Plozasiran Reduces Triglycerides, Pancreatitis Risk in Persistent Chylomicronemia

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Data from the Phase III PALISADE trial (NCT05089084) demonstrated that plozasiran (Arrowhead) significantly reduced triglyceride levels and decreased incidence of pancreatitis compared to placebo in patients with persistent chylomicronemia, including patients with familial chylomicronemia syndrome (FCS).^1,2 These data, published by The New England Journal of Medicine, bolster prior findings on the efficacy of plozasiran in patients with severe hypertriglyceridemia and mixed hyperlipidemia, according to the study investigators.

“We recently announced successful topline results from the Phase III PALISADE study, which evaluated plozasiran in patients with FCS. The study met the primary endpoint of lowering triglycerides and met all key secondary endpoints, including reducing the incidence of acute pancreatitis, compared to placebo,” said Bruce Given, MD, chief medical scientist at Arrowhead, in a prior press release. “…We are adding more context to those results and will show that plozasiran, administered once every three months, consistently maintained the median and mean triglyceride levels over the study period with low variability. These are exciting results, and we are eager to share more of these data at upcoming medical congresses.”³

A genetic recessive disorder, persistent chylomicronemia is commonly caused by FCS and is associated with a greater risk of recurrent acute pancreatitis. Plozasiran is a first-in-class investigational RNA interference medication developed to lower production of apolipoprotein C-III (APOC3), which elevates triglyceride levels in the blood by inhibiting the breakdown of triglyceride rich lipoproteins (TRLs) by lipoprotein lipase and uptake of TRL remnants by hepatic receptors in the liver. Prior clinical studies have shown that plozasiran lowers triglycerides and atherogenic lipoproteins in patients with FCS, severe hypertriglyceridemia, and mixed hyperlipidemia, with a favorable safety profile.³

For the PALISADE trial, investigators randomly assigned 75 patients with persistent chylomicronemia, both with and without a genetic diagnosis, in a 2:1:2:1 ratio to receive subcutaneous plozasiran at a dose of 25 mg or 50 mg or placebo every three months for 12 months. The trial’s primary endpoint was median percent change from baseline in fasting triglyceride levels at 10 months, with key secondary endpoints of percent change in fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in fasting APOC3 level from baseline to 10 months and 12 months, and incidence of acute pancreatitis.

The median triglyceride level at baseline was 2044 mg per deciliter. After 10 months, the median change in fasting triglyceride levels from baseline was −80% among patients in the 25-mg plozasiran cohort, −78% in the 50-mg plozasiran cohort, and −17% in the placebo cohort (P<0.001).

Further, patients in the plozasiran cohort achieved superior results than the placebo cohort across the trial’s secondary endpoints, including incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P=0.03). In terms of safety, adverse event (AE) rates were similar across cohorts. The most common AEs were abdominal pain, nasopharyngitis, headache, and nausea, while severe and serious AEs were less common among patients in the plozasiran cohort compared to placebo.

“Our findings underpin the rapid development of plozasiran for the treatment of extreme hypertriglyceridemia to prevent acute pancreatitis in patients with FCS or other causes of persistent chylomicronemia with a history of pancreatitis,” the study authors concluded. “Beyond pancreatitis, triglyceride-rich lipoproteins may also be causally involved in atherosclerotic and cardiometabolic disease, hypotheses that support further research with plozasiran. Ultimately, the clinical value of plozasiran will depend on further demonstration of long-term efficacy, safety, cost-effectiveness, and equity of access for patients in need.”¹

References

1. Watts G, et al. Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. Published September 2, 2024. N Engl J Med 2024. DOI: 10.1056/NEJMoa2409368.

2. Study of ARO-APOC3 (Plozasiran) in Adults With Familial Chylomicronemia Syndrome (FCS) (PALISADE). ClinicalTrials.gov ID. August 26, 2024. Accessed September 3, 2024. https://clinicaltrials.gov/study/NCT05089084

3. Arrowhead Pharmaceuticals to Advance RNAi-based Plozasiran into Phase 3 CAPITAN Cardiovascular Outcomes Trial. News release. Arrowhead Pharmaceuticals. June 25, 2024. Accessed September 3, 2024. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-advance-rnai-based-plozasiran-phase-3