet the requirement, companies In addition, companies which are offi- special listing systems, which allow com- have sometimes engaged in other busi- cially designated as “innovative pharmas”

20 | Scrip | July 12, 2019 © Informa UK Ltd 2019 COMPANIES/INTERVIEW

by the Ministry of Health and Welfare, or In addition, the country will now allow going support for the broad bio-health sec- companies that are performing well in the scale-up companies as well as foreign tor, will help many bioventures currently stock market with a daily market capital- companies to be listed on Kosdaq using traded on Kosdaq to remain listed without ization above KRW400bn, will be exempt the listing system for special technology having to worry about raising revenues. from the revenue requirements. entities, which at present only permits lo- According to local media, 19 bioventures To evaluate bioventures’ business con- cal small- and medium-sized companies. that debuted on Kosdaq under the special tinuity, the exchange will conduct more Scale-up refers to non-small or medium- technology listing system reported sales detailed reviews that reflect the charac- sized firms whose average sales in the past of less than KRW3bn in 2018, although it teristics of the biotech industry. These will two fiscal years rose by more than 20%. hasn’t yet been five years since they floated include whether firms possess proprietary Foreign companies listed under the on the market. Companies such as Helix- technologies, experience in licensing-out special technology system will be subject mith (formerly known as ViroMed Co. Ltd.), deals, multiple pipeline assets and clini- to external audit rules, and will need to re- CrystalGenomics Inc., Genexine Inc., Alteo- cal stage projects, experience or plans ceive an A rating or above in technology gen Inc. and ABL Bio Corp. are “innovative in co-research or co-development with from multiple recognized rating agencies. pharmas” designated by the health ministry partners, as well as the past research per- The latest rule changes, which are in line and whose market capitalization exceeds formance of their core research workforce. with the South Korean government’s on- KRW400bn. Published online 1 July 2019 UK’s O’Neill ‘Frustrated’ By G20’s ‘Paltry’ AMR Message STEN STOVALL [email protected]

he man who led the UK’s high-pro- O’Neill told Scrip in an exclusive in- The O’Neill Review On Antimicrobial file, government-backed review terview conducted after the Japan G20 Resistance, launched in 2014 under the T on antimicrobial resistance, Lord summit that the lack of concrete ac- sponsorship of former Conservative (Jim) O’Neill, said the lack of AMR prog- tion or suggestions regarding AMR in Party Prime Minister David Cameron, ress at last week’s G20 summit has left the concluding communique “seems to was integral in getting AMR discussed him feeling “annoyed and frustrated” and leave us dead in the water at the global at the Chinese hosted G20 in 2016, and that countries that are truly committed policy level.” which led to it being on the German- hosted G20 meeting agenda in 2017 and the subsequent establishment of a Global AMR R&D Hub aimed at promot- ing research into combating antimicro- bial resistance. “But the statement that came from the Osaka declaration this weekend regard- ing AMR is a bland single paragraph, the wording of which makes clear that none of the G20 countries want to commit to of- fering financial incentives to advance this effort,” O’Neill told Scrip. “I’m nonplussed and frustrated by their declaration because it doesn’t take us any further than where we were two years.” He continued, saying the situation to- day “leaves a crucial gap because no phar- to tackling the health threat should now “I’m nonplussed and maceutical company wants to treat the band together to push the issue forward. frustrated by their search for new antibiotics as an unprofit- Leaders from G20 countries gathered able – or at best a low-profit business.” in Osaka, Japan, from 28-29 June during declaration because He voiced particular disappointment which they discussed economic and geo- with the declaration sentence that said: political issues and the climate crisis. But it doesn’t take us any “We call on interested G20 members and they gave little – if any – attention to com- Global AMR R&D Hub to analyze push and bating the rising threat of antibiotic resis- further than where we pull mechanisms to identify best models tance and the related need to find viable were two years.” – for AMR R&D and to report back to rele- market mechanisms to promote creation vant G20 Ministers.” of new antibiotics. Jim O’Neill TURN TO PAGE 23

scrip.pharmaintelligence.informa.com July 12, 2019 | Scrip | 21 Pipeline Watch - 28 June - 4 July, 2019 Phase II

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Change Lead LOA Event Stage Drug Name Indication Comments To LOA Company/Partner (%) (%) Phase II Spinraza Spinal Muscular Atrophy; Pre- NURTURE; Motor Updated Biogen/Ionis 0 100 (nusinersen) Symptomatic Infants Milestones Achieved Results Phase II TG Therapeutics, RMS-201; Well- Updated ublituximab Multiple Sclerosis 0 52 Inc. Tolerated Long-Term Results Phase II Top- Duchenne Muscular FibroGen, Inc. pamrevlumab Positive Results 0 24 Line Results Dystrophy, Non-Ambulatory Phase II Trial Oral PTH (1- In Postmenopausal Entera Bio, Ltd. Osteoporosis 0 0 Initiation 34) Women Phase II Trial Trigeminal Neuralgia, BHV3000-202; In Biohaven Pharma rimegepant 0 94 Initiation Treatment-Refractory Refractory Patients PIPELINE WATCH Phase II Trial VLA15, VLA15-202; Second Of Valneva SE Lyme Disease 0 27 Initiation vaccine Two Studies Phase Ib/II Calithera Colorectal, Non-Small Cell w/palbociclib; A Scrip’s weekly Pipeline Watch tabulatestelaglenastat the most recently reported 0 10 late-stageTrial Initiation clinicalBiosciences, trial and Inc. regulatory developmentsLung Cancers from the more Glutaminase InhibitorClick here for the entire pipeline Phase I/II Trial Vedanta VE416 (live vs. PNOIT; a with added commentary: than 10,000 drug candidates currently under activeFood researchAllergies worldwide. 24 24 Initiation Biosciences bacteria) microbiome Approachhttp://bit.ly/2mx4jY3 Phase III PIPELINE WATCH, 28 JUNE – 4 JULY 2019 Search

Change Event LOA Lead Company/Partner Drug Name Indication Comments To LOA Stage (%) (%) Phase III Cardiac And ODYSSEY OUTCOMES; The Praluent Published Regeneron/Sano� Metabolic Lancet Diabetes & 0 100 (aliracumab) Results Outcomes Endocrinology, 1 July, 2019 Phase IIIb Episodic Aimovig LIBERTY; Sustained Updated Novartis/Amgen Migraine, 0 100 (erenumab) E�cacy Results Refractory Phase III Episodic Aimovig Updated Novartis/Amgen Migraine, STRIVE; Durable Responses 0 100 (erenumab) Results Refractory Phase IIb Multiple Updated Merck KGaA evobrutinib Sclerosis, Reduces Disease Activity 0 17 Results Relapsing hAATR Phase II/III Tegsedi Amyloidosis NEURO-TTR (Ext.); Durable Updated Akcea Therapeutics, Inc. 0 100 (inotersen) With Safety, E�cacy Results Polyneuropathy Phase III Persistent Revatio Neonates; Missed E�cacy Top-Line P�zer Inc. Pulmonary 0 100 (sildena�l) IV Endpoint Results Hypertension Phase III Xo�uza (baloxavir In�uenza, In Top-Line Roche/Shionogi MINISTONE-2; Positive 0 100 marboxil) Children Results Results Phase III Lupuzor Systemic Lupus Extension Study; Safety Top-Line ImmuPharma PLC 0 51 (rigerimod) Erythematosus Endpoint Met Results Phase III Hepatocellular Trial Hengrui Medicine/Incyte camrelizumab A PD-1 Mab, w/rivoceranib 0 35 Cancer Initiation Phase III Rheumatoid Trial GlaxoSmithKline/MorphoSys otilimab contRAst-1,2,3,X; Head-To- 39 56 Arthritis Initiation Head Studies Phase III donaperminogene Peripheral Trial Beijing Northland Biotech seltoplasmid, NL003; In 20 Centers 0 42 Arterial Disease Initiation gene therapy Phase III S pneumoniae PNEU-PLAN; Catch-Up Trial Merck & Co., Inc. V114, vaccine 0 66 Infections Regimens Initiation Phase II/III Study 305; In Mild Alzheimer's Trial vTv Therapeutics Inc azeliragon Alzheimer/Type 2 0 52 Disease Initiation Diabetes) Source: Biomedtracker | Informa, 2019

22Approvals | Scrip | July 12, 2019 © Informa UK Ltd 2019 Search

Lead Event Type Drug Name Indication Market Comments Company/Partner Approval, Karyopharm With Xpovio (selinexor) Multiple Myeloma, Refractory US Accelerated Therapeutics Dexamethasone ViiV Healthcare Dovato Once-Daily Approval HIV/AIDS EU (GSK) (dolutegravir/lamivudine) Single Pill Cutaneous Squamous Cell Conditional Approval Sano�/Regeneron Libtayo (cemiplimab) EU Carcinoma, Advanced Approval

Approval Retrophin, Inc. Thiola EC (tiopronin) Cystinuria US Enteric Coated Zirabev (bevacizumab- Colorectal, Glioblastoma, Renal Cell, Approval P�zer Inc US Biosimilar bvzr) Cervical Cancers, NSCLC

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

CONTINUED FROM PAGE 21 countries that opposed wanting AMR the market failure in catalysing R&D “That sentence is, for me, almost annoy- as an agenda focus in the first place aimed at developing new antibiotics,” ing because in conducting our [O’Neill four years ago – particularly India, Bra- he stressed. AMR] review we probably devoted around zil and Russia – were trying to actually 50% of our time analyzing such incentives, stop it from being in the Osaka commu- SAYS ‘LIKE-MINDED’ AMR and since our review the small grouping nique at all.” COLLABORATION NEEDED of people who actually focus on these is- “They [India, Brazil and Russia] had tried “We need a like-minded group of coun- sues have embraced our recommenda- to stop its inclusion in the 2017 G20 com- tries to take the initiative themselves to tions, so I’m not sure what further analysis munique as well. But back then the UK had develop viable market models.” is going to do.” the support of the Obama Administration. He noted that the UK under health O’Neill – ex-chair of Goldman Sachs As- From what I understand, the US in Osaka minister Matt Hancock, in proposals an- set Management and a former UK treasury didn’t want to offer any real comments or nounced in January, had introduced a official – said that had the G20 been more views [on AMR].” new formula for paying drug companies detailed on how to address AMR collec- He concluded: “This seems to leave us for NHS drugs aimed to encourage them tively, “then they would have needed to dead in the water at the G-20 level.” to invest in antibiotic research and de- come up with the money to do it, some- Still, going forward, he said there re- velopment, by linking payment to the thing that the leaders were still not pre- mained real hope and potential for prog- potential “health value” of the drug. pared to do. The G20 result is thus a diplo- ress on addressing the global AMR threat. “I hope that pilot by Matt Hancock test- matic nothing, really.” “It’s not all completely gloom and ing a version of market entry reward con- He added that “this lack of movement is doom; there is some progress taking tinues [after the selection of a new Con- scary, because the market failure problem place in some countries, noticeably in servative Party leader and hence prime is getting bigger.” the UK and the US, where we see a re- minister occurs], because it could prove duction in the use of antibiotics in ag- to be the basis for the UK to cooperate COMPLICATED GEOPOLITICS riculture, largely because consumers with like-minded countries, such as the O’Neill said the G20 Osaka declaration on have started to tell food distributors Scandinavian countries, as a way to dem- AMR reflected the current, complicated and wholesalers that they don’t want onstrate ways of developing novel market geopolitical situation. antibiotics-fed meat. And there are oth- mechanisms to address problems posed “The power of the UK voice has dis- er areas where there is some progress, by AMR,” O’Neill said. appeared. And crucially, some of the too,” he said. “The key is to deal with Published online 2 July 2019 Company Move

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From Effective Executive To Company New Role Previous Role Company Date BioCryst Senior Vice President, Business Megan PTC Pharmaceuticals Chief Business O�cer Operations and Program 1-Jul-19 Sniecinski Therapeutics Inc Management Cognito Head, Experimental and Mihaly Hajos Chief Scienti�c O�cer Biogen 26-Jun-19 Therapeutics Inc Translational Neurophysiology Shin Jung- LEO Pharma Chief Executive O�cer Roche Korea Head, Oncology 18-Jun-19 Beom Korea Agile Chief Medical O�cer and Senior Elizabeth ObsEva SA Chief Medical O�cer Therapeutics Vice President, Clinical 15-Jul-19 Garner Inc Development David A. ONL Chief Executive O�cer and Armune Chief Executive O�cer 18-Jun-19 Esposito Therapeutics Director BioScience Inc Jack V. Squarex LLC Chief Executive O�cer Mitotherapeutix Director 1-Jul-19 Talley Zelluna Jens-Peter Lead, Oncology-Western Europe and Immunotherapy Chief Medical O�cer AbbVie 25-Jun-19 Marschner Canada AS Suketu Zimmer Biomet Chief Financial O�cer and Bristol-Myers Senior Vice President, Global (Suky) 1-Jul-19 Click here for all appointments:Holdings Inchttps://bit.ly/2oHWRYnExecutive Vice President Squibb Financial Operations Source: Medtrack | Informa, 2019 Upadhyay scrip.pharmaintelligence.informa.comPromotion July 12, 2019 | Scrip | 23

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Effective Executive To Company New Role Previous Role Date Ping W. Dyadic Chief Financial O�cer Chief Accounting O�cer 27-Jun-19 Rawson International Inc Teri Immunomic Senior Vice President, Research and Chief Scienti�c O�cer 20-Jun-19 Heiland Therapeutics Inc Development Sabina IRRAS AB Chief Financial O�cer Vice President, Finance 24-Jun-19 Berlin Paratek Adam President and Chief Commercial Pharmaceuticals Chief Commercial O�cer 25-Jun-19 Woodrow O�cer Inc Paratek President, Chief Operating O�cer, Chief Evan Loh Pharmaceuticals Chief Executive O�cer and Director 25-Jun-19 Medical O�cer and Director Inc Paratek Randy Chief Development O�cer and Senior Vice President, Regulatory, Quality Pharmaceuticals 25-Jun-19 Brenner Chief Regulatory O�cer and Technical Operations Inc Mitchell Vice President, Head, Finance and Corporate Viela Bio Chief Financial O�cer 1-Jul-19 Chan Strategy Director

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Executive To Company New Role Effective Date Douglas E. Williams AC Immune SA Chairman 28-Jun-19 Roy Twyman AC Immune SA Director 28-Jun-19 Karen McGinnis Alphatec Holdings Inc Director 27-Jun-19 Ken Kessler Pivot Pharmaceuticals Inc Director 24-Jun-19 Sandra E. Poole ViaCyte Inc Director 27-Jun-19 Advisor

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Executive To Company New Role Effective Date Francois Haddad Gmax Biopharm LLC Science Advisor 14-Jun-19 James Philipson Gmax Biopharm LLC Business Advisor 14-Jun-19 Robert Lee Gmax Biopharm LLC Business Advisor 14-Jun-19 Xun Zhu Gmax Biopharm LLC Science Advisor 14-Jun-19 Virginia Pascual NEOVACS SA Scienti�c and Medical Advisory Board Member 27-Jun-19 Other

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Effective Executive From Company Previous Role Move Type Date Daniel P. Zimmer Biomet Holdings Chief Financial O�cer and Executive Vice 1-Jul-19 Retirement Florin Inc President HEADLINE NEWS

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