PURPOSE: Ambrisentan is a propanoic acid-class, ETA-selective endothelin receptor antagonist that has been shown to improve 6-minute walk distance (6MWD) in two Phase 3 placebo-controlled studies (ARIES-1 and ARIES-2). ARIES-E is an ongoing, long term extension study of ARIES-1 and ARIES-2.
METHODS: This is an integrated analysis of 383 patients who received at least 1 dose of ambrisentan (2.5, 5, or 10 mg qd) in ARIES-1, ARIES-2, or ARIES-E. Patients who received placebo in the previous studies were randomized to ambrisentan. Baseline was defined as the time of randomization to the first dose of ambrisentan. This analysis had a data cut-off of November 2006 (mean exposure=1.4 years; maximum exposure=2.8 years).
RESULTS: Baseline characteristics: 63% idiopathic PAH, 37% associated PAH; 46% WHO class I/II, 54% WHO class III/IV; baseline 6MWD was 347±85 meters (m). Nearly all patients with 24 or 48 weeks of exposure were receiving ambrisentan monotherapy (99.1% and 94.0%, respectively). Improvements in 6MWD observed at week 12 for the 2.5, 5, and 10 mg groups (32±6.1 m, 36±5.7 m, and 39±6.1 m, respectively) were maintained through week 48 (34±10.9 m, 41±7.9 m, and 46±7.7 m, respectively). Improvements in WHO functional class and Borg dyspnea index were also maintained with long-term treatment. One year survival was comparable for the 2.5, 5, and 10 mg groups (range: 94.7% to 96.8%). The most frequent adverse events were similar to that observed in the 12-week placebo-controlled studies. The long-term incidence of aminotransferases >3xULN was comparable to the 12-week incidence for patients receiving placebo in the ARIES-1 and ARIES-2 studies.
CONCLUSION: Ambrisentan monotherapy had sustained benefits on 6MWD, WHO functional class, and dyspnea for at least 1 year of treatment in patients with PAH. No new adverse events were clinically notable with long-term exposure and the incidence and severity of aminotransferase abnormalities remained low.
CLINICAL IMPLICATIONS: Long-term ambrisentan monotherapy appears to be well-tolerated and associated with durable improvements in efficacy in patients with PAH.
DISCLOSURE: Ronald Oudiz, Grant monies (from industry related sources) Gilead; Consultant fee, speaker bureau, advisory committee, etc. Gilead; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. ambrisentan