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.


Martin Shkreli [via Getty]

Pris­on­er #87850-053 does not get to add drug de­vel­op­er to his list of cred­its

Just days after Retrophin shed its last ties to founder Martin Shkreli, the biotech is reporting that the lead drug he co-invented flopped in a pivotal trial. Fosmetpantotenate flunked both the primary and key secondary endpoints in a placebo-controlled trial for a rare disease called pantothenate kinase-associated neurodegeneration, or PKAN.

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Hal Barron. GSK

GSK's Hal Bar­ron her­alds their sec­ond pos­i­tive PhI­II for cru­cial an­ti-BC­MA ther­a­py, point­ing to a push for quick OKs in a crowd­ed field

Hal Barron has his second positive round of Phase III data in hand for his anti-BCMA antibody drug conjugate belantamab mafodotin (GSK2857916). And GSK’s research chief says the data paves the way for their drive in search of an FDA approval for treating multiple myeloma.

It’s hard to overestimate the importance of this drug for GSK, a cornerstone of Barron’s campaign to make a dramatic impact on the oncology market and provide some long-lost excitement for the pharma giant’s pipeline. They’re putting this BCMA program at the front of that charge — looking to lead a host of rivals all aimed at the same target.

We don’t know what the data are yet, but DREAMM-2 falls on the heels of a promising set of data delivered 5 months ago for DREAMM-1. There investigators noted that complete responses among treatment-resistant patients rose to 15% in the extra year’s worth of data to look over, with a median progression-free survival rate of 12 months, up from 7.9 months reported earlier. The median duration of response was 14.3 months.

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UP­DAT­ED: An em­bold­ened As­traZeneca splurges $95M on a pri­or­i­ty re­view vouch­er. Where do they need the FDA to hus­tle up?

AstraZeneca is in a hurry.

We learned this morning that the pharma giant — not known as a big spender, until recently — forked over $95 million to get its hands on a priority review voucher from Sobi, otherwise known as Swedish Orphan Biovitrum.

That marks another step down on price for a PRV, which allows the holder to slash 4 months off of any FDA review time.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.

ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology
ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development
CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at help@endpointsnews.com with any issues.

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Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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Bob Smith, Pfizer

Pfiz­er is mak­ing a $500M state­ment to­day: Here’s how you be­come a lead play­er in the boom­ing gene ther­a­py sec­tor

Three years ago, Pfizer anted up $150 million in cash to buy Bamboo Therapeutics in Chapel Hill, NC as it cautiously stuck a toe in the small gene therapy pool of research and development.

Company execs followed up a year later with a $100 million expansion of the manufacturing operations they picked up in that deal for the UNC spinout, which came with $495 million in milestones.

And now they’re really going for it.

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Video: Putting the AI in R&D — with Badhri Srini­vasan, Tony Wood, Rosana Kapeller, Hugo Ceule­mans, Saurabh Sa­ha and Shoibal Dat­ta

During BIO this year, I had a chance to moderate a panel among some of the top tech experts in biopharma on their real-world use of artificial intelligence in R&D. There’s been a lot said about the potential of AI, but I wanted to explore more about what some of the larger players are actually doing with this technology today, and how they see it advancing in the future. It was a fascinating exchange, which you can see here. The transcript has been edited for brevity and clarity. — John Carroll

Am­gen, Al­ler­gan biosim­i­lar of Roche's block­buster Rit­ux­an clears an­oth­er US piv­otal study 

Novartis $NVS may have given up, but Amgen $AMGN and Allergan $AGN are plowing ahead with their knockoff of Roche’s blockbuster biologic Rituxan in the United States.

Their copycat, ABP 798, was found to have a clinically equivalent impact as Rituxan — meeting the main goal of the study involving CD20-positive B-cell non-Hodgkin’s lymphoma patients. This is the second trial supporting the profile of the biosimilar. In January, it came through with positive PK results in patients with rheumatoid arthritis.

Trump ad­min­is­tra­tion re­vives bid to get drug list prices on TV ads

The Trump administration is not giving up just yet. On Wednesday, the HHS filed an appeal against a judge’s decision in July to overturn a ruling obligating drug manufacturers to disclose the list price of their therapies in television adverts — hours before it was stipulated to go into effect.

In May, the HHS published a final ruling requiring drugmakers to divulge the wholesale acquisition cost— of a 30-day supply of the drug — in tv ads in a bid to enhance price transparency in the United States. The pharmaceutical industry has vehemently opposed the rule, asserting that list prices are not what a typical patient in the United States pays for treatment — that number is typically determined by the type of (or lack thereof) insurance coverage, deductibles and out-of-pocket costs. Although there is truth to that claim, the move was considered symbolic in the Trump administration’s healthcare agenda to hold drugmakers accountable in a climate where skyrocketing drug prices have incensed Americans on both sides of the aisle.