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.
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GENCODE data are available from the following gzipped file: http://ftp.ebi.ac.uk/pub/databases/gencode/Gencode_human/release_24/gencode.v24.annotation.gtf.gz. Other preclinical data that support the findings reported in this paper are available from the corresponding authors upon reasonable request.
Regarding the clinical trial portions of the paper, qualified researchers may request data from Amgen clinical studies. Complete details are available at https://wwwext.amgen.com/science/clinical-trials/clinical-data-transparencypractices/clinical-trial-data-sharing-request/.
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Amgen, Inc. and Arrowhead Pharmaceuticals, Inc. funded this work. J. Murray, H. Hamilton, M. Stolina, D. Dwyer and P. Denis supported the in vitro screening and preclinical data. J. Hegge performed some of the preclinical work (mouse and monkey) and supported data preparation for the manuscript. P. Yamaguchi assisted in drafting the preclinical section of the manuscript. J. Wang and the Amgen Clinical Biomarker and Diagnostics group supported Lp(a) assay evaluation and selection. N. Shah and Z. Atter provided statistical support for the clinical study. W. Krall of Wanda Krall Medical Communications, funded by Amgen, and E. Stoltzfus of Amgen provided editorial support.
M.J.K. is an employee of Jacksonville Center for Clinical Research, an organization that has received research grant funds from Amgen and multiple other manufacturers of lipid-lowering agents. M.J.K. has no direct personal financial relationship with Amgen, the manufacturer of olpasiran, and is an unpaid member of the Northeast Florida AHA Board. P.M.M. reports speaker and consulting fees from Amgen and Regeneron; consulting/advisory fees and grant research support from Esperion; grant research support from Ionis, Aegerion and the FH Foundation; speaker fees from Amarin; consulting fees from Stage II Innovations/Renew and Kaneka; advisor fees from Novartis; and fees for genetic testing kits from GB Life Sciences. S.J.B. reports Scientific Advisory Board/Consultant/Speaker for Amgen; and Scientific Advisory Board/Consultant for Sanofi Regeneron, Akcea and Novartis. J.N. and M.H.-I. have nothing to disclose. H.S.W. reports research funding from Amgen and Novo Nordisk; research funding and scientific advisory fees from Novartis; and speaker fees from Esperion. S.M. and T.P. are employees of Arrowhead Pharmaceuticals and have received Arrowhead stock options. M.F., H.K., T.V., W.S., H.W., M.E.D., B.M.R., O.H. and J.H. are employees of Amgen and own Amgen stock. S.M.H. is an officer, executive and shareholder in Amgen; a scientific founder of and shareholder in Tenaya Therapeutics; and serves on the Scientific Advisory Board of the German Centre for Cardiovascular Research. G.F.W. has received honoraria for lectures or advisory boards and research grants from Sanofi, Regeneron, Amgen, Arrowhead, Novartis and Kowa.
Reviewer recognition statement Nature Medicine thanks Kosh Ray, Kathy Wolski and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Editor recognition statement Michael Basson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Supplementary Tables 1, 2 and 4
Transcript sequences were derived from the GENCODE version 24 (BASIC; https://www.gencodegenes.org/) gene model and the human GRCh38 reference genome, downloaded from the OmicSoft Studio software platform (Qiagen). Olpasiran guide and passenger sequences were aligned to the transcript sequences using a simple custom gapless aligner, employing a brute force approach in which the siRNA query sequence was exhaustively scanned as a sliding window across all transcript sequences. miRNA sequences were downloaded from miRBase (version 21; https://www.mirbase.org), and seed sequences (positions 2–7) were checked for human miRNA seed sequences matching the six-nucleotide seed region of the olpasiran guide sequences.
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Koren, M.J., Moriarty, P.M., Baum, S.J. et al. Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a). Nat Med 28, 96–103 (2022). https://doi.org/10.1038/s41591-021-01634-w
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