PUPs A-LONG aimed to evaluate the safety, including inhibitor development, and efficacy of extended half-life (EHL) recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with severe hemophilia A.
This open-label, multicenter, Phase 3 study (NCT02234323) enrolled male PUPs aged <6 years with severe hemophilia A (<1 IU/dL endogenous FVIII) to receive rFVIIIFc. Primary endpoint was inhibitor development (incidence rate=number of patients with inhibitors/number of patients reaching ≥10 exposure days [ED] milestone or with inhibitors). A secondary endpoint was annualized bleed rate.
Of 103 patients receiving ≥1 dose, 80 (77.7%) were <1 year old, 20 (19.4%) had a family history of inhibitors, and 82 (79.6%) had a high-risk hemophilia genotype. Eighty-one patients started on episodic treatment; of these, 69 switched to prophylaxis. Twenty patients started on prophylaxis, and 2 were not assigned a regimen. Eighty-seven (84.5%) patients completed the study. Eighty-seven (84.5%), 85 (82.5%), and 81 (78.6%) patients had ≥10, ≥20, and ≥50 EDs to rFVIIIFc, respectively. Total and high-titer (≥5.00 BU/mL) inhibitor rate was 31.1% (28/90) and 15.6% (14/90), respectively, for patients with ≥10 EDs (3 patients with inhibitors and <10 EDs included). Median time to inhibitor development was 9 EDs (range: 1–53). rFVIIIFc dosing and efficacy data are in Table 1. Twenty-eight (27.2%) patients had 32 rFVIIIFc adverse events assessed as related by the investigator (FVIII inhibition, n=28; soft tissue hemorrhage, n=1; deep vein thrombosis, n=1; device-related thrombosis, n=1; papular rash, n=1). There was 1 non–treatment-related death due to intracranial hemorrhage (onset during screening period before first rFVIIIFc dose).
This was the first prospective study of an EHL, rFVIIIFc, as treatment for PUPs with severe hemophilia A. Overall inhibitor development was within the expected range, although high-titer incidence was lower than that reported in the literature. The data demonstrate that rFVIIIFc was well tolerated and effective in this pediatric patient population.