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

Phase 3

Completed

Conditions: Homozygous Familial Hypercholesterolemia

Interventions: Drug: Evinacumab

Registration Number: NCT04233918

Lead Sponsor: Regeneron Pharmaceuticals

Brief Summary: 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

Detailed Description: Part A is Phase 1b Part B is Phase 3

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

Inclusion Criteria

Diagnosis of functional HoFH by either genetic or clinical criteria as defined in the protocol
LDL-C >130 mg/dL at the screening visit
Body weight ≥15 kg
Receiving stable maximally tolerated therapy*at the screening visit *Maximally tolerated therapy could include a daily statin.
Willing and able to comply with clinic visits and study-related procedures
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

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
For patients entering Part A, unable to temporarily discontinue apheresis from the baseline visit through the week 4 visit
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).
Plasmapheresis within 8 weeks of the screening visit, or plans to undergo plasmapheresis during Part A or Part B
Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins
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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Evinacumab	Evinacumab	Part A: Single intravenous (IV) dose Part B: IV dose every 4 weeks (Q4W) until week 20 Part C: IV dose Q4W

Primary Outcome Measures

Name	Time	Method
Part A: Terminal Half-Life (t1/2) of Evinacumab	Up to week 12	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.
Part A: Maximum Observed Serum Concentration (Cmax) of Evinacumab	At day 12	Cmax was obtained directly from the plasma concentration versus time curve.
Part A: Area Under the Serum Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) of Evinacumab	Up to Week 12	AUClast was defined as area under the serum concentration time-curve from zero to the last measured concentration.
Part B: Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24	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.

Secondary Outcome Measures

Name	Time	Method
Part B: Percent Change in Apolipoprotein B (Apo B) From Baseline to Week 24	Baseline to Week 24	Percent change in Apo B from baseline to Week 24 was reported.
Part B: Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24	Baseline to Week 24	Percent change in Non-HDL-C from baseline to Week 24 was reported.
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	Baseline to Week 24	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.
Part B: Percent Change in Lipoprotein A (Lp[a]) From Baseline to Week 24	Baseline to Week 24	Percent change in Lp(a) from baseline to Week 24 was reported.
Part B: Absolute Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline at Week 24	Baseline, Week 24	Absolute change in LDL-C from baseline at Week 24 was reported
Part A and Part B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Part A: up to Week 24; Part B: up to Week 48	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. 1 participant experienced an AE during part B that was recorded after Part B database lock. This was not reflected in the reported endpoint number of participants of 10.
Part B: Serum Concentration of Total Evinacumab	Pre-dose at Weeks 0, 4, 8, 12; End of infusion at Weeks 0.006, 4.006, 8.006, 12.006 and 24	Serum concentration of total evinacumab was reported. Pre-dose samples at week 0 were assayed and the reported value is based on actual measurement.
Part B: Area Under the Serum Concentration-time Curve at Steady State (AUCtau.ss) of Evinacumab	Post-dose up to day 169	AUCtau.ss was defined as area under the serum concentration-time curve at steady state of evinacumab
Part B: Minimum Serum Concentration at Steady State (Ctrough.ss) of Evinacumab	Post-dose up to day 169	Ctrough.ss was defined as minimum serum concentration at steady state of evinacumab
Part B: Maximum Serum Concentration at Steady State (Cmax,ss) of Evinacumab	Post-dose up to day 169	Maximum serum concentration (Cmax,ss) steady state following drug administration.
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
Part B: Percent Change in Total Cholesterol (TC) From Baseline to Week 24	Baseline to Week 24	Percent change in TC from baseline to Week 24 was reported.
Part B: Percentage of Participants With ≥50 Percent (%) Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24	Week 24	Percentage of participants who achieved reduction in calculated LDL-C ≥ 50% at Week 24 was reported.