About Bosentan

Bosentan (Tracleer®) is an orally active dual endothelin receptor antagonist (ERA). As of the end of 2007, Tracleer® was approved for pulmonary arterial hypertension (PAH) in WHO functional class III & IV in the United States and class III in Europe. In June 2007 Tracleer® was also granted marketing approval by the European Commission for the reduction in the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. Regulatory proceedings to extend the label for Tracleer® to also include digital ulcerations are ongoing on a worldwide basis.

Actelion’s development efforts for bosentan concentrate on compiling evidence in PAH sub-populations to assist doctors in their treatment approach. In addition, Actelion’s development team is actively investigating bosentan’s potential in other endothelin-related diseases. Building on our knowledge about the effects of elevated endothelin levels, we are developing bosentan beyond PAH and digital ulcers as a treatment for idiopathic pulmonary fibrosis (IPF). IPF is a progressive and usually fatal disease of the lungs for which there is currently no approved therapy.

Bosentan in mildly symptomatic pulmonary arterial hypertension (PAH)

Current Status

Discussions on the addition of the EARLY (Endothelin Antagonist tRial in miLdlY symptomatic PAH patients) clinical trial results and therefore the inclusion of WHO functional Class II PAH to the Tracleer® label, are on-going with health authorities around the world.

Supporting Studies

The 185-patient EARLY study was a randomized, double blind, placebo-controlled trial and it is the only randomized controlled trial (RCT) to study a dedicated early-stage, or WHO functional Class II, PAH population. Patients were followed for at least six months and results showed a significant reduction in pulmonary vascular resistance and a delay in time to clinical worsening. A trend towards improvement in exercise capacity was observed.

Bosentan in Pediatric Pulmonary Arterial Hypertension (PAH)

Current Status

Discussions on the filing of a pediatric formulation of bosentan are underway with health authorities.

Supporting Studies

The Phase III open label, single-arm FUTURE-1 (pediatric FormUlation of bosenTan in pUlmonary arterial hypertension) study evaluated the safety and pharmacokinetics of a unique, specially designed, pediatric formulation of bosentan. This study provided the necessary pharmacokinetic data which was presented at the European Society of Cardiology (ESC) in early September 2007. The longer-term safety and efficacy continues to be studied in the FUTURE-2 extension study.

Bosentan in combination with sildenafil

Current Status

The COMPASS program specifically evaluates the efficacy and safety of the use of bosentan in combination with sildenafil, an approved treatment for PAH but one that addresses another pathological pathway of the disease.

Actelion has concluded COMPASS-1, the first clinical trial to provide detailed hemodynamic information on the combination of sildenafil and bosentan.

The COMPASS-2 study is ongoing and investigates the effect on mortality and morbidity of a combination of bosentan with sildenafil versus sildenafil monotherapy.

Supporting Studies

COMPASS-1 demonstrated that the combination of sildenafil together with long-term bosentan therapy produces significant hemodynamic improvements, including a highly significant reduction in mean PVR observed 60 minutes after administration of a single dose of sildenafil 25 mg (-15.2% [95% CI: –20.8 to –9.6]; p < 0.0001) and a decrease in the mean total pulmonary resistance (-13.3% [95% CI: –17.0 to –9.6]; p < 0.0001).

Bosentan in chronic thromboembolic pulmonary hypertension (CTEPH)

Current Status

Actelion has concluded the first-ever placebo-controlled study BENEFiT evaluating BosEntan in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension (CTEPH). Actelion intends to discuss with health authorities the option to broaden the current PAH label for Tracleer® with the inclusion of this disorder.

Supporting Studies

The BENEFiT study met its primary objective with a significant reduction in pulmonary vascular resistance PVR (p<0.0001). In addition, patients on bosentan showed a significant improvement in breathlessness (Borg dyspnea score) with exercise and there was a trend in favor of bosentan towards prevention of worsening WHO functional class.

Bosentan in digital ulcers due to systemic sclerosis

Current Status

In June 2007 the European Commission granted marketing approval for Tracleer® for the reduction in the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. Regulatory proceedings to extend the label for Tracleer® to include digital ulcerations are ongoing on a worldwide basis.

Supporting Studies

RAPIDS-1 (RAndomized Placebo-controlled Investigation of Digital ulcers in Scleroderma) was a placebo-controlled double-blind clinical trial evaluating the prevention of ischemic digital ulcers in 122 patients with systemic sclerosis at 17 centers in Europe and North America. It was the first specifically designed study to look at prevention of ulcer formation. Furthermore, the study is among a very few to demonstrate clinical efficacy in systemic sclerosis.
 
Patients with systemic sclerosis, who had either a history of at least one digital ulcer over the past 12 months or active digital ulcerations at the time of enrolment, were treated with either bosentan (62.5mg bid for four weeks, then 125mg bid for the next 12 weeks) or placebo. The total number of new ulcers during the treatment period was 1.4 for patients on bosentan versus 2.7 for patients on placebo representing a 48% reduction in the number of new digital ulcers.

In late 2003, Actelion initiated a second pivotal Phase III clinical trial, RAPIDS-2 (Randomized Placebo-controlled Investigation of Digital ulcers in Scleroderma) regarding Tracleer® in ischemic digital ulcers secondary to systemic sclerosis. In contrast to the earlier RAPIDS-1 trial, this trial evaluated prevention and healing in a population with more severe forms of the disease at the time of enrolment. The treatment duration was longer and a withdrawal period was implemented in order to assess the evolution of digital ulcerations after treatment interruption. The study enrolled a total of 188 patients in 41 centers worldwide.
 
Patients with systemic sclerosis and at least one digital ulcer were treated with either bosentan (62.5mg bid for four weeks, then 125mg bid for at least 20 weeks and up to 32 weeks) or placebo. The total number of new ulcers over 24 weeks was 1.9 ± 0.2 for patients on bosentan versus 2.7 ± 0.3 for patients on placebo representing a 30% reduction in the number of new digital ulcers. The reduction in digital ulcers was more pronounced in severe patients with more than three active DUs at the start of the study.

Bosentan in idiopathic pulmonary fibrosis

Current Status

In May 2006, data presented from the BUILD program (Bosentan Use in Interstitial Lung Disease) at the American Thoracic Society (ATS) conference provided a strong rationale to further evaluate the safety and efficacy of bosentan in a morbidity/mortality-driven Phase III study in the idiopathic form of pulmonary fibrosis (IPF). Actelion is conducting thi s trial (BUILD-3) in patients suffering from lung biopsy proven IPF with the objective to confirm the BUILD-1 results. The results could be available some time in 2009.

Supporting Studies

In early 2003, Actelion initiated BUILD-1, a clinical trial which addressed the idiopathic form of pulmonary fibrosis. In November 2005, the results of this trial became available and although not statistically significant, positive trends were observed for pre-defined secondary endpoints - such as the combined incidence of death or treatment failure at 12 months (36.1% in the placebo group versus 22.5% in the bosentan group; p=0.076; 95% CL 0.37, 1.05), representing a relative risk reduction of 38%.