A Genetic Driven Strategy
With a precision medicine approach, in post-acute coronary syndrome (ACS) dalcetrapib could reduce the risk of cardiovascular events in patients carrying the ADCY9 rs1967309 AA genotype.
Highly consistent, robust preclinical and clinical data, on cardiovascular events, atherosclerosis as well as biomarkers of cholesterol functions and inflammation support the potential clinical benefit of dalcetrapib treatment in these patients.
Atherosclerosis is a major contributor to CVD. The dal-PLAQUE-2 trial, a prospective Phase 3 clinical study evaluated the effect of dalcetrapib on atherosclerosis disease progression in patients with evidence of coronary artery disease (CAD). A post-hoc analysis of the trial results found a reduction in atherosclerosis in patients with some ADCY9 SNPs, as demonstrated by the reduction of the intima-media thickness (IMT) measured by ultrasonography. This reduction in atherosclerosis was achieved on top of best standard of care and was comparable in magnitude to that reported with statins treatment.
Increased HDL cholesterol efflux has been associated with reduction of cardiovascular events. A post-hoc analysis of the dal-PLAQUE-2 trial results demonstrated allele-specific reduction in cholesterol efflux, with a 22% increase in cholesterol efflux in patients with the ADCY9 rs1967309 AA genotype treated with dalcetrapib.
High sensitivity C-reactive protein (hs-CRP) is a known marker of inflammation and a potential risk factor for CVD. CETP inhibitors have been shown to increase hs-CRP levels in the broad patient populations by 10-15%. A recent publication describes hs-CRP levels measured in 5,243 patients from the dal-OUTCOMES clinical trial. Results demonstrated that patients with the ADCY9 rs1967309 AA genotype did not show significant increase in hs-CRP levels after treatment with dalcetrapib whereas patients with AG and GG genotypes showed increased hs-CRP with dalcetrapib treatment, as compared to placebo.