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) of the Phase 2 MUIR and SHASTA-2 studies, highlighting the potential of plozasiran in treating patients with familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia. The data, simultaneously published in Circulation, demonstrated significant reductions in triglycerides and favorable impacts on various lipoproteins.
PALISADE Study Results
The Phase 3 PALISADE study involved 75 patients with FCS, both genetically confirmed and clinically diagnosed, 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. Baseline median triglyceride levels were 2044 mg/dL. The study revealed that plozasiran, particularly at the 25 mg dose, induced rapid and sustained reductions in apolipoprotein C-III (APOC3) by over 90% and triglycerides by approximately 80%, irrespective of the gene variants causing FCS. A significant proportion of patients maintained triglyceride levels below critical thresholds, with at least half below 500 mg/dL and approximately 75% below 880 mg/dL.
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."
Plozasiran also 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. Notably, LDL-C levels increased 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 SHASTA-2 study (severe hypertriglyceridemia), all receiving plozasiran 25 mg quarterly. The extension demonstrated sustained triglyceride reductions, with mean reductions up to -73% in MUIR patients and -86% in SHASTA-2 patients through 15 months of follow-up. These reductions were maintained from the blinded portion of the studies, where plozasiran produced mean reductions in TGs up to -64% in MUIR and up to -74% in SHASTA-2 at 24 weeks.
Safety and Tolerability
Plozasiran has been generally well-tolerated. 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 studies, common adverse events included COVID-19, upper respiratory tract infection, headache, Type 2 diabetes mellitus, and abdominal pain.
Implications for Hypertriglyceridemia Treatment
These findings suggest that plozasiran could address unmet needs in treating FCS, severe hypertriglyceridemia (SHTG), and mixed hyperlipidemia. FCS, characterized by extremely high triglyceride levels (typically >880 mg/dL), currently lacks adequate therapeutic options in the US. SHTG, defined by triglyceride levels >500 mg/dL, significantly increases the risk of atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis (AP). Plozasiran's ability to substantially reduce triglycerides and improve lipid profiles offers a promising approach to mitigating these risks.
About Plozasiran
Plozasiran is an investigational RNA interference (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 lipids to more normal levels. The drug is currently being investigated in the SUMMIT program of clinical studies, including the PALISADE, SHASTA, MUIR, and CAPITAN studies.
Plozasiran has received Breakthrough Therapy Designation, Orphan Drug Designation, and Fast Track Designation from the FDA, as well as Orphan Drug Designation from the EMA for the treatment of FCS. However, it remains an investigational therapy and has not been approved for any disease.
