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.

Biotech and Big Phar­ma: A blue­print for a suc­cess­ful part­ner­ship

Strategic partnerships have long been an important contributor to how drugs are discovered and developed. For decades, big pharma companies have been forming alliances with biotech innovators to increase R&D productivity, expand geographical reach and better manage late-stage commercialization costs.

Noël Brown, Managing Director and Head of Biotechnology Investment Banking, and Greg Wiederrecht, Ph.D., Managing Director in the Global Healthcare Investment Banking Group at RBC Capital Markets, are no strangers to the importance of these tie-ups. Noël has over 20 years of investment banking experience in the industry. Before moving to the banking world in 2015, Greg was the Vice President and Head of External Scientific Affairs (ESA) at Merck, where he was responsible for the scientific assessment of strategic partnership opportunities worldwide.

Credit: Shutterstock

How Chi­na turned the ta­bles on bio­phar­ma's glob­al deal­mak­ing

Fenlai Tan still gets chills thinking about the darkest day of his life.

Three out of eight lung cancer patients who received a tyrosine kinase inhibitor developed by his company, Betta Pharma, died in the span of a month. Tan, the chief medical officer, was summoned to Peking Union Medical College Hospital, where the head of the clinical trial department told him that the trial investigators would be conducting an autopsy to see if the patients had died of the disease — they were all very sick by the time they enrolled — or of interstitial lung disease, a deadly side effect tied to the TKI class that’s been reported in Japan.

An­gion's or­gan dam­age drug strikes out again, this time in high-risk kid­ney trans­plant pa­tients

After flopping a test in Covid-19 earlier this year, Angion’s lead organ damage drug has now hit the skids again in kidney transplant patients.

Angion and partner Vifor Pharma’s ANG-3777 failed to beat out placebo in terms of improving eGFR, a measure of kidney function, in patients who had received a deceased donor kidney transplant and were at high risk of developing what is known as delayed graft function, according to Phase III results released Tuesday.

An image of Alzheimer's brain tissue. The red show gingipains, a protein from P. gingivalis, intermixing with neurons (yellow) and glial cells (green)

An Alzheimer's dark­horse fails its first big tri­al, but of­fers hope for a long-over­looked hy­poth­e­sis

Three years ago, Cortexyme emerged out of obscurity with some big-name backers and an unorthodox approach to treating Alzheimer’s.

They moved their drug into a pivotal study the next year, offering one of the first major tests for a hypothesis that has fluttered on the outskirts of Alzheimer’s research for decades: that, in many cases, the disease is driven by infectious agents — the havoc they wreak in the brain and the inflammation the body uses to try to fend them off. And that quashing the infection could slow patients’ cognitive decline.

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No­var­tis dumps AveX­is pro­gram for Rett syn­drome af­ter fail­ing re­peat round of pre­clin­i­cal test­ing

Say goodbye to AVXS-201.

The Rett syndrome gene therapy drug made by AveXis — the biotech that was bought, kept separate, then renamed and finally absorbed by Novartis into its R&D division — has been dropped by the biopharma.

In Novartis’ third quarter financial report, the pharma had found that preclinical data did not support development of the gene therapy into IND-enabling trials and beyond. The announcement comes a year after Novartis told the Rett Society how excited it was by the drug — and its potential benefits and uses.

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Peter Nell, Mammoth Biosciences CBO

UP­DAT­ED: Jen­nifer Doud­na spin­out inks a Mam­moth CRISPR deal with Ver­tex worth near­ly $700M

When a company gets its start in gene editing pioneer Jennifer Doudna’s lab, it’s bound to make headlines. But three years in, the fanfare still hasn’t died down for Mammoth Biosciences. Now, the Brisbane, CA-based company is cheering on its first major R&D pact.

Mammoth unveiled a nearly $700 million deal with Vertex on Tuesday morning, good for the development of in vivo gene therapies for two mystery diseases. The stars of the show are Mammoth’s ultra-small CRISPR systems, including two Cas enzymes licensed from Doudna’s lab over the past couple years, Cas14 and Casɸ.

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FDA is much worse than its reg­u­la­to­ry peers at proac­tive­ly dis­clos­ing da­ta, re­searchers find

The European Medicines Agency and Health Canada continue to outpace the FDA when it comes to proactively releasing data on drugs and biologics the agency has reviewed, leading to further questions of why the American agency can’t be more transparent.

In a study published recently in the Journal of Law, Medicine, & Ethics, Yale and other academic lawyers and researchers found that between 2016 and April 2021, the EMA proactively released data for 123 unique medical products, while Health Canada proactively released data for 73 unique medical products between 2019 and April 2021. What’s more, the EMA and Health Canada didn’t proactively release the same data on the same drugs. In stark contrast, the FDA in 2018 only proactively disclosed data supporting one drug that was approved that year.

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No­var­tis' sec­ond at­tempt to repli­cate a stun­ning can­cer re­sult falls flat

Novartis’ hopes of turning one of the most surprising trial data points of the last decade into a lung cancer drug has taken another setback.

The Swiss pharma announced Monday that its IL-1 inhibitor canakinumab did not significantly extend the lives or slow the disease progression of patients with previously untreated locally advanced or metastatic non-small cell lung cancer when compared to standard of-care alone.

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NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

No, sci­en­tists are not any clos­er to pig-to-hu­man trans­plants than they were last week

Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.