143 Lumacaftor/ivacaftor combination therapy in CF patients homozygous for F508del-CFTR with severe lung dysfunction

Abstract

Background Lumacaftor (LUM) increases the quantity of functional cell-surface F508del-CFTR. Ivacaftor (IVA) increases the open probability of cell-surface F508del-CFTR. In vitro, LUM/IVA in combination increased chloride transport more than either alone. Two randomized, double-blind, placebo-controlled phase 3 studies evaluated the efficacy and safety of 24 weeks of LUM/IVA in homozygous F508del CF patients ≥12 y. Methods A total of 1108 patients received either LUM (600 mg qd or 400 mg q12h) in combination with IVA (250 mg q12h) or placebo. The primary endpoint was absolute change in percent predicted FEV1 (ppFEV1) from baseline at Week 24. Key secondary endpoints included BMI, pulmonary exacerbations (PE), and CFQ-R respiratory domain. Results Eighty-one patients who met the eligibility criterion of ppFEV1 ≥ 40 at screening had a ppFEV1 Least squares mean treatment difference vs placebo for change from baseline at week 24 LUM 600 mg qd + IVA 250 mg q12h LUM 400 mg q12h + IVA 250 mg q12h Baseline ppFEV1 Baseline ppFEV1 ≥40 (n = 342) Baseline ppFEV1 Baseline ppFEV1 ≥40 (n = 3336) Absolute ppFEV1 (percentage points)* 3.7 (P = 0.024) 3.3 (P 3.3 (P = 0.036) 2.8 (P BMI (kg/m2) 0.63 (P = 0.023) 0.26 (P 0.29 (P = 0.261) 0.23 (P = 0.001) CFQ-R Respiratory Domain (points) 3.3 (P = 0.446) 3.3 (P = 0.006) −4.2 (P = 0.298) 2.9 (P = 0.017) Pulmonary exacerbations (rate ratio vs placebo) 0.47 (P = 0.030) 0.73 (P = 0.007) 0.59 (P = 0.074) 0.61 (P Conclusion The efficacy and safety of LUM/IVA in the subgroup of patients with severe lung dysfunction was comparable to the overall study population, indicating benefit in these patients.