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.

Vlad Coric (Biohaven)

In an­oth­er dis­ap­point­ment for in­vestors, FDA slaps down Bio­haven’s re­vised ver­sion of an old ALS drug

Biohaven is at risk of making a habit of disappointing its investors. 

Late Friday the biotech $BHVN reported that the FDA had rejected its application for riluzole, an old drug that they had made over into a sublingual formulation that dissolves under the tongue. According to Biohaven, the FDA had a problem with the active ingredient used in a bioequivalence study back in 2017, which they got from the Canadian drugmaker Apotex.

Norbert Bischofberger. Kronos

Backed by some of the biggest names in biotech, Nor­bert Bischof­berg­er gets his megaround for plat­form tech out of MIT

A little over a year ago when I reported on Norbert Bischofberger’s jump from the CSO job at giant Gilead to a tiny upstart called Kronos, I noted that with his connections in biotech finance, that $18 million launch round he was starting off with could just as easily have been $100 million or more.

With his first anniversary now behind him, Bischofberger has that mega-round in the bank.

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Chas­ing Roche's ag­ing block­buster fran­chise, Am­gen/Al­ler­gan roll out Avastin, Her­ceptin knock­offs at dis­count

Let the long battle for biosimilars in the cancer space begin.

Amgen has launched its Avastin and Herceptin copycats — licensed from the predecessors of Allergan — almost two years after the FDA had stamped its approval on Mvasi (bevacizumab-awwb) and three months after the Kanjinti OK (trastuzumab-anns). While the biotech had been fielding biosimilars in Europe, this marks their first foray in the US — and the first oncology biosimilars in the country.

Seer adds ex-FDA chief Mark Mc­Clel­lan to the board; Her­cules Cap­i­tal makes it of­fi­cial for new CEO Scott Bluestein

→ On the same day it announced a $17.5 million Series C, life sciences and health data company Seer unveiled that it had lured former FDA commissioner and ex-CMS administrator Mark McClellan on to its board. “Mark’s deep understanding of the health care ecosystem and visionary insights on policy reform will be crucial in informing our thinking as we work to bring our liquid biopsy and life sciences products to market,” said Seer chief and founder Omid Farokhzad in a statement.

Daniel O'Day

No­var­tis hands off 3 pre­clin­i­cal pro­grams to the an­tivi­ral R&D mas­ters at Gilead

Gilead CEO Daniel O’Day’s new task hunting up a CSO for the company isn’t stopping the industry’s dominant antiviral player from doing pipeline deals.

The big biotech today snapped up 3 preclinical antiviral programs from pharma giant Novartis, with drugs promising to treat human rhinovirus, influenza and herpes viruses. We don’t know what the upfront is, but the back end has $291 million in milestones baked in.

Vas Narasimhan, AP Images

On a hot streak, No­var­tis ex­ecs run the odds on their two most im­por­tant PhI­II read­outs. Which is 0.01% more like­ly to suc­ceed?

Novartis CEO Vas Narasimhan is living in the sweet spot right now.

The numbers are running a bit better than expected, the pipeline — which he assembled as development chief — is performing and the stock popped more than 4% on Thursday as the executive team ran through their assessment of Q2 performance.

Year-to-date the stock is up 28%, so the investors will be beaming. Anyone looking for chinks in their armor — and there are plenty giving it a shot — right now focus on payer acceptance of their $2.1 million gene therapy Zolgensma, where it’s early days. And CAR-T continues to underperform, but Novartis doesn’t appear to be suffering from it.

So what could go wrong?

Actually, not much. But Tim Anderson at Wolfe pressed Narasimhan and his development chief John Tsai to pick which of two looming Phase III readouts with blockbuster implication had the better odds of success.

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Francesco De Rubertis

Medicxi is rolling out its biggest fund ever to back Eu­rope's top 'sci­en­tists with strange ideas'

Francesco De Rubertis built Medicxi to be the kind of biotech venture player he would have liked to have known back when he was a full time scientist.

“When I was a scientist 20 years ago I would have loved Medicxi,’ the co-founder tells me. It’s the kind of place run by and for investigators, what the Medicxi partner calls “scientists with strange ideas — a platform for the drug hunter and scientific entrepreneur. That’s what I wanted when I was a scientist.”

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Af­ter a decade, Vi­iV CSO John Pot­tage says it's time to step down — and he's hand­ing the job to long­time col­league Kim Smith

ViiV Healthcare has always been something unique in the global drug industry.

Owned by GlaxoSmithKline and Pfizer — with GSK in the lead as majority owner — it was created 10 years ago in a time of deep turmoil for the field as something independent of the pharma giants, but with access to lots of infrastructural support on demand. While R&D at the mother ship inside GSK was souring, a razor-focused ViiV provided a rare bright spot, challenging Gilead on a lucrative front in delivering new combinations that require fewer therapies with a more easily tolerated regimen.

They kept a massive number of people alive who would otherwise have been facing a death sentence. And they made money.

And throughout, John Pottage has been the chief scientific and chief medical officer.

Until now.

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H1 analy­sis: The high-stakes ta­ble in the biotech deals casi­no is pay­ing out some record-set­ting win­nings

For years the big trend among dealmakers at the major players has been centered on ratcheting down upfront payments in favor of bigger milestones. Better known as biobucks for some. But with the top 15 companies competing for the kind of “transformative” pacts that can whip up some excitement on Wall Street, with some big biotechs like Regeneron now weighing in as well, cash is king at the high stakes table.

We asked Chris Dokomajilar, the head of DealForma, to crunch the numbers for us, looking over the top 20 deals for the past decade and breaking it all down into the top alliances already created in 2019. Gilead has clearly tipped the scales in terms of the coin of the bio-realm, with its record-setting $5 billion upfront to tie up to Galapagos’ entire pipeline.

Dokomajilar notes:

We’re going to need a ‘three comma club’ for the deals with over $1 billion in total upfront cash and equity. The $100 million-plus club is getting crowded at 164 deals in the last decade with new deals being added towards the top of the chart. 2019 already has 14 deals with at least $100 million in upfront cash and equity for a total year-to-date of over $9 billion. That beats last year’s $8 billion and sets a record.

Add upfronts and equity payments and you get $11.5 billion for the year, just shy of last year’s record-setting $11.8 billion.

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