During the American Heart Association 2019 meeting, Dr. Kosh Ray presented the results of the BETonMACE trial. Dr. Ray and his teams showed apabetalone, a BET protein inhibitor was safe and well-tolerated and could potentially be used to reduce the risk of major adverse cardiovascular events (MACE).
Apabetalone, a bromodomain and extra terminal protein inhibitor (BET) that exerts its effect by methylating DNA, has been demonstrated to potentially have a cardiovascular benefit. However, this conclusion was based on aggregate data from multiple trials. The investigators wanted to conduct a trial to determine whether apabetalone could reduce the incidence of MACE. The investigators enrolled patients with type 2 diabetes mellitus who had a history of acute coronary syndrome 7-90 days prior to the screening visit and a low HDL cholesterol. Patients who were planned to have further revascularization procedures, have or had severe heart failure, have severe renal impairment or evidence of liver cirrhosis or abnormal liver function tests were excluded. The primary endpoint of this study was a composite of cardiovascular death, non-fatal myocardial infarction (MI) or stroke. Patients were first enrolled in a screening period where they were treated with atorvastatin (40-80mg) or rosuvastatin (20-40mg) for 1-2 weeks. Once the screening period was completed, patients were randomized in a 1:1 ratio to either apabetalone (100mg twice daily) or placebo. Patients were followed for a median of 26 months.
Of the 2,425 patients enrolled in the study, 1,212 were randomized to apabetalone and 1,206 were randomized to placebo. In both arms, 89.8% of the patients completed the study. Reasons for non-completion in both arms included the occurrence of an adverse event, withdrawal of consent, death or loss to follow up. The primary endpoint occurred in 12.4% of patients in the placebo group and 10.3% of patients in the apabetalone group (HR 0.82, 95% CI 0.65-1.04), p = 0.11). As part of the prespecified analysis, death from undetermined cause was excluded. While there was a signal that could indicate a potential benefit with Aapabetalone use, the results were not statistically significant (HR 0.79, 95% CI 0.62-1.01, p = 0.06). While the rate of adverse events was similar between the two groups, patients in the apabetalone group had a higher rate of abnormal transaminases and a higher rate of patients discontinued the drug due to abnormal liver function tests.
The study showed that apabetalone was generally safe and well-tolerated, albeit associated with an increased risk of abnormal liver function test. However, apabetalone did not have a significant effect on the incidence of MACE events. Although the results were not statistically significant, the study does provide a signal for efficacy that could potentially be studied in further trials.