WS01.3 Lumacaftor in combination with ivacaftor in patients with cystic fibrosis who are homozygous for the F508del-CFTR mutation

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 primary cell cultures, LUM/IVA combination increased chloride transport more than either agent alone. Methods 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. A total of 1108 patients received either LUM (600 mg qd or 400 mg q12h) in combination with IVA (250 mg q12h) or placebo. Primary endpoint was absolute change in percent predicted FEV 1 (ppFEV 1 ). Key secondary endpoints included relative change in ppFEV 1 , BMI, pulmonary exacerbations, and CFQ-R Respiratory domain. After completion, patients could enter a blinded extension to continue to receive LUM/IVA or, if on placebo, be randomized to one of the LUM/IVA doses. Results Pooled results are shown in Table 1. The incidence of AEs was similar between LUM/IVA and placebo; 4.2% of LUM/IVA and 1.6% of placebo patients discontinued due to an adverse event. Interim analysis after approx. 25% of patients completed an additional 24 weeks in the extension study indicated LUM/IVA results were maintained through 48 weeks. Conclusion LUM/IVA demonstrated rapid, meaningful and sustained improvements across multiple clinical endpoints and was well tolerated in F508del homozygous CF patients. Table 1 . Pooled LUM/IVA efficacy results by dose LUM 600 mg qd + IVA 250 mg q12h (N = 368) LUM 400 mg q12h + IVA 250 mg q12h (N = 368) Least squares mean treatment difference vs placebo for change from baseline at Week 24 Absolute ppFEV 1 (percentage points)* 3.3 (P 2.8 (P Relative ppFEV 1 (%)* 5.6 (P 4.8 (P BMI (kg/m 2 ) 0.28 (P 0.24 (P = 0.0004) CFQ-R Respiratory Domain (points) 3.1 (P = 0.0071) 2.2 (P = 0.0512) Achievement of ≥5% relative improvement from baseline in ppFEV 1 * (odds ratio vs placebo) 2.95 (P 2.22 (P Pulmonary exacerbations (rate ratio vs placebo) 0.70 (P = 0.0014) 0.61 (P