Se­nior FDA of­fi­cials warned that ap­prov­ing $300,000 Duchenne drug will low­er agency stan­dards

In the end, Sarep­ta did many things wrong when it came to de­vel­op­ing a new drug for Duchenne mus­cu­lar dy­s­tro­phy. But it got one very im­por­tant part right. The biotech, with the sup­port of a le­gion of ad­vo­cates in the pa­tient com­mu­ni­ty, won over Janet Wood­cock to their side ear­ly on.

The pow­er­ful CDER di­rec­tor pushed for an ap­proval even in the face of a heat­ed de­bate in­side the FDA, as se­nior of­fi­cials weighed in in op­po­si­tion to her stand. The act­ing chief sci­en­tist at the agency, Lu­ciana Bo­rio, ar­gued that an ap­proval would low­er the agency’s stan­dards and en­cour­age oth­er de­vel­op­ers to pur­sue the same kind of lob­by­ing cam­paigns em­ployed at Sarep­ta. And she ac­cused Sarep­ta of act­ing ir­re­spon­si­bly by know­ing­ly push­ing “mis­lead­ing” in­for­ma­tion about the drug. El­lis Unger, di­rec­tor of the of­fice of drug eval­u­a­tion, scoffed at the da­ta Sarep­ta of­fered, call­ing the drug a “sci­en­tif­i­cal­ly el­e­gant place­bo.”

But FDA Com­mis­sion­er Robert Califf re­fused to over­rule Wood­cock’s de­ci­sion to OK eteplirsen, de­spite shar­ing some of the ma­jor ob­jec­tions raised by of­fi­cials who op­posed putting this drug on the mar­ket at Sarep­ta’s price of $300,000 a year.

Califf’s sum­ma­ry re­view of the ex­tra­or­di­nary show­down over eteplirsen point to prob­lems that would have eas­i­ly killed prac­ti­cal­ly any oth­er mar­ket­ing ap­pli­ca­tion. But with the cen­ter di­rec­tor tak­ing a pas­sion­ate stand in fa­vor of the drug, the com­mis­sion­er says he de­cid­ed that he would de­fer to Wood­cock in view of his lack of tech­ni­cal ex­per­tise in the mat­ter and a suf­fi­cient record of ev­i­dence to war­rant its move in­to the mar­ket.

Both Unger and Bo­rio op­posed Wood­cock’s de­ci­sion to grant an ac­cel­er­at­ed ap­proval for eteplirsen, ac­cord­ing to the Sep­tem­ber 16 memo from Califf as well as their own mem­os. Califf set out to de­ter­mine if the FDA was sig­nif­i­cant­ly low­er­ing the bar for an ap­proval, but ul­ti­mate­ly de­cid­ed that Wood­cock was pur­su­ing a well es­tab­lished track record for be­ing will­ing to take tough, eth­i­cal stands in­side the agency, rather than buck­ling to a lob­by­ing cam­paign.

Ac­cord­ing to Bo­rio, who says that Wood­cock was lean­ing to­ward an OK in 2014, an ap­proval of this flawed ap­pli­ca­tion may set a dan­ger­ous prece­dent that will en­cour­age des­per­ate pa­tients to mount a fu­ri­ous as­sault in fa­vor of oth­er drug ap­provals. Her po­si­tion, out­lined in the memo:

Grant­i­ng ac­cel­er­at­ed ap­proval here on the ba­sis of the da­ta sub­mit­ted could make mat­ters worse for pa­tients with no ex­ist­ing mean­ing­ful ther­a­pies — both by dis­cour­ag­ing oth­ers from de­vel­op­ing ef­fec­tive ther­a­pies for DMD and by en­cour­ag­ing oth­er de­vel­op­ers to seek ap­proval for se­ri­ous con­di­tions be­fore they have in­vest­ed the time and re­search nec­es­sary to es­tab­lish whether a prod­uct is like­ly to con­fer clin­i­cal ben­e­fit. If we were to ap­prove eteplirsen with­out sub­stan­tial ev­i­dence of ef­fec­tive­ness, or on the ba­sis of a sur­ro­gate end­point with a triv­ial treat­ment ef­fect, we would quick­ly find our­selves in the po­si­tion of hav­ing to ap­prove a myr­i­ad of in­ef­fec­tive treat­ments for groups of des­per­ate pa­tients.

Unger, who warned that the safe­ty pro­file of eteplirsen is not yet known and that pa­tients tak­ing the drug could die from treat­ment, was scathing in his as­sess­ment of the ther­a­py.

By al­low­ing the mar­ket­ing of an in­ef­fec­tive drug, es­sen­tial­ly a sci­en­tif­i­cal­ly el­e­gant place­bo, thou­sands of pa­tients and their fam­i­lies would be giv­en false hope in ex­change for hard­ship and risk. I ar­gue that this would be un­eth­i­cal and coun­ter­pro­duc­tive. There could al­so be sig­nif­i­cant and un­jus­ti­fied fi­nan­cial costs – if not to pa­tients, to so­ci­ety.

And the re­view doc­u­ments in­clud­ed Wood­cock’s ex­tra­or­di­nary ar­gu­ment that Sarep­ta need­ed an ac­cel­er­at­ed ap­proval to help its stock price, so it could fund ad­di­tion­al work.

She opined that Sarep­ta in par­tic­u­lar “need­ed to be cap­i­tal­ized.” She not­ed that the spon­sor’s stock went down af­ter the AC meet­ing and went up af­ter FDA sent the June 3, 2016 let­ter. Dr. Wood­cock cau­tioned that, if Sarep­ta did not re­ceive ac­cel­er­at­ed ap­proval for eteplirsen, it would have in­suf­fi­cient fund­ing to con­tin­ue to study eteplirsen and the oth­er sim­i­lar drugs in its pipeline. She stat­ed that, with­out an ap­proval in cas­es such as eteplirsen, pa­tients would aban­don all hope of ap­proval for these types of prod­ucts and would “lapse in­to a po­si­tion of” self-treat­ment.

Sig­nif­i­cant de­fi­cien­cies in the eteplirsen pro­gram, says Califf, in­clude a con­sen­sus that “the poor qual­i­ty of many of the biop­sies and the fail­ure of the spon­sor to im­ple­ment a high-qual­i­ty pro­ce­dure for as­say val­i­da­tion” made it im­pos­si­ble to con­sid­er much of the da­ta in the ap­pli­ca­tion. They all agreed that the drug pro­duced lev­els of dy­s­trophin that were “small com­pared with ex­pec­ta­tions at the out­set of tri­als in hu­mans.”

Sarep­ta “tout­ed” a study that used un­re­li­able mea­sures of the as­say, lead­ing the com­pa­ny to over­state pro­tein ex­pres­sion in fol­low-up biop­sies. That study was de­bunked by FDA ex­perts, Califf says, and should be cor­rect­ed or re­tract­ed. Bo­rio was much more crit­i­cal of Sarep­ta. Her memo states:

I would be re­miss if I did not note that the spon­sor has ex­hib­it­ed se­ri­ous ir­re­spon­si­bil­i­ty by play­ing a role in pub­lish­ing and pro­mot­ing se­lec­tive da­ta dur­ing the de­vel­op­ment of this prod­uct. Not on­ly was there a mis­lead­ing pub­lished ar­ti­cle with re­spect to the re­sults of Study 201/202147 –which has nev­er been re­tract­ed—but Sarep­ta al­so is­sued a press re­lease re­ly­ing on the mis­lead­ing ar­ti­cle and its find­ings.

There is a dis­tinct pos­si­bil­i­ty, the FDA feels, that in­creas­ing the dose would pro­vide enough dy­s­trophin ex­pres­sion, the key bio­mark­er for this dis­ease, to make it work as hoped. But it’s on­ly been test­ed in an­i­mals, nev­er in hu­mans — at least not yet.

And if Sarep­ta had done what the FDA was telling the com­pa­ny to do, says Califf, then they would prob­a­bly al­ready have enough com­pelling da­ta in hand to make a de­ci­sion based on the mer­its of the drug.

Wood­cock ac­tu­al­ly de­cid­ed in fa­vor of an ap­proval on May 4, af­ter tak­ing an “ex­ten­sive and ear­ly in­volve­ment” on the drug, which raised con­cerns about in­ter­fer­ence with “the in­tegri­ty of sci­en­tif­ic re­views” at low­er lev­els in the FDA. Wood­cock com­plet­ed her fi­nal mem­o­ran­dum be­fore Unger had had a chance to com­plete his own.

Once she de­ter­mined her po­si­tion, Wood­cock nev­er budged. Ul­ti­mate­ly, that was enough. What­ev­er else hap­pens, Wood­cock was proved right about Sarep­ta’s stock price. Shares are up 86% in mid-af­ter­noon trad­ing. In a call with an­a­lysts Mon­day af­ter­noon, com­pa­ny of­fi­cials say they will file for an ear­ly ap­proval in Eu­rope be­fore the end of this year.

A new era of treat­ment: How bio­mark­ers are chang­ing the way we think about can­cer

AJ Patel was recovering from a complicated brain surgery when his oncologist burst into the hospital room yelling, “I’ve got some really great news for you!”

For two years, Patel had been going from doctor to doctor trying to diagnose his wheezing, only to be dealt the devastating news that he had stage IV lung cancer and only six months to live. And then they found the brain tumors.

“What are you talking about?” Patel asked. He had never seen an oncologist so happy.

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Mihael Polymeropoulos, Vanda Pharmaceuticals CEO

Phar­ma com­pa­ny con­tin­ues its FDA law­suit spree, this time af­ter agency de­nies fast-track des­ig­na­tion

Vanda Pharmaceuticals is making a name for itself, at least in terms of suing the FDA.

The DC-headquartered firm on Monday filed its latest suit against the agency, with the company raising concerns over the FDA’s failure to grant a fast track designation for Vanda’s potential chronic digestive disorder drug tradipitant, which is a neurokinin 1 receptor antagonist.

Specifically, Vanda said FDA’s “essential point” in its one-page denial letter on the designation pointed to “the lack of necessary safety data,” which was “inconsistent with the criteria for … Fast Track designation.”

Mod­er­na seeks to dis­miss Al­ny­lam suit over Covid-19 vac­cine com­po­nent, claim­ing wrong venue

RNAi therapeutics juggernaut Alnylam Pharmaceuticals made a splash in March when it sued and sought money from both Pfizer and Moderna regarding their use of Alnylam’s biodegradable lipids, which Alnylam claims have been integral to the way both companies’ mRNA-based Covid-19 vaccines work.

But now, Moderna lawyers are firing back, telling the same Delaware district court that Alnylam’s claims can only proceed against the US government in the Court of Federal Claims because of the way the company’s contract is set up with the US government. The US has spent almost $10 billion on Moderna’s Covid-19 vaccine so far.

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Cracks in the fa­cade: Is phar­ma's pan­dem­ic ‘feel good fac­tor’ wan­ing?

The discordant effects of the Covid-19 pandemic on pharma reputation continues. While the overall industry still retains a respectable halo from its Covid-19 quick response and leadership, a new patient group study reveals a different story emerging in the details.

On one hand, US patient advocacy groups rated the industry higher-than-ever overall. More than two-thirds (67%) of groups gave the industry a thumbs up for 2021, a whopping 10 percentage point increase over the year before, according to the PatientView annual study, now in its 9th year.

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Michael Corbo, Pfizer CDO of inflammation & immunology

UP­DAT­ED: Plan­ning ahead for crowd­ed ul­cer­a­tive col­i­tis mar­ket, Pfiz­er spells out PhI­II da­ta on $6.7B Are­na drug

Pfizer has laid out the detailed results behind its boast that etrasimod — the S1P receptor modulator at the center of its $6.7 billion buyout of Arena Pharma — is the winner of the class, potentially leapfrogging an earlier entrant from Bristol Myers Squibb.

Pivotal data from the ELEVATE program in ulcerative colitis — which consists of two Phase III trials, one lasting 52 weeks and the other just 12 weeks — illustrate an “encouraging balance of efficacy and safety,” according to Michael Corbo, chief development officer of inflammation & immunology at Pfizer. The company is presenting the results as a late breaker at Digestive Disease Week.

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Robert Califf (Michael Brochstein/Sipa USA via AP Images)

House Re­pub­li­cans at­tack Chi­na-on­ly da­ta in FDA sub­mis­sions, seek new in­ves­ti­ga­tion in­to re­search in­spec­tions

Three Republican representatives are calling on the FDA to take a closer look at the applications including only clinical data from China.

The letter to FDA commissioner Rob Califf late last week comes as the agency recently rejected Eli Lilly’s anti-PD-1 antibody, which attempted to bring China-only data but ran into a bruising adcomm that may crush the hopes of any other companies looking to bring cheaper follow-ons based only on Chinese data.

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Amid mon­key­pox fears, biotechs spring to ac­tion; Mod­er­na’s CFO trou­ble; Cuts, cuts every­where; Craft­ing the right pro­teins; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

It’s always a bittersweet moment saying goodbye, but as Josh Sullivan goes off to new adventures we are grateful for the way he’s built up the Endpoints Manufacturing section — which the rest of the team will now carry forward. If you’re not already, this may be a good time to sign up for your weekly dose of drug manufacturing news. Thank you for reading and wish you a restful weekend.

Bris­tol My­ers Squibb sues No­var­tis for roy­al­ties sur­round­ing the use of trans­genic mice

Two Big Pharma companies are going to the mat over genetically modified mice in a licensing dispute.

Bristol Myers Squibb is suing Novartis in New York over a dispute concerning an evaluation, research and commercialization agreement stretching back to the late ’90s initially inked between Novartis and BMS’ predecessor Medarex. The deal in question allowed Novartis to use Medarex’s patented transgenic mice to develop therapeutic drugs. Novartis agreed to pay Medarex – and subsequently BMS – a royalty on sales of drugs it developed using the mice.

Co­pay coupons gone wrong, again: Pfiz­er pays al­most $300K to set­tle com­plaints in four states

Pfizer has agreed to pay $290,000 to settle allegations of questionable copay coupon practices in Arizona, Colorado, Kansas, and Vermont from 2014 to 2018.

While the company has not admitted any wrongdoing as part of the settlement, Pfizer has agreed to issue restitution checks to about 5,000 consumers.

A Pfizer spokesperson said the company has “enhanced its co-pay coupons to alleviate the concerns raised by states and agreed to a $30,000 payment to each.”