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.

Up­dat­ed: FDA re­mains silent on or­phan drug ex­clu­siv­i­ty af­ter last year's court loss

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

Illustration: Assistant Editor Kathy Wong for Endpoints News

As mon­ey pours in­to dig­i­tal ther­a­peu­tics, in­sur­ance cov­er­age crawls



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Matt Gline, Roivant Sciences CEO (Photo by John Sciulli/Getty Images for GLG)

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Roche HQ in Basel, Switzerland. (Image credit: Kyle LaHucik/Endpoints News)

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Paul Hudson, Sanofi CEO (Romuald Meigneux/Sipa via AP Images)

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Lynn Baxter, Viiv Healthcare's head of North America

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