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.

2019 Trin­i­ty Drug In­dex Eval­u­ates Ac­tu­al Com­mer­cial Per­for­mance of Nov­el Drugs Ap­proved in 2016

Fewer Approvals, but Neurology Rivals Oncology and Sees Major Innovations

This report, the fourth in our Trinity Drug Index series, outlines key themes and emerging trends in the industry as we progress towards a new world of targeted and innovative products. It provides a comprehensive evaluation of the performance of novel drugs approved by the FDA in 2016, scoring each on its commercial performance, therapeutic value, and R&D investment (Table 1: Drug ranking – Ratings on a 1-5 scale).

How to cap­i­talise on a lean launch

For start-up biotechnology companies and resource stretched pharmaceutical organisations, launching a novel product can be challenging. Lean teams can make setting a launch strategy and achieving your commercial goals seem like a colossal undertaking, but can these barriers be transformed into opportunities that work to your brand’s advantage?
We spoke to Managing Consultant Frances Hendry to find out how Blue Latitude Health partnered with a fledgling subsidiary of a pharmaceutical organisation to launch an innovative product in a
complex market.
What does the launch environment look like for this product?
FH: We started working on the product at Phase II and now we’re going into Phase III trials. There is a significant unmet need in this disease area, and everyone is excited about the launch. However, the organisation is still evolving and the team is quite small – naturally this causes a little turbulence.

Gilead claims Tru­va­da patents in HHS’ com­plaint are in­valid

Back in November, the Department of Health and Human Services took the rare step of filing a complaint against Gilead for infringing on government-owned patents related to the HIV drug Truvada (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (PrEP).

But on Thursday, Gilead filed its own retort, making clear that it does not believe it has infringed on the Centers for Disease Control and Prevention’s (CDC) Truvada patents because they are invalid.

Aymeric Le Chatelier, Ipsen

A $1B-plus drug stum­bles in­to an­oth­er big PhI­II set­back -- this time flunk­ing fu­til­i­ty test -- as FDA hold re­mains in ef­fect for Ipsen

David Meek

At the time Ipsen stepped up last year with more than a billion dollars in cash to buy Clementia and a late-stage program for a rare bone disease that afflicts children, then CEO David Meek was confident that he had put the French biotech on a short path to a mid-2020 launch.

Instead of prepping a launch, though, the company was hit with a hold on the FDA’s concerns that a therapy designed to prevent overgrowth of bone for cases of fibrodysplasia ossificans progressiva might actually stunt children’s growth. So they ordered a halt to any treatments for kids 14 and under. Meek left soon after to run a startup in Boston. And today the Paris-based biotech is grappling with the independent monitoring committee’s decision that their Phase III had failed a futility test.

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Roche's check­point play­er Tecen­triq flops in an­oth­er blad­der can­cer sub­set

Just weeks after Merck’s star checkpoint inhibitor Keytruda secured FDA approval for a subset of bladder cancer patients, Swiss competitor Roche’s Tecentriq has failed in a pivotal bladder cancer study.

The 809-patient trial — IMvigor010 — tested the PD-L1 drug in patients with muscle-invasive urothelial cancer (MIUC) who had undergone surgery, and were at high risk for recurrence.

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UP­DAT­ED: Eli Lil­ly’s $1.6B can­cer drug failed to spark even the slight­est pos­i­tive gain for pa­tients in its 1st PhI­II

Eli Lilly had high hopes for its pegylated IL-10 drug pegilodecakin when it bought Armo last year for $1.6 billion in cash. But after reporting a few months ago that it had failed a Phase III in pancreatic cancer, without the data, its likely value has plunged. And now we’re getting some exact data that underscore just how little positive effect it had.

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UP­DAT­ED: FDA’s golodirsen CRL: Sarep­ta’s Duchenne drugs are dan­ger­ous to pa­tients, of­fer­ing on­ly a small ben­e­fit. And where's that con­fir­ma­to­ry tri­al?

Back last summer, Sarepta CEO Doug Ingram told Duchenne MD families and investors that the FDA’s shock rejection of their second Duchenne MD drug golodirsen was due to some concerns regulators raised about the risk of infection and the possibility of kidney toxicity. But when pressed to release the letter for all to see, he declined, according to a report from BioPharmaDive, saying that kind of move “might not look like we’re being as respectful as we’d like to be.”

He went on to assure everyone that he hadn’t misrepresented the CRL.

But Ingram’s public remarks didn’t include everything in the letter, which — following the FDA’s surprise about-face and unexplained approval — has now been posted on the FDA’s website and broadly circulated on Twitter early Wednesday.

The CRL raises plenty of fresh questions about why the FDA abruptly decided to reverse itself and hand out an OK for a drug a senior regulator at the FDA believed — 5 months ago, when he wrote the letter — is dangerous to patients. It also puts the spotlight back on Sarepta $SRPT, which failed to launch a confirmatory study of eteplirsen, which was only approved after a heated internal controversy at the FDA. Ellis Unger, director of CDER’s Office of Drug Evaluation I, notes that study could have clarified quite a lot about the benefit and risks associated with their drugs — which can cost as much as a million dollars per patient per year, depending on weight.

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Gilead dusts off a failed Ebo­la drug as coro­n­avirus spreads; Ex­elix­is boasts pos­i­tive Ph I/II da­ta

→ Less than a year ago Gilead’s antiviral remdesivir failed to make the cut as investigators considered a raft of potential drugs that could be used against an Ebola outbreak. But it may gain a new mission with the outbreak of the coronavirus in China, which is popping up now around the world.

Gilead put out a statement saying that they’re now in discussions with health officials in the US and China about testing their NUC against the virus. It’s the latest in a growing lineup of biopharma companies that are marshaling R&D forces to see if they can come up with a vaccine or therapy to blunt the spread of the virus, which has now sickened hundreds, killed at least 17 people and led the Chinese government to start quarantining cities.

Alex Karnal (Deerfield)

Deer­field vaults to the top of cell and gene ther­a­py CD­MO game with $1.1B fa­cil­i­ty at Philadel­phi­a's newest bio­phar­ma hub

Back at the beginning of 2015, Deerfield Management co-led a $10 million Series C for a private gene therapy startup, reshaping the company and bringing in new leaders to pave way for an IPO just a year later.

Fast forward four more years and the startup, AveXis, is now a subsidiary of Novartis marketing the second-ever gene therapy to be approved in the US.

For its part, Deerfield has also grown more comfortable and ambitious about the nascent field. And the investment firm is now putting down its biggest bet yet: a $1.1 billion contract development and manufacturing facility to produce everything one needs for cell and gene therapy — faster and better than how it’s currently done.