New Class of Factor VIII Replacement Therapy Prevents Bleeds in Severe Hemophilia A

Treatment with investigational efanesoctocog alfa (formerly BIVV001) — a new class of factor VIII replacement therapy — prevented bleeding episodes in patients with severe hemophilia A, according to results from the phase III XTEND-1 trial.

Among 133 patients, almost all males, who received once-weekly prophylaxis with efanesoctocog alfa 50 IU/kg for 52 weeks (group A), the median annualized bleeding rate was 0 (interquartile range 0-1.04), and the estimated mean annualized bleeding rate was 0.71 (95% CI 0.52-0.97), reported Annette von Drygalski, MD, PharmD, of the University of California San Diego, and colleagues.

In an analysis involving a subgroup of 78 patients, switching from a pre-study standard-care factor VIII prophylaxis regimen to efanesoctocog alfa decreased the mean annualized bleeding rate from 2.96 to 0.69, a reduction of 77%, which showed superiority over pre-study prophylaxis (annualized bleeding rate ratio 0.23, 95% CI 0.13-0.42, P<0.001), they noted in the New England Journal of Medicine.

In a smaller group of 26 men who received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis for 26 weeks (group B), the annualized bleeding rate decreased when patients switched from on-demand treatment to prophylaxis (21.42 versus 0.69).

Overall, 80% of group A and 85% of group B patients had no spontaneous bleeding episodes during the prophylaxis periods. When bleeding events did occur, a single injection of efanesoctocog alfa 50 IU/kg provided effective resolution for 97% of events.

Of note, von Drygalski and team said that once-weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU/dL for approximately 4 days after administration and of 15 IU/dL at day 7.

Furthermore, prophylaxis with efanesoctocog alfa for 52 weeks improved physical health (P<0.001), pain intensity (P=0.03), and joint health (P=0.01).

“Collectively, these results show that by maintaining high sustained factor VIII activity, once-weekly efanesoctocog alfa provided substantial improvements in clinical outcomes and quality of life for patients with severe hemophilia A,” the authors wrote.

Efanesoctocog alfa is currently under review with the FDA for the treatment of hemophilia A, with a target action date of February 28, according to developers Sanofi and Sobi.

Breaking Through the von Willebrand Factor ‘Ceiling’

The ability to provide high, sustained factor VIII activity in patients with hemophilia A has been constrained by the von Willebrand factor-imposed half-life ceiling.

While normalizing factor VIII levels helps protect patients with hemophilia A from spontaneous and traumatic bleeding, thus preserving joint health, von Drygalski and colleagues pointed out that the interaction between factor VIII and endogenous von Willebrand factor limits the half-life of current factor VIII replacement products to 8 to 19 hours.

“Therefore, maintaining factor VIII levels in the normal range (50 to 150 IU per deciliter) or levels that are close to normal (>40 to <50 IU per deciliter) with currently available factor VIII therapies requires frequent administration, which confers a substantial treatment burden on people with hemophilia and their caregivers,” they wrote.

Efanesoctocog alfa circulates independently of endogenous Von Willebrand factor, is designed to overcome that half-life ceiling, and thus extends protection from bleeds with once-weekly dosing. In this study, efanesoctocog alfa had a long geometric mean half-life of 47.0 hours (95% CI 42.3-52.2).

In an editorial accompanying the study, Cindy Leissinger, MD, of Tulane University School of Medicine in New Orleans, said a major advantage of efanesoctocog alfa “is its value as a true factor VIII replacement that can be used to treat acute bleeding and can be measured by standard laboratory assays to allow for monitoring and dose adjustments when needed.”

She also pointed out that while trials of factor VIII gene therapies also show prolonged production of factor VIII, the latest results suggest that factor VIII production in most patients gradually declines over a few years to trough levels demonstrated with weekly efanesoctocog alfa.

“In a crowded field of transformative therapies for hemophilia, efanesoctocog alfa stands out as a winner — a major therapeutic advance that achieves highly protective factor VIII levels with a once-weekly infusion,” Leissinger concluded.

Study Details

For this multicenter study, previously treated patients ages 12 years and older with endogenous factor VIII activity of less than 1 IU/dL (<1%) or a documented genotype known to produce severe hemophilia A were included.

Patients were excluded if they had a positive test for factor VIII inhibitor at screening or a history of a positive inhibitor test, clinical signs or symptoms of a decreased response to factor VIII, other known coagulation disorders, a history of hypersensitivity or anaphylaxis to factor VIII therapies, or major surgery within 8 weeks before screening.

Among the 133 patients in group A, mean age was 33.9 years, 99% were males, 53% were white, and 22% were Asian. Of those with evaluable data during the efficacy period, 65% had no bleeding episodes, while 93% had 0-2 bleeding episodes.

Of the 26 patients in group B, mean age was 42.8, all were men, and all were white.

A total of 362 bleeding events occurred during the study, with the majority (74%) in group B during the on-demand treatment period.