Phase III study of RVX 208 fails to meet endpoint in post-ACS diabetes.- Resverlogix

The first phase III study of RVX 208 (apabetalone), from Resverlogix, failed to meet its primary endpoint in a population of post-ACS patients with diabetes and low HDL cholesterol. But experts agreed that the agent still holds promise for other patient groups. In a meta-analysis of phase II studies, the agent reduced cardiovascular events over placebo, especially among patients with diabetes, low baseline HDL cholesterol, or elevated high-sensitivity C-reactive protein levels. The study included 2,425 patients with diabetes and low HDL cholesterol (less than 40 mg/dL for men and less than 45 mg/dL for women) who had an ACS event within 7-90 days of screening. Patients were recruited from 195 sites in 13 countries then randomized to receive standard of care plus apabetalone 100 mg twice daily (n = 1,212) or placebo (n = 1,206) until 250 adjudicated primary endpoint events (CV death, nonfatal stroke, or MI) occurred.

More than three-quarters of patients in each group received PCI for their index ACS, and the mean time from ACS event to randomization was 38 days. About 90% were previously on high-intensity statins, and more than 90% were on ACE inhibitors/angiotensin receptor blockers, beta-blockers, and antiplatelet agents. Mean baseline LDL-cholesterol levels were 69.7 and 70.9 mg/dL in the apabetalone and placebo groups, respectively.

Compared with the placebo group, patients taking apabetalone had a greater increase in HDL cholesterol (+16.2% vs +10.4%; P = 0.001), a decrease in estimated glomerular filtration rate (eGFR; -0.4 vs +2.1 ml/min/1.73m2; P = 0.03), and a decrease in alkaline phosphatase (-4.8 vs +2.2 U/L; P = 0.003) on follow-up. Over a median follow-up of 26 months, the rate of the primary endpoint was similar between the placebo and apabetalone groups (12.4% vs 10.3%; HR 0.82; 95% CI 0.65-1.04). This finding was similar in the prespecified sensitivity analysis, which excluded deaths of unknown origin (HR 0.79; 95% CI 0.62-1.01).