Bris­tol-My­ers makes Op­di­vo pitch for front­line lung can­cer with open la­bel PhI­II study

De­spite a head start, when Bris­tol-My­ers Squibb and its pi­o­neer­ing check­point in­hibitor Op­di­vo suf­fered a key lung can­cer set­back in 2016, they found them­selves rel­e­gat­ed to the back­seat as Mer­ck’s Keytru­da seized the wheel on the road to im­munother­a­py star­dom. Bris­tol-My­ers has since suf­fered blow af­ter blow in its quest to take a big slice of the lu­cra­tive mar­ket, pep­pered with some small suc­cess­es. On Tues­day, the New Jer­sey drug­mak­er tout­ed pos­i­tive da­ta from a Phase III open-la­bel study in a bid to carve it­self a piece of the front­line lung can­cer mar­ket.

The study, dubbed Check­Mate -9LA, test­ed Bris­tol-My­ers’ Op­di­vo in com­bi­na­tion with its CT­LA-4 Yer­voy in ad­di­tion to chemother­a­py (two cy­cles) ver­sus chemother­a­py alone (up to four cy­cles fol­lowed by op­tion­al peme­trexed main­te­nance ther­a­py if el­i­gi­ble) as a first-line treat­ment in pa­tients with ad­vanced non-small cell lung can­cer (NSCLC) re­gard­less of PD-L1 ex­pres­sion.

The PD-L1 drug met the main tri­al goal of su­pe­ri­or over­all sur­vival at a pre­spec­i­fied in­ter­im analy­sis, the com­pa­ny said, adding that de­tailed da­ta will be pre­sent­ed at a fu­ture med­ical con­fer­ence. The com­pa­ny’s shares $BMY rose more than 5% to $55.94 in Tues­day pre­mar­ket trad­ing.

Sec­ondary end­points in­clud­ed pro­gres­sion-free sur­vival, over­all re­sponse rate, and ef­fi­ca­cy mea­sures ac­cord­ing to bio­mark­ers.

In Jan­u­ary, the com­pa­ny re­scind­ed its ap­pli­ca­tion to mar­ket the Op­di­vo/Yer­voy com­bo in front­line NSCLC cas­es with high tu­mor mu­ta­tion­al bur­den (TMB), af­ter dis­cus­sions with the agency sug­gest­ed they need­ed more da­ta to re­in­force the con­nec­tion be­tween TMB and PD-L1.

The ap­pli­ca­tion was based on the Check­Mate-227 study, in which re­searchers said they had ob­served a “high­ly” sig­nif­i­cant pro­gres­sion-free sur­vival rate in pa­tients with high TMB, re­gard­less of PD-L1 ex­pres­sion. The high TMB group ac­counts for 45% of all front­line pa­tients, the com­pa­ny es­ti­mat­ed at the time. Bris­tol-My­ers had re­designed the study to fo­cus on TMB af­ter stum­bling on a piv­otal tri­al that in­volved a broad­er pa­tient pop­u­la­tion.

Over­all sur­vival da­ta, pre­sent­ed months lat­er, showed that the haz­ard ra­tio in pa­tients get­ting the Op­di­vo/Yer­voy com­bo was com­pa­ra­ble whether they were high or low TMB pa­tients. How­ev­er, the me­di­an over­all sur­vival in pa­tients with high TMB was 23.03 months on the Op­di­vo/Yer­voy arm, ver­sus 16.72 months in the chemother­a­py group. In the low TMB group, the me­di­an OS was 16.20 months and was 12.42 months on the com­bi­na­tion and chemother­a­py arms, re­spec­tive­ly.

The re­sults of Check­Mate-227 sug­gest­ed that Yer­voy has ac­tiv­i­ty in lung can­cer when com­bined with Op­di­vo — but the da­ta sug­gest that pa­tients have to wait for some pe­ri­od of time for the ben­e­fit to man­i­fest, Wolfe Re­search’s Tim An­der­son wrote in a note.

“Chemother­a­py, when giv­en to lung can­cer pa­tients, of­ten shows a fast ini­tial re­sponse, but one that lacks dura­bil­i­ty.  But by com­bin­ing chemother­a­py+Op­di­vo+Yer­voy, BMY may have (fi­nal­ly) found a cock­tail of drugs that de­liv­ers both near- and longer-term ben­e­fit, lead­ing to an ear­ly re­sponse and im­proved long-term sur­vival.”

How­ev­er, An­der­son was cau­tious about the cock­tail’s safe­ty pro­file in Check­Mate -9LA.

“Op­di­vo+Yer­voy by it­self shows tox­i­c­i­ty and adding chemother­a­py in­to the mix will on­ly in­crease this,” he said.  “The com­mer­cial val­ue of CM-9LA will, there­fore, de­pend on the bal­ance be­tween the clin­i­cal ben­e­fit and the tox­i­c­i­ty.  It will on­ly be once full re­sults are pre­sent­ed that this risk:ben­e­fit as­sess­ment will be pos­si­ble.  Ad­di­tion­al­ly, adding a third drug in­to the mix al­so rais­es the cost of ther­a­py some­what.”

Mean­while, the com­pa­ny’s hunt for adop­tion in small cell lung can­cer (SCLC) mar­ket has al­so been punc­tu­at­ed with fail­ure.

Last year saw an Op­di­vo/Yer­voy com­bo miss the pri­ma­ry end­point for over­all sur­vival in the Check­Mate-451 study, where the Bris­tol-My­ers drugs were be­ing eval­u­at­ed as a main­te­nance ther­a­py for SCLC, fol­low­ing an ini­tial round of chemother­a­py. The re­sults came just over a month af­ter the drug­mak­er un­veiled an Op­di­vo flop in the Check­Mate-331 study, which test­ed the im­munother­a­py against the sec­ond-line small cell lung can­cer stan­dard-of-care.

Still, over the years, Op­di­vo has seen some lung can­cer suc­cess — in­clud­ing the ap­proval of the drug in squa­mous NSCLC pa­tients whose can­cer has pro­gressed de­spite plat­inum-based chemother­a­py as well as pa­tients with metasta­t­ic SCLC pa­tients, whose can­cer has pro­gressed af­ter plat­inum-based chemother­a­py and at least one oth­er line of ther­a­py.

The re­sults of Check­Mate -9LA could have an im­pact on As­traZeneca, which is run­ning the PO­SEI­DON tri­al, An­der­son added.

The tri­al is struc­tural­ly sim­i­lar to CM-9LA but with one key dif­fer­ence — in­stead of on­ly giv­ing a short course of chemother­a­py in ad­di­tion to its own check­point in­hibitor Imfinzi  and CT­LA-4 treme­li­mum­ab, it gives chemother­a­py con­tin­u­ous­ly, he said.

“This may or may not be a good thing – it can be pre­dict­ed that more chemother­a­py like­ly yields more tox­i­c­i­ty, but will it yield more ben­e­fit?  Fur­ther­more, AZN’s an­ti-CT­LA4 ther­a­py (treme­li­mum­ab) has yet to show it works in any tu­mor type (by con­trast, BMY’s Yer­voy is al­ready ap­proved in dif­fer­ent set­tings) po­ten­tial­ly re­flec­tive of the fact that it has slight­ly dif­fer­ent prop­er­ties ver­sus Yer­voy.”

Op­di­vo, which is al­so ap­proved for use in a host of oth­er can­cers, gen­er­at­ed about $3.6 bil­lion in the first half of this year. By 2025, Op­di­vo is set to be the fourth best-sell­ing drug in the world with an­nu­al sales fore­cast­ed to hit $12 bil­lion. King Keytru­da, how­ev­er, is ex­pect­ed to take top spot and rake in more than $22 bil­lion, ac­cord­ing to Glob­al­Da­ta cal­cu­la­tions.

2023 Spot­light on the Fu­ture of Drug De­vel­op­ment for Small and Mid-Sized Biotechs

In the context of today’s global economic environment, there is an increasing need to work smarter, faster and leaner across all facets of the life sciences industry.  This is particularly true for small and mid-sized biotech companies, many of which are facing declining valuations and competing for increasingly limited funding to propel their science forward.  It is important to recognize that within this framework, many of these smaller companies already find themselves resource-challenged to design and manage clinical studies themselves because they don’t have large teams or in-house experts in navigating the various aspects of the drug development journey. This can be particularly challenging for the most complex and difficult to treat diseases where no previous pathway exists and patients are urgently awaiting breakthroughs.

Dipal Doshi, Entrada Therapeutics CEO

Ver­tex just found the next big ‘trans­for­ma­tive’ thing for the pipeline — at a biotech just down the street

Back in the summer of 2019, when I was covering Vertex’s executive chairman Jeff Leiden’s plans for the pipeline, I picked up on a distinct focus on myotonic dystrophy Type I, or DM1 — one of what Leiden called “two diseases (with DMD) we’re interested in and we continue to look for those assets.”

Today, Leiden’s successor at the helm of Vertex, CEO Reshma Kewalramani, is plunking down $250 million in cash to go the extra mile on DM1. The lion’s share of that is for the upfront, with a small reserve for equity in a deal that lines Vertex up with a neighbor in Seaport that has been rather quietly going at both of Vertex’s early disease targets with preclinical assets.

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Ahead of ad­comm, FDA rais­es un­cer­tain­ties on ben­e­fit-risk pro­file of Cy­to­ki­net­ic­s' po­ten­tial heart drug

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will meet next Tuesday to discuss whether Cytokinetics’ potential heart drug can safely reduce the risk of cardiovascular death and heart failure in patients with symptomatic chronic heart failure with reduced ejection fraction.

The drug, known as omecamtiv mecarbil and in development for more than 15 years, has seen mixed results, with a first Phase III readout from November 2020 hitting the primary endpoint of reducing the odds of hospitalization or other urgent care for heart failure by 8%. But it also missed a key secondary endpoint analysts had pegged as key to breaking into the market.

Rami Elghandour, Arcellx CEO

Up­dat­ed: Gilead, Ar­cel­lx team up on an­ti-BC­MA CAR-T as biotech touts a 100% re­sponse rate at #ASH22

Gilead and Kite are plunking down big cash to get into the anti-BCMA CAR-T game.

The pair will shell out $225 million in cash upfront and $100 million in equity to Arcellx, Kite announced Friday morning, to develop the biotech’s lead CAR-T program together. Kite will handle commercialization and co-development with Arcellx, and profits in the US will be split 50-50.

Concurrent with the deal, Arcellx revealed its latest cut of data for the program known as CART-ddBCMA, ahead of a full presentation at this weekend’s ASH conference — a 100% response rate among patients getting the therapy. Investors jumped at the dual announcements, sending Arcellx shares $ACLX up more than 25% in Friday’s morning session.

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Christian Itin, Autolus CEO (UKBIO19)

Au­to­lus tips its hand, bags $220M as CAR-T show­down with Gilead looms

The first batch of pivotal data on Autolus Therapeutics’ CAR-T is in, and execs are ready to plot a path to market.

With an overall remission rate of 70% at the interim analysis featuring 50 patients, the results set the stage for a BLA filing by the end of 2023, said CEO Christian Itin.

Perhaps more importantly — given that Autolus’ drug, obe-cel, is going after an indication that Gilead’s Tecartus is already approved for — the biotech highlighted “encouraging safety data” in the trial, with a low percentage of patients experiencing severe immune responses.

David Light, Valisure CEO

Val­isure in the hot seat: New Form 483 over a 2021 in­spec­tion as CEO fires back

The notorious drug testing company Valisure, which has made a name for itself by forcing FDA’s hand with some of its safety-related uncoverings, received a letter this week after the FDA uncovered violations at its Connecticut-based testing lab in 2021.

The letter, which was sent on Dec. 5, stated that the FDA is “concerned” that Valisure was not aware of  drug supply chain security requirements.

WIB22: Am­ber Salz­man had few op­tions when her son was di­ag­nosed with a rare ge­net­ic dis­ease. So she cre­at­ed a bet­ter one

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

Amber Salzman’s life changed on a cold, damp day in Paris over tiny plastic cups of lukewarm tea.

She was meeting with Patrick Aubourg, a French neurologist studying adrenoleukodystrophy, or ALD, a rare genetic condition that causes rapid neurological decline in young boys. It’s a sinister disease that often leads to disability or death within just a few years. Salzman’s nephew was diagnosed at just 6 or 7 years old, and died at the age of 12.

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FDA re­view­ers head back to White Oak in 2023, with lead­er­ship look­ing to ap­pease a new Con­gress

Republicans have taken a stand against the pandemic era habit of lax work-from-home schedules. Now that they’ve wrestled control of the House majority, the FDA’s leadership is playing ball, sending many of the agency’s more than 18,000 employees back to their desks early next year.

Whether this exodus back to White Oak in Silver Spring, MD (many staff will still be allowed to work from home for multiple days per week) will mean more defections to industry and elsewhere remains to be seen.

Bags of shred­ded docs: In­di­an drug­mak­er Lupin hand­ed a Form 483 by FDA in­spec­tors

The generics manufacturer Lupin has been given another Form 483 from the FDA this year.

US regulators inspected Lupin’s pharmaceutical manufacturing site in the town of Mandideep, India from Nov. 14 through Nov. 23, with the 14-page report marking 16 observations.

The inspection report stated that the site did not have the appropriate controls over its computer systems to ensure that changes in “master production” or records are only done by authorized personnel, along with written procedures not being established to conduct annual reviews of records associated with drug batches.