The endothelin-receptor antagonist ambrisentan not only failed to benefit patients with idiopathic pulmonary fibrosis, it also may have facilitated disease progression in an international phase III clinical trial reported May 7 in Annals of Internal Medicine.
The trial was terminated early when an interim analysis of the data showed that patients treated with ambrisentan were more likely than were control subjects receiving placebo to show progression of idiopathic pulmonary fibrosis (IPF) and to require more hospitalizations for respiratory indications, including acute IPF exacerbations and pneumonia. The findings were the same whether the study subjects had concomitant pulmonary hypertension.
Dr. Ganesh Raghu
"The observations in this study provide compelling evidence for ambrisentan as an ineffective treatment for patients with IPF and preclude further clinical evaluation of the drug as therapy for the disease. The data provide a basis for explicit guidance to clinicians not to use ambrisentan to treat patients with IPF, regardless of the presence of pulmonary hypertension," said Dr. Ganesh Raghu of the division of pulmonary and critical care medicine, University of Washington Medical Center, Seattle, and his associates.
The researchers undertook this large phase III study because preclinical data suggested that antagonism of endothelin receptors could lessen the severity of pulmonary fibrosis. And in a phase II study involving patients with a variety of interstitial lung diseases, a related endothelin antagonist, bosentan, had improved survival in the subgroup of patients with IPF.
Ambrisentan is a more selective endothelin A-receptor antagonist than bosentan and is currently approved for the treatment of pulmonary arterial hypertension. Dr. Raghu and his colleagues compared it against a matched placebo in 492 IPF patients treated at 136 clinical sites in North America, South America, Europe, Asia, New Zealand, and Australia.
When approximately 75% of the intended total enrollment of 660 patients was reached, an interim safety and efficacy analysis showed that the drug did not improve the primary endpoint, which was a composite of the time to disease progression, death from any cause, hospitalization for respiratory events, or a decrease in lung function. The trial sponsor, Gilead Sciences, terminated the study, and the findings were analyzed on the subjects enrolled up until that point.
The mean interval of exposure to ambrisentan (329 subjects) or placebo (163 subjects) was approximately 35 weeks. At baseline, patients in the active-treatment group and control group were similar regarding demographic traits, pulmonary hemodynamics, lung function, 6-minute walk distance, and quality of life.
Significantly more patients in the ambrisentan group (27.4%) than in the placebo group (17.2%) showed IPF progression. The active-treatment group also had significantly more respiratory hospitalizations (13.4% vs. 5.5%) and deaths (7.9% vs 3.7%) than did the control group, Dr. Raghu and his associates wrote (Ann. Intern. Med. 2013; 158:641-90).
However, there were no significant differences between the two study groups in the secondary endpoints of diffusion capacity for carbon monoxide; forced vital capacity; 6-minute walk distance; scores on the SF-36, which measures quality of life; or scores on the Transitional Dyspnea Index.
These findings were essentially the same when the data were analyzed according to whether or not patients had concomitant pulmonary hypertension at baseline. However, the subset of patients with pulmonary hypertension was small and not adequately powered to demonstrate a significant difference, so this finding should be interpreted with caution, the investigators said.
Regarding adverse events, significantly more patients taking ambrisentan than placebo reported dyspnea, worsening IPF, dizziness, and peripheral edema. Three times as many patients receiving ambrisentan (3%) dropped out of the study because of safety and tolerability issues, compared with those receiving placebo (1%).
This trial was supported by Gilead Sciences, which was involved in all aspects of the study.