MUNICH — The drug also demonstrated an impact on acute pancreatitis risk. In a prespecified pooled analysis of the SHASTA trials, acute pancreatitis events were reduced by 78% in patients treated with plozasiran versus placebo (P=0.008). The reduction in acute pancreatitis events represented a 4.1% absolute risk reduction with a number needed to treat of 24 to prevent one event over 1 year.

SHASTA-3 and SHASTA-4 were double-blind phase III studies comparing plozasiran 25 mg, given as a subcutaneous injection every 3 months for 12 months, with placebo. Across the two studies, 757 patients were randomized 2:1 to plozasiran versus placebo. Participants in the SHASTA trials were eligible if they had triglyceride levels of 500 mg/dL or greater.

The mean age of participants in the SHASTA trials was 53 years and 22% were women. The SHASTA trials were conducted across 24 countries.

The triglyceride reduction from plozasiran started at 3 months after the first injection and was sustained over 12 months. At 12 months, 91-93% of plozasiran-treated patients achieved triglyceride levels below 500 mg/dL, compared with 50-51% of those on placebo (P<0.001 for both). More than 50% of patients randomized to plozasiran had triglyceride levels reduced below 150 mg/dL, compared with less than 10% of placebo recipients.

The benefits were pronounced in high-risk subgroups. Treatment reduced pancreatitis by 91% among patients with a history of acute pancreatitis versus placebo. Treatment reduced pancreatitis by 100% among patients with triglycerides over 880 mg/dL and a history of pancreatitis.

Plozasiran is an RNA interference therapeutic that targets apolipoprotein C-III (APOC3) to reduce triglycerides by sustained silencing of APOC3 mRNA. Apolipoprotein C-III (APOC3) is produced in the liver and raises triglycerides by slowing catabolism. Severe hypertriglyceridemia is a heterogenous disorder driven by polygenic factors and secondary causes including obesity and type 2 diabetes.

Safety data from the trials indicated no new safety signals were seen in the pooled safety analysis of the SHASTA trials. Treatment-emergent adverse events occurred in 8.3% of patients receiving plozasiran and in 10% of those on placebo. Adverse events leading to study drug discontinuation occurred in 1.4% of the treatment group and 0.8% of the placebo group.

Worsening glycemic control was seen in 14% of treated patients versus 9% of placebo recipients. HbA1c increased slightly in the first 3 months but stabilized and appeared to regress back to normal at 12 months. In a prespecified MRI substudy, there was no emergent increase in liver fat fraction.

Gerald Watts, MD, PhD, from the University of Western Australia, presented the SHASTA trial results at the European Society of Cardiology (ESC) Congress in Munich. The SHASTA trial results were published simultaneously in the New England Journal of Medicine. Borge G. Nordestgaard, MD, from Copenhagen University Hospital, served as an ESC discussant on the plozasiran results.

"Two years ago, we presented the PALISADE trial for FCS [familial chylomicronemia syndrome], which is a disorder which is 500 times less frequent than this one. Now we're presenting a disorder that is in day-to-day clinical practice," Watts said. "If the clinical guidelines support this, if the regulators give it a label, this agent has a good chance really, a very good chance of being game-changing in the clinic."

Nordestgaard noted areas requiring further investigation. "What we do need to know more about is that these patients have a lot of extra risk of [atherosclerotic cardiovascular disease], so that's what we need to study in the future," he said.

Plozasiran gained approval last year to reduce triglycerides in familial chylomicronemia syndrome (FCS) based on the PALISADE trial. Plozasiran received regulatory approval as REDEMPLO® in the United States, European Union, China, Australia, and Canada as an adjunct to diet to reduce triglycerides in adults with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome (FCS). Arrowhead Pharmaceuticals plans to submit data from the SHASTA trials and the MUIR-3 study to the FDA for approval in patients with severe hypertriglyceridemia. Patients could enroll in an open-label extension trial at the same dose for up to 24 months.

Why It Matters

Severe hypertriglyceridemia affects a broader patient population than the rare familial chylomicronemia syndrome for which plozasiran was previously approved. The SHASTA trials demonstrate efficacy in a condition driven by polygenic factors and secondary causes such as obesity and type 2 diabetes, which are common in clinical practice. The reduction in acute pancreatitis events addresses a serious complication associated with elevated triglyceride levels.

Arrowhead will host a conference call and webcast on August 31, 2026 (14:00 CEST/ 8:00 am EDT/ 5:00 am PDT) to discuss the detailed SHASTA-3 and SHASTA-4 results presented at ESC Congress 2026. Long-term efficacy and safety data for plozasiran across a spectrum of hypertriglyceridemia are available from the open-label extension period of SHASTA-2 and MUIR Trials. A study titled "Use of plozasiran across a spectrum of hypertriglyceridemia: Long-term efficacy and safety data from the open-label extension period of SHASTA-2 and MUIR Trials" was published in 2026 in American Journal of Preventive Cardiology.

What's New

The SHASTA-3 and SHASTA-4 studies were global, double-blind, placebo-controlled Phase 3 trials evaluating plozasiran 25 mg administered subcutaneously once every three months in adults with severe hypertriglyceridemia.

Plozasiran reduced the rate of all acute pancreatitis (AP) events by 78% versus placebo (RR 0.22; 95% CI: 0.07, 0.67; p=0.008), corresponding to a 4.1% absolute risk reduction and a number needed to treat of 24 to prevent one AP event over one year.

How Sources Differ

Sources differ on the specific focus of plozasiran data. The American Journal of Preventive Cardiology published a study titled Use of plozasiran across a spectrum of hypertriglyceridemia: Long-term efficacy and safety data from the open-label extension period of SHASTA-2 and MUIR Trials in 2026. SHASTA-3 and SHASTA-4 clinical trial results reported that treatment with plozasiran significantly reduced triglycerides among patients with severe hypertriglyceridemia in two phase III studies, SHASTA-3 and SHASTA-4.

Data availability descriptions vary between sources. SHASTA-3 and SHASTA-4 clinical trial results focused on the significant reduction of triglycerides among patients with severe hypertriglyceridemia in the two phase III studies.

Study protocols and results provide different details on comparisons. SHASTA-3 and SHASTA-4 study protocols described the trials as double-blind phase III studies comparing plozasiran 25 mg, given as a subcutaneous injection every 3 months for 12 months, with placebo. SHASTA-3 and SHASTA-4 clinical trial results reported that at 12 months, 91-93% of plozasiran-treated patients achieved triglyceride levels below 500 mg/dL, compared with 50-51% of those on placebo (P<0.001 for both).

Timing details also differ between protocol and result descriptions. SHASTA-3 and SHASTA-4 study protocols outlined the comparison of plozasiran 25 mg given every 3 months for 12 months against placebo. SHASTA-3 and SHASTA-4 clinical trial results specified that the triglyceride reduction from plozasiran started at 3 months after the first injection and was sustained over 12 months.

Regulatory and data submission contexts present different details regarding hypertriglyceridemia.

Descriptions of the target population vary slightly. SHASTA-3 and SHASTA-4 clinical trial results reported that treatment with plozasiran significantly reduced triglycerides among patients with severe hypertriglyceridemia in two phase III studies.