APOC3 inhibition shows therapeutic potential in severe hypertriglyceridemia

Treatment with plozasiran, an experimental small interfering–RNA drug that targets apolipoprotein C3 (APOC3) gene, helps regulate triglyceride levels, bringing them below the critical threshold associated with acute pancreatitis for most patients with severe hypertriglyceridemia, according to the phase IIb SHASTA-2* study.

All three doses of plozasiran significantly reduced triglyceride levels, the primary endpoint, compared with placebo at week 24. The reductions were dose-dependent, ranging from –49 percent (95 percent confidence interval [CI], −64.0 to −33.7; p<0.001) with 10 mg to −53 percent (95 percent CI, −68.1 to −38.0; p<0.001) with 25 mg and –57 percent (95 percent CI, −71.9 to −42.1; p<0.001) with 50 mg. [JAMA Cardiol 2024;doi:10.1001/jamacardio.2024.0959]

The triglyceride-lowering benefit of plozasiran was driven by decreases in APOC3 levels, which were likewise dose-dependent and significant relative to placebo (10 mg: −68 percent, 95 percent CI, −79.6 to −55.8; 25 mg: −72 percent, 95 percent CI, −83.2 to −59.7; 50 mg: −77 percent, 95 percent CI, −89.1 to −65.8; p<0.001 for all).

Of note, the reductions in both triglycerides and APOC3 lasted for up to week 48, even after the last dose of the drug was given at week 24.

“Nearly all (90.6 percent) patients who received plozasiran achieved a triglyceride concentration of less than 500 mg/dL at 24 weeks, the generally quoted risk threshold for acute pancreatitis. These effects were consistent across key subgroups of interest with minimal interpatient variability in pharmacodynamic response,” the investigators noted. “In addition, 48.4 percent [of patients] achieved normal triglyceride levels [of] less than 150 mg/dL.”

By week 48, triglyceride levels had remained below the said threshold in 76.5 percent of patients.

“The persistent efficacy of plozasiran was unsurprising and accounts for the 12-week dosing interval selected, consistent with its recognized mechanism as an RNA interference therapeutic,” the investigators said.

In terms of safety, the frequency of adverse events (AEs) did not significantly differ between plozasiran-treated and placebo-treated patients. The most common AEs were COVID-19 infection, worsening glycaemic control (which was limited to patients with diabetes at baseline), diarrhoea, urinary tract infection, and headache. Serious AEs were mild to moderate in severity, were not considered related to treatment, and did not lead to treatment discontinuation or death.

The modest worsening of glycaemic control with plozasiran in the highest dose group tested led to study discontinuation in one patient, the investigators noted. “HOMA-IR assessments did not suggest a change in insulin sensitivity. This may point to a change in postprandial glycemia, which could result from increased substrate delivery to the liver to drive gluconeogenesis, due to enhanced hydrolysis of chylomicrons and remnants.”

APOC3 silencing

The APOC3 gene produces APOC3 glycoproteins in the liver and intestine and suppresses lipoprotein lipase (LPL) activity. This consequently reduces the metabolism of triglyceride-rich lipoproteins (TRLs) by adipocytes, contributing to both hypertriglyceridemia and chylomicronemia, the investigators explained. In addition, APOC3 inhibition appears to specifically target postprandial triglyceride levels, believed to trigger acute pancreatitis in patients with severe hypertriglyceridemia. [Science 2008;322:1702-1705]

“Although the study was not powered to detect a difference in pancreatitis events and the acute pancreatitis incidence was low in this study of short duration, there was a numerically reduced rate [seen in] plozasiran-treated patients vs placebo (odds ratio, 0.18, 95 percent CI, 0.02–2.02),” according to the investigators.

“One acute pancreatitis event in a plozasiran-dosed patient occurred after the patient’s triglyceride levels had returned to baseline and well outside the expected dosing interval (12 weeks),” they added.

Furthermore, plozasiran was associated with reductions in remnant cholesterol and ApoB48 level, a marker of chylomicron particle number, as well as increases in high-density lipoprotein cholesterol level through week 48.

“Taken together, these results support the concept that deep and sustained inhibition of APOC3 may provide meaningful protection against a potentially fatal condition that currently has no approved effective therapies,” they said.

SHASTA-2 included 226 patients (mean age 55 years, 78 percent men) with fasting triglyceride levels in the range of 500 to 4,000 mg/dL (mean 897 mg/dL) while receiving stable lipid-lowering treatment. The mean plasma APOC3 level was 32 mg/dL. These patients were randomly assigned to receive two subcutaneous doses of plozasiran (at 10, 25, or 50 mg) or matched placebo on day 1 and at week 12. All of them were followed up through week 48.

*Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia