Plozasiran In FCS: PALISADE Phase 3 And 1-Year Extension

Key Takeaways

• Plozasiran was associated with durable triglyceride lowering through month 24, with similar levels in participants treated during the blinded phase and those who later crossed over from placebo.
• ApoC3 fell substantially, and some participants reached trough triglyceride thresholds below 500 mg/dL and below 880 mg/dL during the extension.
• Mean HbA1c remained stable in those treated with plozasiran throughout the open-label extension, discontinuations stayed low, common adverse events included abdominal pain, COVID-19, nasopharyngitis, headache, and nausea, and pancreatitis endpoints were pending.

Participants who received active treatment earlier and those who later crossed over from placebo reached similar triglyceride levels in the PALISADE phase 3 abstract. The update centered on persistence of effect after the blinded phase. Triglyceride and ApoC3 lowering extended through the blinded period and the first year of open-label follow-up.

PALISADE was a global, multicenter, double-blind, placebo-controlled phase 3 study in patients with familial chylomicronemia syndrome. It enrolled 75 patients whose fasting triglycerides were at least 10 mmol/L (880 mg/dL) despite stable lipid-lowering therapy. Participants were randomized 2:1:2:1 to quarterly subcutaneous plozasiran (25 mg or 50 mg) or volume-matched placebo for 12 months. After the blinded phase, 65 patients entered an ongoing 2-year open-label extension and transitioned to plozasiran 25 mg.

Month 24 corresponded to month 12 of the planned 2-year extension, with lipid effects assessed at trough before the next dose. Median ApoC3 levels were reduced by 89%, and triglyceride lowering remained similar in early-start and crossover participants. At trough, 42% reached triglycerides below 500 mg/dL and 66% reached below 880 mg/dL, while LDL-C increased but remained below 1.4 mmol/L (55 mg/dL). HDL-C increased by 66% to 1.5 mmol/L (27 mg/dL), non-HDL-C fell by 37% to 3.9 mmol/L (152 mg/dL), and VLDL-C fell by 56% to 2.5 mmol/L (98 mg/dL). ApoB was 71 mg/dL at baseline and 81 mg/dL at month 24, and lipid lowering was sustained across both prior treatment pathways.

Premature discontinuations remained low and did not increase during the open-label extension, while treatment-emergent adverse event rates were comparable to the parent study. Mean HbA1c remained stable in those treated with plozasiran throughout the open-label extension. The most commonly reported adverse events were abdominal pain, COVID-19, nasopharyngitis, headache, and nausea overall. Authors also described a favorable benefit-risk profile, although key pancreatitis endpoints will be reported separately. These findings provide durability and safety observations through the first extension year, while pancreatitis outcomes remain to be reported.