Key result
CG-0255 outperforms clopidogrel, achieving ~90% platelet inhibition with rapid onset.
Why the study?
Clopidogrel depends on CYP2C19 oxidation for activation, leading to resistance in patients with loss-of-function alleles, has a slow onset of action, and cannot be formulated for IV administration. CG-0255 is a novel carboxylesterase-activated prodrug designed to bypass CYP metabolism and overcome these limitations.
Does oral CG-0255 (2 to 10 mg) safely achieve rapid inhibition of platelet aggregation compared to clopidogrel 300 mg in healthy volunteers?
Does oral CG-0255 (2 to 10 mg) safely achieve rapid inhibition of platelet aggregation compared to clopidogrel 300 mg in healthy volunteers?
In a Phase I study of healthy volunteers, oral CG-0255 demonstrated rapid, dose-dependent platelet inhibition exceeding 90% within 30 minutes at the 10 mg dose while bypassing CYP2C19 metabolism.
Supports CG-0255 advancement to phase 2 patient trials; leaves open clinical efficacy versus clopidogrel in ACS or PCI.
Clopidogrel is an extremely widely used antiplatelet drug, but with serious shortcomings. It is a prodrug that depends critically on liver CYP oxidation enzyme CYP2C19 for activation to its active metabolite H4. However, large fractions of world population carry loss of function CYP2C19 alleles, ranging from a low ~21% in Latino to a strikingly high ~59% in east Asian population. Known as clopidogrel resistance, US FDA added a black box warning to clopidogrel label. Despite this issue, routine CYP2C19 screening for clopidogrel patients is not performed, putting many patients at risk. Clopidogrel is also slow to take effect and not amenable for IV formulation, limiting its clinical use in emergency. To overcome these issues, we have invented a novel antiplatelet drug CG-0255, which is the world’s first thioester prodrug with a new activation pathway. CG-0255 has been designed to require only abundantly present and widely distributed carboxylesterases for metabolizing to its active metabolite, which is identical to clopidogrel active metabolite H4 generated through CYP metabolism. Thus, CG-0255 completely bypasses the CYP metabolism and overcomes clopidogrel resistance. In addition, CG-0255 has a much faster onset of action and high solubility in water and has been formulated for both IV and oral administration. Here we report the results of an open label phase I study of CG-0255 oral tablets to assess safety, tolerability, pharmacodynamics (PK), and pharmacokinetics (PD: inhibition of platelet aggregation, IPA) in healthy volunteers. It was a single dose escalation study, 4 cohorts with 6 participants each given CG-0255 oral tablets at doses ranging from 2 to 10 mg. Clopidogrel was the positive control and given at 300 mg. Blood samples for PK/PD analysis were collected pre-dosing and at various time points post dosing. VerifyNow was used for IPA measurement. CG-0255 is generally safe and well tolerated. PK analysis shows fast and consistent conversion of CG-0255 to active metabolite H4. PD results indicate that CG-0255 IPA is dose-dependent, easily matching or surpassing that of clopidogrel 300 mg for all doses. At the highest 10 mg dose, CG-0255 IPA reaches over 90% in less than 30 minutes, well above that of clopidogrel. In addition, CG-0255 IPA shows minimum individual variations, and the antiplatelet effect is long lasting due to its irreversible binding to the P2Y12 receptor. These results are consistent with our earlier reported Phase I results for CG-0255 IV injection. In conclusion, CG-0255 is a novel, fast-acting and long-lasting antiplatelet drug. It shares identical metabolite H4 with clopidogrel but relies only on carboxylesterases for activation, overcoming the resistance and other issues associated CYP-based oxidation metabolism. As the only antiplatelet drug available for both IV and oral administrations, CG-0255 fills unmet medical needs and will greatly benefit patients and medical community.
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Wu et al. (2024) studied Healthy volunteers (antiplatelet therapy evaluation) (n=24). CG-0255 oral tablets vs. Clopidogrel 300 mg was evaluated on Safety, tolerability, pharmacokinetics (conversion to active metabolite H4), and pharmacodynamics (inhibition of platelet aggregation [IPA]). Oral CG-0255 (2–10 mg) was safe and produced dose-dependent platelet inhibition surpassing clopidogrel 300 mg, reaching >90% IPA in under 30 minutes at the 10 mg dose.
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