These are references to the properties of lumacaftor alone

2011 Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu PA. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Nat Acad Sci USA 2011; 108:18843-84. [PubMed]

The authors describe the in vitro pharmacology of VX-809, a CFTR corrector. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells, a level associated with mild CF. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.

–    As DF508 is the most frequent CF mutation it is hoped that this corrector will be as therapeutically active as indicated in these studies as it is likely that even 14% of normal CFTR activity will ameliorate the main symptoms associated with complete absent CFTR activity.  However, the corrector does not seem to have the same dramatic effect on DF508 as VX-770 has on the G551D mutation. However, the results of VX-770 in patients with the GF551D mutation added great impetus to the small molecule corrector research and there is now major investment in this area by pharmaceutical companies and the CF Foundation.


2012 Clancy JP. Rowe SM. Accurso FJ. Aitken ML. Amin RS. Ashlock MA. Ballmann M. Boyle MP. Bronsveld I. Campbell PW. De Boeck K. Donaldson SH. Dorkin HL. Dunitz JM. Durie PR. Jain M. Leonard A. McCoy KS. Moss RB. Pilewski JM. Rosenbluth DB. Rubenstein RC. Schechter MS. Botfield M. Ordonez CL. Spencer-Green GT. Vernillet L. Wisseh S. Yen K. Konstan MW. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.  Thorax 2012; 67:12-18. [PubMed]
VX-809,(lumacaftor), a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. This randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo.

The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups.
There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens.

The authors concluded that VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit.


2013 Farinha CM. King-Underwood J. Sousa M. Correia AR. Henriques BJ. Roxo-Rosa M. Da Paula AC. Williams J. Hirst S. Gomes CM. Amaral MD. Revertants, Low Temperature, and Correctors Reveal the Mechanism of F508del-CFTR Rescue by VX-809 and Suggest Multiple Agents for Full Correction. Chem Biol 2013; 20:943-55. [PubMed]
Cystic fibrosis is mostly caused by the F508del mutation, which impairs CFTR protein from exiting the endoplasmic reticulum due to misfolding. VX-809 (lumacaftor)  is a small molecule that rescues F508del-CFTR localization, which recently went into clinical trial but with unknown mechanism of action (MoA).  Herein, the authors assessed if VX-809 is additive or synergistic with genetic revertants of F508del-CFTR, other correctors, and low temperature to determine its MoA. They  explored and integrated those various agents in combined treatments, showing how they add to each other to identify their complementary MoA upon correction of F508del-CFTR.

The authors’ experimental and modeling data, while compatible with putative binding of VX-809 to NBD1:ICL4 interface, also indicate scope for further synergistic F508del-CFTR correction by other compounds at distinct conformational sites/cellular checkpoints, thus suggesting requirement of combined therapies to fully rescue F508del-CFTR.

2013 Ren HY. Grove DE. De La Rosa O. Houck SA. Sopha P. Van Goor F. Hoffman BJ. Cyr DM. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell 2013; 24:3016-24. [PubMed]
CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, the authors explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2.

The authors suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.


2014  Eckford PD. Ramjeesingh M. Molinski S. Pasyk S. Dekkers JF. Li C. Ahmadi S. Ip W. Chung TE. Du K. Yeger H. Beekman J. Gonska T. Bear CE. VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial rescue to the cell surface. Chem Biol 2014; 21(5):666-78. [PubMed]
The most common mutation causing cystic fibrosis (CF), F508del, impairs conformational maturation of CF transmembrane conductance regulator (CFTR), thereby reducing its functional expression on the surface of epithelia. Corrector compounds including C18 (VRT-534) and VX-809 have been shown to partially rescue misfolding of F508del-CFTR and to enhance its maturation and forward trafficking to the cell surface.

The authors show that there is an additional action conferred by these compounds beyond their role in improving the biosynthetic assembly. In vitro studies show that these compounds bind directly to the metastable, full-length F508del-CFTR channel. Cell culture and patient tissue-based assays confirm that in addition to their cotranslational effect on folding, certain corrector compounds bind to the full-length F508del-CFTR after its partial rescue to the cell surface to enhance its function. These findings may inform the development of alternative compounds with improved therapeutic efficacy.

2014 Baroni D. Zegarra-Moran O. Svensson A. Moran O. Direct interaction of a CFTR potentiator and a CFTR corrector with phospholipid bilayers.Euro Biophys J 2014; 43(6-7):341-6.[PubMed]
Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors are new drugs that target the basic CFTR protein defect and are expected to benefit cystic fibrosis patients. To optimise the substances so far proposed for human use, and to minimise unwanted side effects, it is essential to investigate possible interactions between the drugs and cell components. The authors used small-angle X-ray scattering with synchrotron radiation to analyse the effects of two representative drugs, the potentiator VX-770 (Ivacaftor), approved for human use, and the corrector VX-809 (Lumacaftor), on a model phospholipid membrane.

By reconstruction of the electron density profile of unilamellar vesicles treated with VX-770 or VX-809 the authors found that these drugs penetrate the phospholipid bilayer. VX-809 becomes homogeneously distributed throughout the bilayer whereas VX-770 accumulates predominantly in the internal leaflet, behaviour probably favoured by the asymmetry of the bilayer, because of vesicle curvature.
Penetration of the bilayer by these drugs, probably as part of the mechanisms of permeation, causes destabilization of the membrane; this must be taken into account during future drug development.

–     It is still early days in the use of these correctors and potentiators. They have such a profound effect on those treated that it is not surprising they have a variety of other effects and such studies are welcome.

2014 Boyle MP. Bell SC. Konstan MW. McColley SA. Rowe SM. Rietschel E. Huang X. Waltz D. Patel NR. Rodman D. VX09-809-102 study group. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med 2014; 2(7):527-38. [PubMed]

This important multicentre study tested combination treatment with lumacaftor, an investigational CFTR corrector that increases trafficking of phe508del CFTR to the cell surface, and ivacaftor, a CFTR potentiator that enhances chloride transport of CFTR on the cell surface.

The authors assessed three successive cohorts, with the results of each cohort informing dose selection for the subsequent cohort. They recruited patients from 24 cystic fibrosis centres in Australia, Belgium, Germany, New Zealand, and the USA. Eligibility criteria were: confirmed diagnosis of cystic fibrosis, age at least 18 years, and a forced expiratory volume in 1s (FEV1) of 40% or more than predicted.
Cohort 1 included phe508del CFTR homozygous patients randomly assigned to either lumacaftor 200 mg once per day for 14 days followed by addition of ivacaftor 150 mg or 250 mg every 12 h for 7 days, or 21 days of placebo.
Together, cohorts 2 and 3 included phe508del CFTR homozygous and heterozygous patients, randomly assigned to either 56 days of lumacaftor (cohort 2: 200 mg, 400 mg, or 600 mg once per day, cohort 3: 400 mg every 12 h) with ivacaftor 250 mg every 12 h added after 28 days, or 56 days of placebo.
The primary outcomes for all cohorts were change in sweat chloride concentration during the combination treatment period in the intention-to-treat population and safety (laboratory measurements and adverse events). (The study is registered with, number NCT01225211, and EudraCT, number 2010-020413-90).
Cohort 1 included 64 participants. Cohort 2 and 3 combined contained 96 phe508del CFTR homozygous patients and 28 compound heterozygotes. Treatment with lumacaftor 200 mg once daily and ivacaftor 250 mg every 12 h decreased mean sweat chloride concentration by 9.1 mmol/L (p<0.001) during the combination treatment period in cohort 1.
In cohorts 2 and 3, mean sweat chloride concentration did not decrease significantly during combination treatment in any group. Frequency and nature of adverse events were much the same in the treatment and placebo groups during the combination treatment period; the most commonly reported events were respiratory. 12 of 97 participants had chest tightness or dyspnoea during treatment with lumacaftor alone. In pre-planned secondary analyses, a significant decrease in sweat chloride concentration occurred in the treatment groups between day 1 and day 56 (lumacaftor 400 mg once per day group -9.1 mmol/L, p<0.001; lumacaftor 600 mg once per day group -8.9 mmol/L, p<0.001; lumacaftor 400 mg every 12 h group -10.3 mmol/L, p=0.002). These changes were significantly greater than the change in the placebo group. In cohort 2, the lumacaftor 600 mg once per day significantly improved FEV1 from day 1 to 56 (difference compared with placebo group: +5.6 percentage points, p=0.013), primarily during the combination period. In cohort 3, FEV1 did not change significantly across the entire study period compared with placebo (difference +4.2 percentage points, p=0.132), but did during the combination period (difference +7.7 percentage points, p=0003). Phe508del CFTR heterozygous patients did not have a significant improvement in FEV1.

This trial provided evidence that combination lumacaftor and ivacaftor (Orkambi) improves FEV1 for patients with cystic fibrosis who are homozygous for phe508del CFTR, with a modest effect on sweat chloride concentration. These results support the further exploration of combination lumacaftor and ivacaftor as a treatment in this setting.    The abstract of this important study and rather complex study is reproduced in full.

2014 Veit G. Avramescu RG. Perdomo D. Phuan PW. Bagdany M. Apaja PM. Borot F. Szollosi D. Wu YS. Finkbeiner WE. Hegedus T. Verkman AS. Lukacs GL. Some gating potentiators, including VX-770, diminish F508-CFTR functional expression. Translat Med 2014; 6(246): 246ra97. [PubMed]

Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the F508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous F508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function.

The authors show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, they examined its long-term effect in immortalised and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of F508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface F508-CFTR density and function. VX-770-induced destabilisation of F508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilisation of the nucleotide-binding domain 1 (NBD1)-NBD2 interface.

The authors suggest that the reduced correction efficiency of F508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimisation of potentiators to maximise the clinical benefit of corrector-potentiator combination therapy in CF.




2017 Talamo Guevara M, McColley SA. The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis. Expert Opin Drug Saf. 2017 Nov;16(11):1305-1311. doi: 10.1080/14740338.2017.1372419. Epub 2017 Sep 21. [Pubmed]
This article reviews safety of this therapy. Areas covered: Safety findings in ivacaftor, lumacaftor and combined therapy trials, and reported subsequently through post-approval evaluation, were accessed by PubMed and Google searches using key words ‘VX-770’, ‘ivacaftor’, ‘VX-809’, and ‘lumacaftor’. Transaminitis was seen in ivacaftor and combination trials. Non-congenital cataracts were seen in pre-clinical animal studies and in children taking ivacaftor and combined therapy. Dyspnea occurs in some patients taking lumacaftor and combined therapy and usually resolves without stopping treatment. Lumacaftor is a strong inducer of CYP3A while ivacaftor is a CYP3A sensitive substrate. Combination therapy can decrease systemic exposure of medications that are substrates of CYP3A, decreasing therapeutic effect. Co-administration of lumacaftor-ivacaftor with sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic index is not recommended. Expert opinion: Lumacaftor-ivacaftor therapy may be associated with ocular and hepatic side effects. Specific recommendations for monitoring are available. Dyspnea occurs, especially during initiation of treatment. Potential drug interactions should be evaluated in patients taking combination therapy. The risk benefit ratio of lumacaftor-ivacaftor favours therapy.

– A comprehensive summary of the potential problems with these drugs.

2017 Barnaby R, Koeppen K, Nymon A, Hampton TH, Berwin B, Ashare A, Stanton B. Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol. 2017 Nov 16:ajplung.00461.2017. doi: 10.1152/ajplung.00461.2017. [Epub ahead of print] [Pubmed]
Studies were conducted to examine the effects of lumacaftor alone and in combination with ivacaftor (i.e., Orkambi) on the ability of human CF (del508Phe/del508Phe) monocyte derived macrophages (MDMs) to phagocytose and kill P. aeruginosa. Lumacaftor alone restored the ability of CF MDMs to phagocytose and kill P. aeruginosa to levels observed in MDMs obtained from non-CF donors (WT-CFTR). This effect contrasts with the partial correction (~15%) of del508Phe Cl- secretion of airway epithelial cells by lumacaftor. Ivacaftor reduced the ability of lumacaftor to stimulate phagocytosis and killing of P. aeruginosa. Lumacaftor had no effect on P. aeruginosa-stimulated cytokine secretion by CF MDMs. Ivacaftor (5 µM) alone, or in combination with lumacaftor, reduced the secretion of several pro-inflammatory cytokines.

The authors suggest the clinical efficacy of Orkambi may be related in part to the ability of lumacaftor to stimulate phagocytosis and killing of P. aeruginosa by macrophages.

2017 Loo TW, Clarke DM. Corrector VX-809 promotes interactions between cytoplasmic loop one and the first nucleotide-binding domain of CFTR. Biochem Pharmacol. 2017 Jul 15;136:24-31. doi: 10.1016/j.bcp.2017.03.020. Epub 2017 Mar 31.  [Pubmed]
A large number of correctors have been identified that can partially repair defects in folding, stability and trafficking of CFTR processing mutants that cause cystic fibrosis (CF). The best corrector, VX-809 (Lumacaftor), has shown some promise when used in combination with a potentiator (Ivacaftor). Understanding the mechanism of VX-809 is essential for development of better correctors. Here, the authors tested their prediction that VX-809 repairs folding and processing defects of CFTR by promoting interactions between the first cytoplasmic loop (CL1) of transmembrane domain 1 (TMD1) and the first nucleotide-binding domain (NBD1).

Their results (which are detailed in the full summary) suggest that the mechanism by which VX-809 promotes maturation and stability of CFTR is by promoting CL1/NBD1 interactions.


2018 Carlile GWYang QMatthes ELiao JRadinovic SMiyamoto CRobert RHanrahan JWThomas DY.A novel triple combination of pharmacological chaperones improves F508del-CFTR correction.  Sci Rep. 2018 Jul 30;8(1):11404. doi: 10.1038/s41598-018-29276-y  Free PMC Article   [Pubmed]
Pharmacological chaperones (e.g. VX-809, lumacaftor) that bind directly to F508del-CFTR and correct its mislocalization are promising therapeutics for Cystic Fibrosis (CF). However to date, individual correctors provide only ~4% improvement in lung function measured as FEV1, suggesting that multiple drugs will be needed to achieve substantial clinical benefit.
Here the authors  examine if multiple sites for pharmacological chaperones exist and can be targeted to enhance the rescue of F508del-CFTR with the premise that additive or synergistic rescue by multiple pharmacological chaperones compared to single correctors indicates that they have different sites of action.
First, we found that a combination of the pharmacological chaperones VX-809 and RDR1 provide additive correction of F508del-CFTR. Then using cellular thermal stability assays (CETSA) we demonstrated the possibility of a third pharmacologically important site using the novel pharmacological chaperone tool compound 4-methyl-N-[3-(morpholin-4-yl) quinoxalin-2-yl] benzenesulfonamide (MCG1516A).                                                                     All three pharmacological chaperones appear to interact with the first nucleotide-binding domain (NBD1). The triple combination of MCG1516A, RDR1, and VX-809 restored CFTR function to >20% that of non-CF cells in well differentiated HBE cells and to much higher levels in other cell types. Thus the results suggest the presence of at least three distinct sites for pharmacological chaperones on F508del-CFTR NBD1, encouraging the development of triple corrector combinations.


2019 Ferrera L, Baroni D, Moran O. Lumacaftor-rescued F508del-CFTR has a modified bicarbonate permeability.J Cyst Fibros. 2019 Feb 6. pii: S1569-1993(18)30927-5. doi: 10.1016/j.jcf.2019.01.012. [Epub ahead of print] [Pubmed]

Deletion of phenylalanine at position 508, F508del, the most frequent mutation among Cystic fibrosis (CF) patients, destabilizes the protein, thus causing both a folding and a trafficking defect, resulting in a dramatic reduction in expression of CFTR. In vitro treatment with lumacaftor produces an enhancement of anion transport in cells. We studied the permeability properties of the CFTR mutant F508del treated with the corrector lumacaftor, showing that the rescued protein has selectivity properties different than the wild type CFTR, showing an augmented bicarbonate permeability. This difference would indicate a diverse conformation of the rescued F508del-CFTR, that is plausibly reflected on an improper regulation of the airway surface liquid, lessening the efficacy of the corrector. Our findings rather support the idea that a combination of correctors would be required to address the CFTR-dependent bicarbonate permeability.

Loretta Ferrera  is at the Istituto Giannina Gaslini, U.O.C. Genetica Medica, Genova, Italy. 

The authors suggest these findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease and suggest that mucolytic and anti-inflammatory agents should be explored as preventive therapy.

– An interesting combined contribution to the increasing work to understand early lung changes in CF .