Myogen: ambrisentan effective in phase 3 study of hypertension

By Angela McDaniels

Seattle, Dec. 12 - Myogen Inc. said clinical results show that the phase 3 trials evaluating ambrisentan in pulmonary arterial hypertension met the primary efficacy endpoint of improved exercise capacity, the key secondary endpoint of time to clinical worsening and several other secondary efficacy endpoints.

The primary efficacy endpoint of the trial was the placebo-corrected mean change in six-minute walk distance at week 12 compared to baseline. Results demonstrated that with 5 gm of ambrisentan once-daily improved the placebo-corrected mean distance by 59.4 meters and 2.5 mg of ambrisentan improved the placebo-corrected mean distance by 32.3 meters.

For the placebo group, the mean six-minute walk distance at week 12 decreased from baseline by 10.1 meters, the company said.

Improvements in time to clinical worsening compared to placebo were observed for both the 5 mg dose group and the 2.5 mg dose group.

The trial data also demonstrated an apparent survival benefit when compared with predicted survival, effectiveness with once-daily dosing, the potential for dose flexibility, a low incidence and severity of liver function test abnormalities at all doses and no apparent drug-drug interactions with warfarin-type anticoagulants, the company said.

"We believe the robustness of these results is unprecedented for oral therapies for patients with pulmonary arterial hypertension," said J. William Freytag, president and chief executive officer, in a company news release.

"Based on the properties of ambrisentan and the clinical results obtained to date, we believe that, if approved, ambrisentan has the potential to offer significant advantages over other endothelin receptor antagonists for the treatment of pulmonary arterial hypertension. We are excited by the progress of the ambrisentan clinical program and look forward to learning the results of [the trial] in the second quarter of 2006."

Two phase 3 trials began in January 2004 to evaluate the safety and efficacy of ambrisentan. The randomized, double-blind, placebo-controlled trials had identical designs, except for the doses of ambrisentan studied (5 mg and 10mg versus 2.5 mg and 5mg) and the geographic locations of the investigative sites (Europe and the United States).

Both trials were designed to enroll 186 patients (62 patients per dose group). One enrolled 192 patients; the other enrolled 202 patients. In addition, more than 300 patients continue ambrisentan treatment in long-term trials with maximum exposure of more than three years, the company said.

Pulmonary arterial hypertension is a highly debilitating disease characterized by severe constriction of the blood vessels in the lungs leading to very high pulmonary arterial pressures. It can occur with no known underlying cause, or it can occur secondary to diseases such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection. It affects roughly 200,000 patients worldwide, the company said.

Ambrisentan is an investigational drug being developed as a once daily oral therapy for patients with pulmonary arterial hypertension and has been granted orphan drug designation in both the United States and European Union.

It is a non-sulfonamide, propanoic acid-class, type-A selective endothelin receptor antagonist. Endothelin is a small peptide hormone that plays a critical role in the control of blood flow and cell growth. Elevated endothelin blood levels are associated with several cardiovascular disease conditions, including pulmonary arterial hypertension, chronic renal disease, coronary artery disease, hypertension and chronic heart failure, the company said.

Myogen is a biopharmaceutical company based in Denver that develops small molecule therapeutics for the treatment of cardiovascular disorders.

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