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.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

Covid-19 vac­cine boost­ers earn big thumbs up, but Mod­er­na draws ire over world sup­ply; What's next for Mer­ck’s Covid pill?; The C-suite view on biotech; 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.

You may remember that at the beginning of this year, Endpoints News set a goal to go broader and deeper. We are still working towards that, and are excited to share that Beth Snyder Bulik will be joining us on Monday to cover all things pharma marketing. You can sign up for her weekly Endpoints MarketingRx newsletter in your reader profile.

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Roche's Tecen­triq cross­es the fin­ish line first in ad­ju­vant lung can­cer, po­ten­tial­ly kick­ing off gold rush

While falling behind the biggest PD-(L)1 drugs in terms of sales, Roche has looked to carve out a space for its Tecentriq with a growing expertise in lung cancer. The drug will now take an early lead in the sought-after adjuvant setting — but competitors are on the way.

The FDA on Friday approved Tecentriq as an adjuvant therapy for patients with Stage II-IIIA non small cell lung cancer with PD-(L)1 scores greater than or equal to 1, making it the first drug of its kind approved in an early setting that covers around 40% of all NSCLC patients.

No­var­tis de­vel­op­ment chief John Tsai: 'We go deep in the new plat­form­s'

During our recent European Biopharma Summit, I talked with Novartis development chief John Tsai about his experiences over the 3-plus years he’s been at the pharma giant. You can read the transcript below or listen to the exchange in the link above.

John Carroll: I followed your career for quite some time. You’ve had more than 20 years in big pharma R&D and you’ve obviously seen quite a lot. I really was curious about what it was like for you three and a half years ago when you took over as R&D chief at Novartis. Obviously a big move, a lot of changes. You went to work for the former R&D chief of Novartis, Vas Narasimhan, who had his own track record there. So what was the biggest adjustment when you went into this position?

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Amit Etkin, Alto Neuroscience CEO (Alto via Vimeo)

A star Stan­ford pro­fes­sor leaves his lab for a start­up out to re­make psy­chi­a­try

About five years ago, Amit Etkin had a breakthrough.

The Stanford neurologist, a soft-spoken demi-prodigy who became a professor while still a resident, had been obsessed for a decade with how to better define psychiatric disorders. Drugs for depression or bipolar disorder didn’t work for many patients with the conditions, and he suspected the reason was how traditional diagnoses didn’t actually get at the heart of what was going on in a patient’s brain.

Susan Galbraith, Executive VP, Oncology R&D, AstraZeneca

As­traZeneca on­col­o­gy R&D chief Su­san Gal­braith: 'Y­ou're go­ing to need or­thog­o­nal com­bi­na­tion­s'


Earlier in the week we broadcast our 4th annual European Biopharma Summit with a great lineup of top execs. One of the one-on-one conversations I set up was with Susan Galbraith, the oncology research chief at AstraZeneca. In a wide-ranging discussion, Galbraith reviewed the cancer drug pipeline and key trends influencing development work at the pharma giant. You can watch the video, above, or stick with the script below. — JC

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FDA ad­comm votes unan­i­mous­ly in sup­port of a J&J Covid-19 boost­er two months af­ter one-dose shot

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Friday voted 19-0 in favor of authorizing a second shot of J&J’s Covid-19 vaccine to follow at least two months after the initial dose.

Regulators don’t have to follow VRBPAC’s recommendation, but they almost always do. Considering that the CDC’s advisory committee has already been set to review the expanded EUA, VRBPAC’s recommendation is likely to be adopted.

FDA's vac­cine ad­comm unan­i­mous­ly sup­ports Mod­er­na's boost­er in same pop­u­la­tions as Pfiz­er's boost­er

The FDA’s vaccine advisory committee on Thursday voted 19-0 in support of expanding Moderna’s Covid-19 vaccine EUA for booster doses for certain high-risk individuals. FDA is expected to authorize the Moderna booster shortly.

Similarly to the Pfizer booster shot, Moderna’s will likely be authorized for those older than 65, adults at high risk of severe Covid-19, and adults whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk of serious complications of Covid-19. But unlike the Pfizer adcomm, where FDA had to scramble to get the committee to vote in favor of a booster, this committee was unanimous with the Moderna shot.

Rob Califf (AP Photo/Pablo Martinez Monsivais, File)

Biden like­ly to nom­i­nate Ver­i­ly's Rob Califf to lead the FDA again

Capping a controversially long period for the FDA to go without a permanent leader, President Joe Biden is likely to select Verily’s Rob Califf, a former FDA commissioner under President Obama, as the next FDA commissioner nominee.

A former Duke cardiologist and member of the prestigious National Academy of Medicine, Califf will be a welcome face for an agency grappling with high-profile retirements in CBER and CDER. He’ll also return to a role that he was comfortable in for a short stint at the end of Obama’s presidency. The Washington Post first reported the news.