Using Plozasiran to Prevent Pancreatitis and Reduce Triglycerides Level in Patients with Persistent Chylomicronemia
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Reviewed by Dat Tien Nguyen, B.A, ScM.
Translated by Nhi Phuong Quynh Le, B.A |
Posted on February 07th, 2025
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Chylomicrons are lipoprotein particles that the small intestine epithelium uses to transport dietary fats throughout the body and to the liver for repackaging into cholesterol-containing particles like HDL and LDL. Patients with chylomicronemia experience an excessive accumulation of these particles and also suffer from hypertriglyceridemia, which increases the risk of pancreatitis. A recently published study, funded by Arrowhead Pharmaceuticals, explored the effectiveness of plozasiran in managing chylomicronemia and preventing pancreatitis.
The phase 3 clinical trial included 75 participants diagnosed with persistent chylomicronemia, with an average fasting triglyceride level of approximately 2,300 mg/dL. Over 60% of the participants were using fibrates to manage their hypertriglyceridemia, and around 50% were on statins. Additionally, 90% of the patients had experienced at least one episode of pancreatitis, which was not attributed to alcohol use or cholelithiasis.
The participants were randomly assigned to receive quarterly subcutaneous injections of either a placebo or plozasiran, at doses of 25 mg or 50 mg. Plozasiran is a small interfering RNA that specifically targets hepatocytes, where it binds to mRNA transcripts coding for apolipoprotein C-III. This interaction neutralizes the mRNA and reduces the production of apolipoprotein C-III, which is embedded on the surface of chylomicrons, preventing their clearance by lipoprotein lipase and their reuptake by liver cells.
After 10 months, the researchers observed a dramatic 80% reduction in fasting triglyceride levels in patients treated with plozasiran, significantly higher than the 17% reduction seen in the placebo group. Additionally, patients receiving plozasiran were 83% less likely to develop pancreatitis; however, there was a small but statistically insignificant variation in this finding, which could be clarified with a future study involving a larger cohort. Analysis of the reported adverse effects showed no significant differences between the two groups. The authors also noted that there was no increased risk of thrombocytopenia, which had been a concern with volanesorsen, a triglyceride-reducing antisense oligonucleotide.
The phase 3 clinical trial included 75 participants diagnosed with persistent chylomicronemia, with an average fasting triglyceride level of approximately 2,300 mg/dL. Over 60% of the participants were using fibrates to manage their hypertriglyceridemia, and around 50% were on statins. Additionally, 90% of the patients had experienced at least one episode of pancreatitis, which was not attributed to alcohol use or cholelithiasis.
The participants were randomly assigned to receive quarterly subcutaneous injections of either a placebo or plozasiran, at doses of 25 mg or 50 mg. Plozasiran is a small interfering RNA that specifically targets hepatocytes, where it binds to mRNA transcripts coding for apolipoprotein C-III. This interaction neutralizes the mRNA and reduces the production of apolipoprotein C-III, which is embedded on the surface of chylomicrons, preventing their clearance by lipoprotein lipase and their reuptake by liver cells.
After 10 months, the researchers observed a dramatic 80% reduction in fasting triglyceride levels in patients treated with plozasiran, significantly higher than the 17% reduction seen in the placebo group. Additionally, patients receiving plozasiran were 83% less likely to develop pancreatitis; however, there was a small but statistically insignificant variation in this finding, which could be clarified with a future study involving a larger cohort. Analysis of the reported adverse effects showed no significant differences between the two groups. The authors also noted that there was no increased risk of thrombocytopenia, which had been a concern with volanesorsen, a triglyceride-reducing antisense oligonucleotide.