Presentation Details
| Long-term evaluation of liver health in participants who received fidanacogene elaparvovec: Data from a phase 1/2a study with up to 6 years of follow up Jonathan Ducore1, Lindsey A George2, Ben J Samelson-Jones2, John Rasko3, Catherine McGuinn4, Adam Giermasz1, Jerome Teitel5, Katherine High6, Jeremy Rupon7, Annie Fang7, Lynne Smith7, Priya Patel7, Amit Chhabra7, Frank Plonski7, Matko Kalac7. 1UC David Comprehensive Cancer Center, Sacramento, CA, USA.2Children’s Hospital of Philadelphia, Philadelphia, PA, USA.3Centenary Institute, Sydney, Australia.4Weill Cornell Medical Center, New York, NY, USA.5University of Toronto, Toronto, ON, Canada.6University of Pennsylvania, Philadelphia, PA, USA.7Pfizer Inc, New York, NY, USA |
Abstract
Background: Fidanacogene elaparvovec is an adeno-associated virus (AAV) gene therapy for the treatment of hemophilia B (HB) (1, 2). The bioengineered capsid targets hepatocytes necessitating long-term assessment of liver health. Objectives: To evaluate the liver health of recipients of fidancogene elaparvovec as part of the 1-year ph1/2a study (NCT02484092) and 5-year long-term follow-up (LTFU) study (NCT03307980). Methods: Adult male (≥18 years) hemophilia B (FIX activity ≤2%) participants received fidanacogene elaparvovec at a dose of 5 × 1011 vector genomes vg/kg. Participants with a history of hepatitis C (HCV) and/or hepatitis B (HBV) virus infections, or HIV were eligible if health parameters were met. Liver health assessments included periodic liver ultrasound and laboratory evaluations including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alpha fetoprotein assessed at baseline and at scheduled intervals. The cutoff date for the current analysis was August 15, 2023. Results: Fifteen participants were dosed and completed 1 year of follow-up with fourteen entering the LTFU. At data cutoff, individual participant follow-up ranged from 3-6 years and 7 participants completed 6 years following vector administration. In the LTFU study 7 out of 14 participants (50%) have a history of HBV, 10 (71%) have a history of HCV, and 7 (50%) have a history of both HBV and HCV; 2 participants (14%) have HIV. Fidanacogene elaparvovec has been generally well tolerated and the safety profile observed in the LTFU study was consistent with that in the phase 1/2a study (1). Serious Adverse Events (SAEs) were reported in 4 participants; none were considered to be treatment related. Asymptomatic liver abnormalities were noted by liver US in 6 individuals with the most common finding of steatosis in 4 participants, all with BMI >25. Mean ALT for the group remained in the normal range though as shown in Figure 1a, some values >ULN occurred predominantly in participants developing steatosis. There was no clear relationship between HCV, HBV and HIV status with ALT elevation. LFTs of the 3 participants treated with corticosteroids for ALT elevations during the first year (Figure 1b) were within normal limit over time with the exception of participant 7 who notably developed steatosis during the study. No liver masses were detected. Despite the appearance of asymptomatic changes in ALT and liver ultrasound over time, FIX levels and ABR remained stable throughout the duration of follow-up. Conclusions: Fidanacogene elaparvovec was generally well tolerated in HB participants on these studies. Long-term follow-up (up to 6 years) suggests stable long-term liver health. The finding of hepatic steatosis was unexpected and relationship to treatment is not known at this time. As assessed by FIX levels and ABR, participants have had clinical benefit throughout the duration of the study. The phase 3 study (NCT03861273) is ongoing to assess safety and efficacy in a larger cohort of participants. References 1. George LA, et al. N Engl J Med. 2017;377:2215-27. 2. Peyvandi F, Garagiola I. Haemophilia. 2019;25:738-46.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.