Regeneron's Breakthrough Lipid-Lowering Therapy Evkeeza Significantly Reduces Triglyceride Levels in Patients Without Biallelic Mutations in the LPL Pathway

May 19, 2021 /BioonBIOON/ -- Regeneron at the recently convened 70th Annual Scientific`Meeting`(ACC.21) Presented a Phase 2 trial of the novel lipid-lowering drug Evkeeza (evinacumab-dgnb)Clinical Trialdata. The results showed that, in certain patients with severe hypertriglyceridemia, Evkeeza significantly reduced triglyceride levels.

Specifically, for patients with biallelic loss-of-function mutations in lipoprotein lipase (LPL) pathway genes,Treatment with Evkeeza provides essentially no benefit. WhileIn patients with a single mutation or no mutations in LPL pathway genes, treatment with Evkeeza significantly reduced triglyceride levels.

Evkeeza is a monoclonal antibody drug that received U.S. approval in February 2021FDAApproved as an adjunct to other lipid-lowering therapies for the treatment of pediatric and adult patients aged ≥12 years with homozygous familial hypercholesterolemia (HoFH).

Evkeeza is a transformative new therapy for the treatment of HoFH, with a unique mechanism of action; this drug is AmericanFDAApprovedThe first therapy to target and block the function of angiopoietin-like protein 3 (ANGPTL3)，ANGPTL3 is a protein that plays a key role in lipid metabolism.

Professor Robert S. Rosenson, conference presenter and Director of Cardiometabolic Disorders at Mount Sinai Hospital, stated: “This study demonstrates that genotyping is a critical determinant of patient response to pharmacotherapy. For patients with a complete loss-of-function mutation in the lipoprotein lipase (LPL) gene or related genes, Evkeeza is ineffective. However, in other patients, Evkeeza demonstrates excellent efficacy.”

This Phase 2 trial, presented at the AAC meeting, enrolled a total of 51 patients with severe hypertriglyceridemia (53% male) who had triglyceride levels ≥500 mg/dL despite maximally tolerated lipid-lowering therapy and strict dietary adherence, and who had been hospitalized for acute pancreatitis at least once. Acute pancreatitis is the most common complication of severe hypertriglyceridemia.

In the study, these patients were divided into three cohorts: (1) patients with familial chylomicronemia syndrome (FCS) harboring biallelic loss-of-function mutations in APOA5, APOC2, GPIHBP1, LMF1, or LPL (Cohort 1); (2) patients with multifactorial chylomicronemia syndrome (MCS) harboring heterozygous loss-of-function mutations in APOA5, APOC2, GPIHBP1, LMF1, or LPL (Cohort 2); and (3) patients with MCS without mutations in the lipoprotein lipase (LPL) pathway (Cohort 3). Demographic and baseline characteristics were well balanced. Notably, the median baseline fasting triglyceride levels in FCS patients in Cohort 1 markedly exceeded 3000 mg/dL, whereas those in Cohorts 2 and 3 ranged between 1000 and 2000 mg/dL.

In the study, patients were randomized in a 2:1 ratio to receive Evkeeza 15 mg/kg or placebo once every 4 weeks for 12 weeks (double-blind treatment period), followed by all patients receiving Evkeeza once every 4 weeks for 12 weeks (single-blind treatment period), and subsequently a 20-week safety follow-up period. The primary endpoint of the study was the intra-patient change in serum triglyceride levels from baseline to Week 12 of treatment in Cohort 3, including patients who received Evkeeza for 12 weeks during the double-blind period, as well as those who completed placebo treatment during the double-blind period and then completed 12 weeks of Evkeeza treatment during the single-blind period.

Hypertriglyceridemia (Image source: wikidata.org)

The primary endpoint results showed: In Cohort 3, the least squares mean percent change from baseline to Week 12 in triglycerides was -27.1% (standard error: 37.4; 95% CI: -71.2 to 84.6), with a corresponding median percent change of -68.8% (95% CI: -84.1 to -38.8) or 905 mg/dL.

During the double-blind phase: (1)In Cohort 2, the median change in triglycerides in the Evkeeza group was -64.8%., placebo group was 9.4% (p=0.0076); (2)In cohort 3,The median change in triglycerides in the Evkeeza group was -81.7%., placebo group was 80.9% (p=0.0418); (3)In Cohort 1, there was no difference in the median change in triglycerides (p = 0.9495).

Additionally, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein CIII (Apo-CIII), and apolipoprotein B48 (ApoB48) levels in Cohorts 2 and 3 significantly decreased within 12 weeks. These results were also maintained during the single-blind treatment period.

In this trial, throughout the study period, the incidence of treatment-emergent adverse events (TEAEs) was similar between the Evkeeza and placebo groups (71.4% vs. 68.8%), demonstrating a favorable safety profile. The incidence of serious adverse events was 11.4% and 18.8%, respectively. During the double-blind treatment period, the incidence of acute pancreatitis was 8.6% in the Evkeeza group and 12.5% in the placebo group. (Bioon.com)

Original Source: Evinacumab Lowers Triglycerides in Severe Hypertriglyceridemia