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Case Study Of The KIWI Clinical Trial

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subjects 6-11 years old (ppFEV1=95.8% at baseline) and a more progressed disease state in the adult subjects (ppFEV1 = 64.5% at baseline).(36)
The KIWI clinical trial was a two-part, open-label, phase 3 study to evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of ivacaftor in CF patients between two and five years old with at least one CFTR gating mutation. Results from this study expanded the use of ivacaftor to patients as young as two years old (Table 1).(15)
Despite in vitro results demonstrating an increased Isc in F508del-CFTR expressing FRT and HBE cells upon forskolin stimulation,(22) no therapeutic benefit was observed in CF patients homozygous for F508del-CFTR. The DISCOVER trial was a phase 2 study to test
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Part 2 assessed multiple ascending doses of D9-ivacaftor (75mg, 150mg, and 225mg), each administered daily after a high-fat meal for 7 days, compared to placebo.(68) Results presented during the 39th European Cystic Fibrosis Conference demonstrated improved PK of D9-ivacaftor compared to Kalydeco®, including a 40% increase in half-life (D9-ivacaftor t1/2 of ~15hrs; Kalydeco® t1/2 of ~11hrs), reduced clearance rate (D9-ivacaftor CL/F of 3.8L/hr vs. Kalydeco® CL/F of 13.3L/hr), approximately 3-fold increase in exposure (D9-ivacaftor AUC0-inf of 44,916ng*hr/mL vs. Kalydeco® AUC0-inf of 12,925ng*hr/mL), and approximately 3-fold increase in plasma concentrations at 24-hours (D9-ivacaftor C24hrs of 712ng/mL vs. Kalydeco® C24hrs of 169ng/mL). Data shown here are for 150mg doses of both D9-ivacaftor and Kalydeco®.(14, 26, 77) The improved PK profile of D9-ivacaftor along with a safety profile comparable to that of Kalydeco® has allowed progression of D9-ivacaftor into a phase 2 clinical trial to evaluate its safety and efficacy in CF patients with CFTR gating mutations.(69)
QBW-251

QBW-251 is a CFTR potentiator developed by Novartis Pharmaceuticals Inc. In vitro results showed QBW-251 to be an effective potentiator for CFTR gating mutations, including F508del-CFTR. Promising in vitro results led to the initiation of a
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