FDA Accepts Plozasiran NDA for Familial Chylomicronemia Syndrome

The US Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for investigational plozasiran for the treatment of familial chylomicronemia syndrome (FCS), assigning a Prescription Drug User Fee Act (PDUFA) target date of November 18, 2025.

Announced by Arrowhead Pharmaceuticals, Inc. on January 17, 2025, the NDA was accepted based on positive results on plozasiran reported from the Phase 3 PALISADE study. In the acceptance, the FDA indicated no plan to hold an advisory committee meeting.1

“Plozasiran has achieved promising and consistent results in various patient populations representing multiple points on the spectrum of diseases caused by elevated triglycerides,” Chris Anzalone, PhD, president and chief executive officer at Arrowhead, said in a statement.1 “FCS represents the most severe and rare end of the spectrum; however, we believe that substantial unmet medical need exists in severe hypertriglyceridemia and mixed hyperlipidemia, which we are investigating in additional Phase 3 trials as part of the SUMMIT program of clinical studies.”

A severe, rare disease, FCS can lead to notably elevated triglyceride levels (≥880 mg/dL), leading to a substantially higher risk of developing acute pancreatitis and long-term complications, such as diabetes and cognitive issues. Therapeutic options are limited for patients with FCS.2

Plozasiran is a first-in-class investigational RNA interference (RNAi) therapeutic designed by Arrowhead to reduce the production of apolipoprotein C-III (APOC3), a component of triglyceride-rich lipoproteins (TRLs) linked to an increase in triglyceride levels. Multiple clinical trials in the SUMMIT program have observed reductions in triglycerides and multiple atherogenic lipoproteins with plozasiran in FCS (PALISADE), severe hypertriglyceridemia, (MUIR), and mixed hyperlipidemia (CAPITAN).1

The basis of the NDA submission included the positive data from PALISADE, with supplementary confirmatory evidence from the Phase 2 clinical trials in the SUMMIT program. A total of 75 participants were randomized to receive 25 mg plozasiran, 50 mg plozasiran, or matching placebo once every 3 months in the trial.3

Analyses showed PALISADE 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.3

Plozasiran has remained well-tolerated to date across multiple clinical trials. The most frequently reported treatment-emergent adverse events (TEAEs) in PALISADE for the 25 mg dose proposed for marketing approval were abdominal pain, COVID-19, nasopharyngitis, and nausea.1

The FDA previously granted Breakthrough Therapy Designation, Orphan Drug Designation, and Fast Track Designation to plozasiran for FCS.4 Arrowhead indicated plans for further submissions to additional regulatory authorities in 2025 for the approval of investigational plozasiran to treat patients with FCS.1

“With the plozasiran NDA submission and FDA’s acceptance for filing complete, we are laser-focused on our ongoing work to ensure an efficient and successful commercial launch this year, pending FDA review and approval,” Anzalone added.1

References

1. Arrowhead Pharmaceuticals announces acceptance of New Drug Application by U.S. FDA of Plozasiran for the treatment of familial chylomicronemia syndrome. Arrowhead Pharmaceuticals, Inc. January 17, 2025. Accessed January 20, 2025. https://arrowheadpharma.com/news-press/arrowhead-pharmaceuticals-announces-acceptance-of-new-drug-application-by-u-s-fda-of-plozasiran-for-the-treatment-of-familial-chylomicronemia-syndrome/.
2. Regmi M, Rehman A. Familial Hyperchylomicronemia Syndrome. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551655/
3. Campbell P. Palisade: Plozasiran offers hope for treating familial chylomicronemia syndrome. HCP Live. September 2, 2024. Accessed January 20, 2025. https://www.hcplive.com/view/palisade-plozasiran-offers-hope-for-treating-familial-chylomicronemia-syndrome.
4. Iapoce C. FDA grants Breakthrough therapy designation to plozasiran for FCS. HCP Live. September 12, 2024. Accessed January 20, 2025. https://www.hcplive.com/view/fda-grants-breakthrough-therapy-designation-to-plozasiran-for-fcs.