RNA interference agents appear to benefit patients with mixed hyperlipidemia
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Key takeaways:
- Two small interfering RNA therapies lowered triglyceride levels in patients with mixed hyperlipidemia at 24 weeks.
- They also lowered non-HDL and apolipoprotein B.
In two phase 2b trials, RNA interference agents were associated with reductions in triglycerides compared with placebo for patients with mixed hyperlipidemia.
The final results of the MUIR trial of plozasiran (Arrowhead Pharmaceuticals) and of the ARCHES-2 trial of zodasiran (Arrowhead Pharmaceuticals) were presented at the European Atherosclerosis Society Congress and simultaneously published in The New England Journal of Medicine.
MUIR
For the MUIR trial, Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, chief of the section of cardiovascular research and professor of medicine at Baylor College of Medicine, and colleagues randomly assigned 353 patients with mixed hyperlipidemia to plozasiran, a hepatocyte-targeted apolipoprotein C-III small interfering RNA, or placebo. Mixed hyperlipidemia was defined as triglycerides 150 mg/dL to 499 mg/dL and LDL at least 70 mg/dL or non-HDL at least 100 mg/dL. Patients had been taking statins for at least 4 weeks or were unable or unwilling to take statins.
“This is a story about elevated triglycerides, which remain a problem in many individuals that I see in my practice,” Ballantyne said in a press release. “While statins are highly effective in treating high cholesterol, specifically LDL cholesterol, there are still many people who have persistent high triglycerides. Variants in specific genes have been shown to raise triglycerides and the identification of these genes has led to new targets and therapies, such as the therapeutic we are studying in this current trial, plozasiran.”
Patients received a dose of plozasiran 10 mg, 25 mg or 50 mg once every 12 weeks (quarterly), a dose of plozasiran 50 mg once every 24 weeks (half-yearly), or placebo once every 12 or 24 weeks. Across the groups, the mean age ranged from 59 to 63 years and the percentage of women ranged from 35% to 47%.
The primary endpoint of percent change in fasting triglyceride level at week 24 favored the plozasiran groups, Ballantyne and colleagues found. Compared with placebo, the least-squares mean percent change from baseline was 49.8 percentage points with plozasiran 10 mg quarterly (95% CI, –59 to –40.6), 56 percentage points with plozasiran 25 mg quarterly (95% CI, –65.1 to –46.8), 62.4 percentage points with plozasiran 50 mg quarterly (95% CI, –71.5 to –53.2) and 44.2 percentage points with plozasiran 50 mg half-yearly (95% CI, –53.4 to –35; P for all comparisons < .001).
The researchers found that worsening glycemic control at 24 weeks occurred as follows: 10% in the placebo group, 12% in the 10 mg quarterly plozasiran group, 7% in the 25 mg quarterly plozasiran group, 20% in the 50 mg quarterly plozasiran group and 21% in the 50 mg half-yearly plozasiran group.
The plozasiran groups also achieved reductions in non-HDL, apolipoprotein B and remnant cholesterol, and had similar adverse event rates compared with the placebo group, according to the researchers.
“At week 24, the fasting triglyceride levels were below 150 mg/dL in most participants in the plozasiran groups,” Ballantyne and colleagues wrote in NEJM. “The reductions in ApoB and non-HDL cholesterol levels should be interpreted in light of the results of recent studies supporting non-HDL cholesterol and ApoB levels as predictors of the risk of coronary artery disease. Historically, reductions in both non-HDL cholesterol and ApoB, effected through decreases in the LDL cholesterol level, have translated into clinical benefit. In contrast, our findings indicate that the reductions in the non-HDL cholesterol level that were observed in the MUIR trial (involving participants who had been treated with statins and other lipid-lowering therapies) were brought about by reductions in the level of cholesterol remnants rather than reductions in the LDL cholesterol level.”
The final results of another plozasiran trial, SHASTA-2, will be presented at the National Lipid Association Scientific Sessions on June 1.
ARCHES-2
For the ARCHES-2 trial, Robert S. Rosenson, MD, director of metabolism and lipids for the Mount Sinai Health System and professor of medicine in cardiology at the Icahn School of Medicine at Mount Sinai, and colleagues randomly assigned 204 patients with mixed hyperlipidemia (using the same definition as in MUIR) to zodasiran, an RNA interference therapy targeting expression of ANGPTL3 in the liver, or placebo.
“Our study represents one of the first trials of an RNA inhibitor of ANGPTL3 with advantages like durable gene silencing and infrequent dosing,” Rosenson said in a press release. “For patients with mixed hyperlipidemia and persistent elevations in LDL cholesterol and non-HDL cholesterol, zodasiran could expand the opportunities for lowering ‘bad’ cholesterol beyond conventional therapies such as statins, potentially leading to more favorable outcomes for patients.”
Patients received zodasiran 50 mg, 100 mg or 200 mg or placebo on day 1 and week 12 and were followed until week 36. The mean age was approximately 60 years and slightly less than half of patients were women.
The primary endpoint of percent change in triglyceride level at week 24 favored the zodasiran groups, with the difference in change vs. placebo being –51 percentage points in the 50 mg group, –57 percentage points in the 100 mg group and –63 percentage points in the 200 mg group (P for all < .001), according to the researchers.
Compared with the placebo group, ANGPTL levels were lowered by –54 percentage points in the 50 mg zodasiran group, –70 percentage points in the 100 mg zodasiran group and –74 percentage points in the 200 mg zodasiran group at 24 weeks (P for all < .001), Rosenson and colleagues found.
Zodasiran also lowered non-HDL, ApoB and LDL compared with placebo at 24 weeks, according to the researchers.
Patients with diabetes assigned zodasiran 200 mg had a transient elevation in HbA1c levels, but otherwise, adverse events were similar between the groups, the researchers found.
“In this trial involving patients with mixed hyperlipidemia, zodasiran use led to significant decreases in triglyceride levels at 24 weeks,” Rosenson and colleagues wrote in NEJM. “It also led to robust and durable reductions in levels of triglyceride-rich lipoprotein remnants and total atherogenic lipoproteins, including LDL cholesterol, and phenocopied the effects of ANGPTL3 loss-of-function mutations on levels of atherogenic lipoproteins. The overall safety and efficacy of the 200 mg dose of zodasiran, administered quarterly, supports its use in further studies.”
References:
- Ballantyne CM, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2404143.
- Promising results for hyperlipidemia treatment reduces risk of cardiovascular events. https://www.bcm.edu/news/promising-results-for-hyperlipidemia-treatment-reduces-risk-of-cardiovascular-events. Published May 28, 2024. Accessed May 28, 2024.
- RNA inhibitor is shown safe and effective in reducing a wide range of cholesterol and triglyceride levels in the blood in Mount Sinai-led clinical trial. https://www.newswise.com/articles/rna-inhibitor-is-shown-safe-and-effective-in-reducing-a-wide-range-of-cholesterol-and-triglyceride-levels-in-the-blood-in-mount-sinai-led-clinical-trial. Published May 29, 2024. Accessed May 29, 2024.
- Rosenson RS, et al. Late-breaker session 2: New therapeutic agents. Presented at: European Atherosclerosis Society Congress; May 26-29, 2024; Lyon, France.
- Rosenson RS, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2404147.
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Ballantyne CM, et al. New therapeutics. Presented at: European Atherosclerosis Society Congress; May 26-29, 2024; Lyon, France.
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