Alk­er­mes plots course to the FDA af­ter its de­pres­sion drug scores suc­cess in last-stand PhI­II

Just af­ter the start of this year, Alk­er­mes was blast­ed by the news that the first two of three late-stage stud­ies for its de­pres­sion drug ALKS-5461 had failed. An­a­lysts hit the red-alert but­ton and the biotech’s shares $ALKS skid­ded down 44%, wip­ing out $4 bil­lion of mar­ket cap as ex­ecs im­me­di­ate­ly piv­ot­ed and re­searchers scram­bled to sal­vage the third Phase III by re­vamp­ing the tri­al.

To­day, Alk­er­mes says that third tri­al scored a suc­cess. And even though it doesn’t mea­sure up to stan­dard FDA guide­lines, which look for a pos­i­tive read­out from at least two of the three stud­ies, CEO

El­liot Ehrich, Alk­er­mes CMO

Richard Pops plans to fol­low through with his ear­li­er an­nounced strat­e­gy of sound­ing out the agency to see if this drug war­rants a green light now with the da­ta in hand.

Said El­liot Ehrich, M.D., Chief Med­ical Of­fi­cer of Alk­er­mes:

“With these da­ta now in hand, we will move for­ward rapid­ly to meet with the FDA to de­ter­mine the ap­pro­pri­ate next steps to­ward a reg­u­la­to­ry sub­mis­sion for ALKS 5461, with a goal of bring­ing this im­por­tant new med­ica­tion to pa­tients with MDD.”

Shares im­me­di­ate­ly rock­et­ed up 49% on the news.

Alk­er­mes post­ed top line da­ta re­flect­ing a suc­cess for the key dose in the last-stand study.

In the study, ALKS 5461 2mg/2mg met the pre­spec­i­fied pri­ma­ry end­point of sig­nif­i­cant­ly re­duc­ing de­pres­sion scores com­pared to place­bo, as mea­sured by 6-item Mont­gomery–Ås­berg De­pres­sion Rat­ing Scale (MADRS-6) scores (p=0.018). ALKS 5461 2mg/2mg al­so demon­strat­ed sta­tis­ti­cal­ly sig­nif­i­cant re­duc­tions in 10-item MADRS (MADRS-10) scores com­pared to place­bo (p=0.026). The 1mg/1mg dose of ALKS 5461 showed im­prove­ment in de­pres­sive symp­toms in the study, but did not sep­a­rate sig­nif­i­cant­ly from place­bo.

Pops nev­er low­balled ex­pec­ta­tions on this drug, which is used as an ad­junc­tive ther­a­py for treat­ment re­sis­tant pa­tients — a huge po­ten­tial mar­ket. Just be­fore the first round of bad news hit, he called the up­com­ing re­sults in Jan­u­ary a “seis­mic” event in a chat we had at JP Mor­gan. He wasn’t look­ing for the tremors, though, to bring down his stock price.

Some an­a­lysts, in­clud­ing Paul Mat­teis from Leerink, wrote the whole thing off in the wake of the Jan­u­ary de­ba­cle. And while Alk­er­mes man­aged to re­gain some of what it had lost that day, its shares are still far off their 52-week high.

Pops, though, start­ed to re­build the ar­gu­ment for this drug be­fore the 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. And now the plan is to com­bine what they gleaned from FOR­WARD-4 and 5 to make its case.

FOR­WARD-3 sim­ply failed, says Alk­er­mes, due to a high place­bo re­sponse. 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.

Alk­er­mes out­lined its ar­gu­ment for an ap­proval of their drug in a call with an­a­lysts on Thurs­day evening. The key to the turn­about start­ed with their analy­sis of FOR­WARD-4, their sec­ond Phase III study, which failed. The rea­son it failed, they said, is that the study hinged on the de­pres­sion scores at a spe­cif­ic time. To im­prove their odds, in­ves­ti­ga­tors shift­ed from a spe­cif­ic dead­line to com­ing up with an av­er­age score from re­spons­es tracked over weeks for FOR­WARD-5.

Sig­nif­i­cant­ly, Alk­er­mes made the change with­out get­ting any feed­back from the FDA. Un­der care­ful ques­tion­ing by an­a­lysts, they al­so not­ed that MDRS -6 scores have not been used as a pri­ma­ry end­point for a reg­is­tra­tion study be­fore, but felt that it re­flects a re­sponse to the core symp­toms of de­pres­sion.

In a fol­lowup, Pops told me:

The point we were mak­ing was that MADRS-6, which is 6 of the 10 MADRS ques­tions, is fo­cused on the core symp­toms of de­pres­sion.  This end­point had not been used as a pri­ma­ry end­point in a reg­is­tra­tion pro­gram.  But it re­al­ly doesn’t mat­ter, as the study achieved sta­tis­ti­cal sig­nif­i­cance on BOTH MADRS-6 and the full MADRS-10.

Da­ta will be re­leased at an up­com­ing sci­en­tif­ic con­fer­ence.

“This is lit­er­al­ly hot off the press­es,” said Pops.

An ap­proval is far from a slam dunk. A ret­ro­spec­tive analy­sis can be hard to sell. But it’s a lot bet­ter than be­ing forced to ex­plain go­ing 0 for 3. As of to­day, Alk­er­mes is still in the fight. If it goes down now, it will go down swing­ing.

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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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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Hal Barron. GSK

GSK's Hal Bar­ron her­alds their sec­ond pos­i­tive piv­otal 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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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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Why would Am­gen want to buy Alex­ion? An­a­lysts call hot­ly ru­mored takeover un­like­ly, but seize the mo­ment

A rumor that Amgen is closing in on buyout deal for Alexion has sparked a guessing game on just what kind of M&A strategy Amgen is pursuing and how much Alexion is worth.

Mizuho analyst Salim Syed first lent credence to the report out of the Spanish news outlet Intereconomía, which said Amgen is bidding as much as $200 per share. While the source may be questionable, “the concept of this happening doesn’t sound too crazy to me,” he wrote.

FDA asks why No­var­tis took two months to launch for­mal in­ter­nal probe, af­ter AveX­is flagged da­ta ma­nip­u­la­tion

And the plot thickens. Novartis $NVS officials are reportedly now scrambling to explain to the FDA why it took them two months to open an internal investigation into data discrepancies for their $2.1 million gene-therapy for spinal muscular dystrophy — the world’s most expensive drug.

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Build­ing on suc­cess­ful PD-1 pact, Eli Lil­ly li­cens­es di­a­betes drug to Chi­nese part­ners at In­novent

Eli Lilly is expanding its partnership with China’s Innovent in a deal involving a diabetes drug sitting in its Phase I reserves.

The two companies had jointly developed one of China’s first homegrown PD-1 agents, scoring an approval for Tyvyt (sintilimab) late last year for relapsed/refractory classical Hodgkin’s lymphoma. This time around, Lilly is out-licensing a piece of its diabetes pipeline, a leading franchise that has historically produced the top-selling Trulicity and Humalog.

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.

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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