SALT LAKE CITY — The investigational endothelin receptor antagonist ambrisentan appears to provide a more favorable risk/benefit ratio than current therapies do for pulmonary artery hypertension, Dr. Lewis J. Rubin said at the annual meeting of the American College of Chest Physicians.
Results of the phase III randomized double-blind ARIES-I trial demonstrate that ambrisentan has good efficacy as once-daily oral therapy. What sets it apart from other effective endothelin receptor antagonists is that it displayed no liver toxicity in ARIES-I. Indeed, the incidence of liver function test abnormalities in the trial was zero, noted Dr. Rubin, professor of medicine at the University of California, San Diego.
Ambrisentan is a high-affinity propanoic acid-class endothelin receptor type A-selective agent with no interactions with warfarin or sildenafil. Its dosing is 10–100 times less than with bosentan—the endothelin receptor antagonist now on the market—and sitaxsentan, now under FDA review. Bosentan and sitaxsentan are oral twice-daily sulfonamide-class agents, and both are associated with dose-dependent increases in liver function abnormalities that can force treatment discontinuation.
ARIES-I involved 202 patients with pulmonary artery hypertension (PAH) who were randomized to 12 weeks of double-blind placebo or once-daily ambrisentan at 5 or 10 mg. Roughly two-thirds had idiopathic PAH. Most others had PAH associated with connective tissue disease. Most subjects had moderate disease; 58% of patients were WHO class III, while 32% of patients were class II. The mean baseline 6-minute walk distance was 341 m, indicative of moderate impairment.
The primary study end point was change in 6-minute walk distance over 12 weeks. It increased by 43.6 m with 10 mg/day of ambrisentan and 22.8 m with 5 mg, and it decreased by 7.8 m on placebo, suggesting a possible dose-response effect.
ARIES-I broke new ground as the first trial in PAH to use change in plasma brain natriuretic peptide (BNP) as a secondary end point. BNP is a marker of right heart stress. It reflects severity of PAH and is predictive of long-term outcome. BNP dropped by a mean of 62.5 and 149.3 pg/mL in patients on 5 and 10 mg/day of ambrisentan, respectively, while climbing 11.8 pg/mL with placebo.
In terms of other secondary end points, the Borg dyspnea index showed significant improvement in ambrisentan-treated patients. They were also only half as likely to experience clinical worsening during the study period. The ambrisentan arms showed nonsignificant trends for improvement in WHO functional class and on the Short Form-36 physical function scale.
Ambrisentan's chief side effects were peripheral edema, occurring in more than one-quarter of patients, and nasal congestion, in 9%. The edema is an endothelin receptor antagonist-class effect. It is typically mild and readily managed with low-dose diuretics without need for dose adjustment of the anti-PAH drug, Dr. Rubin said.
With a mean extended follow-up of 1.4 years and a maximum of 2.8 years, the incidence of confirmed liver function test abnormalities in ambrisentan-treated ARIES-I participants was 0.5%. That's less than the 3% incidence noted in the placebo arm during the 12-week double-blind treatment period.
Several audience members who have used ambrisentan said it's their impression there is a dose-response effect, although that hasn't been proven. Dr. Rubin agreed.
“I don't think that 10 mg is clearly superior to 7.5 mg, but my sense is that 5–7.5 mg is better than 2.5 mg. My guess is there's a potential advantage to having a range of doses with this drug, so you can start on the low side with the ability to increase,” he said.
Dr. Rubin is a consultant to Myogen Inc., which sponsored ARIES-I and was recently acquired by Gilead Sciences Inc. Giliad filed a new drug application with FDA in December, according to a statement. GlaxoSmithKline will market ambrisentan outside the United States.
Unlike other effective endothelin receptor antagonists, ambrisentan displayed no liver toxicity. DR. RUBIN