Arrowhead Pharmaceuticals Submits FDA Application for Plozasiran in Familial Chylomicronemia Syndrome

Arrowhead Pharmaceuticals, Inc. submitted a new drug application to the FDA for plozasiran (formerly ARO-APOC3) in the treatment of familial chylomicronemia syndrome (FCS), which currently has no FDA-approved treatment. The submission comes after the company announced new results from the PALISADE (NCT05089084) study as well as 2 open-label extensions, MUIR (NCT04998201) and SHASTA-2 (NCT04720534).¹

FCS, Plozasiran, Cholesterol, Familial Chylomicronemia Syndrome| Image Credit: © ugreen | stock.adobe.com

“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,” Bruce Given, MD, chief medical scientist at Arrowhead, said in a news release. “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.”¹

According to the Endocrine Society, FCS is a rare genetic disorder that prevents the body from breaking down triglycerides. It is an inherited disorder, so symptoms can develop in infancy or childhood, but most commonly by adolescence, though some patients may not present with symptoms until adulthood. Symptoms can include lipemia retinalis, eruptive xanthomas, abdominal pain, acute or recurrent pancreatitis, and blood that appears milky. One of the main goals of treatment is to reduce the risk of pancreatitis.²

According to the data presented at the American Heart Association Scientific Sessions 2024, the drug induced sustained reductions in apolipoprotein C-III of greater than 90% and triglycerides of approximately 80%. At least half of the 75 study participants maintained triglyceride levels below 500 mg/dL, which is a threshold associated with an increased risk of acute pancreatitis. Approximately 75% achieved levels below 880 mg/dL and greater than 80% achieved below 1000 mg/dL. Total cholesterol was also decreased with least square mean reductions of approximately 41%, with non-high-density lipoprotein cholesterol and very-low-density lipoprotein cholesterol having a reduction of 50% and 67%, respectively.³

For the open label extension, 418 individuals were included, with patients in MUIR having mixed hyperlipidemia and SHASTA-2 having severe hypertriglyceridemia. Investigators found that the mean reductions in triglycerides were up to 64% in MUIR and up to 74% in SHASTA-2 at 24 weeks. The corresponding trough reductions were maintained up to 73% and 86%, respectively, through the 15-month follow-up.³

Investigators found that the drug was generally well tolerated, with the most frequently reported treatment emergent adverse events being abdominal pain, COVID-19, nasopharyngitis, and nausea.³

In September 2024, the FDA granted breakthrough therapy designation for the drug as an adjunct to diet to reduce triglycerides for patients with FCS.⁴

REFERENCES

1. Arrowhead Pharmaceuticals Submits New Drug Application to U.S. FDA for Plozasiran for the Treatment of Familial Chylomicronemia Syndrome. News release. Arrowhead Pharmaceuticals. November 18, 2024. Accessed November 19, 2024. https://www.businesswire.com/news/home/20241118743198/en/Arrowhead-Pharmaceuticals-Submits-New-Drug-Application-to-U.S.-FDA-for-Plozasiran-for-the-Treatment-of-Familial-Chylomicronemia-Syndrome

2. Endocrine Society. Familial Chylomicronemia Syndrome. January 24, 2022. Accessed November 19, 2024. https://www.endocrine.org/patient-engagement/endocrine-library/familial-chylomicronemia-syndrome

3. Arrowhead Pharmaceuticals Presents New Data at AHA24 from PALISADE Phase 3 Study and Open-Label Extension from MUIR and SHASTA-2 Studies of Plozasiran. News release. Arrowhead Pharmaceuticals. November 18, 2024. Accessed November 19, 2024. https://www.businesswire.com/news/home/20241118400458/en/Arrowhead-Pharmaceuticals-Presents-New-Data-at-AHA24-from-PALISADE-Phase-3-Study-and-Open-Label-Extension-from-MUIR-and-SHASTA-2-Studies-of-Plozasiran

4. Antrim A. FDA Grants Breakthrough Therapy Designation to Plozasiran for Familial Chylomicronemia Syndrome. News release. Pharmacy Times. September 11, 2024. Accessed November 19, 2024. https://www.pharmacytimes.com/view/fda-grants-breakthrough-therapy-designation-to-plozasiran-for-familial-chylomicronemia-syndrome