American Heart Association, 18th November 2024 – Plozasiran, an investigational RNA interference (RNAi) therapeutic, has demonstrated significant reductions in triglycerides and acute pancreatitis in patients with Familial Chylomicronemia Syndrome (FCS) in the Phase 3 PALISADE clinical trial (NCT05089084; Arrowhead Pharmeceuticals). The results of the trial were presented by Dr Gerald F Watts at the American Heart Association Scientific Sessions 2024 and published in Circulation. Currently, there are no FDA-approved drug treatments for FCS in the US.

PALISADE was a placebo-controlled trial involving 75 adult patients with genetically confirmed or clinically diagnosed FCS. At baseline, the median triglyceride level was 2044 mg/dL. Participants were randomly assigned to receive either 25 mg plozasiran (n=26), 50 mg plozasiran (n=24), or a placebo (n=25) every three months for a year. The primary endpoint was the percentage change in fasting triglycerides from baseline compared to the placebo group at Month 10.

The trial found that the median reduction from baseline in the fasting triglyceride level at month ten was -80% in the 25 mg plozasiran group, -78% in the 50 mg plozasiran group, and -17% in the placebo group (p<0.001) The 25 mg dose of plozasiran significantly reduced both apolipoprotein C-III (APOC3) levels by over 90% and triglyceride levels by approximately 80% invariant of FCS genotype. At least half of the patients on plozasiran maintained triglyceride levels below 500 mg/dl, a threshold associated with an increased risk of acute pancreatitis. Around 75% of patients achieved triglyceride levels below 880 mg/dL, and over 80% reached levels below 1000 mg/dL, irrespective of their FCS genotype.

Furthermore, plozasiran treatment also resulted in decreases in total cholesterol (TC) by 41%, non-high-density lipoprotein cholesterol (non-HDL-C) by 50%, and remnant cholesterol or very-low-density lipoprotein cholesterol (VLDL-C) by 67%, and increases in HDL-C by 52% and apolipoprotein-AI (ApoA-I) by 21% at 12 months. 

Plozasiran has generally been well-tolerated in clinical trials to date. The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline. 

The PALISADE trial results demonstrate the potential of plozasiran as a novel and effective treatment for patients with persistent chylomicronemia. The findings suggest that plozasiran can significantly reduce triglyceride levels and the risk of acute pancreatitis, with a favourable safety profile. Based on these positive findings from the PALISADE study, Arrowhead intends to file a New Drug Application with the United States Food and Drug Administration (FDA) by year-end 2024 and plans to seek regulatory approval with additional global regulatory authorities thereafter.

Participants who completed the randomised period of the PALISADE trial were eligible to continue in a 2-part extension period, where all participants receive plozasiran. 

Further research is ongoing to explore the long-term effects of plozasiran and its potential application in other patient populations with high triglyceride levels, such as those with severe hypertriglyceridemia (SHTG) and mixed hyperlipidemia.

Resources:

Arrowhead Pharmaceuticals (2024, September 2) Arrowhead Pharmaceuticals Presents New Pivotal Phase 3 Data at ESC 2024 from PALISADE Study of Plozasiran in Patients with Familial Chylomicronemia Syndrome. Accessed at: https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-presents-new-pivotal-phase-3-data-esc

American Heart Association. (2024, November 18). A Phase 3 Study to Assess the Efficacy and Safety of Plozasiran in Adults with Genetically or Clinically-Defined Familial Chylomicronemia Syndrome at High Risk of Acute Pancreatitis. Accessed at: https://ir.arrowheadpharma.com/static-files/5b38af79-d98e-4bb2-bcc6-4ce39228ee2d

Watts, G, Et Al. NEJM 2024. DOI: https://www.nejm.org/doi/full/10.1056/NEJMoa2409368

Watts, G, Hegele, R, Rosenson, R, et al. Circulation 2024. DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.072860

Clinical Trials. Study of ARO-APOC3 (Plozasiran) in Adults With Familial Chylomicronemia Syndrome (FCS) (PALISADE). Accessed at: https://www.clinicaltrials.gov/study/NCT05089084