The Sarep­ta dilem­ma: Bioethics ex­pert Arthur Ca­plan says it’s time to re­think how to reg­u­late com­pas­sion

Arthur Ca­plan was nev­er en­thu­si­as­tic about the idea of an FDA ap­proval for Ex­ondys 51 (eteplirsen) for Duchenne mus­cu­lar dy­s­tro­phy. When it came through, the not­ed NYU bioethics ex­pert saw it as a de­vi­a­tion from the FDA’s poli­cies on how drugs should be stud­ied and re­viewed, fo­cus­ing on safe­ty and a clear sig­nal of ef­fi­ca­cy.

But there were a lot of things wrong with it.

“The tri­al was poor,” Ca­plan tells me, “and even with small num­bers I think it could have been done bet­ter.” The ve­he­ment pub­lic lob­by­ing by Duchenne fam­i­lies to get it across the fin­ish line al­so didn’t con­vince him that the agency need­ed to make it avail­able.

“Some­times, peo­ple see what they want to see,” he says. “And some­times they’re right. It’s an iffy ba­sis for ap­prov­ing things.”

But this isn’t a sto­ry about a promi­nent bioethi­cist ob­ject­ing to the FDA’s con­tro­ver­sial rul­ing, which hinged en­tire­ly on Janet Wood­cock’s will­ing­ness to over­ride her col­leagues.

At this point, says Ca­plan, de­bat­ing over whether the FDA should or should not have ap­proved the drug is dis­tract­ing from the re­al is­sues at hand. Sarep­ta, he says, was a shot across the bow of the FDA and bio­phar­ma.

“Let’s use the Sarep­ta bat­tle to re­vis­it where we are with com­pas­sion­ate use, what con­sti­tutes ev­i­dence, what will be ac­cept­ed as ev­i­dence and who pays for col­lec­tion of the ev­i­dence and ul­ti­mate­ly ear­ly ac­cess,” says Ca­plan.

Be­cause the next Sarep­ta will be right around the next cor­ner. Fol­lowed by the next, the next and.…

“The FDA should be think­ing hard about this,” says Ca­plan. “This is the first in what will be a long pa­rade of dis­eases that af­fects small num­bers of pa­tients.

“We’re try­ing to bal­ance the chal­lenge of com­pas­sion­ate use against ap­proval and I think we have to re­vis­it the whole sub­ject,” says Ca­plan. “This is a trig­ger to re-ex­am­ine what are we go­ing to do down the road. Are ex­pand­ed ac­cess guide­lines ad­e­quate? Is it time to start re­think­ing what sort of in­for­ma­tion can be pro­vid­ed as ev­i­dence? What about ul­tra rare dis­eases, where the num­bers are small?   What should reg­u­la­tors ex­pect in terms of ‘ev­i­dence’”

Just con­sid­er gene ther­a­py, which is tar­get­ing path­ways where the num­bers are of­ten tiny.

“We have to start to re­think what con­sti­tutes ‘ad­e­quate’ and ‘suf­fi­cient’ ev­i­dence,” do we need more manda­to­ry ex­ten­sive Phase 4 mon­i­tor­ing than now oc­curs he says.

How should de­vel­op­ers and the FDA think about eval­u­at­ing hope­ful ear­ly signs of ef­fi­ca­cy? What tar­gets should you go af­ter? Where should sur­ro­gate end­points play a big role?

“To­day’s tri­al de­signs are not up to what has been ex­pect­ed in terms of ev­i­dence,” says Ca­plan, “and do­ing this on the fly doesn’t make a lot of sense.”

The FDA is be­hind the curve on where the sci­ence is and where con­sumer pres­sures are be­ing ap­plied. If they had been up to speed, says Ca­plan, Sarep­ta could have been guid­ed much ear­li­er to pro­vide more rel­e­vant da­ta with what they had.

“I don’t think they col­lect­ed enough sys­tem­at­ic in­for­ma­tion,” says the ethi­cist. “The FDA might have de­mand­ed more ear­li­er. The com­pa­ny could have done more.”

And how can you even run tri­als when a drug is made avail­able ear­ly to small pa­tient groups with very rare dis­eases through com­pas­sion­ate use, which might be a bet­ter way to go for pa­tients than a place­bo tri­al?

Un­der the old so­cial con­tract be­tween drug com­pa­nies and pa­tients, says Ca­plan, if pa­tients were will­ing to run the risk of be­ing in the con­trol arm, they could sign up for a tri­al to help prove if a drug worked or not — and might get it. In the process, they were will­ing to take a big risk to gain ac­cess and help the process of drug de­vel­op­ment.

That kind of arrange­ment no longer works for pa­tients.

“The new deal is, I want the drug,” says Ca­plan, “I want to help me. So pa­tient groups praise these new drugs, say­ing every­thing is great, I want the drug.”

And they don’t want to be left pay­ing for it out of pock­et, ei­ther, es­pe­cial­ly if you’re talk­ing about a $300,000 a year bill for a rare dis­ease ther­a­py like Ex­ondys 51. But then, nei­ther do in­sur­ers like An­them, which an­nounced late last week that they wouldn’t re­im­burse for a drug the in­sur­er has de­ter­mined is still ex­per­i­men­tal.

“Of course it’s an ex­per­i­men­tal drug,” Ca­plan re­sponds. “They’re not go­ing to be bound by that kind of an FDA de­ci­sion un­til they think there’s ad­e­quate ev­i­dence. And this is es­pe­cial­ly true since it’s very ex­pen­sive.”

So who does pay for these? Of­ten, small biotechs like Sarep­ta can’t af­ford to pay. So when Ca­plan hears state and Fed­er­al law­mak­ers talk about the right to try, he won­ders why they don’t im­me­di­ate­ly start dis­cussing how they pro­pose to pro­vide the funds to pay for it.

That’s an­oth­er part of the dis­cus­sion that’s miss­ing in ac­tion in this de­bate, says the ethi­cist. And it’s past time for the in­dus­try, the FDA, law­mak­ers and pa­tient groups to grap­ple with the re­al­i­ty of cost and all the sci­en­tif­ic is­sues now.

Time has run short for tak­ing a com­pre­hen­sive look at one of the most dif­fi­cult top­ics in the in­dus­try—how best to reg­u­late com­pas­sion.

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

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.

Endpoints Premium

Premium subscription required

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

As­traZeneca touts Imfinzi im­munother­a­py com­bos for lung can­cer in push to dri­ve PD-L1 drug up­take

Facing the big dogs in the PD-(L)1 space, AstraZeneca has taken its own contender Imfinzi into blockbuster territory in its four years on the market but sees even bigger things for the drug. Combinations could be the key, and early results from a mid-stage test are adding some fuel to that strategy.

Imfinzi combined with one of two investigational immunotherapies — a CD73 antibody dubbed oleclumab or an anti-NGK2a named monalizumab — topped Imfinzi alone in terms of overall response and progression-free survival in patients with stage III non-small cell lung cancer whose tumors had not worsened during concurrent chemoradiation, according to interim data from the Phase II COAST trial set to be presented at #ESMO21.

Amgen VP of R&D David Reese

Am­gen rolls out da­ta for KRAS in­hibitor com­bo study in col­orec­tal can­cer, hop­ing to move on from ug­ly ear­ly re­sults

With the first win for its KRAS inhibitor sotorasib in hand, Amgen is pushing ahead with an aggressive clinical plan to capitalize on its first-to-market standing. The drugmaker thinks combinations — in-house or otherwise — could offer a path forward, and one early readout from that strategy is bearing fruit.

A combination of Amgen’s sotorasib and its EGFR inhibitor Vectibix posted an overall response rate of 27% in 26 patients with advanced colorectal cancer (CRC) with the KRAS-G12C mutation, according to data from the larger Phase Ib/II CODEBREAK 101 study set to present at this weekend’s virtual ESMO Congress.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 117,500+ biopharma pros reading Endpoints daily — and it's free.

Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Eu­ro­pean study finds that Gilead­'s Covid-19 an­tivi­ral remde­sivir shows no clin­i­cal ben­e­fit

Gilead’s remdesivir — or Veklury, as it’s marketed in the US — raked in around $2.8 billion last year as the only FDA-approved antiviral to treat Covid-19. But new data from a European study suggest the drug, which has been given to about half of hospitalized Covid patients in the country, has no actual benefit.

The open-label DisCoVeRy trial enrolled Covid-19 patients across 48 sites in Europe to test a handful of treatments, including remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, and hydroxychloroquine. To participate, patients had to show symptoms for seven days and require oxygen support. A total of 429 patients were randomized to receive remdesivir plus standard of care, while 428 were assigned to standard of care alone.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 117,500+ biopharma pros reading Endpoints daily — and it's free.

Gri­fols drops $1B on Ger­man hold­ing com­pa­ny in con­tin­ued plas­ma push

One Spanish biotech is beefing up its plasma therapy operations, and on Friday, it announced that it’s doing so in a billion-dollar deal.

Grifols is now the largest shareholder of Biotest, a company valued at more than $1.8 billion. By teaming up, the two will try to increase the number of plasma therapies available and increase patient access around the world, Grifols said in a press release.

The company did so by acquiring holding company Tiancheng Pharmaceutical, the Germany-based owner of nearly 90% of Biotest shares, for nearly $1.27 billion. Grifols now owns nearly 90% of Biotest voting rights and almost 45% of the total share capital of Biotest.

Covid-19 roundup: FDA re­veals boost­er ad­comm ques­tion; Eli Lil­ly's an­ti­body cock­tail cleared for pre­ven­tion

The FDA released briefing documents this week from the agency and Pfizer each outlining their arguments for today’s Covid-19 booster shot adcomm, but one thing conspicuously missing was the question on which panel members would be voting. But late Thursday night, regulators published that question.

Adcomm members will be asked whether or not the safety and efficacy data from Pfizer/BioNTech’s original Phase III study “support approval” of a booster shot at least six months after the second dose in individuals older than 16. The question notably excludes the real-world data from Israel and other analyses that Pfizer and the Biden administration had said would be a centerpiece of their arguments for boosters.

A Pfiz­er part­ner wel­comes ex-ADC Ther­a­peu­tics CMO Jay Fein­gold to the team; Amid tough sled­ding, Im­muno­vant choos­es Eli Lil­ly alum as CFO

→ Last week we told you about the CMO revolving door at ADC Therapeutics, as Joseph Camardo replaced the departing Jay Feingold. The next opportunity for Feingold in the CMO slot has opened up at antibody-drug conjugate and mAb developer Pyxis Oncology, which has added several new execs and scientific advisory board members in recent months, including ex-Immunovant CFO Pamela Yanchik Connealy. Before his tenure at ADC, Feingold was Daiichi Sankyo’s VP of US medical affairs and chairman of the Global Medical Affairs Oversight Committee. Within weeks in March, Pyxis struck a licensing deal with Pfizer for two of its ADCs and raked in $152 million from a Series B round.

Multiple antibiotic resistant Pseudomonas aeruginosa bacterium

A new way to in­fil­trate (and de­stroy) some of the dead­liest drug-re­sis­tant bugs

About four years ago, Ruben Tommasi, the gregarious scientific chief of antibiotics startup Entasis, walked into a meeting with his top chemist and top biologist to chew over another batch of unchanging results.

“It felt like we were running the same experiment over and over,” Tommasi told Endpoints News. “We had all sort of come to that point in time where we felt like we were banging our heads against the wall.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 117,500+ biopharma pros reading Endpoints daily — and it's free.