Long-term treatment of pulmonary arterial hypertension with macitentan in Japanese patients

Abstract

Objective

Macitentan, a novel dual endothelin receptor antagonist, was approved for the treatment of pulmonary arterial hypertension (PAH) in Japan. However, long-term effects in Japanese patients of macitentan are currently unavailable. This study sought to assess the long-term efficacy and safety of macitentan in Japanese patients with PAH.

Methods

In this multicenter, open-label, clinical extension study (JapicCTI-121986), efficacy was evaluated based on the change from baseline at 24, 48, 72, 96 and 120-week in the 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. In addition, the time to a hospitalization related to PAH and a morbidity/mortality event was determined. As for safety, the incidence of adverse events and changes in laboratory data and vital signs were assessed.

Results

Macitentan was administered at a once-daily dose of 10 mg in 30 PAH patients with a median treatment period of 2.4 years (range, 229–1037 days). The improvements in 6MWD, WHO functional class and NT-pro-BNP at week 24 were maintained throughout the long-term follow-up. Hospitalization related to PAH occurred in 2 patients. Levels of liver enzyme and hemoglobin remained unchanged throughout the study period.

Conclusions

This study suggests that the long-term use of macitentan is well tolerated and effective in Japanese patients with PAH. We concluded that macitentan can be a possible approach to reduce morbidity/mortality in Japanese PAH patients.

Keywords:

• Pulmonary arterial hypertension
• endothelin receptor antagonist
• macitentan
• long-term treatment
• efficacy and safety

Transparency

Declaration of funding

The present study was sponsored by Actelion Pharmaceuticals Japan Ltd. and Nippon Shinyaku Co., Ltd. The sponsors of the study were involved in the study design and in the collection, analysis, and interpretation of data.

Declaration of financial/other relationships

NTahara has received speaker’s fees from Actelion Pharmaceuticals Japan and Nippon Shinyaku. HD has received grant/research funding and speaker’s fees from Actelion Pharmaceuticals Japan and Nippon Shinyaku. KF has received grant/research funding from Actelion Pharmaceuticals Japan and Nippon Shinyaku, and speaker’s fees from Actelion Pharmaceuticals Japan. MF has received grant/research funding from Actelion Pharmaceuticals Japan and Nippon Shinyaku, and speaker’s fees from Nippon Shinyaku. MHatano has received grant/research funding and speaker’s fees from Actelion Pharmaceuticals Japan and Nippon Shinyaku. SI has received speaker fees from Actelion Pharmaceuticals Japan and Nippon Shinyaku. SJ has received grant/research funding from Nippon Shinyaku. YK has received grant/research funding from Actelion Pharmaceuticals Japan, Nippon Shinyaku, Bayer Yakuhin and Pfizer Japan, and speaker’s fees from Actelion Pharmaceuticals Japan and Nippon Shinyaku. TK has received grant/research funding from Actelion Pharmaceuticals Japan, and speaker fees from Actelion Pharmaceuticals Japan and Nippon Shinyaku. MM has received grant/research funding from Actelion Pharmaceuticals Japan. TM has received grant/research funding from Actelion Pharmaceuticals Japan, Nippon Shinyaku, Pfizer Japan, Daiichi-Sankyo, Sanofi, Nippon Boehringer Ingelheim, Astellas, Sumitomo Dainippon, Biotronik Japan, Otsuka, Nihon Medi-Physics, Abbott Japan, MSD, Mitsubishi Tanabe, Teijin, Kowa, Bristol-Myers Squibb, Boston Scientific and Fukuda, and speaker’s fees from Actelion Pharmaceuticals Japan and Nippon Shinyaku. NN has no conflict of interest. YOkano has no conflict of interest. YOzaki has no conflict of interest. TS belonged to the endowed chair by Actelion Pharmaceuticals Japan. SSakai has received grant/research funding from Actelion Pharmaceuticals Japan, Daiichi-Sankyo and Sanofi, and speaker fees from Actelion Pharmaceuticals Japan and Nippon Shinyaku. NTanabe has received grant/research funding from Actelion Pharmaceuticals Japan, Nippon Shinyaku and Bayer Yakuhin, and consultant/advisor fees from Nippon Shinyaku. HW has received consultant/advisor/speaker’s fees from Actelion Pharmaceuticals Japan and Nippon Shinyaku. HY has received speaker’s fees from Actelion Pharmaceuticals Japan and Nippon Shinyaku. KY has no conflict of interest. MHatta is an employee of Actelion Pharmaceuticals Japan. SSasayama has received consultant/advisor fees from Actelion Pharmaceuticals Japan. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work but have no other relevant financial relationships to disclose.

Author contributions

All authors contributed equally to this manuscript.

Acknowledgements

Statistical analyses and medical writing were supported by Actelion Pharmaceuticals Japan Ltd. (Actelion) and Nippon Shinyaku Co., Ltd. (Nippon Shinyaku). The authors express their sincere gratitude to sub-investigators and clinical coordinators.