Metabolism Xagena

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Patients with hypertriglyceridemia, treated with AKCEA-APOCIII-LRx, have experienced dose-dependent reductions in triglyceride levels, apoC-III, and significant reductions in atherogenic lipoproteins

The phase 2 study AKCEA-APOCIII-LRx met primary and key secondary endpoints with significant reductions in triglyceride ( TG ) and apoC-III levels, and a favorable safety and tolerability profile in the treatment of patients with hypertriglyceridemia who have established cardiovascular disease or are at risk for cardiovascular disease.

AKCEA-APOCIII-LRx was designed using Ligand Conjugated Antisense ( LICA ) technology platform to inhibit production of apolipoprotein C-III ( apoC-III ), a protein produced in the liver that plays a central role in the regulation of serum triglycerides.
Epidemiological studies show that apoC-III levels may help predict risk of cardiovascular disease.

The Phase 2 study was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study designed to evaluate the safety, tolerability and efficacy of AKCEA-APOCIII-LRx in patients with hypertriglyceridemia and a clinical diagnosis of cardiovascular disease or who are at high risk of cardiovascular disease.
The study was also designed to identify the optimal dose and dose regimen to lower triglyceride, apoC-III and other lipid and lipoprotein levels for subsequent phase 3 studies.
The study involved 114 patients randomized to four cohorts and in a 4:1 ratio ( treatment : placebo ) within each cohort.
AKCEA-APOCIII-LRx or placebo was administered via subcutaneous injection for at least six months, with some patients treated up to a year. Weekly, bi-weekly, and monthly dosing regimens were explored with total monthly doses ranging from 10 mg to 50 mg.

Data from the phase 2 study have shown:

a) statistically significant dose-dependent reductions in fasting TGs compared to placebo at all dose levels with a 62% reduction at the highest dose ( 50 mg every four weeks ), and with 91% of patients achieving TG levels of less than 150 mg/dL ( 1.7 mmol/L or less ) at this dose at six months;

b) significant reductions in apoC-III ( up to 74% ) and atherogenic lipoproteins including very low-density lipoprotein ( VLDL ) cholesterol ( 60% ), non-high-density lipoprotein ( non-HDL ) cholesterol ( 24% ), and apolipoprotein B, or apoB ( 16% );

c) high-density lipoprotein ( HDL ) cholesterol levels increased by up to 42%;

d) AKCEA-APOCIII-LRx has demonstrated a favorable tolerability and safety profile with mild treatment-emergent adverse events at the injection site being the most frequent.

AKCEA-APOCIII-LRx is an investigational antisense medicine designed to reduce the production of apolipoprotein C-III, or apoC-III.
ApoC-III is a protein produced in the liver that plays a central role in the regulation of serum triglycerides.
Genetically reduced levels of apoC-III are correlated to lower levels of triglycerides and lower risk of cardiovascular disease whereas elevated levels of apoC-III correlate with high triglyceride levels that have been associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome as well as elevated cardiovascular event risk. ( Xagena )

Source: Akcea Therapeutics, 2020