Plozasiran May Help Reduce Cholesterol Levels in Patients With Mixed Hyperlipidemia

Plozasiran (Arrowhead Pharmaceuticals), formerly ARO-APOC3, demonstrated a significant reduction in triglyceride levels at week 24 in patients with mixed hyperlipidemia, a genetic disorder that causes high cholesterol. The results were shown in the double-blind, placebo-controlled phase 2 MUIR trial (NCT04998201) that evaluated the safety and efficacy of plozasiran.¹

Further research is needed to validate the findings and ensure the safety and efficacy of plozasiran for adult patients with mixed hyperlipidemia. Image Credit: © Justlight - stock.adobe.com

Hyperlipidemia, or high cholesterol, is characterized by the excess of lipids or fats in the blood, leading to the increased risk of atherosclerotic cardiovascular disease (ASCVD) due to elevated low-density lipoprotein (LDL) or very low-density lipoprotein (VLDL) cholesterol levels, or non-high-density lipoprotein (HDL). Hyperlipidemia is driven by triglyceride-rich lipoproteins (TRLs), which are metabolized through apolipoprotein C3 (APOC3)–mediated inhibition of lipoprotein lipase.^2,3

Plozasiran is an investigational hepatocyte-targeted APOC3 small interfering RNA designed to reduce production of APOC3, a component of TRLs and a key regulatory of triglyceride metabolism. In September 2024, it was granted breakthrough therapy designation by the FDA for treatment of familial chylomicronemia syndrome, a severe genetic disorder characterized by extremely high triglyceride levels. In the MUIR trial, it demonstrated favorable efficacy for the treatment of adults with mixed hyperlipidemia (i.e., a triglyceride level of 150-499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter).^3,4

A total of 353 participants were randomly assigned 3:1 to receive plozasiran or placebo across four cohorts. The first 3 cohorts received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses), and the fourth cohort received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The primary end point was the percent change in fasting triglyceride level at 24 weeks.³

At 24 weeks, plozasiran demonstrated significant reductions in fasting triglyceride levels across dosages: −49.8 percentage points 10-mg-quarterly dose (95% confidence interval [CI], −59.0 to −40.6), −56.0 percentage points with the 25-mg-quarterly dose (95% CI, −65.1 to −46.8), −62.4 percentage points with the 50-mg-quarterly dose points (95% CI, −71.5 to −53.2), and −44.2 percentage points with the 50-mg-half-yearly dose (95% CI, −53.4 to −35.0) (P<0.001 for all comparisons).³

The researchers observed worsening glycemic control in 10% of participants receiving placebo compared with 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose.³

Further research is needed to validate the findings and ensure the safety and efficacy of plozasiran for adult patients with mixed hyperlipidemia. Plozasiran for mixed hyperlipidemia is also being investigated in the CAPITAN study.⁵

REFERENCES

1. Study of aro-apoc3 in adults with mixed dyslipidemia (muir). ClinicalTrials.gov Identifier: NCT04998201. Updated April 18, 2024. Accessed October 3, 2024. https://clinicaltrials.gov/study/NCT04998201

2. Hyperlipidemia. Cleveland Clinic. August 4, 2022. Accessed October 3, 2024. https://my.clevelandclinic.org/health/diseases/21656-hyperlipidemia

3. Ballantyne, C, Vasas, S, Azizad M, et al. Plozasiran, an rna interference agent targeting apoc3, for mixed hyperlipidemia. N Engl J Med. May 28, 2024. doi: 10.1056/NEJMoa2404143

4. Fda grants breakthrough therapy designation to plozasiran for familial chylomicronemia syndrome. Pharmacy Times. September 11, 2024. Accessed October 3, 2024. https://www.pharmacytimes.com/view/fda-grants-breakthrough-therapy-designation-to-plozasiran-for-familial-chylomicronemia-syndrome

5. Arrowhead pharmaceuticals receives fda breakthrough therapy designation for plozasiran. Business Wire. September 10, 2024. Accessed October 3, 2024. https://www.businesswire.com/news/home/20240910509591/en