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FDA Grants Breakthrough Therapy Designation to Plozasiran for Familial Chylomicronemia Syndrome
FCS is a severe, rare genetic disease in which patients have extremely high triglyceride levels, typically above 880 mg/dL.
Plozasiran (Arrowhead Pharmaceuticals) has been granted breakthrough therapy designation by the FDA for the treatment of adults with familial chylomicronemia syndrome (FCS) as an adjunct to diet to reduce triglycerides. Arrowhead plans to submit a new drug application to the FDA by the end of 2024.1
“There are currently no FDA-approved therapies to specifically treat FCS, leaving physicians with very few options to help their patients,” said Chris Anzalone, PhD, president and CEO of Arrowhead, in a news release. “Results from clinical studies of investigational plozasiran have been highly encouraging and strongly supportive of further development and commercialization in multiple patient populations.”1
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FCS is a severe, rare genetic disease in which patients have extremely high triglyceride levels, typically above 880 mg/dL. Such elevations can lead to serious symptoms including acute and potentially fatal pancreatitis, chronic abdominal pain, diabetes, hepatic steatosis, and cognitive issues.1
Plozasiran is a first-in-class investigational RNA interference drug designed to reduce production of apolipoprotein C-III (APOC3), which is a component of triglyceride-rich lipoproteins (TRLs) and a key regulatory of triglyceride metabolism. APOC3 inhibits breakdown of TRLs by lipoprotein lipase and uptake of TRL remnants by hepatic receptors in the liver. The goal of plozasiran is to reduce the level of APOC3, reducing triglycerides and restoring lipids to normal levels.1
Plozasiran is being investigated in the SUMMIT program of clinical studies, including the recently-completed PALISADE phase 3 trial in patients with FCS, the SHASTA trials in patients with severe hypertriglyceridemia (SHTG), and the MUIR and CAPITAN studies in patients with mixed hyperlipidemia.1
Plozasiran has demonstrated reduced triglycerides and multiple atherogenic lipoproteins in multiple clinical studies involving patients with FCS, SHTG, and mixed hyperlipidemia. Plozasiran also has demonstrated a favorable safety profile and reported treatment-emergent adverse effects (AEs) generally reflect the comorbidities and underlying conditions of the study populations.1
In particular, the PALISADE study (NCT05089084) is evaluating the safety and efficacy of plozasiran in adults with genetically confirmed or clinically diagnosed FCS. The primary end point is percent change from baseline in fasting triglycerides vs placebo at month 10. A total of 75 participants across 39 different sites in 18 countries were randomized to receive 25 mg plozasiran, 50 mg plozasiran, or matching placebo once every 3 months. Individuals who completed the randomized period were eligible to continue in a 2-part extension period during which all participants receive plozasiran.2
The median triglyceride level at baseline was 2044 mg/dL. At 10 months, the median change from baseline in the fasting triglyceride level was -80% in the 25-mg plozasiran group, -78% in the 50 mg group, and -17% in the placebo group. The key secondary end points also showed stronger results in the plozasiran groups than in the placebo group, including incidence of acute pancreatitis.2
Risk of AEs was similar across the groups. The most common AEs were abdominal pain, nasopharyngitis, headache, and nausea, and severe and serious AEs were less common with plozasiran than with placebo.2
“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,” Anzalone said in the news release.1
REFERENCES
1. Arrowhead Pharmaceuticals receives FDA breakthrough therapy designation for plozasiran. News release. BusinessWire. September 10, 2024. Accessed September 11, 2024. https://www.businesswire.com/news/home/20240910509591/en
2. Watts GF, Rosenson RS, Hegele RA, et al. Plozasiran for managing persistent chylomicronemia and pancreatitis risk. New Eng J Med. 2024. doi:10.1056/NEJMoa2409368
