Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR

Objective: Evaluation of the safety, tolerability, and efficacy of lumacaftor/ivacaftor in patients with cystic fibrosis (CF) with severe lung disease. Methods: Patients with CF 12 years of age and older, homozygous for F508del-CFTR, with percent predicted forced expiratory volume in 1 second (ppFEV₁) < 40 received lumacaftor 400 mg/ivacaftor 250 mg every 12 h (full dose) for 24 weeks in an open-label, prospective study (NCT02390219). Dose modification to half dose for 1–2 weeks (including at initiation) was permitted. Safety and tolerability were the primary outcome measures; clinical outcomes were also assessed. Results: Of 46 patients (initiated on full dose: n = 28; initiated on half dose: n = 18), 35 (76%) completed 24 weeks of treatment. The most common adverse events included infective pulmonary exacerbation, abnormal respiration, cough, and dyspnea. Compared with patients initiating on full dose, patients initiating at half dose had less frequent respiratory events (56% vs 71%) of shorter median duration (4 vs 9 days). No dose modifications or discontinuations as a result of respiratory events occurred in patients initiating on half dose who were then increased to the full dose over 2 weeks (versus three each for patients on full dose). Following an initial reduction, ppFEV₁ was similar to baseline from week 4 throughout the remainder of the study (least squares mean [95% confidence interval] at week 24: − 0.4 [− 1.9, 1.1]; p = 0.6249). Compared with the 24 weeks prior to study, the annualized hospitalization rate was lower (rate ratio: 0.41; p = 0.00026) and the duration of intravenous antibiotics was shorter (mean [standard deviation] difference: − 8.52 [24.91] days; p = 0.0369) through study week 24. Conclusions: Compared with patients with higher lung function, respiratory events were more common in patients with ppFEV₁ < 40; aside from these events, the lumacaftor/ivacaftor safety profile was consistent with previous studies. Results suggest that patients with ppFEV₁ < 40 may benefit from treatment initiation at a lower dose with augmented monitoring before increasing to the full dose.