OC 65.3 - A Phase 2 Trial Evaluating the Safety and Antithrombotic Efficacy of AB002, a First-in-class Protein C Activator in End-stage Renal Disease Patients on Heparin-free Hemodialysis

Background: AB002 is a protein C activator enzyme under clinical investigation to safely prevent and treat thrombosis. In animal models, AB002 has potent antithrombotic and anti-inflammatory activity without measurable bleeding side-effects. This phase 2, randomized, double-blind, placebo-controlled trial in end-stage renal disease (ESRD) patients undergoing hemodialysis is the first to clinically assess the safety and efficacy of therapeutic protein C activation.

Aims: ESRD patients are at increased risk of both clotting and bleeding, thus we sought to evaluate the safety and efficacy of AB002 as a short-acting antithrombotic to safely prevent clotting in the extracorporeal circuit during hemodialysis.

Methods: In this single-site study, 36 ESRD patients undergoing heparin-free hemodialysis received a single dose of placebo or AB002 (1.5 µg/kg or 3.0 µg/kg) (NCT03963895). Patients underwent five heparin-free sessions over 10 days and were dosed on the fourth session. The primary endpoint was safety and tolerability and the secondary endpoints were clotting severity in the dialysis circuit and pharmacodynamics. The study was approved by the local ethics review board and all patients provided informed consent.

Results: AB002 demonstrated a favorable safety profile, with no treatment-related adverse events. Clinically relevant bleeding did not occur in any patient, and AB002 did not affect time to hemostasis at the vascular access site. Drug exposure was confirmed by a transient, dose-dependent elevation of APC-PCI. Compared to placebo and pre-treatment sessions, clotting severity in the dialysis circuit was significantly reduced in patients receiving AB002. The frequency of thrombo-occlusive events requiring circuit changeout was 13.9% (21/155) on days in which AB002 was not administered, compared to 0% (0/12) and 8.3% (1/12) at the 1.5 µg/kg and 3.0 µg/kg dose levels, respectively. AB002 also reduced dialysis-induced thrombin-antithrombin generation by up to 75%.

Conclusion(s): Results from this trial support further investigation of AB002 to safely prevent and treat thrombosis in at-risk populations. NIH R44HL147695.