Assessment of Atherosclerotic Plaque Characteristics Change by DCE-MRI With Alirocumab
Assessment of Atherosclerotic Plaque Characteristics Change by DCE-MRI With Alirocumab
Aim 1: To determine whether therapy with Alirocumab, compared to pre-treatment, will
 effectively improve carotid atherosclerotic plaque characteristics by reducing Ktrans and
 LRNC size. To achieve this goal, we will (a) enroll 30 subjects who are intolerant to high
 intensity statin therapy and only able to tolerate low potency statin or low weekly dose of
 high potency statin and have LDL-C ≥70 mg/dl; (b) initiate alirocumab at 150mg subcutaneously
 injection every 2 weeks; (c) perform carotid DCE-MRI scans at baseline, 3, 6 and 12 months;
 (d) perform quantitative analysis for vascular inflammation and plaque LRNC volume and other
 plaque characteristics; (e) compare vascular inflammation and LRNC volume between pre- and
 post-alirocumab at 3, 6 and 12 months.

 Aim 2: To examine associations between reductions in atherogenic lipids (LDL-C, Lp(a),
 non-HDL-C) and changes in atherosclerotic plaque characteristics. To achieve this goal, we
 will (a) perform laboratory assessments of lipids, lipoproteins and apo-lipoproteins at
 baseline and during the study; (b) compare lipids, lipoproteins and apo-lipoproteins levels
 between pre- and post-alirocumab; (c) correlate reductions in atherogenic lipids with changes
 atherosclerotic plaque characteristics.
Acute ischemic events caused by atherosclerosis cardiovascular disease (ASCVD) are primarily
 due to plaque rupture/erosion determined by plaque morphologic characteristics, local
 composition and inflammation, which can be directly assessed using magnetic resonance imaging
 (MRI). Prospective carotid MRI studies have demonstrated: (1) plaques with thin or ruptured
 cap, intraplaque hemorrhage (IPH), neovascularization, or larger lipid-rich necrotic core
 (LRNC) are strongly associated with occurrence of cerebrovascular and coronary events, (2)
 increased LRNC size is significantly associated with increased risk for systemic ASCVD events
 after adjusting for LDL-C or Non-HDL-C levels, (3) increased permeability of adventitial vasa
 vasorum is associated with presence of IPH which increases plaque burden and LRNC progression
 that appears to be resistant to conventional doses of statins, (4) intensive lipid therapy
 decreases carotid LRNC and vascular inflammation, (5) multicenter carotid studies can be
 conducted with good reproducibility and feasibility.

 Unlike previous clinical trials evaluating carotid artery disease using ultrasound based
 technology that showed a weak relationship to systemic and coronary vascular events, recent
 studies have demonstrated predictive value of carotid plaque tissue characteristics for
 subsequent systemic ASCVD events including coronary events. Hellings and colleagues found
 that carotid plaque composition by histology in 818 patients who underwent endarterectomy is
 an independent predictor of future cardiovascular events during long-term post-operative
 follow-up. Specifically, those with carotid IPH and increased neovascularization were at
 significantly higher risk for ASCVD events. The Atherosclerosis Risk in Communities study
 investigators reported that carotid LRNC (HR=1.9, p=0.014) and minimum cap thickness
 (HR=0.67, p=0.03), as identified by MRI, were significantly associated with development of
 ASCVD including coronary events after adjusting for all clinical risk factors, treatment
 variables and biomarkers. The carotid MRI sub-study in AIM-HIGH showed that higher Lp(a)
 levels are associated with high-risk plaque features which are prevalent in subjects with
 established vascular disease and "well-controlled" LDL-C and blood pressure. Thin or ruptured
 cap and a larger LRNC are predictive of systemic ASCVD events that include 83% (15/18) of the
 coronary events in AIM-HIGH, meanwhile, none of the clinical risk factors and lipids were
 predictive of future events.

 Alirocumab has shown substantial lowering in LDL-C, non-HDL-C and Lp(a), with or without
 concomitant statin treatment [43]. It has the potential to be a therapy that can improve
 plaque characteristics leading to reduction of ASCVD events. We propose to conduct a carotid
 MRI pilot study to demonstrate that adding alirocumab for 12 months, in comparison to
 pre-alirocumab therapy, in 30 subjects with documented carotid artery plaques who are not
 able to tolerate high intensity statin therapy and have LDL-C ≥70 mg/dl would improve
 atherosclerotic plaque characteristics by reducing Ktrans and LRNC size.
Inclusion Criteria:

 -  Men and women ≥18 years of age.

 -  Subjects with documented inability to consistently take or tolerate high intensity
 statin therapy and LDL-C ≥70 mg/dL.

 -  Subjects are only able or allowed to take lower potency statin or low weekly dose of
 high potency statin due to concern of drug-to-drug interactions or lack of tolerance
 (pravastatin ≤140 mg, pitavastatin ≤14 mg, simvastatin ≤140 mg, atorvastatin ≤70 mg,
 or rosuvastatin ≤70 mg, weekly) or intolerant of all statin doses and with fasting
 LDL-C ≥100 mg/dL.

 -  Subjects must have significant carotid artery plaque with maximum wall thickness ≥2 mm
 on ultrasound performed within twelve months of screening.

 -  Subject must present with a LRNC on baseline MRI scan.

 -  Subjects must show an adequate image quality for MRI analysis.

 -  Medically stable.

 -  Willing to participate and sign informed consent.

 Exclusion Criteria:

 -  Contraindication to MRI.

 -  Have immediate plans for bilateral carotid endarterectomy.

 -  Had received 2 or more doses of treatment with a PCSK9 inhibitor in the past 4 months.

 -  GFR ≤45 mL/min/1.73 m2 prior to MRI scan.

 -  Claustrophobia.

 -  Pregnant women; breastfeeding women; men and women of childbearing potential who are
 unwilling or unable to use a highly effective method of contraception.

 -  TIA or stroke within the preceding twelve months

 -  Severe carotid stenosis in an asymptomatic patient defined as any one of the
 following:

 1. Greater than or equal to 70% luminal narrowing on any imaging modality

 2. Peak systolic velocity greater than or equal to 250 cm/second

 3. End diastolic velocity greater than or equal to 100 cm/second

 4. Systolic volume ratio greater than or equal to 3.5