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:

Hal Barron and Rick Klausner (GSK, Lyell)

Ex­clu­sive: GSK’s Hal Bar­ron al­lies with Rick Klaus­ner’s $600M cell ther­a­py start­up, look­ing to break new ground blitz­ing sol­id tu­mors

LONDON — Chances are, you’ve heard little or nothing about Rick Klausner’s startup Lyell. But that ends now.

Klausner, the former head of the National Cancer Institute, former executive director for global health at the Gates Foundation, co-founder at Juno and one of the leaders in the booming cell therapy field, has brought together one of the most prominent teams of scientists tackling cell therapy 2.0 — highlighted by a quest to bridge a daunting tech gap that separates some profound advances in blood cancers with solid tumors. And today he’s officially adding Hal Barron and GlaxoSmithKline as a major league collaborator which is pitching in a large portion of the $600 million he’s raised in the past year to make that vision a reality.

“We’ve being staying stealth,” Klausner tells me, then adding with a chuckle: “and going back to stealth after this.”

“Cell therapy has a lot of challenges,” notes Barron, the R&D chief at GSK, ticking off the resistance put up by solid tumors to cell therapies, the vein-to-vein time involved in taking immune cells out of patients, engineering them to attack cancer cells, and getting them back in, and more. “Over the years Rick and I talked about how it would be wonderful to take that on as a mission.”

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First place fin­ish: Eli Lil­ly just moved to fran­chise leader with their sec­ond mi­graine drug OK in 1 year

In a rare twist for Eli Lilly’s historically slow-moving R&D group, the pharma giant has seized bragging rights to a first-in-class new drug approval. And all signs point to an aggressive marketing followup as they look to outclass some major franchise rivals hobbled by internal dissension.

The FDA came through with an OK for lasmiditan on Friday evening, branding it as Reyvow and lining it up — once a substance classification comes through from the DEA — for a major market release. The oral drug binds to 5-HT1F receptors and is designed to stop an acute migraine after it starts. That makes it a complementary therapy to their CGRP drug Emgality, which has a statistically significant impact on preventing attacks.

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Pfizer, South San Francisco — Jeff Rumans for Endpoints News

UP­DAT­ED: Pfiz­er takes aim at a flag­ship fran­chise at Sanofi and Re­gen­eron — and scores a few di­rect hits

Count Pfizer in as a top player in the blockbuster game of JAK1 inhibitors.

Over the weekend the pharma giant posted some stellar Phase III efficacy data for their heavyweight contender abrocitinib in atopic dermatitis (eczema) that lines up ahead of a booming Dupixent (dupilumab), a blockbuster in the portfolios of Regeneron and Sanofi. And they put some real distance ahead of Eli Lilly’s trailing Olumiant, which made a delayed initial arrival on the market for rheumatoid arthritis after the FDA hobbled it with some additional hurdles on safety concerns.

JADE-MONO-1 scores well for Pfizer, teeing up what will be an intensely followed breakdown of the JADE MONO-2 data, which the pharma giant recently top-lined as “similar” to the first Phase III when tested against a placebo — a control group that has been easily outclassed by all the drugs in this market niche.

As of now, Pfizer looks to be equipped to run into the review stage — advantaged by a breakthrough therapy designation that is intended to speed up the regulatory process.

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Allogene HQ Open House on September 17, 2019 in South San Francisco. (Jeff Rumans, Endpoints News)

The next 10 years: Where is biotech head­ed?

The last 10 years have seen a revolution in drug development. Timelines have shortened, particularly in oncology. Regulators have opened up. Investment has skyrocketed. China became a player. Biotechs have multiplied as gene and cell therapy has exploded — offering major new advances in the way diseases are treated, and sometimes cured.

So where are we headed from here? I journeyed out to San Francisco in September to discuss the answer to that question at Allogene’s open house. If the last 10 years have been an eye-opener, what does the next decade hold in store?

Patrick Mahaffy, Getty Images

Court green-lights Clo­vis case af­ter de­tail­ing ev­i­dence the board ‘ig­nored red flags’ on false safe­ty and ef­fi­ca­cy da­ta

Clovis investors have cleared a major hurdle in their long-running case against the board of directors, with a Delaware court making a rare finding that they had a strong enough case against the board to proceed with the action.

In a detailed ruling at the beginning of the month that’s been getting careful scrutiny at firms specializing in biotech and corporate governance, the Delaware Court of Chancery found that the attorneys for the investors had made a careful case that the board — a collection of experts that includes high-profile biotech entrepreneurs, a Harvard professor and well-known investigator as well as Clovis CEO Patrick Mahaffy — repeatedly ignored obvious warnings that Mahaffy’s executive crew was touting inflated, unconfirmed data for their big drug Roci. Serious safety issues were also reportedly overlooked while the company continued a fundraising campaign that brought in more than a half-billion dollars. And that leaves the board open to claims related to their role in the fiasco.

The bottom line:

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Bill Gates backs Gink­go Biowork­s' $350M raise to fu­el the buzzy syn­thet­ic bi­ol­o­gy 'rev­o­lu­tion'

If you want to understand Ginkgo Bioworks, the name should suffice: Bioworks, a spin off “ironworks,” that old industrial linchpin devoted to leveraging scale as a wellspring for vast new industries capable of remaking society. Ginkgo wants to be the ironworks for the revolution it’s heralded with as much fanfare as they can, playing off of one of the buzziest technologies in biotech.

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UCB bags a ri­val to Soliris in $2.1B buy­out deal — but will an in­creas­ing­ly vig­i­lant FTC sign off?

UCB is buying out Ra Pharma $RARX, announcing an acquisition deal that rings up at $48 a share, or $2.1 billion net of cash, and puts them toe-to-toe with Alexion on a clinical showdown.

Ra shares closed at $22.70 on Wednesday.

There’s a small pipeline in play at Ra, but UCB is going for the lead drug — a C5 inhibitor called zilucoplan in Phase III for myasthenia gravis (MG) looking to play rival to Alexion’s Soliris. Soliris has the market advantage, though, with a much earlier approval in MG in late 2017 that UCB feels confident in challenging.

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A new play­er is tak­ing the field in a push for a he­mo­phil­ia A gene ther­a­py, and it’s a big one

BioMarin, the execs at Spark (and buyer-to-be Roche) as well as the Sangamo/Pfizer team have a new rival striding onto the hemophilia block. And it’s a big one.

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Stuck with a PhI­II gene ther­a­py fail­ure at 96 weeks, Gen­Sight prefers the up­beat as­sess­ment

Two years after treatment, the best thing that GenSight Biologics $SIGHT can say about their gene therapy for vision-destroying cases of Leber Hereditary Optic Neuropathy is that it’s just a bit better than a placebo — just maybe because one treatment can cover both eyes.

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