부산대학교 도서관

Background: Etranacogene dezaparvovec, the first gene therapy approved for haemophilia B treatment, was shown to be superior to treatment with continuous prophylactic factor IX in terms of bleeding protection 18 months after gene therapy in a phase 3 trial. We report post-hoc 24-month efficacy and safety data from this trial to evaluate the longer-term effects of etranacogene dezaparvovec in individuals with haemophilia B.
Methods: The phase 3 HOPE-B trial enrolled males aged 18 years or older with inherited haemophilia B, classified as severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level ≥1% and ≤2%), with a severe bleeding phenotype and who were on stable continuous factor IX prophylaxis. Participants were treated with a single infusion of etranacogene dezaparvovec (2 × 10 13 genome copies per kg of bodyweight). The primary endpoint, reported previously, was non-inferiority of the annualised bleeding rate (ABR) during the 52 weeks following stable factor IX expression (defined as months 7-18 after treatment) versus an at least 6-month lead-in period in which participants received their usual continuous factor IX prophylaxis, and is updated here up to month 24. Additional, post-hoc efficacy analyses, including adjusted ABR, factor IX activity, participants within factor IX ranges, and factor IX use, and safety analyses were performed at 24 months after gene therapy. Data were analysed in the full analysis set, which comprised the 54 patients who received at least a partial dose of gene therapy. The trial is ongoing and is registered with ClinicalTrials.gov, number NCT03569891.
Findings: The study began on June 27, 2018, and participants were treated between January, 2019, and March, 2020; the date of data cutoff was April 21, 2022. 54 adult males (40 White, two Asian, one Black or African American, 11 other or missing) received a single intravenous infusion of etranacogene dezaparvovec and were followed for a median of 26·51 months (IQR 24·54-27·99), after a lead-in period of 7·13 months (6·51-7·82). In the updated analysis comparing months 7-24 after gene therapy to the lead-in period, mean adjusted ABR significantly reduced from 4·18 to 1·51 (p=0·0002) for all bleeds and from 3·65 to 0·99 (p=0·0001) for factor IX-treated bleeds. During each 6-month period after gene therapy, at least 67% of participants experienced no bleeding (36 of 54 during months 0-6 and stable thereafter), compared with 14 (26%) of 54 during the lead-in period. 24 months after gene therapy, 1 (2%) participant had one-stage factor IX activity less than 5%, whereas 18 (33%) had factor IX activity more than 40% (non-haemophilia range), with mean factor IX activity stable and sustained at 36·7% (SD 19·0%). 52 (96%) of 54 participants expressed endogenous factor IX, remaining free of factor IX prophylaxis at month 24. No new safety concerns were identified and no treatment-related serious adverse events or treatment-related deaths occurred. The most common treatment-related adverse events were an increase in alanine aminotransferase (nine [17%] of 54 patients), headache (eight [15%]), influenza-like illness (seven [13%]), and an increase in aspartate aminotransferase (five [9%]).
Interpretation: By providing durable disease correction throughout the 24 months after gene therapy, etranacogene dezaparvovec provides a safe and effective therapeutic option for patients with severe or moderately severe haemophilia B.
Funding: uniQure and CSL Behring.
Competing Interests: Conflicts of interest MC has received financial support for research from Anthos, Bayer, CSL Behring/uniQure, Novo Nordisk, and Roche; has received honoraria for lecturing or consultancy from Alexion/AstraZeneca, Bayer, CSL Behring, Daiichi Sankyo, Sobi, and Viatris, all paid to his institution; is a member of the gene therapy working group of the European Association for Haemophilia and Allied Disorders (EAHAD) and the European Reference Network (ERN) EuroBloodNet; and is chair of the working group thrombosis and haemostasis of the Dutch Society of Vascular Medicine (NVIVG), part of the Dutch Internist's Society (NIV). SWP has received consultancy fees from Apcintex, ASC Therapeutics, Bayer, BioMarin, CSL Behring, Equilibra Bioscience, GeneVentiv, HEMA Biologics, Freeline, LFB, Novo Nordisk, Pfizer, Regeneron/Intellia, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, and uniQure; has received research funding from Siemens; and holds a membership on a scientific advisory committee for GeneVentiv and Equilibra Bioscience. WM has received honoraria from Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Takeda/Shire, and uniQure. JA has received consultancy fees and speaker fees from BioMarin, Pfizer, Sparks, uniQure, CSL Behring, SOBI, Sanofi, Novo Nordisk, Bayer, Roche, Takeda/Shire, and Octapharm; and research grants from SOBI, Bayer, Takeda/Shire, and CSL Behring. MR has received research support from Bayer, BioMarin, CSL Behring, Genentech, Grifols, Hema Biologics, LFB, Novo Nordisk, Octapharma, Sanofi, Spark, Takeda, and uniQure; has received consultancy fees from Catalyst Biosciences, CSL Behring, Genentech, Hema Biologics, Kedrion, Novo Nordisk, Pfizer, Sanofi, Takeda, and uniQure; and sits on the board of directors for the Foundation for Women and Girls with Blood Disorders, and Partners in Bleeding Disorders. PvdV has received consultancy fees from Bayer. BE, KP, SLQ, NG, and PEM are employees of CSL Behring, and KP also holds shares in CSL Behring. FWGL has received research support from CSL Behring, Takeda, Sobi, and uniQure; is a consultant for uniQure, Sobi, Biomarin, and Takeda, from which the fees go to the institution; and was a member of the data safety and monitoring board for a study by Roche.
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