Olpasiran
Olpasiran (development code AMG 890, formerly ARO-LPA[1]) is an investigational small interfering RNA (siRNA) therapy developed by Arrowhead Pharmaceuticals and licensed worldwide by Amgen. As of October 2025[update], it is in phase 3 trials to evaluate whether it reduces cardiovascular risk by lowering lipoprotein(a) (Lp(a)).[2] Olpasiran is under investigation to reduce major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD) and elevated Lp(a) concentrations, as well as for individuals at high-risk for a first cardiovascular event and elevated Lp(a) concentrations.[3]
Adverse effects
[edit]In clinical trials, olpasiran was generally well tolerated. The most frequent adverse events were injection-site reactions,[4] which were usually mild.[5] No major safety signals emerged.[6]
Mechanism of action
[edit]Olpasiran is a N-acetylgalactosamine (GalNAc)–conjugated siRNA.[5] After uptake by hepatocytes through the asialoglycoprotein receptor,[7] the antisense strand is incorporated into the RNA-induced silencing complex (RISC),[5] which inhibits expression of the LPA gene. This reduces apolipoprotein(a) production and lowers circulating Lp(a).[4]
Olpasiran is a double-stranded siRNA[7] chemically modified for stability and conjugated with GalNAc[2] to enable hepatocyte targeting.[7]
History
[edit]Olpasiran was originally developed by Arrowhead Pharmaceuticals (as ARO-LPA) and licensed to Amgen in 2016.[8] In 2022, Arrowhead sold a portion of its royalty rights to Royalty Pharma.[9]
Research
[edit]In a phase 1 trial, one dose of olpasiran led to lower Lp(a) levels sustained for up to 6 months.[4] The phase 2 OCEAN(a)-DOSE trial demonstrated dose-dependent, sustained Lp(a) lowering[2] with acceptable tolerability. In OCEAN(a)-DOSE, olpasiran reduced Lp(a) levels by more than 95% at some doses as compared to placebo,[4] with durable suppression persisting for up to 48 weeks after treatment discontinuation.[10] A large phase 3 cardiovascular outcomes trial began in 2022[11] to determine whether Lp(a) reduction with olpasiran decreases events in patients with established ASCVD and a history of cardiovascular events.[2][12]
References
[edit]- ↑ "Olpasiran - Amgen". AdisInsight. Retrieved 3 November 2025.
- 1 2 3 4 Dimitriadis, Kyriakos; Kyriakoulis, Konstantinos G.; Pyrpyris, Nikolaos; Beneki, Eirini; Kamperidis, Vasileios; Kollias, Anastasios; Cenko, Edina; Aznaouridis, Konstantinos; Aggeli, Konstantina; Tsioufis, Konstantinos (2025). "Lipoprotein(a) and aortic stenosis: Practical insights". Nutrition, Metabolism and Cardiovascular Diseases. 35 (10) 104124. doi:10.1016/j.numecd.2025.104124. hdl:11585/1047525. PMID 40425406.
- ↑ o'Donoghue, Michelle L.; Rosenson, Robert S.; López, J. Antonio G.; Lepor, Norman E.; Baum, Seth J.; Stout, Elmer; Gaudet, Daniel; Knusel, Beat; Kuder, Julia F.; Murphy, Sabina A.; Wang, Huei; Wu, You; Shah, Trupti; Wang, Jingying; Wilmanski, Tomasz; Sohn, Winnie; Kassahun, Helina; Sabatine, Marc S. (2024). "The Off-Treatment Effects of Olpasiran on Lipoprotein(a) Lowering". Journal of the American College of Cardiology. 84 (9): 790–797. doi:10.1016/j.jacc.2024.05.058. PMID 39168564.
- 1 2 3 4 De Los Reyes, Chris; Rikhi, Rishi Raj; Doherty, Sean; Hernandez, Sebastian; Mirzai, Saeid; Shapiro, Michael D.; Christof, Michael; McIntosh, Scott; Wong, Nathan D.; Block, Robert C. (2025). "Current Clinical Trials for Treating Elevated Lipoprotein(a)". Current Cardiovascular Risk Reports. 19 (1) 7. doi:10.1007/s12170-025-00759-8. PMC 12282488. PMID 40703143.
- 1 2 3 Górecka, Wiktoria; Berezovska, Daria; Mrozińska, Monika; Nowicka, Grażyna; Czerwińska, Monika E. (2025). "Biological and Biosimilar Medicines in Contemporary Pharmacotherapy for Metabolic Syndrome". Pharmaceutics. 17 (6): 768. doi:10.3390/pharmaceutics17060768. PMC 12196407. PMID 40574081.
- ↑ Almaadawy, Omar; Hesn, Mohamed Mar'ey; Elsalamony, Yomna Ayman; Abobakr, Omar Ayman; Elshimy, Abdelrahman Hossam; Abulkhair, Khaled Alsayed; Negm, Mahmoud Mohamed; Shaban, Ahmed Yasser; Bene-Alhasan, Yakubu; Annie, Frank; Belcher, Adam; Elashery, Ahmed Ramy (2025). "Small interfering RNA effect on lipoprotein(a): A systematic review". The Egyptian Heart Journal. 77 (1) 44. doi:10.1186/s43044-025-00635-1. PMC 12062474. PMID 40338464.
- 1 2 3 Ramírez-Cortés, Fabricio; Ménová, Petra (2025). "Hepatocyte targeting via the asialoglycoprotein receptor". RSC Medicinal Chemistry. 16 (2): 525–544. doi:10.1039/d4md00652f. PMC 11609720. PMID 39628900.
- ↑ Bayer, Max (9 November 2022). "Arrowhead fills quiver with $250M Royalty deal". Fierce Biotech. Retrieved 3 November 2025.
- ↑ Pagliarulo, Ned (9 November 2022). "Arrowhead capitalizes on Amgen drug progress with royalty rights deal | BioPharma Dive". Biopharma Dive. Retrieved 3 November 2025.
- ↑ Cinezan, Corina; Magureanu, Dan Claudiu; Hiceag, Maria Luiza; Rus, Camelia Bianca; Ilias, Ioana Tiberia; Bogdan, Iulia Denisa; Buzle, Alexandra Manuela; Cozma, Angela (2025). "Shared Risk Factors and Molecular Mechanisms Between Aortic Stenosis and Atherosclerosis: A Rationale for Therapeutic Repositioning". International Journal of Molecular Sciences. 26 (17): 8163. doi:10.3390/ijms26178163. PMC 12428528. PMID 40943088.
- ↑ Pagliarulo, Ned. "Amgen to test new way to lower heart risk with large drug trial | BioPharma Dive". Biopharma Dive. Retrieved 3 November 2025.
- ↑ Malick, Waqas A.; Goonewardena, Sascha N.; Koenig, Wolfgang; Rosenson, Robert S. (2023). "Clinical Trial Design for Lipoprotein(a)-Lowering Therapies". Journal of the American College of Cardiology. 81 (16): 1633–1645. doi:10.1016/j.jacc.2023.02.033.