Robert Rosenson, MD: RNAi Therapies Show Promise in Mixed Hyperlipidemia

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Robert Rosenson, MD, discusses the unmet need in mixed hyperlipidemia and the potential for RNA interference therapies in this patient population.

A pair of phase 2 trials examining agents for use in adults with mixed hyperlipidemia underscore the potential of different therapeutic approaches and targets among this patient population.

Presented at the European Atherosclerosis Society 2024 Congress, the MUIR and ARCHES trials, which examined APOC3 inhibitor plozasiran and ANGPTL3 zodasiran, respectively, underline the benefits of targeting APOC3 and ANGPTL3 as therapeutic targets as well as the potential of RNA interference therapies in the management of mixed hyperlipidemia.

MUIR

Presented on May 28, 2024 by Christie Ballantyne, MD, the MUIR trial was a double-blind, randomized, placebo-controlled phase 2b trial of adults with mixed hyperlipidemia, which was defined as a fasting triglyceride level of 150 to 499 mg/dL and either an LDL-C of 70 mg/dL or a non-HDL cholesterol level of 100 mg/dL or greater.1

In total, 353 patients were randomized in a 3:1 ratio to receive plozasiran or placebo within each of 4 cohorts. In the first 3 cohorts, the participants received a subcutaneous injection of plozasiran 10 mg, 25 mg, or 50 mg or placebo on day 1 and at week 12. In the fourth cohort, participants received plozasiran 50 mg or placebo on day 1 and at week 24.

The study cohort had a mean age of 61 years, mean BMI of 32 kg/m2, mean triglyceride levels of 244 mg/dL, mean non-HDL cholesterol levels of 151 mg/dL, mean LDL-C levels of 103 mg/dL, and mean remnant cholesterol levels of 47 mg/dL.1

Upon analysis, results of the trial demonstrated use of plozasiran was associated with significant reductions in fasting triglyceride levels relative to placebo, with least-squares mean percent change from baseline of −49.8 percentage points (95% confidence interval [CI], −59.0 to −40.6) with the 10-mg-quarterly dose, −56.0 percentage points (95% CI, −65.1 to −46.8) with the 25-mg-quarterly dose, −62.4 percentage points (95% CI, −71.5 to −53.2) with the 50-mg-quarterly dose, and −44.2 percentage points (95% CI, −53.4 to −35.0) with the 50-mg-half-yearly dose (P <.001 for all comparisons).1

ARCHES-2

Presented the following morning on May 29, 2024 by Robert Rosenson, MD, the ARCHES-2 trial was a double-blind, placebo-controlled, dose-ranging phase 2b trial of adults with mixed hyperlipidemia, which was defined as a fasting triglyceride level of 150 to 499 mg/dL and either an LDL cholesterol level of 70 mg/dL or a non-HDL cholesterol level of 100 mg/dL or greater.2

In total, 204 patients were randomized in a 3:1 ratio to receive subcutaneous injections of zodasiran at doses of 50, 100, or 200 mg or placebo therapy on day 1 and week 12 and were followed through week 36. The primary outcome of interest for the trial was the percent change in triglyceride levels from baseline to week 24.2

The study cohort had mean age of 61 years, mean BMI of 33 kg/m2, mean triglyceride level of 246 mg/dL, mean non-HDL cholesterol levels of 46 mg/dL, mean LDL-C levels of 97 mg/dL, and mean remnant cholesterol levels of 48 mg/dL.2

Results indicated use of zodasiran was associated with significant and dose-dependent least-squares mean differences in triglyceride levels as compared with placebo at 24 weeks, with placebo-adjusted reductions of -51 percentage points (95% Confidence Interval [CI], -62 to -41), -57 percentage points (95% CI, -67 to -46), and -63 percentage points (95% CI, −74 to −53) with the 50 mg, 100 mg, and 200 mg doses, respectively. Further analysis suggested use was associated with dose-dependent decreases from baseline in ANGPTL3 levels, with placebo-adjusted differences in change of −54 (95% CI, −62 to −46) percentage points, −70 (95% CI, −78 to −62) percentage points, and −74 (95% CI, −81 to −66) percentage points with the 50 mg, 100 mg, and 200 mg doses, respectively. Investigators pointed out these reductions were strongly correlated with triglyceride levels (Pearson correlation coefficient, 0.69).2

Relevant disclosures of interest for Rosenson include Arrowhead, Amgen, CRISPR Therapeutics, Eli Lilly and Company, Kowa, Lilly, Novartis, Precision BioSciences, Regeneron, and Ultragenyx.

References:

  1. Ballantyne CM, Vasas S, Azizad M, et al. Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia. New England Journal of Medicine. Published online May 28, 2024. doi: 10.1056/NEJMoa2404143
  2. Rosenson RS, Gaudet D, Hegele RA, at al. Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia. New England Journal of Medicine. Published online May 29, 2024. doi:10.1056/NEJMoa2404147
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