APOCIII-LRX Reduces Triglyceride Levels in High CV Risk Patients

According to a late-breaking study presented at the European Society of Cardiology (ESC) 2020 Congress, administration of APOCIII-L_RX in patients with hypertriglyceridemia and high cardiovascular (CV) risk was associated with inhibition of apolipoprotein C-III (ApoC-III) and lower levels of triglycerides.

The second-generation antisense oligonucleotide targets hepatic Apo-CIII mRNA. By binding to the liver cells, it increases uptake and allows similar therapeutic effects with lower dosage.

A previous phase 1 study assessed the effects of APOCIII-L_RX in healthy volunteers who had elevated levels triglycerides. The most notable finding from it was that the drug showed dose-dependent reductions in apoC-III, triglycerides, and atherogenic liporoteins. Furthermore, it was associated with an elevation of HDL-C levels.

This time, a team led by Jean-Claude Tardif, MD, Director of the Research Center at the Montreal Heart Institute, conducted the multicenter, double-blind, placebo-controlled, dose-ranging study to assess drug efficacy in patients with fasting plasma triglyceride levels ≥200 and ≤500 mg/dL

Furthermore, enrolled patients (n = 114) had either cardiovascular disease or were at increased risk for cardiovascular disease and other risk factors such as diabetes or hypertension.

Exclusion criteria consisted of cute coronary syndrome, major cardiac surgery, revascularization, stroke / transient ischemic attack within 3 months of screening, heart failure NYHA class III and IV, uncontrolled hypertension, and type 1 or newly diagnosed type 2 diabetes, among other criteria.

Participants were then randomized to receive APOCIII-L_RX (n = 90) or placebo (n = 24) for a minimum of 6 months and a maximum of 12.

They divided all participants into 4 dosing groups: The first group received 10 mg of the drug or placebo every 4 weeks, the second group received 15 mg of drug or placebo ever 2 weeks, the third received 10 mg every week, and the fourth received 50 mg every 4 weeks.

The primary endpoint sought by the investigators was the mean percentage change in fasting triglycerides from baseline at 6 months. Secondary endpoints included change of baseline in ApoC-III, VLDL cholesterol, and non-HDL cholesterol.

Investigators also assessed the proportion of patients who reached a serum triglyceride level of <150 mg/dL or 1.7 mmol/L.

Once all endpoints had been reached, they noted a slight increase in triglyceride levels in the placebo group. However, patients who had received maximum dosage of APOCIII-L_RX (50 mg every 4 weeks) experienced a 60% reduction in triglyceride levels (P<.0001).

The team noted improvements in levels of ApoC-III, VLDL cholesterol, non-HDL cholesterol.

Additionally, 91% patients who received maximum dosage achieved the <150 mg/dL triglyceride level—versus just 4% in the placebo group.

The most frequent treatment-emergent adverse event in the entire APOCIII-L_RX population was injection site erythema (15.6%). A total of 88.9% in the drug group experienced some type of event with 10.0% having experienced a serious event. The investigators noted that the serious adverse events were unrelated to the study drug.

Overall, the drug was well tolerated and showed a favorable safety profile.

“The take-home message is that targeting ApoC-III mRNA with this new drug clearly reduces triglycerides and ultimately may reduce the residual risk in patients with hypertriglyceridemia,” Tardif said in an interview with HCPLive®.