Multiyear Follow-up Study Shows Positive Results for Hemophilia B Gene Therapy

Results of a follow-up study of people with hemophilia B who had been treated with Beqvez (fidanacogene elaparvovec), a gene therapy, showed sustained factor IX activity over three to six years, and during that period, only low-grade adverse effects. The results were published in the New England Journal of Medicine (NEJM) last month.

Hemophilia is a rare genetic bleeding disorder affecting blood clotting, primarily in males. It can lead to life-threatening bleeding, especially in severe cases. Over 38,000 people worldwide live with hemophilia B, a deficiency in clotting protein factor IX. It is less common than hemophilia A, which is caused by a deficiency in clotting protein factor VIII.

Current treatment involves recurrent intravenous infusions of various forms of factor IX to control bleeding episodes. Other drugs such as Qfitlia (fitusiran), Hympavzi (marstacimab), and Alhemo (concizumab) are also used to treat hemophilia B.

Pfizer’s Beqvez was approved by the FDA in April of 2024 based on results from the BENEGENE-2 Study (NCT03861273). It is the second FDA-approved gene therapy for hemophilia B after CSL Behring’s Hemgenix (etranacogene dezaparvovec), which the FDA approved in 2022.

As a one-time treatment, Beqvez is indicated for the treatment of adults with moderate to severe hemophilia B who currently use factor IX prophylaxis therapy or have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes and do not have neutralizing antibodies to adeno-associated viral vector capsid as detected by an FDA-approved test.

John E.J. Rasko, M.B.B.S., Ph.D

The results of the phase 2a follow-up study of Beqvez were reported in NEJM by lead and corresponding author John E. J. Rasko, M.B.B.S., Ph.D., a professor at the Sydney Medical School in Australia, and his team. The follow-up study included 15 participants with severe or moderately severe hemophilia B from the phase 1-2a study.

One year after administration of gene therapy, participants had the opportunity to enroll in a five-year follow-up study for a total of six years of observation. Of those who started, 14 participants completed at least three years of follow-up, with the median follow-up being five and a half years.

Rasko and team evaluated safety endpoints that included adverse events, changes in liver function tests and factor IX inhibitor levels, liver ultrasounds and immune responses to the viral vector delivering the gene therapy. The efficacy endpoints taken into consideration included the annualized rate of treated bleeding events, additional factor IX use, factor IX activity and the number of participants with no treated bleeding episodes.

After the first year, no treatment-related adverse events were reported. Of the nine serious adverse events that were documented in four participants, none were related to the treatment or the coagulation deficiency. Events such as appendicitis, rib fracture and joint dislocation were determined to be unrelated to the therapy. There was no discontinuation or dropout from the study resulting from adverse events or death.

The low-grade adverse events were largely observed in the first year post-infusion. There were increases in aminotransferase levels and fluctuations in liver enzyme levels during the first year, requiring the use of glucocorticoids in three participants, but no treatment was required in the five-year follow-up period. Rasko and his colleagues note that the liver abnormalities were unlikely to be due to therapy given the participants' health history, where several had hepatic steatosis. Lastly, there was a rapid onset of antibodies to the viral vector after administration that remained active throughout the follow-up period, but the response did not appear to interfere with the therapeutic response.

As far as efficacy is concerned, factor IX levels were within a mild hemophilia range over the six-year period. The durability of response was also supported by the observation that no participant resumed factor IX prophylaxis during the trial. Overall, there was a significant reduction in bleeding events when compared to the pre-administration baseline. In line with the reduced bleeding events, ten participants had no treated bleeding episodes throughout the follow-up duration. The bleeding events that did occur were attributed to low levels of factor IX activity.

Rasko and colleagues noted the limitations of the study, including a small patient cohort and the lack of standardized criteria for assessing liver function. They conclude by stating that Beqvez demonstrated low-grade adverse effects while offering a long-term clinical benefit. The treatment is associated with sustained factor IX activity and a significant reduction in bleeding events.