No­var­tis' En­tresto, fac­ing a big come­back in hard-to-treat heart fail­ure pa­tients, scores FDA nod af­ter ad­comm cake­walk

Hard-and-fast rules in drug de­vel­op­ment are hard to come by, but one has long been the stan­dard for mar­ket ap­provals — you have to hit your pri­ma­ry end­points in piv­otal stud­ies. But for No­var­tis’ heart fail­ure med En­tresto, what’s a Phase III miss be­tween friends?

The FDA on Tues­day ap­proved En­tresto, a com­bi­na­tion of neprilysin in­hibitor sacu­bi­tril and an­giotensin re­cep­tor II block­er val­sar­tan, to treat heart fail­ure pa­tients with a pre­served ejec­tion frac­tion (HF­pEF), mak­ing it the first drug on the mar­ket for that pop­u­la­tion.

The drug’s new la­bel cov­ers a com­bined in­di­ca­tion called chron­ic heart fail­ure — both HF­pEF and re­duced ejec­tion frac­tion (HFrEF) — with a “be­low nor­mal” left-ven­tri­cle ejec­tion frac­tion, a vari­able con­di­tion the agency leaves open for physi­cian’s judge­ment. Ei­ther way, No­var­tis thinks its drug could be use­ful for around 5 mil­lion of the more than 6 mil­lion heart fail­ure pa­tients at any one time in the US.

The agency pri­mar­i­ly based its re­view on re­sults from No­var­tis’ Phase III PARAGON-HF study, which, un­like most oth­er suc­cess­ful piv­otal tri­als, didn’t ac­tu­al­ly hit its pri­ma­ry end­point of re­duc­ing the rate of to­tal heart fail­ures and death. De­spite the flop, the FDA urged No­var­tis to pur­sue its ap­pli­ca­tion any­way, ar­gu­ing the study’s de­sign may have pro­duced mis­lead­ing re­sults — the pri­ma­ry end­point’s p-val­ue was 0.06, by the way — and high­light­ing re­sults from pre-spec­i­fied fol­low-up analy­ses that point­ed to sig­nif­i­cant ben­e­fits.

Dave So­ergel, No­var­tis’ glob­al head drug de­vel­op­ment for car­dio­vas­cu­lar, re­nal and me­tab­o­lism, told End­points News the FDA’s de­ci­sion to con­sid­er the to­tal­i­ty of ev­i­dence around En­tresto’s ap­pli­ca­tion was “heart­en­ing” and shot down claims the ap­proval un­der­mined the stan­dard 0.05 p-val­ue that serves as an ef­fi­ca­cy bench­mark across the in­dus­try.

“If we had tak­en PARAGON alone to the agency, would we have got­ten the same re­sponse? I doubt it. But we have thou­sands of pa­tients in ran­dom­ized clin­i­cal tri­als around the globe,” he said. “There isn’t re­al­ly a mag­ic to 0.05 and, in fact, there is reg­u­la­to­ry prece­dent for sup­ple­men­tal in­di­ca­tions based on clin­i­cal tri­als that didn’t hit that num­ber. This isn’t break­ing the mold; on the con­trary, it’s tak­ing a so­phis­ti­cat­ed and ap­pro­pri­ate view of the to­tal­i­ty of the da­ta.”

In De­cem­ber, an FDA ad­vi­so­ry com­mit­tee near­ly unan­i­mous­ly backed the agency’s in­ves­ti­ga­tors, hand­ing down a 12-1 vote in En­tresto’s fa­vor. The ap­proval could open a $5 bil­lion mar­ket to No­var­tis, by some an­a­lysts’ lights, adding to its lead­ing po­si­tion in the treat­ment of heart fail­ure pa­tients with a re­duced ejec­tion frac­tion (HFrEF). That in­di­ca­tion has com­peti­tors, though, in­clud­ing SGLT2 di­a­betes meds like As­traZeneca’s Farx­i­ga and Eli Lil­ly and Boehringer In­gel­heim’s Jar­diance.

Vic­tor Bul­to, No­var­tis’ US phar­ma chief, didn’t want to talk sales pro­jec­tions on a call with End­points and not­ed that the Swiss drug­mak­er didn’t in­tend to ex­pand its team to ac­com­mo­date the rough­ly 2 mil­lion ad­di­tion­al pa­tients En­tresto could cov­er. The pre­scrib­ing physi­cian pool, af­ter all, wont change much.

“Most of the car­di­ol­o­gists are re­al­ly fa­mil­iar with En­tresto and how to use it,” he said. Bul­to al­so high­light­ed the rough­ly $30 bil­lion bur­den heart fail­ure puts on the US health­care sys­tem each year. Thir­ty per­cent of that is tied to hos­pi­tal­iza­tions, he said, mak­ing a risk re­duc­tion there a po­ten­tial­ly boon for pay­ers and providers.

En­tresto’s turn­around at the FDA is a sur­prise giv­en the long re­liance on piv­otal Phase III stud­ies as guide­posts for an ap­proval. No­var­tis ad­mit­ted be­fore the ad­comm vote an ap­proval for En­tresto for HF­pEF would be “un­usu­al but not un­prece­dent­ed.”

But the FDA has shown some will­ing­ness to con­sid­er drugs that don’t hit their check­points in the late-stage set­ting, some­times to its detri­ment. The FDA, for in­stance, in No­vem­ber gave its back­ing to Bio­gen’s ad­u­canum­ab, an­oth­er can­di­date seek­ing a huge un­met clin­i­cal need. In­stead of sup­port­ing the FDA’s ar­gu­ment that a Phase III tri­al flop for adu was mis­lead­ing, an FDA ad­comm shot down the drug’s ap­pli­ca­tion with prej­u­dice. The FDA’s fi­nal de­ci­sion is sched­uled for ear­ly June.

The top 100 bio­phar­ma VCs, Bob Brad­way places $2B bet in can­cer, gene edit­ing pi­o­neer's new big idea, and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Before diving in, we had some news to share: Endpoints is launching a premium weekly report focusing on all things regulatory. Coverage will be led by our new senior editor, Zachary Brennan, who joins us from POLITICO. Arsalan Arif has more details in his Publisher’s Note.

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Robert Bradway (Photographer: Scott Eisen/Bloomberg via Getty Images)

UP­DAT­ED: Am­gen snaps up can­cer drug play­er Five Prime, adding PhI­II-ready FGFR2b drug in $2B M&A play

Amgen is making a long-awaited move on the M&A side, buying South San Francisco-based Five Prime $FPRX for close to $2 billion and adding a slate of new cancer drugs to the pipeline.

Amgen is paying $38 a share, putting the deal value at $1.9 billion. The stock closed at $21.26 last night, giving investors a 78% premium.

The jewel in the crown of this deal is bemarituzumab, which Amgen describes as a first-in-class, Phase III-ready anti-FGFR2b antibody. Amgen was drawn to the bargaining table by Five Prime’s mid-stage data on gastric cancer, satisfied by PFS and OS data helping to validate FGFR2b as a target. Amgen researchers will now expand on the R&D program in other epithelial cancers, including lung, breast, ovarian and other cancers.

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David Liu (Casey Atkins Photography courtesy Broad Institute)

David Liu has a new big idea: pro­teome edit­ing. It could one day shred tau, RAS and some of the worst dis­ease-caus­ing pro­teins

Before David Liu became famous for inventing new forms of gene editing, he was known around academia in part for a more obscure innovation: a Rube Goldberg-esque system that uses bacteria-infecting viruses to take one protein and turn it into another.

Since 2011, Liu’s lab has used the system, called PACE, to dream up fantastical new proteins: DNA base editors far more powerful than the original; more versatile forms of the gene editor Cas9; insecticides that kill insecticide-resistant bugs; enzymes that slide synthetic amino acids into living organisms. But they struggled throughout to master one of the most common and powerful proteins in the biological world: proteases, a set of Swiss army knife enzymes that cut, cleave or shred other proteins in everything from viruses to humans.

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The 2021 top 100 bio­phar­ma in­vestors: As the pan­dem­ic hit and IPOs boomed, VCs swung in­to ac­tion like nev­er be­fore

The global pandemic may have roiled economies, killed hundreds of thousands and throttled entire industries, but the only effect it had on biopharma venture investing was to help turbocharge the field to giddy new heights.

Below you’ll find the new top 100 venture investors in the industry, ranked by the number of deals they were publicly involved in, as tracked by DealForma chief Chris Dokomajilar. The numbers master then calculated the estimated amount of money they put into each deal — divvying up the cash by the number of players — to indicate how they managed their syndicates.

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CMO Levi Garraway (Genentech)

Fo­cus­ing on the bright side, FDA OKs Roche's Actem­ra for rare lung dis­ease de­spite PhI­II flop

Actemra’s failure to hit the primary endpoint in a Phase III study didn’t stop the FDA from granting Roche priority review. And it’s certainly not standing in the way of a sixth approval for Roche’s IL-6 drug.

Regulators have cleared Actemra, or tocilizumab, for systemic sclerosis-associated interstitial lung disease in adult patients. Roche’s big Genentech subsidiary notes that it is the first biologic approved for this rare disease.

As Brain­Storm con­tin­ues to tout ‘clear sig­nal’ on ALS drug, the FDA of­fers a rare pub­lic slap­down on the da­ta

A little more than a week after BrainStorm acknowledged that regulators at the FDA had informed them that the biotech needed more data before it could expect to gain an approval for its ALS treatment NurOwn — while still touting a “clear signal” of efficacy and not ruling out an application — the agency has decided to clarify the record in a most unusual statement.

The FDA statement amounts to a straight slapdown, offering a different set of efficacy numbers from the company’s public presentation last November and ruling out any chance of statistical significance.

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Bruce Cozadd, Jazz CEO (Jazz Pharmaceuticals)

Jazz CEO Bruce Cozadd cam­paigned for 6 months to buy GW Phar­ma. A 90% pre­mi­um sealed the deal — along with $17.6M in ‘re­ten­tion’ in­cen­tives

Jazz CEO Bruce Cozadd didn’t beat around the bush.

In his first video meeting with GW Pharma chief Justin Gover last July 8, he offered to pay $172 a share to get the company, which had beaten the odds in getting its remarkable cannabinoid drug Epidiolex across the regulatory finish line for epilepsy. GW’s stock closed at $129 that day.

Cozadd had already done his homework on the financing to make sure he could swing it the way he wanted. He just needed to do some due diligence before making the non-binding bid firm.

UP­DAT­ED: Not 3 weeks af­ter tak­ing Hu­ma­cyte pub­lic, Ra­jiv Shuk­la launch­es an­oth­er blank check com­pa­ny

One of biotech’s earliest SPAC investors is back with another blank-check company, less than a month after his last effort announced its intent to merge.

Rajiv Shukla is intending to take a third lucky winner public with Alpha Healthcare Acquisition III, filing to go public Thursday with a $150 million raise penciled in. The move comes just a couple of weeks after Shukla’s second SPAC said it would jump to Nasdaq in tandem with Laura Niklason’s Humacyte in a $255 million new investment.

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Paul Hudson, Getty Images

How does Paul Hud­son's $13.5M comp pack­age stack up against oth­er CEOs? He's in the 'first quar­tile'

Paul Hudson arrived at Sanofi like a hurricane, chopping off duds in the pipeline, shaking up the C-suite, striking big M&A deals and jumping into the Covid-19 vaccine race — all in an attempt to reboot a pharma giant notorious for its setbacks.

Now, we’re getting a look at what the CEO brought home in his first year on the job.

When all is said and done, Hudson will have made about $6.7 million in 2020, about $2.5 million of which has already been paid. The bigger figure includes a $2.3 million bonus that’s subject to approval at an April meeting, and another $1.8 million in variable compensation that has yet to be paid.

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