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NEWS 2010

February 17, 2010 Corporate

Nippon Shinyaku enters into a license agreement with Actelion on a novel PAH development compound

Nippon Shinyaku Co., Ltd. (Headquarters: Kyoto, Japan; President: Shigenobu Maekawa) announced today that the company has signed a license agreement with Actelion Pharmaceuticals Ltd. on a novel compound, macitentan, being developed by Actelion as a once-a-day treatment for patients with pulmonary arterial hypertension (PAH)*1).

Macitentan is a highly potent, tissue-targeting dual endothelin receptor*2) antagonist discovered by Actelion. Through complete blockade of tissular endothelin, macitentan is expected to protect tissue from the damaging effect of elevated endothelin, specifically in the cardiovascular system.

Macitentan has a similar mechanism of action to Tracleer® which is currently marketed by Actelion on a worldwide basis.

Actelion is currently conducting a phase III clinical study of macitentan for the treatment of PAH in the world. In Japan, based on this license agreement, the two companies will jointly conduct clinical studies in the future.

In the area of PAH treatments, Nippon Shinyaku and Actelion entered into a license agreement, in April 2008, for the novel non-prostanoid prostacyclin receptor agonist*3) NS-304 (ACT-293987), originally discovered and synthesized by Nippon Shinyaku. According to the license agreement, Actelion is responsible for global development and commercialization of NS-304 outside Japan, whereas the two companies co-develop and co-commercialize in Japan. The two companies are currently conducting clinical studies in Japan and overseas. In addition, Nippon Shinyaku has been marketing a phosphodiesterase-5 inhibitor*4) "adcirca® Tablets 20mg" for the treatment of PAH since December 2009.

There are three different mechanisms of action for the PAH treatments currently used in clinical practice: endothelin receptor antagonism, prostacyclin receptor agonism, and phosphodiesterase-5 inhibition. This license agreement for macitentan enables Nippon Shinyaku to have PAH treatments with all of these three mechanisms of action.

Nippon Shinyaku hopes to contribute to a better life for PAH patients and their families by expanding the range of options in the treatment of this refractory disease.

*1) Pulmonary arterial hypertension (PAH) is a refractory disease with elevated peripheral pulmonary arterial pressure caused by insufficient blood flow through narrowed lumen of pulmonary arteries which carry blood from heart to lung. PAH is classified into primary pulmonary hypertension of unknown cause and secondary pulmonary hypertension associated with certain diseases such as collagen diseases or congenital cardiac disorder.

*2) Tissue-targeting dual endothelin receptor antagonist exerts therapeutic effect by inhibiting potent vasoconstriction and vascular smooth muscle cell proliferation caused by endothelin secreted from vascular endothelial cells.

*3) Non-prostanoid prostacyclin receptor agonist has a totally different structure than those of prostaglandins and stimulates the prostacyclin receptor to increase cyclic AMP levels in pulmonary arterial smooth muscle cells, exert vasodilating effect, and inhibit platelet aggregation and vascular smooth muscle cell proliferation.

*4) Phosphodiesterase-5 hydrolyzes cyclic GMP which relaxes smooth muscle. Phosphodiesterase-5 inhibitor induces pulmonary arterial smooth muscle relaxation and improves pulmonary arterial hemodynamics in PAH by maintaining high cyclic GMP level in pulmonary arterial smooth muscle cells .