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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.

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Fig. 1: Identification of an siRNA with durable Lp(a) gene silencing activity in Lp(a) double transgenic mice and in cynomolgus monkeys.
Fig. 2: Olpasiran pharmacokinetics and pharmacodynamics in cynomolgus monkeys.
Fig. 3: Phase 1 single-ascending-dose study of olpasiran.
Fig. 4: Phase 1 study evaluation of mean (s.e.m.) lipid concentrations.

Data availability

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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Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Contributions

M.J.K., P.M.M., S.J.B., J.N., M.H.-I., H.S.W. and G.F.W. enrolled participants in the clinical study and supervised the clinical components of the trial (clinical review, safety and dose monitoring). M.J.K., P.M.M., S.J.B. and G.F.W. additionally interpreted results and critically revised the manuscript. H.W. and M.E.-D. performed statistical planning and analysis of the clinical study, interpreted the results and critically revised the manuscript. W.S. oversaw the clinical pharmacokinetic and pharmacodynamic data analyses, interpreted the results and critically revised the manuscript. J.H. was involved in the oversight of the clinical study (for example, eligibility, protocol amendments and safety monitoring), study data analysis, interpreting results and revision and drafting of the manuscript. T.V. was involved in safety monitoring, study data analysis, interpreting results and revision of the manuscript. S.M.H. was involved in conceptualization and drafting and revision of the manuscript and interpreting results. H.K. was involved in study data analysis, interpreting results and revision and drafting of the manuscript. B.M.R. oversaw the cynomolgus monkey study and data analysis and interpreted results. M.F. and S.M. were involved in the design and interpretation of the preclinical studies and prepared the preclinical portion of the manuscript. M.F. directed additional safety and manufacturability assessments to select the clinical candidate olpasiran. T.P. designed the siRNA molecules for the in vitro and in vivo screening. O.H. conducted the bioinformatics analysis. All authors reviewed the manuscript, approved the final version and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Michael J. Koren.

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Competing interests

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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Extended data

Extended Data Fig. 1

Phase 1 study schema.

Supplementary information

Supplementary Information

Supplementary Tables 1, 2 and 4

Reporting Summary

Supplementary Table 3

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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