Etranacogene Dezaparvovec Demonstrates Safety and Efficacy in Patients With a History of Chronic HCV/HBV

UniQure and CSL Behring’s etranacogene dezaparvovec (marketed as Hemgenix), an FDA-approved adeno-associated virus vector-based gene therapy for the treatment of hemophilia B, demonstrated efficacy and safety in a subset of patients with a comorbid history of chronic hepatitis C virus or hepatitis B virus (HCBV+) without active viral disease.¹ The results were presented in a poster at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California.

The aforementioned patients were among 57 participants treated with EtranaDez across a phase 2b clinical trial (NCT03489291) and the phase 3 HOPE-B clinical trial (NCT03569891) for the gene therapy. First author of the poster Annette Von Drygalski, MD, PharmD, the director of the Hemophilia and Thrombosis Treatment Center at UC San Diego Health, and colleagues noted that among 52 total evaluable participants, patients with HCBV (n = 31) and patients without HCBV (n = 21) showed no significant differences in the reductions seen in both annualized bleeding rate (ABR) for all bleeds and ABR for Factor IX (FIX)-treated bleeds during the 7 to 36 months posttreatment timeframe. More specifically, the patients with HCBV showed an 81% reduction [95% CI: 65%-89%; P < .00001] in ABR for all bleeds compared to the lead-in period and patients without HCBV showed a 75% reduction [95% CI: 59%-85%; P < .0001] in ABR for all bleeds compared to the lead-in period. For ABR for FIX-treated bleeds the patients with HCBV showed an 87% reduction [95% CI: 74%-94%; P < .0001] and the patients without HCBV showed an 81% reduction [95% CI: 63%-91%; P < .0001] compared to the lead-in period.

Furthermore, following administration of Etranadez, all participants with and without HCBV who were evaluable for uncontaminated FIX activity, excepting 1 patient, showed stable and clinically relevant FIX activity up to 36 months. Drygalski and colleagues noted that 1 patient with HCBV had an early case of alanine transaminase (ALT) elevated to more than double the baseline level and was treated with corticosteroids. At 30 months after receiving EtranaDez, this patient went back on prophylaxis because he experienced increased clinical bleeding and a reduction of FIX activity to less than 5%.

In terms of safety, 1 patient with HCBV experienced a peak ALT elevation of greater than 5x the upper limit of normal. This patient’s ALT elevation was normalized following the administration of corticosteroids. Furthermore, 4 patients with HCBV and 5 patients without HCBV were treated with corticosteroids for treatment-emergent adverse events of increased ALT. In total, 12 cases of increased ALT were reported across 11 patients; 5 of these patients had HCBV and 6 did not have HCBV. A hepatocellular carcinoma was detected in 1 patient with HCBV 1 year after administration of EtranaDez, but the carcinoma was deemed unrelated to the gene therapy via molecular analysis.

“All participants in phase 2b and the majority of participants in HOPE-B had a history of chronic HCV and/or HBV infection without active viral disease or evident preexisting severe liver fibrosis,” Von Drygalski and colleagues wrote.¹ “EtranaDez was observed to be safe and effective in this subpopulation and had similar safety and efficacy characteristics as participants without a history of chronic HCV and/or HBV infection. These results support use of EtranaDez for eligible participants with comorbid controlled chronic HCV or HBV.”

Across all 57 patients who were treated with EtranaDez in the trials, 55 patients had at least 1 uncontaminated measurement of Factor IX (FIX) activity after receiving the gene therapy. It was noted that the 34 of these patients with HCBV were generally older, with ages ranging from 31 to 75 years (median, 49) than the patients without HCBV, who had ages ranging from 19 to 54 years (median, 26). Among the patients with HCBV, 21 patients had HCV only, 2 patients had HBV only, 7 patients had both HCV and HBV, and 4 patients had HCV and a comorbid HIV infection.

A separate analysis of the patients with comorbid HIV infections in these 2 clinical trials was also presented at the ASH 2023 Annual Meeting.² This analysis, presented by Steven W. Pipe, MD, the Laurence A. Boxer Research Professor of Pediatrics and Professor of Pathology at the University of Michigan and director of the Pediatric Hemophilia and Coagulation Disorders Program at CS Mott Children's Hospital, demonstrated the safety and efficacy of EtranaDez in the subpopulation of 5 patients with comorbid controlled HIV infections treated in HOPE-B and the phase 2b trial.

“EtranaDez [was] observed to be safe and effective in a subset of study participants living with HIV,” Pipe and colleagues wrote.² “These results support the use of EtranaDez, the first approved liver-directed AAV-based gene therapy product for the treatment of patients with severe or moderately severe hemophilia B in the US and Europe, for eligible patients with controlled comorbid HIV infection. Owing to the small number of patients with HIV being enrolled in trials, long-term collection of data and special attention in the real-world setting is recommended.”

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REFERENCES
1. Von Drygalski V, O’Connell N, Verhamme P, et al. Adult patients with hemophilia B and with a history of chronic HCV/HBV infection receiving liver-directed gene therapy demonstrated long-term bleeding protection and sustained FIX activity: efficacy and safety results from the HOPE-B trial 3 years after administration of a single dose of etranacogene dezaparvovec. Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract #801
2. Pipe S, Gomez E, Hermans CR, et al. HIV comorbid infection and liver-directed AAV-based gene therapy in adults with severe and moderately severe hemophilia B: efficacy and safety results from phase 2b and the pivotal phase 3 HOPE-B trials 3 years after administration of a single dose ofetranacogene dezaparvovec. Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract #801