Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial: A Randomized Clinical Trial

Abstract

Importance: CER-001 is a negatively charged, engineered pre-β high-density lipoprotein (HDL) mimetic containing apolipoprotein A-I and sphingomyelin. Preliminary studies demonstrated favorable effects of CER-001 on cholesterol efflux and vascular inflammation. A post hoc reanalysis of a previously completed study of intravenous infusion of CER-001, 3 mg/k, showed that the intravenous infusion in patients with a high coronary plaque burden promoted regression as assessed by intravascular ultrasonography.

Objective: To determine the effect of infusing CER-001 on coronary atherosclerosis progression in statin-treated patients.

Design, setting, and participants: A double-blind, randomized, multicenter trial evaluating the effect of 10 weekly intravenous infusions of CER-001, 3 mg/kg, (n = 135) or placebo (n = 137) in patients with an acute coronary syndrome (ACS) and baseline percent atheroma volume (PAV) greater than 30% in the proximal segment of an epicardial artery by intravascular ultrasonography. The study included 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States in patients with ACS presenting for coronary angiography. Patients were enrolled from August 15, 2015, to November 19, 2016.

Interventions: Participants were randomized to receive weekly CER-001, 3 mg/kg, or placebo for 10 weeks in addition to statins.

Main outcomes and measures: The primary efficacy measure was the nominal change in PAV from baseline to day 78 measured by serial intravascular ultrasonography imaging. The secondary efficacy measures were nominal change in normalized total atheroma volume and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated.

Results: Among 293 patients (mean [SD] age, 59.8 [9.4] years; 217 men [79.8%] and 261 white race/ethnicity [96.0%]), 86 (29%) had statin prior use prior to the index ACS and 272 (92.8%) had evaluable imaging at follow-up. The placebo and CER-001 groups had similar posttreatment median levels of low-density lipoprotein cholesterol (74 mg/dL vs 79 mg/dL; P = .15) and high-density lipoprotein cholesterol (43 mg/dL vs 44 mg/dL; P = .66). The primary efficacy measure, PAV, decreased 0.41% with placebo (P = .005 compared with baseline), but not with CER-001 (-0.09%; P = .67 compared with baseline; between group differences, 0.32%; P = .15). Similar percentages of patients in the placebo and CER-001 groups demonstrated regression of PAV (57.7% vs 53.3%; P = .49). Infusions were well tolerated, with no differences in clinical and laboratory adverse events observed between treatment groups.

Conclusions and relevance: Infusion of CER-001 did not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden.

Trial registration: ClinicalTrials.gov Identifier: NCT2484378.

Trial registration: ClinicalTrials.gov NCT02484378.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Nicholls has received esearch support from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi Regeneron, and LipoScience and is a consultant for AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr Nicholls is also supported by a Principal Research Fellowship from the National Health and Medical Research Council of Australia. Dr Kastelein received personal consulting fees from Sanofi, Affiris, Akarna Therapeutics, Amgen Inc, CSL Behring, Regeneron, Staten Biotech, Madrigal, The Medicines Company, Kowa, Eli Lilly, Esperion, Gemphire, Ionis Pharmaceuticals, and Akcea Pharmaceuticals. Dr Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen Inc, Cerenis, Eli Lilly, Esperion, Pfizer, The Medicines Company, Takeda, and Orexigen. Dr Nissen is involved in these clinical trials but receives no personal remuneration for his participation. Dr Nissen consults for many pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. Dr Ray reports grants and/or personal fees from Pfizer, Merck, Shark, and Dohme, AstraZeneca, Sanofi, Aegerion, Regeneron, Abbvie, Kowa, Cerenis, The Medicines Company, Eli Lilly, Esperion, Amgen, Cipla, Algorithm, Takeda, Boehringer Ingelheim, and Novo Nordisk within the last 12 months outside of the submitted work. Dr Schwartz, through his institution, has received research support from Cerenis, The Medicines Company, Resverlogix, Roche, and Sanofi. Dr Worthley is an employee of Genesis Healthcare. Ms Keyserling and Dr Dasseux are employees of Cerenis Pharmaceuticals. Dr Psaltis is supported by a Future Leader Fellowship from the National Heart Foundation of Australia. No other disclosures were reported.

Figures

Figure.. Disposition of Patients During the Course of the Trial

IVUS indicates intravascular ultrasonography.