Macitentan

Macitentan is a highly potent, tissue-targeting endothelin receptor antagonist discovered in an in-house research program. Through complete blockade of tissular endothelin, macitentan is expected to protect tissue from the damaging effect of elevated endothelin, specifically in the cardiovascular system. In preclinical studies, macitentan also exhibited effects suggesting that it maintains the integrity of the vascular wall and improves long-term outcome. Accordingly, macitentan may provide therapeutic benefit in a wide range of cardiovascular indications.

Macitentan in development for PAH

Current status
Macitentan is currently being investigated in the Phase III study SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome). This study is designed to evaluate the safety and efficacy of this highly potent tissue-targeting endothelin receptor antagonist through the primary endpoint of morbidity and all-cause mortality in patients with symptomatic PAH. Global enrollment was completed in December 2009 with a total of 742 patients.

Patients are randomized 1:1:1 to receive two different doses of macitentan (3 mg and 10 mg once daily) or placebo. With around 180 centers participating, in over 40 countries in North and South America, Europe, Asia-Pacific and Africa, this is the largest study in PAH patients and the first to include, from the beginning, a clearly defined morbidity/mortality primary end-point. Study results could become available before the end of 2011, one year ahead of schedule.

Available clinical data
In a phase II study with 379 hypertensive patients, macitentan was significantly better than placebo and better than enalapril in reducing blood pressure 24 hours after drug intake. In this patient population, macitentan was generally well tolerated. The overall frequency of adverse events was similar to those observed in the placebo group. Similar to other endothelin receptor antagonists, macitentan may potentially exhibit known class effects such as a propensity for elevated liver enzymes, which will be monitored in the SERAPHIN study. Additional interaction studies concluded prior to the start of the SERAPHIN study have shown no clinically relevant interaction with warfarin, sildenafil, or ketoconazole (CYP 3A4 inhibitors).

Milestones
2007 – Initiation of Phase III study SERAPHIN study in PAH patients
2005 – Initiation of Phase II dose ranging study
2004 – Entry-into-humans
2003 – Selection of Macitentan for initiation of preclinical studies

Key scientific literature
Iglarz M. et al. Pharmacology of Macitentan, an orally active tissue targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008 Sep 9.