Haemophilia A is a rare genetic disorder in which the blood cannot clot properly; this is caused by a lack of factor VIII, one of the proteins involved in the clotting cascade
About one in 5000 males are born with this genetic mutation, although it is much less common in females.
As well as bleeding problems, those with the condition can experience pain and irreversible joint damage.
The factor VIII protein is encoded by the F8 gene. It is produced in liver sinusoidal cells as well as in endothelial cells elsewhere in the body. Normally, it circulates in the bloodstream bound to von Willebrand factor, which renders it inactive. When blood vessels are damaged, the active protein is released, initiating the cascade that causes blood clots to form.
Treatment relies on factor replacement therapy with factor VIII derived from donated plasma or a recombinant version of another protein in the cascade (factor VIIA).
An alternative has been created by Swedish Orphan Biovitrum, which is being commercialised in conjunction with Sanofi.
Efanesoctocog alfa is a recombinant fusion protein that was designed to decouple factor VIII from von Willebrand factor in circulation; its half-life is prolonged using the company’s XTEN polypeptides, which reduces the half-life limitations that had proved to be problematic in earlier attempts to make recombinant factor VIII products.
A lab study using plasma from patients with haemophilia A showed that it had similar efficacy to recombinant factor VIII in terms of promoting fibrin clot formation and platelet accumulation after injury, with the clot forming capability of the two proving to be indistinguishable.1
In a Phase I study to evaluate its safety, tolerability and pharmacokinetics, repeat doses were given to previously treated adults with severe haemophilia.2
In all, 24 subjects were given four once-weekly doses of either 50 or 66 IU/kg of efanesoctocog alfa. The mean activity was 46% with the lower dose and 69% with the higher one 3 days after administration; the drug was well tolerated with no safety concerns or bleeds. It provided high, sustained factor VIII activity in the near-normal range for 3–4 days after dosing.
Results of a Phase III trial have also been reported.3 The trial included 159 previously treated adults and adolescents aged at least 12 with severe haemophilia A.
Those who had previously received factor VIII prophylaxis were given 50 IU/kg doses once a week for 52 weeks; those who had previously received on-demand therapy were given the same dose on-demand for 26 weeks, followed by another 26 weeks of once-weekly prophylaxis at the same dose.
Weekly doses gave clinically significant bleed protection. In the first group, intrapatient comparison showed better bleed protection to the prior factor VIII prophylaxis, with most bleeds resolving with one injection. Once-weekly doses gave high sustained activity and were associated with significant improvements in physical health from baseline. The most common adverse events were headache, arthralgia, fall and back pain.