APOC3-Targeting Drug Has Benefits in Severe Hypertriglyceridemia

MUNICH, Germany—In patients with severe hypertriglyceridemia, use of the small interfering RNA (siRNA) therapy plozasiran (Redemplo; Arrowhead Pharmaceuticals) decreases triglyceride levels by about 80%, according to results of the SHASTA-3 and SHASTA-4 trials.

In both trials, patients had triglyceride levels of 500 mg/dL or greater and were randomized to placebo or four quarterly subcutaneous injections of plozasiran 25 mg for 1 year. The reductions in triglycerides with plozasiran were evident by 3 months and were associated with lowered risk of acute pancreatitis events.

“Despite lifestyle changes and current lipid-lowering therapies, many patients [with severe hypertriglyceridemia] don’t achieve treatment goals and remain at high risk of acute pancreatitis,” said Gerald Watts, MD, PhD (University of Western Australia, Perth), in a Hot Line session recently at the European Society of Cardiology Congress 2026. 

“The solution,” he added, “is knowledge about [apolipoprotein C-III; APOC3], which is a key regulator of lipid metabolism, a genetically validated therapeutic target, and an agent that puts the mRNA of APOC3 to sleep in the liver, thereby reducing APOC3 and accelerating the catabolism of triglyceride-rich lipoproteins.”

Regulators mandated two trials—SHASTA-3 and SHASTA-4—to  improve the precision of the observation. According to Watts, the results of these trials build on similar observations of the rapid and consistent effect of plozasiran in various patient populations, including those with familial chylomicronemia syndrome (FCS), and support its safety and tolerability.

About 1.4% of those randomized to the drug in SHASTA-3 and SHASTA-4 discontinued it due to treatment-related adverse events, as compared with a discontinuation rate of 0.8% in the placebo group.

Børge G. Nordestgaard, MD, DMSc (Copenhagen University Hospital–Herlev and Gentofte, Denmark), president of the European Atherosclerosis Society, who served as discussant for the trials, called the results “fantastic.”

He noted that in addition to acute pancreatitis, patients with severe hypertriglyceridemia are at excess risk for atherosclerotic cardiovascular disease (ASCVD). With more than 30% of the trial participants having ASCVD at baseline, he said, preventing it in this population should be the next frontier of research now that there is a way to effectively and safely lower extremely elevated triglycerides. 

With the SHASTA-3 and SHASTA-4 results, plozasiran becomes the second APOC3-targeting therapy to show drastic reductions in triglycerides and acute pancreatitis in this patient population with high levels of safety. Last year, CORE-TIMI 72a and CORE2-TIMI 72b demonstrated similar effects with a different drug, the antisense oligonucleotide olezarsen (Tryngolza; Ionis Pharmaceuticals). Compared with placebo, olezarsen 50 mg reduced triglyceride levels by as much as 63% and as much as 72% with the highest dose.

To TCTMD, Brian Bergmark, MD (Brigham and Women’s Hospital, Boston, MA), an investigator on those trials, said the SHASTA findings are in agreement with the olezarsen data with regard to both triglyceride-lowering and reduction in acute pancreatitis events.

“By and large, they’re similar. Numerically, slightly favoring olezarsen, but I think that’s kind of reading too much into the randomness that you get in a trial,” he said. “The safety profile is consistent as far as we can tell.”

A big question now, Bergmark noted, is what the threshold should be for prescribing this type of therapy.

“There are people who are at the very high end of this, who have a triglyceride level consistently above 880 mg/dL, who have had prior pancreatitis episodes. Those people are at very high risk, and this is a total life-changing medication,” he added. 

For those on the lower end of the spectrum, but at or above 500 mg/dL, for whom acute pancreatitis risk may be considered relatively low, Bergmark said this type of therapy becomes a judgment call within a patient conversation.

“I think for many people, it’s totally reasonable. They are at risk. This is going to effectively lower their triglycerides, and if there aren’t any tolerance issues, great. I don’t think we need long-term randomized trials to really parse this,” he added. “We give a lot of people PCSK9 inhibitors who qualify even though their likelihood of having an MI over the next 5 years isn’t that high on an individual basis. I think this is similar.”

Trial Results

For SHASTA-3 and SHASTA-4, Watts and colleagues randomized 757 patients (mean age 53 years; 22% women) from 24 countries. Each trial assigned patients to receive either plozasiran 25 mg or placebo. More than half had diabetes, with a mean HbA1c of 6.4%, and about 20% had a history of acute pancreatitis.

The primary endpoint, the reduction in triglycerides at 12 months, was 79% with plozasiran in SHASTA-3 and 81% in SHASTA-4 but just 27% in the placebo groups of each trial (P < 0.0001).

“When you look at the people who got down to triglycerides of less than 1.7 millimoles per liter, which is normal, . . . the hands have it in plozasiran: 50% by contrast to only 6% [for] placebo,” Watts noted.

In analyses of acute pancreatitis frequency across both trials, there was a reduction with plozasiran of 78%, with a number needed to treat of 24 over 1 year to prevent one additional event. Similarly, for time to first acute pancreatitis event, there was a 74% reduction with plozasiran, with median time to first event of 283 days in the treatment group compared with 182 days in the placebo group.

The effects of plozasiran were even more dramatic in the subgroup of patients who had a prior acute pancreatitis event and triglycerides of 880 mg/dL or higher, where a 100% reduction in acute pancreatitis events was observed with plozasiran versus placebo. Additionally, in patients with a previous acute pancreatitis event and triglycerides of 500 mg/dL or higher, the number needed to treat to prevent one additional acute pancreatitis event was just three over 1 year.

The most common adverse events with plozasiran were worsening glycemic control, seen in 14% of the pooled treatment population across the two trials. Diarrhea occurred in 3.2% and abdominal pain in 6.7%. 

According to Watts, there were no clinically meaningful changes in platelet counts, no meaningful elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) relative to placebo, and no statistically significant treatment-emergent increase in hepatic fat fraction. Despite the glycemic control issues, there also was no significant impact of the drug on long-term  absolute mean levels of HbA1c. Watts noted that after a slight increase in some patients at 3 months, HbA1c “stabilized and appeared to regress back to normal by 12 months.”

Based on these results, Arrowhead Pharmaceuticals, the manufacturer of plozasiran, says it plans to file a supplemental New Drug Application with the US Food and Drug Administration by the end of the year for use of the agent in severe hypertriglyceridemia. The drug was approved in November 2025 for use in adults with FCS.

To TCTMD, Bergmark said that taken together, the SHASTA trials and the CORE-TIMI 72 trials “have established a new evidence bar and a clinical effectiveness that is quite meaningful.” For patients with severe hypertriglyceridemia who are considered candidates for either plozasiran or olezarsen, he said it will be a lifetime commitment to continue taking them to keep their triglyceride levels low enough to reduce their risks.