Abstract Body (Do not enter title and authors here): FCS is a rare treatment-resistant condition with persistent chylomicronemia and increased AP risk. FCS can be diagnosed clinically or genetically. Plozasiran is a siRNA that reduces hepatic apolipoprotein (apo) C-III with potential benefits for adults with FCS and related disorders.

PALISADE was a phase 3, multi-center, double-blind, placebo-controlled trial of 75 adults with genetically- or clinically-defined FCS with persistent chylomicronemia despite standard-of-care. Participants were randomized to quarterly-dosed plozasiran (25 or 50 mg SC) or placebo for 12 months. The primary and key secondary end points, previously reported, were median change in triglycerides (TG) and apo C-III at months 10 and 12 and incidence of AP. Additional secondary and exploratory endpoints reported here included changes in non-HDL-C, HDL-C, LDL-C, remnant cholesterol, and apo B. Data for the 25 mg dose (which performed equivalently to 50 mg and advanced for regulatory approval) is reported here.

Plozasiran lowered median TG by 80% from baseline at Month 10 (primary endpoint, baseline median 2044 mg/dL) and reduced AP incidence (OR: 0.17, 95% CI, 0.03 to 0.94, P= 0.03). All other key secondary end points showed significant responses to plozasiran. Additionally, placebo-adjusted non-HDL-C was reduced by -47%, remnant cholesterol by -65% and total cholesterol by -40% at the clinical 25 mg dose. HDL-C increased by +71% (p<0.001). LDL-C increased from mean of 24 mg/dL at baseline to 49 mg/dL at Month 10 (p<0.05); but apo B was unchanged. Most participants (59%) had genetically confirmed FCS with biallelic or digenic pathogenic variants in the 5 genes encoding proteins regulating lipoprotein lipase activity. The remaining 41% had clinical FCS based on persistent chylomicronemia plus other diagnostic features. No differences in response to treatment were observed between genetically confirmed and clinically defined FCS. The proportion of TEAEs was similar compared to placebo. Severe and serious events were less common with plozasiran than placebo, driven by AP events in the placebo group.

Plozasiran significantly reduced TG and AP incidence in patients with persistent chylomicronemia, regardless of genetic status. Because of its efficacy across the spectrum of subjects with hypertriglyceridemia, plozasiran is being studied for its effects on chylomicronemia-related pancreatitis, and as potential therapy to reduce ASCVD risk in mild to moderate hypertriglyceridemia.