Apabetalone demonstrated tolerability and safety in the phase 3 BETonMACE trial but the study did not meet its primary end point of reduction in major adverse cardiovascular events (MACE).
Kausik K Ray, MD
Apabetalone demonstrated tolerability and safety in the phase 3 BETonMACE trial but the study did not meet its primary end point of reduction in major adverse cardiovascular events (MACE), investigators reported in a late-breaking session presented at American Heart Association (AHA) 2019 Scientific Sessions in Philadelphia.
An international, multi-center, randomized, double-blind, placebo-controlled trial, BETonMACE is the first study to explore whether epigenetic modulation with a selective bromodomain and extra-terminal (BET) protein inhibitor is safe and effective in reducing cardiovascular (CV) risk.
Apabetalone, a BET inhibitor that selectively targets bromodomain 2 (BD2) and exhibits favorable effects on transcription of a variety of atherothrombotic mediators, was compared with standard of care therapy in patients with type 2 diabetes mellitus (T2DM) and low HDL-C after an acute coronary syndrome (ACS).
The primary outcome of the study was time to CV death or non-fatal myocardial infarction (MI) or non-fatal stroke, with a secondary outcome of time to CV death or non-fatal MI or non-fatal stroke or unstable angina or emergency revascularization.
Inclusion criteria comprised patients with ACS in the preceding 7-90 days, T2DM, and HDL-C ≤40 mg/dl for men, ≤45 mg/dl for women. All study participants must receive intensive or maximum tolerated treatment with atorvastatin or rosuvatstatin.
The median age of participants was 62 years, 25% female sex, majority white race (87%). At baseline, MI was the index ACS event in 74% (STEMI 53%, NSTEMI 47%) of patients, with unstable angina constituting 26%. Patients had a median LDL-C 65 mg/dl, HDL-C 33 mg/dl, and HbA1c 7.3% at time of enrollment. The median follow-up was 26 months.
Enrolled between November 2015 and July 2018 at 195 sites across 13 countries, a total of 2425 patients were randomized to receive apabetalone 100 mg orally twice daily or matching placebo (1:1) on top of guideline-recommended standard of care including intensive or maximum-tolerated treatment with atorvastatin or rosuvastatin.
A total of 1212 patients received the study drug, while 1206 received matching placebo. The primary outcome for apabetalone compared with placebo was 10.3% vs. 12.4% (p = 0.11); the rate of cardiovascular death/MI was 9.2% vs 11.5% (p > 0.05); the rate of stroke was 1.4% vs 1.4% (p > 0.05); the all-cause mortality rate was 5.0% vs 5.7% (p > 0.05); the change in HDL-C from baseline at 100 weeks was 16.2% vs 10.4% (p = 0.001); and the change in LDL-C from baseline at 100 weeks 11.5% vs 14.9% (p = 0.35).
The rate of adverse events was similar across treatment groups, with 830 patients (68.5%) in the apabetalone arm and 820 (67.9%) in the placebo arm reporting at least 1 adverse event.
Apabetalone did not significantly reduce the primary endpoint of CV death, non-fatal MI, or stroke, but showed a favorable trend (18% difference in relative risk, which was not statistically significant), indicating that it may be a promising treatment option and suggesting that further studies are warranted.
Presenting author Kausik K Ray, MD, professor of public health at Imperial College London and director of the Imperial Centre for CVD Prevention, noted that the study was powered on a 30% reduction risk of primary end point, and was underpowered to detect smaller difference in events.
The study, “Effect of BET Protein Inhibition With Apabetalone on Cardiovascular Outcomes in Patients With Acute Coronary Syndrome and Diabetes - Results of the BETonMACE Trial,” was presented Saturday, November 16, 2019, at AHA 2019 in Philadelphia, Pennsylvania.