Editorial

Journal of Cystic Fibrosis 13 (2014) 489–490www.elsevier.com/locate/jcf

DOI of origina

http://dx.doi.org/11569-1993/© 201

A cocktail drug therapy for patients with cystic fibrosis?

1 Vertex press release (24 June, 2014): “Two 24-week phase 3 studies oflumacaftor in combination with ivacaftor met primary endpoint with statisticallysignificant improvements in lung function (FEV1) in people with cystic fibrosis

Multiple mutations in the gene encoding the cystic fibrosistransmembrane conductance regulator (CFTR), an epithelial anionchannel, disrupt its normal function, cause a variety of epithelialdisorders and lead to the life-shortening disease cystic fibrosis(CF). Current therapies for CF target disease symptoms. However,directly restoring activity to mutant CFTR is expected to furtheralleviate disease complications in patients with CF leading toimprove quality of life and life expectancy. The recent discovery ofnew drugs that enhance CFTR plasma membrane expression(correctors) and channel activity (potentiators) provides a promis-ing drug therapy for CF. Ivacaftor (VX-770), a CFTR potentiatorapproved by the US Food and Drug Administration (FDA) and theEuropean Medicines Agency (EMA) for patients with CF aged6 years and older carrying the G551D mutation, shows significantimprovement to patients' lung function, elevating the predictedforced expiratory volume in 1 second (FEV1) by about 10% andreducing the time to first pulmonary exacerbation by about 50%[10]. More recently, VX-770 has been approved by the FDA(NDA 203188, www.fda.gov) and recommended by the EMA(EMA/CHMP/365663/2014) for use with an additional eight CFgating (class III) mutations (G178R, S549N, S549R, G551S,G1244E, S1251N, S1255P and G1349D), although, includingG551D, these mutations still just occur in ~5% of CF patientsworldwide.

In this issue of the JCF, Kopeikin et al. [6] use thepatch-clamp technique, the gold standard method for functionalstudies of ion channels, to measure the direct effects of drugs onthe activity of the CFTR channel. Consistent with previousstudies [12,13], the authors found that VX-770 was able tostimulate the most common CF mutant, F508del-CFTR,occurring in ~90% of CF patients and also known to have agating defect (class III) once its major trafficking (class II)defect is rescued. This finding will likely greatly enlarge thedrug market for VX-770. Moreover, the data suggest thatVX-770 could be a prospective chemical template to develop auniversal CFTR potentiator for treating patients with any CFTRgating mutation that reduces channel activity.

To understand the pharmacologic mechanisms how VX-770potentiates CFTR activity, Kopeikin et al. [6] found that thispotentiator stimulated the ATP-dependent channel activity ofF508del-CFTR by increasing both the frequency and the duration

l article: http://dx.doi.org/10.1016/j.jcf.2014.04.003.

0.1016/j.jcf.2014.07.0024 European Cystic Fibrosis Society. Published by Elsevier B.V. A

of channel openings. However, for two reasons, this study alsoshows that CFTR gating by VX-770 was not stronglyATP-dependent. First, the ATP analogue P-dATP, a powerfulstimulator of ATP-dependent channel gating, had marginal effecton F508del-CFTR following the action of VX-770 [6]. Second,the mutation E1371S, which greatly stimulates channel activityby preventing ATP hydrolysis-mediated channel closure, hadmodest effects on the action of VX-770 [6]. These data suggestthat the VX-770-binding site may not be near the ATP bindingpockets of CFTR [11]. Identifying the binding site of VX-770 inCFTR should provide crucial information to guide new drugdevelopment.

Because the F508del mutation reduces both the protein cellsurface expression (class II) and channel activity of CFTR (classIII), a cocktail of drugs combining a corrector to increase proteinplasma membrane levels such as the experimental drug VX-809,also known as lumacaftor [13] and a potentiator to enhance channelactivity such as VX-770 [6,12,13] may form an ideal strategy toimprove F508del-CFTR activity in the cell membrane. Consistentwith this idea, VX-809-treated cells have markedly increased cellsurface expression of F508del-CFTR, possibly by directlyinteracting with CFTR's cytoplasmic domains includingnucleotide-binding domain 1 and the intracellular loops of themembrane-spanning domains [4,5,8]. The present work [6]demonstrates that although VX-809 could not directly activateCFTR channels, at 37 °C this experimental drug deliveredsignificant numbers of channels to the cell surface that wereactivated by cAMP-dependent phosphorylation and furtherstimulated by ATP agonists or VX-770. Together the data arguethat the combination of different correctors and potentiators (i.e.cocktail drug therapy) is likely to be a promising treatment forpatients with CF and the F508del mutation [1]. This idea isreinforced by a recent phase 2 clinical trial that showed significantimprovements in FEV1 in CF patients during the period oftreatment with a combination of VX-809 and VX-770 [2] and isfurther emphasized by the results of the phase 3 combo trial,despite the modest FEV1 improvement reported1.

who have two copies of the F508del mutation” (http://investors.vrtx.com/releasedetail.cfm?ReleaseID=856185).

ll rights reserved.

490 Editorial

It is surprising that in the current study [6], VX-809-treatedcells generated significant F508del-CFTR-mediated currentswithout functional correction of channel gating. This resultcontrasts with previous data [13]. However, the present resultssupport earlier findings [3], suggesting that the proteinprocessing and channel gating defects of F508del-CFTR mayresult from different mechanisms. Thus, it seems appropriate toexpect that different drugs would be required to rescue theindividual defects of F508del-CFTR [1]. In the longer term, amulti-functional drug possibly with fewer side effects than acocktail, is the ultimate goal in CF drug discovery.

A concern is that both the CFTR potentiator VX-770 and thecorrector VX-809 may not be sufficient to restore all functionaldefects caused by the F508del mutation [1]. Indeed, this mutantalso makes CFTR insensitive to cAMP stimulation [9] and lessstable in the cell membrane [7]. It will be interesting to knowwhether this cocktail combination is beneficial to these defects.Moreover, simply activating CFTR activity without restoringphysiological processes in epithelial tissues may not producelong-term benefits for CF patients. Finding new drugs with lowtoxicity suitable for young children and infants with CF isessential because other secondary disease complications likeinflammation, tissue remodeling and fibrosis may occur, causingpermanent tissue damage and preventing restoration of CFTRactivity from curing CF disease. Nevertheless, the cocktailtherapy combining VX-809 and VX-770 shows scientists andpatients with CF a bright light after 25 years of cloudy skies.

Acknowledgments

I thank Drs SC Bell, MD Amaral and DN Sheppard for theirvaluable comments.

References

[1] Amaral MD, Farinha CM. Rescuing mutant CFTR: a multi-task approach to abetter outcome in treating cystic fibrosis. Curr Pharm Des 2013;19:3497–508.

[2] Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E,et al. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor)for treatment of patients with cystic fibrosis who have a phe508del CFTRmutation: a phase 2 randomised controlled trial. Lancet Respir Med2014;2(7):527–38.

[3] Dong Q, Ostedgaard LS, Rogers C, Vermeer DW, Zhang Y, Welsh MJ.Human-mouse cystic fibrosis transmembrane conductance regulator (CFTR)chimeras identify regions that partially rescue CFTR-ΔF508 processing andalter its gating defect. Proc Natl Acad Sci U S A 2011;109:8270–3.

[4] Farinha CM, King-Underwood J, Sousa M, Correia AR, Henriques BJ,Roxo-Rosa M, et al. Revertants, low temperature, and correctors reveal themechanism of F508del-CFTR rescue by VX-809 and suggest multipleagents for full correction. Chem Biol 2013;20:943–55.

[5] He L, Kota P, Aleksandrov AA, Cui L, Jensen T, Dokholyan NV, et al.Correctors of ΔF508 CFTR restore global conformational maturationwithout thermally stabilizing the mutant protein. FASEB J 2013;27:536–45.

[6] Kopeikin Z, Yuksek Z, Yang HY, Bompadre SG. Combined effects ofVX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels. J Cyst Fibros 2014;13:508–14.

[7] Okiyoneda T, Barriere H, Bagdany M, Rabeh WM, Du K, Hohfeld J, et al.Peripheral protein quality control removes unfolded CFTR from theplasma membrane. Science 2010;329:805–10.

[8] Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, et al.Mechanism-based corrector combination restores ΔF508-CFTR foldingand function. Nat Chem Biol 2013;9:444–54.

[9] Ostedgaard LS, Meyerholz DK, Chen JH, Pezzulo AA, Karp PH,Rokhlina T, et al. The ΔF508 mutation causes CFTR misprocessing andcystic fibrosis-like disease in pigs. Sci Transl Med 2011;3:74ra24.

[10] Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P,et al. A CFTR potentiator in patients with cystic fibrosis and the G551Dmutation. N Engl J Med 2011;365:1663–72.

[11] Sheppard DN. Cystic fibrosis: CFTR correctors to the rescue. Chem Biol2011;18:145–7.

[12] Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T,et al. Rescue of CF airway epithelial cell function in vitro by a CFTRpotentiator, VX-770. Proc Natl Acad Sci U S A 2009;106:18825–30.

[13] Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS,et al. Correction of the F508del-CFTR protein processing defect in vitroby the investigational drug VX-809. Proc Natl Acad Sci U S A2011;108:18843–8.

Jeng-Haur ChenDepartment of Physiology, HKU Shenzhen Institute of Research and

Innovation, University of Hong Kong, Li Ka Shing Faculty of Medicine, Facultyof Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, ChinaCorresponding author. Tel.: +852 2819 9512; fax: +852 2855 9730.

E-mail address: jeng-haur-chen@hku.hk.

10 July 2014