Once again No­var­tis’ car­dio team looks to beat the odds us­ing sketchy da­ta and a fa­mil­iar ar­gu­ment

When­ev­er a clin­i­cal tri­al team starts tout­ing the “to­tal­i­ty” of the da­ta, you know they’re in trou­ble.

Bioreg­num Opin­ion Col­umn by John Car­roll

For No­var­tis’ En­tresto (sacu­bi­tril/val­sar­tan) team, that’s the ear­ly go-to po­si­tion on their lat­est round of piv­otal da­ta for the block­buster — which the phar­ma gi­ant be­lieves has megablock­buster po­ten­tial. We al­ready knew that No­var­tis’ team plans to field the drug to reg­u­la­tors in search of a la­bel ex­ten­sion — but now we have a bet­ter idea of the hur­dles it faces. 

And they are steep.

En­tresto flat failed the pri­ma­ry end­point in re­duc­ing the com­pos­ite pri­ma­ry end­point of to­tal (first and re­cur­rent) heart fail­ure hos­pi­tal­iza­tions and car­dio­vas­cu­lar death — hit­ting a 13% re­duc­tion among heart fail­ure pa­tients with pre­served ejec­tion frac­tion (HF­pEF). The p-val­ue was 0.059, which means they couldn’t prove their case for the drug.

No­var­tis’ po­si­tion that this was a nar­row miss rarely pass­es muster at the FDA.

Then they made a sketchy move, switch­ing to a sub-pop­u­la­tion analy­sis which is sure to at­tract lots of skep­ti­cism among reg­u­la­tors — many of whom would have been in­volved in shut­ting down No­var­tis’ last play on that in car­dio with canakinum­ab, where the team shot (and missed) at a par­tic­u­lar sub-pop­u­la­tion where they felt the drug could suc­ceed com­mer­cial­ly. 

Stick­ing with “in­di­vid­u­als with a left ven­tric­u­lar ejec­tion frac­tion equal to or be­low the me­di­an of 57%” in this new study, re­searchers teased out a 22% re­duc­tion on the end­point. In women, it was 27.5%.

“While the re­duc­tion in the pri­ma­ry end­point was not sta­tis­ti­cal­ly sig­nif­i­cant, the to­tal­i­ty of ev­i­dence from PARAGON-HF sug­gests po­ten­tial over­all ben­e­fit of sacu­bi­tril/val­sar­tan com­pared with val­sar­tan in HF­pEF, par­tic­u­lar­ly in pa­tients with ejec­tion frac­tion be­low nor­mal. It al­so high­lights the com­plex­i­ty of HF­pEF and may sug­gest that some treat­ments have a more pro­nounced im­pact in cer­tain pa­tient groups, in­clud­ing women, who are more like­ly to suf­fer from this con­di­tion than men,” said Har­vard’s Scott Solomon in a pre­pared state­ment.

While No­var­tis has been rack­ing up an im­pres­sive slate of pos­i­tive late-stage stud­ies in a va­ri­ety of fields, it hasn’t per­formed well in car­dio — one of the tough­est R&D sec­tors in the busi­ness, where reg­u­la­tors ex­pect pris­tine da­ta be­fore open­ing up la­bels to large num­bers of pa­tients. And No­var­tis likes to push the en­ve­lope in car­dio — though with­out much suc­cess.

Just 9 months ago they trot­ted out pos­i­tive da­ta un­der­scor­ing En­tresto’s abil­i­ty to beat on key sur­vival and re-hos­pi­tal­iza­tion num­bers in a head-to-head study with the cheap ACE in­hibitor enalapril. But some ex­perts in the field al­so ques­tioned why they used a low dose of the cheap ri­val when sig­nif­i­cant num­bers of pa­tients typ­i­cal­ly are pre­scribed a high­er dose.

No­var­tis, though, ap­pears in­tent on test­ing reg­u­la­tors’ in­creased open­ness to some­thing less than the gold stan­dard, mak­ing this a new case study on just what stan­dards the FDA plans to en­force. And if they do get by reg­u­la­tors, they will still face plen­ty of ques­tions from pay­ers, who had erect­ed some stiff bar­ri­ers to this drug af­ter its first ap­proval in 2015.

Ini­tial­ly a slow-mov­ing prod­uct ham­pered by physi­cians re­luc­tant to adopt a new med and pay­ers who were none too hap­py with the price, En­tresto is now com­fort­ably hit­ting its block­buster stride. But No­var­tis wants to add bil­lions more in an­nu­al sales, and its lat­est tri­al fail­ure won’t make that task any eas­i­er.

Scott Gottlieb, AP Images

Scott Got­tlieb is once again join­ing a team that en­joyed good times at the FDA un­der his high-en­er­gy stint at the helm

Right after jumping on Michael Milken’s FasterCures board on Monday, the newly departed FDA commissioner is back today with news about another life sciences board post that gives him a ringside chair to cheer on a lead player in the real-world evidence movement — one with very close ties to the FDA.

Aetion is reporting this morning that Gottlieb is joining their board, a group that includes Mohamad Makhzoumi, a general partner at New Enterprise Associates, where Gottlieb returned after stepping out of his role at the FDA 2 years after he started.

Gottlieb — one of the best connected execs in biopharma — knows this company well. As head of FDA he championed the use of real-world evidence to help guide drug developers and the agency in gaining greater efficiencies, which helped set up Aetion as a high-profile player in the game.

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Deborah Dunsire. Lundbeck

UP­DAT­ED: Deb­o­rah Dun­sire is pay­ing $2B for a chance to leap di­rect­ly in­to a block­buster show­down with a few of the world's biggest phar­ma gi­ants

A year after taking the reins as CEO of Lundbeck, Deborah Dunsire is making a bold bid to beef up the Danish biotech’s portfolio of drugs in what will likely be a direct leap into an intense rivalry with a group of giants now carving up a growing market for new migraine drugs.

Bright and early European time Monday morning the company announced that it will pay up to about $2 billion to buy Alder, a little biotech that is far along the path in developing a quarterly IV formulation of a CGRP drug aimed at cutting back the number of crippling migraines patients experience each month. In a followup call, Dunsire also noted that the company will likely need 200 to 250 reps for this marketing task on both sides of the Atlantic. And analysts were quick to note that the dealmaking at Lundbeck isn’t done, with another $2 billion to $3 billion available for more deals to beef up the pipeline.

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San Diego cou­ple charged with steal­ing trade se­crets, open­ing Chi­nese biotech as DOJ crack­down con­tin­ues

A San Diego couple has been charged with stealing trade secrets from a US hospital and opening a business based off those secrets in China as the controversial industry-wide crackdown on alleged corporate espionage continues. On the same day, the Department of Justice announced they had arrested Beijing representative Zhongsan Liu for allegedly trying to obtain research visas for government recruiters.

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UP­DAT­ED: Bio­gen pulls the plug on prized IPF drug from $562M+ Stromedix buy­out

One of Biogen’s attempts to branch out has flopped as the biotech scraps a mid-stage program for idiopathic pulmonary fibrosis.

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Tower Bridge in London [Shutterstock]

#UK­BIO19: Join GSK’s Hal Bar­ron and a group of top biotech ex­ecs for our 2nd an­nu­al biotech sum­mit in Lon­don

Over the past 10 years I’ve made a point of getting to know the Golden Triangle and the special role the UK biopharma industry plays there in drug development. The concentration of world class research institutes, some of the most accomplished scientists I’ve ever seen at work and a rising tide of global investment cash leaves an impression that there’s much, much more to come as biotech hubs are birthed and nurtured.

It’s fi­nal­ly over: Bio­gen, Ei­sai scrap big Alzheimer’s PhI­I­Is af­ter a pre­dictable BACE cat­a­stro­phe rais­es safe­ty fears

Months after analysts and investors called on Biogen and Eisai to scrap their BACE drug for Alzheimer’s and move on in the wake of a string of late-stage failures and rising safety fears, the partners have called it quits. And they said they were dropping the drug — elenbecestat — after the independent monitoring board raised concerns about…safety.

We don’t know exactly what researchers found in this latest catastrophe, but the companies noted in their release that investigators had determined that the drug was flunking the risk/benefit analysis.

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Warts for the win: Aclar­is' lead drug clears piv­otal study

Aclaris Therapeutics has found a way to get rid of the warts and all.

The company — which earlier this month decided to focus on its arsenal of kinase inhibitors — on Monday unveiled positive data from a pivotal study testing its lead experimental drug for use in common warts.

The drug, A-101, was tested in a 502-patient study called THWART-2 — patients enrolled had one to six warts before qualifying for the trial. Patients either self-administered A-101 topical solution or a vehicle twice a week over a two-month period. A higher proportion of patients on the drug (a potent hydrogen peroxide topical solution) saw their warts disappear at day 60, versus the vehicle (p<0.0001) — meeting the main goal of the study.  Each secondary endpoint also emerged in favor of A-101, the company said.

Charles Nichols, LSU School of Medicine

Could psy­che­delics tack­le the obe­si­ty cri­sis? A long­time re­searcher in the field says his lat­est mouse study sug­gests po­ten­tial

Psychedelics have experienced a renaissance in recent years amid a torrent of preclinical and clinical research suggesting it might provide a path to treat mood disorders conventional remedies have only scraped at. Now a preclinical trial from a young biotech suggests at least one psychedelic compound has effects beyond the mind, and — if you believe the still very, very early hype — could provide the first single remedy for some of the main complications of obesity.

Ac­celeron drops a de­vel­op­ment pro­gram as #2 drug fails to spark func­tion­al ben­e­fits in pa­tients with a rare neu­ro­mus­cu­lar ail­ment

Acceleron is scrapping a muscular dystrophy development program underway for its number 2 drug in the pipeline after pouring over some failed mid-stage secondary data.

Gone is the ACE-083 project in patients with facioscapulohumeral muscular dystrophy. Their drug hit the primary endpoint on building muscle but flopped on key secondaries for functional improvements in patients, which execs felt was vital to the drug’s success.