Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Abstract

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis.Eligible subjects were adults with idiopathic pulmonary fibrosis of ,3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo.Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n5119) or placebo (n559). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients.In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. @ERSpublications Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point

Comorbidities in interstitial lung diseases

“…Bosentan was found to be nonefficacious in two large placebo-controlled IPF trials [78,79] and in another large placebo-controlled evaluation in IPF, ambrisentan was associated with increased risk of disease progression and respiratory hospitalisations [80]. A recent trial of macitentan in IPF was also unsuccessful [81]. Taken together, these data provide no support for an antifibrotic interstitial effect of these therapies, despite supportive pre-clinical data.…”

Pulmonary vascular and cardiac impairment in interstitial lung disease

“…versus placebo in pulmonary hypertension due to IPF was discontinued prematurely due to increased rates of death and serious adverse effects in the riociguat study arm. Negative randomised trial results have already been reported in IPF for nonselective (bosentan [80]) and selective (ambrisentan [81], macitentan [82]) endothelin receptor antagonists. Ambrisentan has actually been contraindicated in IPF patients, regardless of the presence of pulmonary hypertension, due to its association with increased rate of disease progression and respiratory hospitalisation [81].…”

Pulmonary Hypertension in the Course of Diffuse Parenchymal Lung Diseases—State of Art and Future Considerations

“…Another negative study was published by Rhagu et al, who investigated the effect of macitentan in IPF patients (Music Trial) [59]. The primary endpoint (FVC change) was not achieved.…”