Assessing the Impact of Intensification of Lipid Lowering Therapy With Guidelines-based Evinacumab Administration on Coronary Plaque Volumes Measured by Coronary Computed Tomography Angiography (CCTA) in Patients With Homozygous Familial Hypercholesterolemia (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.

Primary outcomes

• Stabilization or regression of atherosclerotic coronary plaques as measured by CCTA in Evinacumab patients vs conventional ones [Baseline, 6 months, 12 months, 18-24 months]: This measure will compare the change in percent of non-calcified coronary plaque volume (NCPV) between baseline and follow-up, as assessed by CCTA, in HoFH patients receiving intensified lipid lowering therapy including Evinacumab versus those managed with conventional lipid-lowering therapy under routine clinical care.

Secondary outcomes

• Change in absolute NCPV, TPV and CPV [Baseline, 6 months, 12 months, 18-24 months]: Asses changes in absolute NCPV, total plaque volume (TPV) and calcified plaque volume (CPV) from baseline to follow-up within each treatment group.
• Change in percent NCPV, PAV and CPV [Baseline, 6 months, 12 months, 18-24 months]: Asses changes in percent NCPV, percent atheroma volume (PAV) and percent CPV from baseline to follow-up within each treatment group.
• Change in absolute and percent NCPV, TPV, CPV and PAV [Baseline, 6 months, 12 months, 18-24 months]: Assess Differences in change between groups (Evinacumab vs. conventional therapy) for absolute and percent NCPV, TPV, CPV, and PAV.
• Low attenuation non-calcified plaque volume [Baseline, 6 months, 12 months, 18-24 months]: Assess low attenuation non-calcified plaque volume (ideally <30 HU)
• Change in segment involvement score [Baseline, 6 months, 12 months, 18-24 months]: Assess changes in segment involvement score
• Change in absolute and percent of LDL-Cholesterol levels [Baseline, 6 months, 12 months, 18-24 months]: Assess changes in LDL-Cholesterol levels (absolute and percent) between baseline and follow-up, both within and between treatment groups.
• Positive remodeling [Baseline, 6 months, 12 months, 18-24 months]: Assess remodeling index (if positive > 1.1)
• Combined features defining high-risk plaque [Baseline, 6 months, 12 months, 18-24 months]: Assess combined features defining high-risk plaque
• Change in plaque phenotype conversion [Baseline, 6 months, 12 months, 18-24 months]: Assess changes in plaque phenotype conversion (e.g. from non-calcified to calcified).

Other outcomes

• Changes in patient reported outcomes (SAQ-7) [Baseline, 6 months, 12 months, 18-24 months]: Assess symptoms related to angina pectoris using a standard questionnaire (SAQ-7) from baseline to follow-up in the intensified treatment and conventional treatment comparator group and also between the two groups. The Seattle Angina Questionnaire is used to assess the frequency and impact of chest pain, chest tightness, or angina over the previous four weeks. The questionnaire evaluates physical limitation during daily activities, frequency of angina episodes, frequency of nitroglycerin use, the extent to which symptoms limit enjoyment of life, and overall satisfaction with current symptom status. Responses are provided using Likert-type scales, with higher scores reflecting better health status and fewer symptom-related limitations.
• Change in PCAT attenuation in RCA [Baseline, 6 months, 12 months, 18-24 months]: Assess changes in PCAT Attenuation (Hounsfield Units) in Right Coronary Artery (RCA).
• Characterization of supravalvular atherosclerosis [Baseline, 6 months, 12 months, 18-24 months]: Characterization of supravalvular atherosclerosis as assessed by available CCTA, including its presence, distribution, and potential changes over time.
• Changes in patient reported outcomes (Rose Dyspnea Scale) [Baseline, 6 months, 12 months, 18-24 months]: Assess symptoms related to dyspnea using a standard questionnaire (Rose Dyspnea Scale) from baseline to follow-up in the intensified treatment and conventional treatment comparator group and also between the two groups. The Dyspnea Score ranges from 0 to 4: a score of 0 indicates no dyspnea; 1 indicates dyspnea only when hurrying or walking up a hill; 2 indicates dyspnea when walking on level ground with people of the same age; 3 indicates dyspnea when walking at one's own pace on level ground; 4 indicates dyspnea during activities of daily living such as washing or dressing.
• Changes in patient reported outcomes (PHQ-2) [Baseline, 6 months, 12 months, 18-24 months]: Assess symptoms related to depression using a standard questionnaire (PHQ-2) from baseline to follow-up in the intensified treatment and conventional treatment comparator group and also between the two groups. Over the last two weeks, patients are asked how often they have been bothered by specific problems. The first item assesses little interest or pleasure in doing things and the second assesses feeling down, depressed, or hopeless. Each item is scored on a 4-point scale: 0 for "not at all," 1 for "several days," 2 for "more than half the days," and 3 for "nearly every day." The total score is calculated by summing the scores of the two items.
• Change in PCAT Attenuation in LAD [Baseline, 6 months, 12 months, 18-24 months]: Assess changes in PCAT Attenuation (Hounsfield Units) in Left Anterior Descending Artery (LAD).

Sex: All, ages: 12 Years to any

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.