Macitentan for IPF falls short in MUSIC trial

Blair Westerly, MD

Effective treatment for idiopathic pulmonary fibrosis continues to elude patients and clinicians alike.  Multiple classes of medications have been studied, none with convincing data demonstrating efficacy.  Because of the proposed  contribution of endothelin-1 to the pathogenesis of IPF, receptor antagonists of this growth factor have previously been evaluated in IPF, but with disappointing results: bosentan (Tracleer) failed to improve IPF outcomes in 2011's BUILD-3, and ambrisentan (Letairis) bit the dust as an IPF treatment in 2013. Macitentan (Opsumit), a novel dual endothelin receptor antagonist by Actelion, was the new hope in a recent phase II study by the MUSIC Study Group. 

What They Did

178 eligible patients with IPF diagnosed within the last 3 years by usual interstitial pattern on surgical lung biopsy were randomized in a 2:1 (macitentan:placebo) fashion to evaluate the primary endpoint that 10 mg of macitentan daily "positively affected" FVC versus placebo.  To be eligible, FVC had to be above 50% predicted and DLCO above 30% predicted, so the group was in the mild-moderate impairment range.  Like the BUILD-3 trial, patients were excluded if they had extensive honeycombing and they could not have received immunosuppressive, antifibrotic or anticoagulant drugs or NAC within 4 weeks of enrollment. Secondary endpoints included time to IPF worsening or death, safety and tolerability.

What They Found

There were no differences in baseline characteristics between the two groups. Analysis was performed both by an "all-randomized" set and "per protocol" set, the latter excluding 27 patients in the macitentan group and 10 in the placebo group. There was no difference in the primary outcome, whether analyzed as "all randomized" or "per protocol", with both groups showing a similar decline in median FVC at 1 year. There were no significant differences in secondary endpoints, though there was an early trend favoring placebo for time to IPF worsening or death (HR 1.56, 95% CI 0.73-3.33, p=0.2428), which was driven mostly by more acute exacerbations in the macitentan group (5.9% vs 1.7% placebo). Anemia and peripheral edema were more common in the macitentan group, which was not surprising since it was previously seen with other endothelin receptor antagonists in different patient populations.

What It Means

Macitentan (Opsumit) was approved by the FDA in October 2013 to treat pulmonary arterial hypertension, based on its ability to delay disease progression in PAH. Unfortunately, macitentan does not appear to be "MUSIC" to the ears of physicians and patients with IPF.  The inclusion of patients with biospy proven UIP and mild-moderate disease targeted a group that previous data had suggested might benefit from endothelin receptor antagonists, at least in terms of dyspnea and health-related quality of life, but to no avail. Macitentan was well tolerated and perhaps it could be considered in conjunction with additional therapies to target multiple pathways implicated in IPF. As with other trials in IPF, the primary outcome could be questioned in its ability to identify an effect of the study drug, but the design was  admirable and the dropout rate was low. Meanwhile, when comes to  effective therapy for IPF, we continue to wait for a trial to hit the right note. Raghu, G et al.  Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomized controlled music trial. Eur Respir J 2013;42:1622-1632