VX-809

VX-809 (Lumacaftor, VRT 826809) is a potent CFTR corrector that increases F508del-CFTR-mediated chloride transport amd improves F508del-CFTR maturation in FRT cells with EC50 of 0.1 and 0.5 uM, respectively; improves F508del-CFTR processing in the endoplasmic reticulum and enhances chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC50=81 nM) ; exhibits biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability after F508del-CFTR corrected by VX-809.Fibrosis Phase 3 Discontinued (In Vitro) :In fischer rat thyroid (FRT) cells, Lumacaftor improves F508del-CFTR maturation by 7.1±0.3 fold (n=3) compared with vehicle-treated cells (EC50, 0.1±0.1 μM; n=3) and enhances F508del-CFTR-mediated chloride transport by approximately fivefold (EC50, 0.5±0.1 μM; n=3) . At Lumacaftor concentrations greater than 10 μM, the response is reduced, resulting in a bell-shaped dose-response relationship with an IC50 of approximately 100 μM. Lumacaftor is orally bioavailable in rats and achieved in vivo plasma levels significantly above concentrations required for in vitro efficacy. Lumacaftor produces a concentration-dependent increase in the HRP luminescence signal after incubation with cells at 37°C or 27°C in both cell lines, with a similar EC50 value of approximately 0.3 μM. In F508-HRP CFBE41o- cells at 37°C, Lumacaftor increases the signal maximally to approximately 250 luminescence arbitrary units (a.u.) over the DMSO control baseline of approximately 60 a.u., representing an approximately 4-fold signal increase. Similarly, with the R1070W-HRP CFBE41o- cells, Lumacaftor increases the signal maximally to approximately 220 a.u. over the DMSO control baseline of approximately 85 a.u., representing an approximately 2.5-fold signal increase. Therefore, both cell lines produced robust signals with a good dynamic range for high-throughput screening. (In Vivo) :Oral dosing of 1 mg/kg Lumacaftor in male Sprague-Dawley rats results in a Cmax of 2.4±1.3 μM with a t1/2 of 7.7±0.4 h (mean±SD; n=3), indicating that that Lumacaftor is orally bioavailable and able to reach plasma levels that significantly exceeded EC50s for F508del-CFTR correction.