Elsevier

American Heart Journal

Volume 169, Issue 5, May 2015, Pages 736-742.e1
American Heart Journal

Clinical Investigation
Valvular and Congenital Heart Disease
The effect of an apolipoprotein A-I–containing high-density lipoprotein–mimetic particle (CER-001) on carotid artery wall thickness in patients with homozygous familial hypercholesterolemia: The Modifying Orphan Disease Evaluation (MODE) study

https://doi.org/10.1016/j.ahj.2015.01.008Get rights and content

Background

Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease because of exposure to elevated low-density lipoprotein cholesterol (LDL-C) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for cardiovascular disease prevention, but the residual risk in HoFH remains high, emphasizing the need for additional therapies. In the present study, we evaluated the effect of serial infusions with CER-001, a recombinant human apolipoprotein A-I (apoA-I)–containing high-density lipoprotein–mimetic particle, on carotid artery wall dimensions in patients with HoFH.

Methods and results

Twenty-three patients (mean age 39.4 ± 13.5 years, mean LDL-C 214.2 ± 81.5 mg/dL) with genetically confirmed homozygosity or compound heterozygosity for LDLR, APOB, PCSK9, or LDLRAP1 mutations received 12 biweekly infusions with CER-001 (8 mg/kg). Before and 1 hour after the first infusion, lipid values were measured. Magnetic resonance imaging (3-T magnetic resonance imaging) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. After CER-001 infusion, apoA-I increased from 114.8 ± 20.7 mg/dL to 129.3 ± 23.0 mg/dL. After 24 weeks, mean vessel wall area (primary end point) decreased from 17.23 to 16.75 mm2 (P = .008). A trend toward reduction of mean vessel wall thickness was observed (0.75 mm at baseline and 0.74 mm at follow-up, P = .0835).

Conclusions

In HoFH, 12 biweekly infusions with an apoA-I–containing high-density lipoprotein–mimetic particle resulted in a significant reduction in carotid mean vessel wall area, implying that CER-001 may reverse atherogenic changes in the arterial wall on top of maximal low-density lipoprotein–lowering therapy. This finding supports further clinical evaluation of apoA-I–containing particles in patients with HoFH.

Section snippets

Methods

This phase 2 study (clinical trial register NCT01412034) was conducted in accordance with the Declaration of Helsinki and in compliance with current Good Clinical Practice. The multicenter study was designed by the sponsor (Cerenis Therapeutics Holding, Toulouse, France) in collaboration with the academic investigators. The protocol was approved by the local institutional review boards, and all participants provided written informed consent. This study was funded by a research grant from

Baseline characteristics

Baseline characteristics are listed in Table I. Twenty-three patients were included, of whom 11 were homozygous carriers of LDLR mutations, 3 were homozygous carriers of apoB mutations, 6 were compound heterozygous carriers of LDLR mutations, and 3 were double heterozygous carriers of LDLR and apoB mutations. The mean age was 39.4 years ± 13.4 years, and baseline lipid profiles showed a mean LDL-C level of 214.2 ± 81.5 mg/dL and an HDL-C level of 42.6 ± 11.6 mg/dL. All 23 patients were using

Main findings

In the current trial, we found that plasma apoA-I levels transiently increased significantly in patients with HoFH after infusion therapy with CER-001, an HDL-mimetic particle. We observed a beneficial effect on MVWA, the primary efficacy outcome, and a concomitant trend toward a reduction in MVWT after treatment with 12 infusions of CER-001 during a 24-week period. Infusions with CER-001 were generally well tolerated. These data imply that CER-001 infusions may reverse atherogenic artery wall

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