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 drug intended for the treatment of familial chylomicronemia syndrome (FCS). This marks a significant step toward addressing a critical unmet need in patients with this rare and severe genetic disorder.
The application is based on data from the Phase 3 PALISADE study, which demonstrated the efficacy and safety of plozasiran in reducing triglyceride levels and the risk of acute pancreatitis in FCS patients. With no currently approved therapies for FCS in the U.S., plozasiran offers a potential new treatment option for this high-risk population.
Plozasiran's Mechanism and Clinical Data
Plozasiran, previously known as ARO-APOC3, is an RNA interference (RNAi) therapeutic designed to reduce the production of apolipoprotein C-III (APOC3). APOC3 is a key regulator of triglyceride metabolism, and its reduction aims to lower triglyceride levels and restore lipid balance.
The Phase 3 PALISADE study (NCT05089084) was a placebo-controlled trial involving 75 adults with genetically confirmed or clinically diagnosed FCS across 39 sites in 18 countries. Participants were randomized to receive 25 mg or 50 mg of plozasiran, or a placebo, once every three months. The study's primary endpoint was the percent change from baseline in fasting triglycerides at Month 10.
Key findings from the PALISADE study include:
- A median change from baseline of 80% in triglycerides in the plozasiran 25 mg group.
- A statistically significant 83% reduction in the risk of developing acute pancreatitis compared to placebo in the pooled plozasiran 25 mg and 50 mg groups.
These results were presented at the American Heart Association Scientific Sessions 2024 (AHA24) and the European Society of Cardiology (ESC) Congress 2024, with simultaneous publications in Circulation and The New England Journal of Medicine.
Addressing Familial Chylomicronemia Syndrome
FCS is a rare genetic disease characterized by extremely high triglyceride levels (typically >880 mg/dL), often resulting from various 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. The absence of approved therapies in the U.S. underscores the urgency for new treatment options.
Arrowhead's Broader Strategy
"The NDA submission for investigational plozasiran represents an important milestone for Arrowhead," said Chris Anzalone, Ph.D., President and CEO at Arrowhead. He highlighted the company's commitment to advancing RNAi-based medicines for diverse therapeutic areas. Arrowhead also intends to submit applications for approval of investigational plozasiran for the treatment of patients with FCS to additional regulatory authorities in 2025.
Bruce Given, M.D., chief medical scientist at Arrowhead, emphasized the potential of plozasiran to improve the quality of life for FCS patients and reduce their risk of life-threatening acute pancreatitis. The company is working diligently to make plozasiran available to patients as quickly as possible, pending FDA review and approval.
Safety and Tolerability
In the PALISADE study, plozasiran was generally well-tolerated. The most frequently reported treatment-emergent adverse events for the 25 mg dose were abdominal pain, COVID-19, nasopharyngitis, and nausea.
Arrowhead has also established an expanded access program (EAP) for some individuals living with FCS, providing access to plozasiran while it awaits regulatory approval.
