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.

Tesla and SpaceX founder Elon Musk gestures to the audience after being recognized by President Trump following the successful launch of a Falcon 9 rocket at the Kennedy Space Center. (via Getty Images)

Tes­la chief Elon Musk teams up with Covid-19 play­er Cure­Vac to build 'R­NA mi­cro­fac­to­ries'

Elon Musk has joined the global tech crusade now underway to revolutionize vaccine manufacturing — now aimed at delivering billions of doses of a new mRNA vaccine to fight Covid-19. And he’s cutting right to the front.

In a late-night tweet Wednesday, the Tesla chief announced:

Tesla, as a side project, is building RNA microfactories for CureVac & possibly others.

That’s not a lot to go on. But the tweet comes a year after Tesla’s German division in Grohmann and CureVac filed a patent on a “bioreactor for RNA in vitro transcription, a method for RNA in vitro transcription, a module for transcribing DNA into RNA and an automated apparatus for RNA manufacturing.” CureVac, in the meantime, has discussed a variety of plans to build microfactories that can speed up the whole process for a global supply chain.

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Elias Zerhouni (Photo by Vincent Isore/IP3/Getty Images)

Elias Zer­houni dis­cuss­es ‘am­a­teur hour’ in DC, the de­struc­tion of in­fec­tious dis­ease R&D and how we need to prep for the next time

Elias Zerhouni favors blunt talk, and in a recent discussion with NPR, the ex-Sanofi R&D and ex-NIH chief had some tough points to make regarding the pandemic response.

Rather than interpret them, I thought it would be best to provide snippets straight from the interview.

On the Trump administration response:

It was basically amateur hour. There is no central concept of operations for preparedness, for pandemics, period. This administration doesn’t want to or has no concept of what it takes to protect the American people and the world because it is codependent. You can’t close your borders and say, “OK, we’re going to be safe.” You’re not going to be able to do that in this world. So it’s a lack of vision, basically just a lack of understanding, of what it takes to protect the American people.

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Sec­ond death trig­gers hold on Astel­las' $3B gene ther­a­py biotech's lead pro­gram, rais­ing fresh con­cerns about AAV

Seven months after Astellas shelled out $3 billion to acquire the gene therapy player Audentes, the biotech company’s lead program has been put on hold following the death of 2 patients taking a high dose of their treatment. And there was another serious adverse event recorded in the study as well, with a total of 3 “older” patients in the study affected.

The incidents are derailing plans to file for a near-term approval, which had been expected right about now.

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George Yancopoulos (Regeneron)

UP­DAT­ED: Re­gen­eron co-founder George Yan­copou­los of­fers a com­bat­ive de­fense of the po­lice at a high school com­mence­ment. It didn’t go well

Typically, the commencement speech at Yorktown Central School District in Westchester — like most high schools — is an opportunity to encourage students to face the future with confidence and hope. Regeneron president and co-founder George Yancopoulos, though, went a different route.

In a fiery speech, the outspoken billionaire defended the police against the “prejudice and bias against law enforcement” that has erupted around the country in street protests from coast to coast. And for many who attended the commencement, Yancopoulos struck the wrong note at the wrong time, especially when he combatively challenged someone for interrupting his speech with a honk for “another act of cowardness.”

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Pfiz­er shares surge on pos­i­tive im­pact of their mR­NA Covid-19 vac­cine — part­nered with BioN­Tech — in an ear­ly-stage study

Pfizer and their partners at the mRNA specialist BioNTech have published the first glimpse of biomarker data from an early-stage study spotlighting the “robust immunogenicity” triggered by their Covid-19 vaccine, which is one of the leaders in the race to vanquish the global pandemic.

Researchers selected 45 healthy volunteers 18-55 years of age for the study. They were randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1, “a lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein RBD.” Their responses were compared against the effect of a natural, presumably protective defense offered by a regular infection.

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An ex­pe­ri­enced biotech is stitched to­geth­er from transpa­cif­ic parts, with 265 staffers and a fo­cus on ‘new bi­ol­o­gy’

Over the past few years, different teams at a pair of US-based biotechs and in labs in Japan have labored to piece together a group of cancer drug programs, sharing a single corporate umbrella with research colleagues in Japan. But now their far-flung operations have been knit together into a single unit, creating a pipeline with 10 cancer drug development programs — going from early-stage right into Phase III — and a host of discovery projects managed by a collective staff of some 265 people.

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Joseph Kim, Inovio CEO (Andrew Harnik, AP Images)

Pos­i­tive Covid-19 vac­cine da­ta? New mouse study? OWS in­clu­sion? Yep, but some­how, the usu­al tid­bits from In­ovio back­fire

You don’t go more than 40 years in biotech without ever getting a product to market unless you can learn the art of writing a promotional press release. And Inovio captures the prize in baiting the hook.

Tuesday morning Inovio, which has been struggling to get its Covid-19 vaccine lined up for mass manufacturing, put out a release that touched on virtually every hot button in pandemic PR.

There was, first and foremost, an interim snapshot of efficacy from their Phase I program for INO-4800.

Jan van de Winkel, Genmab CEO

Seat­tle Ge­net­ics, Gen­mab turn on TV for a high­light reel in cer­vi­cal can­cer — but a ri­val biotech promis­es a bet­ter show

Seattle Genetics $SGEN and their partners at Genmab $GMAB polished up some positive Phase II numbers for their antibody drug conjugate tisotumab vedotin — you can call it TV — for recurrent cervical cancer. And while they mapped out a shortcut to a potential quick approval, the big challenge for this team is being presented by a rival biotech which muscled its way into the spotlight for the same indication a year ago.

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Dan Gold, MEI Pharma CEO

De­vel­op­ment part­ners at MEI, Helsinn dump a high-risk PhI­II AML study af­ter con­clud­ing it would fail sur­vival goal

Four years after Switzerland’s Helsinn put $25 million of cash on the table for an upfront and near-term milestone to take MEI Pharma’s drug pracinostat into a long-running Phase III trial for acute myeloid leukemia, the partners are walking away from a clinical pileup.

The drug — an HDAC inhibitor — failed to pass muster during a futility analysis, as researchers concluded that pracinostat combined with azacitidine wasn’t going to outperform the control group in the pivotal.