Richard Pazdur (Flatiron Health via YouTube)

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. 

The Big Phar­ma dis­card pile; Lay­offs all around while some biotechs bid farewell; New Roche CEO as­sem­bles top team; 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.

With earnings seasons in full swing, we’ve listened in on all the calls so you don’t have to. But news is popping up from all corners, so make sure you check out our other updates, too.

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Sen. Ron Wyden (D-OR) (Francis Chung/E&E News/Politico via AP Images)

In­fla­tion re­bates in­com­ing: Wyden calls on CMS to move quick­ly as No­var­tis CEO pledges re­ver­sal

Senate Finance Chair Ron Wyden (D-OR) this week sent a letter to the head of the Centers for Medicare & Medicaid Services seeking an update on how and when new inflation-linked rebates will take effect for drugs that see major price spikes.

The newly signed Inflation Reduction Act requires manufacturers to pay a rebate to Medicare when they increase drug prices faster than the rate of inflation.

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Trodelvy notch­es a win in most com­mon form of breast can­cer

Following a promise last year to go “big and fast in breast cancer,” Gilead has secured a win for Trodelvy in the most common form.

The drug was approved to treat HR-positive, HER2-negative breast cancer patients who’ve already received endocrine-based therapy and at least two other systemic therapies for metastatic cancer, Gilead announced on Friday.

Trodelvy won its first indication in metastatic triple-negative breast cancer back in 2020, and has since added urothelial cancer to the list. HR-positive HER2-negative breast cancer accounts for roughly 70% of new breast cancer cases worldwide per year, according to senior VP of oncology clinical development Bill Grossman, and many patients develop resistance to endocrine-based therapies or worsen on chemotherapy.

David Kirn, 4D Molecular Therapeutics CEO (via website)

FDA places hold on 4D Mol­e­c­u­lar’s Fab­ry gene ther­a­py

4D Molecular Therapeutics quietly tucked an FDA clinical hold on its Fabry gene therapy into an SEC filing.

Meanwhile, the biotech issued a press release the same day after the closing bell on Thursday touting an IND for another asset, in diabetic macular edema.

The California biotech had paused enrollment of patients in its two trials of the Fabry gene therapy (4D-310) last month after three patients experienced kidney issues, all of which were resolved within four weeks. At the time, 4DMT said it would wait until the second half of this year to look at 12-month clinical data on six patients in the Phase I/II trials, one in the US and one in Taiwan and Australia.

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Raymond Stevens, Structure Therapeutics CEO

Be­hind Fri­day's $161M IPO: A star sci­en­tist, GPCR drug dis­cov­ery and a plan to chal­lenge phar­ma in di­a­betes

What does it take to pull off a $161 million biotech IPO these days?

In Structure Therapeutics’ case, it means having a star scientist co-founder paired with the computational drug discovery company Schrödinger, $198 million in private funding from blue-chip investors, almost six years of research work on G protein-coupled receptors and a slate of oral, small-molecule drugs, with an eye on the huge and growing diabetes and weight-loss market.

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Af­ter 13 years, Ramy Mah­moud steps in­to CEO seat at Opti­nose; Ru­pert Vessey set to ex­it Bris­tol My­ers in Ju­ly

After 13 years as president and COO at Optinose, Ramy Mahmoud has stepped into a new role as its CEO. He is taking the place of Peter Miller, who stepped down earlier this week, though Miller is still staying with the company as a consultant.

In 2010, the two business partners joined Optinose to take it in a new direction, transforming it from a delivery platform to product company. They previously worked together at Johnson & Johnson, when Miller was president at Janssen and Mahmoud headed medical affairs. Miller said after he learned about Optinose, “I did what I always do, which is find people smarter than me to talk with about the idea. And the first person I called was Ramy … and I said, ‘Hey, Ramy, what do you think of this technology?’”

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FDA ap­proves GSK's ane­mia drug with safe­ty warn­ing — af­ter bat­ting back sim­i­lar drugs

GSK has secured the first of four US approvals it’s hoping for this year, as the FDA greenlit daprodustat as a treatment for anemia due to chronic kidney disease.

But the FDA limited the use of the drug, to be marketed as Jesduvroq, to patients who have been receiving dialysis for at least four months and stopped short of approving it for patients not dependent on dialysis — in line with the recommendations of the advisory committee it consulted.

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Photo: Julia Weeks/AP Images

FDA ax­es re­quire­ment for pos­i­tive Covid test be­fore Paxlovid use

FDA announced today that doctors and pharmacists can now prescribe Paxlovid to patients without a positive test for Covid-19.

CDER Director Patrizia Cavazzoni reissued Paxlovid’s authorization letter Wednesday, saying it has revised the authorization to “no longer require positive results of direct SARS-CoV-2 viral testing.” The EUA now requires instead that adults and kids 12 years of age and older have a “current diagnosis of mild-to-moderate COVID-19.”

Te­va drops out of in­dus­try trade group PhRMA

Following in AbbVie’s footsteps, Teva confirmed on Friday that it’s dropping out of the industry trade group Pharmaceutical Research and Manufacturers of America (PhRMA).

Teva didn’t give a reason for its decision to leave, saying only in a statement to Endpoints News that it annually reviews “effectiveness and value of engagements, consultants and memberships to ensure our investments are properly seated.”

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