S69 Retrospective analysis of physiological response patterns to tezacaftor/ivacaftor in patients with cystic fibrosis homozygous for F508del-CFTR or heterozygous for f508del-CFTR and a residual function mutation

Abstract

Introduction and objectives Tezacaftor/Ivacaftor (TEZ/IVA), a new CFTR modulator combination, improves forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in patients aged ≥12 years with CF homozygous for F508del-CFTR (F/F; EVOLVE, NCT02347657) and heterozygous for F508del-CFTR and a second allele with a CFTR mutation predicted to have residual function (F/RF; EXPAND, NCT02392234). Long-term safety and efficacy are being assessed in an ongoing open-label extension study (EXTEND, NCT02565914). Benefits in lung function may result from two mechanisms: 1) reduced airway resistance (Raw) due to decreased narrowing; and 2) improved breathing capacity (BC) due to opening of collapsed airways. This study assessed the contribution of each mechanism to TEZ/IVA therapy in F/F and F/RF populations. Methods Retrospective analysis of spirometry data from placebo and treatment groups of EVOLVE, EXPAND, and EXTEND was conducted. Changes in FEV1 (δFEV1) were calculated as a function of changes in Raw (δ[FEV1/FVC]·FVC) and BC (δFVC·[FEV1/FVC]). Results By day 15 of EVOLVE or EXPAND, TEZ/IVA treatment was associated with significant improvements in FEV1 compared with placebo in F/F (+108±194 vs –16±176 mL) and F/RF (203±207 vs 0±199 mL) patients aged ≥12 years. Improvements persisted over time. Increases in FEV1 due to both reduced Raw and improved BC were observed; improved BC accounted for the majority of FEV1 increase (66% in F/F and 61% in F/RF). Raw improvements appeared to plateau between 8–12 weeks, but BC improvements continued through the last observation in EXTEND: 84 weeks in F/F patients and 56 weeks in F/RF patients. Conclusions Results suggest that TEZ/IVA improves lung function in patients with F/F and F/RF by reducing Raw and increasing BC. Reduction in Raw occurs early and appears to plateau, while BC progressively increases over time. These findings suggest TEZ/IVA treatment results in short-term improvement in airway obstruction caused by mucus occlusion and airway smooth muscle constriction, and long-term improvement from recruitment and beneficial remodeling of lung parenchyma. Abstract previously submitted to the North American Cystic Fibrosis Conference, Denver, CO, 18–20 October, 2018 Sponsored by Vertex Pharmaceuticals Incorporated