<div>Abbreviations: lum/iva: lumacaftor/ivacaftor; ETI:
elexecaftor/tezacaftor/ivacaftor; tez/iva: tezacaftor/ivacaftor; UA:
urinalysis, BMP: basic metabolic panel; OCPs: oral contraceptives.</div><div>References</div><div>1. Incorporated VP. FDA Approves KALYDECO® (ivacaftor) as First and Only
CFTR Modulator to Treat Eligible Infants With CF as Early as Four Months
of Age2020 September 25, 2020.</div><div>2. Incorporated VP. Vertex Announces FDA Approvals of TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor), SYMDEKO®
(tezacaftor/ivacaftor and ivacaftor) and KALYDECO® (ivacaftor) for Use
in People With CF With Certain Rare Mutations. 2020.</div><div>3. Davies JC, Wainwright CE, Sawicki GS, Higgins MN, Campbell D, Harris
C, Panorchan P, Haseltine E, Tian S, Rosenfeld M, Group AS. Ivacaftor in
Infants Aged 4 to &lt;12 Months With Cystic Fibrosis and a Gating
Mutation: Results of a 2-Part Phase 3 Clinical Trial. Am J Respir Crit
Care Med 2020.</div><div>4. Pilewski JM, De Boeck K, Nick JA, Tian S, DeSouza C, Higgins M, Moss
RB. Long-Term Ivacaftor in People Aged 6 Years and Older with Cystic
Fibrosis with Ivacaftor-Responsive Mutations. Pulm Ther
2020;6(2):303-313.</div><div>5. Higgins M, Volkova N, Moy K, Marshall BC, Bilton D. Real-World
Outcomes Among Patients with Cystic Fibrosis Treated with Ivacaftor:
2012-2016 Experience. Pulm Ther 2020;6(1):141-149.</div><div>6. Volkova N, Moy K, Evans J, Campbell D, Tian S, Simard C, Higgins M,
Konstan MW, Sawicki GS, Elbert A, Charman SC, Marshall BC, Bilton D.
Disease progression in patients with cystic fibrosis treated with
ivacaftor: Data from national US and UK registries. J Cyst Fibros 2019.</div><div>7. Bessonova L, Volkova N, Higgins M, Bengtsson L, Tian S, Simard C,
Konstan MW, Sawicki GS, Sewall A, Nyangoma S, Elbert A, Marshall BC,
Bilton D. Data from the US and UK cystic fibrosis registries support
disease modification by CFTR modulation with ivacaftor. Thorax
2018;73(8):731-740.</div><div>8. Griese M, Costa S, Linnemann RW, Mall MA, McKone EF, Polineni D, Quon
BS, Ringshausen FC, Taylor-Cousar JL, Withers NJ, Moskowitz SM, Daines
CL. Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor for
&gt;/=24 Weeks in People With CF and &gt;/=1 F508del
Allele: Interim Results of an Open-Label Phase Three Clinical Trial. Am
J Respir Crit Care Med 2020.</div><div>9. Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey
BW, Rowe SM, Sass LA, Tullis E, McKee CM, Moskowitz SM, Robertson S,
Savage J, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Taylor-Cousar
JL, Group VXS. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic
Fibrosis and One or Two Phe508del Alleles. N Engl J Med
2018;379(17):1612-1620.</div><div>10. Middleton P, Mall MA, Drevinek P, Lands LC, McKone EF, Polineni D.
Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single
Phe508del Allele. NEJM 2019;381:1809-1819.</div><div>11. Ejiofor LCK, Mathiesen IHM, Jensen-Fangel S, Olesen HV, Skov M,
Philipsen LKD, Pedersen CL, Pressler T. Patients with cystic fibrosis
and advanced lung disease benefit from lumacaftor/ivacaftor treatment.
Pediatr Pulmonol 2020;55(12):3364-3370.</div><div>12. Tong K, Barker D, France M, Burr L, Greville H, Visser S, Middleton
P, Wainwright C, Dorahy D, Wark P. Lumacaftor/ivacaftor reduces
exacerbations in adults homozygous for Phe508del mutation with severe
lung disease. J Cyst Fibros 2020;19(3):415-420.</div><div>13. O’Shea KM, O’Carroll OM, Carroll C, Grogan B, Connolly A,
O’Shaughnessy L, Nicholson T, Gallagher CG, McKone EF. The efficacy of
Elexacaftor/Tezacaftor/Ivacaftor in patients with cystic fibrosis and
advanced lung disease. Eur Respir J 2020.</div><div>14. Aalbers BL, de Winter-de Groot KM, Arets HGM, Hofland RW, de Kiviet
AC, van Oirschot-van de Ven MMM, Kruijswijk MA, Schotman S, Michel S,
van der Ent CK, Heijerman HGM. Clinical effect of lumacaftor/ivacaftor
in F508del homozygous CF patients with FEV1 &gt;/= 90%
predicted at baseline. J Cyst Fibros 2020;19(4):654-658.</div><div>15. Davies JC, Sermet-Gaudelus I, Naehrlich L, Harris RS, Campbell D,
Ahluwalia N, Short C, Haseltine E, Panorchan P, Saunders C, Owen CA,
Wainwright CE, Group VXI. A phase 3, double-blind, parallel-group study
to evaluate the efficacy and safety of tezacaftor in combination with
ivacaftor in participants 6 through 11 years of age with cystic fibrosis
homozygous for F508del or heterozygous for the F508del-CFTR mutation and
a residual function mutation. J Cyst Fibros 2020.</div><div>16. Shaw M, Khan U, Clancy JP, Donaldson SH, Sagel SD, Rowe SM, Ratjen
F, Network PIotCFFTD. Changes in LCI in F508del/F508del patients treated
with lumacaftor/ivacaftor: Results from the prospect study. J Cyst
Fibros 2020;19(6):931-933.</div><div>17. Ratjen F, Davis SD, Stanojevic S, Kronmal RA, Hinckley Stukovsky KD,
Jorgensen N, Rosenfeld M, Group SS. Inhaled hypertonic saline in
preschool children with cystic fibrosis (SHIP): a multicentre,
randomised, double-blind, placebo-controlled trial. Lancet Respir Med
2019;7(9):802-809.</div><div>18. Kerem E, Cohen-Cymberknoh M, Tsabari R, Wilschanski M, Reiter J,
Shoseyov D, Gileles-Hillel A, Pugatsch T, Davies JC, Short C, Saunders
C, DeSouza C, Sullivan JC, Doyle JR, Chandarana K, Kinnman N. Ivacaftor
in People With Cystic Fibrosis and a 3849+10kb C –&gt;T or
D1152H Residual Function Mutation. Ann Am Thorac Soc 2020.</div><div>19. Nick JA, St Clair C, Jones MC, Lan L, Higgins M, Team VXS. Ivacaftor
in cystic fibrosis with residual function: Lung function results from an
N-of-1 study. J Cyst Fibros 2020;19(1):91-98.</div><div>20. Berkers G, van der Meer R, Heijerman H, Beekman JM, Boj SF, Vries
RGJ, van Mourik P, Doyle JR, Audhya P, Yuan ZJ, Kinnman N, van der Ent
CK. Lumacaftor/ivacaftor in people with cystic fibrosis with an
A455E-CFTR mutation. J Cyst Fibros 2020.</div><div>21. Beekman JM. Individualized medicine using intestinal responses to
CFTR potentiators and correctors. Pediatr Pulmonol 2016;51:S23-S34.</div><div>22. Burghard MM, Berkers GG, Ghijsen SS, Hollander-Kraaijeveld FF, de
Winter-de Groot KK, van der Ent CK, Heijerman HH, Takken TT, Hulzebos
HE. Long-term effects of ivacaftor on nonpulmonary outcomes in
individuals with cystic fibrosis, heterozygous for a S1251N mutation.
Pediatr Pulmonol 2020;55(6):1400-1405.</div><div>23. Quon BS, Ramsook AH, Dhillon SS, Mitchell RA, Boyle KG, Wilcox PG,
Guenette JA. Short-term effects of Lumacaftor/Ivacaftor (Orkambi) on
exertional symptoms, exercise performance, and ventilatory responses in
adults with cystic fibrosis. Respir Res 2020;21(1):135.</div><div>24. Lundberg JO NS, Weitzberg E, Kollberg H, Alving K. Exhaled NO in
paediatric asthma and cystic fibrosis. Arch Dis Child
1996;75(4):323-326.</div><div>25. Thomas SR KS, Scott SF, Hodson ME, Barnes PJ. Nasal and exhaled
nitric oxide is reduced in adult patients with cystic fibrosis and does
not correlate with cystic fibrosis genotype. Chest 2000;117:1085-1089.</div><div>26. Gostelie R, Stegeman I, Berkers G, Bittermann J, Ligtenberg-van der
Drift I, Kipshagen PV, de Winter-de Groot K, Speleman L. The impact of
ivacaftor on sinonasal pathology in S1251N-mediated cystic fibrosis
patients. PLoS One 2020;15(7):e0235638.</div><div>27. Walker WT LA, Harris A, Cole J, Lucas JS. Upper and lower airway
nitric oxide levels in primary ciliary dyskinesia, cystic fibrois and
asthma. Respiratory Medicine 2013;107:380-386.</div><div>28. Rachel M BM, Aebisher D, Galiniak S. Exhaled nitric oxide in
pediatric patients with respiratory disease. J Breath Res 2019;18:13.</div><div>29. Grasemann H, Klingel M, Avolio J, Prentice C, Gonska T, Tullis E,
Ratjen F. Long-term effect of CFTR modulator therapy on airway nitric
oxide. Eur Respir J 2020;55(1).</div><div>30. Grasemann H. GT, Avolio J. Effect of iva therapy on exhaled nitric
oxide in patients with cystic fibrosis. J Cyst Fibros 2015;14:727-732.</div><div>31. Kotha K SR, Naren AP et al. Concentration of fractional excretion of
nitric oxide (FeNO): a potential airway biomarker of restored CFTR
function. J Cyst Fibros 2015;14:733-740.</div><div>32. Munck A, Kerem E, Ellemunter H, Campbell D, Wang LT, Ahluwalia N,
Owen CA, Wainwright C. Tezacaftor/ivacaftor in people with cystic
fibrosis heterozygous for minimal function CFTR mutations. J Cyst Fibros
2020;19(6):962-968.</div><div>33. McKone EF, DiMango EA, Sutharsan S, Barto TL, Campbell D, Ahluwalia
N, Higgins M, Owen CA, Tullis E. A phase 3, randomized, double-blind,
parallel-group study to evaluate tezacaftor/ivacaftor in people with
cystic fibrosis heterozygous for F508del-CFTR and a gating mutation. J
Cyst Fibros 2020.</div><div>34. Munce D, Lim M, Akong K. Persistent recovery of pancreatic function
in patients with cystic fibrosis after ivacaftor. Pediatr Pulmonol
2020;55(12):3381-3383.</div><div>35. Hutchinson I MP. Appearance of Pancreatic Sufficiency and
Discontinuation of Pancreatic Enzyme Replacement Therapy in Children
with Cystic Fibrosis on Ivacaftor. Ann Am Thorac Soc 2021;18:182-183.</div><div>36. Wright BA, Cannon ME, Ramsey LJ. Reversing the irreversible: Another
potential benefit of CFTR modulators. Pediatr Pulmonol
2020;55(11):2844-2845.</div><div>37. Smith H, Rayment JH. Sustained recovery of exocrine pancreatic
function in a teenager with cystic fibrosis treated with ivacaftor.
Pediatr Pulmonol 2020.</div><div>38. Moheet A, Beisang D, Zhang L, Sagel SD, VanDalfsen JM, Heltshe SL,
Frederick C, Mann M, Antos N, Billings J, Rowe SM, Moran A, Network
PIotCFFTD. Lumacaftor/ivacaftor therapy fails to increase insulin
secretion in F508del/F508del CF patients. J Cyst Fibros 2020.</div><div>39. Misgault B, Chatron E, Reynaud Q, Touzet S, Abely M, Melly L,
Dominique S, Troussier F, Ronsin-Pradel O, Gerardin M, Mankikian J,
Cosson L, Chiron R, Bounyar L, Porzio M, Durieu I, Weiss L, Kessler R,
Kessler L. Effect of one-year lumacaftor-ivacaftor treatment on glucose
tolerance abnormalities in cystic fibrosis patients. J Cyst Fibros
2020;19(5):712-716.</div><div>40. Moran A, Brunzell C, Cohen R, Katz M, Marshall b, Onady G et al.
Clinical care guidelines for CF related diabetes mellitus. Diabetes Care
2010;33:2697-2708.</div><div>41. Secunda KE, Guimbellot JS, Jovanovic B, Heltshe SL, Sagel SD, Rowe
SM, Jain M. Females with Cystic Fibrosis Demonstrate a Differential
Response Profile to Ivacaftor Compared with Males. Am J Respir Crit Care
Med 2020;201(8):996-998.</div><div>42. Ladores S, Bray LA, Brown J. Two Unanticipated Pregnancies While on
Cystic Fibrosis Gene-Specific Drug Therapy. J Patient Exp 2020;7(1):4-7.</div><div>43. O’Connor KE, Goodwin DL, NeSmith A, Garcia B, Mingora C, Ladores SL,
Rowe SM, Krick S, Solomon GM. Elexacafator/tezacaftor/ivacaftor resolves
subfertility in females with CF: A two center case series. J Cyst Fibros
2020.</div><div>44. Nash EF, Middleton PG, Taylor-Cousar JL. Outcomes of pregnancy in
women with cystic fibrosis (CF) taking CFTR modulators - an
international survey. J Cyst Fibros 2020;19(4):521-526.</div><div>45. Taylor-Cousar JL. CFTR modulators: impact on fertility, pregnancy
and lactation in women with cystic fibrosis. J Clin Med 2020;9:2706.</div><div>46. Brennan S, Marmor I, Schafer C, Ko J, Torres Garcia JA, Rosman IS,
Coughlin C, Coverstone A, White AJ. Serum sickness-like reaction
following initiation of elexacaftor/tezacaftor/ivacaftor therapy.
Pediatr Pulmonol 2020.</div><div>47. Hu MK, Wood G, Dempsey O. ’Triple therapy’ (elexacaftor, tezacaftor,
ivacaftor) skin rash in patients with cystic fibrosis. Postgrad Med J
2020.</div><div>48. Montemayor K, Claudio AT, Carson S, Lechtzin N, Christianson MS,
West NE. Unmasking catamenial hemoptysis in the era of CFTR modulator
therapy. J Cyst Fibros 2020;19(4):e25-e27.</div><div>49. Rotolo SM, Duehlmeyer S, Slack SM, Jacobs HR, Heckman B. Testicular
pain following initiation of elexacaftor/tezacaftor/ivacaftor in males
with cystic fibrosis. J Cyst Fibros 2020;19(5):e39-e41.</div><div>50. Albright JC, Houck AP, Pettit RS. Effects of CFTR modulators on
pharmacokinetics of tobramycin during acute pulmonary exacerbations in
the pediatric cystic fibrosis population. Pediatr Pulmonol 2020.</div><div>51. Baker E, Harris WT, Rowe SM, Rutland SB, Oates GR. Tobacco smoke
exposure limits the therapeutic benefit of tezacaftor/ivacaftor in
pediatric patients with cystic fibrosis. J Cyst Fibros 2020.</div><div>52. Loukou I, Moustaki M, Plyta M, Douros K. Longitudinal changes in
lung function following initiation of lumacaftor/ivacaftor combination.
J Cyst Fibros 2020;19(4):534-539.</div><div>53. Burgel PR, Munck A, Durieu I, Chiron R, Mely L, Prevotat A,
Murris-Espin M, Porzio M, Abely M, Reix P, Marguet C, Macey J,
Sermet-Gaudelus I, Corvol H, Bui S, Lemonnier L, Dehillotte C, Da Silva
J, Paillasseur JL, Hubert D, French Cystic Fibrosis Reference Network
Study G. Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in
Patients with Cystic Fibrosis. Am J Respir Crit Care Med
2020;201(2):188-197.</div><div>54. Salvatore D, Carnovale V, Majo F, Padoan R, Salvatore M, Taruscio D,
Amato A, Ferrari G, Campagna G. Cystic fibrosis with non-G551D gating
mutations in Italy: Epidemiology and clinical characteristics. Pediatr
Pulmonol 2020.</div><div>55. Sala MA, Jain M. Combination Therapy with Lumacaftor-Ivacaftor in
Cystic Fibrosis. Keeping It Real. Am J Respir Crit Care Med
2020;201(2):133-134.</div><div>56. Tong K BD, France M, Burr L, Greville H, Visser S, MIddleton P,
Wainwright C, Dorahy D, Wark P. Lum/iva reduces exacerbations in adults
homozygous for F508del mutation with severe lung disease. Journal of
Cystic Fibrosis 2020;19:415-420.</div><div>57. Olivereau L, Nave V, Garcia S, Perceval M, Rabilloud M, Durieu I,
Reynaud Q. Adherence to lumacaftor-ivacaftor therapy in patients with
cystic fibrosis in France. J Cyst Fibros 2020;19(3):402-406.</div><div>58. Schwarz C, Sutharsan S, Epaud R, Klingsberg RC, Fischer R, Rowe SM,
Audhya PK, Ahluwalia N, You X, Ferro TJ, Duncan ME, Bruinsma BG.
Tezacaftor/ivacaftor in people with cystic fibrosis who stopped
lumacaftor/ivacaftor due to respiratory adverse events. J Cyst Fibros
2020.</div><div>59. Smith A, Barry M. Utilisation, expenditure and cost-effectiveness of
cystic fibrosis drugs in Ireland: a retrospective analysis of a national
pharmacy claims database. BMJ Open 2020;10(11):e040806.</div><div>60. Wherry K, Williamson I, Chapman RH, Kuntz KM. Cost-Effectiveness of
Ivacaftor Therapy for Treatment of Cystic Fibrosis Patients With the
G551D Gating Mutation. Value Health 2020;23(10):1332-1339.</div><div>61. Cobanoglu N, Ozcelik U, Cakir E, Sismanlar Eyuboglu T, Pekcan S,
Cinel G, Yalcin E, Kiper N, Emiralioglu N, Sen V, Sen HS, Ercan O,
Cokugras H, Kilinc AA, Al Shadfan LM, Yazan H, Altintas DU, Karagoz D,
Demir E, Kartal Ozturk G, Bingol A, Basaran AE, Sapan N, Cekic S,
Celebioglu E, Aslan AT, Gursoy TR, Tugcu G, Ozdemir A, Harmanci K,
Yildirim GK, Kose M, Hangul M, Tamay Z, Suleyman A, Yuksel H, Yilmaz O,
Ozcan G, Topal E, Can D, Korkmaz Ekren P, Caltepe G, Kilic M, Ozdogan S,
Dogru D. Patients eligible for modulator drugs: Data from cystic
fibrosis registry of Turkey. Pediatr Pulmonol 2020.</div><div>62. Desai S, Lam GY, Sykes J, Stephenson AL, Quon BS. Eligibility of
CFTR modulators for the adult-diagnosed cystic fibrosis population. J
Cyst Fibros 2020;19(5):840-841.</div><div>63. McGarry M. Transparency and diversity in cystic fibrosis research.
Lancet 2020;396(10251):601.</div><div>64. McGarry ME. Triple Therapy for Cystic Fibrosis with a Phe508del CFTR
Mutation. N Engl J Med 2020;382(7):684.</div><div>65. De Boeck K, Lee T, Amaral M, Drevinek P, Elborn JS, Fajac I, Kerem
E, Davies JC. Cystic fibrosis drug trial design in the era of CFTR
modulators associated with substantial clinical benefit: stakeholders’
consensus view. J Cyst Fibros 2020;19(5):688-695.</div><div>66. Mayer-Hamblett N, van Koningsbruggen-Rietschel S, Nichols DP,
VanDevanter DR, Davies JC, Lee T, Durmowicz AG, Ratjen F, Konstan MW,
Pearson K, Bell SC, Clancy JP, Taylor-Cousar JL, De Boeck K, Donaldson
SH, Downey DG, Flume PA, Drevinek P, Goss CH, Fajac I, Magaret AS, Quon
BS, Singleton SM, VanDalfsen JM, Retsch-Bogart GZ. Building global
development strategies for cf therapeutics during a transitional cftr
modulator era. J Cyst Fibros 2020;19(5):677-687.</div><div>67. Magaret A, Warden M, Simon N, Heltshe S, Mayer-Hamblett N.
Real-world evidence in cystic fibrosis modulator development:
Establishing a path forward. J Cyst Fibros 2020;19(3):e11-e12.</div><div>68. Mall MA, Mayer-Hamblett N, Rowe SM. Cystic Fibrosis: Emergence of
Highly Effective Targeted Therapeutics and Potential Clinical
Implications. Am J Respir Crit Care Med 2020;201(10):1193-1208.</div><div>69. George A, Smith B, Sawicki GS, Goetz DM. Survey of patients with
cystic fibrosis and caregivers decisions regarding CFTR modulators.
Pediatr Pulmonol 2020.</div><div>70. Gifford AH, Mayer-Hamblett N, Pearson K, Nichols DP. Answering the
call to address cystic fibrosis treatment burden in the era of highly
effective CFTR modulator therapy. J Cyst Fibros 2020;19(5):762-767.</div><div>71. NCT04378153 CgI. Impact of Discontinuing Chronic Therapies in People
With Cystic Fibrosis on Highly Effective CFTR Modulator Therapy
(SIMPLIFY).</div><div>72. Konstan MW, VanDevanter DR, Rowe SM, Wilschanski M, Kerem E,
Sermet-Gaudelus I, DiMango E, Melotti P, McIntosh J, De Boeck K, Group
ACS. Efficacy and safety of ataluren in patients with nonsense-mutation
cystic fibrosis not receiving chronic inhaled aminoglycosides: The
international, randomized, double-blind, placebo-controlled Ataluren
Confirmatory Trial in Cystic Fibrosis (ACT CF). J Cyst Fibros
2020;19(4):595-601.</div><div>73. Peabody Lever JE, Mutyam V, Hathorne HY, Peng N, Sharma J, Edwards
LJ, Rowe SM. Ataluren/ivacaftor combination therapy: Two N-of-1 trials
in cystic fibrosis patients with nonsense mutations. Pediatr Pulmonol
2020;55(7):1838-1842.</div><div>74. van Koningsbruggen-Rietschel S, Conrath K, Fischer R, Sutharsan S,
Kempa A, Gleiber W, Schwarz C, Hector A, Van Osselaer N, Pano A,
Corveleyn S, Bwirire D, Santermans E, Muller K, Bellaire S, Van de Steen
O. GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for
the F508del mutation: A randomized phase 2A trial (PELICAN). J Cyst
Fibros 2020;19(2):292-298.</div><div>75. Kazani S, Rowlands DJ, Bottoli I, Milojevic J, Alcantara J, Jones I,
Kulmatycki K, Machineni S, Mostovy L, Nicholls I, Nick JA, Rowe SM,
Simmonds NJ, Vegesna R, Verheijen J, Danahay H, Gosling M, Ayalavajjala
PS, Salman M, Strieter R. Safety and efficacy of the cystic fibrosis
transmembrane conductance regulator potentiator icenticaftor (QBW251). J
Cyst Fibros 2020.</div><div>76. Drevinek P, Pressler T, Cipolli M, De Boeck K, Schwarz C, Bouisset
F, Boff M, Henig N, Paquette-Lamontagne N, Montgomery S, Perquin J,
Tomkinson N, den Hollander W, Elborn JS. Antisense oligonucleotide
eluforsen is safe and improves respiratory symptoms in F508DEL cystic
fibrosis. J Cyst Fibros 2020;19(1):99-107.</div>