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.

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.

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.