Robert Rosenson, MD: ARCHES-2 and Zodasiran in Mixed Hyperlipidemia

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Robert Rosenson, MD, discusses the results of the ARCHES-2 trial and how it informs the potential of ANGPTL3 inhibition as well as RNAi therapies.

At the European Atherosclerosis Society 2024 Congress, cardiologists received their formal introduction to zodasiran, an angiopoietin-like 3 (ANGPTL3)-targeting RNA interference therapy.

Examined in the phase 2b ARCHES-2 trial, results of the study suggest zodasiran was well-towered and use was associated with significant, dose-dependent reductions in triglycerides up to 63% with the greatest dose of zodasiran and further analysis demonstrating benefits on other lipid parameters among adults with mixed hyperlipidemia.1

“The potent reductions in serum lipids and lipoproteins and favorable safety profile seen in the ARCHES-2 clinical study of zodasiran suggest its potential to treat residual ASCVD risk in patients with elevated triglyceride rich lipoproteins,” said principal investigator Robert Rosenson, MD, professor of Medicine (Cardiology) at the Icahn School of Medicine at Mount Sinai and director of Lipids and Metabolism for the Mount Sinai Health System.2 “The genetic data around ANGPTL3 as a target are very compelling and support further Phase 3 studies to determine whether the large reductions in triglyceride rich lipoproteins observed after zodasiran treatment can replicate the genetic data and reduce ASCVD risk.”

A double-blind, placebo-controlled, dose-ranging phase 2b trial, ARCHES-2 enrolled 204 adults with mixed hyperlipidemia and randomized them in 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. Per trial protocol, mixed hyperlipidemia 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.1

Upon analysis, 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 (P <.001 for all comparisons). Further analysis revealed these were sustained out to week 36 of the trial, with placebo-adjusted differences in triglyceride levels of −34 percentage points (95% CI, −45 to −24), −38 percentage points (95% CI, −49 to −27), and −51 percentage points (95% CI, −62 to −41) with the 50 mg, 100 mg, and 200 mg doses, respectively.1

Additionally, dose-dependent decreases from baseline in ANGPTL3 levels were observed in the trial, with placebo-adjusted difference 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.

For more on the results of the study and the potential of RNA interference therapies, specifically, those targeting ANGPTL3, check out our interview with Rosenson.

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


  1. Rosenson RS, Gaudet D, Hegele RA, et al. Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia. N Engl J Med. Published online May 29, 2024. doi:10.1056/NEJMoa2404147
  2. Arrowhead Pharmaceuticals presents New phase 2 data of Zodasiran in patients with mixed hyperlipidemia. Arrowhead Pharmaceuticals, Inc. May 29, 2024. Accessed May 30, 2024.