FDA slams In­cyte's PD-1 over sin­gle-arm study, low re­sponse and tri­al deaths

The ever-grow­ing PD-1 land­scape could see a new en­trant as an In­cyte pro­gram is slat­ed for an FDA de­ci­sion next month. But first, the biotech will have to get through an ad­comm Thurs­day, and brief­ing doc­u­ments from the agency ap­pear to cast doubt over how ef­fec­tive the can­di­date re­al­ly is.

Atop the is­sues is whether or not the com­pound reti­fan­limab has enough da­ta for an ac­cel­er­at­ed ap­proval, af­ter In­cyte treat­ed sec­ond-line pa­tients with squa­mous car­ci­no­ma of the anal canal in a sin­gle-arm tri­al. In­cyte’s study showed an over­all re­sponse rate of just 14% among 94 pa­tients, and the FDA says they’re un­sure whether this would cor­re­spond to a clin­i­cal ben­e­fit in a larg­er, place­bo-con­trolled tri­al.

The fig­ure fell well short of the 25% rate In­cyte told reg­u­la­tors they were seek­ing with the study, ac­cord­ing to doc­u­ments de­tail­ing the biotech’s Sep­tem­ber 2020 meet­ing. At that time, the FDA said the BLA pack­age would be stronger with da­ta from a big­ger tri­al and not­ed an ad­comm would be like­ly with just the one tri­al, but In­cyte sub­mit­ted their pitch two months lat­er.

Reg­u­la­tors al­so raised con­cerns over the tri­al’s de­mo­graph­ics, high­light­ing there was on­ly one Black pa­tient and four His­pan­ic or Lati­no pa­tients. And giv­en that HIV in­creas­es the risk of de­vel­op­ing this spe­cif­ic can­cer by about 15- to 35-fold, the FDA said it’s un­clear how the pro­gram could af­fect these pa­tients since on­ly nine HIV-pos­i­tive in­di­vid­u­als took part in the study.

Much like oth­er late­com­er PD-1 play­ers, In­cyte is tar­get­ing an in­di­ca­tion where the big­ger names have yet to win ap­proval. Ef­fi­ca­cy da­ta in the sec­ond-line set­ting for this can­cer are lim­it­ed and pa­tients gen­er­al­ly end up tak­ing more chemother­a­py if they progress af­ter their first round of treat­ments.

Nonethe­less, the FDA at­tempt­ed to draw some cross-tri­al com­par­isons be­tween In­cyte and oth­er small, ex­per­i­men­tal stud­ies. Look­ing at tri­als test­ing Op­di­vo, Keytru­da, and two dif­fer­ent chemo reg­i­mens, reg­u­la­tors found ORRs be­tween 17% and 33%, fig­ures nu­mer­i­cal­ly high­er than In­cyte’s re­port­ed fig­ure.

Among these tri­als, on­ly Op­di­vo’s en­rolled more than two dozen pa­tients, with Bris­tol My­ers Squibb hav­ing re­cruit­ed 37 par­tic­i­pants.

Gen­er­al­ly speak­ing, the FDA said, check­point in­hibitors us­ing ac­cel­er­at­ed ap­proval path­ways with ORR as their pri­ma­ry end­point have not gone on to con­firm clin­i­cal ben­e­fit in big­ger stud­ies. Out of the 76 check­point in­hibitor ap­provals grant­ed by the agency, 35 were giv­en an ac­cel­er­at­ed OK, the FDA said. Of those 35, nine of the 10 to fail con­fir­ma­to­ry tri­als had pre­vi­ous­ly used a sin­gle-arm study look­ing at ORR.

Those oth­er drugs had been green­lit main­ly due to their du­ra­tion of re­sponse fig­ures, but the FDA is un­cer­tain over In­cyte’s da­ta here as well. While most oth­er pro­grams had pro­longed re­spons­es last­ing years, In­cyte re­port­ed a me­di­an of on­ly 9.5 months among the 13 re­spon­ders.

There al­so ap­peared to be a dis­pute be­tween how the FDA and In­cyte in­ter­pret­ed the study’s safe­ty da­ta. In its re­port, In­cyte says there was on­ly one death con­nect­ed to a side ef­fect from the treat­ment, but reg­u­la­tors say there were 10 fa­tal treat­ment-re­lat­ed ad­verse events. The FDA said, how­ev­er, that the safe­ty pro­file was con­sis­tent with PD-1 ther­a­pies in oth­er set­tings.

Whether In­cyte’s next study is con­duct­ed to con­firm an ac­cel­er­at­ed ap­proval or if it’s part of a new pack­age fol­low­ing a CRL, the com­pa­ny plans to read out da­ta by the end of 2024.

Should reti­fan­limab win ap­proval, an­a­lysts have said it like­ly won’t be a block­buster. Tru­ist’s Srikri­pa De­varakon­da mod­eled peak world­wide sales in this par­tic­u­lar dis­ease at $43 mil­lion — al­though new in­di­ca­tions such as lung can­cer and Merkel cell car­ci­no­ma may push it to around $500 mil­lion. SVB Leerink, mean­while, is pro­ject­ing about $100 mil­lion in peak sales in 2030.

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

Fresh off Fer­Gene's melt­down, David Meek takes over at Mi­rati with lead KRAS drug rac­ing to an ap­proval

In the insular world of biotech, a spectacular failure can sometimes stay on any executive’s record for a long time. But for David Meek, the man at the helm of FerGene’s recent implosion, two questionable exits made way for what could be an excellent rebound.

Meek, most recently FerGene’s CEO and a past head at Ipsen, has become CEO at Mirati Therapeutics, taking the reins from founding CEO Charles Baum, who will step over into the role of president and head of R&D, according to a release.

Jacob Van Naarden (Eli Lilly)

Ex­clu­sives: Eli Lil­ly out to crash the megablock­buster PD-(L)1 par­ty with 'dis­rup­tive' pric­ing; re­veals can­cer biotech buy­out

It’s taken 7 years, but Eli Lilly is promising to finally start hammering the small and affluent PD-(L)1 club with a “disruptive” pricing strategy for their checkpoint therapy allied with China’s Innovent.

Lilly in-licensed global rights to sintilimab a year ago, building on the China alliance they have with Innovent. That cost the pharma giant $200 million in cash upfront, which they plan to capitalize on now with a long-awaited plan to bust up the high-price market in lung cancer and other cancers that have created a market worth tens of billions of dollars.

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FDA hands ac­cel­er­at­ed nod to Seagen, Gen­mab's so­lo ADC in cer­vi­cal can­cer, but com­bo stud­ies look even more promis­ing

Biopharma’s resident antibody-drug conjugate expert Seagen has scored a clutch of oncology approvals in recent years, finding gold in what are known as “third-gen” ADCs. Now, another of their partnered conjugates is ready for prime time.

The FDA on Monday handed an accelerated approval to Seagen and Genmab’s Tivdak (tisotumab vedotin-tftv, or “TV”) in second-line patients with recurrent or metastatic cervical cancer who previously progressed after chemotherapy rather than PD-(L)1 systemic therapy, the companies said in a release.

Jay Bradner (Jeff Rumans for Endpoints News)

Div­ing deep­er in­to in­her­it­ed reti­nal dis­or­ders, No­var­tis gob­bles up an­oth­er bite-sized op­to­ge­net­ics biotech

Right about a year ago, a Novartis team led by Jay Bradner and Cynthia Grosskreutz at NIBR swooped in to scoop up a Cambridge, MA-based opthalmology gene therapy company called Vedere. Their focus was on a rather narrow market niche: inherited retinal dystrophies that include a wide range of genetic retinal disorders marked by the loss of photoreceptor cells and progressive vision loss.

But that was just the first deal that whet their appetite.

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The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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Ex­elix­is pulls a sur­prise win in thy­roid can­cer just days ahead of fi­nal Cabome­tyx read­out

Exelixis added a thyroid cancer indication to its super-seller Cabometyx’s label on Friday — months before the FDA was expected to make a decision, and days before the company was set to unveil the final data at #ESMO21.

At a median follow-up of 10.1 months, differentiated thyroid cancer patients treated with Cabometyx (cabozantinib) lived a median of 11 months without their disease worsening, compared to just 1.9 months for patients given a placebo, Exelixis said on Monday.

Dave Lennon, former president of Novartis Gene Therapies

Zol­gens­ma patent spat brews be­tween No­var­tis and Re­genxbio as top No­var­tis gene ther­a­py ex­ec de­parts

Regenxbio, a small licensor of gene therapy viral vectors spun out from the University of Pennsylvania, is now finding itself in the middle of some major league patent fights.

In addition to a patent suit with Sarepta Therapeutics from last September, Novartis, is now trying to push its smaller partner out of the way. The Swiss biopharma licensed Regenxbio’s AAV9 vector for its $2.1 million spinal muscular atrophy therapy Zolgensma.

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Volker Wagner (L) and Jeff Legos

As Bay­er, No­var­tis stack up their ra­dio­phar­ma­ceu­ti­cal da­ta at #ES­MO21, a key de­bate takes shape

Ten years ago, a small Norwegian biotech by the name of Algeta showed up at ESMO — then the European Multidisciplinary Cancer Conference 2011 — and declared that its Bayer-partnered targeted radionuclide therapy, radium-223 chloride, boosted the overall survival of castration-resistant prostate cancer patients with symptomatic bone metastases.

In a Phase III study dubbed ALSYMPCA, patients who were treated with radium-223 chloride lived a median of 14 months compared to 11.2 months. The FDA would stamp an approval on it based on those data two years later, after Bayer snapped up Algeta and christened the drug Xofigo.

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