Plozasiran lowers triglycerides, reduces pancreatitis risk in chylomicronemia
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Key takeaways:
- Plozasiran lowered triglycerides and reduced risk for pancreatitis vs. placebo in patients with chylomicronemia.
- The benefit occurred regardless of whether a patient’s chylomicronemia was genetically confirmed.
In patients with persistent chylomicronemia, plozasiran, a small interfering RNA therapy, was associated with lower triglyceride levels and reduced risk for pancreatitis, researchers reported at the European Society of Cardiology Congress.
“Chylomicrons are normally introduced in the blood after fat in your meal is processed by the gut wall and subsequently incorporated into these triglyceride-rich particles. The chylomicrons subsequently travel in the lymphatic system and are delivered into the circulation via the lymphatic duct,” Gerald F. Watts, DSc, MD, PhD, FRCP, FRACP, FCSANZ, head of the cardiometabolic service in the departments of cardiology and internal medicine at Royal Perth Hospital and Winthrop Professor of Cardiometabolic Medicine at the University of Western Australia in Perth, told Healio. “The particles need to be broken down by an enzyme called lipoprotein lipase to deliver fatty acids for use by muscle and stored in fat tissue. Chylomicronemia occurs when you can’t clear fat. Excessive chylomicronemia can cause damage to tissues, most importantly the pancreas. We now have a very effective way of correcting chylomicronemia, plozasiran, a first-in-class silencing RNA therapy (small interfering RNA, siRNA) that stops the production in the liver of apolipoprotein C-III. ApoC-III antagonizes the action of the lipoprotein lipase that hydrolyzes and clears the particles and plozasiran silences this inhibitor. What we hoped to do with this intervention was to reduce excessively high triglycerides in the blood (reflective of chylomicronemia) to a level that would reduce the incidence of pancreatitis.”
The easiest way to identify people with chylomicronemia is via elevated triglyceride levels (> 10 mmol/L or 1,000 mg/dL), he said.
Plozasiran vs. placebo
For the PALISADE trial, Watts and colleagues randomly assigned 75 patients with persistent chylomicronemia, regardless of whether they had a genetic diagnosis, to plozasiran (Arrowhead Pharmaceuticals) 25 mg, plozasiran 50 mg or placebo. The mean age was approximately 45 years, about half the patients were women, the median baseline triglyceride level was 2,044 mg/dL, about 90% had a history of acute pancreatitis and most were taking medications such as statins, fibrates and omega-3 fatty acids. The results were simultaneously published in The New England Journal of Medicine.
The development of plozasiran, an injection administered once every 3 months, was inspired by a gene linked to very low levels of ApoC-III, the carriers of which have greatly reduced risk for heart disease and pancreatitis, Watts told Healio. The silencing RNA therapy “puts the expression of the gene for ApoC-III in the liver to sleep, so you don’t make any ApoC-III,” Watts told Healio. “By this mechanism, the ApoC-III is not made, and you can clear your fat very effectively, even if you have a genetic defect, and you can knock down your ApoC-III by over 90%. In parallel with that, you can knock down triglycerides dramatically and prevent pancreatitis.”
The primary endpoint of median change from baseline to 10 months in fasting triglyceride level favored both plozasiran groups over the placebo group (plozasiran 25 mg, –80%; plozasiran 50 mg, –78%; placebo, –17%; P < .001), according to the researchers.
Compared with placebo, plozasiran greatly lowered risk for pancreatitis at 1 year (pooled plozasiran group, 4%; placebo group, 20%; OR = 0.17; 95% CI, 0.03-0.94; P = .03), Watts and colleagues found.
The plozasiran groups also had reduced ApoC-III levels at 10 months and 12 months compared with the placebo group (P for all comparisons < .001), according to the researchers.
Hypothesis ‘clearly confirmed’
“What we hypothesized was clearly confirmed in this study,” Watts told Healio. “Triglyceride levels were reduced by 80%. Only two of 50 patients receiving plozasiran developed acute pancreatitis compared with 5 of 20 patients on placebo, representing 83% lower odds of acute pancreatitis with plozasiran. About 75% of those in the plozasiran group attained triglycerides below 10 mmol/L or 880 mg/dL, with 50% achieving triglycerides less than 5 mmol/L or 500 mg/dL, the therapeutic levels recommended by expert guidelines to prevent pancreatitis. That is the first time statistical significance in reductions of acute pancreatitis events has been demonstrated in a controlled clinical trial.”
Overall adverse events were similar between the groups, with the most common being abdominal pain, nasopharyngitis, headache and nausea, but serious or severe adverse events were less common with plozasiran than with placebo, Watts and colleagues found.
“The benefit was seen irrespective of a pathogenic loss-of-function gene variant affecting lipoprotein lipase,” Watts told Healio. “It benefited people with severe genetic deficiencies as well as people who expressed the phenotype but did not have that recordable gene abnormality.”
The findings mean that “for people who get recurrent pancreatitis, or people with severe chylomicronemia at risk for pancreatitis, we now have an effective treatment to lower triglycerides and prevent pancreatitis, which we didn’t have before,” Watts told Healio.
Another agent, olezarsen (Ionis Pharmaceuticals), an antisense oligonucleotide targeting messenger RNA for ApoC-III, was shown to reduce triglycerides and risk for pancreatitis in patients with familial chylomicronemia in the BALANCE trial, but that trial was restricted to patients with genetically confirmed chylomicronemia, Watts told Healio.
Plozasiran is not yet approved for commercial use in the U.S., but, as Healio previously reported, it received a breakthrough therapy designation from the FDA, and Arrowhead plans to file an application for approval by the end of 2025.
Reference:
For more information:
Gerald F. Watts, DSc, MD, PhD, FRCP, FRACP, FCSANZ, can be reached at gerald.watts@uwa.edu.au.
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Watts GF, et al. Late-breaking science: Smaller trials, trial updates and other studies on lipid therapy. Presented at: European Society of Cardiology Congress; Aug. 30-Sept. 2, 2024; London (hybrid meeting).
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