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A large phase III randomized trial testing Ambrisentan (Letairis) for early idiopathic pulmonary fibrosis was stopped early after an interim analysis of the data showed possible harm. The results were reported in Annals of Internal Medicine.
Patients being treated with Letairis had more evidence of progression of idiopathic pulmonary fibrosis and were hospitalized more often, including diagnoses of acute exacerbations of IPF and pneumonia. There were 492 patients in the trial, at 136 clinical sites around the world.
At the time of termination (at an interim safety analysis at 75% of planned enrollment), 27% of ambrisentan-taking patients showed IPF progression, compared to 17% of placebo patients. The Letairis arm also had more hospitalizations for respiratory exacerbations (13% vs 6%) and deaths (8% vs 4%) compared to placebo control patients. These findings were all statistically significant. Patients with and without concomitant pulmonary hypertension appeared to be at risk, although there were not enough patients to confirm this statistically.
Lead author Ganesh Raghu of the University of Washington said,
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 ... regardless of the presence of pulmonary hypertension.
Hope for ambrisentan was stoked when an earlier phase II study testing bosentan (another ERA) suggested improved survival among the subgroup of patients with IPF. The BUILD-3 trial subsequently failed to show any clear benefit of bosentan in the treatment of IPF, either. These trial results were disappointingly reminiscent of PANTHER-IPF (NEJM 2012), which was also stopped early for apparent harm caused by azathioprine (Imuran) and prednisone as treatment for IPF.
The phosphodiesterase-5 inhibitor sildenafil still holds favor as treatment for advanced idiopathic pulmonary fibrosis among some experts, based on a 2010 trial in NEJM showing small benefits in quality of life, dyspnea and oxygenation (but not 6-minute walk distance, the primary outcome) among patients taking sildenafil. Treatment of GERD has been linked to slower IPF progression in a small study; pirfenidone so far has not.
Ganesh Raghu et al. Treatment of Idiopathic Pulmonary Fibrosis With Ambrisentan: A Parallel, Randomized Trial. Annals of Internal Medicine 2013; 158(9):641-649.