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Results from the Phase III BENEGENE-2 trial (NCT03861273) show that Beqvez (fidanacogene elaparvovec) administered at one of the lowest doses for an adeno-associated virus (AAV) gene therapy for hemophilia B effectively elevated factor IX levels and significantly lowered bleeding and factor IX consumption.1,2 The authors of the study, published by The New England Journal of Medicine, noted that an ongoing extended follow-up study up to 15 years following administration of the gene therapy will offer additional insight into the efficacy of Beqvez in the treatment of hemophilia B.
The one-time gene therapy was approved by the FDA in April 2024 to treat adults with moderate to severe hemophilia B and who currently use factor IX prophylaxis therapy, have a history of severe hemorrhage, or who suffer from frequent serious bleeding episode with no neutralizing antibodies to the AAV serotype.3
“[Beqvez] is an AAV vector that is designed to deliver transgene production of FIX-R338L for hemophilia B. The transgene leverages the hepatic-control region of the gene encoding apolipoprotein E (APOE), a liver-specific human α1-antitrypsin promoter, and a codon-optimized FIX-R388L minigene,” the study authors wrote. “In a phase 1–2a study and a longer-term follow-up study, treatment with [Beqvez] resulted in sustained factor IX activity in the range of mild hemophilia to normal, with associated low occurrences of bleeding and a reduction in exogenous factor IX consumption. These results were achieved with one of the lowest vector doses reported in hemophilia gene-therapy trials to date (5×1011 vector genome copies per kilogram).”1
Hemophilia B is a rare genetic bleeding disorder that inhibits normal blood clotting because of deficiencies in factor IX that cause longer bleeding periods. According to data from the World Federation of Hemophilia, more than 38,000 people currently live with hemophilia B globally.3
The open-label BENEGENE-2 trial evaluated Beqvez at a dose of 5×1011 vector genome copies per kilogram of body weight. Eligibility criteria included males aged 18 to 65 years with hemophilia B and a factor IX level of 2% or less, and previous administration of at least six months of treatment with prophylactic factor IX concentrate. The trial’s primary endpoint in testing for noninferiority was the annualized bleeding rate from week 12 to month 15 following administration of Beqvez compared to the prophylaxis lead-in period. Investigators also evaluated superiority, additional efficacy endpoints, and safety.
Among 316 men screened for the lead-in study, 204 (64.6%) were deemed ineligible, of whom 188 men had presence of anti-AAV neutralizing antibodies. Among 45 individuals administered Beqvez, 44 completed at least 15 months of follow-up.
The results showed a 71% reduction in annualized bleeding rate for all bleeding episodes in those administered Beqvez, dropping from 4.42 (95% confidence interval [CI], 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98), which translates a treatment difference of −3.15 episodes (95% CI, −5.46 to −0.83; P=0.008). Investigators stated that this finding demonstrates the noninferiority and superiority of Beqvez to prophylaxis.
Further, at 15 months, mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0) by one-stage SynthASil assay. Twenty-eight patients (62%) were administered glucocorticoids for elevated aminotransferase levels, reduced factor IX levels, or both, beginning between days 11 and 123.
In terms of safety, there were no infusion-related serious adverse events, thrombotic events, development of factor IX inhibitors, or malignant conditions reported.
“In this study, factor IX levels after [Beqvez] 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 study authors concluded. “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 (but not hemophilia A).”1
References
1. Cuker A, et al. Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B. Published September 25, 2024. N Engl J Med 2024;391:1108-1118. DOI: 10.1056/NEJMoa2302982. Vol. 391 No. 12.
2. A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy With PF-06838435 in Adult Males With Moderately Severe to Severe Hemophilia B (BENEGENE-2). ClinicalTrials.gov. Updated August 23, 2024. Accessed October 1, 2024.
3. U.S. FDA Approves Pfizer’s BEQVEZ™ (fidanacogene elaparvovec-dzkt), a One-Time Gene Therapy for Adults with Hemophilia B. Pfizer. April 26, 2024. Accessed October 1, 2024. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-beqveztm-fidanacogene-elaparvovec