FDA dis­miss­es Alk­er­mes’ pitch on ‘5461, de­mand­ing new de­pres­sion tri­als in a dam­ag­ing set­back

Alk­er­mes $ALKS made a high-stakes gam­ble that the FDA would con­sid­er ap­prov­ing their big de­pres­sion drug ALKS-5461 on the ba­sis of a sin­gle pos­i­tive Phase III study — and they lost. The biotech re­port­ed Mon­day morn­ing that the agency had is­sued a refuse-to-file let­ter for the drug, se­ri­ous­ly de­lay­ing any shot at an OK.

Ac­cord­ing to the com­pa­ny state­ment, the FDA is de­mand­ing more clin­i­cal tri­als to pro­vide a full set of da­ta as well as a “bioavail­abil­i­ty study to gen­er­ate ad­di­tion­al bridg­ing da­ta be­tween ALKS 5461 and the ref­er­ence list­ed drug, buprenor­phine.”

Alk­er­mes’ shares im­me­di­ate­ly plunged more than 20% in pre-mar­ket trad­ing, wip­ing out close to $2 bil­lion in mar­ket cap.

Fac­ing years of ex­pen­sive new clin­i­cal tri­al work, Alk­er­mes ex­ecs im­me­di­ate­ly served no­tice that they plan to ap­peal the de­ci­sion.

“We strong­ly be­lieve that the clin­i­cal de­vel­op­ment pro­gram, in­clud­ing da­ta from more than 1,500 pa­tients with MDD, pro­vides sub­stan­tial ev­i­dence of ALKS 5461’s con­sis­tent an­ti­de­pres­sant ac­tiv­i­ty and a fa­vor­able ben­e­fit-risk pro­file,” said CEO Richard Pops.

“To say we were sur­prised is an un­der­state­ment,” Pops said in a call with an­a­lysts Mon­day, not­ing all the da­ta that were gath­ered to­geth­er and their on­go­ing dis­cus­sions with the FDA through the fil­ing.

An­a­lysts im­me­di­ate­ly start­ed as­sess­ing the dam­age, which will be sig­nif­i­cant.

“This is crit­i­cal and is clear­ly be­low ex­pec­ta­tions,” not­ed Ever­core ISI’s Umer Raf­fat. “It was my base case that the on­go­ing add’l Ph 3 would suf­fice … but that doesn’t ap­pear to be the case.”

Asked if Alk­er­mes was pre­pared to go ahead with a new Phase III pro­gram, Pops de­murred.

“I think the smart thing to do is to wait to see the whites of the FDA’s eyes in a Type A meet­ing,” he said.

Their drug hit back-to-back Phase III fail­ures ear­ly in 2017, send­ing the com­pa­ny’s stock in­to a tail­spin. But a re­designed third Phase III hit with pos­i­tive da­ta, en­cour­ag­ing Pops to be­lieve that he could make a case for the drug by com­bin­ing all of the da­ta. De­vel­op­ers typ­i­cal­ly set up a trio of piv­otal tri­als in de­pres­sion, hop­ing that two out of three can es­cape be­ing tak­en down by a high place­bo re­sponse.

Pops start­ed to re­build the ar­gu­ment for this drug be­fore the ini­tial Phase III dust­up had qui­et­ed down. The com­pa­ny cit­ed a trend to­ward sta­tis­ti­cal sig­nif­i­cance and not­ed that a post hoc analy­sis as­cer­tained that the en­tire 2mg/2mg dose group in one study — FOR­WARD-4 — achieved the crit­i­cal end­point on the Mont­gomery–Ås­berg De­pres­sion Rat­ing Scale (MADRS-6) scores. Re­searchers went back to the draw­ing board, adding new pa­tients and re­jig­ging its sta­tis­ti­cal analy­sis plan for FOR­WARD-5.

FOR­WARD-3 sim­ply failed, says Alk­er­mes, due to a high place­bo re­sponse, a com­mon fea­ture in de­pres­sion. Un­like For­ward-4 and For­ward-5, though, For­ward-3 did not use what’s called a se­quen­tial par­al­lel com­par­i­son de­sign, or SPCD. In an SPCD study, the first round of place­bo pa­tients who don’t re­spond to the drug are re-ran­dom­ized be­tween the drug arm and the sug­ar pill, in or­der to quell the high place­bo re­spons­es that have scut­tled nu­mer­ous oth­er tri­als for de­pres­sion.

What are Alk­er­mes’ chances of chang­ing the FDA’s de­ci­sion? Not good. Top of­fi­cials are well es­tab­lished, of­fer­ing re­peat­ed sig­nals that they’re will­ing to be flex­i­ble on the da­ta when need­ed. If this drug failed to get past Janet Wood­cock as well as FDA com­mis­sion­er Scott Got­tlieb, af­ter the FDA re­versed three oth­er re­jec­tions ear­ly in Got­tlieb’s tenure at the agency, it’s un­like­ly cir­cum­stances will change now.

The RTF no­tice is a par­tic­u­lar­ly harsh blow for Pops, who’s been in­sist­ing to in­vestors that the com­pa­ny would get this past reg­u­la­tors and on­to the mar­ket. Fail­ing to even get past the ini­tial re­view and have the ap­pli­ca­tion spurned at the door will not sit well with com­pa­ny back­ers.


Mi­no­ryx and Sper­o­genix ink an ex­clu­sive li­cense agree­ment to de­vel­op and com­mer­cial­ize lerigli­ta­zone in Chi­na

September 23, 2020 – Hong Kong, Beijing, Shanghai (China) and Mataró, Barcelona (Spain)  

Minoryx will receive an upfront and milestone payments of up to $78 million, as well as double digit royalties on annual net sales 

Sperogenix will receive exclusive rights to develop and commercialize leriglitazone for the treatment of X-linked adrenoleukodystrophy (X-ALD), a rare life-threatening neurological condition

FDA chief Stephen Hahn on Capitol Hill earlier this week (Getty Images)

As FDA’s work­load buck­les un­der the strain, Trump again ac­cus­es the agency of a po­lit­i­cal hit job

Peter Marks appeared before a virtual SVB Leerink audience yesterday and said that his staff at FDA’s CBER is on the verge of working around the clock. Manufacturing inspections, policy work and sponsor communications have all been pushed down the to-do list so that they can be responsive to Covid-related interactions. And the agency’s objective right now? “To save as many lives as we can,” Marks said, likening the mortality on the current outbreak as equivalent to “a nuclear bomb on a small city.”

President Donald Trump reacts after signing an executive order following his remarks on his healthcare policies yesterday in Charlotte, North Carolina (Getty Images)

Op-ed: Will phar­ma re­al­ly pay for Trump’s lat­est law­less promise to 33 mil­lion Medicare ben­e­fi­cia­ries? Not like­ly

Sitting atop the executive branch, President Donald Trump is the ultimate authority at the FDA. He can fast track any vaccine to approval himself. If it came to that, of course.

What he can’t do is unilaterally order the legislative branch to loosen the Treasury’s coffers for $6.6 billion. Nor can he command pharmaceutical companies to pay for $200 vouchers sent to 33 million Medicare beneficiaries for prescription drugs before the election.

President Donald Trump and FDA Commissioner Stephen Hahn (AP Images)

FDA is­sues fi­nal rule al­low­ing im­por­ta­tion of drugs from Cana­da — but al­so keeps the pow­er to re­voke it

Just over a month away from the presidential election, the FDA has issued a final regulation fulfilling President Trump’s promise to let states import certain prescription drugs from Canada.

On Thursday, Trump told a crowd in North Carolina that the new rule goes into effect “today.” But the published regulation states that it won’t take effect for 60 days. And even then, it could be a while before cheaper drugs make it across the border.

The win­dow is wide open as four more biotechs join the go-go IPO class of 2020

It’s another day of hauling cash in the biopharma world as four more IPOs priced Friday and a fifth filed its initial paperwork.

The biggest offering comes from PMV Pharma, an oncology biotech focusing on p53 mutations, which raised $211.8 million after pricing shares at $18 apiece. Prelude Therapeutics, developing PRMT5 inhibitors for rare cancers, was next with a $158 million raise, pricing shares at $19 each. Graybug Vision raised $90 million after pricing at $16 per share for its wet AMD candidates, and breast cancer biotech Greenwich Lifesciences brought up the rear with a small, $7 million raise after pricing shares at $5.75.

J&J of­fers PhI/IIa da­ta show­ing its sin­gle-dose vac­cine can stir up suf­fi­cient im­mune re­sponse

Days after J&J dosed the first participants of its Phase III ENSEMBLE trial, the pharma giant has detailed the early-stage data that gave them confidence in a single-dose regimen.

Testing two dose levels either as a single dose or in a two-dose schedule spaced by 56 days in, the scientists from Janssen, the J&J subsidiary developing its vaccine, reported that the low dose induced a similar immune response as the high dose. The interim Phase I/IIa results were posted in a preprint on medRxiv.

Daniel O'Day, Gilead CEO (Kevin Dietsch/UPI/Bloomberg via Getty Images)

Play-by-play of Gilead­'s $21B Im­munomedics buy­out de­tails a fren­zied push — and mints a new biotech bil­lion­aire

Immunomedics had not really been looking for a buyout when the year began. Excited by its BLA for Trodelvy, submitted to the FDA in late 2019, executive chairman Behzad Aghazadeh started off looking for potential licensing deals and zeroed in on four potential partners, including Gilead, following January’s JP Morgan Healthcare Conference in San Francisco. Such talks advanced throughout the year, with discussions advancing to the second round in mid-August.

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New York governor Andrew Cuomo (AP Images)

An­drew Cuo­mo says New York will un­der­take its own vac­cine re­view process, and wouldn’t rec­om­mend trust­ing the fed­er­al gov­ern­ment

The concerns keep mounting over President Donald Trump’s politicization of the FDA and other federal agencies guiding the development of a safe and effective vaccine. And today, the telegenic New York governor Andrew Cuomo appeared to introduce even more politics into the matter — latest in an ongoing series of incidents that have cast the proudly independent FDA in starkly political terms.

During his daily press conference Cuomo said that the state will review any coronavirus vaccines approved by the federal government, citing a lack of trust in the Trump administration. The announcement comes one day after Trump accused the FDA of making an “extremely political” move in proposing stricter vaccine guidance.

President Trump walks past HHS secretary Alex Azar (Getty Images)

Azar falls in line un­der Trump again. Ex­perts say he's re­in­forc­ing a dark sig­nal sent to the FDA

In the latest incident where Alex Azar has steadfastly taken the side of President Donald Trump over that of the FDA, the HHS secretary was noncommittal this morning when asked if he supports the attempt by his subordinates at the FDA to strengthen guidelines for a vaccine EUA.

Appearing on NBC’s Today Show, the HHS secretary muddied the waters, stating that the guidance that matters is the one that is “actually already out there.”