American Heart Association
American Heart Association
November 18, 2019
4 min read

Apabetalone fails to benefit MACE, but ‘cautious optimism’ remains

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PHILADELPHIA — Among adults with recent ACS and type 2 diabetes, treatment with the BET inhibitor apabetalone for 26 months failed to show benefit on major adverse cardiac events compared with placebo, although researchers observed some favorable trends that warrant further study.

At 26 months, the primary endpoint of the BETonMACE trial — time to first occurrence of CV death, nonfatal MI or stroke — occurred in 10.3% of patients assigned apabetalone (Resverlogix Corp.) vs. 12.4% assigned placebo, for an HR of 0.82 (95% CI, 0.65-1.04). In a prespecified sensitivity analysis excluding deaths of unknown origin, the HR was 0.79 (95% CI, 0.62-1.01), Kausik K. Ray, MD, MPhil, from the Imperial Center for Cardiovascular Disease Prevention and Imperial College London, reported at the American Heart Association Scientific Sessions.

"Preclinical, mechanistic studies can suggest potential, but cannot determine is a treatment ultimately works, Ray told Healio. "An outcomes trial is required, and even if an outcomes trial is done, it does not tell you what the mechanism is. Based on strong biological plausibility and promising phase 2 data, this largest study of epigenetic medication in a high-risk population with coronary disease and diabetes show s the potential of this therapy to reduce CV events safely. The compelling signals for a large treatment effect suggest a trial of between 4,000 and 5,000 people with 400 to 500 events in a similar population would be adequately powered to test this approach in reducing CVD. A follow-up study is now needed."

Apabetalone is a first-in-class BET inhibitor that selectively targets bromodomain, resulting in favorable effects on transcription of a variety of atherothrombotic mediators. In a pooled analysis of phase 2 trials, apabetalone reduced the incidence of death or nonfatal CV outcomes compared with placebo, with more prominent benefits in participants with conditions associated with BET system activation, such as type 2 diabetes, high levels of C-reactive protein or low HDL.

“That gave us a scenario from which to design a cardiovascular outcomes trial,” Ray said during a presentation here.

The randomized, double-blind trial enrolled 2,425 adults with ACS in the preceding 7 to 90 days, type 2 diabetes and an HDL level less than 40 mg/dL for men and 45 mg/dL for women. MI was the index ACS event for 74% of participants (53% STEMI), with 26% experiencing unstable angina. Median age was 62 years, 25% of participants were women and 87% were white. Use of high-intensity statin treatment was 91% at study entry, with a median LDL of 65 mg/dL. Median HbA1c was 7.3%.

Participants were randomly assigned oral apabetalone 100 mg twice daily (n = 1,212) or placebo (n = 1,206) on top of guideline-recommended standard care, including intensive or maximum-tolerated treatment with atorvastatin or rosuvastatin. Median follow-up time was 26 months. The study continued until 250 primary endpoints had accrued, Ray said.

“We think this first proof-of-concept trial shows promise for epigenetic modification with apabetalone,” Ray said during a presentation. “There were favorable trends observed in all components of the primary endpoint, with the exception of stroke, with a nominal difference in heart failure hospitalization. We feel, based on these results, that further studies of this approach are probably warranted.”


Compared with placebo, participants in the apabetalone group experienced a greater increase in HDL (16.2% vs. 10.4%; P = .001), a decrease in estimated glomerular filtration rate (eGFR; median, –0.4 mL/min/1.73 m2 vs. 2.1 mL/min/1.73 m2) and a decrease in alkaline phosphatase (median, –4.8 U/L vs. 2.2 U/L; P = .003).

“There are no real biomarkers we can measure,” Ray said. “If we look at differences in biomarkers between apabetalone and placebo, HDL, eGFR and alkaline phosphatase were statistically different, but these [differences] were small, and it is uncertain what the clinical significance of this is.”

Ray said several hypothesis-generating findings across the key secondary endpoints deserve further study and show promising potential for the drug, including a lower incidence of first hospitalization for HF in the apabetalone arm vs. placebo (2.4% vs. 4%; HR = 0.59; 95% CI, 0.38-0.94).

Apabetalone was generally well tolerated with an overall incidence of adverse events similar to placebo, Ray said. However, discontinuation of treatment due to elevated liver function tests was more frequent with apabetalone.

Cautious optimism

Svati H. Shah, MD, MHS, associate director of clinical translation at the Duke Molecular Physiology Institute, said BETonMACE was likely a negative trial due to low statistical power, with an event rate in the placebo group that was lower than expected. The modeled effect size of 30% with apabetalone was not achieved in this study.

Shah said more research is needed beyond this first phase 3 trial.

“Given the large body of preclinical and human studies, as well as a suggestion of effects on HF in subgroups, and the concordance of nonsignificant effects across the secondary endpoints, there is cautious optimism for this drug,” Sha said. “While it is not ready for use in patients, I would say that these results suggest an adequately powered clinical trial is needed.” – by Regina Schaffer


Ray K, et al. Late Breaking Science I. Outside the Box: New Approaches to CVD Risk Reduction. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Disclosures: Ray reports he has received honoraria from Akcea, Algorithm, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cerenis, Cipla, Dr. Reddys, Eli Lilly, Esperion, Kowa, MSD, Novo Nordisk, Pfizer, Resverlogix, Sanofi, The Medicines Company and Zuelling Pharma. Shah reports she has received research support from Verily and is an investigator on an unlicensed patent of metabolite biomarkers of human heart failure, with the patent owned by Duke University.