medwireNews: Treatment with the small interfering RNA plozasiran significantly reduces mean triglyceride levels in individuals with “extreme and persistent” chylomicronemia compared with placebo, report researchers from the PALISADE trial.
Participants receiving plozasiran, including individuals with genetically confirmed familial chylomicronemia syndrome (FCS) – a rare autosomal recessive disorder linked to chylomicronemia – also had a significantly reduced incidence of pancreatitis versus those treated with placebo.
“Our findings underpin the rapid development of plozasiran for the treatment of extreme hyper- triglyceridemia to prevent acute pancreatitis in patients with FCS or other causes of persistent chylomicronemia with a history of pancreatitis,” write Gerald Watts (University of Western Australia, Perth) and colleagues in The New England Journal of Medicine.
The team randomly assigned 75 individuals (mean age 46 years, 51% women) with recurring fasting triglyceride levels of more than 1000 mg/dl that were resistant to standard lipid-lowering therapy, to receive plozasiran 25 mg (n=26), plozasiran 50 mg (n=24), or placebo (n=25).
Baseline triglyceride levels were a respective median 2008, 1902, and 2053 mg/dL in the plozasiran 25 mg and 50 mg and placebo groups, and 59% of participants had pathogenic disease variants in the five genes that encode proteins regulating lipoprotein lipase activity.
The remaining participants met other criteria including having a history of acute pancreatitis not caused by alcohol or cholelithiasis, recurrent hospitalizations due to severe abdominal pain with no known cause, and childhood pancreatitis, note Watts et al.
At the 10-month follow up, the group observed reductions from baseline in median fasting triglyceride levels of 80%, 78%, and 17% among the plozasiran 25 mg, plozasiran 50 mg, and placebo groups, respectively.
This equated to significantly greater overall percentage reductions in fasting triglyceride levels in the plozasiran versus placebo groups, at 59 and 53 percentage points for the plozasiran 25 mg and 50 mg groups, respectively, reports the team.
Similarly, triglyceride levels at a mean 10 and 12 months after baseline were significantly lower in both plozasiran groups versus placebo. Indeed, “[m]arked reductions in the median triglyceride level were present as early as 1 month after trial initiation,” note Watts and colleagues.
The reduction in levels from baseline were a respective 60 and 51 percentage points greater at the 10- and 12-month timepoints for those who received plozasiran 25 mg and 50 mg than for those who received placebo.
A total of 38 suspected cases of acute pancreatitis emerged during the trial, with nine episodes confirmed in seven participants, of whom 4% took plozasiran and 20% placebo. This gave a significant odds ratio for pancreatitis of 0.17 in favor of the plozasiran recipients compared with their peers taking placebo.
Watts and co-authors explain that plozasiran reduces the production and secretion of hepatic apolipoprotein C-III, “a small glycoprotein, predominantly synthesized by the liver, that is a major determinant of triglyceride levels.”
They report that while apolipoprotein C-III levels changed “minimally” with placebo after 10 and 12 months of treatment, levels reduced significantly in both the plozasiran 25 mg and 50 mg groups by a respective 93% and 96% at 10 months, and by 89% and 88% at 12 months.
“Beyond pancreatitis, triglyceride-rich lipoproteins may also be causally involved in atherosclerotic and cardiometabolic disease, hypotheses that support further research with plozasiran,” the researchers comment, concluding that “[u]ltimately, 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.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group
