Type: Oral
Session: 801. Gene Therapies: The Long and the Short of Clinical Trials in Blood Disorders
Hematology Disease Topics & Pathways:
Bleeding and Clotting, Research, clinical trials, Biological therapies, adult, hemophilia, Clinical Research, Diseases, Gene Therapy, Therapies, Study Population, Human
Aim: To report long-term efficacy and safety data of etranacogene dezaparvovec from the HOPE-B trial over a period of 3 years post-treatment.
Methods: In this pivotal phase 3 open-label, single-arm trial, adult male participants with severe or moderately severe hemophilia B (FIX ≤2%), with or without preexisting AAV5 neutralizing antibodies (NAbs), were infused with a single dose (2×1013 gc/kg) of etranacogene dezaparvovec, following a ≥6-month lead-in period of receiving their usual FIX prophylaxis. Efficacy (bleeding rates, aPTT-based FIX activity levels, FIX consumption) and safety data (adverse events [AEs]) during Years 1, 2, and 3 post-treatment with etranacogene dezaparvovec are reported.
Results: Of 54 participants who received etranacogene dezaparvovec, 52 completed 36 months of follow-up.
Mean annualized bleeding rate (ABR) for all bleeds during Months 7-36 post-treatment was significantly reduced by 64% (mean ABR 1.52) compared with the ≥6-month lead-in period (mean ABR 4.17; P=0.0004). Total number of bleeds (all types) were 136 during the ≥6-month lead-in period and decreased to 55 during Year 1, 48 during Year 2, and 37 during Year 3 post-treatment. Median [range] bleeds per participant decreased from 2.0 [0-10] during the lead-in period and remained stable to 0.0 [0-4] during Year 1, 0.0 [0-10] during Year 2, and 0.0 [0-8] during Year 3. Superior bleeding protection was in line with the level of transgene-derived endogenous FIX expression.
The mean±SD (median; range) endogenous FIX activity level (ie. in the absence of exogenous FIX exposure) of participants was 41.5 IU/dL ±21.7 (39.9; 5.9-113, n=50) at Year 1, 36.7 IU/dL ±19.0 (33.9; 4.7-99.2, n=50) at Year 2, and sustained at 38.6 IU/dL ±17.8 (36.0; 4.8-80.3, n=48) at Year 3 post-treatment. Pharmacodynamic profile was not significantly different in participants with AA5 NAb undetected or titer ≤1:678.
At 3 years post-treatment, 51 (94%) remained free of continuous FIX prophylaxis. One participant who lacked efficacy (highest AAV5 NAbs titer of 1:3212) and 1 who received a 10% partial dose of treatment did not discontinue prophylaxis; 1 participant eventually had his FIX levels declined to 2-5% range; his bleeding phenotype returned, and he resumed prophylaxis per protocol at month 30 post-treatment. During Year 2 and Year 3 post-treatment, 37 (70%) and 39 (75%) participants received no FIX infusion, respectively. Overall mean annualized FIX consumption decreased by 96% over 3 years post-treatment compared to the ≥6-month lead-in period (–246,763 IU/kg/participant, including those receiving FIX prophylaxis post-treatment; P<0.0001).
During the 3 years post-dose, all participants experienced at least 1 treatment-emergent AE (TEAE); of 709 events, 541 (76%) were mild, 137 (19%) were moderate, and 31 (4%) were severe. There were no serious AEs related to treatment [a serious AE of hepatocellular carcinoma (HCC) and a death were reported previously before Year 2 and determined to be unrelated to treatment]. A total of 38/54 (70%) participants experienced 96 treatment-related TEAEs, of which 95% occurred before 6 months post-treatment. The most common AE was an increase in alanine transaminase (ALT), for which 9 (16.7%) participants received supportive care with reactive corticosteroids for a mean duration of 81.4 days (SD: 28.6; range: 51-130 days). No new deaths, no new HCC, and no late treatment-related ALT elevations or thromboembolic events were reported.
Conclusion: Long-term follow-up during the HOPE-B trial has shown that a single-dose of etranacogene dezaparvovec resulted in long-term endogenous FIX Padua expression and superior bleeding protection compared to FIX prophylaxis in participants without or with AAV NAb titer ≤1:678, with a favorable safety profile over 3 years post-administration.
Disclosures: Pipe: Takeda: Consultancy; Sanofi: Consultancy; Regeneron/Intellia: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy; LFB: Consultancy; Freeline: Consultancy; HEMA Biologics: Consultancy; GenVentiv: Consultancy; Equilibra Bioscience: Consultancy; CSL Behring: Consultancy; BioMarin: Consultancy; Bayer: Consultancy; ASC Therapeutics: Consultancy; Apcintex: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy. van der Valk: Bayer: Consultancy. Verhamme: CSL Behring, Roche, CAP-DCF, Bayer HealthCare; LeoPharma; Boehringer Ingelheim; Daiichi Sankyo; Pfizer; Sanofi-Aventis; ThromboGenics: Consultancy. Kampmann: BioMarin Pharmaceuticals, CSL Behring, NovoNordisk AS: Consultancy; CSL Behring: Speakers Bureau. Leebeek: CSL Behring, Takeda, UniQure: Consultancy, Research Funding; Sobi: Research Funding; Biomarin: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees. Coppens: Anthos, Bayer, CSL Behring/uniQure, Novo Nordisk and Roche: Research Funding; Alexion/AstraZeneca, Bayer, CSL Behring, Daiichi Sankyo, Sobi and Viatris: Consultancy, Honoraria. Meijer: Octapharma: Membership on an entity's Board of Directors or advisory committees; UniQure: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion and CSL Behring: Speakers Bureau. Key: Biomarin: Consultancy, Ended employment in the past 24 months, Honoraria; Novo Nordisk: Consultancy, Other: Chair of hemophilia grants study section; Uniqure/CSL: Consultancy, Ended employment in the past 24 months, Other: HOPE-B trial (hemophilia gene therapy) Steering Committee; Genentech: Consultancy. Visweshwar: Biogen Idec: Consultancy. Young: Takeda: Consultancy, Research Funding; Genentech/Roche: Consultancy; Hema Biologics/LFB: Consultancy; Spark: Consultancy, Speakers Bureau; Sanofi Genzyme: Consultancy, Speakers Bureau; Genentech, Inc.: Research Funding; Hema Biologics: Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy; Viatris: Patents & Royalties. Lemons: CSL Behring, NovoNordisk: Consultancy. Klamroth: Sobi: Honoraria, Other: Advisory board; Sanofi: Honoraria, Other: Advisory board; Roche/Chugai: Honoraria, Other: Advisory board; Pfizer: Honoraria, Other: Advisory board; Octapharma: Honoraria, Other: Advisory board; Bayer: Honoraria, Other: Advisory board; BioMarin: Honoraria, Other: Advisory board; Takeda: Honoraria, Other: Advisory board; Novo Nordisk: Honoraria, Other: Advisory board; Grifols: Honoraria, Other: Advisory board; Biotest: Honoraria, Other: Advisory board; CSL Behring: Honoraria, Other: Advisory board. Miesbach: Bayer: Consultancy, Research Funding, Speakers Bureau; Regeneron: Consultancy; uniQure: Consultancy; Sanofi: Consultancy; Roche: Consultancy, Speakers Bureau; LFB: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Biotest: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Chugai: Consultancy, Speakers Bureau; BioMarin: Consultancy, Speakers Bureau; Takeda/Shire: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Astermark: BioMarin: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; CSL Behring: Honoraria, Speakers Bureau; Sanofi: Honoraria; Roche: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Octapharma: Honoraria, Speakers Bureau; SOBI: Honoraria, Speakers Bureau. O'Connell: Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Freeline: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Speakers Bureau; UniQure: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kazmi: BioMarin Pharmaceuticals, CSL Behring: Consultancy. Galante: CSL Behring: Current Employment. LeQuellec: CSL Behring: Current Employment. Monahan: CSL Behring: Current Employment. Hermans: Bayer, Takeda, Roche, CSL Behring, Novo Nordisk, Pfizer, Sobi, LFB, OctaPharma, Uniqure and Biomarin: Consultancy.
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