United Therapeutics Corporation and Eli Lilly and Company announced the results of a pivotal 16-week study showing that a once-daily dose of tadalafil was generally well tolerated, improved exercise capacity and improved time to clinical worsening in patients with pulmonary arterial hypertension (PAH).

The randomized, double-blind, 16-week, placebo-controlled phase-3 study followed 405 patients with PAH, either treatment-naive or taking bosentan, randomized to placebo or tadalafil 2.5 mg, 10 mg, 20 mg or 40 mg orally. Results from the study entitled, 'Tadalafil Therapy for Pulmonary Arterial Hypertension', were published in today's issue of Circulation.

The study formed the basis of the United States Food and Drug Administration (FDA) approval to market tadalafil tablets for the treatment of PAH under the brand name Adcirca.

"PAH is a rare, life-threatening disease," said lead investigator Dr Nazzareno Galie, associate professor of Cardiology at the University of Bologna and head of the Pulmonary Hypertension Centre at the Institute of Cardiology. "The results of this study are encouraging for PAH clinicians and the patients they treat."

The randomized, double-blind, 16-week, placebo-controlled phase-3 study monitored 405 patients with idiopathic PAH or PAH associated with anorexigen use, connective tissue disease, human immunodeficiency virus (HIV) infection, or congenital systemic-to-pulmonary shunts.

Patients were randomized in groups and received one of five treatments, tadalafil 2.5 mg, 10 mg, 20 mg, 40 mg or placebo, orally once a day as monotherapy or as add-on therapy to bosentan. The primary endpoint was change from baseline to Week 16 in six-minute walk distance (6MWD). Demographics, clinical data and health-related quality of life data were collected at baseline. Clinical and health-related quality of life data were collected again at weeks eight and sixteen.

Tadalafil increased 6MWD in a dose-dependent manner, only the 40 mg dose met the pre-specified level of statistical significance of less than 0.01 (p<0.01). Overall, the placebo-corrected treatment effect was 33m (95 per cent confidence-interval, 15m to 50m). In the bosentan-naive group, the treatment effect was 44m (95 per cent confidence-interval, 20m to 69m), as compared to 23m (95 per cent confidence-interval, -2m to 48m) in patients on background bosentan therapy.

Among secondary objectives, patients administered tadalafil 40 mg showed improvement in time to clinical worsening, as compared to placebo (5 per cent for tadalafil 40 mg, versus 16 per cent with placebo). Additionally, the incidence of clinical worsening was reduced in the 40 mg tadalafil group (p=0.038; relative risk reduction 68 per cent less than placebo).

Improvements in the tadalafil 40 mg dose group, compared to placebo, from baseline to Week 16 were observed in six of the eight domains of the SF-36 health survey and for all sections of the EQ-5D questionnaire.

The most commonly reported adverse events for tadalafil 40 mg were headache (42 percent for tadalafil 40 mg, versus 15 per cent with placebo), myalgia (14 per cent for tadalafil 40 mg, versus 4 per cent with placebo) and flushing (13 per cent for tadalafil 40 mg, versus 2 per cent with placebo). Most adverse events were reported as mild or moderate and discontinuation rates were similar across all treatment groups.

Adcirca is a prescription medicine used to treat PAH, a life-threatening disease that constricts the flow of blood through the pulmonary vasculature.

United Therapeutics Corporation is a biotechnology company focused on the development and commercialization of unique products to address the unmet medical needs of patients with chronic and life-threatening cardiovascular and infectious diseases and cancer.