Lumacaftor-ivacaftor in the treatment of cystic fibrosis: design, development and place in therapy

Abstract

Lumacaftor-ivacaftor is a combination of two small molecule therapies targeting the basic defect in cystic fibrosis (CF) at a cellular level. It is a precision medicine and its effects are specific to individuals with two copies of the p.Phe508del gene mutation. The drug combination works by restoring functioning CF transmembrane conductance regulator (CFTR) protein in cell surface membranes and was the first CFTR modulator licensed for the homozygous p.Phe508del genotype. The drug is a combination of a CFTR corrector and potentiator. Lumacaftor, the corrector, works by increasing the trafficking of CFTR proteins to the outer cell membrane. Ivacaftor, the potentiator, works by enabling the opening of what would otherwise be a dysfunctional chloride channel. In vivo lumacaftor-ivacaftor improves Phe508del-CFTR activity in airways, sweat ducts and intestine to approximately 10-20% of normal CFTR function with greater reductions in sweat chloride levels in children versus adults. Its use results in a modest improvement in lung function and a decreased rate of subsequent decline. Perhaps more importantly, those treated report increased levels of well-being and their rate of respiratory exacerbations is significantly improved. This review traces the development and use of this combination of CFTR modulators, the first licensed drug for treating the homozygous p.Phe508del CF genotype at the intracellular level by correcting the protein defect.

Keywords: DF508; Orkambi; Phe508del; corrector; modifier; modulator.

Figure 1

CFTR corrector (1) and potentiator (2) modulators work together to improve CFTR Function on the cell surface.

Figure 2

Change from baseline in percentage of predicted FEV1: Lumacaftor-ivacaftor (LUM-IVA) versus placebo. Note: Reprinted from Lancet Respir Med, 5(2), Konstan MW, McKone EF, Moss RB, et al, Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study, 107–118, Copyright 2017, with permission from Elsevier.19).

Figure 3

Lumacaftor-ivacaftor (LUM/IVA) treatment effects on projected annual rate of pulmonary exacerbations. Note: Reprinted from Lancet Respir Med, 5(2), Konstan MW, McKone EF, Moss RB, et al, Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study, 107–118, Copyright 2017, with permission from Elsevier.