Safety, Tolerability, and Pharmacodynamics of AZD3366 (Optimized Human CD39L3 Apyrase) Alone and in Combination With Ticagrelor and Acetylsalicylic Acid: A Phase 1, Randomized, Placebo-Controlled Study

• Published in: Journal of the American Heart Association 2024-06, Vol.13 (11), p.e033985
• Main Authors: Kardassis, Dimitris, Egnell, Ann-Charlotte, Åstrand, Magnus, Daniels, Samuel J, Whatling, Carl, Fjellström, Ola, Gabrielsen, Anders
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate; Adult; Apyrase - administration & dosage; Apyrase - metabolism; Aspirin - administration & dosage; Aspirin - adverse effects; Aspirin - pharmacokinetics; Blood Platelets - drug effects; Blood Platelets - metabolism; cardiovascular disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Dual Anti-Platelet Therapy; Female; human recombinant apyrase; Humans; Male; Middle Aged; Original Research; phase 1; platelet activation; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - adverse effects; Platelet Aggregation Inhibitors - pharmacokinetics; Purinergic P2Y Receptor Antagonists - administration & dosage; Purinergic P2Y Receptor Antagonists - adverse effects; Purinergic P2Y Receptor Antagonists - pharmacokinetics; Purinergic P2Y Receptor Antagonists - pharmacology; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacokinetics; safety; Ticagrelor - administration & dosage; Ticagrelor - adverse effects; Ticagrelor - pharmacokinetics; Treatment Outcome; Young Adult
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.123.033985

ADP and ATP are importantly involved in vascular and thrombotic homeostasis, via multiple receptor pathways. Blockade of ADP P2Y receptors inhibits platelet aggregation and represents an effective cardiovascular disease prevention strategy. AZD3366 (APT102), a long-acting recombinant form of an optimized CD39L3 human apyrase, has effectively reduced ATP, ADP, and platelet aggregation and provided tissue protection in preclinical models, features that could be very beneficial in treating patients with cardiovascular disease. We conducted this phase 1, first-in-human study of single ascending doses of intravenous AZD3366 or placebo, including doses added to dual antiplatelet therapy with ticagrelor and acetylsalicylic acid. The primary objective was safety and tolerability; secondary and exploratory objectives included pharmacokinetics, pharmacodynamics (measured as inhibition of platelet aggregation), adenosine diphosphatase (ADPase) activity, and ATP/ADP metabolism. In total, 104 participants were randomized. AZD3366 was generally well tolerated, with no major safety concerns observed. ADPase activity increased in a dose-dependent manner with a strong correlation to AZD3366 exposure. Inhibition of ADP-stimulated platelet aggregation was immediate, substantial, and durable. In addition, there was a prompt decrease in systemic ATP concentration and an increase in adenosine monophosphate concentrations, whereas ADP concentration appeared generally unaltered. At higher doses, there was a prolongation of capillary bleeding time without detectable changes in the ex vivo thromboelastometric parameters. AZD3366 was well tolerated in healthy participants and demonstrated substantial and durable inhibition of platelet aggregation after single dosing. Higher doses prolonged capillary bleeding time without detectable changes in ex vivo thromboelastometric parameters. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04588727.