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Myogen Reports Positive Top Line Results for Second Ambrisentan Pivotal Phase 3 Trial in Pulmonary Arterial Hypertension
ARIES-1 Confirms Efficacy and Safety Results Observed in ARIES-2; NDA Submission Expected in Fourth Quarter
DENVER, C.O. -- April 10, 2006 -- Myogen, Inc. today announced positive top line results of the ARIES-1 trial, the second pivotal Phase 3 trial evaluating ambrisentan, an oral endothelin receptor antagonist (ERA), in pulmonary arterial hypertension (PAH).
The trial met the primary efficacy endpoint of improved exercise capacity for both ambrisentan dose groups, with an excellent safety profile and no observed liver function abnormalities in the ambrisentan treatment groups.
On the basis of the results of ARIES-1 & -2, Myogen expects to submit the ambrisentan New Drug Application to the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2006.
The primary efficacy endpoint of the ARIES-1 trial was the placebo-corrected mean change in six-minute walk distance (6MWD) at week 12 compared to baseline. Results of the trial demonstrated that with once-daily dosing, 10 mg of ambrisentan improved the placebo-corrected mean 6MWD by 51.4 meters (P =.0001) and 5 mg of ambrisentan improved the placebo-corrected mean 6MWD by 30.6 meters (P =.0084), indicating improved exercise capacity. For the placebo group, the mean 6MWD at week 12 decreased from baseline by 7.8 meters.
Time to clinical worsening did not reach statistical significance likely due to the relatively low incidence of clinical worsening events observed in the trial. Other secondary endpoints had clinically relevant improvements that achieved p values of less than 0.05 but were not considered statistically significant due to the pre-specified approach for multiple comparisons.
The trial safety results demonstrated ambrisentan was generally well tolerated. The most frequent adverse event was peripheral edema. No patients treated with ambrisentan developed serum aminotransferase concentrations greater than three times the upper limit of the normal range at any time during the 12 week treatment period, compared to two patients in the placebo group, only one of which was confirmed upon re-test. Ambrisentan had no apparent effect on the activity or dosing of warfarin-type anticoagulants commonly co-administered to patients with PAH.
The delivery of the ARIES-1 trial results triggers a $5.25 million milestone payment under Myogen's ambrisentan sublicense agreement with GlaxoSmithKline.
"With two positive, well-controlled studies demonstrating robust efficacy and a safety database of more than 400 patients on long-term treatment, we have the foundation for high quality regulatory submissions worldwide," said Dr. Michael Gerber, Senior Vice President of Clinical Development and Regulatory Affairs for Myogen. "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 PAH."
In January 2004, Myogen announced the initiation of two pivotal Phase 3 clinical trials, ARIES-1 and ARIES-2, evaluating the safety and efficacy of ambrisentan in patients with PAH. The ARIES trials were randomized, double-blind, placebo-controlled trials of identical design except for the doses of ambrisentan studied and the geographic locations of the investigative sites. Both trials were designed to enroll 186 patients (62 patients per dose group).
ARIES-1 evaluated once-daily doses of 5 mg and 10 mg of ambrisentan. ARIES-2 evaluated once-daily doses of 2.5 mg and 5 mg of ambrisentan. The primary efficacy endpoint was exercise capacity, measured as the mean change from baseline at 12 weeks in the 6MWD compared to placebo. Secondary endpoints include time to clinical worsening, World Health Organization (WHO) functional class, SF-36(TM) Health Survey, and Borg dyspnea index.
ARIES-1 enrolled 202 patients primarily from the United States while ARIES-2 enrolled 192 patients primarily from Europe. In addition, approximately 400 patients continue ambrisentan treatment in long-term trials with maximum exposure of more than three years.
To date, the results of clinical studies have indicated that ambrisentan may provide some or all of the following benefits to PAH patients:
-- Improvement in exercise capacity that is significant, early in onset and durable
-- Significant improvement in time to clinical worsening
-- Low incidence and severity of liver function test abnormalities at all doses treated
-- Comparable benefit in exercise capacity in patients with WHO functional class II and class III symptoms
-- An apparent survival benefit when compared with predicted survival based on the National Institutes of Health Registry formula
-- Effectiveness with once-daily dosing and the potential for dose flexibility
-- Potential utility in resuming endothelin receptor antagonist (ERA) treatment in patients who have discontinued treatment with the alternative ERAs, bosentan or sitaxsentan, or both, due to liver function abnormalities
-- No clinically relevant drug-drug interactions with warfarin-type anticoagulants or sildenafil, a PDE-5 inhibitor
About Pulmonary Arterial Hypertension
PAH is a highly debilitating disease characterized by severe constriction of the blood vessels in the lungs leading to very high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from extreme shortness of breath as the heart struggles to pump against these high pressures causing such patients to ultimately die of heart failure. PAH 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. PAH afflicts approximately 200,000 patients worldwide.
About Ambrisentan
Ambrisentan is an investigational drug being developed as a once daily oral therapy for patients with PAH and has been granted orphan drug designation for the treatment of PAH in both the United States and European Union. GlaxoSmithKline sublicensed commercial rights for ambrisentan outside of the United States.
Ambrisentan 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 believes that agents that block the detrimental effects of endothelin may provide significant benefits in the treatment of these conditions.
SOURCE: Myogen, Inc.
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