Trial Outcomes & Findings for Safety and Efficacy Following Repeat-Dose of Evinacumab (Anti-ANGPTL3) in Patients With Severe Hypertriglyceridemia (sHTG) at Risk for Acute Pancreatitis (NCT NCT03452228)

A total of 17 centers enrolled participants in Italy, Canada, the United Kingdom of Great Britain and Northern Ireland, and the United States.

Based upon information (or lack of information) on genotype in medical history at screening, eligible patients were enrolled into 1 of 3 cohorts; 51 of 74 patients screened were randomized and treated during the double-blind treatment period (DBTP).

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

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.

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.

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.

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.

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.

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.

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.

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.

Concentrations of total evinacumab in serum by time and DBTP treatment group reported

Concentrations of total ANGPTL3 in serum by time and DBTP treatment group reported

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.

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.

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.

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.