FDA staff large­ly un­fazed by CV sig­nal in Am­gen os­teo­poro­sis drug tri­als

FDA staff braved the snow and the fed­er­al shut­down to post their re­view of Am­gen’s once-re­ject­ed os­teo­poro­sis drug on Mon­day, un­der­scor­ing that the ef­fi­ca­cy of the drug in post­menopausal women had been es­tab­lished, and sug­gest­ing that the CV sig­nal ob­served in two tri­als may not be a sig­nif­i­cant wor­ry.

The re­view comes days af­ter Am­gen and part­ner UCB se­cured Japan­ese ap­proval for the drug, ro­mosozum­ab, and pre­cedes a meet­ing of in­de­pen­dent ex­perts on Wednes­day who will make their rec­om­men­da­tion on the ap­prov­abil­i­ty of the drug in the Unit­ed States. Ro­mosozum­ab — which is to be sold un­der the brand name Eveni­ty — func­tions pre­dom­i­nant­ly as a bone an­a­bol­ic agent that stim­u­lates bone growth.

The mon­o­clon­al an­ti­body was test­ed in three late-stage stud­ies: the 7,180-pa­tient FRAME study in post­menopausal women with os­teo­poro­sis, which test­ed the drug against a place­bo; the 4,093-pa­tient ARCH study in post­menopausal women in os­teo­poro­sis, which test­ed the drug against an os­teo­poro­sis drug orig­i­nal­ly made by Mer­ck called al­en­dronate; and the 245-pa­tient BRIDGE study in men with os­teo­poro­sis, which test­ed the drug against a place­bo.

All three piv­otal stud­ies showed the drug was ef­fec­tive, but the ARCH and BRIDGE tri­al demon­strat­ed a sig­nal of car­dio­vas­cu­lar-re­lat­ed se­ri­ous ad­verse events, which led to the FDA is­su­ing a com­plete re­sponse let­ter to the com­pa­nies, af­ter they had ap­plied for ap­proval in post­menopausal women with os­teo­poro­sis. Tak­ing in­to ac­count the CV sig­nal and feed­back from the FDA about the pauci­ty of an­a­bol­ic agents, the duo re-sub­mit­ted an ap­pli­ca­tion to mar­ket drug last year, but for a nar­row­er pa­tient pop­u­la­tion: post­menopausal women with os­teo­poro­sis who car­ry a high risk of frac­ture. They al­so pro­posed a boxed warn­ing as well as a pre­cau­tion for car­dio­vas­cu­lar risk on the drug’s la­bel, if ap­proved. Mean­while, the drug is un­der re­view in Eu­rope.

Glob­al­ly, 1 in 3 women over age 50 will ex­pe­ri­ence os­teo­porot­ic frac­tures, ac­cord­ing to the In­ter­na­tion­al Os­teo­poro­sis Foun­da­tion.

In its re­view, FDA staff agreed that the ef­fec­tive­ness of ro­mosozum­ab for the treat­ment of post­menopausal os­teo­poro­sis had been es­tab­lished, but ques­tioned whether the CV sig­nal seen in ARCH and BRIDGE were gen­er­al­iz­able to the US pop­u­la­tion, giv­en that en­rolled pa­tients from the US on­ly ac­count­ed for 1.8% of the ARCH study, and 1.4% of the BRIDGE study. In their sug­gest­ed ques­tions for in­de­pen­dent pan­el, the agency’s re­view­ers did not stress the CV is­sue.

“The docs read most­ly be­nign and dis­cus­sion/vot­ing ques­tions are not as crit­i­cal on CV risk, sup­port­ing a fa­vor­able pan­el vote on Wed (1/16) and an even­tu­al ap­proval lat­er in H1:19,” Jef­feries an­a­lysts wrote in a note, adding that Lil­ly’s os­teo­poro­sis drug For­teo car­ries a black box warn­ing high­light­ing the risk of can­cer and still rakes in about $2 bil­lion.

The drug “rep­re­sents a mod­est $500 mil­lion world­wide up­side op­por­tu­ni­ty not wide­ly ac­count­ed by con­sen­sus, and the drug has shown strong ef­fi­ca­cy (beat­ing Fos­amax by 48-50%) along with an ac­cept­able safe­ty pro­file. The pri­or safe­ty sig­nal seen in the small­er of two key Phase III stud­ies (ARCH vs FRAME) seems more spu­ri­ous than con­cern­ing to us,” they not­ed.

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.