Pharmacokinetics and Pharmacodynamics of Ionis-FXIRx, an Antisense Inhibitor of Factor XI, in Patients with End-Stage Renal Disease on Hemodialysis

Abstract

BACKGROUNDPatients with end-stage renal disease (ESRD) on hemodialysis are at high risk of both thrombotic and bleeding events. Experimental and clinical data indicate that reducing factor XI (FXI), a key component of the intrinsic pathway, prevents thrombosis without causing bleeding. FXI activity can be lowered with IONIS-FXIRx, a 2nd generation antisense oligonucleotide that specifically reduces human FXI mRNA expression in the liver. This study sought to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-FXIRx in participants with ESRD. METHODSIn this Phase 2 multicenter study, we enrolled a total of 49 ESRD patients: (A) 6 participants receiving chronic in-center hemodialysis (HD) to receive an open-label single-dose of 300 mg IONIS-FXIRx either 5 minutes before or 10 minutes after HD and assessed the effects of HD on peak (Cmax) and the extent of exposure (AUC0-24hr) parameters of IONIS-FXIRx and (B) another 43 participants in a double-blind design to one of two multiple-dose regimens (200 mg or 300 mg) IONIS-FXIRx or placebo for 12 weeks with 12 weeks of additional follow up. In the double-blind portion, IONIS-FXIRx was administered subcutaneously ~10 minutes after HD. For PK, plasma trough concentration and apparent elimination half-life (t1/2λz) were evaluated. The PD parameters including FXI activity and antigen, aPTT, prothrombin time (PT), and INR were evaluated in the per-protocol population (N= 34) that was defined as all participants who received the complete protocol-specified administration of IONIS-FXIRx or placebo through week 8 and who did not have any major protocol violations. The rate and frequency of clotting on the HD filters and circuit were qualitatively measured with a clotting scale as an exploratory PD analysis. RESULTSThe PK cohort included 6 males (5 white) with a mean age of 61 years. The plasma PK profile of IONIS-FXIRx was not significantly altered whether injected before or after HD. After multiple dosing, plasma Cmax values were dose-dependent and similar between Day 1 (first dose) and Day 78 (last dose), suggesting no accumulation of IONIS-FXIRx in ESRD participants after 12-weeks of dosing. After treatment cessation, IONIS-FXIRx had an apparent elimination half-life of approximately 2 weeks. In the double-blind portion of the study, 22 (51.2%) of the participants were male, 24 (55.8%) were white and the mean age was 59 years. Attenuation of FXI activity was associated with a reduction in the incidence of severe clotting events on both the air filter and dialyzer (Table). The reduction in severe clotting events was observed when FXI activity was < 0.4 U/mL. Consistent with prior observations in healthy subjects, IONIS-FXIRx prolonged aPTT in a time and dose-dependent manner with maximum mean percent changes from baseline of 53.3% (p < 0.05) for the 200 mg dose group and 75.6% (p < 0.05) for the 300 mg dose group at Week 14, but had no effect on PT. Treatment emergent adverse events (TEAEs) were mostly mild; participants reporting serious TEAEs were 1 (16.7%) for the PK cohort, 4 (30.8%) for placebo and 3 (20.0%) each for the 200 mg and 300 mg IONIS-FXIRx dose groups. There were no drug-related SAEs and no drug-related major or clinically-relevant non-major bleeding events. Minor bleeds were primarily observed in the 300 mg multiple-dose group at AV fistula/graft sites but did not correlate with reduction of FXI activity. No clinically significant reductions in platelet counts were reported during the study. CONCLUSIONSThis study demonstrated that (i) HD had no effect on IONIS-FXIRx PK, (ii) IONIS-FXIRx was well tolerated and produced sustained, and dose-dependent reductions in FXI antigen and activity, and (iii) IONIS-FXIRx reduced severe dialysis circuit clotting events beyond standard heparin use. Collectively, these data support further evaluation of IONIS-FXIRx as a potentially safe, effective antithrombotic therapy in ESRD patients on HD. [Display omitted] DisclosuresBethune:Ionis Pharmaceuticals: Employment. Walsh:Population Health Research Institute: Employment; Ionis Pharmaceuticals: Consultancy. Jung:Ionis Pharmaceuticals: Employment. Yu:Ionis Pharmaceuticals: Employment. Geary:Ionis Pharmaceuticals: Employment. Bhanot:Ionis Pharmaceuticals: Employment.