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:

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.

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 is 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 is 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.

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 120,300+ biopharma pros reading Endpoints daily — and it's free.

Bris­tol My­ers pledges to sell its Ac­celeron shares as ac­tivist in­vestors cir­cle Mer­ck­'s $11.5B buy­out — re­port

Just as Avoro Capital’s campaign to derail Merck’s proposed $11.5 billion buyout of Acceleron gains steam, Bristol Myers Squibb is leaning in with some hefty counterweight.

The pharma giant is planning to tender its Acceleron shares, Bloomberg reported, which add up to a sizable 11.5% stake. Based on the offer price, the sale would net Bristol Myers around $1.3 billion.

To complete its deal, Merck needs a majority of shareholders to agree to sell their shares.

Some can­cer pa­tients now have to find oth­er op­tions as Bris­tol My­er­s' Abrax­ane falls in­to short­age from man­u­fac­tur­ing woes

When Beth Hogan, a metastatic pancreatic cancer patient, showed up for her infusion at Yale’s Smilow Cancer Hospital in New Haven, CT on Oct. 11, she said she was informed that day that she would not be receiving Bristol Myers Squibb’s Abraxane, part of her combo treatment, because of a shortage.

“I was told we don’t know when you can have it,” she told Endpoints News via email, adding that she doesn’t expect to receive any Abraxane this coming Monday at her treatment appointment either, and she doesn’t know when things will change.

Michel Vounatsos, Biogen CEO (Credit: World Economic Forum/Valeriano Di Domenico)

Up­dat­ed: Bio­gen sells just $300K worth of Aduhelm in Q3, as ques­tions on long-term vi­a­bil­i­ty re­main

Barely anyone is accessing Biogen’s controversial Alzheimer’s treatment, with the company reporting just $0.3 million in Aduhelm sales in the third quarter. Although investors will be looking to the longer term, when CMS may decide to cover the drug and open the floodgates for more reimbursement, use of the drug is currently stalled.

Since June, when the FDA first signed off on the drug under its accelerated pathway, Biogen said Wednesday that it’s sold a total of $2 million worth of Aduhelm. That’s a far cry from the peak Wall Street sales estimate of about $9 billion in annual sales, and even a ways away from the sell-side consensus of about $17 million in Q3 sales.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 120,300+ biopharma pros reading Endpoints daily — and it's free.

Leen Kawas (L) has resigned as CEO of Athira and will be replaced by COO Mark Litton

Ex­clu­sive: Athi­ra CEO Leen Kawas re­signs af­ter in­ves­ti­ga­tion finds she ma­nip­u­lat­ed da­ta

Leen Kawas, CEO and founder of the Alzheimer’s upstart Athira Pharma, has resigned after an internal investigation found she altered images in her doctoral thesis and four other papers that were foundational to establishing the company.

Mark Litton, the company’s COO since June 2019 and a longtime biotech executive, has been named full-time CEO. Kawas, meanwhile, will no longer have ties to the company except for owning a few hundred thousand shares.

Endpoints Premium

Premium subscription required

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

Eli Lil­ly or­dered to pay roy­al­ties on block­buster di­a­betes drugs, though ex­act dam­ages are un­clear

A federal court found Eli Lilly in breach of a royalty agreement with an Arizona company, likely sending the case — which deals with Lilly’s blockbuster diabetes drugs — to a trial.

The Arizona District Court ordered Lilly to pay the royalties to Tucson, AZ-based Research Corporation Technologies, per an opinion delivered Tuesday, stemming from a 1990 agreement involving materials used in manufacturing Lilly’s insulin products. Lilly had agreed to pay a 2% royalty on worldwide sales, and the exact amount of damages will be determined in a trial, Judge Scott Rash wrote.

Sen. Richard Durbin (D-IL, foreground) and Sen. Richard Blumenthal (D-CT) (Patrick Semansky/AP Images)

Sen­a­tors back FDA's plan to re­quire manda­to­ry pre­scriber ed­u­ca­tion for opi­oids

Three Senate Democrats are backing an FDA plan to require mandatory prescriber education for opioids as overdose deaths have risen sharply over the past decade, with almost 97,000 American opioid-related overdose deaths in the past year alone.

While acknowledging a decline in overall opioid analgesic dispensing in recent years, the FDA said it’s reconsidering the need for mandatory prescriber training through a REMS given the current situation with overdoses, and is seeking input on the aspects of the opioid crisis that mandatory training could potentially mitigate.