Orkambi

Orkambi was approved in 2015 for patients ≥2 years homozygous for F508del. Lumacaftor partially rescues misfolded F508del CFTR from ER degradation so more reaches the apical membrane; ivacaftor then increases the open-channel probability of CFTR at the surface, restoring chloride transport. Clinical effect is modest (small FEV1 improvement, reduced exacerbations) and limited by drug-drug interactions (lumacaftor is a strong CYP3A inducer) and adverse effects (dyspnea, transaminitis). Orkambi has largely been superseded by elexacaftor/tezacaftor/ivacaftor (Trikafta), which is more effective and approved for any patient with at least one F508del allele. Key boards point: modulators only work if a functional CFTR can be coaxed to the membrane.