HDL Mimetic Effective in Patients with Genetic Lipid Abnormalities: MODE, SAMBA

June 02, 2014

MADRID, SPAIN — A couple of small phase 2 studies provide some evidence that an HDL mimetic, one that failed in the treatment of ACS patients, might be successful in reducing the burden of atherosclerosis in patients with genetic lipid abnormalities.

In the first study[1], known as the Modifying Orphan Disease Evaluation (MODE) study, patients with homozygous familial hypercholesterolemia (HoFH) who received 12 biweekly infusions of CER-001 (Cerenis Therapeutics), an engineered lipoprotein particle that mimics pre-beta HDL, had a statistically significant reduction in the carotid mean vessel-wall area and vessel-wall volume assessed by 3-T magnetic resonance imaging (MRI). There was a trend toward improvements in carotid mean vessel-wall thickness, but the results did not achieve statistical significance.

The second study[2], known as SAMBA, which included just seven patients with familial hypoalphalipoproteinemia, a genetic abnormality that results in low levels of HDL cholesterol, treatment with CER-001 increased cholesterol efflux and decreased atherosclerotic burden measured by MRI.

The results of MODE and SAMBA were presented here today at the European Atherosclerosis Society 2014 Congress (EAS 2014). As reported previously, CER-001 consists of a combination of recombinant human apolipoprotein A1 (apoA1), the major structural protein of HDL, and two phospholipids. The drug is designed to increase apoA1 and the number of HDL particles and in doing so accelerate reverse cholesterol transport and lower the atheroma burden in patients with subclinical atherosclerosis.

In both MODE and SAMBA, treatment with CER-001 raised apoA1 levels, with Dr Ruud Kootte (Academic Medical Center, Amsterdam, the Netherlands), who presented the SAMBA data, reporting the apoA1 levels peaked at four hours after the infusion and HDL-cholesterol levels peaked about one hour after the CER-001 infusion.

CHI-SQUARE vs MODE and SAMBA

The promise of CER-001 took a bit of a hit this year, with negative results from another study testing the drug in patients with acute coronary syndromes (ACS). As reported by heartwire , the phase 2b Can HDL Infusions Significantly Quicken Atherosclerosis Regression (CHI-SQUARE) study failed to show a difference between placebo and CER-001 on the end point of nominal change in atheroma volume assessed with intravascular ultrasound (IVUS).

Speaking with heartwire , Dr Loek Smits (Academic Medical Center, Amsterdam, the Netherlands), who presented the MODE data, said the most apparent difference between CHI-SQUARE and the positive MODE and SAMBA studies is the trials investigated different patient populations. In addition, CHI-SQUARE assessed atherosclerosis in the coronary artery with IVUS, whereas the latest two trials assessed atherosclerosis of the carotid artery. While he couldn't speak to IVUS, the MODE and SAMBA trials used MRI to assess changes in atherosclerotic burden, a modality he says is "very accurate."

In the MODE trial, which included 23 HoFH patients, all were treated with a statin, 83% were receiving ezetimibe (Zetia, Merck/Schering-Plough), and 48% were undergoing lipoprotein apheresis, making them an aggressively treated group of patients, said Smits.

In terms of the results, treatment with CER-001 reduced carotid mean vessel-wall area approximately 2.5%.

"Treatment-induced changes in MRI parameters haven't been validated yet, so we honestly don't know," said Smits, when asked whether or not the 2.5% reduction is clinically significant. He pointed out, however, that the reduction, while small, indicates to researchers they are regressing atherosclerosis over a relatively short time period in a difficult-to-treat group of patients receiving maximum therapy. "The clinical consequences of it remain to be established," said Smits, "but this proof-of-concept study shows that HDL-directed therapy in an LDL-centered disease may work."

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