Ionis and SOBI’s olezarsen cuts pancreatitis risk by 85% in sHTG phase 3 trials

Swedish Orphan Biovitrum AB (STO: SOBI) and Ionis Pharmaceuticals have reported decisive Phase 3 data from the CORE and CORE2 studies evaluating olezarsen in patients with severe hypertriglyceridemia. Presented as a late-breaker at the 2025 American Heart Association Scientific Sessions in New Orleans, the RNA-based therapy achieved an 85 percent reduction in acute pancreatitis events over 12 months and lowered fasting triglycerides by up to 72 percent. These results mark a turning point in the treatment of a condition long plagued by limited therapeutic options and recurrent life-threatening complications.

With nearly 1,100 patients enrolled across the two studies, the program represents the largest clinical investigation ever conducted in this high-risk lipid disorder. Importantly, the triglyceride-lowering benefit was sustained for one year, and safety outcomes favored olezarsen over placebo. The results were simultaneously published in The New England Journal of Medicine, further elevating the clinical credibility of the findings.

How did olezarsen perform in reducing triglycerides and pancreatitis events in high-risk sHTG patients?

The pivotal studies met their primary endpoint by delivering up to a 72 percent placebo-adjusted mean reduction in fasting triglyceride levels at six months, with the effect maintained through 12 months. Equally significant was the 85 percent reduction in adjudicated acute pancreatitis events in the olezarsen-treated arms. Among patients who received olezarsen, 86 percent achieved triglyceride levels below 500 mg/dL, the threshold considered critical for reducing the risk of pancreatitis.

A total of 22 pancreatitis events were observed among 17 patients in the placebo group, while only seven events occurred in five patients treated with olezarsen. The investigational RNA therapy was administered via monthly subcutaneous injections at either 50 mg or 80 mg doses. Both dosages showed consistent efficacy across the broader population and the more severe subgroup defined by multifactorial chylomicronemia syndrome, characterized by triglyceride levels exceeding 880 mg/dL.

These results represent the first time an investigational therapy in sHTG has demonstrated statistically significant reductions in both triglyceride levels and acute pancreatitis events, positioning olezarsen as a potential disease-modifying therapy for a population underserved by current lipid-lowering drugs.

Why are the CORE and CORE2 results seen as a landmark for sHTG treatment?

Cardiologist Dr. Nicholas Marston of Brigham and Women’s Hospital, who presented the results, said that for specialists treating sHTG, the most pressing concern has always been managing the serious consequences of acute pancreatitis. He noted that patients with recurrent attacks often experience frequent hospitalizations, high morbidity, and limited treatment options. According to Dr. Marston, the data from CORE and CORE2 are a welcome advance, as they offer evidence that olezarsen can help most patients achieve triglyceride levels below the risk threshold for life-threatening events.

The data were also strongly endorsed by Swedish Orphan Biovitrum AB’s Head of R&D and Chief Medical Officer Lydia Abad-Franch, who said the results validated the company’s confidence in olezarsen as a therapy capable of transforming quality of life for patients. She confirmed that Swedish Orphan Biovitrum AB is preparing to submit a marketing authorization application to the European Medicines Agency in 2026 for multifactorial chylomicronemia syndrome.

What made the CORE and CORE2 studies pivotal in trial design and scale?

The CORE (NCT05079919) and CORE2 (NCT05552326) studies were global, randomized, double-blind, placebo-controlled trials enrolling 617 and 446 patients respectively. Participants were 18 years and older with fasting triglyceride levels equal to or greater than 500 mg/dL. Notably, 43 percent of patients had extremely high levels above 880 mg/dL, which is often associated with multifactorial chylomicronemia syndrome and an even greater risk of acute pancreatitis.

Participants were maintained on standard lipid-lowering therapy and randomized to receive either 50 mg or 80 mg of olezarsen or placebo every four weeks for 12 months. The primary endpoint was percent reduction in fasting triglycerides at six months. The reduction in acute pancreatitis events served as a key secondary endpoint and was clinically meaningful given the morbidity associated with recurrent pancreatitis attacks.

Importantly, more than 90 percent of patients who completed CORE and CORE2 have opted into an open-label extension study, suggesting strong patient and physician confidence in the long-term use of olezarsen.

How is the safety profile shaping up for olezarsen in long-term lipid management?

Olezarsen demonstrated a favorable safety and tolerability profile in both trials. Adverse events were balanced across arms, with 75 percent of participants in the olezarsen 50 mg group and 76 percent in the 80 mg group reporting treatment-emergent events, compared to 75 percent in the placebo group. Serious adverse events occurred less frequently in the treatment arms, nine percent in the 50 mg group and eleven percent in the 80 mg group, versus fourteen percent in the placebo group.

The most commonly reported side effects were injection site reactions, which were generally mild and occurred more frequently with olezarsen than with placebo. Ten percent of patients in the 50 mg group and seventeen percent in the 80 mg group reported injection site reactions, compared to just one percent in the placebo group.

These safety results are expected to play a critical role in regulatory decision-making and support broader adoption once the therapy is approved for commercial use.

How could the Phase 3 pancreatitis reduction data influence regulatory approval timelines and expand olezarsen’s commercial market access globally?

Swedish Orphan Biovitrum AB confirmed that it plans to file a marketing application with the European Medicines Agency for olezarsen in multifactorial chylomicronemia syndrome in 2026. Ionis Pharmaceuticals, which holds commercial rights in the United States, Canada, and China, is on track to file a supplemental new drug application for the broader sHTG indication with the United States Food and Drug Administration by the end of 2025.

Olezarsen has already been approved in both the United States and European Union under the brand name TRYNGOLZA for the ultra-rare condition of familial chylomicronemia syndrome, a monogenic disorder affecting triglyceride metabolism. Approval in the more prevalent sHTG and multifactorial chylomicronemia syndrome segments would dramatically expand the therapy’s addressable market.

Analysts estimate that more than 2 million people are living with severe hypertriglyceridemia across the top five European Union countries, including nearly 700,000 individuals considered to have multifactorial chylomicronemia syndrome. The therapeutic and commercial opportunity, therefore, extends beyond rare disease into broader cardiovascular risk management.

How does olezarsen’s RNA-based mechanism position it within the next generation of metabolic therapies?

Olezarsen is part of a growing class of RNA-targeted therapeutics developed to modulate specific proteins at the genetic expression level. It works by reducing production of apolipoprotein C-III, a liver-derived protein that inhibits triglyceride metabolism and clearance. By suppressing apoC-III, olezarsen enhances triglyceride breakdown, reduces circulating lipid levels, and in turn lowers the risk of pancreatitis and other lipid-related complications.

The partnership model between Swedish Orphan Biovitrum AB and Ionis Pharmaceuticals also reflects a new commercial template in rare and metabolic diseases. Under their agreement, Swedish Orphan Biovitrum AB holds exclusive rights to commercialize olezarsen outside the United States, Canada, and China, while Ionis focuses on development and regulatory execution in its core markets. This division of labor allows for faster market penetration, especially in regions with diverse regulatory landscapes and healthcare systems.

Institutional sentiment has responded positively to olezarsen’s dual efficacy in lipid lowering and pancreatitis prevention, with analysts pointing to its potential to complement or even replace current standard-of-care therapies such as fibrates and omega-3 fatty acids. Given the moderate efficacy and tolerability limitations of existing drugs, olezarsen’s targeted RNA mechanism offers a more precise and potentially longer-lasting intervention.

What could approval of olezarsen mean for long-term management of severe hypertriglyceridemia?

If regulatory approvals go through as planned in the United States and Europe, olezarsen could become the first approved therapy to directly reduce pancreatitis risk in patients with severe hypertriglyceridemia. This would mark a major milestone not only for patients but also for prescribers, payers, and policy makers aiming to address the healthcare burden posed by lipid-driven emergencies.

By moving upstream in triglyceride metabolism and showing clinical relevance in both triglyceride lowering and event prevention, olezarsen could redefine care pathways for patients at the highest risk. Its role could extend beyond acute event prevention to chronic risk mitigation, especially in populations with metabolic syndrome, type 2 diabetes, and polygenic lipid disorders.

As the open-label extension continues and real-world data begins to emerge, olezarsen’s long-term safety and economic value will be key to unlocking broader payer acceptance and inclusion in treatment guidelines.

Key takeaways from olezarsen’s pivotal phase 3 results in severe hypertriglyceridemia

• Olezarsen reduced acute pancreatitis events by 85% in the CORE and CORE2 trials among patients with severe hypertriglyceridemia.
• The investigational RNA therapy lowered fasting triglyceride levels by up to 72% at six months, with effects sustained through 12 months.
• A total of 86% of olezarsen-treated patients achieved triglyceride levels below 500 mg/dL, considered a high-risk threshold for pancreatitis.
• Nearly 1,100 patients were enrolled across both trials, making this the largest phase 3 program ever conducted in this disease setting.
• The subgroup with multifactorial chylomicronemia syndrome (baseline triglycerides ≥880 mg/dL) showed results in line with the overall population.
• Safety was favorable, with serious adverse events occurring less frequently in olezarsen-treated groups than in placebo arms.
• Injection site reactions were the most common adverse event but were typically mild and manageable.
• Over 90% of trial participants opted into the open-label extension study, suggesting strong patient confidence in long-term treatment.
• Swedish Orphan Biovitrum AB will submit a European Medicines Agency filing for olezarsen in multifactorial chylomicronemia syndrome in 2026.
• Ionis Pharmaceuticals is preparing to file a supplemental new drug application in the United States for the broader sHTG indication by end-2025.
• Olezarsen is already approved as TRYNGOLZA for familial chylomicronemia syndrome, but the new indication could dramatically expand its market.