Contact Activation Inhibitor and Factor XI Antibody, AB023, Produces Safe, Dose-Dependent Anticoagulation in a Phase 1 First-In-Human Trial

Abstract

Objective- Factor XI (FXI) contributes to thrombotic disease while playing a limited role in normal hemostasis. We generated a unique, humanized anti-FXI antibody, AB023, which blocks factor XIIa-mediated FXI activation without inhibiting FXI activation by thrombin or the procoagulant function of FXIa. We sought to confirm the antithrombotic activity of AB023 in a baboon thrombosis model and to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adult subjects. Approach and Results- In a primate model of acute vascular graft thrombosis, AB023 reduced platelet and fibrin accumulation within the grafts by >75%. To evaluate the safety of AB023, we performed a first-in-human study in healthy adult volunteers without any serious adverse events. Overall, 10 of 21 (48%) subjects experienced 20 treatment-emergent adverse events, with 7 of 16 (44%) subjects following active treatment and 3 of 5 (60%) subjects following placebo. AB023 did not increase bleeding or prothrombin times. Anticoagulation was verified by a saturable ≈2-fold prolongation of the partial thromboplastin time for over 1 month after the highest dose. Conclusions- AB023, which inhibits contact activation-initiated blood coagulation in vitro and experimental thrombus formation in primates, produced a dose-dependent duration of limited anticoagulation without drug-related adverse effects in a phase 1 trial. When put in context with earlier observations suggesting that FXI contributes to venous thromboembolism and cardiovascular disease, although contributing minimally to hemostasis, our data further justify clinical evaluation of AB023 in conditions where contact-initiated FXI activation is suspected to have a pathogenic role. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03097341.

Keywords: factor XI; factor XII; hemostasis; thrombosis.

Conflict of interest statement

Disclosures

A. Gruber, C. U. Lorentz, E. I. Tucker, N. G. Verbout, and M. Wallisch are employees of Aronora, Inc., and they as well as OHSU may have a financial interest in the results of this study. J.J. Shatzel serves as a medical consultant for Aronora, Inc.

Figures

Figure 1:. Binding properties of AB023.

(A) Western blots of non-reducing 10% polyacrylamide gel of human FXI (lane 1) and human FXI in which the A1, A2, A3, or A4 domain has been replaced with the corresponding domain from prekallikrein (PK). (B) Western blots of non-reducing 10% polyacrylamide gel of individual human FXI apple domains (A1-A4) linked to recombinant tPA. AB023 recognizes the A2 domain of human FXI. (C) Binding of AB023 to human FXI (closed circles), human FXIa (open square). (D) AB023 concentration-dependently inhibits FXIIa activation of FXI. (E) AB023 does not prevent activation of FXI by thrombin. (F) AB023 prolongs the aPTT in a concentration dependent manner in plasma from human (black circles), baboons (open squares), cynomolgus monkeys (open circles) and rats (open diamonds). *The FXI/PKA4 chimeric protein (A4*) is a dimeric molecule created by replacing Cys326 with alanine in PK A4 domain.

Figure 2:. AB023 reduces platelet-rich thrombus growth in a primate thrombosis model.

Effect of AB023 (1.0 mg/kg, IV) on platelet (A-C) deposition on (A) collagen-coated (4 mm diameter, 2 cm long) vascular grafts and (B) 10 cm downstream of the collagen-coated graft (“tail”). (C) Platelet deposition in both the graft + tail combined. (D-F) Fibrin deposition within the collagen graft (D), tail (E) and graft + tail combined (F) in control treated (black bar) and after AB023 treatment. Values are mean ± SEM, n = 4 experiments/ group in 4 animals. *p

Figure 3:. Dose escalation schedule for the AB023 first-in human phase 1 clinical trial.

Each cohort was dosed sequentially. Once subjects were screened and met eligibility criteria, they were randomized to receive either AB023 or placebo at a 4:1 ratio, except for cohort 1 where the AB023: placebo ratio was 4:2 to accommodate 2 sentinel subjects (1 active and 1 placebo). Before dose escalation to the next dose, all safety data was collected from each subject through Day 28 and reviewed by a safety review committee during a dose escalation safety review meeting.

Figure 4:. Coagulation parameters from all subjects from the AB023 phase 1, single ascending dose, randomized, placebo-controlled trial.

Four cohorts were administered a single dose of AB023 (cohort 1: 0.1 mg/kg, red squares, cohort 2: 0.5 mg/kg, blue triangles, cohort 3: 2.0 mg/kg, green inverted triangles, and cohort 4: 5.0 mg/kg, orange diamonds, n = 4 for each dose level) or placebo (all placebo-dosed subjects are grouped together (n = 5, black circles). (A) BT data from all subjects post AB023 or placebo administration. For each cohort, results from both left and right arms and 1h and 24h post-dose are combined. There was no statistical difference in BT found in any cohort compared to placebo. (B) PT time from all subjects pre- and post-dose. There was no statistical difference in PT found in any cohort compared to placebo. (C) aPTT of cohorts 1–4 for the duration of the phase 1 clinical trial in days (d) and (D) aPTT data from the first 120 hours (h) post-dose. Data represents mean ± SEM. Numbers in parentheses indicate the number of subjects at that time point. *blood sample taken within 24h of time point indicated. **blood sample taken within 48h of time point indicated.

Figure 5:. Mean AB023 plasma concentrations after a single IV dose.

Plasma concentration of AB023 from all cohorts after a single injection of AB023 (cohort 1: 0.1 mg/kg, red squares, cohort 2: 0.5 mg/kg, blue triangles, cohort 3: 2.0 mg/kg, green inverted triangles, and cohort 4: 5.0 mg/kg, orange diamonds, n = 4 for each dose level. Data represents mean ± SEM.