Prothena re­vives its for­mer lead drug, aim­ing for a small­er pop­u­la­tion with more se­vere cas­es

A high-pro­file AL amy­loi­do­sis pro­gram once left for dead has got­ten new life.

Prothena is push­ing for­ward with its for­mer lead can­di­date NEOD001, now called bir­tamimab, in a Phase III study de­spite the ex­per­i­men­tal drug’s crash and burn in a Phase IIb tri­al rough­ly three years ago. The study eval­u­at­ed bir­tamimab in rare, sec­ond-line cas­es of the dis­ease, and re­searchers al­so looked at the front­line set­ting in a Phase III that had been ex­pect­ed to fail.

But af­ter tak­ing an­oth­er look at the da­ta, Prothena say they found an un­ex­pect­ed sur­vival ben­e­fit in pa­tients at high risk for ear­ly mor­tal­i­ty, and are now plow­ing ahead with the con­fir­ma­to­ry study in those with the most se­vere man­i­fes­ta­tion of the dis­ease.

Gene Kin­ney

“The sur­vival ben­e­fit ob­served in the Mayo Stage IV pa­tients is not a sub­tle sur­vival ben­e­fit,” CEO Gene Kin­ney told End­points News. “We had pa­tients that were do­ing quite well in the more mild sub­groups, so ob­vi­ous­ly you would not be ex­pect­ed to show a sig­nal on sur­vival in pa­tients that were al­ready sur­viv­ing well.”

AL amy­loi­do­sis, like most of the dis­eases Kin­ney said Prothena aims to treat, is a pro­tein dys­reg­u­la­tion dis­ease. Pa­tients af­flict­ed with AL amy­loi­do­sis gen­er­al­ly see de­posits of mis­fold­ed pro­teins build up in the heart and oth­er vi­tal or­gans, and the the­o­ry be­hind bir­tamimab is that it can clear these ac­cu­mu­la­tions di­rect­ly.

So why did Prothena change its mind? Kin­ney broke it down like this: In more mild cas­es of the dis­ease, bir­tamimab did not see much ben­e­fit over place­bo in ei­ther pre­vi­ous study. The haz­ard ra­tio in the Phase III among all pa­tients was 0.835, a fig­ure that ul­ti­mate­ly spurred Prothena to drop the pro­gram at the rec­om­men­da­tion of the in­de­pen­dent mon­i­tor­ing board.

When con­duct­ing a deep­er analy­sis on the da­ta, how­ev­er, Prothena found a sta­tis­ti­cal­ly sig­nif­i­cant sur­vival ben­e­fit among the 77 Stage IV pa­tients af­ter 9 months. In the 38-per­son drug arm, 74% of pa­tients were still alive in that time­frame, as op­posed to 49% in the place­bo group. That dif­fer­ence mea­sured out to a haz­ard ra­tio of 0.413 and a p-val­ue of p=0.025.

Prothena al­so found ben­e­fits in a few sec­ondary end­points among these pa­tients, specif­i­cal­ly a pa­tient-re­port­ed ques­tion­naire mea­sur­ing im­pact on qual­i­ty of life and a six-minute walk test.

“This ob­vi­ous­ly re­quired our at­ten­tion,” Kin­ney said. “You don’t see a haz­ard ra­tio on an end­point like all-cause mor­tal­i­ty and just com­plete­ly ig­nore it, but at the same time we re­al­ly want­ed to scru­ti­nize this da­ta and make sure that these da­ta weren’t telling us some­thing that may not be true.”

Af­ter dou­ble- and triple-check­ing these new­ly dis­cov­ered da­ta with key opin­ion lead­ers and out­side sta­tis­ti­cal ex­perts, Kin­ney said, Prothena went to the FDA to try to fig­ure out a path for­ward. Reg­u­la­tors agreed the pro­gram could go ahead un­der a spe­cial pro­to­col as­sess­ment agree­ment, look­ing at the Stage IV pa­tients.

The new tri­al will have the same pri­ma­ry end­point of all-cause mor­tal­i­ty and will be event-based. It’s ex­pect­ed to launch some­time in the mid­dle of this year, and Prothena will be look­ing for a p-val­ue of p≤0.1 to con­firm the ben­e­fit. Kin­ney said the goal is to en­roll up to 150 pa­tients, who will be ran­dom­ized to the ac­tive arm 2-to-1.

Once about half of the mor­tal­i­ty events need­ed to as­sess ef­fi­ca­cy oc­cur, a num­ber Prothena is not dis­clos­ing, the com­pa­ny will con­duct an in­ter­im analy­sis on the study. The com­pa­ny doesn’t plan to re­lease da­ta; rather, it will de­ter­mine whether the tri­al should con­tin­ue as planned or be stopped due to “over­whelm­ing ef­fi­ca­cy.”

Kin­ney said he doesn’t know how long the tri­al might take, and that it de­pends on en­roll­ment and the study it­self. But with bir­tamimab’s check­ered past in the rearview mir­ror, the com­pa­ny is mov­ing ahead with a new con­fi­dence over a pro­gram that, at one point, had been pro­ject­ed for $1.5 bil­lion in peak sales.

“When you’re look­ing at the po­ten­tial sur­vival ben­e­fit of a mol­e­cule, it re­quires see­ing a lack of sur­vival in the con­trol arm,” Kin­ney said. “That’s why eval­u­at­ing this im­pact in these Mayo Stage IV pa­tients where they do have the high­est risk in ear­ly mor­tal­i­ty, we saw such a mean­ing­ful sur­vival ben­e­fit.”

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

Stéphane Bancel, Moderna CEO

'This is not go­ing to be good': Mod­er­na CEO Ban­cel warns of a 'ma­te­r­i­al drop' in vac­cine ef­fi­ca­cy as Omi­cron spreads

Even as public health officials remain guarded about their comments on the likelihood Omicron will escape the reach of the currently approved Covid-19 vaccines, there’s growing scientific consensus that we’re facing a variant that threatens to overwhelm the vaccine barricades that have been erected.

Stéphane Bancel, the CEO of Moderna, one of the leading mRNA players whose quick vault into the markets with a highly effective vaccine created an instant multibillion-dollar market, added his voice to the rising chorus early Tuesday. According to Bancel, there will be a significant drop in efficacy when the average immune system is confronted by Omicron. The only question now is: How much?

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 124,400+ biopharma pros reading Endpoints daily — and it's free.

Philip Dormitzer, new GSK global head of vaccines R&D

Glax­o­SmithK­line poach­es Pfiz­er's vi­ral vac­cines lead in rush to cap­i­tal­ize on fu­ture of mR­NA

GlaxoSmithKline has appointed Philip Dormitzer, formerly chief scientific officer of Pfizer’s viral vaccines unit, as its newest global head of vaccines R&D, looking to leverage one of the leading minds behind Pfizer and BioNTech’s RNA collaboration that led to Covid-19 jab Comirnaty, the British drug giant said Tuesday.

Dormitzer had been with Pfizer for a little more than six years, joining up after a seven-year stint with Novartis, where he reached the role of US head of research and head of global virology for the company’s vaccines and diagnostics unit.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 124,400+ biopharma pros reading Endpoints daily — and it's free.

In­tro­duc­ing End­points Stu­dio, a new way to ad­ver­tise with End­points-craft­ed brand­ing cam­paigns

Since our start in 2016, Endpoints has grown fast while executing our mission to cover biopharma’s most critical developments for industry pros worldwide. As readership has grown, our advertising business has too. Endpoints advertising partners support the mission and engage their desired audiences through announcements on our email and web platforms, brand recognition in our event coverage and sponsorships of Endpoints daily and weekly reports.

Lan Huang, BeyondSpring CEO

Months af­ter shock­ing in­vestors with lung can­cer win, Be­yond­Spring's lead drug hits road­block at the FDA

BeyondSpring shocked investors in early August after its once-marginal lead drug suddenly showed a lot of promise in a common form of lung cancer. With hopes high, the FDA has now slammed the door on that drug in another indication — does that spell bad news for BeyondSpring’s Cinderella story?

The FDA issued BeyondSpring a complete response letter for its plinabulin in combination with granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia, effectively shutting down the drug’s immediate chances at a marketing approval, the biotech said Wednesday.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 124,400+ biopharma pros reading Endpoints daily — and it's free.

With on­ly burns to show in gene ther­a­py, Astel­las inks deal with AAV spe­cial­ist Dyno in push for a bet­ter cap­sid

On the hunt for a better AAV capsid for gene therapy, Eric Kelsic’s Dyno Therapeutics has set itself apart with its focus on machine learning to help speed discovery. Now, Japanese drugmaker Astellas — fresh off a slate of gene therapy burns — is taking a bet on Dyno as it looks to the future.

Astellas and Dyno will work together as part of an R&D pact to develop next-gen AAV vectors for gene therapy using Dyno’s CapsidMap platform directed at skeletal and cardiac muscle, the companies said Wednesday. Under the terms of the deal, Dyno will design AAV capsids for gene therapy, while Astellas will be responsible for conducting preclinical, clinical and commercialization activities for gene therapy product candidates using the capsids.

J&J and Sanofi's mul­ti­ple myelo­ma tit-for-tat con­tin­ues, as sub­cu­ta­neous Darza­lex wins com­bo ap­proval

J&J and Sanofi have gone back and forth in their multiple myeloma tug-of-war. Earlier this year, Sanofi notched an approval of Sarclisa in combination with Amgen’s Kyprolis to try to outflank the big conglomerate, but J&J is clapping back.

Wednesday afternoon, Amgen announced that the subcutaneous version of J&J’s blockbuster Darzalex is also now approved as a combo with Kyprolis and dexamethasone. The green light came through for adults with relapsed or refractory multiple myeloma who had progressed on one to three earlier lines of therapy.

As first Omi­cron case in US crops up, re­searchers won­der: which an­ti­bod­ies, vac­cines will hold up?

As Covid-19 drug and vaccine developers race to figure out which of their products might be hampered by the new variant, the CDC on Wednesday afternoon announced the first confirmed case of the Omicron variant (B.1.1.529) in the US, found in San Francisco.

The unidentified individual was a traveler who returned from South Africa on Nov. 22, 2021, was fully vaccinated, and had mild symptoms that the CDC described as improving. All close contacts have been contacted and have tested negative, the centers said.

FDA ad­comm nar­row­ly votes in fa­vor of Mer­ck­'s an­tivi­ral for out­pa­tient Covid-19

With little explanation for why Merck’s potential Covid-19 antiviral was less effective in reducing Covid hospitalizations and deaths in a full analysis of a Phase III trial versus an interim look, the FDA’s antimicrobial drugs advisory committee on Tuesday voted 13-10 in favor of the pill’s benefits outweighing the risks for adults within 5 days of developing Covid symptoms.

Molnupiravir will likely be authorized by FDA in the coming days for adults with mild or moderate Covid-19. While Pfizer’s antiviral may prove to be more effective, Merck’s pill will be another weapon in the armamentarium of Covid-19 treatments for countries around the world, adding to the mAb treatments already in use in the outpatient space from Regeneron, Eli Lilly and Vir/GlaxoSmithKline.