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Gene therapy for hemophilia B allowed almost three-fourths of patients to discontinue prophylactic factor IX therapy with no increase in bleeding, results of the pivotal BENEGENE-2 trial showed.

The annualized rate of bleeding for total bleeding episodes decreased by 71% after treatment with fidanacogene elaparvovec (Beqvez), while the mean annualized rate of bleeding for treated bleeding episodes was reduced by 78%, reported Adam Cuker, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and co-authors in the .

The results met prespecified criteria for noninferiority compared with factor IX prophylaxis and provided the basis for FDA approval of the therapy earlier this year.

"In this study, factor IX levels after fidanacogene elaparvovec therapy, as compared with prophylaxis, were associated with an amelioration of the bleeding phenotype and a significant reduction in the annualized bleeding rate and the annualized total factor IX consumption," the authors wrote. "These findings offer additional evidence that transduction of the FIX-R338L variant can produce hemostatic competence at the reported factor IX activity level."

"The majority (>80%) of the participants had factor IX activity in the mild-hemophilia range for a sustained period of 15 to 24 months, a finding that shows durable efficacy similar to that observed in other trials of gene therapy for hemophilia B," they added.

Standard of care for hemophilia B is episodic intravenous administration of factor IX replacement, Cuker and co-authors noted in their introduction. Current prophylactic therapies do not provide a cure, eliminate symptoms, or prevent joint damage.

Other non-factor IX agents that reduce antithrombin synthesis and monoclonal antibodies that neutralize the inhibitory activity of tissue factor pathway inhibitors have either been approved or are in advanced stages of clinical development, the authors noted. However, those agents still require regular administration.

Gene therapy can eliminate the need for ongoing treatment and the burden of regular disease management. The FDA approved etranacogene dezaparvovec (Hemgenix) as the first gene therapy for hemophilia B in 2022. Administered as a single infusion, the therapy consists of an adeno-associated virus (AAV) serotype 5 vector expressing FIX-R338L.

Fidanacogene elaparvovec delivers transgene production of FIX-R338L. In a phase I-IIa trial with long-term follow-up, the gene therapy led to sustained factor IX activity in the range of mild hemophilia to normal, associated with few episodes of bleeding and reduced factor IX prophylaxis. Results of the 15-patient study provided the basis for the phase III BENEGENE-2 trial that led to the therapy's approval.

BENEGENE-2 included men ages 18-65 with hemophilia B, defined as a factor IX level ≤2%, with at least a 6-month history of factor IX prophylaxis. After screening and exclusions (primarily for anti-AAV antibodies), 45 patients received a single infusion of fidanacogene elaparvovec, and 44 completed at least 15 months of follow-up.

The primary endpoint was the annualized rate of treated and untreated bleeding episodes from 12 weeks to 15 months after treatment, as compared with the factor IX prophylaxis lead-in period.

The results showed that the annualized bleeding rate decreased from 4.42 episodes at baseline to 1.28 at 15 months, a difference that not only met noninferiority but also superiority versus factor IX prophylaxis (P=0.008). At 15 months, the mean factor IX activity was 26.9%.

A total of 28 patients received glucocorticoid treatment for increased liver enzymes or decreased factor IX levels between 11 and 123 days. No infusion-related serious adverse events, thrombotic events, or malignancies occurred, as well as no development of factor IX inhibitors.

"The findings from this phase III study showed that fidanacogene elaparvovec had a favorable benefit-risk profile providing efficacy at one of the lowest doses of AAV-based gene therapy studied for hemophilia B," the authors concluded. "An ongoing extended follow-up study to 15 years after gene therapy will provide further insights regarding the effects of fidanacogene elaparvovec."

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