Safety and Efficacy Following Repeat-Dose of Evinacumab (Anti-ANGPTL3) in Patients With Severe Hypertriglyceridemia (sHTG) at Risk for Acute Pancreatitis

Study Overview
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Brief Summary
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The primary objective is to determine the change in Triglyceride (TG) levels following 12 weeks of repeated Intravenous (IV) doses of evinacumab.

Official Title
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A Phase 2, Randomized, Placebo-Controlled Study of Safety and Efficacy, Following Repeat-Dose Administration of Evinacumab (Anti-ANGPTL3) in Patients With Severe Hypertriglyceridemia (sHTG) at Risk for Acute Pancreatitis

Conditions
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Severe Hypertriglyceridemia (sHTG)

Intervention / Treatment
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* Drug: evinacumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Previous documentation in the patient's medical records of a fasting serum TG measurement ≥ 1000 mg/dL (11.3 mmol/L) on more than 1 occasion, and all fasting TG values ≥500 mg/dL (5.6 mmol/L) at screening History of a hospitalization and diagnosis of acute pancreatitis in the past 10 years On stable lipid-modifying diet with or without medications (eg, statins, niacin, omega-3 fatty acids). Lipid-modifying diet and doses of medications should be stable for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitors) prior to screening Body mass index (BMI) of 18-40 kg/m2 Key Exclusion Criteria: A hospital or clinic discharge diagnosis of acute pancreatitis within 12 weeks of screening Lipid apheresis or plasma exchange treatment within the last 4 weeks or plans to undergo apheresis or plasma exchange during the time frame of the study History of class 3/4 heart failure at any time in the past, or hospitalization for heart failure, diagnosis of a myocardial infarction, stroke, Transient ischemic attack (TIA), unstable angina, Coronary artery bypass surgery (CABG), Percutaneous coronary intervention (PCI), carotid surgery/stenting within 3 months before the screening visit History of bleeding disorders, esophageal varices, heparin induced thrombocytopenia, or contraindications to receiving heparin (eg, allergic reaction to heparin) Previous treatment with Glybera® in the past 5 years or treatment with lomitapide or mipomersen in the past 6 months Pregnant or breast feeding women Note: Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: evinacumab<br> | Drug: evinacumab<br>* Administered by Intravenous (IV)<br>* Other names: REGN1500;|
| Experimental: Placebo<br> | Drug: Placebo<br>* Administered by Intravenous (IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Fasting Triglycerides (TG) Level Following 12 Weeks of Repeated IV Doses of Evinacumab in Actual Cohort 3 Participants | For participants randomized to evinacumab treatment group, baseline (Week 0) TG was defined as the geometric mean of all available TG results at day -28, day -14 and week 0; for participants randomized to placebo treatment group, baseline (Week 12) TG was defined as the geometric mean of all available TG results at weeks 6, 8, and 12. | Participants randomized to evinacumab: Week 0 corresponds to Baseline and 12 weeks treatment corresponds to Week 12 of the DBTP; Participants randomized to placebo: Week 12 corresponds to Baseline and 12 weeks treatment corresponds to Week 24 of the SBTP | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Fasting TG Level Following 2 to 24 Weeks of Repeated IV Doses of Evinacumab Overall Group | Percent change from baseline in fasting TG level following 2 to 24 weeks of repeated IV doses of evinacumab overall group during DBTP and SBTP was reported. | DBTP: Baseline, Weeks 2, 4, 6, 8, 12; SBTP: Weeks 16, 20, and 24 | 
| Percent Change From Baseline in Fasting TG Level Following 2 to 24 Weeks of Repeated IV Doses of Evinacumab in Actual Cohorts 1, 2, and 3 | Percent change from baseline in fasting TG level following 2 to 24 weeks of repeated IV doses of evinacumab in actual cohorts 1, 2, and 3 participants were reported. | Weeks 2, 4, 6, 8, 12, 16, 20, and 24 | 
| Change From Baseline in Total Score of Participants Reported Abdominal and Gastrointestinal (GI) Symptoms Using Hypertriglyceridemia and Acute Pancreatitis Symptom Scale (HAP-SS) | HAP-SS: 19-item measure of symptoms with a 24-hour recall period. 4 pain items were captured on 0-10-point severity NRS, each scored 0 (No pain) to 10 (Worst possible pain), while 15 non-pain items captured on 5-point frequency Likert scale, each scored from 1 (None of the time) to 5 (All of the time). Pain domain 4 items: stomach pain average, worst stomach pain, worst back pain, stomach pain after eating (score range: 0 to 40). Abdominal symptoms domain 6 items: bloated, nausea, vomiting, passed excessive gas, diarrhea, light-colored or greasy stool (score range: 6 to 30). Physical symptoms domain 5 items: fever, insomnia, excessive sweating, dizziness, racing heart rate (score range 5 to 25). Other symptoms domain 4 items: fatigue, loss of appetite, hungry after eating, felt full after eating a small amount (score range 4 to 20). All items were transformed on to total score ranges from 0 (no symptoms) to 100 (severe symptoms). Negative change indicates better condition. | Baseline, Week 12 (DBTP), Week 24 (SBTP) | 
| Change From Baseline in Total Score of Participants Reported Dietary Behavior Questionnaire (HAP-DB) | Dietary habits and impact were measured by the Hypertriglyceridemia and Acute Pancreatitis Dietary Behavior (HAP-DB) questionnaire, a 6- item measure of dietary behavior that had a 24-hour recall period using a 5-point frequency Likert scale (1= None of the time to 5= All of the time) and a dietary impact total score, ranging from 6 (no impact) to 30 (severe impact). The six HAP-DB items were: 1 -amount of food eaten), 2 -fatty or greasy food), 3 -carbohydrates), i4 (-sugar or sugary foods), 5 -alcohol intake), 6 -skipped meal). The total score was calculated as the sum of the six item scores and then transformed to a 0-100 score, where lower score indicates less of an issue with dietary behaviors. Transformed score = 100 * (score - minimum possible score) / (maximum - minimum possible score). Change from baseline in total score of participants reported daily dietary habits and impact questionnaire during DBTP and SBTP was reported. | Baseline, Week 12 (DBTP), Week 24 (SBTP) | 
| DBTP: Change From Baseline in Degree of Pancreatic Injury/Inflammation Through 18F-2-Fluoro-2-Deoxy-D Glucose Positron Emission Tomography (18F-FDG-PET) Imaging Following 12 Weeks of Treatment With Evinacumab Assessed by 18F-FDG SUVmax and SUVmean | 18F-FDG-PET is a molecular imaging modality that has demonstrated high sensitivity in the in vivo detection of glycolytic tissues, including tumors and inflammatory foci. 18F-FDG PET has been applied in a clinical setting to the assessment of inflammation for a variety of indications, including auto immune pancreatitis, atherosclerosis and infection. 18F-FDG-PET was performed at baseline (placebo run-in period) and following 12 weeks of study treatment (double-blind treatment period) as a method to measure inflammation in the pancreas. Here, SUVmax was standardized uptake values maximum and SUVmean was mean standardized uptake values were reported. | Participants randomized to evinacumab: Week 0 corresponds to Baseline and 12 weeks treatment corresponds to Week 12 of the DBTP; Participants randomized to placebo: Week 12 corresponds to Baseline and 12 weeks treatment corresponds to Week 24 of the SBTP | 
| DBTP: Change From Baseline in Degree of Pancreatic Injury/Inflammation Through Diffusion Weighted-Magnetic Resonance Imaging (DW-MRI) Following 12 Weeks of Treatment With Evinacumab Assessed by Apparent Diffusion Coefficient (ADC) | In DW-MRI the random diffusion of water molecules occurring within intracellular, extracellular and intravascular spaces were measured, enabling detection of macroscopic soft tissue pathology such as edema, necrosis and fibrosis. The ADC was a principal metric quantified in DW-MRI experiments, where ADC values was mapped across a region of interest at a spatial resolution of  3*3*5 cubic millimeter (mm^3). Normal pancreas ADCs were considered as (1.77±0.32)*103 square-millimeters per second (mm^2/sec) while acute pancreatitis ADCs were (1.32±0.32)* 103 mm^2/sec showing a significant window for measuring projected inflammatory changes in pancreas. DW-MRI was performed at baseline (placebo run-in period) and following 12 weeks of study treatment (double-blind treatment period) as a method to measure inflammation in the pancreas. Change from baseline in degree of pancreatic injury/inflammation through DW-MRI following 12 weeks of treatment with evinacumab assessed by ADC was reported. | Participants randomized to evinacumab: Week 0 corresponds to Baseline and 12 weeks treatment corresponds to Week 12 of the DBTP; Participants randomized to placebo: Week 12 corresponds to Baseline and 12 weeks treatment corresponds to Week 24 of the SBTP | 
| SBTP: Change From Baseline to Degree of Pancreatic Injury/Inflammation Through DW-MRI Following 24 Weeks of Treatment With Evinacumab as Assessed by ADC | In DW-MRI, the random diffusion of water molecules occurring within intracellular, extracellular and intravascular spaces were measured, enabling detection of macroscopic soft tissue pathology such as edema, necrosis and fibrosis. The ADC was a principal metric quantified in DW-MRI experiments, where ADC values was mapped across a region of interest at a spatial resolution of  3*3*5 mm^3. Normal pancreas ADCs were considered as (1.77±0.32)*103 mm^2/sec while acute pancreatitis ADCs are (1.32±0.32)* 103 mm^2/sec showing a significant window for measuring the projected inflammatory changes in the pancreas. Change from baseline to degree of pancreatic injury/inflammation through DW-MRI following 24 weeks of treatment with evinacumab assessed by ADC was reported. | Baseline (Week 0 DBTP), Week 24 (SBTP) | 
| Total Evinacumab Concentration in Serum | Concentrations of total evinacumab in serum by time and DBTP treatment group reported | Up to 44 weeks | 
| Total Angiopoietin-like (ANGPTL3) Concentration in Serum | Concentrations of total ANGPTL3 in serum by time and DBTP treatment group reported | Up to 44 weeks | 
| Number of Participants With Antidrug Antibodies (ADA) | ADA were classified as the following: 1) Negative any time (negative in ADA assay at all time points); 2) Pre-existing immunoreactivity (ADA positive response at baseline with all post treatment ADA results negative or ADA positive response at baseline with all post treatment responses less than 9-fold of baseline titer levels); 3) Treatment-boosted Response (ADA positive response in assay post first dose that is at least 9-fold over baseline titer levels, when baseline results were positive); 4) Treatment-emergent ADA response (ADA positive response post first dose, when baseline results were negative or missing). Number of participants with ADA by DBTP treatment group reported. | Up to 44 weeks | 
| DBTP: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs are AEs that developed or worsened or became serious during the respective TEAE period. Number of participants who experienced a TEAE/serious TEAE during the DBTP reported. | From first dose of DB treatment to day of last dose of DB treatment + 24 weeks (if not proceeding to SBTP) or up to day before first dose of SB treatment in SBTP | 
| SBTP: Number of Participants With TEAEs and Serious TEAEs | TEAEs are AEs that developed or worsened or became serious during the respective TEAE period. Number of participants who experienced a TEAE/serious TEAE during the SBTP reported. | From day of first SB study treatment to day of last SB treatment + 24 weeks | 
| Number of Participants With Liver Function Laboratory Abnormalities in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP), and Total Bilirubin | The number of participants with laboratory abnormalities in ALT, AST, ALP, and total bilirubin that fell into the pre-defined potentially clinically significant value (PCSV) categories reported: ALT: greater than (>)2 upper limit of normal (ULN) and baseline (BL) less than or equal to (<=) 2 ULN, less than (>) 3 ULN and baseline <= 3 ULN, >5 ULN and baseline <= 5 ULN, >10 ULN and baseline ≤ 10 ULN, >20 ULN and baseline <= 20 ULN; AST: >2 ULN and baseline ≤ 2 ULN, >3 ULN and baseline <= 3 ULN, >5 ULN and baseline <= 5 ULN, >10 ULN and baseline <= 10 ULN, >20 ULN and baseline <= 20 ULN; ALP: > 1.5 ULN and baseline <= 1.5 ULN; Total Bilirubin (TB): > 1.5 ULN and baseline <= 1.5 ULN, > 2 ULN and baseline <= 2 ULN. | Baseline up to 44 weeks |