Plozasiran: a small interfering RNA therapy for hypertriglyceridemia and familial chylomicronemia syndrome.

摘要

Plozasiran (Redemplo®) is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides. It degrades ApoC-III mRNA and results in reduced levels of hepatic and serum ApoC-III protein, which leads to an increased clearance of serum triglycerides. In the phase 3 PALISADE trial, plozasiran 25 mg reduced fasting triglyceride levels by approximately 80% at 10 months in patients with familial chylomicronemia syndrome (FCS) and was associated with a lower incidence of pancreatitis compared with placebo. This provides supportive, yet not definitive, evidence for pancreatitis prevention as the PALISADE trial was powered to investigate triglyceride lowering. Across completed clinical studies, plozasiran demonstrated a generally favorable safety profile, with a low incidence of thrombocytopenia and adverse events primarily limited to abdominal pain, nasopharyngitis, headache, and nausea. Hyperglycemia was observed in some patients with preexisting diabetes or prediabetes at baseline. Ongoing phase 3 trials (SHASTA-3, SHASTA-4, SHASTA-5, SHASTA-10, MUIR-3 and CAPITAN) are further evaluating the efficacy and safety of plozasiran in broader populations with hypertriglyceridemia, including its potential role in reducing cardiovascular risk and preventing pancreatitis. Compared with earlier ApoC-III-targeted antisense oligonucleotides, plozasiran offers the advantages of less frequent dosing, sustained pharmacodynamic effects, and potentially a more favorable tolerability profile based on indirect evidence, positioning it as a promising therapeutic option for patients with FCS and other severe hypertriglyceridemia disorders inadequately managed with existing therapies. Plozasiran (Redemplo®) is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides. Across completed clinical studies, plozasiran demonstrated a generally favorable safety profile, with a low incidence of thrombocytopenia and adverse events primarily limited to abdominal pain, nasopharyngitis, headache, and nausea. Compared with earlier ApoC-III–targeted antisense oligonucleotides, plozasiran offers the advantages of less frequent dosing, sustained pharmacodynamic effects, and potentially a more favorable tolerability profile based on indirect evidence, positioning it as a promising therapeutic option for patients with familial chylomicronemia syndrome and other severe hypertriglyceridemia disorders inadequately managed with existing therapies.