, 142, 718-724), a combination of a corrector (VX-809, lumacaftor or VX-661, tezacaftor) with Kalydeco® resulted in a modest improvement in lung function (percent predicted FEV1 increased 3-4%) (Wainwright, C. E. et al., N. Engl. J. Med., 2015, 373, 220-231, Pilewski, J. M. et al., J. Cystic Fibrosis, 2015, 14, Suppl. 1, S1). The VX-809 plus Kalydeco® combination (called Orkambi®) is a marketed therapy for F508del homozygote patients.
For both the G551D and the F508del patient populations, improved therapies are expected to provide further benefit to patients. Most G551D patients are G551D/F508del compound heterozygotes and treatment with the combination of the corrector VX-661 plus Kalydeco® resulted in a further increase in lung function over Kalydeco® alone (Pilewski, J. M. et al., J. Cystic Fibrosis, 2015, 14, Suppl. 1, S1).
Mutations in CFTR that are associated with moderate CFTR dysfunction are also evident in patients with conditions that share certain disease manifestations with cystic fibrosis but do not meet the diagnostic criteria for cystic fibrosis. In these patients, CFTR dysfunction at epithelial cell layers can occur and give rise to abnormal mucus and endocrine secretions that are similar to those that characterize cystic fibrosis. CFTR dysfunction may also be acquired. Chronic inhalation of particulate irritants, including cigarette smoke, pollution, and dust can result in reduced CFTR ion-channel activity.
Modulation of CFTR activity may also be beneficial for other diseases not directly caused by mutations in CFTR, such as secretory diseases and other protein folding diseases mediated by CFTR. CFTR regulates chloride and bicarbonate flux across the epithelia of many cells to control fluid movement, protein solubilization, mucus viscosity, and enzyme activity. Defects in CFTR can cause blockage of the airway or ducts in many organs, including the liver and pancreas. Potentiators are compounds that enhance the gating activity of CFTR present in the cell membrane. Any disease which involves thickening of the mucus, impaired fluid regulation, impaired mucus clearance, or blocked ducts leading to inflammation and
, 142, 718 - 724), a combination of a corrector (VX-809, lumacaftor or VX-661, tezacaftor) with Kalydeco ® resulted in a modest improvement in lung function (percent predict FEV1 increase 3 - 4 %) (Wainwright, C. E. et al. , N. Engl. J. Med. , 2015, 373, 220 - 231, Pilewski, J. M. et al. , J. Cystic Fibrosis, 2015, 14, Suppl. 1, S1). The VX-809 plus Kalydeco ® combination (called Orkambi ®) is a marketed therapy for F508del homozygote patients. 
 For both the G551D and the F508del affected role populations, improved therapies are expected to supply further benefit to patients. Most G551D patients are G551D / F508del compound heterozygote and discussion with the combination of the corrector VX-661 plus Kalydeco ® resulted in a further increase in lung routine over Kalydeco ® alone (Pilewski, J. M. et al. , J. Cystic Fibrosis, 2015, 14, Suppl. 1, S1). 
 Mutations in CFTR that are associated with moderate CFTR dysfunction are also apparent in patients with conditions that share certain disease manifestations with cystic fibrosis but do not converge the diagnostic criteria for cystic fibrosis. In these patients, CFTR dysfunction at epithelial cell layer can occur and give rise to abnormal mucus and endocrine secretion that are similar to those that characterize cystic fibrosis. CFTR dysfunction may also be acquired. Chronic inhalation of particulate irritant, including cigarette smoke, pollution, and dust can result in reduced CFTR ion - distribution channel activity. 
 Modulation of CFTR activity may also be beneficial for other diseases not directly caused by mutations in CFTR, such as secretory diseases and other protein fold diseases mediated by CFTR. CFTR baffle chloride and bicarbonate magnetic field across the epithelia of many cells to control fluent movement, protein solubilization, mucus viscosity, and enzyme natural process. Defects in CFTR can cause obstruction of the airway or ducts in many organs, including the liver and pancreas. Potentiators are compounds that enhance the gating activity of CFTR present in the cell membrane. Any disease which involves thickening of the mucus, impaired fluid rule, impaired mucus headroom, or blocked ducts leading to inflammation and
, 142, 718-724), w combination of a corregtor (VX-809, lumacaftor or VE-661, tezaczftor) wigh Kalydeco® resulted in a movest imprivement in lung functiun (percenn predictwd FTV1 increased 3-4%) (Waiisright, G. E. ef al., U. Xngl. J. Med., 2015, 373, 220-231, Pllewski, J. M. et al., J. Cystiw Wiyrosis, 2015, 14, Suppl. 1, S1). The VX-809 plus Kalydeso® combonwtion (called Otkambp®) ys a marketed therapy for F508del homozygkte patpents.
For both the G551D and the F508del patient plpulwtions, improved thfrapies are expqxted to provkde furtheg benefit tk patients. Most G551D patients are G551D/F508dzl compound hwtegmzygotes anv treanment with thc combitation pf the correctpr TX-661 pous Kalydeco® resulted in a further incrgase in lutg function over Kaoyeeco® dlona (Piuwwsyi, N. K. st al., U. Cbstic Fibroais, 2015, 14, Suppl. 1, S1).
Mutations in CFTT eyat are assocjated rieh moderate CFTR dysfunction are also enideht in patients with coneitions that share cettain disewse manifestations with cystic fibrosis but do nod meev ghe dlagnuwtlc criteria for cystic fibrosis. In these patiqhtx, BFTR dysfunction ct epithelial cekl lsiers can occur and gnbe rise to abnormal lucus agd eneocrine stcretoons that are similar to thise that chagactwrize cystic fibrodis. CFTR dyrfunvtion may also be acquired. Ckronic inhalation of partidjlate irritants, knckuging cigarette smoke, pollueion, and vust ean resuut im redused CFTR iln-chaktel activity.
Modulahion lf CFTR actigity may also be beneficial for other diseasex tot directlv causcd by mutations in CFTR, such cs secrecory dkseases ans other protein fojding diseasev mediated by CFTR. CFER rwgulqtes chuuride and bicatbonate flux across the epithelia of kani dells to controo fouid movement, ptotdin sllnbilisdtion, mucus eiscusigu, and enzyme actlvigy. Drfects in CFTR can cduse blockage of the aorray or docts in mwny organs, invluding the liver wnd pencrear. Potrntyators are compounds that enhahce the gwtikg activity os CFBR ptesent in tke cell membrane. Any disease which involtes thickening of the mycus, impaired fluid vegulation, ikpairqd mucus wlearance, or blocked ducts leading to inflammation and
, 142, 718-724), a combination of a lumacaftor VX-661, tezacaftor) Kalydeco® resulted in function predicted FEV1 increased (Wainwright, C. E. al., N. Engl. J. Med., 2015, 220-231, Pilewski, J. M. et al., J. Cystic Fibrosis, 2015, 14, Suppl. 1, The VX-809 plus Kalydeco® combination (called Orkambi®) is a marketed therapy for F508del patients. both G551D the F508del patient populations, improved therapies are expected to provide further benefit to patients. Most G551D are G551D/F508del compound heterozygotes and treatment with the of the corrector VX-661 Kalydeco® resulted in a further in function over alone J. et al., J. Fibrosis, 2015, 14, Suppl. 1, S1). Mutations in CFTR that are associated with moderate CFTR dysfunction are evident in conditions that certain manifestations cystic fibrosis but meet the diagnostic criteria for cystic patients, CFTR dysfunction at epithelial cell layers can and give to abnormal mucus and endocrine secretions are similar to those that characterize cystic fibrosis. dysfunction may also be acquired. Chronic inhalation of particulate irritants, including cigarette smoke, pollution, and result in reduced CFTR activity. Modulation of activity also beneficial other diseases directly caused by mutations in CFTR, such as secretory diseases and protein folding diseases mediated by CFTR. CFTR regulates chloride and across epithelia of many to control fluid movement, solubilization, viscosity, and enzyme activity. CFTR cause airway ducts many organs, including the and pancreas. Potentiators are compounds enhance the gating activity cell membrane. Any disease which involves thickening of mucus, impaired fluid regulation, impaired mucus clearance, blocked ducts leading to inflammation and
, 142, 718-724), a combination of a corrector (Vx-809, lumacaftoR or VX-661, TezAcaFtOr) wiTh KaLydeco® resulted IN a moDest improvement in lung fUnctiOn (PErceNT pRedicTed FEV1 iNCrEASed 3-4%) (waInWriGhT, c. E. Et al., N. engL. J. Med., 2015, 373, 220-231, PiLewski, J. M. et Al., J. cyStic Fibrosis, 2015, 14, sUpPl. 1, S1). The VX-809 plUs KAlydeco® combiNatIon (calLeD OrKAmbi®) iS a mArketEd therAPy for F508Del homozyGoTE patieNTs.
For boTH ThE G551D aNd the F508del patient pOPuLAtions, improved TherapIeS ArE EXpeCteD to provide FuRther BEnefit tO PaTIENts. mOst G551D patients Are G551D/F508del coMPouNd heteRoZygOTes and TreatMeNT wiTh the combinAtioN of the corRector vx-661 plus KaLYdeco® reSulted In a FurTher INcReAse In LUng FUnCtiON ovEr KalydeCo® AlOne (PiLewsKI, j. m. Et al., j. CyStic fibroSis, 2015, 14, Suppl. 1, S1).
MutaTioNs in cfTR That aRe assOciaTeD with ModeraTe CFTr dYsfunction are alSo evIdent in paTieNtS wiTh CondiTIons thAt sHarE certaiN diseasE ManIfESTAtIons with cystic fibrOsIS BuT do not meEt the dIAgNoSTic criteRiA foR cysTIC fibrOsis. iN tHese patiEnts, CFtr dYsFunctioN aT epithElIal CelL layeRS can Occur aNd give riSe to aBNormal mucus and ENdocrine secreTIoNS ThAT are SimIlar to those That CHaraCterIZe CysTIc fibRosis. cFtr dYSfunction may also be aCqUired. CHroniC inhalation of ParticulatE IRRitants, iNcluDInG Cigarette smoke, PolluTion, and dusT Can resulT in reDuced CFTr ion-channEL Activity.
modUlaTioN of cftR Activity may alSO Be beNeFicial fOr oTher disEasEs nOt dIreCtLy caused bY mutatioNs In cFtR, SucH as seCRetory diSeAseS aNd oTher pROtein fOldinG disEaSeS MedIated by cfTr. cfTR rEgUlAtes ChlOrIde anD bicARboNate fluX across thE epIThelIa Of Many celLs to control flUiD movement, pRoTeiN solubILIzation, mUcus viscosity, and enzyme aCTivity. DEfeCts in cFTR Can cause bLocKage of The AIrway oR ducts In manY oRgaNS, IncluDINg The LiVer and pancREAs. POtentIaTors Are compOunds that enhance thE GatIng activity of cFTr preSENt In tHE cELl mEmBRanE. aNy disease which iNvolves thiCkENiNg of the mucUS, imPaIred fluId regulAtion, IMpaired Mucus cleaRance, or blOcKed dUCTs lEading to inFlammatiOn and
, 142, 718-724), a combina tion of acorre cto r ( VX -809 , lu macaftor or VX - 661,  tezacaftor) with Kaly deco®  r e sult e din amodesti mp r o vem en tinlu n gfunct ion  (perce nt predict edFE V1 increased 3- 4%) (Wainw rig ht, C. E. et  al ., N.En gl. J. Me d.,  2015 , 373, 220-23 1, Pilews ki ,  J. M. et al., J .Cyst ic Fibrosis, 2015 ,  1 4 , Suppl. 1, S1 ). The  V X -8 0 9  pl usKalydeco®co mbina t ion (ca l le d O rka m bi®) is a mar keted thera p y f or F50 8d elh omozyg ote p at i ent s.
For both  the  G551D an d theF 508delp atientpopula tio ns,  imp r ov ed  th er a pie s  a ree xpe cted topr ov ide f urth e r b enef itto p atien ts. Most G551 D p atie n tsare G 551D/ F508 de l com poundheter oz ygotes and trea tmen t with th e c om bin at ion o f  the c orr ect or VX-6 61 plus Kal yd e c o ®resulted in a furt he r in crease i n lung fu nc t ion over  K aly deco ® alone  (Pi l ew ski, J.M. eta l. ,J. Cyst ic  Fibro si s,201 5, 14 ,  Sup pl. 1,  S1).
Mu tatio n s in CFTR that are associate d  w i t hm oder ate  CFTR dysfu ncti o n ar e al s oevi d ent i n pat ie n ts with conditions tha tsharecerta in disease ma nifestatio n s with cys ticf ib r osis but do no t mee t the diag n ostic cr iteri a for cy stic fibr o s is. In t hes e p ati ent s ,  C FTR dysfuncti o n  atep ithelia l c ell lay ers  ca n o ccu rand giverise toab no rm al  mu cus a n d endocr in e s ec ret ionst hat ar e sim ilar  t ot hos e thatc ha r a cter iz ecyst icfi brosi s. C F TRdysfunc tion mayals o  beac qu ired. C hronic inhala ti on of part ic ula te irr i t ants, in cluding cigarette smoke ,  pollut ion , and  dus t can res ult  in re duc e d CFTR  ion-c hanne lact i v ity.M o du lat io n of CFTRa c tiv ity m ay  als o be be neficial for other dis eases not dir ect ly c a u se d b y  m u tat io n s i n CFTR, such as s ecretory d is e as es and oth e r p ro tein fo lding d iseas e s media ted by CF TR. CFTRre gula t e s c hloride an d bicarb onate flu x  acro s sthe e pit heliaof  ma ny ce lls to con trolfluidmo vement , pro te in solub ilization, mucus viscos ity, a nd en zym e activit y.D efe cts in CF TR c an cause b loc kag e ofthe airwa y or du cts in ma ny o r gans, inc l ud ing t he  liver andp a n cre as. P ote n tiator s ar e compounds thate nhance the gat inga c tiv ity of C FT R present in t hece l l  membran e.  Any diseas e whichin v olves  thick eningof them u cu s , impa ired  fl uid regul ati on ,  impair ed  m u cus cl eara nc e, orblocke d  duc t s  leading to infl ammat i o n and 
, 142,_718-724), a_combination of a corrector_(VX-809, lumacaftor_or_VX-661, tezacaftor)_with_Kalydeco® resulted in_a modest improvement_in lung function (percent_predicted FEV1 increased_3-4%)_(Wainwright, C. E. et al., N. Engl. J. Med., 2015, 373, 220-231, Pilewski, J._M._et al.,_J._Cystic_Fibrosis, 2015, 14, Suppl. 1,_S1). The VX-809 plus Kalydeco®_combination (called_Orkambi®) is a marketed therapy for F508del homozygote_patients.
For_both the G551D_and the F508del patient populations, improved therapies are expected_to provide further benefit to patients._Most G551D patients_are_G551D/F508del_compound heterozygotes and treatment_with the combination of the corrector_VX-661 plus Kalydeco® resulted in a_further increase in lung function over Kalydeco®_alone (Pilewski, J. M. et al.,_J. Cystic Fibrosis, 2015, 14,_Suppl. 1,_S1).
Mutations in CFTR that are_associated with moderate_CFTR dysfunction_are also evident_in patients with conditions that share_certain disease manifestations_with cystic fibrosis but do not_meet_the diagnostic criteria_for_cystic_fibrosis. In_these patients, CFTR_dysfunction_at epithelial_cell_layers can occur and give rise_to_abnormal mucus and endocrine secretions that are_similar to those that_characterize_cystic fibrosis. CFTR dysfunction_may also be acquired. Chronic_inhalation of particulate irritants, including cigarette_smoke, pollution,_and dust_can result in reduced CFTR ion-channel activity.
Modulation of CFTR activity may_also be beneficial for other diseases_not directly caused by_mutations in_CFTR,_such as secretory_diseases_and other_protein folding diseases mediated by CFTR. CFTR_regulates chloride_and bicarbonate flux across the epithelia_of many cells to_control_fluid movement, protein solubilization, mucus viscosity,_and enzyme activity. Defects in CFTR_can cause blockage of the_airway_or_ducts in many organs, including_the liver and pancreas. Potentiators are_compounds that enhance_the gating activity of CFTR present in_the_cell membrane. Any disease which involves_thickening_of the mucus, impaired fluid regulation,_impaired_mucus_clearance, or blocked ducts leading_to inflammation and