For pulmonary arterial hypertension, no liver function effect with ambrisentan

Trial showed long-term safety and survival of patients treated with ambrisentan.

Issue: August 2007

SAN FRANCISCO — Clinical trial results demonstrated safety and efficacy of the endothelin selective receptor antagonist ambrisentan for the treatment of pulmonary arterial hypertension, according to researchers.

Patients who had previously failed therapy with the endothelin antagonists bosentan (Tracleer, Actelion) and/or sitaxsentan because of significant liver function test abnormalities did not have liver abnormalities with ambrisentan (Letairis, Gilead), according to study data presented at the American Thoracic Society 2007 Annual Meeting. The risk for such liver abnormalities necessitates monthly monitoring with bosentan and sitaxsentan.

Long-term results of ARIES-E, which included patients from the ARIES-1 and ARIES-2 trials, were presented by Ronald J. Oudiz, MD, associate professor of medicine at the UCLA School of Medicine, Torrance, Calif. ARIES-1 and ARIES-2 were randomized, double blind, placebo-controlled trials in which patients were assigned to ambrisentan doses between 2.5 mg and 10 mg once daily for 12 weeks.

In these trials, pulmonary arterial hypertension therapy with ambrisentan improved six-minute walk distance, time to clinical worsening, World Health Organization functional class, Borg Dyspnea score, SF-36 Health Survey status and B-type natriuretic peptide levels (which correlate with mean pulmonary arterial pressure and pulmonary vascular resistance). Ambrisentan was well tolerated. Serum aminotransferase abnormalities greater than three times upper limits of normal did not occur.

The ARIES-E objective was to evaluate long-term safety, durability of efficacy improvements and survival of patients with pulmonary arterial hypertension treated with ambrisentan. Among 383 patients included in the trial, the mean age was 51 years (79% women). Median years since onset of pulmonary arterial hypertension was 0.5. Most patients had idiopathic pulmonary arterial hypertension (63%) or pulmonary arterial hypertension secondary to connective tissue disease (32%). The mean six-minute walk distance at baseline was 347 meters; the Borg Dyspnea Index was 3.9, and WHO class mostly II (43%) or III (46%).

Among 316 evaluable patients, the mean exposure to ambrisentan was 39 weeks (maximum 109 weeks). Few dose adjustments were required (about 4% increase, 2% decrease), according to Oudiz, and 92.8% remained on ambrisentan monotherapy at week 48, the data cut-off. Six-minute walk distance increased from baseline by approximately 40 meters and persisted at that level through week 48. Borg Dyspnea Index scores dropped by approximately 0.6 and generally persisted at the reduced level; WHO functional class improvements increased through week 24 and persisted. Similarly, levels of B-type natriuretic peptide diminished by 37% at week 24. One-year survival was 95% for all patients and 97% for patients with idiopathic pulmonary arterial hypertension. Oudiz pointed out that National Institutes of Health-predicted survival for this population is 72% (D’Alonzo et al, Ann Intern Med. 1991). Most deaths were attributed to worsening right HF.

The ambrisentan safety profile in this long-term trial was similar to that of the 12-week placebo-controlled studies. Most events occurred in the first 12 weeks of treatment. The most common events were peripheral edema, headache, upper respiratory tract infection and dizziness. Nearly all reported peripheral edema was mild-to-moderate with no ambrisentan discontinuations related to the edema.

Among 383 patients with a mean exposure of 1.4 years (maximum 2.8 years), 2.1% had aspartate transaminase/alanine transaminase > three times the upper limits of normal and < five times the upper limits of normal, with no discontinuations of ambrisentan required. One patient (0.3%) with AST/ALT > eight times the upper limits of normal required discontinuation of multiple drugs. Oudiz said that 2.3% of patients assigned to placebo in ARIES-1 and ARIES-2 had AST/ALT > three times the upper limits of normal.

Results of a further study of ambrisentan showed rates of liver abnormalities at one year to be similar to 12-week rates among patients with pulmonary arterial hypertension who had discontinued bosentan and/or sitaxsentan because of serum aminotransferase abnormalities. Median duration of endothelin receptor antagonist therapy with bosentan or sitaxsentan before first failure due to liver function test abnormality was 16 weeks, according to Michael D. McGoon, MD, from the Mayo Clinic, Rochester, Minn. With ambrisentan at doses of either 2.5 mg/day, 5 mg/day or 10 mg/day, only one of these patients out of 31 evaluable required a temporary reduction in ambrisentan dose on account of a 3.2 times the upper limits of normal ALT elevation at week 12, McGoon said.

Liver function test elevations caused no patients to discontinue therapy, however. Improvements were reported for all of the efficacy parameters evaluated in the ARIES studies.

“Patients who have failed bosentan and/or sitaxsentan due to liver function test abnormalities can be successfully treated with ambrisentan,” McGoon said.

The FDA granted approval of ambrisentan 5 mg and 10 mg tablets in June. It is indicated for the once-daily treatment of pulmonary arterial hypertension (WHO group 1) in patients with WHO functional class II or III symptoms to improve exercise capacity and delay clinical worsening.

“I’m not sure I agree with the FDA label phrasing because it can be easily interpreted as implying attribution of aminotransferase increases to ambrisentan, such as are attributable to bosentan use,” Oudiz said. “Although I have been administering ambrisentan for four years and have seen no such increases, I understand [the FDA’s] need to be extra conservative given the relatively small population treated to date.” – by Walter Alexander

For more information:

Oudiz RJ. ARIES-E long-term safety and efficacy of ambrisentan in pulmonary arterial hypertension. Mini symposium B15.
McGoon M. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function abnormalities: One year follow-up.
Both presented at: the American Thoracic Society 2007 Annual Meeting; May 18-23, 2007; San Francisco.