Arrowhead announces new PALISADE study results

Arrowhead (ARWR) announced new results from the Phase 3 PALISADE study and the open-label extension from the Phase 2 MUIR and SHASTA-2 studies of investigational plozasiran. These data were presented in two oral presentations at the American Heart Association Scientific Sessions and PALISADE data was simultaneously published in the AHA journal, Circulation. In PALISADE, 75 patients with FCS, with or without a genetic diagnosis, were randomly assigned to receive subcutaneous plozasiran at 25 mg or 50 mg or placebo every three months for 12 months. At baseline, the median triglyceride level was 2044 mg/dL. Forty-four patients had genetically confirmed FCS and 31 patients had clinically diagnosed FCS. Plozasiran, at the 25 mg dose being proposed for marketing approval, induced rapid, deep, and sustained reductions in apolipoprotein C-III, of greater than 90%, and in triglycerides, of approximately 80%, independent of gene variants causing FCS. At least half of the patients maintained TGs below 500 mg/dL, a threshold associated with increased risk of acute pancreatitis, with approximately 75% achieving levels below 880 mg/dL, and greater than 80% achieving levels below 1000 mg/dL, invariant of FCS genotype. Plozasiran decreased total cholesterol with least square mean reductions of 41%, non-high-density lipoprotein cholesterol of 50%, and remnant cholesterol or very-low-density lipoprotein cholesterol of -67%, with reciprocal increases in HDL-C of 52%, and apolipoprotein-AI of 21% at 12 months. Plozasiran increased low-density lipoprotein cholesterol levels without increases in total ApoB or ApoB-100. In the OLE, a total of 418 subjects from the Phase 2 MUIR study in patients with mixed hyperlipidemia and the SHASTA-2 study in patients with severe hypertriglyceridemia entered the extension in which all received plozasiran 25 mg dosed quarterly. 10, 25, or 50 mg of plozasiran in the blinded portion of the studies produced mean reductions in TGs up to -64% in MUIR and up to -74% in SHASTA-2 at 24 weeks representing the trough after the second quarterly dose. Corresponding trough reductions in the extension were maintained up to 73% in patients from MUIR and 86% in patients from SHASTA-2 through 15 months follow-up. Favorable sustained reductions in TGs and APOC3, decreases in remnant cholesterol, non-HDL-C, favorable changes in apoB, and increases in HDL-C were observed, with no changes in LDL-C or Lp(a) and remained durable over the duration of the open-label extension. No worsening of HbA1c and no new onset diabetes mellitus were observed, providing further evidence that long-term safety appears favorable with repeated dosing and longer observation periods.