HTRS2025.O8C.4 Efficacy and Safety of Giroctocogene Fitelparvovec in Adults With Moderately Severe to Severe Hemophilia A: Results From the Phase 3 AFFINE Gene Therapy Trial

Background: The effectiveness of damoctocog alfa pegol for the prevention and treatment of bleeding in previously treated children with severe hemophilia A was demonstrated in the PROTECT VIII Kids trial (NCT01775618).Children aged < 12 years were excluded from damoctocog alfa pegol's initial marketing authorization application because of observed loss of efficacy and/or hypersensitivity reactions occurring within the first 4 exposure days (EDs) in some children aged < 6 years due to an immune response to PEG.These responses were not seen in children aged ≥7 years.Objectives: To evaluate the risk of hypersensitivity and loss of efficacy associated with anti-PEG antibodies during the first 4 EDs with damoctocog alfa pegol in children aged 7 to < 12 years.Methods: The phase 3, multicenter, open-label, single-arm Alfa-PROTECT study (NCT05147662) comprised a 6-month main study (completed) with ≥50 EDs, and an 18 month extension (ongoing).In the main study, patients received 40 IU/kg (up to 60 IU/kg at the investigator's discretion) of damoctocog alfa pegol prophylaxis, twice weekly.The primary endpoint (estimated by a Bayesian model including prior information from PRO-TECT VIII Kids) was the incidence of adverse events of special interest (AESI) -hypersensitivity or loss of efficacy -leading to discontinuation during the first 4 EDs.Secondary endpoints included adverse reactions, development of anti-drug antibodies, annualized bleeding rate, and utilization.Results: In total, 35 patients (safety analysis set [SAF]) received at least 1 dose of study drug.The median (range) treatment duration was 182 (7-198) days with a median of 53 (1-59) EDs.Median age at baseline was 8 years (Table 1).Of the SAF, 32 had documented bleed and utilization data for ≥3 months (Table 2) and 31 had ≥50 damoctocog alfa pegol EDs.In the SAF, 21/35 patients (60%) experienced ≥1 adverse event (AE), all mild or moderate, and 3/35 patients (9%) had AEs related to the study drug.Study-drug-related AEs of injection site pain or injection site itch of moderate intensity occurred in 2 patients, not leading to treatment disruption.Loss of efficacy at Day 12, due to high-titer anti-PEG antibodies (after 2nd ED), leading to treatment interruption occurred in one patient; this was considered a study-drug-related AESI.Antibodies disappeared and patient resumed treatment 2 months later.Mean and median of the posterior distribution of the true incidence of AESI were 2.1% and 1.59%, respectively (90% CI [0.18; 5.76%]).No AEs resulted in study drug discontinuation, no deaths were reported.Mean (SD) number of bleeds in the 12 months before screening was 3.25 (5.6), and during the study the mean (SD) annualized number of treated bleeds was 1.3 (2.7).Conclusions: These data confirm the safety profile of damoctocog alfa pegol in children aged 7 to < 12 years with severe hemophilia A, and secondary endpoints indicate effectiveness of treatment in this population.

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