Apabetalone/RVX-208 Clinical Development
Commencing in the fall of 2015, Resverlogix has initiated a Phase 3 clinical trial "BETonMACE" with apabetalone (also known as RVX-208) for high-risk cardiovascular disease patients with type 2 diabetes mellitus and low HDL. Approximately 15% of the patient population will also have chronic kidney disease (CKD). The primary endpoint is the time to first occurrence of Major Adverse Cardiac Events (MACE).
Summary of Clinical Trials
COMPLETED PHASE 2B CLINICAL TRIALS
SUSTAIN: Phase 2b clinical trial 24-week, multi-center, double-blind, randomized, parallel group, placebo-controlled trial of 176 patients with established CVD. RVX-208 significantly increased HDL-C, the primary endpoint. SUSTAIN also successfully met secondary endpoints, showed increases in levels of Apo-AI and large HDL particles, both believed to be important factors in enhancing reverse cholesterol transport activity.
ASSURE: Phase 2b, 26-week, multi-center, double-blind, randomized, parallel group, placebo-controlled trial led by Cleveland Clinic. This trial assessed the early impact of atherosclerosis regression by treatment of RVX-208 in high risk cardiovascular disease (CVD) subjects. There were 281 Patients that received two Intra-Vascular Ultrasound (IVUS) procedures. The primary endpoint in ASSURE, -0.6% change in PAV was not met. The RVX-208 treated group had -0.4% median plaque regression (p=0.08). Multiple secondary IVUS endpoints such as Total Atheroma Volume (TAV) and 10mm worst occluded TAV were met with high statistical significance with p<0.001 and p<0.001, respectively. Additional secondary lipid biomarker endpoints such as HDL and ApoA-I were also met 10.73% p<0.001, 11.69% p<0.001, respectively.
POST HOC ANALYSIS: SUSTAIN & ASSURE
In post hoc analysis of the SUSTAIN and ASSURE trials, pooled data analysis demonstrated statistically significant increases in ApoA-I and other markers of reverse cholesterol transport. Beneficial effects were also observed on cardiovascular (CVD) biomarkers, such as high-sensitivity C-reactive protein, alkaline phosphatase, and components of the complement and coagulation cascades. RVX-208 treatment also had an effect on the incidence of Major Adverse Cardiac Events (MACE); defined as composite of death, non-fatal myocardial infarction, coronary revascularization procedures, and hospitalization for unstable angina or heart failure.
Data from this analysis demonstrated a 55% relative risk reduction (RRR) in the incidence of MACE in CVD patients, and a more pronounced 77% RRR in patients with a history of diabetes mellitus. Taken together, the combined effects of BET inhibition on multiple biologies known to impact vascular risk may, in part, explain the reduction in MACE events – a promising finding for this class of compounds.