Io­n­is, Akcea team face some tough ques­tions on safe­ty as FDA in­sid­ers pon­der risks linked to volane­sors­en

Re­searchers for Io­n­is’ $IONS ma­jor­i­ty-owned spin­out Akcea will have plen­ty of per­suad­ing to do this week if they ever ex­pect to get their drug volane­sors­en on the mar­ket.

The FDA in­ter­nal re­view came out to­day, re­flect­ing the same deep con­cerns that an­a­lysts have ex­pressed about the safe­ty of a drug that has been linked with re­peat­ed in­stances of sud­den and dan­ger­ous drops in platelet counts. Platelets are need­ed to trig­ger the clot­ting that stops bleed­ing.

Akcea’s shares $AK­CA im­me­di­ate­ly tum­bled 15% on the neg­a­tive tone of the in­ter­nal re­view.

James Smith

In a memo to the ad­vi­so­ry com­mit­tee meet­ing on Thurs­day, James Smith, the deputy di­rec­tor of the Di­vi­sion of Me­tab­o­lism and En­docrinol­o­gy Prod­ucts, spot­light­ed a gen­er­al agree­ment that the drug has a clear­ly pos­i­tive ef­fect on reg­u­lat­ing plas­ma triglyc­eride for pa­tients with rare cas­es of fa­mil­ial chy­lomi­crone­mia syn­drome. That’s a sur­ro­gate end­point for the dis­ease.

But is the ben­e­fit re­al­ly worth the risk of bleed­ing? That’s the big ques­tion that the de­vel­op­ers face this week. Reg­u­la­tors are al­so some­what per­plexed by Akcea’s wish to switch the dos­ing reg­i­men and their platelet mon­i­tor­ing strat­e­gy to some­thing that was nev­er test­ed in the clin­i­cal tri­als. 

From Smith’s note:

Al­though the re­views high­light sev­er­al safe­ty/tol­er­a­bil­i­ty is­sues, the pri­ma­ry fo­cus for both the ap­pli­cant and the re­view­ers has been the risk of throm­bo­cy­tope­nia (low blood platelet counts) and re­sult­ing po­ten­tial for se­ri­ous bleed­ing….(S)ome pa­tients can ex­hib­it a rapid and un­pre­dictable re­duc­tion in platelets to ex­treme­ly low lev­els. In CS6, no pa­tients as­signed to place­bo had a platelet count fall be­low 100,000/uL com­pared with 18 (55%) of 33 pa­tients as­signed to volane­sors­en…Switch­ing to bi­week­ly dos­ing and/or dose in­ter­rup­tions have not al­ways led to a suf­fi­cient­ly time­ly re­cov­ery of platelet count; some pa­tients have re­quired treat­ment with pred­nisone, hos­pi­tal­iza­tion, and/or ad­min­is­tra­tion of IVIG. To date, se­ri­ous bleed­ing events have not been ob­served in this rel­a­tive­ly lim­it­ed safe­ty data­base, but the re­view­ers high­light a high­er risk of non-se­ri­ous bleed­ing-re­lat­ed ad­verse events with volane­sors­en (e.g., epis­taxis, pe­techi­ae). Some of these events oc­curred at platelet lev­els where spon­ta­neous bleed­ing would be un­ex­pect­ed, sug­gest­ing the pos­si­bil­i­ty of an ab­nor­mal­i­ty of platelet func­tion as well as an ef­fect on platelet count.

Io­n­is re­port­ed a lit­tle more that a year ago that it had achieved its ef­fi­ca­cy end­point in Phase III. But five pa­tients were forced out of the tri­al due to a threat­en­ing de­cline in platelet counts. Grade 4 throm­bo­cy­tope­nia oc­curred in three pa­tients, which end­ed af­ter they stopped dos­ing. There were no with­drawals due to platelet counts af­ter the com­pa­ny be­gan mon­i­tor­ing the side ef­fect.

If they do get an ap­proval, says Smith, it will have to come with a REMS. But right now, that looks like the best case sce­nario.

UP­DAT­ED: Mer­ck pulls Keytru­da in SCLC af­ter ac­cel­er­at­ed nod. Is the FDA get­ting tough on drug­mak­ers that don't hit their marks?

In what could be an early shot in the battle against drugmakers that whiff on confirmatory studies to support accelerated approvals, the FDA ordered Bristol Myers Squibb late last year to give up Opdivo’s approval in SCLC. Now, Merck is next on the firing line — are we seeing the FDA buckling down on post-marketing offenders?

Merck has withdrawn its marketing approval for PD-(L)1 inhibitor Keytruda in metastatic small cell lung cancer as part of what it describes as an “industry-wide evaluation” by the FDA of drugs that do not meet the post-marketing checkpoints on which their accelerated nods were based, the company said Monday.

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Michael Shpigelmacher

Khosla joins bet on un­con­ven­tion­al start­up look­ing to send drug de­liv­er­ing ro­bots in­to the brain

When Michael Shpigelmacher started the project, he knew he’d have to fund it himself. Every other effort of its kind was academic, rejected as too risky by investors.

Shpigelmacher, a robotics geek and entrepeneur who had drifted into consulting for pharma, wanted to build the real-life equivalent of technology from the 1960s film Fantastic Voyage, the one where a submarine crew is shrunk to “about the size of a microbe” and sent on a mission to repair a scientist’s brain. He scanned the literature, found the lab that was working on the most advanced project — at the Max Planck Institute in Germany, it turned out — and started funding them with money from his own account, along with some seed cash from friends and family.

Bob Nelsen (Photo by Michael Kovac/Getty Images)

With stars aligned and cash in re­serve, Bob Nelsen's Re­silience plans a makeover at 2 new fa­cil­i­ty ad­di­tions to its drug man­u­fac­tur­ing up­start

Bob Nelsen’s new, state-of-the-art drug manufacturing initiative is taking shape.

Just 3 months after gathering $800 million of launch money, a dream team board and a plan to shake up a field where he found too many bottlenecks and inefficiencies for the era of Covid-19, Resilience has snapped up a pair of facilities now in line for a retooling.

The company has acquired a 310,000-square-foot plant in Boston from Sanofi along with a 136,000-square-foot plant in Ontario to add to a network which CEO Rahul Singhvi says is just getting started on building his company’s operations up. The Sanofi deal comes with a contract to continue manufacturing one of its drugs.

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Pascal Soriot, AstraZeneca CEO (AP Images)

Pas­cal So­ri­ot cash­es in As­traZeneca’s chips on Mod­er­na for $1.2B cash in­jec­tion

While still working to prove its own Covid-19 vaccine, AstraZeneca has reportedly capitalized on the success of another.

The company has sold off its 7.7% stake in Moderna and turned it into $1.2 billion in cash, according to the Times, beefing up the reserves just as Pascal Soriot is wrapping up his $39 billion acquisition of Alexion and its rare disease pipeline.

AstraZeneca’s stock sale follows a similar move by Merck in December. But like its pharma brethren, the British giant is keeping its R&D collaborations with Moderna.

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Af­ter bail­ing on Covid-19 vac­cines, Mer­ck will team up with J&J to pro­duce its shot as part of un­usu­al Big Phar­ma pact

Merck took a big gamble when it opted to jump into the Covid-19 vaccine race late, and made an equally momentous decision to back out in late January. Now, looking to chip in on the effort, Merck reportedly agreed to team up with one of the companies that has already crossed the finish line.

President Joe Biden on Tuesday is expected to announce a partnership between drugmakers Merck and Johnson & Johnson to jointly produce J&J’s recombinant protein Covid-19 vaccine that received the FDA’s emergency use authorization Saturday, the Washington Post reported.

Ab­b­Vie tees up a biotech buy­out af­ter siz­ing up their Parkin­son's drug spun out of Ke­van Shokat's lab

AbbVie has teed up a small but intriguing biotech buyout after looking over the preclinical work it’s been doing in Parkinson’s disease.

The company is called Mitokinin, a Bay Area biotech spun out of the lab of UCSF’s Kevan Shokat, whose scientific explorations have formed the academic basis of a slew of startups in the biotech hub. One of Shokat’s PhD students in the lab, Nicholas Hertz, co-founded Mitokinin using their lab work on PINK1 suggesting that amping up its activity could play an important role in regulating the mitochondrial dysfunction contributing to Parkinson’s disease pathogenesis and progression.

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Paul Sekhri

The next big biotech su­per­star? Paul Sekhri has some thoughts on that

It occasionally occurs to Paul Sekhri that if they pull this off, his company will be on the front page of the New York Times and a lead story in just about every major news outlet on the planet. He tries not to dwell on it, though.

“I just want to be laser-focused on getting to that point,” Sekhri says, before acknowledging, “Yes, it absolutely crossed my mind.”

Sekhri, a longtime biopharma executive with tenures at Sanofi and Novartis, is now entering year three as CEO of eGenesis, the biotech that George Church protégé Luhan Yang founded to genetically alter pigs so that they can be used for organ transplants. He led them through one megaround and has just closed another, raising $125 million from 17 different investors to push the first-ever (humanized) pig to human transplants into the clinic.

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Fi­bro­Gen shares skid low­er as a sur­prise ad­comm rais­es risks on roxa OK

FibroGen will likely have to delay its US rollout for roxadustat once again.

In an unexpected move, the FDA is convening its Cardiovascular and Renal Drugs Advisory Committee to review the NDA in an advisory committee meeting. The date is yet to be confirmed.

Just a few weeks ago, SVB Leerink analyst Geoffrey Porges predicted that the roxa approval could come ahead of the PDUFA date on March 20 — effusive despite already being let down once by the FDA’s extension of its review back in December. AstraZeneca, which is partnered with FibroGen on the chronic kidney disease-related anemia drug, disclosed regulators had requested further clarifying analyses of clinical data.

In­tro­duc­ing End­pointsF­DA+, our new pre­mi­um week­ly reg­u­la­to­ry news re­port led by Zachary Bren­nan

CRLs. 483s. CBER, CDER and RWE. For biopharma professionals, these acronyms command attention because of the fundamental role FDA plays in drug development. Now Endpoints is doubling down on regulatory coverage, and launching a weekly report focusing on developments out of White Oak, with analysis and insight into what it all means.

Coverage will be led by our new senior editor, Zachary Brennan. He joins Endpoints from POLITICO, where he covered pharma. Prior to that he was the managing editor for Regulatory Focus, a news publication from the Regulatory Affairs Professionals Society.