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Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b,
Stephen J Nicholls1, Rishi Puri2, Kathy Wolski2
1South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia. stephen.nicholls@sahmri.com.
Background:
Bromodomain and extra-terminal (BET) proteins regulate transcription of lipoprotein and inflammatory factors implicated in atherosclerosis. The impact of BET inhibition on atherosclerosis progression is unknown.
Methods:
ASSURE was a double-blind, randomized, multicenter trial in which 323 patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels were randomized in a 3:1 fashion to treatment with the BET protein inhibitor RVX-208 200 mg or placebo for 26 weeks. Plaque progression was measured with serial intravascular ultrasound imaging. Lipid levels, safety, and tolerability were also assessed.
Results:
During treatment, apolipoprotein (apo)A-I increased by 10.6% with placebo (P < 0.001 compared with baseline) and 12.8% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.18. HDL-C increased by 9.1% with placebo (P < 0.001 compared with baseline) and 11.1% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.24. Low-density lipoprotein cholesterol (LDL-C) decreased by 17.9% with placebo (P < 0.001 compared with baseline) and 15.8% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.55. The primary endpoint, the change in percent atheroma volume, decreased 0.30% in placebo-treated patients (P = 0.23 compared with baseline) and 0.40% in the RVX-208 group (P = 0.08 compared with baseline), between groups P = 0.81. Total atheroma volume decreased 3.8 mm(3) in the placebo group (P = 0.01 compared with baseline) and 4.2 mm(3) in the RVX-208 group (P < 0.001 compared with baseline), P = 0.86 between groups. A greater incidence of elevated liver enzymes was observed in RVX-208-treated patients (7.1 vs. 0%, P = 0.009).
Conclusion:
Administration of the BET protein inhibitor RVX-208 showed no greater increase in apoA-I or HDL-C or incremental regression of atherosclerosis than administration of placebo.
Trial Registration:
ClinicalTrials.gov identifier-NCT01067820.
Insights
The BET protein inhibitor RVX-208 did not significantly improve atherosclerosis progression or HDL-C levels compared to placebo in patients with coronary disease. RVX-208 was associated with a higher incidence of elevated liver enzymes.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Molecular Biology
Background:
- Bromodomain and extra-terminal (BET) proteins influence genes related to atherosclerosis.
- The effect of BET inhibition on atherosclerosis progression was previously unknown.
Purpose of the Study:
- To evaluate the impact of the BET inhibitor RVX-208 on atherosclerosis progression in patients with coronary artery disease and low HDL-C.
Main Methods:
- The ASSURE trial was a double-blind, randomized, multicenter study involving 323 patients.
- Patients received either 200 mg of RVX-208 or placebo for 26 weeks.
- Atherosclerosis progression was assessed using intravascular ultrasound, alongside lipid levels and safety monitoring.
Main Results:
- RVX-208 did not show a significant difference in the change of percent atheroma volume or total atheroma volume compared to placebo.
- Both groups showed increases in apolipoprotein A-I and HDL-C, with no significant between-group difference.
- Low-density lipoprotein cholesterol decreased in both groups, with no significant difference.
- Elevated liver enzymes occurred more frequently in the RVX-208 group (7.1% vs. 0%).
Conclusions:
- RVX-208 did not demonstrate superior efficacy over placebo in improving atherosclerosis markers or HDL-C levels.
- The BET inhibitor RVX-208 showed a higher incidence of elevated liver enzymes.
- Further research is needed to understand the role of BET inhibition in cardiovascular disease.
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