Therapy improved exercise capacity of patients with pulmonary artery hypertension

Issue: August 2006

SAN DIEGO — Ambrisentan improved the exercise capacity of patients with pulmonary arterial hypertension in ARIES-2, a 12-week, multicenter phase-3 study.

Horst Olschewski, MD, professor of medicine and chairman of the pulmonary division at the Medical University of Graz, Austria, told an audience during his presentation at the American Thoracic Society 2006 International Conference that patients given once-daily oral doses of ambrisentan (Myogen Inc.) showed statistically significant improvements over placebo in the study’s primary endpoint, six-minute-walk distance, which is a standard measure of exercise capacity in patients with pulmonary artery hypertension.

The past decade has seen substantial strides in treating pulmonary arterial hypertension (PAH). PAH is characterized by extensive vascular remodeling and high levels of circulating endothelin, a powerful vasoconstrictor and smooth muscle proliferation mediator, in pulmonary vasculature. This tissue contains two distinct endothelin-receptor types: Both “A” and “B” receptors reside on smooth muscle cells and mediate vasoconstriction and cell proliferation. But only B receptors are found on pulmonary endothelial cells, where they enhance blood flow by clearing endothelin from circulation and secreting factors that relax smooth muscle.

Ambrisentan, an oral endothelin blocker, is moderately selective for the A receptor. In contrast, FDA-approved bosentan (Tracleer, Actelion Pharmaceuticals) is nonselective, whereas sitaxsentan (Thelin, Encysive Pharmaceuticals), now awaiting approval, is highly A-selective.

ARIES-2 investigators enrolled 192 participants, mostly World Health Organization Functional Class II and III. Of those participants, 65 were randomized to placebo, 64 to 2.5 mg ambrisentan once daily, and 63 to 5.0 mg ambrisentan per day.

During the 12-week study period, 22 participants withdrew or died, leaving 170 who completed the study: 54 on placebo, 58 on 2.5 mg ambrisentan, and 58 on 5.0 mg ambrisentan. Per trial protocol, participants for whom no six-minute-walk distance (6WMD) data were collected at the time of withdrawal due to clinical worsening or death were assigned an imputed final 6MWD value of zero meters. By this analysis, placebo-corrected improvements at 12 weeks were 59.4 m (P=.0002) for the 5.0 mg ambrisentan group and 32.3 m (P=.0219) for the 2.5 mg group. Because more participants in the placebo group died than in the ambrisentan groups (six placebo, three 2.5 mg ambrisentan, and zero 5.0 mg ambrisentan participants) or withdrew during the study, removal of these participants’ imputed “zero-meter” scores shrank placebo-corrected improvements to a still-robust 42 m (P=.0032) for the 5.0 mg group and 26 m (P=.0532, narrowly missing statistical significance) for the 2.5 mg group.

Placebo-adjusted clinical worsening achieved strong statistical significance at 12 weeks at both the 5.0 mg (P=.0076) and 2.5 mg (P=.0048) ambrisentan doses. Borg Dyspnea Index changes were also statistically significant (2.5 mg, P=.0367; 5.0 mg, P=.0384). WHO Functional Class improvements, another secondary endpoint, did not reach statistical significance even when both ambrisentan-dosed groups were combined.

Only 9% of participants on 2.5 mg ambrisentan and 6% on 5.0 mg ambrisentan suffered serious adverse events compared with 19% of those on placebo. – by Bruce Goldman

For more information:

Olschewski H. Ambrisentan improves exercise capacity and time to clinical worsening in patients with pulmonary arterial hypertension: results of the ARIES-II study. Presented at: American Thoracic Society 2006 International Conference; May 19-24, 2006; San Diego.