The use of extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc) appeared to be safe and effective in young boys with previously untreated severe hemophilia A, according to results of the PUPs A-LONG study presented at the International Society on Thrombosis and Haemostasis (ISTH) 2020 Virtual Congress.
About 25% to 40% of patients with hemophilia A who receive recombinant FVIII replacement therapy will develop inhibitors. rFVIIIFc is a recombinant clotting factor therapy developed for hemophilia A with Fc fusion technology to prolong FVIII circulation in the body, explained presenter Christoph Könings, MD, PhD, of University Hospital Frankfurt in Germany. The longer half-life allows less frequent dose administration.
PUPs A-LONG is an open-label, multicenter, phase III study that enrolled boys under the age of 6 with previously untreated hemophilia A. Patients received rFVIIIFc and were followed to monitor inhibitor development (primary endpoint) and annualized bleeding rate (ABR).
At least one dose of rFVIIIFc was given to 103 patients, most of whom were under age 1 (77.7%). About 1 in 5 patients (19.4%) had a family history of inhibitors, and almost 80% had a high-risk genotype.
A total of 81 patients started on episodic treatment with rFVIIIFc; of these, 69 switched to prophylactic treatment during the study. Twenty patients started the trial on prophylaxis and 2 were not assigned a regimen.
Eighty-seven patients (84.5%) completed the study, and the exposure to rFVIIIFc was high: 84.5% of patients had 10 or more exposure days, 82.5% had 20 or more, and 78.6% had 50 or more.
The incidence of inhibitor development (defined as the number of patients with inhibitor divided by the number of patients with ≥10 exposure days with inhibitor) was 31.1%, with 15.6% of patients developing high-titer inhibitors (≥5.00 BU/mL). The median time to inhibitor development was 9 exposure days (range = 1-53).
The researchers wrote that “overall inhibitor development was in the range that can be expected, although high-titer incidence was lower than that reported in the literature [for patients receiving recombinant FVIII].”
For the secondary endpoint of ABR, the study authors noted that patients who received episodic treatment had a median ABR of 2.24 and those who received prophylactic treatment had a rate of 1.49. In both groups, a median of one injection was required for resolution of a bleeding episode (see TABLE).
Serious treatment-related adverse events occurred in 27.2% of patients who received rFVIIIFc. These events included FVIII inhibition (n=28), soft tissue hemorrhage (n=1), and thrombosis, including clots associated with a vascular access device (n=2). One patient died from intracranial hemorrhage during the screening period of the trial prior to the first dose.
These findings are limited by the small patient population, the open-label design, and the lack of a comparator arm.
Könings C, et al. Final results of PUPs A-LONG study: Evaluating safety and efficacy of rFVIIIFc in previously untreated patients with haemophilia A. Abstract OC 03.2. Presented at ISTH 2020 Virtual Congress; July 12-14, 2020.