Arrowhead Pharmaceuticals has announced the submission of a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for plozasiran (formerly ARO-APOC3) for the treatment of familial chylomicronemia syndrome (FCS). This submission follows promising results from the Phase 3 PALISADE study and two open-label extension studies, MUIR and SHASTA-2.
FCS is a rare genetic disorder where the body cannot effectively break down triglycerides, leading to a high risk of acute pancreatitis and a diminished quality of life for patients. Currently, there are no FDA-approved treatments available for FCS, highlighting the critical unmet need that plozasiran aims to address.
Clinical Trial Data
The data presented at the American Heart Association Scientific Sessions 2024 showcased plozasiran's efficacy. The drug induced significant and sustained reductions in apolipoprotein C-III, exceeding 90%, and triglyceride levels, approximately 80%. Notably, half of the 75 participants in the study achieved triglyceride levels below 500 mg/dL, a threshold linked to a higher risk of acute pancreatitis. Furthermore, 75% reached levels below 880 mg/dL, and over 80% achieved levels below 1000 mg/dL. The treatment also reduced total cholesterol by approximately 41%, non-high-density lipoprotein cholesterol by 50%, and very-low-density lipoprotein cholesterol by 67%.
The open-label extension studies, MUIR (mixed hyperlipidemia) and SHASTA-2 (severe hypertriglyceridemia), included 418 participants. Results indicated mean triglyceride reductions of up to 64% in MUIR and up to 74% in SHASTA-2 at 24 weeks. These reductions were sustained through the 15-month follow-up, with trough reductions reaching up to 73% and 86%, respectively.
Safety and Tolerability
Plozasiran was generally well-tolerated across the studies. The most frequently reported treatment-emergent adverse events included abdominal pain, COVID-19, nasopharyngitis, and nausea.
Regulatory Status
In September 2024, the FDA granted breakthrough therapy designation to plozasiran as an adjunct to diet for reducing triglycerides in patients with FCS. This designation is intended to expedite the development and review of drugs for serious conditions where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies.
"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. FCS represents the most severe end of the spectrum in which many patients have a very poor quality of life and are at high risk of developing acute pancreatitis, which can be life threatening," said Bruce Given, MD, chief medical scientist at Arrowhead. "There are currently no approved therapies in the US to treat FCS, so we are working tirelessly to get plozasiran to patients as quickly as possible, pending FDA review and approval."
