PAH Drug, Opsumit, Seen to Prevent and Treat Lung Disease in a Mouse Model of Scleroderma

Researchers at University College London (UCL) and Actelion Pharmaceuticals presented a study investigating the therapeutic effect of macitentan (Opsumit) in a mouse model of pulmonary hypertension associated with systemic scleroderma (SSc). The presentation, titled “Macitentan Responsiveness Supports the Validity of a Murine Model of Pulmonary Hypertension in Scleroderma Associated with altered TGFbeta/BMPRII Signalling,” took place at the recent 4^th Systemic Sclerosis World Congress in Lisbon, Portugal.

Pulmonary arterial hypertension (PAH), a condition characterized by the narrowing of, and damage to, the arteries in the lung, is a common complication of scleroderma. According to the Pulmonary Hypertension Association, between 8 to 21 percent of all scleroderma patients eventually develop PAH.

Previously, the researchers showed that an imbalance between transforming growth factor beta (TGF-β) and bone morphogenetic protein receptor type II (BMPRII) signaling leads to the development of PH, following pulmonary endothelial injury, in transgenic mice models.

Researchers now aimed to evaluate the therapeutic effects of macitentan on a transgenic mouse strain model of scleroderma. Macitentan (Opsumit) is an endothelin receptor antagonist (ERA) developed by Actelion Pharmaceuticals, currently approved by the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of PAH.

The scientists induced endothelial injury, and subsequently PH, in transgenic mice. Control animals (wild type) were also used in the experiment. The mice were treated with macitentan or placebo to assess treatment and prevention of PH. The development of PH was assessed by histology and immunohistochemistry assays.

Results showed that all transgenic mice developed inflammatory cell infiltrates and hypertrophy of smooth muscle layers. Animals receiving placebo had an elevated right ventricular mass index, as compared to the normal right ventricular mass observed in mice that received macitentan. Moreover, animals that received macitentan experienced normalization of right ventricular systolic pressure, and did not show any arterial occlusion.

Concluding their findings, the researchers in the presentation’s abstract said, “Macitentan prevents and treats the development of histological and haemodynamic PH in the mouse model of SSc [scleroderma]. The pivotal role for perturbed endothelin activity in a model that replicates the imbalance of TGF-β and BMPRII signalling seen in PAH-SSc lung is shown. It underpins the value of this model as a platform for experimental therapeutic studies.”