Patients with
kidney failure on
hemodialysis (KF-HD) are at high risk for both atherothrombotic events and
bleeding. This Phase IIb study evaluated the dose-response of fesomersen, an inhibitor of hepatic
Factor XI expression, versus placebo, for
bleeding and
atherothrombosis in patients with KF-HD. Patients were randomized to receive fesomersen 40, 80, or 120 mg once-monthly, or matching placebo, for up to 12 months. The primary safety endpoint was a composite of major
bleeding and clinically relevant non-major
bleeding (MB/CRNMB). Exploratory endpoints included post-dialysis arterio-venous (AV)-access
bleeding, major atherothrombotic events (composite of fatal or non-fatal
myocardial infarction,
ischemic stroke, acute limb
ischemia/major
amputation, systemic
embolism, symptomatic
venous thromboembolism), AV-access
thrombosis, and clotting of the
hemodialysis circuit. Of 308 participants randomized, 307 received study treatment and were analyzed. Fesomersen led to a dose-dependent and sustained reduction of steady-state median FXI levels by 53.6% (40 mg group), 71.3% (80 mg group), 86.0% (120 mg group), versus 1.9% in the placebo group. MB/CRNMB events occurred in 6.5% (40 mg group), 5.1% (80 mg group), 3.9% (120 mg group), and in 4.0% of those receiving placebo (pooled fesomersen versus placebo P = 0.78). Major atherothrombotic events occurred in 1 patient (1.3%) in each treatment arm. MB/CRNMB
bleeding and post-dialysis AV-access
bleeding were not related to predicted FXI levels. Lower predicted FXI levels were associated with reductions in
hemodialysis circuit clotting (P = 0.002) and AV-access
thrombosis (P = 0.014). In patients with KF-HD, fesomersen produced a dose-dependent reduction in FXI levels associated with similar rates of major
bleeding compared with placebo. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT04534114.