Severe adverse events mar the end of Roche’s PhIII for ‘breakthrough’ hemophilia drug


Daniel O’Day, Roche CEO

With Phase III data looming for its closely-watched hemophilia drug ACE910 (emicizumab), Roche says that investigators have tracked four serious cases of blood clotting among patients taking the therapy. And the news immediately buoyed shares of both Shire and Novo Nordisk, which are first in line for seeing their franchises take a hit from the experimental therapy.

Roche says that there were two cases of thromboembolic events and two cases of thrombotic microangiopathy among patients with breakthrough bleeding who were being treated with Shire’s FEIBA and Novo’s NovoSeven, bypassing agents that carry a thrombosis warning, according to Reuters.

Here’s the statement Roche sent to Endpoints News:

What we have so far are 4 spontaneously reported SAE (serious adverse events). And 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.

In collaboration with our Steering Committee and IDMC, composed of well-recognized hemophilia experts, we have a risk mitigation strategy we believe will be effective in reducing the risk of this type of adverse event and allow us to gain more information to inform our understanding of these safety events.

The current recommendation is to avoid the use of one specific bypassing agent and if necessary, to use it starting with the lower range of the recommended labeled dose and perform dosing under monitoring.

Importantly, all of these adverse events have resolved and two of the patients have since restarted emicizumab and have not experienced a recurrence of the adverse event to date.

Right now there’s no certainty over what, if any, impact the adverse events will have on the drug’s fate, but any kind of cloud over the drug spells some immediate relief for Shire and Novo Nordisk, which has been particularly under the gun recently on the diabetes front. Biogen, meanwhile, is spinning out its portfolio of hemophilia drugs.

Novo Nordisk CEO Lars Rebien Sørensen

Novo Nordisk CEO Lars Rebien Sørensen

Chief Executive Officer Lars Rebien Sørensen, known for making blunt comments, identified ACE910 as “the key threat” to its blockbuster franchise, built around NovoSeven, according to an in-depth analysis from Bloomberg today. And Shire, which just acquired Baxalta and its portfolio of hemophilia drugs, saw its shares spike on the London exchange after the first reports hit.

The news about these adverse events amounts to the first dent in ACE910’s formidable reputation. Roche’s Daniel O’Day has been an outspoken champion for this drug, citing it repeatedly as one of the pharma giant’s biggest late-stage programs. And analysts have repeatedly tapped it as a likely blockbuster, able to generate billions in annual revenue.

Their drug—an anti-factor IXa/X bispecific which mimics the function of Factor VIII, even in the presence of FVIII inhibitors—is nearing the end of a major, Roche-style Phase III program with a drug blessed by the FDA with a breakthrough drug designation. Two Phase III studies have begun in children and adults who have acquired Factor VIII inhibitors. Another Phase III in patients without the FVIII inhibitors is starting, and there’s a fourth Phase III planned for a once-every-4-weeks dose, to see if they can come up with an easier administration schedule than the once-weekly injection they’re working with now.

Investigators say that their followup of 18 patients in the key proof of concept study revealed that emicizumab cut the bleeding rate of patients by more than 95% after a followup review lasting up to 32.6 months long. And that’s what they expect to prove in Phase III.

But ACE910 isn’t the only breakthrough therapy in the pipeline. BioMarin grabbed the spotlight at a major scientific conference last summer with data that nailed down hard evidence that its gene therapy for hemophilia A demonstrated a high chance of restoring patients’ natural clotting abilities, reducing or eliminating bleeding episodes and pointing them down the road to a normal life. And company investigators are now hustling BMN 270 into a Phase IIb study that could be used to gain an accelerated approval for a potential blockbuster.

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