FDA ex­perts turn thumbs down on Karyopharm’s trou­bled pitch for an ac­cel­er­at­ed OK — but not all of them

The Karyopharm team $KP­TI took on a tough chal­lenge on Tues­day, try­ing to over­come an over­whelm­ing­ly crit­i­cal re­view by FDA reg­u­la­tors in win­ning over a pan­el of out­side ex­perts brought in to re­view their pitch for an ac­cel­er­at­ed ap­proval of se­linex­or for mul­ti­ple myelo­ma.

They lost, but nev­er­the­less found con­sid­er­able sup­port for this drug among the pan­elists.

The pan­el vot­ed 8 to 5 against an ap­proval, say­ing af­fir­ma­tive­ly that the FDA should take a wait-and-see at­ti­tude un­til the ran­dom­ized piv­otal study wraps to­ward the end of the year.

Karyopharm’s stock — bat­tered last Fri­day — took an­oth­er tum­ble af­ter the bell, drop­ping 19%.

FDA rep­re­sen­ta­tives were po­lite about it, but out­lined mul­ti­ple prob­lems with the da­ta that Karyopharm pre­sent­ed: Miss­ing da­ta due to dropouts, un­ac­cept­able re­al world ev­i­dence, an ab­sence of ev­i­dence of pos­i­tive sin­gle agent ac­tiv­i­ty (there are neg­a­tive re­sults), most­ly par­tial re­spons­es and much, much more — all in­for­ma­tion that the biotech failed to spot­light in the lead-up to the NDA. In one study the FDA cit­ed, the over­all sur­vival rate was worse in the se­linex­or arm.

Then there was the tox­i­c­i­ty pro­file, with a high fre­quen­cy of treat­ment emer­gent ad­verse events among pa­tients tak­ing the drug. The agency cit­ed a 94% rate of grade 3 or grade 4 ad­verse event. 10 deaths were due to a fa­tal ad­verse event in the main sin­gle arm study used for the ac­cel­er­at­ed ap­proval. And 9 in 10 pa­tients re­quired a dose mod­i­fi­ca­tion, with a ma­jor­i­ty re­quir­ing 2 mod­i­fi­ca­tions.

Giv­en the lim­it­ed ef­fi­ca­cy and tox­i­c­i­ty, the FDA as­sert­ed, “it is un­clear whether the ben­e­fit out­weighs the risk.” 

That’s not some­thing you want to hear in a pan­el re­view.

Mean­while, a piv­otal tri­al is un­der­way, and if a pa­tient de­mand­ed it, there are av­enues that pa­tients could use to get the drug with­out an ac­cel­er­at­ed ap­proval.

The FDA’s on­col­o­gy pan­el is not a tough group, on av­er­age, to win over. There’s a big ap­petite for new drugs to treat can­cer pa­tients who have failed mul­ti­ple ther­a­pies, and a low bar on safe­ty. Not get­ting past that at this stage will like­ly set the bar high­er for when Karyopharm comes back with their piv­otal da­ta — pro­vid­ed that the agency goes ahead and re­jects it, as they have clear­ly in­di­cat­ed that they plan to.

The sig­nif­i­cant num­ber of votes in Karyopharm’s fa­vor, de­spite the FDA’s po­si­tion, does un­der­score just how anx­ious many of these ex­perts are about of­fer­ing ear­ly ap­provals, even when mul­ti­ple drugs are ap­proved for the same in­di­ca­tion. The bias is in fa­vor of more op­tions, which was clear­ly on dis­play here.

Dana Far­ber’s David Har­ring­ton joined the mi­nor­i­ty in fa­vor of pro­vid­ing an ac­cel­er­at­ed ap­proval. “The da­ta are not con­clu­sive in ei­ther di­rec­tion,” he said, but…”I think we do pa­tients some po­ten­tial ben­e­fit if this is used con­struc­tive­ly.”

Just a slight nudge in its fa­vor from reg­u­la­tors may well have been enough to win an ap­proval, de­spite the tri­al is­sues. And that once again gets back to whether the de­vel­op­ers have a close work­ing re­la­tion­ship with the agency.

The biotech’s case wasn’t good enough, though, with the ma­jor­i­ty sid­ing with the reg­u­la­tors who have the fi­nal say now. Tox­i­c­i­ty was a ma­jor is­sue with the ex­perts who sided against a quick OK.

At best, Karyopharm like­ly faces a lengthy de­lay re­fil­ing an NDA. And that is if the Phase III da­ta are pos­i­tive.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

No, sci­en­tists are not any clos­er to pig-to-hu­man trans­plants than they were last week

Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.

UP­DAT­ED: Agenus calls out FDA for play­ing fa­vorites with Mer­ck, pulls cer­vi­cal can­cer BLA at agen­cy's re­quest

While criticizing the FDA for what may be some favoritism towards Merck, Agenus on Friday officially pulled its accelerated BLA for its anti-PD-1 inhibitor balstilimab as a potential second-line treatment for cervical cancer because of the recent full approval for Merck’s Keytruda in the same indication.

The company said the BLA, which was due for an FDA decision by Dec. 16, was withdrawn “when the window for accelerated approval of balstilimab closed,” thanks to the conversion of Keytruda’s accelerated approval to a full approval four months prior to its PDUFA date.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 120,400+ biopharma pros reading Endpoints daily — and it's free.

Marty Duvall, Oncopeptides CEO

On­copep­tides stock craters as it pulls can­cer drug Pepax­to from the mar­ket

Shares of Oncopeptides crashed more than 70% in early Friday trading after the company said it’s pulling its multiple myeloma drug Pepaxto (melphalan flufenamide) from the US market after failing a confirmatory trial. The move will force the company to close its US and EU business units and enact significant layoffs.

The FDA had scheduled an adcomm meeting next Thursday to discuss Pepaxto, which first won accelerated approval in February and costs about $19,000 per course of treatment. The committee was to weigh in on whether the confirmatory trial demonstrated a worse overall survival in the treatment arm compared to the control arm.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 120,400+ biopharma pros reading Endpoints daily — and it's free.

How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data are messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data are exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Pfiz­er pitch­es its Covid-19 vac­cine for younger chil­dren ahead of ad­comm next week

Pfizer will present its case to the FDA’s vaccine adcomm next week, seeking authorization for a lower-dose version of its Covid-19 vaccine for kids ages 5 through 12, which the Biden administration said will likely begin rolling out early next month.

Two primary doses of the 10 µg vaccine (the dose for those ages 12 and up is 30 μg) given 3 weeks apart in this group of children “have shown a favorable safety and tolerability profile, robust immune responses against all variants of concern including Delta, and vaccine efficacy of 90.7% against laboratory-confirmed symptomatic COVID-19,” the company said in briefing documents ahead of next Tuesday’s meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.

Jay Flatley, new Zymergen CEO

Fol­low­ing Au­gust melt­down, Zymer­gen hints at sal­vage plans — cut­ting jobs and rene­go­ti­at­ing loans

Two months after a spectacular implosion that saw its founding CEO leave his post amid customer reports its only product didn’t work, Zymergen provided the first peek behind the curtain for its plans moving forward.

In an SEC filing Wednesday, Zymergen told regulators it would slash about 100 jobs and had renegotiated a $100 million loan from Perceptive that loomed like a storm cloud over the company, moving up the maturity date 18 months to June 30, 2022. Jed Dean, one of Zymergen’s three co-founders and VP of operations, will also step down at the end of the month.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 120,400+ biopharma pros reading Endpoints daily — and it's free.

Sanofi, Re­gen­eron etch out an­oth­er PhI­II vic­to­ry for Dupix­ent, eas­ing se­vere itch and clear­ing le­sions

Sanofi and Regeneron can boast of another inflammatory disease where Dupixent has proven effective.

The best-selling drug, which targets both IL-4 and IL-13, has delivered a clean sweep in a Phase III trial for prurigo nodularis, a chronic disease characterized by itch so intense that it can affect patients’ sleep and psychology. Thick skin lesions can cover most of the body.

On the primary endpoint, 37% of patients taking Dupixent saw a clinically meaningful reduction in itch compared to 22% of those on placebo (p=0.0216) at week 12. All secondary endpoints were also met, including clearance of skin lesions and improvement in quality of life.

David Lockhart, ReCode Therapeutics CEO

Pfiz­er throws its weight be­hind LNP play­er eye­ing mR­NA treat­ments for CF, PCD

David Lockhart did not see the meteoric rise of messenger RNA and lipid nanoparticles coming.

Thanks to the worldwide fight against Covid-19, mRNA — the genetic code that can be engineered to turn the body into a mini protein factory — and LNPs, those tiny bubbles of fat carrying those instructions, have found their way into hundreds of millions of people. Within the biotech world, pioneers like Alnylam and Intellia have demonstrated just how versatile LNPs can be as a delivery vehicle for anything from siRNA to CRISPR/Cas9.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 120,400+ biopharma pros reading Endpoints daily — and it's free.