Two trials of olezarsen cut triglycerides — and, unusually, cut pancreatitis too

Lipid trials usually report lipids. The two olezarsen trials published in the New England Journal of Medicine on 8 November report something harder to get: fewer episodes of the disease the lipids cause [s1].

Severe hypertriglyceridaemia raises the risk of acute pancreatitis, a painful and sometimes life-threatening inflammation of the pancreas [s1]. The efficacy and safety of olezarsen had not been established in that population before these trials [s1]. CORE-TIMI 72a and CORE2-TIMI 72b assessed acute pancreatitis events across both trials and found a difference [s1].

What was tested

Olezarsen is an antisense oligonucleotide that targets the messenger RNA of apolipoprotein C-III, a protein that inhibits triglyceride clearance [s1][s2]. Reduce the protein, and the body clears triglycerides better [s1][s2]. The investigators describe highly effective therapies to reduce triglyceride levels as lacking [s2].

CORE-TIMI 72a and CORE2-TIMI 72b were double-blind, randomised, placebo-controlled trials [s1]. Patients with severe hypertriglyceridaemia were assigned 1:1:1 to olezarsen 50 mg, olezarsen 80 mg, or placebo, given monthly for 12 months [s1]. The primary outcome was the percent change in triglyceride level at 6 months, reported as the placebo-adjusted difference for each dose [s1]. A total of 1,061 patients were included in the primary analysis — 617 in CORE-TIMI 72a and 444 in CORE2-TIMI 72b [s1].

The lipid results

At 6 months, the placebo-adjusted least-squares mean change from baseline in triglyceride level was −62.9 percentage points with olezarsen 50 mg and −72.2 percentage points with 80 mg in CORE-TIMI 72a, and −49.2 percentage points with 50 mg and −54.5 percentage points with 80 mg in CORE2-TIMI 72b (P<0.001 for every comparison against placebo) [s1].

Decreases in triglycerides, apolipoprotein C-III, remnant cholesterol and non-HDL cholesterol were all greater with olezarsen than placebo (P<0.001 for all comparisons) [s1].

The two trials did not produce identical numbers: at both doses the reduction reported in CORE2-TIMI 72b was smaller than the one reported in CORE-TIMI 72a [s1]. The published abstract does not explain the gap, and it is worth registering rather than averaging away.

The pancreatitis result

The incidence of acute pancreatitis was lower with olezarsen than with placebo, at a mean rate ratio of 0.15 (95% CI, 0.05 to 0.40; P<0.001) [s1].

That is a large effect, and the confidence interval, while wide, sits well away from 1. Pancreatitis events in this population are uncommon, so the underlying counts will be small — which is why the interval runs from 0.05 to 0.40 rather than settling near its midpoint [s1]. The direction and the statistical significance are clear; the precise magnitude is not.

The safety signal

The incidence of any adverse event appeared to be similar across trial groups [s1]. Three specific findings were not evenly distributed.

Elevations in liver-enzyme levels and thrombocytopenia — a platelet count below 100,000 per microlitre — were more common with the 80 mg dose of olezarsen than with the 50 mg dose [s1]. And a dose-dependent increase in hepatic fat fraction was noted [s1].

That pattern is the practical tension in these results. The 80 mg dose lowered triglycerides more in both trials, and it also carried more of the laboratory abnormalities [s1]. A dose-dependent rise in liver fat, in a drug intended for long-term use, is the kind of finding that longer follow-up exists to resolve.

How it fits with the moderate-risk trial

Olezarsen was tested in a different population earlier this year. ESSENCE-TIMI 73b enrolled patients with moderate hypertriglyceridaemia — triglycerides of 150 to 499 mg per decilitre — and elevated cardiovascular risk, or with severe hypertriglyceridaemia at 500 mg per decilitre or above [s2]. A total of 1,349 patients were in the primary efficacy analysis, with a median age of 64, 40% women, and a median baseline triglyceride level of 238.5 mg per decilitre [s2].

At 6 months, the placebo-adjusted least-squares mean change in triglycerides was −58.4 percentage points in the 50 mg group (95% CI, −65.1 to −51.7) and −60.6 percentage points in the 80 mg group (95% CI, −67.1 to −54.0), both P<0.001 [s2]. Serious adverse events appeared similar across groups [s2].

Read together, the trials show consistent triglyceride lowering across a wide range of baseline severity, with the clinical-event evidence coming specifically from the severe population [s1][s2].

What remains unanswered

Neither trial reports cardiovascular outcomes. Lowering triglycerides and remnant cholesterol is biologically plausible as cardiovascular prevention, but plausibility is not evidence, and these trials do not supply it.

Twelve months of monthly dosing is the exposure period in CORE and CORE2 [s1]. Both trials, and ESSENCE-TIMI 73b, were funded by Ionis Pharmaceuticals, olezarsen's developer [s1][s2].

Nothing here is guidance about treatment. What the trials establish is that an apoC-III-targeting antisense drug lowers triglycerides substantially in severe hypertriglyceridaemia and was associated with fewer acute pancreatitis events over a year, at a dose where the laboratory trade-offs still need watching.

Sources

• [s1] Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk, The New England Journal of Medicine, 8 November 2025. https://doi.org/10.1056/NEJMoa2512761
• [s2] Targeting APOC3 with Olezarsen in Moderate Hypertriglyceridemia, The New England Journal of Medicine, 30 August 2025. https://doi.org/10.1056/NEJMoa2507227