Arrowhead Pharmaceuticals has announced the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for plozasiran, an investigational RNA interference (RNAi) therapeutic, for the treatment of familial chylomicronemia syndrome (FCS). This submission marks a significant step toward providing a potential treatment option for a severe and rare genetic disease that currently lacks FDA-approved therapies.
The NDA is based on positive results from the Phase 3 PALISADE study, which demonstrated statistically significant reductions in triglycerides (TGs), apolipoprotein C-III (APOC3), and the incidence of acute pancreatitis (AP). The study met its primary endpoint and all multiplicity-controlled key secondary endpoints.
PALISADE Study Results
The PALISADE study (NCT05089084) was a Phase 3 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 25 mg plozasiran, 50 mg plozasiran, or placebo once every three months.
The results showed that plozasiran achieved deep and durable reductions in triglycerides, with a median change from baseline of 80% in the 25 mg plozasiran group. Furthermore, the pooled plozasiran groups (25 mg and 50 mg) demonstrated an 83% reduction in the risk of developing acute pancreatitis compared to placebo.
According to Bruce Given, M.D., chief medical scientist at Arrowhead, the SUMMIT program of clinical studies of plozasiran has achieved promising and consistent results in various patient populations representing multiple points on the spectrum of elevated triglycerides. He emphasized that FCS represents the most severe end of the spectrum, where patients face a poor quality of life and a high risk of life-threatening acute pancreatitis.
Familial Chylomicronemia Syndrome (FCS)
FCS is a severe and rare genetic disease often caused by various monogenic mutations. It leads to extremely high triglyceride (TG) levels, typically exceeding 880 mg/dL. These severe elevations can result in serious signs and symptoms, including acute and potentially fatal pancreatitis, chronic abdominal pain, diabetes, hepatic steatosis, and cognitive issues. Currently, there are no therapeutic options that can adequately treat FCS in the US.
About Plozasiran
Plozasiran, previously known as ARO-APOC3, is a first-in-class investigational RNAi therapeutic designed to reduce the production of apolipoprotein C-III (APOC3). APOC3 is a component of triglyceride-rich lipoproteins (TRLs) and a key regulator of triglyceride metabolism. By reducing the level of APOC3, plozasiran aims to lower triglycerides and restore lipids to more normal levels.
In multiple clinical studies, plozasiran has demonstrated reductions in triglycerides and multiple atherogenic lipoproteins in patients with FCS, severe hypertriglyceridemia (SHTG), and mixed hyperlipidemia. The most frequently reported treatment-emergent adverse events for the 25 mg dose were COVID-19, upper respiratory tract infection, headache, Type 2 diabetes mellitus, and abdominal pain.
Arrowhead's Perspective
"The NDA submission for investigational plozasiran represents an important milestone for Arrowhead as we advance multiple potential new medicines developed using our proprietary Targeted RNAi Molecule (TRiMTM) platform," said Chris Anzalone, Ph.D., President and CEO at Arrowhead. He added that this submission is the culmination of over 15 years of innovation and commitment by Arrowhead employees, investigators, patients, and caregivers.
Arrowhead also intends to submit applications for approval of investigational plozasiran for the treatment of patients with FCS to additional regulatory authorities in 2025.
