On-Demand Treatment of Bleeding Episodes in Patients with Hereditary Factor X Deficiency Using a High-Purity Factor X Concentrate: Data from 2 Clinical Trials and a Data-Collection Study

Introduction: Hereditary factor X (FX) deficiency is a rare bleeding disorder characterized by spontaneous joint, mucosal, and muscle bleeds as well as intracranial hemorrhage. Women and girls may also experience menorrhagia. In the past, hereditary FX deficiency has been treated with fresh frozen plasma or a prothrombin complex concentrate, both of which contain variable amounts of FX. Plasma-derived FX (pdFX) is a high-purity FX concentrate approved in the United States for on-demand treatment of patients with hereditary FX deficiency aged 12 years and older and for perioperative management of bleeding in patients with mild hereditary FX deficiency. pdFX is approved in the European Union for treatment and prophylaxis of bleeding episodes as well as perioperative management in patients with hereditary FX deficiency.

Objectives: To present efficacy and safety data from 2 phase 3 clinical studies and 1 data-collection study evaluating pdFX for on-demand treatment of bleeds in patients with hereditary FX deficiency.

Methods: Results from 2 phase 3 clinical studies and 1 data-collection study of patients with severe (FX activity [FX:C] <1 IU/dL) or moderate (FX:C 1-5 IU/dL) FX deficiency are included. TEN01 was a prospective, open-label, multicenter, nonrandomized study of subjects aged ≥12 years. Bleeds were treated with an initial dose of 25 IU/kg pdFX followed by additional doses as needed. TEN02 was a prospective, open-label, multicenter, nonrandomized study in children less than 12 years old. In TEN01 and TEN02, pdFX efficacy was assessed as excellent, good, poor, or unassessable. TEN05 was a retrospective, multicenter data-collection study in patients of any age who received ≥1 dose of pdFX on a compassionate-use basis. Investigators retrospectively rated pdFX treatment of bleeds as effective (with hemostasis achieved with the expected number of doses for the severity of the bleed), not effective, or unknown. In TEN05, dosing was at the discretion of the investigator. All protocols were approved by each center's local or national independent ethics committee. All subjects provided written informed consent prior to enrollment.

Results: A total of 19 subjects were analyzed from the 2 prospective clinical trials; 12 of these subjects were also included in the retrospective data-collection study. Ages ranged from 1 to 58; 16 of 19 patients were aged ≥12 years. FX deficiency was severe in 17 patients and moderate in 2 patients. During the studies, 326 bleeds were reported, with a median of 12 (range 1-59) bleeds per patient in TEN01, 4 (1-5) bleeds per patient in TEN02, and 5.5 (2-26) bleeds per patient in TEN05. Of these 326 bleeds, 270 bleeds in 18 subjects were treated with pdFX and evaluated. Severity was major for 108 bleeds, minor for 116 bleeds, and not rated for 46 bleeds. Reported bleed causes were menorrhagia (n=97), spontaneous (n=93), trauma or injury (n=75), other (n=3), and unknown (n=2). Bleed locations were mucosal (n=117), joint (n=79), muscle (n=38), other (n=30), and unknown (n=6). Most bleeds (n=230, 85.5%) were treated with a single pdFX infusion (the maximum number of infusions for a single bleed was 12). The total factor dose per bleed per subject ranged from 7.92 to 82.0 IU/kg, with a median of 25.0 IU/kg in TEN01, 31.7 IU/kg in TEN02, and 23.8 IU/kg in TEN05. Treatment effectiveness was assessed by investigators as excellent or good in 43 of 44 rated bleeds (97.7%) in TEN01 and TEN02. One was rated poor in TEN01. In TEN05 pdFX was reported as effective in all 79 rated bleeds (100%). In TEN01, 6 adverse events in 2 patients were reported as related or possibly related to pdFX treatment; all were mild or moderate. No adverse events in TEN02 were considered related or possibly related to pdFX treatment, and no adverse drug reactions or safety concerns were reported in TEN05. No thromboembolic events, inhibitor development, or hypersensitivity reactions were reported in the 3 studies.

Conclusions: Across 3 studies, pdFX was rated as effective at treating a variety of bleeds in patients with FX deficiency. Only one dose of pdFX was needed to treat most (85.5%) bleeds. At the doses used in these studies, on-demand pdFX treatment was well tolerated in pediatric and adult subjects.