Preclinical studies evaluating XYNTHA in hemophilia A dogs without inhibitors demonstrated safe and effective restoration of hemostasis. XYNTHA demonstrated a toxicological profile that was similar to the toxicological profile observed with the predecessor product. Toxicity associated with XYNTHA was primarily associated with anti-FVIII neutralizing antibody generation first detectable at 15 days of repeat dosing in high (approximately 735 IU/kg/day) level dosed non-human primates.

Clinical Studies

The efficacy of XYNTHA was evaluated in Study 1, in which subjects received XYNTHA on a prophylaxis treatment regimen, with on-demand treatment administered as clinically indicated. Ninety-four (94) subjects were enrolled and treated with at least one dose and all are included in the intent-to-treat (ITT) population. Eighty-nine (89) subjects accrued ≥ 50 exposure days. From the 94 subjects enrolled, thirty (30) evaluable subjects participated in the PK study and received at least 1 PK dose. Twenty-five (25) evaluable subjects with FVIII:C ≤ 1% completed both the first (PK1) and the second (PK2) assessments [see CLINICAL PHARMACOLOGY]. Median age for the 94 treated subjects was 24 years (mean 27.7 and range 12-60 years). All subjects had ≥ 150 previous exposure days with baseline FVIII activity level of ≤ 2%.

In the open-label safety and efficacy period, all 94 subjects received XYNTHA for routine prophylaxis at the dose of 30 ± 5 IU/kg 3 times a week with provisions for dose escalation based on pre-specified criteria. Seven (7) dose escalations were prescribed for 6 subjects during the course of the study. Forty-three (43) of ninety-four (94), i.e. 45.7%, subjects reported no bleeding while on routine prophylaxis. The median annualized bleeding rate (ABR) for all bleeding episodes was 1.9 (mean 3.9, range 0 to 42.1).

Fifty-three (53) of 94 subjects received XYNTHA for on-demand treatment for a total of 187 bleeding episodes (Table 3). Seven of these bleeding episodes occurred in subjects prior to switching to a prophylaxis treatment regimen. One hundred ten of one hundred eighty (110/180) bleeds (61.1%) occurred ≤ 48 hours after the last dose and 38.9% (70 of 180 bleeds) occurred > 48 hours after the last dose. The majority of bleeds reported to occur ≤ 48 hours after the last prophylaxis dose were traumatic (64 of 110 bleeds; 58.2%). Forty-two (42) of 70 bleeds (60%) reported to occur > 48 hours after the last prophylaxis dose were spontaneous. The on-demand treatment dosing regimen was determined by the investigator. The median dose for on-demand treatment was 30.6 IU/kg (range, 6.4 to 74.4 IU/kg).

Table 3: Time Interval Between Last Prophylaxis Dose of XYNTHA and Start of Bleed

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