Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects With Coronary Artery Disease

Gurbel PA, Bliden KP, Turner SE, et al.,
Arterioscler Thromb Vasc Biol. 2016 Jan;36(1):189-97. doi: 10.1161/ATVBAHA.115.306777

A novel type of antiplatelet agent provided rapid, specific, dose-dependent and reversible inhibition of platelet protease-activated receptor-1 (PAR1) in subjects with coronary artery disease or multiple coronary artery disease risk factors. The agent tested is PZ-128, a pepducin: a lipidated peptide. Pepducins specifically target the cytoplasmic surface of their cognate receptor and can act as antagonists. PZ-128 is a cell-penetrating lipopeptide pepducin that selectively inhibits PAR1-G protein signalling on the inner leaflet of the lipid bilayer. PZ-128 is being developed for prevention of acute thrombotic complications when acute coronary syndrome (ACS) patients are undergoing percutaneous coronary intervention (PCI).

PAR1 or PAR4 inhibition is being evaluated as a strategy to target thrombin-induced platelet activation; vorapaxar and atopaxar are oral PAR1 inhibitors that were associated with a reduction in ischemic event occurrence without an increase in major bleeding in phase 2 studies. However, in the TRACER trial, acute and then chronic administration of vorapaxar was not associated with reduced events, but instead increased major bleeding and intracranial haemorrhage. It is postulated that the bleeding may be reduced when inducing reversible inhibition of PAR1 signalling by a parenteral strategy, in high-risk patients undergoing PCI.

In this study, 31 subjects received 1 to 2 hours continuous intravenous infusion (0.01-2 mg/kg).
- PZ-128 rapidly and dose-dependently inhibited PAR1 platelet aggregation with moderate to high levels of platelet inhibition stimulated by 8 µmol/L SFLLRN observed with doses > 0.5-mg/kg.
- The platelet inhibitory effects of PZ-128 were sustained for at least 6 hours after the start of infusion, and reversible.
- Platelet inhibition with PZ-128 was specific for the PAR1 receptor, as aggregation stimulated by a PAR4 agonist, AD or collagen was not significantly affected.
- The antiplatelet effect of PZ-128 was higher in subjects who concomitantly received aspirin.
- Pharmacokinetic analyses revealed a plasma half-life of 1.3 to 1.8 hours. Little or no PZ-128 was detected in urine in all subjects at any time point.
- PZ-128 had no significant effects on coagulation, haemostasis parameters of bleeding, at any dose. Nor did it affect clinical chemistry and ECG parameters.
- PZ-128 was well-tolerated up to doses of 0.3-mg/kg with a 1-hour infusion. At higher doses, transient adverse events, e.g. tingling or a numb sensation in the skin, were noted and resolved by 24 hours.
Acute allergic reactions occurred at the highest doses of PZ-128. In a cohort receiving 0.5-mg/kg via a 2-hour instead of 1-hour infusion, along with antiallergic premedication, none of the subjects experienced an allergic response.

Thus, fast-acting parenteral PAR1 blockade via PZ-128 may represent a promising novel antiplatelet agent. The 0.5-mg/kg dose of PZ-128 infused >2 hours will be further evaluated in an upcoming multicentre phase 2 study in PCI/ACS patients.

Find the article online at Arterioscler Thromb Vasc Biol