Myogen makes further progress with ambrisentan

Myogen (Westminster, Colorado, US) has announced top line results for its AMB-222 open-label study of ambrisentan, its once-daily oral therapy for pulmonary arterial hypertension (PAH), which illustrate the drug's potential utility in resuming endothelin receptor antagonist (ERA) treatment in patients who have discontinued bosentan or sitaxsentan treatment due to serum aminotransferase (liver function) abnormalities.

Trials took place in 36 patients with PAH; 31 of which had previously discontinued bosentan, two of which had discontinued sitaxsenta and three of which had discontinued both.

Patients received 2.5mg of ambrisentan, a type-A selective endothelin receptor antagonist, once-daily for four weeks and then 5mg once daily for a further eight weeks. The primary endpoint of the trial was the incidence of serum aminotransferase concentrations greater than three-times the upper limit of the normal range (3xULN) during the 12-week evaluation period that were related to ambrisentan and resulted in discontinuation of drug. No incidents occurred, although one patient had a transient serum aminotransferase test result greater than 3xULN at week 12 that resulted in dose reduction from 5mg to 2.5mg. The patient remains on ambrisentan and has not had a recurrence greater than 3xULN.

Patients have continued to receive the therapy for up to nine months (mean exposure of six months), during which time no further occurrence of serum aminotransferase concentrations greater than 3xULN have been observed.

Including the results of the recent ARIES-2 trial, the Phase II trial AMB-220 and its related long-term study AMB-220-E, ambrisentan has demonstrated utility in triggering significant improvement in exercise capacity that is early in onset and durable; utility in significantly improving time to clinical worsening; apparent survival benefit according to the National Institutes of Health Registry formula; effectiveness with once-daily dosing and the potential for dose flexibility; low incidence/severity of liver function test abnormalities at all doses and no apparent drug-drug interactions with warfarin-type anticoagulants.

'Ambrisentan has a chemical structure that differs from those of bosentan and sitaxsentan. We believe that this distinction may underlie [its] low propensity to cause liver function abnormalities,' said to Michael J Gerber, senior vice president of clinical development and regulatory affairs for Myogen.

Currently in Phase III development, Ambrisentan has been granted orphan drug designation for the treatment of PAH in the US and EU.