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.

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