US companies push ahead with PAH treatments

PR Pharmaceuticals (PRP), a Colorado, US-based biopharmaceutical company, has filed an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) for PulmoLAR, a treatment for pulmonary arterial hypertension (PAH).

A potentially life-threatening blood vessel disorder of the lung in which pressure in the pulmonary artery rises above normal levels, the symptoms of PAH include shortness of breath, fatigue, chest pain, dizzy spells and fainting. It is considered an orphan disease as there are less than 200,000 people with the condition in the US.

The company's first clinical product, PumloLAR contains the active ingredient 2-methoxyestradiol (2ME), an endogenous, non-estrogenic metabolite of estradiol that has demonstrated an ability to reduce endothelial cell production of endothelin-1 and increase synthesis of prostacyclin in in vitro studies. A proprietary, sustained-release, injectable formulation administered by subcutaneous injection, PRP says it can provide up to 30 days of treatment per administration. It was granted Orphan Drug Status by the FDA in April 2005.

Stevan P. Tofovic, MD, PhD, assistant professor at the University of Pittsburgh School of Medicine and principal investigator on the use of PulmoLAR in animal models of PAH, said: 'Our work indicates treatment with PulmoLAR has a dramatic effect in improving survival, reducing the damage to the arteries of the lungs and preventing subsequent right heart failure. We've also shown reduced injury and significant improvements in survival in a recently completed study in an animal model of PAH in which we compared 2-methoxyestradiol to some of the leading drugs used to treat PAH in humans. These results are very encouraging and we are excited to see PulmoLAR progress to clinical testing.'

Dr Claude Piche, PRP's vice president of Clinical Development and Regulatory Affairs at PRP, described the IND as 'a milestone for our company'.

Meanwhile, Myogen, a biopharmaceutical also based in Colorado, has announced positive results for its randomised, double-blind, placebo-controlled ARIES-2 trial, the first pivotal Phase III trial evaluating Ambrisentan, an oral endothelin receptor antagonist (ERA) under development as a once daily oral therapy, in PAH.

The primary efficacy endpoint of improved exercise capacity, assessed through the placebo-corrected mean change in six-minute walk distance (6MWD) at week 12 compared to baseline, was met. Results of the trial demonstrated that with once-daily dosing, 5mg of Ambrisentan improved the placebo-corrected mean 6MWD by 59.4 metres (p=0.0002), while 2.5 mg improved it by 32.3m (p=0.0219). For the placebo group, the mean 6MWD at week 12 decreased from baseline by 10.1 meters.

The key secondary endpoint of time to clinical worsening was also met, with improvements compared to placebo observed for both the 5mg dose group (p=0.0076) and the 2.5 mg dose group (p=0.0048).

Ambrisentan was generally well tolerated: the most frequent side-effect was headache, which occurred in 12.7% of patients in the 5mg dose group and 7.8% in the 2.5 mg dose group, compared to 6.2% in the placebo group.

'We believe the robustness of these results is un-precedented for oral therapies for patients with PAH,' said J. William Freytag, president and ceo of Myogen. 'We are excited by the progress of the Ambrisentan clinical programme and look forward to learning the results of ARIES-1 in the second quarter of 2006.'

The ARIES-1 trial is designed to be identical to ARIES-2 except for the doses of Ambrisentan studied (5mg and 10mg in the case of ARIES-1), and the geographic locations of the investigative sites (Europe for ARIES-2 and the US for ARIES-1). ARIES-2 enrolled 192 patients while ARIES-1 has enrolled 202 patients.

Furthermore, 300 patients are receiving Ambrisentan treatment in long-term trials with maximum exposure of more than three years.

Myogen was also boosted by news that Tracleer, Actelion's PAH drug, failed to show any effects on 6MWD in patients suffering from either idiopathic pulmonary fibrosis (BUILD-1) or pulmonary fibrosis related to systemic sclerosis (BUILD-2).

The results are a setback for the Swiss company as it looks to grow 'above and beyond Tracleer' in the face of stiff competition from Pfizer's Revatio - a drug which uses the active ingredient in Viagra, sildenafil citrate - in the PAH market. Approved in 34 countries and with regulatory reviews ongoing in others, Tracleer posted sales of CHF455.1m (€295.8m) in 2005, but with no treatments currently on the market for lung disease, analysts believed that positive data in the BUILD trials could have doubled its sales potential.