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Abstract: TH-PO976

Antithrombotic Treatment With Fesomersen vs. Placebo in Patients With ESKD on Hemodialysis (ESKD-HD)

Session Information

Category: Dialysis

  • 701 Dialysis: Hemodialysis and Frequent Dialysis

Author

  • Winkelmayer, Wolfgang C., Baylor College of Medicine, Houston, Texas, United States

Group or Team Name

  • For the RE-THINC Investigators
Background

Patients with ESKD-HD are at high risk for both atherothrombotic events and bleeding. Fesomersen, a ligand-conjugated antisense oligonucleotide drug, targets a region of the FXI mRNA to selectively and specifically inhibit expression of FXI. We performed a randomized placebo-controlled dose-ranging phase 2 study in patients with ESKD-HD to evaluate bleeding and atherothrombotic complications relative to fesomersen dose and individual predicted FXI levels.

Methods

Patients received fesomersen 40, 80, or 120 mg once-monthly, or matching placebo, for up to 12 months. The main safety outcome was the composite of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). Other outcomes included major atherothrombotic events (fatal/nonfatal myocardial infarction or stroke; systemic embolism; acute limb ischemia/amputation; venous thromboembolism), arterio-venous (AV)-access thrombosis, clotting of the HD circuit, and post-dialysis AV-access bleeding.

Results

Following randomization, 307 patients received study treatment. Fesomersen led to a dose-dependent and sustained median reduction of steady-state FXI levels by 53.1%, 72.2% and 86.6% in the 40, 80, and 120 mg groups, respectively. MB or CRNMB events occurred in 6.5% (1 MB, 4 CRNMB), 5.1% (1 MB, 3 CRNMB), 3.9% (2 MB, 1 CRNMB) of the fesomersen 40, 80, and 120 mg groups, respectively, compared with 4.0% (3 CRNMB) of those receiving placebo (not significant). MB or CRNMB and post-dialysis AV-access bleeding were not related to predicted FXI levels. Occurrence of AV-access thrombosis (P<0.05) and HD circuit clotting (P<0.01) diminished with decreasing FXI levels. Major atherothrombotic events occurred in only 4 patients, 1 (1.3%) in each treatment arm. A total of 19 fesomersen recipients underwent major surgery during the study (non-prespecified subgroup). At the time of surgery, predicted FXI levels were <0.2, 0.2-<0.5, and ≥0.5 U/ml in 0, 8 (42.1%), and 11 (57.9%), respectively; no associated MB or CRNM bleeding events were observed.

Conclusion

Fesomersen did not significantly increase the risk of bleeding in patients with ESKD-HD. Incidences of HD circuit clotting and AV-access thrombosis diminished significantly with decreasing FXI levels.

Funding

  • Commercial Support