BETonMACE Clinical Trial Details

Using BET protein inhibition to prevent MACE

Trial Summarized By: Pradyumna Agasthi, MD | Reviewed/Approved by: Larry Allen, MD, MHS

Effect of BET Protein Inhibition With Apabetalone on Cardiovascular Outcomes in Patients With Acute Coronary Syndrome and Diabetes

The goal of BETonMACE was to examine whether treatment with apabetalone compared to standard of care therapies improves CV outcomes in patients with T2DM and low HDL-C after an acute coronary syndrome (ACS).

Key Findings

In patients with ACS, DM, and low HDL-C, apabetalone, a selective BET protein inhibitor, did not significantly improve CV outcomes. CV outcomes trend was favorable.

Commentary

BETonMACE with P.I. Kausik Ray

Kausik Ray, MD, FAHA explains whether treatment with apabetalone compared to standard of care therapies improves CV outcomes in patients with T2DM and low HDL-C after an acute coronary syndrome (ACS). DR. Ray is a deputy director of Imperial College London's Clinical Trials Unit.

Commentary: BETonMACE with Svati Shah

Svati Shah, MD, MHS comments on the results of BETonMACE, which were presented during Scientific Sessions 2019. Dr. Shah was a discussant during the trial's presentation, and is also Associate Director of Clinical Translation at Duke Molecular Physiology Institute.

Purpose: To determine if BET inhibition will increase the time to MACE in high-risk patients with recent ACS, T2DM and low HDL-C.

Trial Design: Phase 3; n=2425; multi-center (185 sites, 13 countries), double-blinded, placebo-controlled trial. High-risk patients with ACS, T2DM and low HDL-C were randomized to high-intensity statin therapy (atorvastatin or rosuvastatin) + BET inhibitor (100 mg. orally twice a day) or high-intensity statin therapy + placebo. Average or 26.5 months follow-up.

Primary Endpoints: Time to MACE (CV death, non-fatal MI, or stroke).

Results: Reduction in MACE with BET inhibition in this patient population did not reduce the primary endpoint significantly.

  high-intensity statin + BET inhibitor high-intensity statin + placebo
Primary endpoint MACE 125 events
10.3%		 149 events 12.4%
Primary endpoint MACE sensitivity analysis HR 0.82, p=0.11
HR 0.79, p=0.06

Detailed Results

Trial summarized by Pradyumna Agasthi, MD

Clinical Question: The goal of BETonMACE was to examine whether treatment with apabetalone compared to standard of care therapies improves CV outcomes in patients with T2DM and low HDL-C after an acute coronary syndrome (ACS).

Key Findings: Apabetalone did not have a significant effect on the incidence of the primary composite endpoint (CV death, non-fatal MI or stroke) [HR 0.82 (95% CI 0.65 vs 1.04); p=0.11]. In secondary analyses, the rate of hospitalization for congestive heart failure was lower in the treatment group [HR 0.59 (95% CI 0.38 – 0.94)]

Impression: Apabetalone does not decrease CV death/non-fatal MI/stroke compared to placebo in diabetic patients with recent ACS.

Background: Bromodomain and extra-terminal (BET) proteins are epigenetic transcription modulators of inflammation, thrombogenesis, and lipoprotein metabolism that contribute to atherothrombosis. BET inhibitors are small molecule epigenetic regulators of chromatin structure and gene expression with therapeutic potential in atherosclerosis. Apabetalone is the first in class BET inhibitor that selectively targets bromodomain 2 (BD2), resulting in favorable effects on transcription of a variety of atherothrombotic mediators (1, 2, 3). A pooled analysis of phase 2 trials showed that apabetalone reduced the incidence of death or non-fatal cardiovascular (CV) outcomes compared with placebo, with more prominent benefits in patients with conditions associated with BET system activation, such as type 2 diabetes mellitus (T2DM), high C-reactive protein, or low HDL-cholesterol(4).

Purpose: A trial to examine whether treatment with apabetalone compared to standard of care therapies improves CV outcomes in patients with T2DM and low HDL-C after an acute coronary syndrome (ACS).

Trial Design

  • International, multicenter, randomized, double-blind, placebo-controlled trial, phase
  • N=2425
  • Apabetalone (N=1212)
  • Placebo (N=1206)
  • Setting: 195 sites in 13 countries
  • Enrollment: November 2015 – July 2018
  • Median follow-up: 26 months
  • Analysis: Intention-to-treat
  • Primary Outcome: Time to the first occurrence of CV death, non-fatal myocardial infarction (MI), or stroke.

Trial Population

  • Inclusion criteria:
    • Patients with ACS in the preceding 7-90 days, T2DM (HbA1C>6.5%), and HDL-C ≤40 mg/dl for men, ≤45 mg/dl for women
    • All patients must receive intensive or maximum tolerated treatment with atorvastatin or rosuvastatin
  • Exclusion criteria:
    • Planned further coronary revascularization
    • Previous or current diagnosis of severe heart failure (NYHA Class IV)
    • Coronary artery bypass grafting within 90 days prior to Visit 1
    • Severe renal impairment (eGFR <30 ml/min/1.7m2 or need for dialysis)
    • Evidence of cirrhosis from liver imaging or biopsy
    • Liver transaminases >1.5 x upper limit of normal at screening visit
  • Baseline characteristics:
    • Index event: Myocardial infarction (74%) [NSTEMI 47%, STEMI 53%]; Unstable Angina (26%)
    • Demographics: Median age 62 years, 25% female sex, majority white race (87%)
    • Statins: Use of high intensity statin treatment was 91%
    • Biomarkers: median LDL-C 65 mg/dl, HDL-C 33 mg/dl, and HbA1c 7.3% at time of enrollment

Interventions

  1. Patients randomized 1:1 to apabetalone (100mg BID) or matching placebo
  2. Adjudication of all outcome events performed by an independent clinical endpoints committee unaware of trial group assignments and lipid levels
  3. An independent data and safety monitoring committee oversaw the study and performed two pre-specified interim efficacy reviews

Outcomes - Comparisons are apabetalone versus placebo

  1. Primary Outcomes:
    • Time to first occurrence of MACE (CV death or non-fatal MI or non-fatal stroke)
      • 125 (10%) vs 149 (12.4%) [ 0.82 (95% CI 0.65 vs 1.04); p=0.11
  2. Secondary Outcomes:
    • First occurrence of primary endpoint or hospitalization for unstable angina or emergency revascularization procedure
      • 144 (11.9%) vs 166 (13.85) [0.85(95% CI 0.68 – 1.06)]
    • First and recurrent primary end points events
      • 171 vs 203 [0.79 (95% CI 0.60 – 1.06)]
    • Cardiovascular death or non-fatal myocardial infarction
      • 112(9.2%) vs 139 (11.5%) [0.79 (95% CI 0.61 – 1.01)]
    • Coronary heart disease death vs non-fatal myocardial infarction
      • 110 (9.1%) vs 136 (11.3%) [0.79 (95% CI 0.61-1.02)]
    • Non-fatal myocardial infarction
      • 77 (6.4%) vs 94 (7.8%) [ 0.80 (95% CI 0.59 – 1.08)]
    • Cardiovascular Death
      • 45 (3.7%) vs 55 (4.6%) [ 0.81 (95% CI 0.54 – 1.19)]
    • Stroke
      • 17 (1.4%) vs 17 (1.4%) [ 1.01 (95% CI 0.52 – 1.98)]
    • All-Cause mortality
      • 61 (5%) vs 69 (5.7%) [ 0.88 (95% CI 0.62 -1.24)]
    • First hospitalization for congestive heart failure
      • 29 (2.4%) vs 48 (4.0%) [ 0.59 (95% CI 0.38 – 0.94)]
    • First and recurrent hospitalization for congestive heart failure
      • 29 (2.4%) vs 48 (4.0%) [ 0.47 (95% CI 0.27 – 0.83)]
  3. Safety Outcomes:
    • Patients with at least one adverse event
      • 830 (68.5%) vs 820 (67.9)
    • Adverse event leading to discontinuation
      • 114(9.4%) vs 69 (5.7%)
    • Patients with at least one serious adverse event
      • 354 (29.2%) vs 339 (28.1%)
    • Death
      • 61 (5%) vs 72 (6%)
    • Cardiovascular death
      • 34 (2.8%) vs 42 (3.5%)
    • ALT >3x ULN
      • 78 (6.4%) vs 18 (1.5%)
    • ALT >5x ULN
      • 40 (3.3%) vs 9 (0.7%)
    • Discontinuation due to LFT elevation
      • 35 (2.9%) vs 11 (0.9%)
  4. Subgroup analysis: All analysis are for primary outcome
    • eGFR (p=0.032)
      • eGFR < 60 : 13(10.4%) vs 35 (21.3%); HR 0.50 [95% CI (0.28 - 0.96)]
      • eGFR > 60: 112(10.3%) vs 114(11.0%) HR 0.94 (95% CI (0.73 – 1.22)]
    • LDL cholesterol (p=0.024)
      • < Median: 48 (8.1%) vs 78 (13.1%); HR 0.60 [95% CI (0.42 -0.86)]
      • > Median: 64 (9.9%) vs 67 (10.2%); HR 1.06 95% CI (0.67 vs 1.34)]

Sponsor: Resverlogix

Related Science 

  • Di Bartolo, Belinda A., et al. "Translating evidence of HDL and plaque regression." Arteriosclerosis, thrombosis, and vascular biology 38.9 (2018): 1961-1968.
  • Kulikowski, Ewelina, et al. "Selective BET Inhibitors Are Useful for Normalizing Inflammation Leading to Reduced Cardiovascular Disease (CVD) in Humans." Arteriosclerosis, Thrombosis, and Vascular Biology 37.suppl_1 (2017): A19-A19.
  • Tsujikawa, Laura, et al. "Apabetalone (rvx-208) Decreases Risk of Major Adverse Cardiovascular Events in Diabetes Mellitus Patients With Cvd by Attenuating Monocyte Adhesion to Endothelial Cells." Arteriosclerosis, Thrombosis, and Vascular Biology 38.Suppl_1 (2018): A669-A669.

References and Sources 

  • Presented by: Kausik K Ray, AHA Scientific Sessions 2019, Philadelphia, PA
  • BETonMACE Abstract
  • Kausik K. Ray's presentation slides (PDF)
  • Discussant slides (PPSX)
  • ClinicalTrials.gov Identifier: NCT02586155
  • Wasiak, Sylwia, et al. "Benefit of apabetalone on plasma proteins in renal disease." Kidney international reports 3.3 (2018): 711-721.
  • Gilham, Dean, et al. "Apabetalone downregulates factors and pathways associated with vascular calcification." Atherosclerosis 280 (2019): 75-84.
  • Tsujikawa, Laura M., et al. "Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism." Clinical epigenetics 11.1 (2019): 102.
  • Nicholls, Stephen J., et al. "Selective BET protein inhibition with apabetalone and cardiovascular events: a pooled analysis of trials in patients with coronary artery disease." American Journal of Cardiovascular Drugs 18.2 (2018): 109-115.

Key Words 

Acute coronary syndrome; Apabetalone; MACE; BET proteins

Related clinical topics 

Epigenetics; Vascular inflammation; Reverse cholesterol transport; Vascular calcification