BET inhibitor therapy did not meet primary endpoint of reducing MACE in post-ACS patients with T2DM
Effect of BET Protein Inhibition With Apabetalone on Cardiovascular Outcomes in Patients With Acute Coronary Syndrome and Diabetes - Results of the BETonMACE Trial
Presented during the AHA Scientific Sessions 2019 by Kausik K Ray (Imperial Coll London, London, United Kingdom).
Introduction and methods
Evidence suggests that BET protein inhibition with apabetalone may favorably impact pathways implicated in CV and kidney disease. Moreover, phase 2 trials suggest a potential benefit with apabetalone treatment, as lower MACE has been observed compared to placebo (HR: 0.56, p=0.02), also in patients with diabetes (HR: 0.43, P=0.02).
BETonMACE further explored the effect of apabetalone on MACE. Patients with type 2 diabetes (T2DM, HbA1c >6.5% of with a history of diabetes medication), an acute coronary syndrome (ACS) 7-90 days prior to screening and with low HDL-c (<40 mg/dL for males, or <45 mg/dL for females) were included. The primary endpoint was time to first occurrence of CV death or non-fatal MI or stroke. During the screening period, 2425 patients were subjected to a statin run-in period in which they received 40-80 mg atorvastatin or 20-40 rosuvastatin for 1-2 weeks. After that, patients were randomized to apabetalone 100 mg b.i.d. plus standard of care (SOC) or to matching placebo plus SOC. The treatment period lasted until 250 adjudicated primary events had occurred. After the end of treatment, there was a 3-5 weeks follow-up period. 89.8% Of patients in both treatment groups completed the trial. Time from index ACS to randomization was 38 days, and slightly less than 80% had PCI for the index ACS. Patients were very well treated, with about 90% receiving high-intensity statins, over 90% were on ACEi and beta-blockers and about 99% received antiplatelet agents and about 88% dual antiplatelet therapy.
- Baseline LDL-c was 69.7±29.8 mg/dL in the apabetalone group and 70.9±32.4 mg/dL in the placebo group. Apabetalone increased LDL-c by 11.5%, as compared with 14.9% with placebo (P=0.35).
- Baseline HDL-c was 33.3±5.1 mg/dL in the apabetalone group and 33.3±5.1 mg/dL in the placebo group. Apabetalone increased HDL-3 by 16.2% and placebo by 10.4% (P=0.001).
- The primary efficacy endpoint showed an HR of 0.82 (95%CI: 0.65-1.04, P=0.11) over a median follow-up of 26 months (12.4% vs. 10.3%).
- In a pre-specified sensitivity analysis excluding deaths of undetermined cause, the primary end point yielded an HR of 0.79 (95%CI: 0.62-1.01, P=0.06).
- Of key secondary endpoints, only first hospitalization for congestive HF was significantly reduced with apabetalone vs. placebo (HR: 0.59, 95%CI: 0.38-0.94). Point estimates of other key secondary endpoints were all non-significant but consistently in the direction of favouring apabetalone, except stroke.
- Subgroup analyses showed significant interactions with the treatment effect for LDL-c < or ≥median, with better treatment effect for those with LDL-c
- Liver function tests showed ALT >3xULN more often in the apabetalone group (6.4%) than in the placebo group (1.5%), and ALT >5x ULN was seen in 3.3% vs. 0.7%, respectively.
Apabetalone did not have a significant effect on incidence of CV death, non-fatal MI or stroke.
Favorable trends were observed for the primary endpoint and key components except stroke with a nominal difference in HF hospitalization
Apabetalone was generally well tolerated with an overall incidence of adverse events similar to that in the placebo group. However, discontinuation of treatment due to elevated liver function tests was more frequent with apabetalone.
An explanation for the non-significant results may lie in that the observed event rate in the placebo groups (9.7%) was somewhat lower than anticipated (10.5%) at 18 months, and that the study was powered to detect a 30% reduction in risk of the primary endpoint, and underpowered to detect a smaller difference in events.
As discussant Svati Shah (Duke University School of Medicine, Durham, NC) summed up what BETonMACE added to pre-existing insights on apabetalone. She considered possible reasons for the trial being negative: in addition to a lack of power and the possibility that the drug does not reduce MACE, she also mentioned pleiotropic effects and heterogeneity in background of revascularization. . The suggestion of an effect on HF hospitalization and in subgroups with lower LDL-c or lower eGFR may incite some optimism, but these signs are not clear enough to start using the drug in patients. Although these data may give rise to cautious optimism, first an adequately powered randomized clinical trial should be done.
- Our reporting is based on the information provided during AHA Scientific Sessions 2019 -