Safety and Efficacy of the Contact Activation Inhibitor AB023 in Patients with End-Stage Renal Disease on Chronic Hemodialysis: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial
Bibliographic record
Abstract
Background: End stage renal disease (ESRD) patients on chronic hemodialysis (HD) repeatedly have their blood exposed to artificial surfaces within the hemodialysis circuit, which triggers contact system-initiated coagulation. Clot formation within the HD circuit results in blood loss, decreased HD efficiency, and device circuit failure. Heparin reduces circuit clotting but it is not tolerated by all patients. Mounting experimental data suggest that contact system inhibition is antithrombotic without significantly compromising hemostasis. AB023 is a unique recombinant anti-factor (F) XI antibody that interferes with the interactions of FXI and FXII without inhibiting FXI activation by thrombin or the activation of FIX by activated FXI. This study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of AB023 in patients with ESRD on chronic HD. Methods: In this phase 2, randomized, double-blind, placebo-controlled, single-administration study, AB023 (0.25 or 0.5 mg/kg) or placebo was injected into the HD circuit of 24 ESRD patients at the start of heparin-free HD (NCT03612856). All patients underwent three pre-dose HD procedures and four monitored post-dose HD sessions. In total, the study encompassed 168 individual HD sessions, 72 of which occurred pre-dose and 96 of which occurred post-dose. Safety parameters, including time to hemostasis at HD access site, prothrombin time, physical examinations, vital signs, electrocardiograms, clinical chemistry, immunogenicity and other adverse events (AEs), were recorded. Clotting within the hemodialyzer circuit was assessed using a visual clotting scale by investigators who were blinded to treatment. The frequency of circuit clot obstructions requiring dialyzer exchange was also recorded. Pharmacokinetic and pharmacodynamic parameters, including activated partial thromboplastin times, were also assessed. The study was approved by an ethics review board and all subjects provided written informed consent. Results: AB023 demonstrated a favorable safety profile in ESRD patients. No drug-related AEs were noted. Clinically relevant bleeding did not occur in any patient, and the time to hemostasis at the HD access site was unchanged after AB023 administration. As expected, the aPTT was prolonged after AB023 administration, reaching saturation at both dose levels (about 2-fold prolongation) immediately after dosing, and remaining prolonged for up to 9 days with the high dose. Compared with pretreatment, the frequency of occlusive events requiring circuit exchange decreased by 68% and 50% in subjects given the 0.25 and 0.5 mg/kg AB023 respectively, while the number of occlusive events was numerically unchanged in the placebo arm. Likewise, the number of saline flushes required to maintain circuit patency decreased by 44% and 85%, and the incidence of high-grade clotting in the hemodialyzer as assessed by visual scoring decreased by 15% and 43% on day 1, 8% and 35% by day 3, and 0% and 19% by day 5 in the 0.25 and 0.5 mg/kg cohorts, respectively. Conclusions: Anticoagulation with AB023 was well-tolerated and reduced clot formation within the HD circuit of ESRD patients. These findings suggest that inhibiting contact system activation could reduce medical device-initiated blood clot formation in patients. Disclosures Lorentz: Aronora, Inc.: Current Employment. Verbout:Aronora, Inc.: Current Employment. Shatzel:Aronora, Inc.: Consultancy. Wallisch:Aronora, Inc.: Current Employment. Markway:Aronora, Inc.: Current Employment. Tucker:Aronora, Inc.: Current Employment. Gruber:Aronora, Inc.: Current Employment, Current equity holder in private company.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".