PHILADELPHIA – The experimental antiplatelet drug compound CG-0255 demonstrated several advantages over clopidogrel and was well-tolerated by patients, according to new phase I trial results. Xiaowu Chen, PhD, of Shanghai CureGene Pharmaceutical Co. Ltd., presented these findings during a Featured Science session Sunday at the American Heart Association Scientific Sessions 2023. Shanghai CureGene is the developer of the drug. Is another antiplatelet drug really needed? Chen answered his own question by saying that orally administered clopidogrel, which is widely prescribed and has a reasonable safety profile, also has the problem of “clopidogrel resistance” in some patients. CYP2C19 is required to metabolize clopidogrel, but a substantial portion of the population has CYP2C19 loss of function, which leads to lower or no efficacy. The rates of CYP2C19 loss of function are approximately 21% in the Hispanic population, 29% in white subjects, 39% in Black people and 59% in East Asians. This led the U.S. Food and Drug Administration to require a black-box warning for clopidogrel, issued in 2010, saying that clinicians should “consider alternative treatment or treatment strategies in patients identified as CY2C19 poor metabolizers.” Chen added that other antiplatelets, such as orally administered ticagrelor and prasugrel and intravenously administered cangrelor, also have their various issues and limitations. This means new drugs are needed to fill the void in some patients to provide more consistent platelet inhibition and a better balance between efficacy and safety, specifically bleeding. Chen said CG-0255 is the world’s first non-disulfide thiol prodrug designed for both intravenous and oral dosing. The experimental compound was designed to rely on esterases to be metabolized to its active metabolite, H4, which is an irreversible P2Y12 receptor inhibitor, to overcome resistance and avoid the need for genotyping. It was also designed to have a rapid onset and does not metabolism in any CYPs, meaning there should be a low potential for drug-drug interaction (DDI), and to be taken in low doses. The phase I trial is an open-label, single-ascending-dose study to assess the drug’s safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). The primary outcome was inhibition of platelet aggregation. The trial enrolled five cohorts of six healthy subjects each at a center in Los Angeles. Half of the participants are white, one-third are Black, 13.3% are Asian and 3.3% are biracial. The reference drug is cangrelor. CG-0255 was found to be well-tolerated, with no drug-related adverse effects observed. The drug quickly converted to H4, in a matter of minutes. The drug was also found to be “highly potent,” with a >90% inhibition of platelet aggregation, a fast onset of action (approximately 15 minutes), and irreversible P2Y12 inhibition with minimal inter-individual variability. The trial showed that both CG-0255 and cangrelor have rapid onset of action and maximal platelet inhibition. Cangrelor showed a rapid loss of effect after the infusion was stopped, transition to oral antiplatelet drugs was difficult because of DDI, and it required both a bolus and infusion. CG-0255, meanwhile, has a long-lasting effect, a “straightforward” transition to oral antiplatelet drugs, and only a bolus was required, Chen said. Chen said the design goals of CG-0255 were “fully realized” by “overcoming major clopidogrel issues” while likely retaining clopidogrel’s safety profile. The phase I trial is ongoing, and FDA has granted a “special pathway” toward approval, Chen said. The agency has agreed that if CG-0255 demonstrates bioequivalence to cangrelor (intravenous) or clopidogrel (oral), using platelet inhibition as the biomarker, no large-scale phase III efficacy trial would be required. Chen said the U.S. pivotal trials for both the intravenous and oral forms of CG-0255 are expected to be complete in 2024, and approval could come by 2026. “CG-0255 is a potentially best-in-class novel antiplatelet drug,” he said, noting its “breakthrough prodrug design” and several advantages over clopidogrel. Photo Credit: Jason Wermers/CRTonline.org Photo Caption: Xiaowu Chen, PhD, presents phase I trial results of the experimental antiplatelet compound CG-0255 during a Featured Science session Sunday at the American Heart Association Scientific Sessions in Philadelphia.