Apabetalone Falls Short in Diabetic ACS Patients With Low HDL: BETonMACE
The phase III trial failed to meet its primary endpoint, but some hold out hope for this new drug class in other populations.
PHILADELPHIA, PA—The first phase III study of a novel drug that inhibits the bromodomain extra-terminal (BET) protein pathway through epigenetic modification 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.
Apabetalone, manufactured by Resverlogix, belongs to a new class of compounds that binds with BET proteins to affect antithrombotic, anti-atherosclerotic, and anti-inflammatory pathways. 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,
While the drug did not significantly reduce the primary endpoint in this patient population, “we think this first, proof-of-concept trial really shows promise about epigenetic modification with apabetalone,” said Kausik Ray, MD (Imperial College, London, England), who presented the BETonMACE findings at the American Heart Association (AHA) 2019 Scientific Sessions. “Favorable trends were observed in all components of the primary endpoint, with the exception of stroke with a nominal difference in heart failure hospitalization,” he pointed out. “We feel that based on these results that further studies of this approach are probably warranted.”
For the study, Ray and colleagues included 2,425 patients with diabetes and low HDL cholesterol (< 40 mg/dL for men and < 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. At this time, “it's uncertain what the clinical significance of this is,” Ray said.
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).
Because of the lack of difference in the primary endpoint, Ray said that all other findings from the study should be “considered nominal, hypothesis-generating, or exploratory.” Still, there were consistent trends favoring apabetalone for all components of the primary endpoint other than stroke. With apabetalone, there was a nominally significant reduction in hospitalization for heart failure (HR 0.59; 95% CI 0.38-0.94). The results were consistent across subgroups, but those with low LDL cholesterol at baseline and a lower eGFR seemed to have an advantage with the study drug.
Adverse events occurred with similar frequency in the apabetalone arm compared with the placebo group (68.5% vs 67.9%), although adverse event discontinuations were more frequent with apabetalone (9.4% vs 5.7%). The rate of serious adverse events were “identical,” according to Ray, at 29.2% for the study drug and 28.1% for placebo.
“In summary, apabetalone did not significantly reduce the primary endpoint,” Ray concluded. “The observed event rate was slightly lower than what we had anticipated, . . . but importantly this study was calibrated for a 30% event reduction and was underpowered to detect these smaller differences in events. Apabetalone was generally well-tolerated with an overall incidence of adverse events similar to placebo, [although] discontinuation of treatment due to liver function was more frequent.”
Svati Shah, MD (Duke University School of Medicine, Durham, NC), who discussed the findings during the session, stressed that it was important to remember that the trial was negative overall. She agreed with Ray, however, that the study likely did not meet its primary endpoint because of low power.
“Other potential reasons for a negative trial are that the drug does not actually work on MACE, unintended pleiotropic events, or heterogeneity of the effects in the background of revascularization,” Shah suggested. “In prespecified secondary endpoints, apabetalone decreased heart failure hospitalization of an ongoing significant association, and while we have to view these results with caution, it's interesting to know that apabetalone has known effects on cardiac hypertrophy and cardiac fibrosis markers.”
The finding that apabetalone seemed to lower the rate of the primary endpoint events in patients with lower than median LDL cholesterol is perhaps “a surrogate for compliance or relatedly the LDL paradox,” she added. Patients with eGFR below the median also showed a beneficial effect of apabetalone, Shah noted, “and while again this has to be viewed with caution, there is biological plausibility,” for an effect in these patients.
“Given the large body of preclinical human studies as well as a suggestion of the effects on heart failure and subgroups and the concordance of nonsignificant effects across the secondary endpoints, there is cautious optimism for this drug,” said Shah. “While it's not ready for use in patients, I would say that these results suggest that an adequately powered clinical trial is needed.”
This trial should be larger and potentially focus on “higher-risk subgroups, such as patients with heart failure or patients with chronic kidney disease,” Shah advised.
Ray K. Effect of BET protein inhibition with apabetalone on cardiovascular outcomes in patients with acute coronary syndrome and diabetes: results of the BETonMACE trial. Presented at: AHA 2019. November 16, 2019. Philadelphia, PA.
- Ray reports receiving honoraria from Amgen, Sanofi, Regeneron, Esperion, Medicines Company, Boehringer Ingelheim, Novo Nordisk, Kowa, Resverlogix, Dr Reddys, Cipla, Algorithm, Zuelling Pharma, Silence Therapeutics, Cerenis, Lilly, Astra Zeneca, Bayer, Akcea, MSD, and Novartis; and research grants from Amgen, Sanofi, Regeneron, MSD, and Pfizer.
- Shah reports receiving research support from the National Heart, Lung, and Blood Institute, the American Heart Association, Bristol-Myers Squibb, and Project Baseline.