Arrowhead Pharmaceuticals presented new data at the American Heart Association Scientific Sessions 2024 (AHA24) from the Phase 3 PALISADE study and open-label extension (OLE) studies of plozasiran, an investigational RNA interference (RNAi) therapeutic. The data indicate that plozasiran induces significant and sustained reductions in triglycerides (TG) and impacts a wider spectrum of lipoproteins in patients with familial chylomicronemia syndrome (FCS), severe hypertriglyceridemia, and mixed hyperlipidemia.
PALISADE Study Results
The Phase 3 PALISADE study enrolled 75 patients with FCS, both with and without genetic confirmation, who were randomized to receive subcutaneous plozasiran at 25 mg (n=26) or 50 mg (n=24) or placebo (n=25) every three months for 12 months. The median baseline triglyceride level was 2044 mg/dL. Results showed that plozasiran, at the 25 mg dose, induced rapid, deep, and sustained reductions in apolipoprotein C-III (APOC3), of greater than -90%, and in triglycerides (TG), of approximately -80%, independent of gene variants causing FCS.
Bruce Given, M.D., chief medical scientist at Arrowhead, stated, "In the Phase 3 PALISADE study in patients with and without a genetic confirmation of familial chylomicronemia syndrome (FCS), plozasiran induced deep and sustained reductions in triglycerides and impacted a wider spectrum of lipoproteins that may be involved with atherosclerotic cardiovascular disease. Importantly, responses were independent of specific known gene variants causing FCS."
Furthermore, plozasiran decreased total cholesterol (TC) with least square (LS) mean reductions of -41%, non-high-density lipoprotein cholesterol (non-HDL-C) of -50%, and remnant cholesterol or very-low-density lipoprotein cholesterol (VLDL-C) of -67%, with reciprocal increases in HDL-C of 52%, and apolipoprotein-AI (ApoA-I) of 21% at 12 months. It also increased low-density lipoprotein cholesterol (LDL-C) levels without increases in total ApoB or ApoB-100.
MUIR and SHASTA-2 OLE Results
The open-label extension included 418 subjects from the Phase 2 MUIR study (mixed hyperlipidemia) and the SHASTA-2 study (severe hypertriglyceridemia), all receiving plozasiran 25 mg quarterly. The OLE data demonstrated sustained reductions in TGs up to -73% in patients from MUIR and up to -86% in patients from SHASTA-2 through 15 months of follow-up.
These reductions were accompanied by favorable changes in other lipid parameters, including decreases in remnant cholesterol and non-HDL-C, favorable changes in apoB, and increases in HDL-C. No worsening of HbA1c and no new onset diabetes mellitus were observed.
Safety and Tolerability
In the PALISADE study, the most frequently reported treatment emergent adverse events for the 25 mg dose were abdominal pain, COVID-19, nasopharyngitis, and nausea. Across all clinical studies, the most frequently reported adverse events for the 25 mg dose were COVID-19, upper respiratory tract infection, headache, Type 2 diabetes mellitus, and abdominal pain. Overall, plozasiran has been generally well-tolerated to date.
About Plozasiran
Plozasiran is an investigational RNAi therapeutic designed to reduce the production of apolipoprotein C-III (APOC3), a key regulator of triglyceride metabolism. By reducing APOC3 levels, plozasiran aims to lower triglycerides and restore lipid levels to a more normal state. It is currently being investigated in the SUMMIT program of clinical studies, including the PALISADE Phase 3 study in patients with FCS, the SHASTA studies in patients with SHTG, and the MUIR and CAPITAN studies in patients with mixed hyperlipidemia.
Plozasiran has received Breakthrough Therapy Designation, Orphan Drug Designation, and Fast Track Designation from the FDA for the treatment of patients with FCS, as well as Orphan Drug Designation from the EMA.
