The risks keep rising for Roche’s haemophilia hope

Roche’s rising haemophilia star emicizumab is far from untarnished on the safety front, but news of a patient death in its ongoing pivotal programme takes concerns to a new level. The big question is whether the apparent thrombosis risk is a threat to approval.

Assuming no further reports emerge this seems unlikely in its first indication, haemophiliacs with inhibitors, where unmet need has won the project breakthrough therapy designation. But the novel bispecific antibody has much to prove; until safety concerns can be dismissed forecasts that emicizumab will shake up the haemophilia space, becoming the second-biggest selling product by 2022, remain of the blue sky variety (see table below).

Lofty sales forecasts are largely based on an assumption that Roche will be able to command a premium price in the inhibitor space, where options are very limited. These patients – who have developed antibodies that render front-line factor VIII clotting factors ineffective – are at very high risk of uncontrolled bleeding. The few therapies available are not particularly effective and either very complex, very expensive, or associated with clotting risks.

These last two issues are associated with the two so-called bypassing agents that are used as rescue agents – Novo’s NovoSeven and Shire’s Feiba.

Although nothing has been confirmed, the clotting risk that has emerged with emicizumab – also called ACE910 – seems to be associated with Feiba, a coagulation complex.

Before news of the patient death Roche had revealed four serious clotting events among the 109 patients in the Haven 1 trial, the successful pivotal study testing emicizumab in the inhibitor population. All had received Feiba to treat breakthrough bleeds, and all resolved.

According to Roche’s statement on the death the patient first experienced a serious rectal bleed, was treated with Feiba, then developed thrombotic microangiopathy (TMA), tiny blood clots in the capillaries. Treatment of the haemorrhage was complicated because the patient declined blood transfusions, and investigators concluded that death was caused by rectal haemorrhage, which was unrelated to emicizumab, the company said.

Two of the other previous serious adverse events were also TMA; two were thromboembolic events.

“This does not create a new problem, but enhances a problem we already know for ACE910,” Bernstein’s Ronny Gal commented. “And it puts the burden on Roche to demonstrate a validated way to rescue patients on ACE910 who have a bleed.”

He pointed out that in the inhibitor market where there are fewer options it will be possible to use a product with less-validated rescue options. Not so the no-inhibitor market, where patients are well treated.

With a novel mechanism of action – emicizumab mimics factor VIII by binding to both factors IXa and X – this project was always going to face very close scrutiny. At the very least, a requirement for Roche to study the concomitant use of emicuzimab with bypassing agents, post-approval, looks likely. It is hard to imagine this issue not being highlighted on any label. Neither can a delay to approval be completely ruled out.

Limiting factor?

Until full data from Haven 1 are presented at a conference later this year, it is hard to assess what all this means for emicizumab’s commercial potential. Roche has only said that primary and secondary endpoints were met – bleeds over 24 weeks were significantly reduced – and the magnitude of the benefit is keenly awaited (Roche finds safe Haven in emicizumab, December 22, 2016).

Peak sales estimates vary widely, with Credit Suisse going for $2.5bn while Jefferies has $5bn, but even the bottom end of this range is only possible with success in both the inhibitor and no-inhibitor markets.

Roche believes that, because emicizumab is distinct in structure from factor VIII, patients should not go on to develop inhibitors, which would clearly be a huge finding. However, this has yet to be proven – the Haven 3 study, being run in no-inhibitor patients, should yield data in late 2017.

Many believe that the product’s once-weekly subcutaneous delivery will prove an advantage over the infusions necessary for the factor VIII agents, which partly explains the bullish forecasts. But, with the market moving towards prophylactic use of the new longer-acting versions of the very well-known factor VIII agents, Roche will have to work hard to press home any advantage. 

To contact the writer of this story email Amy Brown in London at [email protected] or follow @ByAmyBrown on Twitter