No Plaque Reduction With Mimetic HDL Agent in ACS: CARAT Phase 2 Trial

Larry Hand

March 27, 2017

WASHINGTON, DC — Infusing an engineered HDL-cholesterol mimetic into patients who recently have had acute coronary syndrome (ACS) did not reduce the volume of plaque in arteries as measured by intravascular ultrasound (IVUS) compared with placebo, according to results of a phase 2 clinical trial[1].

"Short-term treatment with CER-100 3 mg/kg did not produce a significant effect on coronary disease progression measured by IVUS," Dr Stephen J Nicholls (South Australian Health and Medical Research Institute, Adelaide) said during a presentation at the American College of Cardiology (ACC) 2017 Scientific Sessions.

"Early studies demonstrated potential coronary plaque regression infusing low-dose CER-100 in high-plaque ACS patients," he said. But like other HDL studies, this study was disappointing.

CER-001, being developed by Cerenis Therapeutics, Lebège, France, is a pre-beta HDL-C mimetic that contains apolipoprotein A-I and sphingomyelin.

Dr Stephen Nicholls

Nicholls and colleagues conducted the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial (CARAT)[2].

In this proof-of-concept study, the researchers randomized 301 participants (mean age 60, about 80% male) to receive standard of care plus CER-001 (n=151) or placebo (n=150). Researchers conducted IVUS imaging prior to treatment and at study end.

Participants had 10 infusions of 3-mg/kg CER-001 or placebo, with 135 in the CER-001 group and 137 in the placebo group completing the study.

At baseline, 28% of participants were taking statins, and more than 60% of both groups had hypertension.

As for the primary end point of median change in percentage of atheroma volume, participants in the placebo group experienced a change of -0.41 ( P=0.01), compared with -0.09 (P=0.67) for CER-001, but the difference did not reach statistical significance (P=0.15).

For the entire vessel length, change in total atheroma volume reached -6.6 mm3 in the placebo group (P<0.001), compared with -5.6 mm3 in the CER-001 group (P<0.001), but again the difference did not reach significance (P=0.64).

For the most diseased 10-mm segment, CER-001 was better, with a change of -3.5 mm3 (P<0.001), compared with -3.0 mm3 (P<0.001), although the difference also did not reach statistical significance (P=0.51).

Placebo outperformed CER-001 in the percentage of patients showing regression: 57.7% vs 53.3%, respectively, for percentage of atheroma volume and 70.8% vs 67.4%, respectively, for total atheroma volume.

Adverse events were few and similar between groups.

"Ten infusions of CER-100 were well tolerated," Nicholls confirmed. "These results occurred on a background of contemporary therapy, which includes intensive statin therapy."

"However, the lack of benefit with short-term therapy with CER-001 3 mg/kg in CARAT suggests that this is not a promising strategy for ACS patients," Nicholls said. "Whether HDL therapy can impact plaque or clinical events in the setting of contemporary therapy remains to be determined, although with each disappointing study result the considerable challenge remains.

"Whether CER-100 impacts other settings remains to be determined," he added.

Dr Deepak L Bhatt (Brigham and Women's Hospital, Boston, MA), a panelist at a later news conference, said, "Intravascular ultrasound is a very powerful and precise method of assessing plaque, and I think this shows the value. I would encourage those who are investigating this compound to keep up the research. This shouldn't discourage further research."

Nicholls later told heartwire from Medscape, "I think there are still some shots in the HDL space. Time will tell whether that will move forward. Whether negative effects of other HDL studies will affect the ability to go forward, I don't think they should, but I think that would be an important consideration."

Cerenis Therapeutics sponsored this research. Nicholls reported consulting for a number of companies.

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