Results from the Hemophilia Α Cohort of the Non-Investigational Lead-in Study: Prospective Collection of Bleeding Rate in Participants with Hemophilia Α Prior to Phase 3 Study (AFFINE) of Giroctocogene Fitelparvovec
Authors: Frenzel Laurent , Kavakli Kaan , Leavitt Andrew D. , Antmen Ali Bülent , Matino Davide , Ozelo Margareth , Alzahrani Hazza , Konkle Barbara A. , de los Angeles Resa Maria , Fang Annie F. , Healy Jasmine , Agathon Delphine , Biondo Francesca , Plonski Frank 
Published: December 2024

Introduction: Giroctocogene fitelparvovec (PF-07055480) is a liver-directed recombinant adeno-associated virus serotype 6 (AAV6) gene therapy vector encoding a B-domain-deleted variant of human factor VIII (FVIII) that enables sustained endogenous FVIII expression. AFFINE (NCT04370054) is an ongoing, pivotal phase 3 trial to evaluate the efficacy and safety of giroctocogene fitelparvovec in individuals with hemophilia A. The primary endpoint of the AFFINE trial is to demonstrate non-inferiority in total (treated and untreated) annualized bleeding rate (ABR) compared with routine prophylactic FVIII replacement therapy collected prospectively in a separate lead-in trial. We present the results of the lead-in trial initiated to establish prospective bleeding and infusion rates while on FVIII prophylaxis replacement therapy in the usual care setting of participants with hemophilia A. The baseline data obtained in this trial will be used for comparison with data collected post gene therapy for those participants who subsequently enrolled in the giroctocogene fitelparvovec phase 3 AFFINE trial.
Methods: This study (NCT03587116) is a prospective, noninterventional, phase 3 lead-in trial that enrolled adult men ≥18 to &lt;65 years old with moderately severe to severe hemophilia A (FVIII ≤1%) on stable prophylaxis FVIII replacement therapy who tested negative for neutralizing antibodies (nAb) to AAV6. The trial is multi-regional in 18 countries in North America, South America, Asia Pacific, Europe, and the Middle East. Participants were instructed to record infusions and bleeding events in an electronic diary, with most participants providing ≥6 months of data prior to entry in the phase 3 AFFINE trial. Selected safety data (serious adverse events [SAEs] and medically important events of FVIII inhibitor, thrombotic events, and factor hypersensitivity reactions) of FVIII replacement therapy were also collected.
Results: In all, 241 patients with hemophilia A were screened and 101 were enrolled in the hemophilia A cohort of this lead-in trial (data for the hemophilia B cohort have been presented previously). The most common reason for screen failure was nAb positivity at screening in 115 (82.1%) of the 140 screen failures. The mean (range) age of those enrolled was 31.8 (18 to 64) years. Most participants were 18-44 years of age (84 [83.2%]), White (78 [77.2%]), and not Hispanic or Latino (76 [75.2%]). Target joints were identified in 47 (46.5%) participants. Overall, 84 (83.2%) participants had ≥180 days of follow-up; the mean (SD) follow-up duration of these participants was 351.3 (197.32) days and 23 (22.8%) had ≥1 year of follow-up. Overall, 17 (16.8%) participants had &lt;180 days of follow-up; the mean (SD) follow-up duration of these participants was 84.8 (43.64) days. The overall mean (SD) follow-up duration was 306.5 (206.55) days. The mean (SD) total ABR was 6.1 (10.6), mean (SD) treated ABR was 4.87 (7.2), and mean (SD) annualized infusion rate (AIR) was 127.1 (51.8). The mean (SD) annualized total FVIII replacement therapy consumption was 304,998 (153,932) IU. Of the 101 participants, 4 (4.0%) experienced 4 SAEs (hemorrhoidal hemorrhage, upper gastrointestinal hemorrhage, wound infection, and B-cell lymphoma; n=1 [1.0%] each); all SAEs were severe except upper gastrointestinal hemorrhage, which was moderate in severity. No adverse events of special interest were reported, and no safety signals were identified for FVIII replacement therapy.
Conclusions: The ABR and AIR collected in this lead-in trial are representative of FVIII prophylaxis in hemophilia A populations. Although FVIII prophylaxis was well tolerated, with no emerging safety signals, a total ABR of 6.1 illustrates the limitations of current standard of care prophylaxis. The total ABR reported in a subset of participants who went on to enroll in the phase 3 AFFINE trial of giroctocogene fitelparvovec will be used as the comparator for the primary endpoint evaluating noninferiority post gene therapy, in accordance with the AFFINE trial protocol.