The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial

Abstract

End-stage renal disease (ESRD) patients on chronic hemodialysis have repeated blood exposure to artificial surfaces that can trigger clot formation within the hemodialysis circuit. Dialyzer clotting can lead to anemia despite erythropoietin and iron supplementation. Unfractionated heparin prevents clotting during hemodialysis, but it is not tolerated by all patients. Although heparin-free dialysis is performed, intradialytic blood entrapment can be problematic. To address this issue, we performed a randomized, double-blind, phase 2 study comparing AB023, a unique antibody that binds factor XI (FXI) and blocks its activation by activated FXII, but not by thrombin, to placebo in 24 patients with ESRD undergoing heparin-free hemodialysis. Patients were randomized to receive a single predialysis dose of AB023 (0.25 or 0.5 mg/kg) or placebo in a 2:1 ratio, and safety and preliminary efficacy were compared with placebo and observations made prior to dosing within each treatment arm. AB023 administration was not associated with impaired hemostasis or other drug-related adverse events. Occlusive events requiring hemodialysis circuit exchange were less frequent and levels of thrombin-antithrombin complexes and C-reactive protein were lower after AB023 administration compared with data collected prior to dosing. AB023 also reduced potassium and iron entrapment in the dialyzers, consistent with less blood accumulation within the dialyzers. We conclude that despite the small sample size, inhibition of contact activation-induced coagulation with AB023 was well tolerated and reduced clotting within the dialyzer. This trial was registered at www.clinicaltrials.gov as #NCT03612856.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Enrollment, randomization, populations for analysis, and study timeline in the AB023 phase 2 clinical trial. Thirty-seven patients were screened for study eligibility. Ten patients did not meet inclusion/exclusion criteria and were not enrolled in the study. An additional 3 patients terminated the study early, prior to randomization on study day 1. Twenty-four patients were randomized and all 24 patients completed the study. All randomized patients were confined to the clinic from study day −8 to study day 6, after which they returned to the clinic on study days 8, 10, and 12 to continue heparin-free hemodialysis. Predose hemodialysis occurred on study days −7, −5, and −3. Dosing occurred on study day 1, and postdosing hemodialysis occurred on study days 1, 3, 5, 8, 10, and 12. The red diamonds represent hemodialysis days in which data were collected, and the blue diamonds represent heparin-free hemodialysis sessions that were performed in the clinic, but no data were collected. Cohorts were dosed sequentially, starting with cohort 1 (0.25 mg/kg or matching placebo). Once cohort 1 was completed, dosing for cohort 2 began (0.5 mg/kg or matching placebo). Placebo from both cohorts were pooled together for analysis. All 24 patients randomized were included in the safety and efficacy analyses. Two patients from the 0.25 mg/kg group were excluded from the PK analysis; 1 patient was excluded because the percent of AUC0-inf extrapolated (AUC%extrap) was very high (63%) and therefore did not meet the prespecified criteria for inclusion of the PK analyses, and 1 patient was excluded from the summary statistics because the 0.17-hour AB023 concentration was an outlier. AEs, adverse events; SAE, serious adverse event.

Figure 2.

Visual scores, dialyzer circuit change outs, saline flush events, and blood clot markers in the treatment arms. (A) The percent of severe clotting events (as defined as a visual score of ≥3) in each group (placebo, red bars; 0.25 mg/kg, blue bars; and 0.5 mg/kg, light green bars) within the hemodialysis cartridge. Predose data combine all predose hemodialysis days (study days −7, −5, and −3). (B) The bars represent the percent of occlusive events requiring change out of the hemodialysis circuit postdose (study days 1, 3, and 5 combined) compared with predose (study days −7, −5, and −3 combined). (C) Likewise, the bars represent the percent of hemodialysis circuit saline flushes required to maintain circuit patency postdose (study days 1, 3, and 5 combined) compared with predose (study days −7, −5, and −3 combined). (D-E) AB023 significantly reduces blood clot markers within the hemodialysis cartridge. AB023 (0.5 mg/kg) significantly reduced potassium (D) and iron (E) retained within the hemodialysis cartridge due to blood clotting on study day 1 compared with placebo. (F) AB023 may limit systemic increases in TAT after hemodialysis sessions. Predose samples were averaged, and shown is the percentage of predose potassium, iron, and TAT concentrations. n = 8 for placebo, n = 7 for 0.25 mg/kg, and 0.5 mg/kg potassium and iron groups (dialyzers were damaged upon receipt). Data represent mean ± SEM. *P < .05.

Figure 3.

AB023 blunts dialysis associated plasma CRP generation. Time course of plasma CRP on study day 1 predose through 48 hours postdose expressed as the percentage of control of baseline (predose) in the placebo group (red circles), the 0.25 mg/kg group (blue circles), and the 0.5 mg/kg group (light green circles). CRP induction at 24 hours postdose is significantly blunted in the 0.5 mg/kg group compared with placebo. Data are mean ± SEM. *P < .05 for the 0.5 mg/kg group compared with placebo.

Figure 4.

PD and PK parameters from all subjects from the AB023 phase 2 clinical trial. Two cohorts were administered a single dose of AB023 (cohort 1, 0.25 mg/kg [n = 8, blue circles]; cohort 2, 0.5 mg/kg [n = 8, light green circles]) or placebo (all placebo-dosed subjects from both cohorts are grouped together [n = 8, red circles]). (A) aPTT for all groups from study day 1 predose (represented as 0 hours on the x-axis) until the end of the trial in hours. Arrowheads show study days where hemodialysis took place. (B) The aPTT data from panel A are expanded to show the first 24 hours postdose on study day 1 so that the data from the early postdose time points can be more clearly seen. (C) PT time from all subjects predose (study days −7, −5, and −3) and postdose (study days 1, 3, 5, and 12). There was no statistical difference in PT found in any cohort compared with placebo. (D) Mean AB023 plasma concentrations after a single IV dose. Plasma concentration of AB023 from both cohorts after a single injection of AB023 (0.25 mg/kg, blue circles; 0.5 mg/kg, light green circles; n = 8 for each dose level). Data represent mean ± SEM.

Figure 4.

PD and PK parameters from all subjects from the AB023 phase 2 clinical trial. Two cohorts were administered a single dose of AB023 (cohort 1, 0.25 mg/kg [n = 8, blue circles]; cohort 2, 0.5 mg/kg [n = 8, light green circles]) or placebo (all placebo-dosed subjects from both cohorts are grouped together [n = 8, red circles]). (A) aPTT for all groups from study day 1 predose (represented as 0 hours on the x-axis) until the end of the trial in hours. Arrowheads show study days where hemodialysis took place. (B) The aPTT data from panel A are expanded to show the first 24 hours postdose on study day 1 so that the data from the early postdose time points can be more clearly seen. (C) PT time from all subjects predose (study days −7, −5, and −3) and postdose (study days 1, 3, 5, and 12). There was no statistical difference in PT found in any cohort compared with placebo. (D) Mean AB023 plasma concentrations after a single IV dose. Plasma concentration of AB023 from both cohorts after a single injection of AB023 (0.25 mg/kg, blue circles; 0.5 mg/kg, light green circles; n = 8 for each dose level). Data represent mean ± SEM.