Aim: Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease (CVD), due to exposure to elevated Low-density lipoprotein cholesterol (LDL-c) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for CVD 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 apoA-I-containing HDL-mimetic particle, on carotid artery wall dimensions in HoFH patients. Methods and results: 23 patients (mean age 39.4 ± 13.5; mean LDL-c 214.2 ± 81.5 mg/dl) with genetically confirmed homozygosity or compound heterozygosity for LDLR, APOB, PCSK9 or LDLRAP1 mutations received twelve bi-weekly infusions with CER-001 (8 mg/kg). Before and one hour after the first infusion, lipid values were measured. Magnetic Resonance Imaging (3T MRI) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. Following 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 endpoint) decreased from 17.23 to 16.75 mm2 (p=0.008). A trend towards reduction of mean vessel wall thickness was observed (0.75 mm at baseline, 0.74 mm at follow-up; p=0.0835). Conclusion: In HoFH, twelve bi-weekly infusions with an apoA-I-containing HDL-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 LDL lowering therapy. This finding supports further clinical evaluation of apoA-I-containing particles in HoFH patients .

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 / Hovingh, G. Kees; Smits, Loek P.; Stefanutti, Claudia; Soran, Handrean; Kwok, See; De Graaf, Jacqueline; Gaudet, Daniel; Keyserling, Constance H.; Klepp, Heather; Frick, Jennifer; Paolini, John F.; Dasseux, Jean Louis; Kastelein, John J. P.; Stroes, Erik S.. - In: AMERICAN HEART JOURNAL. - ISSN 0002-8703. - ELETTRONICO. - 169:5(2015), pp. 736-742.e1. [10.1016/j.ahj.2015.01.008]

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

STEFANUTTI, Claudia;
2015

Abstract

Aim: Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease (CVD), due to exposure to elevated Low-density lipoprotein cholesterol (LDL-c) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for CVD 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 apoA-I-containing HDL-mimetic particle, on carotid artery wall dimensions in HoFH patients. Methods and results: 23 patients (mean age 39.4 ± 13.5; mean LDL-c 214.2 ± 81.5 mg/dl) with genetically confirmed homozygosity or compound heterozygosity for LDLR, APOB, PCSK9 or LDLRAP1 mutations received twelve bi-weekly infusions with CER-001 (8 mg/kg). Before and one hour after the first infusion, lipid values were measured. Magnetic Resonance Imaging (3T MRI) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. Following 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 endpoint) decreased from 17.23 to 16.75 mm2 (p=0.008). A trend towards reduction of mean vessel wall thickness was observed (0.75 mm at baseline, 0.74 mm at follow-up; p=0.0835). Conclusion: In HoFH, twelve bi-weekly infusions with an apoA-I-containing HDL-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 LDL lowering therapy. This finding supports further clinical evaluation of apoA-I-containing particles in HoFH patients .
2015
Adult; Apolipoprotein A-I; Cholesterol, LDL; Coronary Artery Disease; Female; Humans; Hyperlipoproteinemia Type II; Lipids; Male; Middle Aged; Phospholipids; Rare Diseases; Recombinant Proteins; Carotid Intima-Media Thickness; Cardiology and Cardiovascular Medicine; Medicine (all)
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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 / Hovingh, G. Kees; Smits, Loek P.; Stefanutti, Claudia; Soran, Handrean; Kwok, See; De Graaf, Jacqueline; Gaudet, Daniel; Keyserling, Constance H.; Klepp, Heather; Frick, Jennifer; Paolini, John F.; Dasseux, Jean Louis; Kastelein, John J. P.; Stroes, Erik S.. - In: AMERICAN HEART JOURNAL. - ISSN 0002-8703. - ELETTRONICO. - 169:5(2015), pp. 736-742.e1. [10.1016/j.ahj.2015.01.008]
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