Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis

Abstract

Vertex Pharmaceuticals.

Nasospheroids permit measurements of CFTR-dependent fluid transport

“…The average slopes of the fitted lines were estimated to be -8.85 ( [-24.39, 6.70], P = 0.6765). Because clinical efficacy was not demonstrated with lumacaftor alone (27), we also evaluated the effect of 24-hour treatment with both lumacaftor and ivacaftor (5 μM), representative of the currently approved clinical regimen for F508del homozygotes using Orkambi (58)(59)(60)(61)(62). Combination treatment reveals a synergistic effect with both an increase in average fractional reduction and the resulting estimated mean slope becoming more negative than lumacaftor (-15.77 [-27.15, -4.39]), representing a significant reduction in size (P < 0.0001 compared with untreated CF, Figure 3C and Table 1) and greater restoration of CFTR activity.…”

Metabolomic responses to lumacaftor/ivacaftor in cystic fibrosis

“…Comparing Ivacaftor in patients with Gly551Asp mutation to the combined therapy for those with Phe508del mutations, the combined therapy of Lumacaftor/Ivacaftor in that CF population is significantly less effective in improving two key outcomes, lung function, and body mass index (BMI). In addition, the long‐term clinical significance of Lumacaftor/Ivacaftor and the ability to determine who will respond most robustly to the medication are not well understood …”

Cystic Fibrosis–Associated Liver Disease in Lung Transplant Recipients

“…Lumacaftor is a CFTR corrector that showed no significant clinical effect in individuals with CF when used alone. The use in clinical trials of lumacaftor in combination with ivacaftor, however, improved pulmonary function and lowered rates of pulmonary exacerbations in patients with CF homozygous for Phe508del . Unfortunately, the effects of these agents in the gastrointestinal and biliary tracts are not well characterized .…”

“…CFTR mutations manifest as epithelial cell dysfunction in the airways, biliary tract, pancreas, gut, sweat glands, paranasal sinuses, and genitourinary tract. The clinical manifestations of this dysfunction include respiratory tract infections, bronchiectasis, pancreatic insufficiency, malabsorption, intestinal obstruction, liver disease, and male infertility …”