A Multicenter, Retrospective Data Collection Study on the Compassionate Use of a Plasma-Derived Factor X Concentrate to Treat Patients with Hereditary Factor X Deficiency

Introduction: Congenital factor X (FX) deficiency (FXD) is a rare bleeding disorder characterized by spontaneous joint and mucocutaneous bleeding and gastrointestinal or intracranial hemorrhage. A high-purity plasma-derived FX concentrate (pdFX; Coagadex^®, Bio Products Laboratory, Elstree, UK) is licensed in the United States (US) and European Union to treat congenital FXD. This open-label, multicenter, international study collected retrospective data on compassionate use of pdFX in subjects with hereditary FXD.

Methods: This study included subjects of any age with hereditary FXD (irrespective of severity) who received pdFX on a compassionate use basis as routine prophylaxis (RP), on-demand (OD) treatment, short-term prevention, and/or perisurgical hemostatic cover. Dosing was set at the discretion of the investigator and tailored to each patient. Data collection lasted from date of first dose of compassionate use until data cutoff (31 December 2015). Retrospective efficacy assessments included number of bleeds/year/subject, total dose/year/subject, dose to treat a bleed, investigator's efficacy assessment in treating a bleed (effective, not effective, or unknown), and investigator's overall efficacy assessment during compassionate use (excellent, good, poor, or unassessable). All subjects (or a parent/guardian) provided written informed consent; the protocol was approved by appropriate independent ethics committees.

Results: All 15 enrolled subjects from 12 study centers in 5 countries (Germany, Spain, Turkey, the United Kingdom, and the US) received ≥1 pdFX dose for compassionate use. Of these, 13 subjects were aged ≥12 years (mean, 22.8 years) and 2 were aged <12 years, 8 (53.3%) were female, 12 (80.0%) were white, 3 (20.0%) were Asian, and all subjects had moderate or severe FXD (FX activity [FX:C] <5 IU/dL).

Of the 15 patients, 7 received only RP, 7 received only OD, and 1 patient alternated between OD and RP treatment. Of the 8 subjects on RP, 4 received pdFX once weekly (of whom 2 changed for a short period to dosing every 2 days), 3 received pdFX every 3 days, and 1 received pdFX every 15 days. Overall, these 8 subjects received a total of 1239 RP infusions (mean 154.9 infusions/subject, range 39-492), with a mean dose/infusion/subject of 32.5 IU/kg (range 21.9-53.6). The 2 subjects aged <12 years received larger RP doses than the 6 older subjects, with mean doses/infusion/subject of 51.1 vs 26.3 IU/kg, respectively.

Twelve subjects (8 OD, 4 RP; all aged ≥12 years) reported 88 bleeds, of which 34 were rated as minor (epistaxis, gum bleed, mild menorrhagia, or superficial hematoma), 7 as major (severe gastrointestinal bleeding, intracerebral hemorrhage, severe hemarthrosis, major menorrhagia, or large/complicated muscle hematoma), and 47 were not rated for severity; 37 bleeds were menorrhagic, 28 were traumatic, 17 were spontaneous, 4 were other, and 2 had unknown cause. pdFX efficacy was rated as effective for the 79 bleeds (including 1 subdural hematoma) that received on-demand pdFX treatment. Mean pdFX dose was 22.2 IU/kg/infusion/subject, with a mean number of 9.5 infusions/subject to treat a bleed. Subjects in the OD population experienced more bleeds than subjects in the RP population.

Two subjects underwent 1 dental procedure each, each of which required only 1 presurgical pdFX dose (27.1 and 28.5 IU/kg); the third surgery, a portacath insertion, required 6 infusions to prevent postoperative bleeding (1 presurgical dose of 72.8 IU/kg + 5 doses of 48.5 IU/kg at days 1, 2, 3, 5, and 15 post surgery). Two successful pregnancies/childbirths were also reported, with no abnormal bleeding complications and no efficacy or safety concerns reported.

The mean duration of compassionate use was 87.6 weeks for the 15 subjects, with a range of 15-211 weeks (0.3 to 4.0 years). Over the 1373 infusions administered across 25.2 subject-years in this study, investigators rated overall pdFX efficacy use as excellent in 14 (93.3%) subjects and good in 1 (6.7%) subject. No adverse drug reactions, safety concerns, infusion site reactions, tolerability issues, or inhibitor development were reported during pdFX compassionate use.

Conclusion: The higher bleed rate in OD versus RP use and the duration of treatment (up to 4 years) support the efficacy and safety of pdFX demonstrated in prospective clinical studies and its continued use in the treatment of subjects with hereditary FXD.

Funding: BPL