Clinical Trial: Plozasiran Prevents Recurrent Pancreatitis in Adults With Very Severe Hypertriglyceridemia—Results of a Post Hoc Analysis of the Phase 3 <scp>PALISADE</scp> Study

BACKGROUND: Patients with persistent chylomicronaemia (PC) are at high risk for acute pancreatitis (AP). Plozasiran, a small interfering RNA, reduces hepatic apolipoprotein C-III, significantly lowers triglyceride (TG) levels and reduces risk of AP. AIM: To assess the effect of plozasiran on recurrent AP in patients with severe hypertriglyceridemia and history of pancreatitis. METHODS: PALISADE was an international, multicentre, double-blind, placebo-controlled trial. Patients with extreme hypertriglyceridemia were randomised 2:1:2:1 to receive subcutaneous plozasiran (25- or 50-mg) or volume-matched placebo, quarterly for 12 months. This post hoc analysis involved participants with a history of at least one prior episode of AP. Primary and alpha-controlled secondary endpoints included the incidence of expert-adjudicated AP and pancreatitis-related hospitalisations. RESULTS: The analysis included 67 participants with median baseline TG > 22.6 mmol/L (2000 mg/dL). Plozasiran-treated participants experienced a > 75% reduction in median TG, with median levels falling below 5.65 mmol/L (500 mg/dL). Incident AP occurred in 5 of 22 in the placebo group versus 2 of 45 in the pooled plozasiran group, representing an 83% (HR, 0.17; 95% CI [0.03, 0.87], p < 0.017) reduction in risk for recurrent AP in the plozasiran group. AP severity, hospitalisation rates for abdominal pain, and length of hospital stay were lower in the plozasiran group. CONCLUSIONS: Plozasiran significantly lowered circulating TG levels, with substantial reduction in recurrent AP for participants with very severe hypertriglyceridemia and history of AP. Plozasiran is the first therapy to demonstrate a statistically significant reduction in recurrent AP in a prospective randomised trial of patients with familial chylomicronaemia syndrome (FCS). TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05089084.