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.

Med­ical an­i­ma­tion: Mak­ing it eas­i­er for the site and the pa­tient to un­der­stand

Medical animation has in recent years become an increasingly important tool for conveying niche information to a varied audience, particularly to those audiences without expertise in the specialist area. Science programmes today, for example, have moved from the piece-to-camera of the university professor explaining how a complex disease mechanism works, to actually showing the viewer first-hand what it might look like to shrink ourselves down to the size of an ant’s foot, and travel inside the human body to witness these processes in action. Effectively communicating a complex disease pathophysiology, or the novel mechanism of action of a new drug, can be complex. This is especially difficult when the audience domain knowledge is limited or non-existent. Medical animation can help with this communication challenge in several ways.
Improved accessibility to visualisation
Visualisation is a core component of our ability to understand a concept. Ask 10 people to visualise an apple, and each will come up with a slightly different image, some apples smaller than others, some more round, some with bites taken. Acceptable, you say, we can move on to the next part of the story. Now ask 10 people to visualise how HIV’s capsid protein gets arranged into the hexamers and pentamers that form the viral capsid that holds HIV’s genetic material. This request may pose a challenge even to someone with some virology knowledge, and it is that inability to effectively visualise what is going on that holds us back from fully understanding the rest of the story. So how does medical animation help us to overcome this visualisation challenge?

Alice Shaw, Lung Cancer Foundation of America

Top ALK ex­pert and can­cer drug re­searcher Al­ice Shaw bids adieu to acad­e­mia, hel­lo to No­var­tis

Jay Bradner has recruited a marquee oncology drug researcher into the ranks of the Novartis Institutes for BioMedical Research. Alice Shaw is jumping from prestigious posts intertwined through Mass General, Harvard and Dana-Farber to take the lead of NIBR’s translational clinical oncology group.

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Christine Bunt, Robert Langer. Verseau

Armed with Langer tech and $50M, Verseau hails new check­point drugs un­leash­ing macrophages against can­cer

The rising popularity of CD47 has propelled the “don’t-eat-me” signal to household name status in the immuno-oncology world. But just as PD-(L)1 merely represents the most fruitful of all checkpoints regulating T cells, Verseau Therapeutics is convinced that CD47 is one of many regulators one can modulate to stir up or tame the immune system.

“Macrophages are interesting because we were all educated probably 20 years ago that they are the big eaters in the immune system, but they’re really the orchestrators of the immune system,” CEO Christine Bunt said.

Hal Barron, GSK's president of R&D and CSO, speaks to Endpoints News founder and editor John Carroll in London at Endpoints' #UKBIO19 summit on October 8, 2019

[Video] Cel­e­brat­ing tri­al fail­ures, chang­ing the cul­ture and al­ly­ing with Cal­i­for­nia dream­ers: R&D chief Hal Bar­ron talks about a new era at GSK

Last week I had a chance to sit down with Hal Barron at Endpoints’ #UKBIO19 summit to discuss his views on R&D at GSK, a topic that has been central to his life since he took the top research post close to 2 years ago. During the conversation, Barron talked about changing the culture at GSK, a move that involves several new approaches — one of which involves celebrating their setbacks as they shift resources to the most promising programs in the pipeline. Barron also discussed his new alliances in the Bay Area — including his collaboration pact with Lyell, which we covered here — frankly assesses the pluses and minuses of the UK drug development scene, and talks about his plans for making GSK a much more effective drug developer.

This is one discussion you won’t want to miss. Insider and Enterprise subscribers can log-in to watch the video.

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Mi­rati preps its first look at their KRAS G12C con­tender, and they have to clear a high bar for suc­cess

If you’re a big KRAS G12C fan, mark your calendars for October 28 at 4:20 pm EDT.

That’s when Mirati $MRTX will unveil its first peek at the early clinical data available on MRTX849 in presentations at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston.

Mirati has been experiencing the full effect of a rival’s initial success at targeting the G12C pocket found on KRAS, offering the biotech some support on the concept they’re after — and biotech fans a race to the top. Amgen made a big splash with its first positive snapshot on lung cancer, but deflated sky-high expectations as it proved harder to find similar benefits in other types of cancers.

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The FDA will hus­tle up an ex­pe­dit­ed re­view for As­traZeneca’s next shot at a block­buster can­cer drug fran­chise

AstraZeneca paid a hefty price to partner with Daiichi Sankyo on their experimental antibody drug conjugate for HER2 positive breast cancer. And they’ve been rewarded with a fast ride through the FDA, with a straight shot at creating another blockbuster oncology franchise.

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Sean Parker, AP

Sean Park­er helps cre­ate a CRISPRed cell ther­a­py 2.0 play — and he’s got a high-pro­file set of lead­ers on the team

You can rack up one more high-profile debut effort in the wave of activity forming around cell therapy 2.0. It’s another appealing Bay Area group that’s attracted some of the top hands in the business to a multi-year effort to create a breakthrough. And they have $85 million in hand to make that first big step to the clinic.

Today it’s Ken Drazan and the team at South San Francisco-based ArsenalBio that are coming from behind the curtain for a public bow, backed by billionaire Sean Parker and a collection of investors that includes Beth Seidenberg’s new venture investment operation based in LA.
Drazan — a J&J Innovation vet with a long record of entrepreneurial endeavors — exited the stage in 2018 when his last mission ended as he stepped aside as president of Grail. It wasn’t long, though, before he was helping out with a business plan for ArsenalBio that revolved around the work of a large group of interconnected scientists supported by the Parker Institute for Cancer Immunology.

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CSL ac­cus­es ri­val Pharm­ing of par­tic­i­pat­ing in a scheme to rip off IP on HAE while re­cruit­ing se­nior R&D staffer

Pharming has landed in the middle of a legal donnybrook after recruiting a senior executive from a rival R&D team at CSL. The Australian pharma giant slapped Pharming with a lawsuit alleging that the Dutch biotech’s new employee, Joseph Chiao, looted a large cache of proprietary documents as he hit the exit. And they want it all back.
Federal Judge Juan Sanchez in the Eastern District Pennsylvania court issued an injunction on Tuesday prohibiting Chiao from doing any work on HAE or primary immune deficiency in his new job and demanding that he return any material from CSL that he may have in his possession. And he wants Pharming to tell its employees not to ask for any information on the forbidden topics.
For its part, Pharming fired off an indignant response this morning denying any involvement in extracting any kind of IP from CSL, adding that it’s cooperating in the internal probe that CSL has underway.

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Eli Lil­ly’s first PhI­II show­down for their $1.6B can­cer drug just flopped — what now?

When Eli Lilly plunked down $1.6 billion in cash to acquire Armo Biosciences a little more than a year ago, the stars seemed aligned in its favor. The jewel in the crown they were buying was pegilodecakin, which had cleared the proof-of-concept stage and was already in a Phase III trial for pancreatic cancer.

And that study just failed.

Lilly reported this morning that their cancer drug flopped on overall survival when added to FOLFOX (folinic acid, 5-FU, oxaliplatin), compared to FOLFOX alone among patients suffering from advanced pancreatic cancer.

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