Severe hypertriglyceridemia (sHTG) is a condition that plasma triglyceride level greater than 500 mg/dL. Elevated triglyceride levels can increase risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic fatty liver, and acute pancreatitis. Apolipoprotein C3 (APOC3) is a glycoprotein produced primarily in the liver and intestine, and it plays a key role in inhibiting lipoprotein lipase (LPL), thereby reducing the metabolism of triglyceride-rich lipoproteins (TRLs) by adipocytes and slowing hepatic TRL uptake, contributing to both hypertriglyceridemia and chylomicronemia. Plozasiran is a double-stranded small interfering RNA (siRNA) that is administered subcutaneously and designed to selectively degrade the messenger RNA coding for APOC3. As shown in the phase 1 study data, plozasiran provides significant and durable APOC3 reductions.

SHASTA-2 randomized clinical trial was conducted to evaluate the efficacy and safety of repeated administration of plozasiran in patients with sHTG.

The SHASTA-2 study is a placebo-controlled, double-blinded, randomized clinical trial. Patients with fasting triglyceride levels of 500-4000 mg/dl under lipid-lowering treatment were enrolled in this study. Plozasiran (10, 25, 50 mg) or placebo was given to participants subcutaneously at weeks 0 and 12 with patients followed up to week 48. The primary end-point evaluated the difference in means between each dose group and pooled placebo groups of percentage triglyceride change from baseline at week 24; secondary end-points included changes in other lipoproteins (APOC3, total apolipoprotein B [ApoB], non–high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDLC], HDL C, and remnant cholesterol.

Of 229 patients, 226 were included in the primary analyses. The mean age of the patients was 55 years. Of the included patients, 78% were males. Plozasiran induced significant dose-dependent placebo-adjusted reductions in triglyceride levels and APOC3 at week 24 with the highest dose. Among plozasiran-treated patients, approximately 90.6% achieved a triglyceride level of less than 500 mg/dL. Plozasiran was associated with dose-dependent increases in LDL levels. However, apolipoprotein B levels did not increase, and non-HDL-C levels decreased significantly at all doses. There were also significant durable reductions in remnant cholesterol and ApoB48 as well as increases in HDL-C level through week 48. Adverse event rates were similar in plozasiran-treated patients vs. placebo.

This study shows that Plozasiran significantly reduces serum triglyceride levels and improves triglyceride-related lipoproteins in patients with sHTG. Although an increase in LDL-C levels was observed, decreases in apoB48 and non-HDL-C levels were observed. Long-term follow-up studies are needed to investigate the effect of the improvement in plasma lipid levels achieved with the use of plozasiran on clinical outcomes.

An important finding is that triglyceride levels decrease below 500 mg/dl in 90.6% of patients after using Plozasiran. As it is known, this level significantly reduces the risk of acute pancreatitis. Its effect on hypertriglyceridemia-related complications such as ASCVD needs to be assessed in long-term clinical follow-up.