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

ABSTRACT 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 &gt; 22.6 mmol/L (2000 mg/dL). Plozasiran‐treated participants experienced a &gt; 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 &lt; 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