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.

Tar­get­ing a Po­ten­tial Vul­ner­a­bil­i­ty of Cer­tain Can­cers with DNA Dam­age Re­sponse

Every individual’s DNA is unique, and because of this, every patient responds differently to disease and treatment. It is astonishing how four tiny building blocks of our DNA – A, T, C, G – dictate our health, disease, and how we age.

The tricky thing about DNA is that it is constantly exposed to damage by sources such as ultraviolet light, certain chemicals, toxins, and even natural biochemical processes inside our cells.¹ If ignored, DNA damage will accumulate in replicating cells, giving rise to mutations that can lead to premature aging, cancer, and other diseases.

Fol­low biotechs go­ing pub­lic with the End­points News IPO Track­er

The Endpoints News team is continuing to track IPO filings for 2021, and we’ve designed a new tracker page for the effort.

Check it out here: Biopharma IPOs 2021 from Endpoints News

You’ll be able to find all the biotechs that have filed and priced so far this year, sortable by quarter and listed by newest first. As of the time of publishing on Feb. 25, there have already been 16 biotechs debuting on Nasdaq so far this year, with an additional four having filed their S-1 paperwork.

Steve Cutler, Icon CEO (Icon)

In the biggest CRO takeover in years, Icon doles out $12B for PRA Health Sci­ences to fo­cus on de­cen­tral­ized clin­i­cal work

Contract research M&A had a healthy run in recent years before recently petering out. But with the market ripe for a big buyout and the Covid-19 pandemic emphasizing the importance of decentralized trials, Wednesday saw a tectonic shift in the CRO world.

Icon, the Dublin-based CRO, will acquire PRA Health Sciences for $12 billion in a move that will shake up the highest rungs of a fragmented market. The merger would combine the 5th- and 6th-largest CROs by 2020 revenue, according to Icon, and the merger will set the newco up to be the second-largest global CRO behind only IQVIA.

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Tom Barnes (Orna)

The mR­NA era is here. MPM be­lieves the fu­ture be­longs to oR­NA — and Big Phar­ma wants a seat at the ta­ble

If the ultra-fast clinical development of Covid-19 vaccines opened the world’s eyes to the promises of messenger RNA, the subsequent delays in supply offered a crash course on the ultra-complex process of producing them. Even before the formulation and fill-finish steps, mRNA is the precious end product from an arduous journey involving enzyme-aided transcription, modification and purification.

For Bristol Myers Squibb, Novartis Institutes for Biomedical Research, Gilead’s Kite and Astellas, it’s time to rethink the way therapeutic RNA is engineered.

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Tal Zaks, Moderna CMO (AP Photo/Rodrique Ngowi, via still image from video)

CMO Tal Zaks bids Mod­er­na a sur­prise adieu as biotech projects $18.4B in rev­enue, plots post-Covid ex­pan­sion

How do you exit a company after six years in style? Developing one of the most lucrative and life-saving products in pharma history is probably not the worst way to go.

Tal Zaks, Moderna’s CMO since 2015, will leave the mRNA biotech in September, the biotech disclosed in their annual report this morning. The company has already retained the recruitment firm Russell Reynolds to find a replacement.

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Glax­o­SmithK­line re­thinks strat­e­gy for Covid-19 an­ti­body — not the Vir ones — af­ter tri­al flop. Is there hope in high-risk pa­tients?

In the search for a better Covid-19 therapeutic, GlaxoSmithKline and Vir have partnered up on two antibodies they hope have a chance. GSK is also testing its own in-house antibody, and early results may have shut the door on its widespread use.

A combination of GSK’s monoclonal antibody otilimab plus standard of care couldn’t best standard of care alone in preventing death and respiratory failure in hospitalized Covid-19 patients after 28 days, according to data from the Phase IIa OSCAR study unveiled Thursday.

Mod­er­na's Stéphane Ban­cel plans to dou­ble down on vac­cine pro­duc­tion, new vari­ants as mR­NA rules in pan­dem­ic fight

Stéphane Bancel thought he’d be sleeping more by now.

The 48-year-old Moderna CEO figured that by 2021 he’d have his vaccine through the clinic, authorized, and in mass production — that the hard part would be over. Instead, he’s still working Saturdays and Sundays, talking with his lab and manufacturing teams and fielding calls with two to three world leaders a day to answer their concerns about supply and emerging new variants.

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S&P ex­pects steady ero­sion in Big Phar­ma's cred­it pro­file in 2021 as new M&A deals roll in — but don't un­der­es­ti­mate their un­der­ly­ing strength

S&P Global has taken a look at the dominant forces shaping the pharma market and come to the conclusion that there will be more downgrades than upgrades in 2021 — the 8th straight year of steady decline.

But it’s not all bad news. Some things are looking up, and there’s still plenty of money to be made in an industry that enjoys a 30% to 40% profit margin, once you factor in steep R&D expenses.

Ken Frazier, Merck CEO (Bess Adler/Bloomberg via Getty Images)

UP­DAT­ED: Mer­ck takes a swing at the IL-2 puz­zle­box with a $1.85B play for buzzy Pan­dion and its au­toim­mune hope­fuls

When Roger Perlmutter bid farewell to Merck late last year, the drugmaker perhaps best known now for sales giant Keytruda signaled its intent to take a swing at early-stage novelty with the appointment of discovery head Dean Li. Now, Merck is signing a decent-sized check to bring an IL-2 moonshot into the fold.

Merck will shell out roughly $1.85 billion for Pandion Pharmaceuticals, a biotech hoping to gin up regulatory T cells (Tregs) to treat a range of autoimmune disorders, the drugmaker said Thursday.

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