Richard Pazdur (Flatiron Health via YouTube)

UP­DAT­ED: FDA ad­vi­sors rec­om­mend against ap­prov­ing Eli Lil­ly’s PD-1, cast­ing shad­ow over fu­ture of Chi­na-made can­cer drugs

In a live­ly and some­times con­tentious hear­ing, the FDA’s On­co­log­ic Drugs Ad­vi­so­ry Com­mit­tee (ODAC) near­ly unan­i­mous­ly rec­om­mend­ed against ap­prov­ing Eli Lil­ly and In­novent’s an­ti-PD-1 an­ti­body sin­til­imab, deal­ing a blow to “me-too” can­cer drug­mak­ers hop­ing to reach the mar­ket based sole­ly on da­ta from Chi­na.

But the pan­el’s con­cerns were large­ly over­shad­owed by FDA of­fi­cials tear­ing in­to Lil­ly over not mak­ing good on its promis­es to in­crease tri­al di­ver­si­ty, sub­mit­ting the ap­pli­ca­tion with­out con­sult­ing reg­u­la­tors be­fore the tri­al con­clud­ed and mis­rep­re­sent­ing in­ter­ac­tions with the agency dur­ing its pre­sen­ta­tion.

The top two FDA reps at the hear­ing, on­col­o­gy chief Richard Paz­dur and Di­rec­tor Di­vi­sion of On­col­o­gy 2 Harpreet Singh, both said the study did not meet “good clin­i­cal prac­tice” stan­dards and suf­fered da­ta in­tegri­ty is­sues. They both asked re­peat­ed­ly whether there were any in­stances of fraud­u­lent da­ta re­port­ing, giv­en how a 2016 in­ves­ti­ga­tion found about 80% of da­ta from tri­als con­duct­ed in Chi­na are coun­ter­feit.

In the wake of the news, Lil­ly is­sued a some­what apolo­getic state­ment to End­points News, which read in full:

While we are dis­ap­point­ed with the out­come of to­day’s ODAC as it re­lates to the in­ves­ti­ga­tion­al prod­uct sin­til­imab, we ap­pre­ci­at­ed the op­por­tu­ni­ty to pub­licly dis­cuss the ap­pli­ca­tion and broad­er is­sues re­lat­ed to sin­gle-coun­try clin­i­cal tri­als. We had hoped that sin­til­imab could have played a pos­i­tive role for pa­tients and the U.S. health­care sys­tem through an ag­gres­sive pric­ing strat­e­gy. We ac­knowl­edge that the land­scape has changed dra­mat­i­cal­ly on a num­ber of fronts since the ORI­ENT-11 study was con­duct­ed and the sin­til­imab ap­pli­ca­tion was ini­ti­at­ed. Lil­ly whole­heart­ed­ly agrees with the im­por­tance of ethics in clin­i­cal tri­al con­duct and clin­i­cal tri­al di­ver­si­ty. We have long-stand­ing ini­tia­tives in place to ad­vance di­ver­si­ty and in­clu­sion in Lil­ly-con­duct­ed clin­i­cal tri­als. Along with In­novent, we will con­tin­ue to work with the FDA as it com­pletes its re­view of the sin­til­imab ap­pli­ca­tion.

Lil­ly re­mains com­mit­ted to bring­ing for­ward med­i­cines with the po­ten­tial to mean­ing­ful­ly im­prove treat­ment par­a­digms for pa­tients with can­cer.

Ear­li­er Thurs­day, the pan­elists were os­ten­si­bly sup­posed to dis­cuss whether or not Lil­ly’s tri­al, dubbed ORI­ENT-11, could be ap­plic­a­ble and gen­er­al­iz­able to the US pop­u­la­tion. ORI­ENT-11 was con­duct­ed en­tire­ly in Chi­na, rais­ing ques­tions at the FDA about if the pos­i­tive da­ta seen would re­main the same in a more het­ero­ge­neous set­ting.

Dis­cus­sion soon de­volved in­to a pub­lic flog­ging, how­ev­er, with Paz­dur and Singh tak­ing Lil­ly to task over not just the di­ver­si­ty is­sues, but the na­ture of the study it­self. Lil­ly and In­novent used pro­gres­sion-free sur­vival as their pri­ma­ry end­point, but most of the pre­vi­ous PD-1 drug stud­ies have nabbed ap­proval based on over­all sur­vival.

In ad­di­tion, while Lil­ly and In­novent were con­duct­ing the study, Paz­dur and Singh con­tend­ed that the stan­dard of care for non-small cell lung can­cer — the in­di­ca­tion in which Lil­ly is seek­ing ap­proval — changed to Mer­ck’s Keytru­da plus chemother­a­py. The reg­u­la­tors point­ed to one Keytru­da study in par­tic­u­lar, KEYNOTE-189, they said was par­a­digm-shift­ing in lung can­cer. Lil­ly and In­novent did not up­date their in­formed con­sent guid­ance to al­low pa­tients in the con­trol arm to take Keytru­da, with Singh ac­cus­ing the drug­mak­ers of pre­vent­ing pa­tients from get­ting the best avail­able drugs.

Harpreet Singh

Lil­ly, for its part, not­ed the ORI­ENT-11 tri­al was orig­i­nal­ly de­signed to ob­tain ap­proval in Chi­na. Once the com­pa­ny saw the da­ta, it ap­proached the FDA with the study, Lil­ly VP of gas­troin­testi­nal on­col­o­gy strat­e­gy David Fer­ry told the pan­el.

This, too, drew the ire of FDA of­fi­cials. In both its pre­sen­ta­tion to the com­mit­tee and while clar­i­fy­ing ques­tions for the pan­el mem­bers, reg­u­la­tors crit­i­cized Lil­ly for not con­sult­ing with the FDA at all un­til the study read out topline da­ta. Com­pet­ing nar­ra­tives emerged dur­ing the pre­sen­ta­tions about the time­line of the in­ter­ac­tions be­tween the two par­ties, with Lil­ly claim­ing it met three times be­fore sub­mit­ting its BLA.

Af­ter Singh cas­ti­gat­ed Lil­ly for mis­rep­re­sent­ing its con­ver­sa­tions with the FDA, she threat­ened to re­lease all pri­vate cor­re­spon­dences to the pub­lic. Singh said that some fed­er­al reg­u­la­tions may al­low for flex­i­bil­i­ty on for­eign da­ta in cer­tain in­stances, but on­ly when the FDA can val­i­date the da­ta through in­spec­tions and train­ing in­ves­ti­ga­tors.

“I find this in­cred­i­bly mis­lead­ing,” Singh said to Lil­ly at one point. “We used much stronger lan­guage in in­vok­ing the reg­u­la­tions, and would be hap­py to pro­vide all the in­fo in­to the pub­lic record.”

Com­pa­ny ex­ecs apol­o­gized mul­ti­ple times dur­ing the hear­ing, with one say­ing, “It’s cer­tain­ly not our in­tent to mis­char­ac­ter­ize our in­ter­ac­tions with the agency.”

Pan­elists vot­ed 14-1 that a new tri­al should be re­quired for ap­proval. Most of the pan­elists agreed more so that the da­ta and ORI­ENT-11 pro­to­col were not good enough to rec­om­mend an OK, but split over how to bet­ter de­sign an ap­pro­pri­ate study. Through­out the meet­ing, FDA vouched to be­gin in­clud­ing more Chi­nese da­ta in mul­ti-re­gion­al clin­i­cal stud­ies.

A pos­i­tive rec­om­men­da­tion — and po­ten­tial ap­proval — were like­ly to be dif­fi­cult for Lil­ly. Late last week, FDA on­col­o­gy chief Richard Paz­dur wrote in The Lancet that drug ap­pli­ca­tions seek­ing ap­proval based on da­ta from a “sin­gle for­eign coun­try” need to be rep­re­sen­ta­tive of the US pop­u­la­tion in or­der for reg­u­la­tors to be flex­i­ble (gen­er­al­ly, the FDA re­quires com­pa­nies to con­duct piv­otal stud­ies at least in part in the US).

Paz­dur’s ar­ti­cle proved to be an about-face from ear­li­er pub­lic com­ments made at a med­ical con­fer­ence in 2019 when, while re­count­ing a re­cent trip to Chi­na, he said the FDA would ac­cept ap­pli­ca­tions based sole­ly on Chi­nese da­ta. In an in­ter­view with STAT News on Tues­day, Paz­dur de­fend­ed the flip, de­clar­ing, “I have a right to change my mind.”

While dis­cussing the is­sues with the pan­elists, Paz­dur al­so took a step fur­ther, ad­dress­ing that for­mer AACR com­ments “should not be viewed as reg­u­la­to­ry pol­i­cy.” He al­so de­scribed how treat­ment land­scapes have changed in the last three years, both due to im­prove­ments in sur­vival da­ta and how the Covid-19 pan­dem­ic has changed the pub­lic’s de­sire for di­ver­si­ty in all as­pects of life.

“Sin­gle coun­try sub­mis­sions are a step back­ward in achiev­ing the racial di­ver­si­ty we need in the Unit­ed States,” Paz­dur said, “and we want peo­ple to un­der­stand this is a ma­jor goal not just in on­col­o­gy sub­mis­sions but through­out all sub­mis­sions at the FDA.”

Lil­ly is un­like­ly to be the on­ly com­pa­ny af­fect­ed by this rul­ing, as sev­er­al oth­ers are at­tempt­ing to get drugs on the Amer­i­can mar­ket through Chi­nese-on­ly da­ta. Paz­dur said in his Lancet ar­ti­cle — and the FDA said in its pre­sen­ta­tion — that there are about 25 such ap­pli­ca­tions ei­ther un­der re­view, planned to be sub­mit­ted or cur­rent­ly un­der de­vel­op­ment.

Most no­tably, the biotech EQRx is de­vel­op­ing a large suite of drugs in-li­censed from Chi­nese com­pa­nies with the goal of dis­rupt­ing pric­ing mod­els in the US. One of its two lead pro­grams is an an­ti-PD-L1 an­ti­body, known as sug­e­mal­imab, which EQRx has said it could price at a 40% to 50% dis­count.

Lil­ly had at­tempt­ed a sim­i­lar price dis­rup­tion strat­e­gy, with on­col­o­gy head Ja­cob Van Naar­den say­ing Wednes­day the com­pa­ny had plans to dis­count the drug by as much as 40% com­pared to oth­er PD-1s on the mar­ket. So far, each of the sev­en an­ti-PD-1 and an­ti-PD-L1 drugs ap­proved by the FDA has been priced the same at $150,000 per year.

But the FDA does not take pric­ing in­to ac­count when re­view­ing drugs, a point ham­mered re­peat­ed­ly in Paz­dur’s 2019 com­ments, his Lancet ar­ti­cle and the FDA pre­sen­ta­tion Thurs­day. Reg­u­la­tors told pan­elists that all dis­cus­sion of pric­ing would not be al­lowed.

David Fredrick­son

Even be­fore ODAC made its rec­om­men­da­tion and the FDA had thor­ough­ly tongue-lashed Lil­ly and In­novent, the ram­i­fi­ca­tions of the po­ten­tial “no” vote were be­ing felt in the in­dus­try. Dur­ing As­traZeneca’s fourth-quar­ter and FY2021 earn­ings call ear­li­er Thurs­day, ex­ec­u­tive VP of on­col­o­gy David Fredrick­son said he feels more con­fi­dent now about the com­pa­ny’s Tagris­so fran­chise, es­sen­tial­ly telling Lil­ly, “I told you so.”

Un­like sin­til­imab, Tagris­so is an EGFR-TKI in­hibitor ap­proved for EGFR-mu­tat­ed NSCLC in the first-line set­ting.

“I’ve been fair­ly con­sis­tent­ly want­i­ng to raise the fact that Chi­na-on­ly stud­ies that don’t have over­all sur­vival, and that com­pare against an old stan­dard of care, bring with them some reg­u­la­to­ry risks,” he said, adding lat­er, “I do think that cer­tain­ly, the ODAC from to­day, the brief­ing doc­u­ments do give me more con­fi­dence that there is reg­u­la­to­ry hur­dles in front of the com­pe­ti­tion that’s seek­ing to come in from some of the com­peti­tors that we’ve seen.”

CEO Pas­cal So­ri­ot piled on, not­ing, “I’m not sure that de­clar­ing a price be­fore an ODAC is a good strat­e­gy.”

This ar­ti­cle has been up­dat­ed to in­clude com­ment from Eli Lil­ly as well as ad­di­tion­al con­text on the land­scape of Chi­nese-on­ly da­ta, in­clud­ing com­ments from As­traZeneca ex­ec­u­tives David Fredrick­son and Pas­cal So­ri­ot. 

Pi­o­neer­ing Click Chem­istry in Hu­mans

Reimagining cancer treatments

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, which is nearly one in six deaths. Recently, we have seen incredible advances in novel cancer therapies such as immune checkpoint inhibitors, cell therapies, and antibody-drug conjugates that have revamped cancer care and improved survival rates for patients.

Despite this significant progress in therapeutic targeting, why are we still seeing such a high mortality rate? The reason is that promising therapies are often limited by their therapeutic index, which is a measure of the effective dose of a drug, relative to its safety. If we could broaden the therapeutic indices of currently available medicines, it would revolutionize cancer treatments. We are still on the quest to find the ultimate cancer medicine – highly effective in several cancer types, safe, and precisely targeted to the tumor site.

Justin Klee (L) and Joshua Cohen, Amylyx co-CEOs (Cody O'Loughlin/The New York Times; courtesy Amylyx)

Ad­vo­cates, ex­perts cry foul over Amy­lyx's new ALS drug, cit­ing is­sues with price, PhI­II com­mit­ment

Not 24 hours after earning the first ALS drug approval in five years, Amylyx Pharmaceuticals’ Relyvrio is already drawing scrutiny. And it’s coming from multiple fronts.

In an investor call Friday morning, Amylyx revealed that it would charge about $158,000 per year, a price point that immediately drew backlash from ALS advocates and some outside observers. The cost reveal had been highly anticipated in the immediate hours after Thursday evening’s approval, though Amylyx only teased Relyvrio would cost less than previously approved drugs.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 151,400+ biopharma pros reading Endpoints daily — and it's free.

Land­mark Amy­lyx OK spurs de­bate; Some... pos­i­tive? Alzheimer's da­ta; Can­cer tri­al bot­tle­neck; Sanofi's CRISPR bet; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

After brief stops in Paris and Boston, John Carroll and the Endpoints crew are staying on the road in October with their return for a live/streaming EUBIO22 in London. The hybrid event fireside chats and panels on mRNA, oncology and the crazy public market. We hope you can join him there.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 151,400+ biopharma pros reading Endpoints daily — and it's free.

Joshua Cohen (L) and Justin Klee, Amylyx co-CEOs

Up­dat­ed: Af­ter long and wind­ing road, FDA ap­proves Amy­lyx's ALS drug in vic­to­ry for pa­tients and ad­vo­ca­cy groups

For just the third time in its 116-year history, the FDA has approved a new treatment for Lou Gehrig’s disease, or ALS.

US regulators gave the thumbs-up to the drug, known as Relyvrio, in a massive win for patients and their families. The approval, given to Boston-area biotech Amylyx Pharmaceuticals, comes after two years of long and contentious debates over the drug’s effectiveness between advocacy groups and FDA scientists, following the readout of a mid-stage clinical trial in September 2020.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 151,400+ biopharma pros reading Endpoints daily — and it's free.

Nooman Haque, head of life sciences and healthcare at Silicon Valley Bank, and John Carroll

I’m head­ed to Lon­don soon for #EU­BIO22. Care to join me?

It was great getting back to a live ESMO conference/webinar in Paris followed by a live pop-up event for the Endpoints 11 in Boston. We’re staying on the road in October with our return for a live/streaming EUBIO22 in London.

Silicon Valley Bank’s Nooman Haque and I are once again jumping back into the thick of it with a slate of virtual and live events on October 12. I’ll get the ball rolling with a virtual fireside chat with Novo Nordisk R&D chief Marcus Schindler, covering their pipeline plans and BD work.

Up­dat­ed: Al­ny­lam re­in­forces APOL­LO-B patisir­an da­ta be­fore head­ing to the FDA

Weeks after uncorking some mostly positive data for patisiran in transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy, Alnylam is bolstering its package with new exploratory and subgroup data before shipping it off to regulators.

The RNAi drug maintained “generally consistent” benefits in efficacy and quality of life across several prespecified subgroups at month 12, Alnylam announced on Friday afternoon, including age, baseline tafamidis use, ATTR amyloidosis type, baseline six-minute walk test score and others.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 151,400+ biopharma pros reading Endpoints daily — and it's free.

#AAO22: J&J’s first look at com­mon eye dis­ease port­fo­lio pads the case for PhII of gene ther­a­py

CHICAGO — While the later-stage drug developers in the geographic atrophy field are near the finish line, Johnson & Johnson’s Janssen is taking a more deliberate route, with a treatment that it hopes to be a one-time fix.

The Big Pharma will take its Hemera Biosciences-acquired gene therapy into a Phase II study later this year in patients with GA, a common form of age-related macular degeneration that impacts about five million people worldwide. To get there, Janssen touted early-stage safety data at the American Academy of Ophthalmology annual conference Saturday morning, half a day after competitors Apellis and Iveric Bio revealed their own more-detailed Phase III analyses.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 151,400+ biopharma pros reading Endpoints daily — and it's free.

Jerome Durso, Intercept Pharmaceuticals CEO

In­ter­cep­t's OCA fails a PhI­II NASH tri­al, rais­ing fresh doubts about its years­long quest for an OK

Intercept Pharmaceuticals has run into another big setback in its yearslong quest to win an approval for OCA in NASH. The biotech put out word Friday morning that its Phase III REVERSE study failed the primary endpoint for the liver disease, sending its share price into a tailspin.

There was no significant improvement in fibrosis among the patients suffering from cirrhosis who were treated with obeticholic acid, with investigators hunting for a minimum 1-stage histological improvement in the disease after 18 months of therapy.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 151,400+ biopharma pros reading Endpoints daily — and it's free.

Bo Cumbo, new Solid Bio CEO

Sol­id Bio gets a new CEO, $75M cash and drops lead drug as big in­vestors ju­ry-rig a merg­er deal

Three months after Endpoints News broke the story that gene therapy outfit AavantiBio had gutted its CMC group in a reorganization, the biotech’s CEO has helped engineer a merger with struggling penny stock player Solid Bio. And he’s going to remain in charge of the combined operation, as Solid founder Ilan Ganot steps aside.

The merger news this morning features some high-profile investors.

Perceptive Advisors, RA Capital Management and Bain Capital Life Sciences are leading a $75 million raise to add to the pool of cash Solid will have after the tie-up. That will leave Solid $215 million in cash as Bain’s Adam Koppel jumps on the board — enough to pay for ops and get through some key data milestones on their way into 2025.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 151,400+ biopharma pros reading Endpoints daily — and it's free.