A randomized, placebo-controlled phase 3 study of plozasiran in patients with familial chylomicronemia syndrome: PALISADE - 1 year open label extension

Abstract Familial Chylomicronemia Syndrome (FCS) is a rare genetic dyslipidemia. The core defect is absence or impairment of lipoprotein lipase (LPL) activity, resulting in severe hypertriglyceridemia and an increased risk of acute pancreatitis (AP). Apolipoprotein C-III (ApoC3) is an essential regulator of the metabolism of triglyceride (TG)-rich lipoproteins through both LPL-dependent and LPL-independent pathways. Plozasiran, a siRNA, targets and silences APOC3 messenger RNA in the liver, thereby reducing ApoC3 production. We report the long-term efficacy and safety of plozasiran in FCS patients. 75 FCS patients from The PALISADE study, a Phase 3, global, multicenter, double-blind, placebo-controlled trial and with fasting TG ≥10 mmol/L (880 mg/dL) on stable, lipid-lowering therapy were randomized 2:1:2:1 to plozasiran (25, 50 mg) or volume-matched placebo administered subcutaneously, quarterly for 12 months before being offered entry into a 2 year ongoing open-label extension during which they transitioned to receive plozasiran 25 mg. 65 patients entered the OLE; the median baseline TG levels were ~24 mmol/L (2103 mg/dL). Median reductions in TG at Month 24 (Month 12 of the OLE, trough prior to next dose) of -76% occurred, achieving median levels of 5 mmol/L (444 mg/dL), with similar levels for those who started on plozasiran during the double-blind period and those who crossed over from placebo. These reductions were associated with reduced median levels of ApoC3 by -89%. Mean LDL-C levels increased consistent with the double-blind period but remained below 1.4 mmol/L (55 mg/dL). Mean HDL-C also increased by 66% to 1.5 mmol/L (27 mg/dL). Reductions of -37% occurred in non-HDL-C to mean levels of 3.9 mmol/L (152 mg/dL). Reductions of -56% occurred in VLDL-C to mean levels of 2.5 mmol/L (98 mg/dL). ApoB levels (71 mg/dL) were well below threshold levels at baseline and remained low at Month 24 (81 mg/dL). 42% of patients reached TG of 500 mg/dL, 66% reached 880 mg/dL in the OLE period, measured at trough. Key pancreatitis endpoints will be reported. Plozasiran showed a favorable safety profile for annualized event rates consistent with the parent study and other studies to date. Premature discontinuations remained low and did not increase during the OLE period. The rates of treatment-emergent adverse events (TEAE) were comparable to those reported in the parent study; most commonly reported were abdominal pain, COVID-19, nasopharyngitis, headache and nausea. Mean HbA1C remained stable in those treated with plozasiran throughout the OLE. Plozasiran demonstrated a favorable benefit-risk profile in the OLE consistent with other safety data to date. Deep and durable reductions in circulating ApoC3 and TG levels seen in the blinded phase of the study have continued during the first 12 months of the OLE. Plozasiran appears to be a promising new therapy to lower severely elevated plasma TG in patients suffering from FCS.