Abstract
Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) with sustained receptor binding properties developed by Actelion Pharmaceuticals Ltd. In October 2013, oral macitentan 10 mg once daily received its first global approval in the US, followed closely by Canada, for the treatment of pulmonary arterial hypertension (PAH). The drug has also received a positive opinion in the EU from the Committee for Medicinal Products for Human Use for the treatment of PAH, and is under regulatory review in several other countries for the same indication. Endothelin (ET)-1 influences pathological changes via two ET receptor subtypes (ETA and ETB), to which it binds with high affinity. ET-1 is implicated in several forms of vascular disease making it a valid target for the treatment of pulmonary vascular diseases such as PAH. Clinical development is underway for other indications, including Eisenmenger syndrome, ischaemic digital ulcers secondary to systemic sclerosis, and glioblastoma. Macitentan was also evaluated in idiopathic pulmonary fibrosis; however, a phase 2 trial did not meet its primary endpoint and further investigation in this indication was discontinued. Macitentan was developed by modifying the structure of bosentan in the search for an optimal dual ERA with improved efficacy and tolerability compared with other ERAs. This article summarizes the milestones in the development of macitentan leading to this first approval for PAH.
Similar content being viewed by others
References
Seferian A, Simonneau G. Therapies for pulmonary arterial hypertension: where are we today, where do we go tomorrow? Eur Respir Rev. 2013;22(129):217–26.
Sitbon O, Morrell N. Pathways in pulmonary arterial hypertension: the future is here. Eur Respir Rev. 2012;21(126):321–7.
Bolli MH, Boss C, Binkert C, et al. The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012;55(17):7849–61.
US FDA. FDA approves Opsumit to treat pulmonary arterial hypertension [media release]. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm371362.htm. Accessed 18 Oct 2013.
Actellion Pharmaceutials Ltd. Actelion receives Health Canada approval of Opsumit (macitentan) for the long-term treatment of pulmonary arterial hypertension [media release]. http://www.actelion.com. Accessed 12 Nov 2013.
Actelion Pharmaceuticals US Inc. Full prescribing information: Opsumit® (macitentan) tablets. 2013. http://opsumit.com/splash/pdf/OPSUMIT-Full-Prescribing-Information.pdf. Accessed 30 Oct 2013.
European Medicines Agency. Summary of opinion: Opsumit (macitentan). 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002697/WC500153142.pdf. Accessed 30 Oct 2013.
Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809–18.
Actelion Pharmaceuticals Ltd. Actelion receives US FDA approval of Opsumit (macitentan) for the treatment of pulmonary arterial hypertension [media release]. http://www.actelion.com/en/journalists/news-archive.page?newsId=1736781. Accessed 18 Oct 2013.
Actelion. MAESTRO (macitentan in Eisenmenger syndrome to restore exercise capacity) [ClinicalTrials.gov identifier NCT01743001] US National Institutes of Health, ClinicalTrials.gov. 2013. http://clinicaltrials.gov/ct2/show/NCT01743001?term=macitentan+Eisenmenger&rank=1. Accessed 31 Oct 2013.
Actelion. Macitentan for the treatment of digital ulcers in systemic sclerosis patients (DUAL-1) [ClinicalTrials.gov identifier NCT01474109] US National Institutes of Health, ClinicalTrials.gov. 2013. http://clinicaltrials.gov/ct2/show/NCT01474109?term=macitentan+ischaemic+digital+ulcers&rank=1. Accessed 31 Oct 2013.
Actelion. Macitentan in combo with dose-dense temozolomide in patients with recurrent glioblastoma [ClinicalTrials.gov identifier NCT01499251] US National Institutes of Health, ClinicalTrials.gov. 2013. http://clinicaltrials.gov/ct2/show/NCT01499251?term=macitentan+glioblastoma&rank=1. Accessed 31 Oct 2013.
Raghu G, Million-Rosseau R, Moorganti A, et al. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Resp J. 2013. doi:10.1183/09031936.00104612.
Actelion Study Meta Data Registry (SMADAR). A multi-center, double-blind, randomized, placebo-active-controlled, dose-ranging study to evaluate the efficacy and safety of Actelion-1 in subjects with mild-to-moderate essential hypertension. 2013. http://trials.actelion.com/asp/Trial_Registry/RStudyInfo.asp?ST=AC-055-201. Accessed 18 Nov.
Nippon Shinyaku Co Ltd. Nippon Shinyaku enters into a license agreement with Actelion on a novel PAH development compound [media release]. http://www.nippon-shinyaku.co.jp/english/news/ns2010/2154. Accessed 17 Feb 2010.
Iglarz M, Binkert C, Morrison K, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736–45.
Gatfield J, Mueller Grandjean C, Sasse T, et al. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS One. 2012. doi:10.1371/journal.pone.0047662.
Corallo C, Pecetti G, Iglarz M, et al. Macitentan slows down the dermal fibrotic process in systemic sclerosis: in vitro findings. J Biol Regul Homeost Agents. 2013;27(2):455–62.
Iglarz M, Landskroner K, Rey M, et al. Optimization of tissue targeting properties of macitentan, a new dual endothelin receptor antagonist, improves its efficacy in a rat model of pulmonary fibrosis associated with pulmonary arterial hypertension [abstract no. A6445]. Am J Respir Crit Care Med. 2011;183:D36.
Sen S, Chen S, Feng B, et al. Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist. Life Sci. 2012;91:658–68.
Kim S-J, Kim JS, Kim SW, et al. Macitentan (ACT-064992), a tissue-targeting endothelin receptor antagonist, enhances therapeutic efficacy of paclitaxel by modulating survival pathways in orthotopic models of metastatic human ovarian cancer. Neoplasia. 2011;13(2):167–79.
Kim S-J, Kim JS, Kim SW, et al. Antivascular therapy for multidrug-resistant ovarian tumors by macitentan, a dual endothelin receptor antagonist. Transl Oncol. 2012;5(1):39–47.
Sidharta PN, van Giersbergen PLM, Halabi A, et al. Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977–84.
Sidharta PN, van Giersbergen PLM, Dingemanse J. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. J Clin Pharmacol. 2013;53(11):1131–8.
Sidharta PN, Lindegger N, Reseski K, et al. Macitentan, a novel dual endothelin receptor antagonist, does not prolong the QT/QTC interval in a thorough QTC study in healthy subjects [abstract no. PIII-61]. Clin Pharmacol Ther. 2013;93:S108–9.
Bruderer S, Hopfgartner G, Seiberling M, et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012;42(9):901–10.
Bruderer S, Marjason J, Sidharta PN, et al. Pharmacokinetics of macitentan in caucasian and Japanese subjects: the influence of ethnicity and sex. Pharmacology. 2013;91(5–6):331–8.
Sidharta PN, Lindegger N, Ulc I, et al. Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment. J Clin Pharmacol. 2013;. doi:10.1002/jcph.193.
Weiss J, Theile D, Ruppell MA, et al. Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. Eur J Pharmacol. 2013;701(1–3):168–75.
Atsmon J, Dingemanse J, Shaikevich D, et al. Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects. Clin Pharmacokinet. 2013;52(8):685–92.
Bruderer S, Aanismaa P, Homery M-C, et al. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012;14(1):68–78.
Author information
Authors and Affiliations
Corresponding author
Additional information
This profile has been extracted and modified from the Adis R&D Insight drug pipeline database. Adis R&D Insight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch.
Rights and permissions
About this article
Cite this article
Patel, T., McKeage, K. Macitentan: First Global Approval. Drugs 74, 127–133 (2014). https://doi.org/10.1007/s40265-013-0156-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40265-013-0156-6