Prothena’s lead drug NEOD001 just im­plod­ed in 2 late-stage stud­ies — and there’s noth­ing left to sal­vage

Prothena’s lead drug has de­ci­sive­ly failed a cru­cial Phase IIb study for rare, sec­ond-line cas­es of AL amy­loi­do­sis. And af­ter con­clud­ing that their Phase III for front­line use is al­so head­ed to fail­ure, the biotech’s ex­ec­u­tive team is scrap­ping the whole pro­gram.

Gene Kin­ney

In a pre­view of the re­sults be­ing re­leased this morn­ing for one of the most close­ly watched cat­a­lysts of Q2, Prothena $PR­TA CEO Gene Kin­ney said the com­pa­ny faced a very dif­fi­cult de­ci­sion, and had on­ly one re­al op­tion.

“We are a sci­ence-led com­pa­ny,” Kin­ney told me. “I’m a sci­en­tist my­self.” And when you’re up against some­thing like this, he said, you have to “pay at­ten­tion to the da­ta and take the most ap­pro­pri­ate steps for­ward.”

It’s not pret­ty, and there will be no hunt for sil­ver lin­ings for a drug once reck­oned as a po­ten­tial block­buster worth around $1.5 bil­lion in peak sales. There will be no at­tempt to re­vive the ef­fort.

Prothena’s shares dropped 62% Mon­day morn­ing. And as an­a­lysts’ bleak as­sess­ments hit, things got even worse. By mid-af­ter­noon the stock was down near­ly 70%, wip­ing out close to a bil­lion dol­lars in mar­ket cap af­ter start­ing the day at $1.4 bil­lion.

“We’ve had a large set­back here with this pro­gram,” says the CEO, who is turn­ing to re­view “the most op­ti­mal way of mov­ing for­ward…All of us at Prothena had gen­uine­ly hoped that we had a drug that would help pa­tients suf­fer­ing from this dis­ease.”

Neil Wood­ford

Right now, Prothena plans to bring the Phase III to an end as they look over the fi­nal da­ta. But there’s no ques­tion in Kin­ney’s mind that the tri­als had foundered, with the Phase IIb de­liv­er­ing noth­ing sta­tis­ti­cal­ly sig­nif­i­cant on the pri­ma­ry or sec­ondary end­points. 

Some of those end­points slight­ly fa­vored the drug, oth­ers slight­ly fa­vored the place­bo.

The haz­ard ra­tio in the Phase III tri­al was at 0.84 when they de­cid­ed to drop the ef­fort at the rec­om­men­da­tion of the in­de­pen­dent mon­i­tor­ing board.

The pri­ma­ry end­point of the Phase IIb PRON­TO study was a mea­sure­ment of car­diac best re­sponse us­ing the high­ly re­gard­ed bio­mark­er for NT-proB­NP as a like­ly sur­ro­gate for sur­vival. Prothena had told in­vestors and an­a­lysts that a suc­cess here could trig­ger a re­quest for ac­cel­er­at­ed ap­proval at the FDA. 

“This is the worst case sce­nario for this pro­gram un­for­tu­nate­ly for PR­TA at this time,” not­ed Jef­feries an­a­lyst Michael Lee.

The re­sults will be a par­tic­u­lar­ly bit­ter pill for Neil Wood­ford to swal­low. The UK in­vestor bet heav­i­ly on Prothena’s suc­cess with NEOD001, reg­u­lar­ly of­fer­ing his en­thu­si­as­tic en­dorse­ment of the com­pa­ny and the team in charge. Now he’ll have to ac­count for an­oth­er painful set­back on the port­fo­lio, af­ter the stock falls far be­low what he paid to buy in.

The bru­tal­ly bad news for in­vestors comes on the heels of a sig­nif­i­cant step for­ward for Prothena. The biotech re­cent­ly signed a rich, pre­clin­i­cal li­cens­ing deal with Cel­gene to beef up its fledg­ling neu­ro­sciences pipeline — with $150 mil­lion in cash tied to it — in­clud­ing an Alzheimer’s pro­gram for tau.

That ef­fort will take the spot­light, along with an­oth­er clin­i­cal pro­gram and the pre­clin­i­cal work un­der way on oth­er drugs.

AL amy­loi­do­sis is a rare con­di­tion that’s di­ag­nosed in about 3,000 peo­ple a year in the US, though it may al­so well be un­der­diag­nosed, ac­cord­ing to Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter. In the dis­ease, rogue plas­ma cells pro­duce an im­munoglob­u­lin light-chain pro­tein that pro­duces amy­loid, which is de­posit­ed in or­gans and gums the works, ca­pa­ble of se­vere dam­age. 

As there are no drugs ap­proved for the con­di­tion, doc­tors of­ten turn to au­tol­o­gous stem cell trans­plants fol­low­ing chemother­a­py to erad­i­cate the er­rant plas­ma cells. Treat­ment al­so some­times in­volved mul­ti­ple myelo­ma drugs like Vel­cade, with ev­i­dence that carfil­zomib and dara­tu­mum­ab can tamp down on the pro­duc­tion of the plas­ma cells. There are a va­ri­ety of stud­ies now in the clin­ic for myelo­ma drugs in this con­di­tion, but any ded­i­cat­ed drug that can mod­i­fy the dis­ease will find a big mar­ket.

Prothena’s share­hold­ers have had a lot to fret about on this de­vel­op­ment pro­gram. The com­pa­ny’s chief med­ical of­fi­cer, Sarah Noon­berg, abrupt­ly re­signed in Feb­ru­ary — less than a year af­ter the Bio­Marin vet joined Prothena — which in­evitably spurred some buzz on Twit­ter. More sig­nif­i­cant­ly, Sahm Ad­ran­gi’s Ker­ris­dale of­fered up one of their Nas­daq SWAT at­tacks on the drug and the com­pa­ny.

Ker­ris­dale set the chances of suc­cess in these tri­als at 0%.

“Prothena’s car­diac best re­sponse rate is mere­ly a byprod­uct of well-doc­u­ment­ed nat­ur­al vari­ance,” Ker­ris­dale not­ed, “and we be­lieve there is no chance of NEOD001 pro­duc­ing sta­tis­ti­cal­ly sig­nif­i­cant re­sults in its cur­rent Phase 2b and Phase 3 tri­als.”

Next up for Prothena is their ex­per­i­men­tal Parkin­son’s drug, PRX002/RG7935, which is al­lied with Roche. It is their on­ly oth­er clin­i­cal stage pro­gram, fol­low­ing a de­ci­sion last fall to scrap a pro­gram for PRX003. 

Kin­ney says an­oth­er pre­clin­i­cal pro­gram will soon be ad­vanced in­to hu­man stud­ies, and there’s plen­ty of cash on hand. The biotech, which had 125 staffers on hand at the end of 2017, al­so list­ed $422 mil­lion in cash — lat­er aug­ment­ed with Cel­gene’s $150 mil­lion buy-in.

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.

Roivant par­lays a $450M chunk of eq­ui­ty in biotech buy­out, grab­bing a com­pu­ta­tion­al group to dri­ve dis­cov­ery work

New Roivant CEO Matt Gline has crafted an all-equity upfront deal to buy out a Boston-based biotech that has been toiling for several years now at building a supercomputing-based computational platform to design new drugs. And he’s adding it to the Erector set of science operations that are being built up to support their network of biotech subsidiaries with an eye to growing the pipeline in a play to create a new kind of pharma company.

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The fu­ture of mR­NA, J&J's vac­cine ad­comm, Mer­ck­'s $1.85B au­toim­mune bet and more

Welcome to the third installment of Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

If this report was helpful in recapping it all for you, please do share it with your colleagues.

Get ready for FDA’s third Covid-19 vaccine

On the heels of a ringing endorsement from FDA reviewers earlier in the week, J&J‘s single-dose vaccine — which proved 66% effective at preventing symptomatic Covid-19, and 85% effective at stopping severe disease 28 days after administration — the advisory committee convened by the agency voted unanimously to recommend its emergency use authorization. It was “a relatively easy call,” according to one of the committee members — although that doesn’t mean they didn’t have questions. Jason Mast has the highlights from the discussion, including new information from the company, on this live blog.

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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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Roche and Genen­tech re­searchers plot $53M dis­cov­ery quest aimed at spark­ing a 'Holy moly' piv­ot in neu­ro R&D

Roche and Genentech have committed $53 million to back a 10-year quest aimed at going back to the drawing board to use new technology and fresh scientific insights to generate a pipeline of drugs for neurological diseases.

Researchers from both Roche and its big South San Francisco hub — mixing teams from gRED and pRED this time — will mix it up with the scientists drawn together for the Weill Neurohub — formed in 2019 as a joint research partnership involving UCSF, Berkeley and the University of Washington — in an exploration of the field to develop new therapies for some of the toughest diseases in drug R&D: Alzheimer’s, Parkinson’s, Huntington’s, ALS and autism.

Am­gen, As­traZeneca speed to­ward fil­ing next-gen an­ti­body for asth­ma af­ter un­cork­ing full late-stage da­ta

On the hunt for a novel competitor to Sanofi and Regeneron’s Dupixent in severe asthma, Amgen and AstraZeneca posted “exciting” results from their next-gen antibody late last year. Now, the partners are showing their hands, and the results look good enough for approval.

Amgen and AstraZeneca’s tezepelumab plus standard of care cut the rate of severe asthma attacks by 56% at the one-year mark compared with SOC alone, according to full data from the Phase III NAVIGATOR study presented Friday at the virtual American Academy of Allergy, Asthma & Immunology meeting. And those significant results were consistent regardless of patients’ baseline eosinophil counts.

With dust set­tled on ac­tivist at­tack, Lau­rence Coop­er leaves Zio­pharm to a new board

Laurence Cooper has done his part.

In the five years since he left a tenured position at Houston’s MD Anderson Cancer Center to become CEO of Boston-based Ziopharm, he’s steered the small-cap immunotherapy player through patient deaths in trials, clinical holds, short attacks and, most recently, an activist attack on the board.

So when the company has “fantastic news” like an IND clearance for a TCR T cell therapy program, he’s ready to pass on the baton.

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Doug Ingram (file photo)

Why not? Sarep­ta’s third Duchenne MD drug sails to ac­cel­er­at­ed ap­proval

Sarepta may be running into some trouble with its next-gen gene therapy approach to Duchenne muscular dystrophy. But when it comes to antisense oligonucleotides, the well-trodden regulatory path is still leading straight to an accelerated approval for casimersen, now christened Amondys 45.

We just have to wait until 2024 to find out if it works.

Amondys 45’s approval was unceremonious, compared to its two older siblings. There was no controversy within the FDA over approving a drug based on a biomarker rather than clinical benefit, setting up a powerful precedent that still haunts acting FDA commissioner Janet Woodcock as biotech insiders weighed her potential permanent appointment; no drama like the FDA issuing a stunning rejection only to reverse its decision and hand out an OK four months later, which got more complicated after the scathing complete response letter was published; no anxious tea leaf reading or heated arguments from drug developers and patient advocates who were tired of having corticosteroids as their loved ones’ only (sometimes expensive) option.

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