Abstract 14971: Revacept (Dimeric GPVI-Fc) Does Not Alter Bleeding Time in Humans, but Effectively Inhibits Collagen-Induced Platelet Aggregation. Results of a Clinical Phase I Trial.
Background: GPVI-dependent blocking of vascular collagen sites is an attractive target for an activation-specific treatment of acute atherosclerotic diseases, such as myocardial infarction or stroke. The soluble dimeric GPVI-Fc fusion protein (PR-15, Revacept) has been shown to reduce platelet activation by blocking vascular collagen sites and to be safe in preclinical studies.
Objective: To assess safety, tolerability, pharmacokinetics, and pharmacodymamics of Revacept in a single center, open label, dose escalating phase I study with 5 dose levels.
Methods and Results: In a first in man study (Eudra CT 2005-004656-12, NCT 01042964), 30 healthy male subjects received a single IV administration of either 10 mg, 20 mg, 40 mg, 80 mg, or 160 mg Revacept. There were no relevant drug-related adverse events, no drug-related changes of laboratory parameters (biochemistry and haematology, coagulation parameters). There were no drug-related changes of blood pressures, nor pulse rates, nor of ECG parameters (including 24h holter monitoring). Bleeding times did not vary significantly between the groups, and even tended to decrease at higher doses of Revacept. No anti-Revacept antibodies occurred. The plasma concentration — time courses of each dosage of Revacept showed a narrow variation and a typical concentration- and time-dependence. Collagen-induced platelet aggregation was dose-dependently inhibited up to 48 hours at lower doses and for 7 days after higher dose levels. In contrast, ADP- or thrombin (TRAP)-dependent platelet aggregation remained unaltered.
Conclusions: This Phase I study demonstrated that Revacept is a safe and well tolerated new compound with a clear dose-dependent pharmacokinetic profile and a dose-related, highly specific pharmacodynamic action.
- © 2010 by American Heart Association, Inc.