AMSTERDAM, The Netherlands—A new oral agent  known as RVX-208 has failed to induce more than a trend toward plaque regression compared with placebo at 6-month follow-up. Findings from the ASSURE study were presented in a Hot Line session at the European Society of Cardiology Congress on September 2, 2013.

RVX-208 (Resverlogix; Calgary, Canada) is a bromodomain and extra-terminal protein inhibitor that induces ApoA-1 synthesis and had subsequent favorable effects on HDL-related measures and cholesterol efflux, said researcher Stephen Nicholls, MD, of the University of Adelaide (Adelaide, Australia).

For the ASSURE trial, investigators sought to evaluate the early effects of RVX-208 on progression of coronary atherosclerosis compared to baseline in CAD patients with low HDL-C levels.

Primary Endpoint Not Met

ASSURE included 323 patients with symptomatic CAD, angiographic stenosis greater than 20%, and low HDL cholesterol levels (defined as < 40 mg/dL in men and < 45 mg/dL in women). Patients were randomized 1:3 to placebo (n = 80) or RVX-208 (n = 243; 100 mg twice daily for 26 weeks).

Assessment of changes in biochemical parameters over the study period showed positive changes in LDL cholesterol, HDL cholesterol, ApoA-I, ApoB, total and large HDL, and high-sensitivity CRP in both groups (P = 0.08 vs. placebo for all). Differences between groups were not significant.

IVUS follow-up at 26 weeks was complete in the target vessels of 281 patients (87%). Among them, the primary IVUS efficacy parameter of median change in percent atheroma volume reflected no difference between groups (-0.30 for placebo vs. -0.40 for RVX-208; P = 0.81). While there was no difference compared with baseline in the placebo group, those treated with RVX-208 showed a favorable trend (table 1).

Table 1. Primary Efficacy Endpoint: Percent Atheroma Volume

Analyses looking at change in total atheroma volume separately in the whole segment and in the most diseased 10 mm again revealed no difference between groups (P = 0.86 and P = 0.79, respectively). Changes from baseline, however, were significant for both placebo and RVX-208 (table 2).

Table 2. Secondary Efficacy Endpoint: Total Atheroma Volume

The fraction of patients exhibiting regression according to assessment of percent atheroma volume was 56.2% in the placebo group and 56.3% in the RVX-208 group (P = 0.99). For total atheroma volume, findings also were similar (54.8% vs. 55.3%, P = 0.94).

While cardiovascular events were somewhat more common in the placebo group (13.8% vs. 7.4%, P = 0.09), liver abnormalities (ALT/AST >3x ULN), as observed in previous study, were more common in the RVX-208 group (0 vs. 7.1% , P = 0.009) and creatinine kinase elevations >3x ULN were numerically higher (0% vs. 1.3%, P = 0.58).

‘Search Continues’ for HDL Therapy

Dr. Nicholls concluded, “Administration of RVX-208 for 26 weeks did not produce an incremental benefit on atherosclerotic plaque compared with placebo.” Regarding the potential protective properties of HDL—and the immense effort underway to find new therapeutic agents for patients with CAD—he said, “The search continues.

Asked what could account for the striking benefits in the placebo group, Dr. Nicholls told TCTMD in an interview, “We wish we knew, but keep in mind that these were very well-treated patients who were seen by a physician 11 times over 26 weeks. This is as good as a placebo group ever does.”

Discussant John Chapman, BSc, PhD, DSc, of Hôpital de la Pitié (Paris, France), commented after the presentation, “Insights from HDL infusion trials suggest that the low absolute magnitude of the increases in ApoA-1 and HDL with this agent would remain largely inadequate to warrant its development as an antiatherosclerotic agent.”

He emphasized that ASSURE “did not by any means directly evaluate the so-called HDL hypothesis. The quest for agents that modulate apoA-1 and HDL metabolism and function in cardiometabolic disease must therefore be maintained despite this setback.”

Study Details

Mean age was approximately 58 years, and the mean level of HDL-C was 39.0 mg/dL in both groups. While average values for percent atheroma volume were similar in both groups at 36.2% for placebo and 38.1% for RVX-208 (P = 0.11), both the total atheroma volume and atheroma volume in the most diseased 10-mm segment were higher in the RVX-208 group (P < 0.001 and P = 0.05, respectively).

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