Arrowhead Pharmaceuticals presents new pivotal phase III data at ESC 2024 from PALISADE study of plozasiran in patients with familial chylomicronemia syndrome

PALISADE successfully met its primary endpoint and all multiplicity-controlled key secondary endpoints, including statistically significant reductions in triglycerides (TGs), apolipoprotein C-III (APOC3) and the incidence of acute pancreatitis (AP). These data were presented in a late-breaking oral presentation at the European Society of Cardiology (ESC) Congress 2024 and simultaneously published in The New England Journal of Medicine (see citation).

Details are as follows: Title: A Randomised, Placebo-Controlled Phase 3 Study of Plozasiran in Patients with Familial Chylomicronemia Syndrome • Date: September 2 • Presenter: Prof. Gerald Watts, University of Western Australia • Session: Small trials, trial updates and other studies on lipid therapy • Session Type: Late Breaking Science

Selected Results; In PALISADE, 75 patients with persistent chylomicronemia, with or without a genetic diagnosis, were randomly assigned to receive subcutaneous plozasiran at 25 mg (n=26) or 50 mg (n=24) or placebo (n=25) every three months for 12 months. At baseline, the median triglyceride level was 2044 mg/dL. A total of 44 patients (59%) had genetically confirmed FCS and 31 patients (41%) had clinically diagnosed persistent chylomicronemia suggestive of FCS. At month 10, the median reduction from baseline in the fasting triglyceride level (the primary endpoint) was -80% in the 25 mg plozasiran group, -78% in the 50 mg plozasiran group and -17% in the placebo group (p<0.001). marked reductions in the median triglyceride level below guideline-directed risk thresholds associated with acute pancreatitis occurred as early as one month after trial initiation and showed modest variation throughout the 12-month blinded treatment period. the mean percentage change in triglyceride level was similar to median values. at month 10, apoc3 was significantly reduced with median reductions of -93% in the 25 mg plozasiran group, -96% in the 50 mg plozasiran group, and -1% in the placebo group (p><0.001).

The final alpha-controlled secondary efficacy end point compared the incidence of positively adjudicated acute pancreatitis in a pre-specified pooled analysis of the 25 mg and the 50 mg plozasiran groups versus the pooled placebo group. Among the 38 suspected cases of acute pancreatitis that were referred for adjudication, nine episodes in seven patients were positively adjudicated. Plozasiran demonstrated statistical significance for this endpoint, with patients receiving plozasiran achieving an 83% reduction in the risk of developing acute pancreatitis versus placebo. A total of two cases occurred in two of 50 patients (4%) receiving plozasiran and seven cases occurred in five of 25 patients (20%) receiving placebo (odds ratio, 0.17, p=0.03).

Safety and Tolerability Plozasiran demonstrated a favorable safety profile in the PALISADE study. The most common adverse events were abdominal pain, Covid-19, nasopharyngitis, headache, nausea, back pain, upper respiratory tract infection and diarrhea. Adverse events among the patients in the two plozasiran dose groups were generally similar to those in the placebo group. Severe and serious adverse events were more common in the placebo group. Hyperglycemia was observed in a limited number of patients in the treatment groups, but was confined to patients with pre-diabetes and diabetes.

See- Watts GF, Rosenson RS et al. "Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk". New Engl J Med published online September 2024, doi:10.1056/NEJMoa2409368