PhII fail­ure in rare neu­rode­gen­er­a­tive dis­ease? No mat­ter, Bio­gen will mo­tor on in Alzheimer's

Bio­gen’s fierce fo­cus on dis­or­ders of the brain has hit an­oth­er road­block.

On Fri­day, the US drug­mak­er — which re­cent­ly res­ur­rect­ed its amy­loid-tar­get­ing Alzheimer’s drug, ad­u­canum­ab — said its an­ti-tau drug, go­suranemab, failed a mid-stage study in pa­tients with pro­gres­sive supranu­clear pal­sy (PSP), a rare brain dis­or­der that re­sults from de­te­ri­o­ra­tion of brain cells that con­trol move­ment and thought.

Bio­gen, which li­censed the mon­o­clon­al an­ti­body from Bris­tol-My­ers Squibb, said it is aban­don­ing test­ing the drug in PSP pa­tients, but will con­tin­ue to in­ves­ti­gate its use in Alzheimer’s pa­tients with mild cog­ni­tive im­pair­ment, giv­en dif­fer­ences in dis­ease pathol­o­gy, it said.

In pa­tients with PSP, the build-up of tau typ­i­cal­ly oc­curs in the frontal cor­tex. While in Alzheimer’s, tau tends to ac­cu­mu­late in the hy­po­thal­a­mus and brain stem.

“It’s un­clear what the pre­cise im­pli­ca­tions are from the PSP fail­ure – we’re sure Bio­gen will con­duct in-depth analy­ses – but on the sur­face, it leads us to ques­tion the vi­a­bil­i­ty of tar­get­ing in­tra-cel­lu­lar tau with an an­ti­body. The ba­sic premise be­hind the tau an­ti­body ap­proach is to pre­vent the “spread­ing” of tau from neu­ron to neu­ron, though as we un­der­stand it, at a giv­en time point, very lit­tle tau is sit­ting out­side of the cell, and most mis­fold­ed tau is path­o­gen­ic in­side neu­rons,” Stifel’s Paul Mat­teis wrote in a note.

“Thus, we would view these da­ta in PSP – which is the­o­ret­i­cal­ly an en­riched in­di­ca­tion for test­ing the tau an­ti­body hy­poth­e­sis – as al­so neg­a­tive for the prospects of Bio­gen’s tau pro­gram in Alzheimer’s, giv­en that the lat­ter is more het­ero­ge­neous, and the same po­ten­tial ‘an­ti­body tar­get ac­cess is­sues’ may al­so be a rel­e­vant chal­lenge.”

Bio­gen did not of­fer much de­tail on the failed PASS­PORT study, ex­cept to say go­suranemab had failed to in­duce a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment in the PSP rat­ing scale at week 52 — the main study goal — and that it had al­so dis­ap­point­ed in key clin­i­cal sec­ondary end­points.

Ex­pec­ta­tions for the PSP pro­gram were al­ready low, Cred­it Su­isse’s Evan Seiger­man wrote in a note.

“Tau tar­get­ing as­sets have so far been dif­fi­cult to de­vel­op (Ab­b­Vie dis­con­tin­ued its pro­gram in PSP due to lack of ef­fi­ca­cy). De­spite ev­i­dence of CSF free tau sup­pres­sion, it re­mains a chal­lenge to prove how this trans­lates in­to clin­i­cal ben­e­fit,” he said. “The com­pa­ny plans on con­tin­u­ing the de­vel­op­ment of ‘092 in Alzheimer’s dis­ease ‘due to dif­fer­ences in dis­ease pathol­o­gy,’ but as we were with PSP have low con­fi­dence in the pro­gram.”

The go­suranemab study in Alzheimer’s pa­tients, dubbed TAN­GO, has en­rolled over 650 pa­tients with an es­ti­mat­ed pri­ma­ry com­ple­tion date of May 2021, ac­cord­ing to clin­i­cal­tri­als.gov.

But the quest for treat­ments to pre­vent and treat Alzheimer’s, the most com­mon form of de­men­tia, is lit­tered with fail­ure. For long, re­searchers were par­tial to the amy­loid hy­poth­e­sis, which sug­gests that tar­get­ing be­ta-amy­loid plaques that col­lect be­tween neu­rons and dis­rupt cell func­tion could make a ma­te­r­i­al im­pact on the pro­gres­sion of the dis­ease.

How­ev­er, set­back af­ter set­back seem­ing­ly put the nail in the amy­loid cof­fin ear­li­er this year af­ter Bio­gen, one of the last flag bear­ers of the the­o­ry ac­knowl­edged their fail­ure. But in a dra­mat­ic twist in Oc­to­ber, Bio­gen in­di­cat­ed it had res­ur­rect­ed its faith in the amy­loid the­o­ry, at least in a sub­set of pa­tients, fol­low­ing a pro­tract­ed pe­ri­od of da­ta min­ing.

Mean­while, re­searchers are al­so look­ing at tau. Ini­tial­ly, an­ti-tau ther­a­pies were fo­cused on in­hibit­ing ki­nas­es or tau ag­gre­ga­tion, or on sta­bi­liz­ing mi­cro­tubules (which help guide nu­tri­ents and mol­e­cules from the cell body to the ax­on and den­drites) — but most of these ap­proach­es have been aban­doned due to tox­i­c­i­ty or a lack of ef­fi­ca­cy, or both. Sci­en­tists are now look­ing at de­vel­op­ing tau-tar­get­ing im­munother­a­pies.

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

Fewer Approvals, but Neurology Rivals Oncology and Sees Major Innovations

This report, the fourth in our Trinity Drug Index series, outlines key themes and emerging trends in the industry as we progress towards a new world of targeted and innovative products. It provides a comprehensive evaluation of the performance of novel drugs approved by the FDA in 2016, scoring each on its commercial performance, therapeutic value, and R&D investment (Table 1: Drug ranking – Ratings on a 1-5 scale).

How to cap­i­talise on a lean launch

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?
We spoke to Managing Consultant Frances Hendry to find out how Blue Latitude Health partnered with a fledgling subsidiary of a pharmaceutical organisation to launch an innovative product in a
complex market.
What does the launch environment look like for this product?
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.

Gilead dusts off a failed Ebo­la drug as coro­n­avirus spreads; Ex­elix­is boasts pos­i­tive Ph I/II da­ta

→ Less than a year ago Gilead’s antiviral remdesivir failed to make the cut as investigators considered a raft of potential drugs that could be used against an Ebola outbreak. But it may gain a new mission with the outbreak of the coronavirus in China, which is popping up now around the world.

Gilead put out a statement saying that they’re now in discussions with health officials in the US and China about testing their NUC against the virus. It’s the latest in a growing lineup of biopharma companies that are marshaling R&D forces to see if they can come up with a vaccine or therapy to blunt the spread of the virus, which has now sickened hundreds, killed at least 17 people and led the Chinese government to start quarantining cities.

Aymeric Le Chatelier, Ipsen

A $1B-plus drug stum­bles in­to an­oth­er big PhI­II set­back -- this time flunk­ing fu­til­i­ty test -- as FDA hold re­mains in ef­fect for Ipsen

David Meek

At the time Ipsen stepped up last year with more than a billion dollars in cash to buy Clementia and a late-stage program for a rare bone disease that afflicts children, then CEO David Meek was confident that he had put the French biotech on a short path to a mid-2020 launch.

Instead of prepping a launch, though, the company was hit with a hold on the FDA’s concerns that a therapy designed to prevent overgrowth of bone for cases of fibrodysplasia ossificans progressiva might actually stunt children’s growth. So they ordered a halt to any treatments for kids 14 and under. Meek left soon after to run a startup in Boston. And today the Paris-based biotech is grappling with the independent monitoring committee’s decision that their Phase III had failed a futility test.

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Alex Karnal (Deerfield)

Deer­field vaults to the top of cell and gene ther­a­py CD­MO game with $1.1B fa­cil­i­ty at Philadel­phi­a's newest bio­phar­ma hub

Back at the beginning of 2015, Deerfield Management co-led a $10 million Series C for a private gene therapy startup, reshaping the company and bringing in new leaders to pave way for an IPO just a year later.

Fast forward four more years and the startup, AveXis, is now a subsidiary of Novartis marketing the second-ever gene therapy to be approved in the US.

For its part, Deerfield has also grown more comfortable and ambitious about the nascent field. And the investment firm is now putting down its biggest bet yet: a $1.1 billion contract development and manufacturing facility to produce everything one needs for cell and gene therapy — faster and better than how it’s currently done.

Tri­fec­ta of sick­le cell dis­ease ther­a­pies ex­tend life ex­pectan­cy, but are not cost-ef­fec­tive — ICER

Different therapeutic traits brandished by the three approved therapies for sickle cell disease all extend life expectancy, but their impact on quality of life is uncertain and their long-term cost-effectiveness is not up to scratch according to the thresholds considered reasonable by ICER, the non-profit concluded in a draft guidance report on Thursday.

Sickle cell disease (SCD), which encompasses a group of inherited red blood cell disorders that typically afflict those of African ancestry, impacts hemoglobin — and is characterized by episodes of searing pain as well as organ damage.

Roche's check­point play­er Tecen­triq flops in an­oth­er blad­der can­cer sub­set

Just weeks after Merck’s star checkpoint inhibitor Keytruda secured FDA approval for a subset of bladder cancer patients, Swiss competitor Roche’s Tecentriq has failed in a pivotal bladder cancer study.

The 809-patient trial — IMvigor010 — tested the PD-L1 drug in patients with muscle-invasive urothelial cancer (MIUC) who had undergone surgery, and were at high risk for recurrence.

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UP­DAT­ED: Eli Lil­ly’s $1.6B can­cer drug failed to spark even the slight­est pos­i­tive gain for pa­tients in its 1st PhI­II

Eli Lilly had high hopes for its pegylated IL-10 drug pegilodecakin when it bought Armo last year for $1.6 billion in cash. But after reporting a few months ago that it had failed a Phase III in pancreatic cancer, without the data, its likely value has plunged. And now we’re getting some exact data that underscore just how little positive effect it had.

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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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