Evaluate the Efficacy and Safety of Evinacumab in Pediatric Patients With Homozygous Familial Hypercholesterolemia

A Three-Part, Single-Arm, Open-Label Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Evinacumab in Pediatric Patients With Homozygous Familial Hypercholesterolemia

The primary objective for Part A of the study is to assess the pharmacokinetics (PK) of evinacumab in pediatric patients with homozygous familial hypercholesterolemia (HoFH).

The primary objective for Part B of the study is to demonstrate a reduction of low-density lipoprotein cholesterol (LDL-C) by evinacumab in pediatric (5 to 11 years of age) patients with HoFH.

The secondary objective for Part A of the study is to evaluate the safety and tolerability of evinacumab administered intravenous (IV) in pediatric patients with HoFH.

The secondary objectives for Part B of the study are:

• To evaluate the effect of evinacumab on other lipid parameters (ie, apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), lipoprotein a [Lp(a)]) in pediatric patients with HoFH
• To evaluate the safety and tolerability of evinacumab administered IV in pediatric patients with HoFH
• To assess the PK of evinacumab in pediatric patients with HoFH
• To assess the immunogenicity of evinacumab in pediatric patients with HoFH over time
• To evaluate patient efficacy by mutation status

Study Overview

• Status: Completed
• Conditions: Homozygous Familial Hypercholesterolemia
• Intervention / Treatment: Drug: Evinacumab

Detailed Description

Part A is Phase 1b Part B is Phase 3

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Regeneron Research Center
• Austria
  • Vienna, Austria, 1090
    • Regeneron Research Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Regeneron Research Site
• Taiwan
  • Taipei, Taiwan, 11217
    • Regeneron Research Center
• Ukraine
  • Kyiv, Ukraine, 04209
    • Regeneron Research Site
• United States
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Regeneron Research Site
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Regeneron Research Site
  • Kansas
    • Kansas City, Kansas, United States, 66190
      • Regeneron Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Regeneron Research Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19106
      • Regeneron Research Center
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • Regeneron Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 9 years (Child)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Diagnosis of functional HoFH by either genetic or clinical criteria as defined in the protocol
2. LDL-C >130 mg/dL at the screening visit
3. Body weight ≥15 kg
4. Receiving stable maximally tolerated therapy*at the screening visit *Maximally tolerated therapy could include a daily statin.
5. Willing and able to comply with clinic visits and study-related procedures
6. Parent(s) or legal guardian(s) must provide the signed informed consent form (ICF). Patients ≥5 years of age (or above age determined by the IRB/EC and in accordance with the local regulations and requirements) must also provide informed assent forms (IAFs) to enroll in the study, and sign and date a separate IAF or ICF signed by the parent(s)/legal guardian(s) (as appropriate based on local regulations and requirements)

Key Exclusion Criteria:

1. Background pharmacologic LMT, nutraceuticals or over-the-counter (OTC) therapies known to affect lipids, at a dose/regimen that has not been stable for at least 4 weeks (8 weeks for PCSK9 inhibitors) before the screening visit and patient is unwilling to enter the run-in period
2. For patients entering Part A, unable to temporarily discontinue apheresis from the baseline visit through the week 4 visit
3. Receiving lipid apheresis, a setting (if applicable) and schedule that has not been stable for approximately 8 weeks before the screening visit or an apheresis schedule that is not anticipated to be stable over the duration of the treatment period (48 weeks).
4. Plasmapheresis within 8 weeks of the screening visit, or plans to undergo plasmapheresis during Part A or Part B
5. Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins
6. Newly diagnosed (within 3 months prior to randomization visit) diabetes mellitus or poorly controlled diabetes as defined in the protocol

Note: Other protocol-defined criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Evinacumab; Part A: Single intravenous (IV) dose Part B: IV dose every 4 weeks (Q4W) until week 20 Part C: IV dose Q4W	Drug: Evinacumab; Part A: Single IV dose Part B & C: IV dose Q4W; Other Names: REGN1500; Evkeeza™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Maximum Observed Serum Concentration (Cmax) of Evinacumab	Cmax was obtained directly from the plasma concentration versus time curve.	At day 12
Part A: Area Under the Serum Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) of Evinacumab	AUClast was defined as area under the serum concentration time-curve from zero to the last measured concentration.	Pre-dose at Week 0; End of infusion at Week 0.006, 1, 2, 4, 8 and 12
Part A: Terminal Half-Life (t1/2) of Evinacumab	T1/2 was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.	Pre-dose at Week 0; End of infusion at Week 0.006, 1, 2, 4, 8 and 12
Part B: Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24	Percent change was calculated as 100 multiplied by (calculated LDL-C value at Week 24 minus calculated LDL-C value at baseline) divided by calculated LDL-C value at baseline.	Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A and Part B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Any untoward medical occurrence in a participant who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAE was defined as AE starting/worsening after first intake of study drug. TEAE included participants with both serious and non-serious AEs.	Part A: up to Week 24; Part B: up to Week 48
Part B: Percent Change in Apolipoprotein B (Apo B) From Baseline to Week 24	Percent change in Apo B from baseline to Week 24 was reported.	Baseline to Week 24
Part B: Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24	Percent change in Non-HDL-C from baseline to Week 24 was reported.	Baseline to Week 24
Part B: Percent Change in Total Cholesterol (TC) From Baseline to Week 24	Percent change in TC from baseline to Week 24 was reported.	Baseline to Week 24
Part B: Percentage of Participants With ≥50 Percent (%) Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24	Percentage of participants who achieved reduction in calculated LDL-C ≥ 50% at Week 24 was reported.	Week 24
Part B: Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 in Participants Who Have Negative/Negative and Null/Null Mutations	Participants with HoFH was classified based on the phenotype of the Low-density lipoprotein receptor (LDLR) mutation(s), ranging from defective mutations (where the LDLR retains some LDL-binding functionality) to null or negative mutations where no functioning LDLR was expressed. Participants who have LDLR activity <15% are considered null and participants whose LDLR activity was impaired but >15% are LDLR defective. Percent change in calculated LDL-C from baseline to Week 24 in participants who have negative/negative and null/null mutations was reported.	Baseline to Week 24
Part B: Percent Change in Lipoprotein A (Lp[a]) From Baseline to Week 24	Percent change in Lp(a) from baseline to Week 24 was reported.	Baseline to Week 24
Part B: Absolute Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline at Week 24	Absolute change in LDL-C from baseline at Week 24 was reported	Baseline, Week 24
Part B: Serum Concentration of Total Evinacumab	Serum concentration of total evinacumab was reported. Pre-dose samples at week 0 were assayed and the reported value is based on actual measurement.	Pre-dose at Weeks 0, 4, 8, 12; End of infusion at Weeks 0.006, 4.006, 8.006, 12.006 and 24
Part B: Maximum Serum Concentration at Steady State (Cmax,ss) of Evinacumab	Maximum serum concentration (Cmax,ss) steady state following drug administration.	Post-dose on Days 1, 29, 57, 85 and 169
Part B: Area Under the Serum Concentration-time Curve at Steady State (AUCtau.ss) of Evinacumab	AUCtau.ss was defined as area under the serum concentration-time curve at steady state of evinacumab	Post-dose on Days 1, 29, 57, 85 and 169
Part B: Minimum Serum Concentration at Steady State (Ctrough.ss) of Evinacumab	Ctrough.ss was defined as minimum serum concentration at steady state of evinacumab	Post-dose on Days 1, 29, 57, 85 and 169
Part B: Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 in Participants Who Have by Null/Null vs. Non-null/Null and Negative/Negative vs.Non-negative/Negative Mutations		Baseline to Week 24

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2020
• Primary Completion (Actual): January 31, 2022
• Study Completion (Actual): May 30, 2023

Study Registration Dates

• First Submitted: January 6, 2020
• First Submitted That Met QC Criteria: January 16, 2020
• First Posted (Actual): January 18, 2020

Study Record Updates

• Last Update Posted (Actual): June 7, 2023
• Last Update Submitted That Met QC Criteria: June 5, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: HoFH
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II; Homozygous Familial Hypercholesterolemia
• Other Study ID Numbers: R1500-CL-17100; 2019-001931-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
• IPD Sharing Time Frame: Individual anonymized participant data will be considered for sharing once the indication has been approved by a regulatory body, if there is legal authority to share the data and there is not a reasonable likelihood of participant re-identification.
• IPD Sharing Access Criteria: Qualified researchers may request access to anonymized patient level data or aggregate study data when Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency [EMA], Pharmaceuticals and Medical Devices Agency [PMDA], etc) for the product and indication, has the legal authority to share the data, and has made the study results publicly available (eg, scientific publication, scientific conference, clinical trial registry).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No