Lumacaftor is indicated as a therapy for patients ages 12 and older with Cystic Fibrosis who possess the common F508del mutation. This oral therapy was awarded FDA Breakthrough Therapy Designation in 2013 to be used in conjunction with Ivafactor.
Lumacaftor has proven in vitro to correct p.Phe508del CFTR misprocessing and also increase the localized protein on cell surfaces. When combined with Ivacaftor in vitro clinical outcomes are greatly improved in patients six years of age and older who possess at least one copy of class III mutations as part of their CF diagnosis. In vitro and in vivo data indicates that Lumacaftor is primarily metabolized via glucuronidation and oxidation.
Mode of Action:
Lumacaftor rescues the cell surface expression of CFTR and acts to correct and repair protein. By binding to the misfolded protein both during and after synthesis, Lumacaftor elicits traffic to cell surfaces, thus helping to correct the defect. By improving the conformational stability of F508del-CFTR Lumacaftor increases both trafficking and processing of mature protein to the cell surface.
Lumacaftor metabolizes in the body and increases levels of mature CFTR in F508del HBE cells. The exposure of Lumacaftor is exactly two-fold higher in healthy adult volunteers when compared to exposure in patients with Cystic Fibrosis. Twice daily dosing for approximately 7 days of treatment with Lumacaftor in patients gleaned an accumulation ratio of approximately 1.9 of steady-state plasma concentration. Lumacaftor is 99% bound to plasma proteins, mainly to albumin, and the half-life is 26 hours in patients with CF.
Lumacaftor has not shown toxicity but should be dispensed with an abundance of caution to patients who have advanced liver disease. Side effects reported from patients with CF who were administered 200 milligrams of Lumacaftor via the Lumacaftor/Ivacaftor combination therapy were dyspnea, nausea, diarrhea, an increase in blood creatine phosphokinase and tiredness.
http://www.nejm.org/doi/full/10.1056/NEJMoa1409547#t=articleBackgroundVertex Pharmaceuticals. May 29, 2012.
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