First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results

Christoph Königs, Margareth C Ozelo, Amy Dunn, Roshni Kulkarni, Beatrice Nolan, Simon A Brown, Michele Schiavulli, Sriya Gunawardena, Sutirtha Mukhopadhyay, Deepthi Jayawardene, Bent Winding, Manuel Carcao, Christoph Königs, Margareth C Ozelo, Amy Dunn, Roshni Kulkarni, Beatrice Nolan, Simon A Brown, Michele Schiavulli, Sriya Gunawardena, Sutirtha Mukhopadhyay, Deepthi Jayawardene, Bent Winding, Manuel Carcao

Abstract

PUPs A-LONG evaluated the safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was the occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at the study start, 20 (19%) had a family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI], 21.8% to 41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI, 8.8% to 24.7%). The median (range) time to high-titer inhibitor development was 9 (4-14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 nontreatment-related death due to intracranial hemorrhage (onset before the first rFVIIIFc dose). The overall median (interquartile range [IQR]) ABR was 1.49 (0.00-4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within the expected range, although high-titer inhibitor development was on the low end of the range reported in the literature. rFVIIIFc was well-tolerated and effective for prophylaxis and treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).

© 2022 by The American Society of Hematology.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Incidence of inhibitor development by EDs and titer. The cumulative incidence of inhibitor development was estimated using the Kaplan-Maier method among those in the safety analysis set (n = 103) according to titer; a high-titer inhibitor was a confirmed inhibitor ≥5 BU/mL, and a low-titer inhibitor was a confirmed inhibitor ≥0.6 and <5 BU/mL. For patients without an inhibitor, follow-up time was censored at the last ED at the time of analysis. The table contains the estimated cumulative incidence of inhibitor development at the 10, 20, and 50 ED milestones.

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