The landscape of familial chylomicronemia syndrome (FCS) treatment is evolving rapidly, with new therapies on the horizon offering hope to patients with this rare and debilitating genetic disorder. The U.S. Food and Drug Administration (FDA) has recently approved Ionis Pharmaceuticals' Tryngolza (olezarsen) as the first-ever treatment for adults living with FCS. Meanwhile, Arrowhead Pharmaceuticals' plozasiran is under FDA review, potentially offering another option for managing this challenging condition. Both drugs target apolipoprotein C-III (APOC3), a key regulator of triglyceride metabolism, using RNA-based mechanisms. These developments mark a significant advancement in addressing the unmet medical needs of individuals with FCS, who often face severe hypertriglyceridemia and increased risk of acute pancreatitis.
Tryngolza: A New Era in FCS Treatment
On December 19, 2024, Ionis Pharmaceuticals announced the FDA approval of Tryngolza (olezarsen) as an adjunct to diet for reducing triglyceride levels in adults with FCS. This approval marks a pivotal moment, as it is the first FDA-approved treatment to significantly lower triglyceride levels and reduce the risk of acute pancreatitis events in FCS patients when used with a low-fat diet (≤20 grams of fat per day). Tryngolza is administered via a once-monthly subcutaneous autoinjector.
The FDA's decision was based on positive data from the Phase 3 Balance clinical trial, a global, multicenter, randomized, double-blind, placebo-controlled study. In the Balance study, Tryngolza 80 mg demonstrated a statistically significant placebo-adjusted mean reduction in triglyceride levels of 42.5% from baseline to six months (p=0.0084). Reductions from baseline to 12 months were further improved, with Tryngolza achieving a placebo-adjusted 57% mean reduction in triglycerides. The trial also demonstrated a substantial, clinically meaningful reduction in acute pancreatitis events over 12 months; one patient (5%) experienced one episode of acute pancreatitis in the Tryngolza group compared with seven patients (30%) who experienced 11 total episodes of acute pancreatitis in the placebo group.
"With no treatment options previously available, we were limited to relying only on extremely strict diet and lifestyle changes as the sole preventative treatment option," said Alan Brown, M.D., FNLA, FACC, FAHA, clinical professor of medicine, Rosalind Franklin University of Medicine and Science; Balance trial investigator. "The FDA approval of Tryngolza is an important moment for people living with FCS, their families and physicians who now, for the first time, have a treatment that significantly lowers triglycerides and decreases the risk of potentially life-threatening acute pancreatitis events, as an adjunct to a low-fat diet. I am excited to have a medicine I can prescribe to my patients that has been shown to change the course of their disease."
Plozasiran: Another Promising Candidate
Arrowhead Pharmaceuticals is also seeking FDA approval for its investigational drug, plozasiran, for the treatment of FCS. On January 17, 2025, Arrowhead announced that the FDA had accepted its New Drug Application (NDA) for plozasiran, with a Prescription Drug User Fee Act (PDUFA) action date of November 18, 2025. The FDA has indicated that it is not currently planning to hold an advisory committee meeting for plozasiran.
The NDA is based on positive results from the Phase 3 PALISADE study, which met its primary endpoint of percentage change from baseline in fasting triglycerides versus placebo at Month 10. Plozasiran achieved durable reductions in triglyceride levels, with an 80% median change from baseline in the 25 mg dose cohort. Key secondary endpoint analysis revealed a statistically significant 83% reduction in the risk of acute pancreatitis with plozasiran, compared with placebo, in the pooled 25 mg and 50 mg cohorts.
Plozasiran, previously called ARO-APOC3, is a first-in-class investigational RNA interference (RNAi) therapeutic designed to reduce production of apolipoprotein C-III (APOC3), a key regulator of triglyceride metabolism. APOC3 increases triglyceride levels in the blood by inhibiting breakdown of triglyceride rich lipoproteins (TRLs) by lipoprotein lipase and uptake of TRL remnants by hepatic receptors in the liver. The goal of treatment with plozasiran is to reduce the level of APOC3, thereby reducing triglycerides and restoring lipids to more normal levels.
FCS: A Challenging Condition
Familial chylomicronemia syndrome (FCS) is a rare, genetic disease characterized by extremely elevated triglyceride levels, typically over 880 mg/dL. This condition is often caused by various monogenic mutations and leads to impaired function of the enzyme lipoprotein lipase (LPL). The resulting severe elevations in triglycerides can lead to various serious signs and symptoms, including acute and potentially fatal pancreatitis, chronic abdominal pain, diabetes, hepatic steatosis, and cognitive issues. Currently, there are limited therapeutic options to adequately treat FCS, with an estimated impact on up to approximately 3,000 people in the U.S., the vast majority of whom remain undiagnosed.
Safety and Tolerability
Both Tryngolza and plozasiran have demonstrated generally favorable safety profiles in clinical trials. The most common adverse reactions associated with Tryngolza include injection site reactions, decreased platelet count, and arthralgia. In the PALISADE study of plozasiran, the most frequently reported treatment emergent adverse events for the 25 mg dose were abdominal pain, COVID-19, nasopharyngitis, and nausea.
Looking Ahead
The approval of Tryngolza and the ongoing review of plozasiran represent significant milestones in the treatment of FCS. These RNA-targeted therapies offer the potential to substantially reduce triglyceride levels and decrease the risk of acute pancreatitis, improving the quality of life for individuals with this rare and challenging condition. As these drugs become available, it is anticipated that more patients will be diagnosed and receive appropriate treatment, leading to better outcomes and reduced disease burden.
