Promise of Gene Therapy for Hemophilia A and B

Advances in adeno-associated virus 5 (AAV5) vector gene delivery platforms and genome designs have led to development of efficient gene therapy for hemophilia A and hemophilia B. Now, two industry-funded, open-label, single-arm, multicenter, phase 3 trials show promising results with longer follow-up.

In the GENEr8-1 study, 134 men with severe hemophilia A (factor VIII <1%) who were receiving factor VIII prophylaxis were given a single infusion of valoctocogene roxaparvovec, an investigational therapy. The mean annualized rate of treated bleeding events decreased by 84.5% from baseline to 2 years after the infusion (P<0.001). Factor VIII utilization decreased by 98.2%. The estimated transgene-derived half-life of factor VIII production was 123 weeks.

The most common adverse event was alanine aminotransferase elevation, which was treated with immunosuppressants. Although anti-AAV5 antibodies developed in all participants after the infusion, this did not impact factor VIII activity. No major safety signals were noted.

The HOPE-B study enrolled 54 men with moderate-to-severe hemophilia B (factor IX activity ≤2%) regardless of their AAV5 neutralizing antibody status. Participants received factor IX prophylaxis during a 6-month lead in period, followed by a single infusion of etranacogene dezaparvovec (Padua variant of factor IX).

The annualized bleeding rate decreased significantly from 4.19 during the lead-in period to 1.51 during months 7 to 18 after treatment. Use of factor IX concentrate decreased significantly. Factor IX activity was sustained irrespective of preexisting AAV5 neutralizing antibody status as long as titers were ≤678 (titer common in general population).

Seven participants had infusion-related adverse events. Hepatocellular carcinoma developed in one participant but was unrelated to viral integration. Vector DNA clearance was confirmed in semen and blood specimens obtained from 33 and 25 participants, respectively. All participants had an AAV5 humoral immune response within 6 weeks after treatment.