Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA

Abstract

Reverse cholesterol transport (RCT) contributes to the anti-atherogenic effects of HDL. Patients with the orphan disease, familial hypoalphalipoproteinemia (FHA), are characterized by decreased tissue cholesterol removal and an increased atherogenic burden. We performed an open-label uncontrolled proof-of-concept study to evaluate the effect of infusions with a human apoA-I-containing HDL-mimetic particle (CER-001) on RCT and the arterial vessel wall in FHA. Subjects received 20 infusions of CER-001 (8 mg/kg) during 6 months. Efficacy was assessed by measuring (apo)lipoproteins, plasma-mediated cellular cholesterol efflux, fecal sterol excretion (FSE), and carotid artery wall dimension by MRI and artery wall inflammation by (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography scans. We included seven FHA patients: HDL-cholesterol (HDL-c), 13.8 [1.8-29.1] mg/dl; apoA-I, 28.7 [7.9-59.1] mg/dl. Following nine infusions in 1 month, apoA-I and HDL-c increased directly after infusion by 27.0 and 16.1 mg/dl (P = 0.018). CER-001 induced a 44% relative increase (P = 0.018) in in vitro cellular cholesterol efflux with a trend toward increased FSE (P = 0.068). After nine infusions of CER-001, carotid mean vessel wall area decreased compared with baseline from 25.0 to 22.8 mm(2) (P = 0.043) and target-to-background ratio from 2.04 to 1.81 (P = 0.046). In FHA-subjects, CER-001 stimulates cholesterol mobilization and reduces artery wall dimension and inflammation, supporting further evaluation of CER-001 in FHA patients.

Keywords: apolipoprotein A-I; familial hypoalphalipoproteinemia; reverse cholesterol transport.

Fig. 1.

Study scheme. FSE studies were performed if the subject consented to these additional analyses.

Fig. 2.

Lipoprotein profile changes and apoA-I kinetics after 1 month of treatment. Plasma was obtained at baseline and 1, 4, 8, and 24 h after the start of the ninth infusion. Changes in plasma cholesterol levels (A), HDL-c levels (B), LDL-c levels (C), VLDL-c levels (D), and apoA-I levels (E) following CER-001 infusion are depicted. Data represent baseline-corrected medians with IQRs. Values at every time point were compared with baseline. A P value <0.05 was considered statistically significant and is depicted with an asterisk.

Fig. 3.

Plasma-mediated cellular cholesterol efflux. Plasma-mediated cellular cholesterol efflux was analyzed in vitro using J774 macrophages. Cholesterol efflux capacity from plasma derived 1, 4, 8, and 24 h after infusion was compared with baseline efflux capacity. Data represent baseline-corrected medians with IQRs. A P value <0.05 was considered statistically significant and is depicted with an asterisk.

Fig. 4.

Imaging results. MVWA and TBR_max of the carotid arteries, as assessed by MRI and FDG-PET/CT scan, respectively, were compared between baseline and after 1 month of nine CER-001 infusions. MVWA was also measured after 6 months with 11 additional CER-001 infusions. For TBR_max, the index vessel was chosen. Representative pre- and posttreatment 3T MRI and FDG-PET/CT scans are depicted in (A) and (C). In the case of the MRI, the original images and the ROI are shown. The results of both scans are shown in (B) and (D). Data represent medians with IQRs. A P value <0.05 was considered statistically significant.