Use of Fidanacogene Elaparvovec, a Gene Therapy Vector, to Deliver a Stable, Fully Functional Human Factor IX Transgene for the Treatment of Hemophilia B: A Combined Analysis of Safety

Background Fidanacogene elaparvovec is a non-replicating, recombinant, liver-tropic, adeno-associated virus-based (rAAV) gene therapy that transfers a high-activity variant of human factor IX (FIX) FIX-R338L for the treatment of hemophilia B (HB). Data from a phase 1/2a fidanacogene elaparvovec trial and its long-term follow-up (LTFU) demonstrated sustained FIX activity in the mild hemophilia to normal range, with low bleeding rates and a reduction in FIX infusions up to 6 years post dosing. In the ongoing, phase 3 BENEGENE-2 trial, fidanacogene elaparvovec resulted in FIX activity levels in the mild hemophilia to normal range and a reduction in annualized bleeding rate up to 4 years post dosing. Fidanacogene elaparvovec was recently approved for use in Canada, the United States, and Europe. As a novel therapeutic modality, the long-term safety of rAAV hemophilia gene therapies is unknown. To address this, we report a combined analysis of fidanacogene elaparvovec safety across its clinical development. Methods Data from the phase 1/2a trial (NCT02484092, completed), its LTFU study (NCT03307980, cutoff August 15, 2023), and the BENEGENE-2 trial (NCT03861273, cutoff August 30, 2023) were included. Men ≥18 years with HB (FIX ≤2%) received a single intravenous infusion of 5×1011 vg/kg fidanacogene elaparvovec. Patients with AAV capsid neutralizing antibodies, baseline alanine transaminase (ALT) or aspartate transaminase (AST) >2× upper limit of normal (ULN) or bilirubin >1.5× ULN were excluded. Safety endpoints included adverse events (AEs) and serious AEs (SAEs) in the first year post dosing. In the subsequent follow-up after Year 1, non-serious gene therapy-related AEs were reported together with SAEs. AEs of special interest (hypersensitivity reactions, thrombotic events, FIX inhibitors, hepatic malignancies, elevated transaminases), clinical laboratory results, and hepatic evaluations were included. Participants were followed for up to 6 years. Results Data from 60 unique participants (phase 1/2a, n=15 dosed; LTFU for those dosed in phase 1/2a, n=14; BENEGENE-2, n=45 dosed) who received fidanacogene elaparvovec were included. The median follow-up duration was 5.8 (range 1-6) years for phase 1/2a and its LTFU and 2.8 (range 1.2-4.0) years for BENEGENE-2. The total safety experience was based on 204.8 participant-years of follow-up. All participants have >1 year of follow-up, 54 (90%) >2 years, and 29 (48%) >3 years. Most participants had severe HB (80% with FIX activity <1%), 75% were White, with median age of 30.5 (range 18-62) years, and median body mass index (BMI) 28 (range 18-48) kg/m2 at baseline. In the first year of follow-up, 52/60 (87%) participants had AEs and 5 (8%) had SAEs. The most frequently reported AEs were increased ALT (n=12 [20%]; mild, n=9; moderate, n=3) and nasopharyngitis (n=11 [18%]; mild, n=8; moderate, n=3). In the total follow-up period, 52/60 (87%) participants had AEs and 11 (18%) had SAEs. The most frequently reported AE was increased ALT (n=12 [20%]) and SAE of anemia (n=2 [3%]). Age, BMI and geographic region had no impact on the incidence of AEs. In the first year of follow-up, 31/60 (52%) participants were treated with corticosteroids for increased transaminases and/or decreased FIX levels (median duration 98 [range, 41-276] days). All corticosteroid treatments were completed within 1 year post gene therapy. No participants initiated corticosteroid treatment after 1 year. With up to 6 years' follow-up, there have been no FIX inhibitors or hepatic malignancies, and no gene therapy-related elevated transaminases that failed to improve/resolve with immunosuppressive treatment. Overall, 11 (18%) participants had mild-to-moderate events within the scope of hypersensitivity; no acute hypersensitivity events or infusion-related reactions were assessed as related to fidanacogene elaparvovec. There were no deaths or discontinuations due to an AE. Liver ultrasounds from Year 1 of the LTFU study onwards showed 4 participants had steatosis and 1 had cirrhosis; 1 participant in BENEGENE-2 had hepatic stenosis/polycystic kidney disease and 1 had a polyp in the gall bladder. None of these findings were considered related to gene therapy. Conclusions This combined analysis demonstrates the favorable safety profile of fidanacogene elaparvovec in the largest dataset with the longest follow-up for an HB gene therapy. LTFU will continue for up to 15 years.

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