This observational, multicenter, retrospective and prospective study aims to evaluate the impact of intensified lipid-lowering therapy including Evinacumab on coronary atherosclerotic plaque burden in patients with Homozygous Familial Hypercholesterolemia (HoFH).

HoFH is a rare genetic disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels from early life and a markedly increased risk of premature atherosclerotic cardiovascular disease. Despite combination lipid-lowering therapy, many patients do not achieve recommended LDL-C targets and remain at high cardiovascular risk.

Evinacumab, a monoclonal antibody targeting angiopoietin-like protein 3 (ANGPTL3), has demonstrated significant LDL-C reduction in clinical trials. However, real-world evidence on its impact on coronary plaque progression is limited.

The study will compare HoFH patients receiving intensified lipid-lowering therapy including Evinacumab with patients receiving conventional lipid-lowering therapy without Evinacumab. Coronary plaque burden and phenotype will be assessed using coronary computed tomography angiography (CCTA) performed as part of routine clinical practice.

Approximately 52 patients will be enrolled across European centers. The primary objective is to evaluate changes in non-calcified coronary plaque volume between baseline and 18-24 months' follow-up. Secondary objectives include evaluation of total plaque burden, high-risk plaque characteristics, and LDL-C reduction. Exploratory analyses will assess patient-reported outcomes, pericoronary adipose tissue characteristics, and supravalvular atherosclerosis.

All data are collected from routine clinical care. No additional procedures are mandated by the protocol. This study aims to generate real-world imaging evidence on the effect of intensified lipid-lowering therapy including Evinacumab on coronary atherosclerosis in HoFH.

This is a multicenter, international, non-profit, observational study with retrospective and prospective data collection evaluating the real-world impact of intensified lipid-lowering therapy including Evinacumab on coronary atherosclerosis in patients with Homozygous Familial Hypercholesterolemia (HoFH).

Background and Rationale

HoFH is characterized by markedly elevated LDL-C levels due to impaired LDL receptor function, leading to accelerated and diffuse atherosclerosis and early cardiovascular morbidity and mortality. Despite aggressive combination therapy (statins, ezetimibe, PCSK9 inhibitors, lomitapide, and lipoprotein apheresis), most patients fail to reach LDL-C targets.

Evinacumab is a fully human monoclonal antibody directed against ANGPTL3 and lowers LDL-C independently of LDL receptor activity. Clinical trials have demonstrated approximately 50% LDL-C reduction in HoFH patients. However, the effect of Evinacumab on coronary plaque burden and phenotype in real-world clinical practice has not been systematically evaluated.

Coronary computed tomography angiography (CCTA) allows non-invasive quantification of total plaque burden, differentiation of calcified and non-calcified plaque, and identification of high-risk plaque features. Imaging-based plaque assessment represents a validated surrogate of atherosclerosis progression and cardiovascular risk.

Study Design

This is a non-interventional, observational study conducted in approximately 25 European centers. The study includes both retrospective data (up to 30 months prior to enrollment) and prospective follow-up (up to 24 months).

Patients are allocated to cohorts based exclusively on routine clinical care decisions:

• Intensified Treatment Group: HoFH patients who initiated Evinacumab as add-on therapy to stable background lipid-lowering treatment within 24 months before enrollment.
• Conventional Treatment Group: HoFH patients receiving standard lipid-lowering therapy without Evinacumab, either due to lack of availability or clinical decision not to initiate treatment.

No therapeutic interventions are mandated or modified by the study protocol.

Study Population

Approximately 52 patients are expected to be enrolled (approximately 35 in the intensified treatment group and 17 in the conventional treatment group). Eligible patients must have a clinical or genetic diagnosis of HoFH and available baseline and follow-up CCTA scans performed according to routine clinical practice.

Objectives

Primary Objective:

To assess whether intensification of lipid-lowering therapy including Evinacumab is associated with stabilization or regression of coronary atherosclerotic plaques compared with conventional therapy, as measured by change in percent non-calcified plaque volume (NCPV) between baseline and follow-up CCTA.

Secondary Objectives:

• To evaluate changes in total plaque volume, calcified plaque volume, and percent atheroma volume.
• To assess changes in high-risk plaque characteristics (low-attenuation plaque, positive remodeling).
• To evaluate changes in LDL-C levels between groups.

Exploratory Objectives:

• To evaluate changes in patient-reported outcomes (SAQ-7, Rose Dyspnea Scale, PHQ-2).
• To assess changes in pericoronary adipose tissue (PCAT) attenuation in RCA and LAD.
• To characterize the presence and progression of supravalvular atherosclerosis.

Imaging Analysis

CCTA scans performed in routine care will be analyzed centrally using standardized, FDA-cleared artificial intelligence-based quantitative software. Blinded core laboratory analysis will ensure consistency across sites.

Statistical Considerations

The primary endpoint is the annualized change in percent NCPV from baseline to 18-24 months. Between-group comparisons will be performed using appropriate parametric or non-parametric tests. Secondary and exploratory endpoints will be analyzed descriptively and comparatively.

Safety

As a non-interventional study, safety data will be collected from routine clinical documentation. Treatment decisions remain under the responsibility of the treating physician.

Conclusion

This study will provide real-world imaging data on the effect of intensified lipid-lowering therapy including Evinacumab on coronary plaque burden and phenotype in HoFH patients. The findings may contribute to optimizing cardiovascular risk management strategies in this high-risk population.

Inclusion Criteria (intensified treatment group - Evinacumab):

1. Willing and able to provide written informed consent form/assent form for the use of retrospective and prospective data.
2. Male or female patients aged ≥12 years old at time of enrolment (exception for Italy and France ≥18 years).
3. Clinical or genetic diagnosis of Homozygous Familial Hypercholesterolemia (HoFH) according to the consensus statement by Cuchel et al, 2023; EHJ (14).
4. Patients who initiated Evinacumab (at the approved dosage and administration) within 24 months before enrolment as add-on to lipid-lowering treatment (with statins, ezetimibe, PCSK9i and/or other agents or treatment) at stable dose for at least 30 days before Evinacumab initiation, as per routine clinical care and no change in dosing is anticipated.
5. Availability of a baseline CCTA performed at least 6 months prior or 1 month after Evinacumab initiation and a follow-up CCTA performed 18-24 months after Evinacumab initiation.
6. LDL-cholesterol ≥ 140 mg/dl (3.5 mmol/L) despite lipid-lowering treatment.

Inclusion criteria (conventional treatment group - No Evinacumab)

1. Willing and able to provide written informed consent form/assent form for the use of retrospective and prospective data.

2. Male or female patients aged ≥12 years old at time of enrolment (exception for Italy and France ≥18 years).

3. Clinical or genetic diagnosis of Homozygous Familial Hypercholesterolemia (HoFH) according to the consensus statement by Cuchel et al, 2023; EHJ (14).

4. Patients with HoFH on standard lipid-lowering therapy (statins, ezetimibe, PCSK9i and/or other agents or treatment) at stable dose for at least 30 days before a baseline CCTA and with a follow-up CCTA after 18-24 months from the baseline one.

   • Required lipid lowering therapies: statin, ezetimibe and PCSK9 directed therapy (unless discontinuation due to <15% LDL-cholesterol reduction).
   • Optional additional lipid-lowering therapies:
   • Lipoprotein apheresis, at stable intervals for at least 3 months.
   • Lomitapide, at stable dose for at least 3 months.

5. LDL-cholesterol ≥ 140 mg/dl (3.5 mmol/L) despite lipid-lowering treatment.

Exclusion criteria (intensified treatment group - Evinacumab)

1. Patients participating in a clinical trial with an investigational drug within the last 6 months.
2. Patients treated outside of Evinacumab approved indication.
3. Inability to access adequate retrospective clinical data from medical records.
4. Inability or unwillingness to provide informed consent/assent or refusal to participate.
5. Previous multi-vessel coronary artery bypass grafting (CABG). Patients with single-vessel CABG are not excluded.
6. Pregnancy at the time of the LLT administration.
7. Moderate to severe renal impairment, or end-stage renal disease (ESRD) undergoing kidney transplantation or chronic renal replacement therapy.

Exclusion criteria (conventional treatment group - No Evinacumab)

1. Participation in any interventional clinical trial involving investigational drugs within the last 6 months.
2. Inability to access adequate retrospective clinical data from medical records.
3. Inability or unwillingness to provide informed consent/assent or refusal to participate.
4. Previous multi-vessel coronary artery bypass grafting (CABG). Patients with single-vessel CABG are not excluded.
5. Moderate to severe renal impairment, or end-stage renal disease (ESRD) undergoing kidney transplantation or chronic renal replacement therapy.
6. Pregnancy at the time of the LLT administration.

Intensified treatment group:

Male and Female HoFH patients aged ≥12 (exception for Italy and France ≥18 years) who initiated commercially available Evinacumab (at the approved dosage and administration) as add-on lipid-lowering treatment at stable dose for at least 30 days before Evinacumab initiation, in the routine clinical care.

Conventional treatment group:

Male and Female HoFH patients aged ≥12 (exception for Italy and France ≥18 years) on standard lipid-lowering therapy at stable dose for at least 30 days before the baseline CCTA from:

1. countries where Evinacumab will not be commercially available within the next 18 months;
2. participating countries who have the explicit wish not to receive treatment with Evinacumab.

The EVOLVE-HoFH study collects observational data on patients treated with Evinacumab and/or conventional lipid-lowering therapies in compliance with data protection regulations (GDPR) and Good Clinical Practice (GCP) guidelines. At this time, individual participant data (IPD) sharing is not planned to ensure confidentiality and adherence to ethical and legal requirements. However, aggregated study results will be made available through scientific publications and regulatory reports.