Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a).

Abstract

Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5-8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran (ClinicalTrials.gov: NCT03626662 ), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71-97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9 mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration.

• Authors: Michael J Koren, Patrick Maurice Moriarty, Seth J Baum, Joel Neutel, Martha Hernandez-Illas, Howard S Weintraub, Monica Florio, Helina Kassahun, Stacey Melquist, Tracy Varrieur, Saptarsi M Haldar, Winnie Sohn, Huei Wang, Mary Elliott-Davey, Brooke M Rock, Tao Pei, Oliver Homann, Jennifer Hellawell, Gerald F Watts
• Journal: Nature medicine (Nat Med) Vol. 28 Issue 1 Pg. 96-103 (01 2022) ISSN: 1546-170X [Electronic] United States
• PMID: 35027752 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Lipoprotein(a)
• RNA, Small Interfering
• olpasiran

Topics

• Adult
• Animals
• Female
• Humans
• Male
• Mice
• Middle Aged
• Hyperlipidemias (drug therapy)
• Lipoprotein(a) (blood, genetics)
• Macaca fascicularis
• Mice, Transgenic
• RNA, Small Interfering (genetics)