Safety and efficacy of Lumacaftor/Ivacaftor in pediatric cystic fibrosis patients

Abstract

Introduction/Aim: Lumacaftor/Ivacaftor (LUM/IVA) was well tolerated and improved lung function and other efficacy endpoints in patients with cystic fibrosis (CF) aged ≥6 years homozygous for F508del in two 24-week phase 3 studies (NCT01897233; NCT02514473). A preplanned interim analysis was conducted after all patients reached week 24 of a subsequent 96-week open-label extension (OLE; NCT02544451). Methods: Patients continued LUM/IVA (LUM 200 mg/IVA 250 mg q12h [6-11 years] or LUM 400 mg/IVA 250 mg q12h [≥12 years]), or if previously receiving placebo, were assigned to LUM/IVA regimens by age. Primary endpoint was safety (up to OLE week 72); secondary endpoints included absolute change from baseline in lung clearance index (LCI2.5), sweat chloride, body mass index (BMI), and percent predicted FEV1 (ppFEV1). Results: Of 260 eligible patients, 240 enrolled in the OLE and 229 completed ≥24 weeks. Most adverse events (AEs) were mild (36.8%) or moderate (48.5%); the most common were cough (47.3%), infective pulmonary exacerbation (30.1%), pyrexia (18.8%), nasal congestion (16.3%), and headache (15.5%). Serious AEs were reported in 40 patients (16.7%); 6 (2.5%) discontinued because of AEs. Predefined respiratory events were more frequent in placebo patients initiating LUM/IVA vs those continuing LUM/IVA (19.8% vs 8.4%); all were mild or moderate, and none led to discontinuation. Twenty-eight patients (11.7%) had AST or ALT >3×ULN. LCI2.5 and ppFEV1 improvements were maintained after 48 weeks in patients continuing LUM/IVA: absolute mean change from week 0 (95% CI): -1.07 (-1.49, -0.65), P<0.0001 and 2.8 (0.7-4.9), P=0.0090, respectively; patients previously receiving placebo had similar significant, rapid, sustained improvement in LCI2.5: -0.97 (-1.48, -0.47); P=0.0002. Improvements in sweat chloride and BMI occurred in all patients. Conclusion: LUM/IVA treatment for up to 48 weeks was well tolerated and led to durable improvements across multiple endpoints. Safety profile was consistent with phase 3 studies, with no new safety concerns.L6220914132018-05-16 <br />