Predictors Not Identified for Return to Prophylaxis Post Fidanacogene Elaparvovec Hemophilia B Gene Therapy


No unifying characteristics were found in a small subset of 6 patients from the BENEGENE-2 trial.

Laurent Frenzel, MD, PhD

Laurent Frenzel, MD, PhD

Investigators on the phase 3 BENEGENE-2 trial (NCT03861273) characterized a group of patients with hemophilia B that returned to prophylaxis (RTP) after treatment with fidanacogene elaparvovec (Pfizer). Due to the small subset of patients (n = 6), predictors of loss of response and RTP were not able to be identified.1

Data from the analysis were presented at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California, by Laurent Frenzel, MD, PhD, Department of Hematology, Institut Necker, Paris, France.

“The limited number of participants and lack of consistent patterns and demographic features make identifying predictors of potential RTP challenging. Although all RTP participants were treated with corticosteroids during this study, not all participants treated with corticosteroids RTP of FIX. Predictors of loss of response have not been identified and further work is ongoing to potentially identify factors associated with increased risk of RTP,” Frenzel and coauthors wrote in their abstract.1

Forty-five participants with baseline FIX activity ≤2% in the BENEGENE-2 trial received a 5e11 vg/kg dose of fidanacogene elaparvovec. Prophylaxis was suspended after infusion and RTP was considered at the investigator’s discretion with guidelines of at least 2 consecutive central laboratory FIX activity levels assessed to be at most 2% at least 2 weeks apart and/or at least 2 spontaneous joints bleeds within 4 weeks and/or at least 3 spontaneous bleeds overall.

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The mean age of all 45 study participants was 33.2 years (range, 18–62) and the 6 RTP participants had a mean age of 28.3 years (range, 18-47), of whom 4 were under 30 years of age. The 6 RTP participants had region, race, and weight characteristics representative of the study population. These participants initially responded to the gene therapy with peak FIX activity levels over 5%, which then variably decreased with a time to RTP ranging from 155 to623 days after infusion. Reasons for RTP included low FIX activity in 5 participants (1 with a history of intracerebral hemorrhage) and increased bleeds in 1 participant. Five participants had at least 1 bleeding event prior to RTP.1

Clinical Takeaways

  • In the phase 3 BENEGENE-2 trial, a subset of hemophilia B patients (n=6) returned to prophylaxis (RTP) after treatment with fidanacogene elaparvovec.
  • With limited participants, no consistent patterns or demographic features predicting RTP were found. The RTP group, treated with corticosteroids during the study, displayed variable responses to gene therapy, necessitating further investigation to identify factors associated with increased risk of RTP.
  • Fidanacogene elaparvovec was recently approved in Canada under the name Beqvez.

The RTP participants received at least 1 course of corticosteroids for a presumed cellular immune response, with maximum alanine aminotransferase levels 1 to 2 times the upper limit of normal. Two RTP participants were evaluated and were negative for capsid peptides, compared with 4 participants who took corticosteroids, did not RTP, and were positive for capsid.

Fidanacogene elaparvovec has also just been approved in Canada under the name Beqvez, for the treatment of patients with moderately severe-to-severe hemophilia B with congenital Factor IX (FIX) deficiency who are negative for neutralizing antibodies to variant adeno-associated virus (AAV) serotype Rh74.2

"Our team at McMaster University is proud to have been a clinical trial site in Canada that studied this therapy," investigator Alfonso Iorio, MD Professor and Chair, Health Research Methods, Evidence, and Impact, McMaster University, said in a statement."This new treatment shows potential in reducing the burden of frequent infusions by providing, with a single infusion, a persistent liver production of FIX, which could help improve the life of those affected."

Click here to read more coverage of ASH 2023.

1. Frenzel L, Kavakli K, Klamroth R, et al. Characterizing a cohort of patients with hemophilia B treated with fidanacogeneelaparvovec from the phase 3 Benegene-2 study who returned to factor IX prophylaxis. Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract #2257
2. Health Canada approves Pfizer Canada's gene therapy in hemophilia B. News release. Pfizer Canada. January 3, 2024.
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