+Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.
+1. In this randomized controlled trial, fidanacogene elaparovovec therapy significantly reduced the mean annualized rate of bleeding in adult men with hemophilia B.
+2. Fidanacogene elaparovovec administration was associated with sustained increased factor IX activity, with the majority of participants having factor IX activity in the mild hemophilia range.
+Evidence Rating Level: 2 (Good)
+Hemophilia B is a genetic bleeding disorder that increases the risk of bleeding and bruising due to deficient levels of clotting factor IX. Hemophilia B is treated with recombinant or plasma-derived intravenous factor IX replacement injections. These frequent intravenous prophylactic injections are burdensome on patients and their families. The adeno-associated virus (AAV) vector that expresses the high activity factor IX variant, FIX-R338L, was the first gene therapy product approved for hemophilia B in the United States and Europe. Fidanacogene elaparovovec is an AAV vector that delivers transgene production of FIX-R338L for hemophilia B, and it has shown sustained factor IX activity and decreased bleeding in phase 1-2a studies. The present phase three trial investigated the efficacy of a single intravenous infusion of fidanacogene elaparovovec at reducing bleeding episodes compared to the current prophylactic treatment in adult men aged 18-65 with hemophilia B. Compared to the baseline after the prophylactic treatment phase, the fidanacogene elaparovovec gene therapy resulted in a 71% reduction in bleeding episodes. Most participants had sustained levels of factor IX activity in the mild hemophilia range. Limitations of this study included the generalizability of findings, the limited follow-up, the underrepresentation of Black patients, and the lack of a control group. Overall, the results of this trial indicated that fidanacogene elaparovovec was efficacious at reducing bleeding and sustaining factor IX activity in adult men with hemophilia B.
In-Depth [prospective cohort]:
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+This phase three trial assessed the efficacy of a single intravenous infusion of fidanacogene elaparovovec on bleeding outcomes in adult men with hemophilia B. Men aged 18 to 65 with hemophilia B who had received factor IX prophylaxis treatment for at least six months and agreed to stop prophylaxis after fidanacogene elaparovovec infusion were eligible for participation. Individuals with detectable anti-AAV antibodies, a history of or positive test for factor IX inhibitors, and clinically significant diseases besides hemophilia B were excluded from this trial. A total of 45 participants were eligible and received a single intravenous infusion of fidanacogene elaparovovec. The primary endpoint of this trial was the annualized bleeding rate from week 12 to month 15 after infusion with the gene therapy compared to the prophylaxis lead-in period. The annualized bleeding rate was 4.42 (95% Confidence Interval [CI], 1.80-7.05) after the prophylaxis lead in period and 1.28 (95% CI, 0.57-1.98) from week 12 to month 15 after fidanacogene elaparovovec therapy, with the treatment difference estimate of -3.15 episodes (95% CI, -5.46 to -0.83; p=0.008). This finding suggested that fidanacogene elaparovovec was both non-inferior and superior to prophylaxis. The mean factor IX activity at month 15 was 26.9% and was maintained above 5% in 82% of participants at month 24. The majority (<80%) of participants had factor IX activity in the mild hemophilia range for 15 to 24 months after gene therapy infusion. Overall, this phase three trial revealed that a single infusion of fidanacogene elaparovovec significantly reduced bleeding episodes and sustained factor IX activity compared to prophylaxis in adult men with hemophilia B.
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