Factor VIII circulates in a tight complex with von Wildebrand Factor, both stabilizing the FVIII and modulating the plasma half-life. Efanesoctocog alfa is designed to shield FVIII from “von Wildebrand Factor-imposed half-life limitations.” The design represents a new class of FVIII replacement therapies.

In the multicenter, open-label, nonrandomized XTEND-1 clinical trial (NCT04161495), investigators evaluated patients 12 years or older with severe hemophilia A who had been treated previously with a FVIII replacement therapy. One hundred fifty-nine patients received once weekly efanesoctocog alfa 50 IU/kg intravenously. In arm A, prophylaxis was administered for 52 weeks, and in arm B, it was administered on-demand for 26 weeks followed by 26 weeks of prophylactic administration. The primary study endpoint was annualized bleeding rate (ABR); in terms of efficacy, ABR was 0 (mean 0.71). In terms of safety, efanesoctocog alfa was well-tolerated.

The FDA granted efanesoctocog alfa a Breakthrough Designation on June 1, 2022. This first-in-class drug is a fusion protein FVIII replacement with tentative dosing of 50 IU/kg IV once weekly.

Both hemophilia A and B are characterized by ineffective clot formation due to insufficient thrombin generation, explained Cuellar. Fitusiran is designed to lower antithrombin and promote thrombin generation to restore hemostasis. It is a subcutaneous, small interfering RNA (siRNA) that both interferes with antithrombin translation and finds and degrades RNA antithrombin.

In the open-label, randomized, phase 3 Atlas-A/B trial (NCT03417245), 120 patients aged 12 or older with severe hemophilia A or B, previously treated with on-demand factor therapy, were randomly assigned to receive either once-monthly 80 mg subcutaneous fitusiran as a prophylactic therapy, or on-demand factor therapy. Once monthly dosing, Cuellar noted, has not been seen before.

Like efanesoctocog alfa, the primary endpoint was ABR. Investigators found a reduction of ABR of 89.9% vs factor on-demand therapy. Median ABR for treated bleeds was 0.0, vs 21.8. Two patients experienced vascular thrombotic events, 1 of which was deemed not associated with the therapy. More safety data are being collected before the drug is submitted to the FDA.

Fitusiran is an RNA interfering therapy targeting antithrombin in the liver. Tentative administration is 80 mg subcutaneously once a month, with other dosing options under investigation.

In sickle cell, the pipeline is primarily focused on gene therapy and gene editing therapy. “That’s where it’s all going,” said Cuellar. “That’s where a lot of the evidence is.”

Drug therapies in sickle cell are still in the early phases of research, with several agents under investigation targeting hemoglobin (HbS) polymerization, pro-adhesive molecules, and inflammation. Agents include mitapivat, in phase 1/2 research; rivipansel and inclacumab, in phase 2 and 3 research, respectively; crizanlizumab, which is FDA approved; and regadenoson and canakinumab, both in phase 2 research.