Roche confirms patient death in ACE910 PhIII hemophilia trial, spurring new questions about top blockbuster hopeful

Just a few months after reporting a slate of serious adverse events for its pivotal Phase III study of emicizumab (ACE910) for hemophilia, Roche has raised fresh questions about the safety of the drug following the death of one of the patients in the trial.

In a statement given to the European Haemophilia Association, Roche says that the patient in their HAVEN-1 study died following two serious adverse events.

It is our understanding that a patient experienced a serious rectal hemorrhage (the first reported SAE) and received bypassing agents, including repeated doses of activated prothrombin complex (aPCC), after which the patient developed signs of Thrombotic Microangiopathy (TMA, the second SAE). The preliminary assessment is that the clinical and laboratory characteristics of this case of TMA are consistent with what was observed in the two previously reported cases; however, our evaluation of the available information is ongoing.

The investigator concluded that the patient died as a result of the rectal hemorrhage and that Roche’s drug was not responsible.

Daniel O’Day

The report, though, raises fresh questions about the drug’s safety after investigators had to fend off persistent questions about 4 spontaneously reported SAEs after two patients had thromboembolic events and two patients developed thrombotic microangiopathy, or TMA. That news helped briefly buoy Shire and Novo Nordisk, which both see a big rival to their blockbuster hemophilia franchises in emicizumab.

Roche reported that “these events were seen with the concomitant use of multiple doses of a bypassing agent with emicizumab while treating a breakthrough bleed; in some cases the bypassing agent at doses exceeding the recommended labeled doses.”

Leerink’s Jason Gerberry, who’s been cheerleading for Shire’s hemophilia franchise, sees this as a positive for established drugs. And he trumpeted growing fears that ACE910 has been tied far too frequently to serious cases of TMA.

As we’ve previously noted, MEDACorp hemophilia specialists generally believe TMA is occurring at too high of a rate in HAVEN-1 vs. the non-existence of TMA with standard of care. While specialists generally believe the TMA is an issue caused by the combination of the two treatments, the root cause is not understood and thus it remains a possibility that the TMA’s could be an ACE910 monotherapy issue given the Mab’s long half-life. In our view, ACE910 continues to pose a risk to a portion of SHPG’s FEIBA franchise ($900m total) given the high unmet need in HA inhibitor segment, but we are of the view that ACE910 will get more modest traction in the HA non-inhibitor population where Shire derives $2.8bn (~18-19% of sales).

Long one of Roche’s top prospects, as laid out by pharma chief Daniel O’Day, Genentech researchers say that the drug hit the primary as well as all the secondary endpoints in their late-stage test. The big goal was a statistically significant drop in the number of bleeds among patients with inhibitors to factor VIII. And one of the secondaries was a reduction in bleeds recorded in an “intra-patient comparison in people who had received prior bypassing agent prophylaxis treatment.”

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