Managing surgery in hemophilia with recombinant factor VIII Fc and factor IX Fc: Data on safety and effectiveness from phase 3 pivotal studies

Abstract

Background: Surgical procedures impose hemostatic risk to people with hemophilia, which may be minimized by optimal factor (F) replacement therapy.

Methods: This analysis evaluates the efficacy and safety of extended half-life factor replacement recombinant FVIII and FIX Fc fusion proteins (rFVIIIFc and rFIXFc) during surgery in phase 3 pivotal (A-LONG/Kids A-LONG and B-LONG/Kids B-LONG) and extension (ASPIRE and B-YOND) studies. Dosing regimens were determined by investigators. Injection frequency, dosing, blood loss, transfusions, and hemostatic response were assessed.

Results: Forty-five major (n = 31 subjects) and 90 minor (n = 70 subjects) procedures were performed in hemophilia A; 35 major (n = 22) and 62 minor (n = 37) procedures were performed in hemophilia B. Unilateral knee arthroplasty was the most common major orthopedic procedure (hemophilia A: n = 15/34; hemophilia B: n = 8/24). On the day of surgery, median total dose in adults/adolescents was 81 IU/kg for rFVIIIFc and 144 IU/kg for rFIXFc; most major procedures required ≤2 injections (including loading dose). Through days 1-14, most major procedures had ≤1 injection/day. Hemostasis was rated excellent (rFVIIIFc: n = 39/42; rFIXFc: n = 29/33) or good (n = 3/42; n = 4/33) in evaluable major surgeries, with blood loss comparable with subjects without hemophilia. Most minor procedures in adults/adolescents required one injection on the day of surgery, including median loading dose of 51 IU/kg (rFVIIIFc) and 80 IU/kg (rFIXFc). No major treatment-related safety concerns were identified. No subjects developed inhibitors or serious vascular thromboembolic events.

Conclusions: rFVIIIFc and rFIXFc were efficacious and well tolerated for the management of perioperative hemostasis across a wide spectrum of major and minor surgeries in hemophilia.

Keywords: factor IX fc fusion protein; factor VIII Fc fusion protein; hemophilia A; hemophilia B; recombinant fusion proteins; safety; surgical procedures.

FIGURE 1

Number of injections of rFVIIIFc on day of surgery and postoperative days 1–14 in major orthopedic and nonorthopedic surgeries^a. ^aDose shown only for surgical events where dosing of rFVIIIFc was given in conjunction with the surgical intervention (and for a specific day/period); one major surgery did not have information on rFVIIIFc dosing on the day of surgery and is not included in this figure. ^bIncludes one subject from Kids A‐LONG (arm K‐wire replacement). ^cIncludes loading dose. Loading dose was defined as the first dose administered on the day of surgery. If there was no dose administered on the day of surgery, the loading dose was defined as the dose administered 1 day before surgery. ^dIncludes one subject from Kids A‐LONG (dental extraction). Abbreviations: rFVIIIFc, recombinant factor VIII Fc fusion protein

FIGURE 2

Number of injections of rFIXFc on day of surgery and postoperative days 1–14 in major orthopedic and non‐orthopedic surgeries^{a. a}Dose shown only for surgical events where dosing of rFIXFc was given in conjunction with the surgical intervention (and for a specific day/period). ^bIncludes loading dose. Loading dose was defined as the first dose administered on the day of surgery. If there was no dose administered on the day of surgery, the loading dose was defined as the dose administered 1 day before surgery. ^cIncludes one subject from Kids B‐LONG (tonsillectomy). ^dOne rectal fistula closure and one liver resection. Abbreviation: rFIXFc, recombinant factor IX Fc fusion protein