Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXIRx in Patients With ESRD

Abstract

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.

Keywords: FXI; anticoagulation; antisense oligonucleotide; hemodialysis; pharmacokinetics; randomized controlled trial.

Graphical abstract

Figure 1

Disposition of study participants. Three patients in the placebo group experienced protocol deviations and were excluded from the per-protocol population owing to disallowed concomitant treatment with warfarin (n = 1) and clopidogrel (n = 2). The 200 mg and 300 mg IONIS-FXI_Rx groups had 3 patients in each group who were excluded from the per-protocol population owing to incomplete dosing to week 8. Adverse events that led to discontinue treatment were as follows: In the PK cohort, 1 participant discontinued owing to sepsis with hemoptysis deemed unlikely related to IONIS-FXI_Rx. In the 200 mg group, 1 participant discontinued treatment owing to hepatic enzyme increased during hospitalization with pneumonia deemed unlikely related to IONIS-FXI_Rx. In the 300 mg group, 1 participant discontinued treatment owing to arteriovenous fistula site hemorrhage judged possibly related to IONIS-FXI_Rx. ITT, intent-to-treat; PK, pharmacokinetics.

Figure 2

Mean (±SD) IONIS-FXI_Rx concentrations after a single 300 mg dose administered to 6 participants after HD (day 1) and 5 participants before HD (day 29). Note: 1 of the 6 participants did not receive the day 29 dose owing to an intercurrent illness unrelated to IONIS-FXI_Rx. HD, hemodialysis.

Figure 3

Effect of IONIS-FXI_Rx 200 mg and 300 mg on FXI activity compared with placebo during the 78-day treatment period and subsequent 85-day washout period. Points represent mean; whiskers represent SEM (intent-to-treat population). Red arrowheads indicate dosing day. FXI, factor XI; LLN, lower limit of normal; ULN, upper limit of normal.