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’s golodirsen CRL: Sarep­ta’s Duchenne drugs are dan­ger­ous to pa­tients, of­fer­ing on­ly a small ben­e­fit. And where's that con­fir­ma­to­ry tri­al?

Back last summer, Sarepta CEO Doug Ingram told Duchenne MD families and investors that the FDA’s shock rejection of their second Duchenne MD drug golodirsen was due to some concerns regulators raised about the risk of infection and the possibility of kidney toxicity. But when pressed to release the letter for all to see, he declined, according to a report from BioPharmaDive, saying that kind of move “might not look like we’re being as respectful as we’d like to be.”

He went on to assure everyone that he hadn’t misrepresented the CRL.

But Ingram’s public remarks didn’t include everything in the letter, which — following the FDA’s surprise about-face and unexplained approval — has now been posted on the FDA’s website and broadly circulated on Twitter early Wednesday.

The CRL raises plenty of fresh questions about why the FDA abruptly decided to reverse itself and hand out an OK for a drug a senior regulator at the FDA believed — 5 months ago, when he wrote the letter — is dangerous to patients. It also puts the spotlight back on Sarepta $SRPT, which failed to launch a confirmatory study of eteplirsen, which was only approved after a heated internal controversy at the FDA. Ellis Unger, director of CDER’s Office of Drug Evaluation I, notes that study could have clarified quite a lot about the benefit and risks associated with their drugs — which can cost as much as a million dollars per patient per year, depending on weight.

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2019 Trin­i­ty Drug In­dex Eval­u­ates Ac­tu­al Com­mer­cial Per­for­mance of Nov­el Drugs Ap­proved in 2016

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For start-up biotechnology companies and resource stretched pharmaceutical organisations, launching a novel product can be challenging. Lean teams can make setting a launch strategy and achieving your commercial goals seem like a colossal undertaking, but can these barriers be transformed into opportunities that work to your brand’s advantage?
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FH: We started working on the product at Phase II and now we’re going into Phase III trials. There is a significant unmet need in this disease area, and everyone is excited about the launch. However, the organisation is still evolving and the team is quite small – naturally this causes a little turbulence.

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The FDA has de­val­ued the gold stan­dard on R&D. And that threat­ens every­one in drug de­vel­op­ment

Bioregnum Opinion Column by John Carroll

A few weeks ago, when Stephen Hahn was being lightly queried by Senators in his confirmation hearing as the new commissioner of the FDA, he made the usual vow to maintain the gold standard in drug development.

Neatly summarized, that standard requires the agency to sign off on clinical data — usually from two, well-controlled human studies — that prove a drug’s benefit outweighs any risks.

Over the last few years, biopharma has enjoyed an unprecedented loosening over just what it takes to clear that bar. Regulators are more willing to drop the second trial requirement ahead of an accelerated approval — particularly if they have an unmet medical need where patients are clamoring for a therapy.

That confirmatory trial the FDA demands can wait a few years. And most everyone in biopharma would tell you that’s the right thing for patients. They know its a tonic for everyone in the industry faced with pushing a drug through clinical development. And it’s helped inspire a global biotech boom.

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New play­ers are jump­ing in­to an old vac­cine game as pan­dem­ic pan­ic spreads fast — putting their tech to the test

When the CNN news crew in Wuhan caught wind of the Chinese government’s plan to quarantine the city of 11 million people, they made a run for one of the last trains out — their Atlanta colleagues urging them on. On the way to the train station, they were forced to skirt the local seafood market, where the coronavirus at the heart of a brewing outbreak may have taken root.

And they breathlessly reported every moment of the early morning dash.

In shuttering the city, triggering an exodus of masked residents who caught wind of the quarantine ahead of time, China signaled that they were prepared to take extreme actions to stop the spread of a virus that has claimed 17 lives, sickened many more and panicked people around the globe.

CNN helped illustrate how hard all that can be.

The early reaction in the biotech industry has been classic, with small-cap companies scrambling to headline efforts to step in fast. But there are also new players in the field with new tech that has been introduced since the last of a series of pandemic panics that could change the usual storylines. And they’re volunteering for a crash course in speeding up vaccine development — a field where overnight solutions have been impossible to prove.

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Roche cracks Chi­na's ADC mar­ket open as Kad­cy­la scores its first breast can­cer OK in the coun­try

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He called himself a “global citizen,” and traveled often across three-plus continents. While CEO of AstraZeneca, he commissioned a flight service — media-dubbed AstraZeneca airlines — from Cambridge to the company’s other European hub in Gothenburg. He made few, if any, public statements on the environment or his companies’ impact on it.

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Partnered with PTC Therapeutics, the Roche drug was tested in 41 patients aged 1-7 months with type 1 SMA, a rare genetic muscle-wasting disease. The trial, dubbed FIREFISH, measured efficacy via the proportion of infants sitting without support after 12 months of treatment, and longer.

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Things are no different, as the coronavirus outbreak in Wuhan, China takes hold. There have been close to 300 confirmed human infections in China, and at least four deaths. Coronaviruses are a large family of viruses, which include MERS and SARS. On Tuesday, the CDC reported the virus was detected in a US traveler returning from Wuhan.