Abstract Number: OC 67.4
Meeting: ISTH 2021 Congress
Background: Etranacogene dezaparvovec, an investigational gene therapy for hemophilia B, comprises an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua-variant human factor IX (FIX) transgene and liver-specific promoter. The HOPE-B phase 3 trial (NCT03569891) is ongoing and 6 month efficacy and safety outcomes have been reported.
Aims: To describe a serious adverse event of hepatocellular carcinoma (HCC) detected at 1 year follow-up in a trial participant.
Methods: HOPE-B is an open-label, single-dose, single-arm, international trial in adult males with FIX≤2% on routine FIX prophylaxis (n=54). Participants with a history of, or well-controlled, hepatitis B/C infection were permitted in the study. Patients with cirrhosis or advanced fibrosis (fibroscan ≥9KPa) were excluded. Participants received a single intravenous dose of etranacogene dezaparvovec (2×1013gc/kg) and will be followed for 5 years. Liver-specific assessments include twice-yearly assessment of alpha-fetoprotein and annual ultrasound.
Results: A liver lesion was detected by ultrasound in one participant during routine study assessment at 1 year post-dose. The participant was >65 years old, with a history of hepatitis C (eradicated 3 years prior to enrolment), hepatitis B and evidence of non-alcoholic fatty liver changes on biopsy. Hepatic ultrasound at study entry was normal. Alpha-fetoprotein, alanine-aminotransferase, and aspartate-aminotransferase levels were within normal limits and stable during the preceding study year. FIX activity was stable in the mild to nonhemophilic range without apparent upward/downward trend. Following surgical resection, tissue will undergo analysis for vector copy number and integration sites.
Conclusions: This is the first reported case of HCC in a participant undergoing liver-directed AAV-based gene therapy. Risk factors for HCC are prevalent in the hemophilia population, including this participant. A full investigation will be conducted into possible contributing factors. Ultrasound monitoring of all participants enrolled in etranacogene dezaparvovec clinical trials will be increased to twice yearly regardless of HCC risk.
To cite this abstract in AMA style:Schmidt M, R Foster G, Coppens M, Thomsen H, Cooper D, Dolmetsch R, K Sawyer E, Heijink L, W Pipe S. Liver Safety Case Report from the Phase 3 HOPE-B Gene Therapy Trial in Adults with Hemophilia B [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/liver-safety-case-report-from-the-phase-3-hope-b-gene-therapy-trial-in-adults-with-hemophilia-b/. Accessed October 20, 2021.
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