Arrowhead Pharmaceuticals has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for plozasiran, an investigational drug for the treatment of familial chylomicronemia syndrome (FCS). This submission marks a significant step forward as there are currently no FDA-approved therapies for this rare and severe genetic disease. The company intends to pursue additional regulatory approvals in other regions in 2025.
The NDA is supported by data from the SUMMIT program, including the Phase 3 PALISADE study. The PALISADE trial met its primary endpoint and key secondary endpoints, demonstrating statistically significant reductions in triglycerides (TGs), apolipoprotein C-III (APOC3), and the incidence of acute pancreatitis (AP).
Key Findings from the PALISADE Study
The Phase 3 PALISADE study (NCT05089084) was a placebo-controlled trial designed to evaluate the efficacy and safety of plozasiran in adults with genetically confirmed or clinically diagnosed FCS. A total of 75 subjects were randomized to receive either 25 mg plozasiran, 50 mg plozasiran, or placebo once every three months.
Plozasiran achieved significant reductions in triglycerides, with a median change from baseline of 80% in the 25 mg group. Furthermore, the pooled plozasiran groups (25 mg and 50 mg) showed an 83% reduction in the risk of developing acute pancreatitis compared to placebo. The most common treatment-emergent adverse events reported for the 25 mg dose were abdominal pain, COVID-19, nasopharyngitis, and nausea.
"The NDA submission for investigational plozasiran represents an important milestone for Arrowhead," said Chris Anzalone, Ph.D., President and CEO at Arrowhead. "We believe in the potential of RNAi to make a meaningful impact on patients, and this first NDA submission is the culmination of over 15 years of innovation and commitment."
About Familial Chylomicronemia Syndrome (FCS)
FCS is a rare genetic disorder characterized by extremely high triglyceride levels (typically >880 mg/dL), often due to monogenic mutations. These elevated triglyceride levels can lead to severe health complications, including acute and potentially fatal pancreatitis, chronic abdominal pain, diabetes, hepatic steatosis, and cognitive issues. Currently, there are no adequate therapeutic options available in the U.S. to treat FCS.
Mechanism of Action of Plozasiran
Plozasiran, previously known as ARO-APOC3, is an investigational RNA interference (RNAi) therapeutic. It 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) and the uptake of TRL remnants by hepatic receptors in the liver. By reducing APOC3 levels, plozasiran aims to lower triglyceride levels and restore lipid balance.
Bruce Given, M.D., chief medical scientist at Arrowhead, stated, "There are currently no approved therapies in the U.S. to treat FCS, so we are working tirelessly to get plozasiran to patients as quickly as possible, pending FDA review and approval."
Regulatory Designations
Plozasiran has been granted Breakthrough Therapy Designation, Orphan Drug Designation, and Fast Track Designation by the U.S. Food and Drug Administration, as well as Orphan Drug Designation by the European Medicines Agency, underscoring the urgent need for effective treatments for FCS.
