Phase 2 study of the factor XI antisense inhibitor IONIS-FXIRx in patients with end-stage renal disease

Abstract Background End-stage renal disease (ESRD) patients requiring hemodialysis (HD) have an increased risk of thrombotic events and bleeding. Antisense reduction of factor XI (FXI) with IONIS-FXIRx is a novel strategy that may safely reduce the risk of thrombotic events. Methods This multicenter study enrolled 49 patients receiving HD in two parts. First, 6 participants (PK cohort) received one open-label 300 mg dose of IONIS-FXIRx both before and after HD. Subsequently, 43 participants were treated in a double-blind randomized design with 200 mg or 300 mg IONIS-FXIRx or placebo for 12 weeks. IONIS-FXIRx pharmacokinetics, pharmacodynamics, and adverse events were evaluated (ClinicalTrials.gov: NCT02553889). Results IONIS-FXIRx pharmacokinetics were consistent with previous studies and similar whether injected before or after HD. No accumulation of IONIS-FXIRx 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-FXIRx 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. Conclusions IONIS-FXIRx reduced FXI activity in ESRD patients receiving HD. Further studies are needed to determine the benefit-risk profile of FXI as a therapeutic target for patients that require HD.