Arrowhead Pharmaceuticals' plozasiran, an investigational RNA interference (RNAi) therapeutic, has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the treatment of adults with familial chylomicronemia syndrome (FCS). This rare genetic disease is characterized by extremely high triglyceride levels, leading to a risk of acute and potentially fatal pancreatitis. The designation aims to expedite the drug's development and review, potentially offering a significant improvement over existing therapies.
Clinical Trial Results and Efficacy
The Breakthrough Therapy Designation was supported by data from the Phase 3 PALISADE trial, which demonstrated that plozasiran reduced triglycerides by 80% from baseline and decreased the risk of developing acute pancreatitis by 83% in patients with genetically confirmed and clinically diagnosed FCS. These results were presented at the European Society of Cardiology (ESC) Congress 2024 and published in The New England Journal of Medicine.
Gerald F. Watts, Winthrop Professor of Cardio-metabolic Medicine at the University of Western Australia, noted, "Plozasiran demonstrated very deep reductions in triglycerides in the PALISADE study and is the only investigational medicine to achieve a statistically significant reduction in the risk of developing acute pancreatitis in patients with genetically confirmed and clinically diagnosed FCS in a controlled study."
Mechanism of Action
Plozasiran, previously known as ARO-APOC3, is designed to reduce the production of apolipoprotein C-III (APOC3), a key regulator of triglyceride metabolism. APOC3 inhibits the breakdown of triglyceride-rich lipoproteins (TRLs), leading to increased triglyceride levels in the blood. By reducing APOC3 levels, plozasiran aims to restore lipid levels to a more normal range.
Regulatory Pathway and Future Plans
Arrowhead Pharmaceuticals intends to submit a New Drug Application (NDA) to the FDA by the end of 2024 and plans to seek regulatory approval from additional global regulatory authorities thereafter. Plozasiran has also been granted Orphan Drug Designation and Fast Track Designation by the FDA, as well as Orphan Drug Designation by the European Medicines Agency.
Chris Anzalone, Ph.D., President and CEO of Arrowhead, stated, "There are currently no FDA-approved therapies to specifically treat FCS, leaving physicians with very few options to help their patients... Receiving FDA breakthrough therapy designation for plozasiran provides important benefits and the potential to expedite the process of getting plozasiran to the patients who need it."
About the PALISADE Trial
The PALISADE study (NCT05089084) is a Phase 3 placebo-controlled trial evaluating the efficacy and safety of plozasiran in adults with genetically confirmed or clinically diagnosed FCS. The primary endpoint is the percent change from baseline in fasting triglycerides versus placebo at Month 10. The trial randomized 75 subjects across 39 sites in 18 countries to receive 25 mg plozasiran, 50 mg plozasiran, or matching placebo once every three months.
