Use of plozasiran across a spectrum of hypertriglyceridemia: Long-term efficacy and safety data from the open-label extension period of SHASTA-2 and MUIR Trials

Plozasiran, a hepatocyte-targeted siRNA against apolipoprotein C-III, has demonstrated substantial reductions in triglycerides (TGs) and related atherogenic lipoproteins across a spectrum of hypertriglyceridemia (HTG), leading to its approval for familial chylomicronemia syndrome in the United States, and subsequently in Canada and China. Long-term data suggest maintenance of these effects beyond the blinded treatment periods, supporting further evaluation of plozasiran across a broad spectrum of HTG. Safety and efficacy were assessed in this open-label extension (OLE) of two phase 2b, randomized, double-blind trials, SHASTA-2 ( n = 229) including patients with severe HTG (TG >500 mg/dL) and MUIR ( n = 353) including patients with mixed hyperlipidemia (TG 150–499 mg/dL, LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL). Participants initially received plozasiran at the assigned dose level in the randomized study before eventually transitioning to a regimen of 25 mg Q3M. Treatment-emergent adverse events (TEAEs), change in fasting TGs, and atherogenic lipoproteins were measured over a two-year follow-up. Plozasiran produced sustained TG reductions relative to baseline, over 24 months in the OLE. In SHASTA-2, mean TG reductions from baseline were -77% and -79% at Months 12 and 24, respectively, compared with -71%, at Month 6 of the index study (25 mg). In MUIR, reductions were -62% and -63%, versus -56% at Month 6, compared to baseline. Favorable effects were also observed for other secondary endpoints including remnant cholesterol, non-HDL-C, ApoB, HDL-C, and LDL-C. Common TEAEs included diabetes, COVID-19, upper respiratory tract infection, and back pain, consistent with prior studies; HbA1c levels remained stable. Long-term open-label treatment with plozasiran resulted in sustained TG reductions compared to baseline, across a broad range of HTG, with a safety profile consistent with earlier trials. (Funded by Arrowhead Pharmaceuticals, Inc.; ClinicalTrials.gov number NCT05413135)