FDA of­fi­cials: There was “no sci­en­tif­ic ba­sis” for Duchenne drug OK as Sarep­ta com­plained of “dire fi­nan­cial” con­di­tion

Janet Wood­cock

Two se­nior FDA of­fi­cials mount­ed a ve­he­ment as­sault on Janet Wood­cock’s de­ci­sion to push through an ap­proval of Sarep­ta’s Duchenne mus­cu­lar dy­s­tro­phy drug Ex­ondys 51. New doc­u­ments post­ed by the FDA, in­clud­ing a round of mem­os on the is­sue in Sep­tem­ber, warned FDA Com­mis­sion­er Robert Califf that he was al­low­ing an ap­proval even though Wood­cock had not con­sid­ered all the analy­sis they had done to un­der­score the com­pa­ny’s weak case, adding that there was no sci­en­tif­ic ba­sis to con­clude that the drug was rea­son­ably like­ly to ben­e­fit pa­tients.

The agency has al­ready post­ed some of the mem­os of­fered up in the lead-up to the ap­proval de­ci­sion, along with Califf’s de­ci­sion that he would de­fer to Wood­cock, who over­ruled the agency’s re­view­ers as well as Lu­ciano Bo­rio and El­lis Unger, the act­ing chief sci­en­tist and di­rec­tor of the Of­fice of Drug Eval­u­a­tion at the FDA. But these mem­os from Sep­tem­ber hit hard on their con­clu­sion that Wood­cock was de­vi­at­ing wide­ly from the agency’s stan­dards for an ap­proval in al­low­ing Ex­ondys 51 on the mar­ket af­ter the biotech had pro­vid­ed on­ly a “mere scin­til­la” of ev­i­dence of ef­fi­ca­cy.

Robert Califf

In a memo to Califf on Sep­tem­ber 14, Unger wrote that he had con­duct­ed an analy­sis of the ev­i­dence on dy­s­trophin pro­duc­tion, which Wood­cock did not take in­to con­sid­er­a­tion be­fore reach­ing her de­ci­sion:

I think it will be im­por­tant for the reg­u­la­to­ry record to re­flect that there was no sci­en­tif­ic ba­sis un­der­ly­ing the con­clu­sion of “rea­son­ably like­ly” in this case. This was sim­ply a judg­ment call by Dr. Wood­cock. (Dr. Wood­cock might have al­so tak­en the po­si­tion that, in this des­per­ate pa­tient pop­u­la­tion, any dy­s­trophin pro­duc­tion would suf­fice as a ba­sis for ac­cel­er­at­ed ap­proval, but she didn’t state this.)

In Unger’s opin­ion, the FDA al­so need­ed to more care­ful­ly con­sid­er the im­pact the de­ci­sion on eteplirsen would have on oth­er rare dis­ease drug ap­pli­ca­tions:

We all agree that each sit­u­a­tion must be eval­u­at­ed on its own mer­its; how­ev­er, I fail to see how DMD dif­fers in­trin­si­cal­ly from oth­er rare neu­ro­log­i­cal dis­eases, e.g., Alexan­der dis­ease, Cana­van dis­ease, Ear­ly in­fan­tile GM1 gan­gliosi­do­sis, Krabbe dis­ease, Metachro­mat­ic leukody­s­tro­phy, Nie­mann–Pick dis­ease, Pelizaeus–Merzbach­er dis­ease, Pompe dis­ease, Sand­hoff dis­ease, and X- linked adrenoleukody­s­tro­phy. Based on what you have writ­ten in your draft memo, it is not clear to me why a stan­dard of any in­crease in the sur­ro­gate end­point wouldn’t ap­ply for these dis­eases.

“Per­haps grant­i­ng ac­cel­er­at­ed ap­proval to drugs that show a mere scin­til­la of an ef­fect on a sur­ro­gate end­point rep­re­sents a stroke of bril­liance – one that will stim­u­late in­vest­ment in the de­vel­op­ment of drugs for these dis­or­ders. But in my opin­ion, this ap­proach should re­ceive broad­er pub­lic (and FDA) in­put be­fore be­ing im­ple­ment­ed.

Unger al­so not­ed:

Her (Wood­cock’s) is­suance of a de­ci­sion­al mem­o­ran­dum pri­or to care­ful con­sid­er­a­tion of my fi­nal re­view rep­re­sents a crit­i­cal de­vi­a­tion from pro­to­col….

Un­aware of my fi­nal con­clu­sions on this mat­ter, Dr. Wood­cock did not re­but the above rea­son­ing. As I not­ed (and the SDR Board ap­peared to agree), she pro­vid­ed no co­gent ra­tio­nale for her de­ci­sion that the bare­ly de­tectable amount of dy­s­trophin pro­duced is “rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit.

Calif, though, had al­ready made up his mind the day be­fore:

I have con­clud­ed that al­though I be­lieve that both views are ra­tio­nal and re­flect ex­tra­or­di­nary ded­i­ca­tion to the top­ic, there is no ba­sis up­on which I should over­rule Dr. Wood­cock’s de­ci­sion, and that ad­di­tion­al ex­ter­nal re­view is not in­di­cat­ed.

Lu­ciano Bo­ria, the act­ing chief sci­en­tist, al­so crit­i­cized Califf for fail­ing to grap­ple with the “mi­nus­cule” amount of da­ta that Sarep­ta had of­fered. In a memo dat­ed Sep­tem­ber 14, Bo­rio wrote Califf:

(Y)our draft de­ci­sion­al memo seems to down­play the sig­nif­i­cance of the very small amount of dy­s­trophin re­port­ed in the eteplirsen NDA (see, e.g., pages 4-5 of your draft de­ci­sion­al memo). In fact, your draft de­ci­sion­al memo nev­er once cites the 0.3% in­crease in dy­s­trophin pro­duc­tion shown by Study 301 (or the 0.93% de­tect­ed in Stud­ies 201/202). In­stead, your draft de­ci­sion­al memo at­trib­ut­es the sci­en­tif­ic dis­agree­ment to: (1) a lack of con­sen­sus on the ap­pro­pri­ate thresh­old for clin­i­cal ben­e­fit both with­in CDER and in the sci­en­tif­ic lit­er­a­ture, and (2) con­cerns re­gard­ing the cor­re­la­tion be­tween dy­s­trophin pro­duc­tion and clin­i­cal out­comes in Study 201/202. To me, the crux of the dis­agree­ment is not whether there is an ap­pro­pri­ate thresh­old, but whether such a minis­cule (sic) amount of dy­s­trophin is rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit. Your draft de­ci­sion­al memo does not ad­dress that is­sue. In my view, it is not suf­fi­cient to say that no thresh­old has been es­tab­lished and that, there­fore, any in­crease in dy­s­trophin pro­duc­tion is rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit.

In the months ahead of the show­down in­side the FDA, reg­u­la­tors re­peat­ed­ly ex­pressed their will­ing­ness to help speed the work they asked for to pro­vide ad­di­tion­al ev­i­dence of dy­s­trophin pro­duc­tion, which pro­voked Sarep­ta’s Shamim Ruff, their head of reg­u­la­to­ry af­fairs, to fret about the “dire fi­nan­cial con­straints” the com­pa­ny was forced to deal with as a re­sult of the de­lays at the FDA.

“We must start the process by June 6, 2016,” Ruff wrote.”There is no room for flex­i­bil­i­ty with this date due to our dire fi­nan­cial con­straints as a re­sult of the on­go­ing de­lays.”

Here’s a look at all the doc­u­ments re­leased by the FDA:

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

Kathy High (file photo)

Gene ther­a­py pi­o­neer Kathy High has left Spark af­ter com­plet­ing $4.3B union with Roche

Kathy High dedicated the past seven years of her life shepherding experimental gene therapies she’s developed at Children’s Hospital of Philadelphia toward the market as president and head of R&D at Spark Therapeutics. Now that the biotech startup is fully absorbed into Roche — with an FDA approval, a $4.3 billion buyout and a promising hemophilia program to boast — she’s ready to move on.

Roche confirmed her departure with Endpoints News and noted “she will take some well-deserved time off and then will begin a new chapter in a sabbatical at a university.”

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Deborah Dunsire

The fourth CGRP mi­graine drug is here. Time for Lund­beck to prove it's worth $2B

They may be late, but Lundbeck is now officially in the game for preventing migraine with CGRP drugs.

The FDA has OK’d eptinezumab, the prize in Lundbeck’s $2 billion acquisition of Alder. Like rival offerings from Amgen/Novartis, Eli Lilly and Teva, the antibody blocks the calcitonin gene-related peptide, which is believed to dilate blood vessels in the brain and cause pain.

It will now be sold as Vyepti. The company has yet to announce a price. Amgen and Novartis had set the wholesale acquisition cost of their pioneering Aimovig at $6,900 for a year’s supply before raising it slightly this year; Lilly and Teva had followed suit with Emgality and Ajovy.

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Tal Zaks (Moderna via YouTube)

For two decades, a new vac­cine tech­nol­o­gy has been slow­ly ap­proach­ing prime time. Now, can it stop a pan­dem­ic?

Two months before the outbreak, Moderna CMO Tal Zaks traveled from Cambridge, MA to Washington DC to meet with Anthony Fauci and the leaders of the National Institutes of Health.

For two years, Moderna had worked closely with NIH researchers to build a new kind of vaccine for MERS, one of the deadliest new viruses to emerge in the 21st century. The program was one test for a new technology designed to be faster, cheaper and more precise than the ways vaccines had been made for over a century. They had gathered evidence the technology could work in principle, and Fauci, the longtime head of the National Institute of Allergy and Infectious Diseases and a longtime advocate for better epidemic preparedness, wanted to see if it, along with a couple of other approaches, could work in a worst-case scenario: A pandemic.

“[We were] trying to find a test case for how to demonstrate if our technology could rapidly prepare,” Zaks told Endpoints News.

Zaks and Fauci, of course, wouldn’t have to wait to develop a new test. By year’s end, an outbreak in China would short circuit the need for one and throw them into 24/7 work on a real-world emergency. They also weren’t the only ones with new technology who saw a chance to help in a crisis.

An ocean away, Lidia Oostvogels was still on vacation and relaxing at her mother’s house in Belgium when her Facebook started changing. It was days after Christmas and on most people’s feeds, the news that China had reported a novel virus to the World Health Organization blurred into the stream of holiday sweaters and fir trees. But on Oostvogels’s feed, full of vaccine researchers and virus experts, speculation boiled: There was a virus in China, something contained to the country, but “exotic,” “weird,” and maybe having to do with animals. Maybe a coronavirus.

Lidia Oostvogels

“I was immediately thinking like, ‘Hey, this is something that if needed, we can play a role,'” Oostvogels told Endpoints.

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Christos Kyratsous (via LinkedIn)

He built a MERS treat­ment in 6 months and then the best Ebo­la drug. Now Chris­tos Kyrat­sous turns his sights on Covid-19

TARRYTOWN, NY — In 2015, as the Ebola epidemic raged through swaths of West Africa, Kristen Pascal’s roommates sat her down on their couch and staged an intervention.

“Are you sure this is what you want to be doing with your life?” she recalls them asking her.

Special report

Pascal, a research associate for Regeneron, had been coming home at 2 am and leaving at 6 am. At one point, she didn’t see her roommate for a week. For months, that was life in Christos Kyratsous’ lab as the pair led a company-wide race to develop the first drug that could effectively treat Ebola before the outbreak ended. For Pascal, that was worth it.

“I’m ok, I don’t have Ebola,” Pascal told them. “I see that death toll rising and I can’t not do something about it.”

Last August, Regeneron learned they had succeeded: In a large trial across West Africa, their drug, REGN-EB3, was vastly more effective than the standard treatments. It was surprise news for the company, coming just 10 months into a trial they thought would take several years and a major victory in the global fight against a deadly virus that killed over 2,000 in 2019 and can carry a mortality rate of up to 90%.

For Kyratsous and Pascal, though, it brought only fleeting reprieve. Just four months after the NIH informed them REGN-EB3 worked, Kyratsous was back in his office reading the New York Times for updates on a new outbreak on another continent, and wondering alongside Pascal and senior management whether it was time to pull the trigger again.

In late January, as the death toll swelled and the first confirmed cases outside China broke double digits, they made a decision. Soon they were back on the phone with the multiple government agencies and their coronavirus partners at the University of Maryland’s Level 3 bio lab. The question was simple: Can Kyratsous and his team use a process honed over two previous outbreaks, and create a treatment before the newest epidemic ends? Or worse, if, as world health experts fear, it doesn’t vanish but becomes a recurrent virus like the flu?

“Christos likes things immediately,” Matt Frieman, Regeneron’s coronavirus collaborator at the University of Maryland, told Endpoints. “That’s what makes us good collaborators: We push each other to develop things faster and faster.”

Kristen Pascal (Regeneron)

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The first time Regeneron tried to respond to a global outbreak, it was something of a systems test, Kyratsous explains from his office at Regeneron’s Tarrytown headquarters. Kyratsous, newly promoted, has crammed it with photos of his family, sketches of viral vectors and a shark he drew for his 3-year-old son. He speaks rapidly – an idiosyncrasy his press person says has only been aggravated this afternoon by the contents of his “Regeneron Infectious Diseases”-minted espresso glass – and he gesticulates with similar fluidity, tumbling through antibodies, MERS, the novel coronavirus, Ebola-infected monkeys.

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Tim Mayleben (file photo)

Es­pe­ri­on's goldilocks cho­les­terol fight­er wins FDA ap­proval — will its 'tra­di­tion­al' pric­ing ap­proach spur adop­tion?

It’s more effective than decades-old statins but not as good as the injectable PCSK9 — the goldilocks treatment for cholesterol-lowering, bempedoic acid, has secured FDA approval.

Its maker, Esperion Therapeutics, is betting that their pricing strategy — a planned list price of between $10 to $11 a day — will help it skirt the pushback the PCSK9 cholesterol fighters, Repatha and Praluent, got from payers for their high sticker prices.

The sky-high expectations for the pair of PCSK9 drugs that were first approved in 2015 quickly simmered — and despite a 60% price cut, coupled with data showing the therapies also significantly cut cardiovascular risk, sales have not really perked up.

Esperion is convinced that by virtue of being a cheaper oral therapy, bempedoic acid will hit that sweet spot in terms of adoption.

“We’re kind of like the old comfortable shoe,” Esperion’s chief commercial officer Mark Glickman remarked in an interview with Endpoints News ahead of the decision date. “It’s an oral product, once-daily and nontitratable — these are things that just resonate so true with patients and physicians and I think we’ve kind of forgotten about that.”

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James Collins, Broad Institute via Youtube

UP­DAT­ED: A space odyssey for new an­tibi­otics: MIT's ma­chine learn­ing ap­proach

Drug development is complex, expensive and comes with lousy odds of success — but in most cases, if you make it across the finish line brandishing a product with an edge (and play your cards right) it can be a lucrative endeavor.

As it stands, the antibiotic market is cursed — it harbors the stink of multiple bankruptcies, a dearth of innovation, and is consequently barely whetting the voracious appetites of big pharma or venture capitalists. Enter artificial intelligence — the biopharma industry’s cure-all for the pesky process of making a therapeutic, including data mining, drug discovery, optimal drug delivery, and addressable patient population.

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Gilead los­es two more patent chal­lenges on HIV pill, set­ting up court­room fight in Delaware

Gilead sustained two more losses in their efforts to rid themselves of an activist-backed patent lawsuit from the US government over a best-selling HIV pill.

Urged on by activists seeking to divert a portion of Gilead’s revenue to clinics and prevention programs, the Department of Health and Human Services made a claim to some of the patents for the best-selling HIV prevention drug, Truvada, also known as PrEP. Gilead responded by arguing in court that HHS’s patents were invalid.

Today, the US Patent and Trademark Office ruled that Gilead was likely to lose the last two of those challenges as well. The USPTO ruled against Gilead on the first two patents earlier this month.

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Jim Scholefield via PR Newswire

Mer­ck los­es its chief dig­i­tal of­fi­cer, spot­light­ing tal­ent hunt for the hottest ti­tle in Big Phar­ma

Over the last few years we’ve seen the chief digital officer title become one of the hottest commodities in Big Pharma as global organizations hunt the best talent to sharpen the cutting edge of their tech platforms.

But Merck just discovered how hard it may be to keep them focused on pharma.

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