Abstract: FR-PO0130
Safety, Tolerability, Pharmacokinetics, and Target Engagement of Single and Multiple Ascending Doses of Intravenous AZD4144, a Small Molecule NLRP3 Inhibitor for Treatment of AKI
Session Information
- AKI: Epidemiology and Clinical Trials
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 102 AKI: Clinical, Outcomes, and Trials
Authors
- Olson, Stephen W., Translational Science and Clinical Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States
- Pearce, Andy, Projects, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
- Schaffner, Hannah, Translational Science and Clinical Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States
- Varma, Vijayalakshmi, Translational Science and Clinical Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States
- Egeland, Erlend Johannessen, Clinical Pharmacology & Pharmacometrics, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Eketjäll, Susanna, DMPK, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- MacPhee, Iain, Late-Stage Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
Background
Acute kidney injury (AKI) is associated with progression to chronic kidney disease and increased mortality. Irrespective of etiology, AKI pathophysiology involves inflammation that persists despite resolution of the pathogenic insult. NLRP3 inflammasome-mediated cytokine activation (IL-1β, IL-18), pyroptosis, and NETosis contribute to cyclical maladaptive cellular repair in AKI. AZD4144 has demonstrated inhibition of IL-1β and IL-18 release and NETosis in vitro and preserved renal function in preclinical models of AKI. We assessed the safety, tolerability, pharmacokinetics and target engagement of AZD4144 in healthy participants following a single ascending dose (SAD) and multiple ascending doses (MAD).
Methods
This phase 1, single-blind, placebo-controlled study enrolled healthy participants. The study included three SAD and three MAD cohorts, consisting of low, medium and high dose groups. Each cohort received IV AZD4144 (N=6) or placebo (N=2). AZD4144 was infused over 1 hour on Day 1 in all cohorts, with repeated infusions on Days 4 to 12 in MAD cohorts. Target engagement was investigated in collected PBMCs stimulated ex vivo.
Results
24 participants in the SAD cohort and 23 participants in the MAD cohort completed the study. No significant adverse events, adverse events of severe intensity, QTc abnormalities, or new infections occurred. Hy’s Law criteria was not met in any case. The most common adverse event was infusion site reactions which were all mild and not attributed to AZD4144. Systemic AZD4144 plasma exposure (AUC and Cmax) increased in a dose-proportional manner after single and repeated dosing. With repeated dosing, AZD4144 did not display time-dependent change in pharmacokinetics. Half-life ranged from 18 to 22 hours, supporting once-daily dosing. AZD4144 demonstrated robust, dose-dependent, durable inhibition (>90%) of IL-1β and Il-18 production by PBMCs stimulated ex vivo.
Conclusion
AZD4144 was safe and well tolerated in healthy participants, had pharmacokinetics supporting once daily IV infusion, and displayed robust, dose-dependent inhibition of ex vivo stimulated IL-18 and IL-1b secretion.
Funding
- Commercial Support – AstraZeneca