Bris­tol-My­ers craters af­ter block­buster check­point drug Op­di­vo fails key lung can­cer study

Bris­tol-My­ers Squibb an­nounced this morn­ing that Op­di­vo has flopped in a late-stage study on non-small cell lung can­cer, pre­sent­ing a stun­ning set­back for the star ther­a­py. Its shares $BMY im­me­di­ate­ly plunged 18%, wip­ing out bil­lions in mar­ket val­ue, while ri­val Mer­ck $MRK—a run­ner-up in the check­point mar­ket—saw its shares soar 10%.

Re­searchers had re­cruit­ed a broad pop­u­la­tion of 541 pre­vi­ous­ly un­treat­ed first line pa­tients whose tu­mors ex­pressed PD-L1 at ≥ 5%, a key bio­mark­er used to iden­ti­fy pa­tients most like­ly to re­spond. The Op­di­vo arm was com­pared to a group who re­ceived their physi­cian’s choice of al­ter­na­tive ther­a­pies. But this time, in the first ma­jor re­ver­sal for Bris­tol-My­ers, the drug failed to de­liv­er a sig­nif­i­cant im­prove­ment in pro­gres­sion-free sur­vival.

The fo­cus now may cen­ter on the lev­el of PD-L1 ex­pres­sion used to qual­i­fy pa­tients. Last fall, when the FDA ex­pand­ed its ap­proval of Op­di­vo to NSCLC pa­tients whose can­cer had spread af­ter chemo, FDA can­cer czar Richard Paz­dur not­ed:

“While Op­di­vo showed an over­all sur­vival ben­e­fit in cer­tain non-small cell lung can­cer pa­tients, it ap­pears that high­er ex­pres­sion of PD-L1 in a pa­tient’s tu­mor pre­dicts those most like­ly to ben­e­fit.”

“The missed re­sult like­ly re­flects the fact that BMY pushed the en­ve­lope too far in de­sign­ing its tri­al,” not­ed Bern­stein’s Tim An­der­son. “Specif­i­cal­ly, as men­tioned in the press re­lease to­day, they chose a “cut-off val­ue” for PDL1 ex­pres­sion of 5%.  This is in-line with what we had been say­ing (that 5% was the val­ue), where­as the con­sen­sus view had been that the cut-off was 10%.  By mak­ing it 5%, BMY was in essence try­ing to broad­en the pa­tient pop­u­la­tion where it could claim a ben­e­fit (had re­sults been pos­i­tive, of course), but failed re­sults sug­gest they like­ly made it too broad, mean­ing they en­rolled pa­tients with too lit­tle PDL1 ex­pres­sion, and this soured the over­all analy­sis.  The pop­u­la­tion MRK stud­ied was nar­row­er.”

I/O in­vest­ment spe­cial­ist Brad Lon­car had this to say:

Bris­tol’s more ag­gres­sive strat­e­gy of fo­cus­ing on a broad­er pop­u­la­tion rather than high PD-L1 ex­pres­sors has worked out for them in lat­er stages of dis­ease, but it looks like that has fi­nal­ly reached its lim­it. This is a very dis­ap­point­ing re­sult, but I think they de­serve cred­it for try­ing to help as many pa­tients as pos­si­ble.

Mer­ck has been lag­ging far be­hind Bris­tol-My­ers Squibb in the check­point sales race, with

Gio­van­ni Caforio, Bris­tol-My­ers Squibb CEO

Op­di­vo OK’d for use with­out a di­ag­nos­tic test while Keytru­da pa­tients have to be screened. Free of test­ing pa­tients, Op­di­vo has raced far ahead on the sales front. But Keytru­da—which was test­ed in pa­tients with a PD-L1 ex­pres­sion of 50%—looks to have the edge now in a key mar­ket­place.

These two pi­o­neer­ing drugs work es­sen­tial­ly the same way. They both dis­man­tle a hur­dle that can­cer cells re­ly on to es­cape an at­tack by the im­mune sys­tem. That has proven to be a game-chang­er in many types of can­cer, where new com­bi­na­tions are now be­ing test­ed to pro­vide a one-two punch against can­cer cells.

Gio­van­ni Caforio, the CEO at Bris­tol, had this to say:

While we are dis­ap­point­ed Check­Mate -026 did not meet its pri­ma­ry end­point in this broad pa­tient pop­u­la­tion, we re­main com­mit­ted to im­prov­ing pa­tient out­comes through our com­pre­hen­sive de­vel­op­ment pro­gram, in­clud­ing the on­go­ing Phase 3 Check­Mate -227 study ex­plor­ing the po­ten­tial of the com­bi­na­tion of Op­di­vo plusYer­voy for PD-L1 pos­i­tive pa­tients, and Op­di­vo plus Yer­voy, or Op­di­vo plus chemother­a­py in PD-L1 neg­a­tive pa­tients.


via Brad Lon­car

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

Joshua Brumm, Dyne Therapeutics CEO

FDA or­ders DMD tri­al halt, rais­ing ques­tions about a whole class of promis­ing drugs

Dyne Therapeutics’ stock took a nasty hit this morning after the biotech put out word that the FDA had slapped a clinical hold on their top program for Duchenne muscular dystrophy. And now speculation is bouncing around Biotwitter that there could be a class effect at work here that would implicate other drug developers in the freeze.

Dyne execs didn’t have a whole lot to say about why the FDA sidelined their IND for DYNE-251 in DMD while “requesting additional clinical and non-clinical information for” the drug.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Chamath Palihapitiya and Pablo Legorreta

Bil­lion­aires Chamath Pal­i­hapi­tiya and Pablo Legor­re­ta hatch an $825M SPAC for cell ther­a­py biotech

Three years after Royalty Pharma chief Pablo Legorreta led a group of investors to buy up a pair of biotechs and create a new startup called ProKidney, the biotech is jumping straight into an $825 million public shell created by SPAC king and tech billionaire Chamath Palihapitiya.

ProKidney was founded 6 years ago but really got going at the beginning of 2019 with the $62 million acquisition of inRegen, which was working on an autologous — from the patient — cell therapy for kidney disease. After extracting kidney cells from patients, researchers expand the cells in the lab and then inject them back into patients, aiming to restore the kidneys of patients suffering from CKD.

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Michel Vounatsos, Biogen CEO (Credit: World Economic Forum/Ciaran McCrickard)

An un­ortho­dox pro­pos­al for Bio­gen's Medicare-man­dat­ed Aduhelm tri­al

Biogen has gone full blitz since Medicare announced it would only cover its new Alzheimer’s drug when used in clinical trials, accusing the agency of discriminating against Alzheimer’s patients and trying to get physicians to change regulators’ minds.  Critics, meanwhile, cheered what they see as a necessary wall protecting payers and patients from an unproven and unsafe drug.

Far less attention, though, has gone to what a Medicare-funded clinical trial would actually look like. Biogen has operated as if it would be a standard late-stage Alzheimer’s trial, enrolling a couple thousand patients and giving half placebo.

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