Abstract Body (Do not enter title and authors here): Evategrel (CG-0255) is world’s first thioether prodrug relying only on carboxylesterases for metabolizing to its active metabolite, which is identical to clopidogrel’s active metabolite H4 generated through CYP metabolism. Through a fast, consistent, and one-step hydrolytic bioactivation, evategrel was designed to overcome major issues of clopidogrel: resistance, relatively weak potency, slow onset of action, and lack of intravenous (IV) formulation for emergency settings. Evategrel is also the first P2Y12 inhibitor that can be formulated for both IV and oral administration.

US Phase I results were reported previously. These follow up pilot and bridging trials were carried out in healthy volunteers to further assess safety, pharmacokinetics (PK), and pharmacodynamics (PD: Inhibition of Platelet Aggregation, IPA, measured by VerifyNow). For the pilot IV study, evategrel was given by IV bolus on day 1, followed by switching to clopidogrel on either day 2 or 3, depending on evategrel doses. Clopidogrel treatment continued until day 7, cangrelor was used for comparison. For the oral study, a loading dose of 4 or 8 mg was given on day 1, followed by 0.5 or 1 mg maintenance dose from days 2 to 7. Clopidogrel and prasugrel were used for comparison. Bridging studies in China were dose escalation trials.

Evategrel is safe and well tolerated. PK analysis shows fast and consistent conversion to H4 with minimal interpersonal variation. PD results indicate that evategrel is potent with fast onset of action: ≤ 15 min for IV and ≤ 30 min for oral dosing. There is excellent IPA-dose linearity, ~100% IPA is achieved at highest doses while at lower 2 mg dose, evategrel’s IPA is ~40%, similar to that of 300 mg clopidogrel. Comparing with clopidogrel, the interpersonal variation of IPA is much smaller. No significant bleeding events were observed among 128 subjects given evategrel single or multiple doses, including 79 (62%) subjects whose maximal IPA is high, ranging from 80 – 100%.

In conclusion, data from all the trials indicate that evategrel indeed overcomes clopidogrel resistance and is highly potent with fast onset, excellent dose linearity, and no drug-drug interactions observed. No significant bleeding or other adverse events were observed. IV bolus is convenient for emergency and surgical settings. Orally evategrel’s IPA at very low doses matches or greatly surpasses that of clopidogrel. Evategrel fills unmet medical needs and will truly benefit patients.