Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXI(Rx) in Patients With ESRD

INTRODUCTION: Patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) have an increased risk of thrombotic events and bleeding. Antisense reduction of factor XI (FXI) with IONIS-FXI(Rx) is a novel strategy that may safely reduce the risk of thrombotic events. METHODS: This multicenter study enrolled 49 patients receiving HD in 2 parts. First, 6 participants (pharmacokinetics [PK] cohort) received 1 open-label 300 mg dose of IONIS-FXI(Rx) both before and after HD. Subsequently, 43 participants were treated in a double-blind, randomized design with 200 mg or 300 mg IONIS-FXI(Rx) or placebo for 12 weeks. The PK, pharmacodynamics (PD), and adverse events of IONIS-FXI(Rx) were evaluated (ClinicalTrials.gov: NCT02553889). RESULTS: The PK of IONIS-FXI(Rx) was consistent with previous studies and similar whether injected before or after HD. No accumulation of IONIS-FXI(Rx) was observed after repeat administration. By day 85, mean levels of FXI activity fell 56.0% in the 200 mg group, 70.7% in the 300 mg group, and 3.9% in the placebo group compared with baseline. FXI antigen levels paralleled FXI activity. Dose-dependent prolongation of activated partial thromboplastin time (aPTT) was observed, with no changes in international normalized ratio (INR). IONIS-FXI(Rx) was not associated with drug-related serious adverse events. In the randomized phase of the study, major bleeding events occurred in 0 (0.0%; 200 mg), 1 (6.7%; 300 mg), and 1 (7.7%; placebo) patients and were not considered related to treatment. CONCLUSION: IONIS-FXI(Rx) reduced FXI activity in patients with ESRD receiving HD. Further studies are needed to determine the benefit-risk profile of FXI as a therapeutic target for patients who require HD.