This document provides an overview of cystic fibrosis pathophysiology and treatments. It discusses traditional therapies such as inhaled DNase and hypertonic saline as well as newer CFTR modulator therapies. Most notably, it outlines the development of ivacaftor for G551D mutations in 2012 and its approval for additional mutations. It also discusses lumacaftor-ivacaftor and tezacaftor-ivacaftor combinations for treating the F508del mutation, representing progress toward treating the underlying cause of cystic fibrosis. Overall, the document traces the story of cystic fibrosis treatment from 1950 to present day and provides optimism about continued therapeutic advances.

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New Frontiers in
Cystic Fibrosis
Pulmonary and Critical Care Symposium 2018
Marc McClelland, MD
Spectrum Health Medical Group
June 1, 2018
No conflicts of interest

3. Objectives
Overview of CF pathophysiology and Treatment
“Old school”: Traditional Therapies in CF
“New School”: CFTR Modulators
The Next Generation of CFTR Modulators
Cause for Optimism

4. Pathophysiology
CFTR mutations affect epithelial cells, thus
affecting:
■ Airways (sinuses, lungs)
■ Pancreas (endocrine and exocrine)
■ GI tract (liver/ biliary system, intestines)
■ Reproductive organs
■ Skin

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MYRIAD EFFECTS OF CF

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7. Summary
(patients over age 6 yrs)
Class A recommendations
(substantial benefit)
■ Recombinant DNase
■ Inhaled tobramycin, aztreonam
(PsA +)
Class B recommendations
(moderate benefit)
■ NSAIDs (ibuprofen)
■ Macrolides (azithromycin)
■ Bronchodialators (b2 adrenergic
receptor agonists)
■ Hypertonic saline (7%)
■ Airway Clearance Therapy
Class D recommendations (no benefit
or potential harm)
■ Oral corticosteriods ( 6–18 yrs, chronic)
■ Inhaled corticosteroids
■ Anti-staphylococcus antibiotics (chronic)
Class I recommendations (insufficient
information)
■ Leukotriene antagonists, oral
corticosteroids (adults), anticholinergics,
N acetyl cysteine, and cromolyn
CF-Foundation recommended therapies

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Inhaled DNase (dornase alfa)
• Decreases sputum viscosity
• Cleaves DNA from degenerating
neutrophils
• Improves lung function (FEV1)
• Reduces exacerbations
• Rate of decline in FEV1 is reduced
• Generally treated daily
• Alternate day dosing may be equally
effective
NEJM 1994; 331
AJRCCM 2007
Ped Pulm 2011
Lancet 2001

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Inhaled DNase (dornase alpha)
Age > 6 yo
Moderate to severe disease (FEV1 <69%)
■ Ten RCT, 3 cross-over, six without comparator, Cochrane review
(2005)
■ Total n = 3140
■ Recommendation = A (strength of evidence good, benefit substantial)
Mild disease (FEV1 = 70%–89%)
■ Three RCT, one cross-over
■ Total n = 520
■ Recommendation = B (strength of evidence fair, benefit moderate)
Coch Data Syst Rev 2016

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Inhaled 7% Hypertonic Saline
• Age > 6
• High osmolality of the solution draws water from
the airways to re-establish the aqueous surface
layer
• Administered twice daily
• Modest improvements in lung function
• Fewer pulmonary exacerbations
NEJM 2006
NEJM 2006
Coch Data Syst Rev 2009

11. Hypertonic Saline
Age > 6 yo
■ Three RCT, one cross-over trial,
and six trials without comparators
■ Total n = 520
■ Two RCT, two RCO compared with recombinant
DNase
■ Total n = 284
■ Cochrane review (2005)
■ Recommendation = B (level of evidence fair, net
benefit moderate)

12. Airway Clearance Therapy (ACT)
• All people with CF should perform airway clearance to
maintain lung function and improve quality of life (level of
evidence, fair; net benefit, moderate).
• No form of ACT has been shown to be superior to another
form of ACT.
• ACT should be individualize to patient.
12
Coch Data Syst Rev 2015
J Ped 1997
Thorax 2013

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Chest Physiotherapy
1950: Postural
drainage and
percussion
Positive expiratory
pressure (PEP)
devices
High frequency chest
wall oscillatory devices
(percussion vest)
Remains a standard of
CF care despite lack of
evidence of benefit

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Exercise!
Not well studied in CF
Meta-analysis showed modest improvements in exercise
capacity, PFT, and health-related quality of life
Patients with CF should participate in exercise programs
Pulmonary rehab for those with moderate to severe disease

15. Chronically Inhaled Tobramycin
PsA+ (persistent), and > 6 yo
Moderate to severe disease (FEV1 <69%)
■ Three RCT, one RCO, two 1-arm trials, Cochrane review (2006)
■ Total n = 679
■ Recommendation = A (level of evidence good, net benefit substantial)
Mild disease (FEV1 = 70%–89%)
■ Two RCT (n = 202)
■ Recommendation = B (level of evidence fair, net benefit moderate)

16. Reprinted with permission from Ramsey B, et al. N Engl J Med. 1999;340(1):23-30.
Inhaled Tobramycin (300 mg BID)
Phase III trial, 24 weeks randomized, placebo-controlled
Inhaled Tobramycin

17. Inhaled aztreonam
Dose: 75 mg three times daily
Increased time to exacerbation
Improvement in FEV1
Decreased respiratory symptoms
17
AJRCCM 2008
Chest 2009

18. Macrolides (chronic)
PsA+ (persistent), and > 6 yo
■ Two RCT, one crossover trial, one clinical trial, Cochrane
review (2005)
■ Total n = 296
■ Recommendation = B (level of evidence fair, net benefit
substantial)
JAMA 2003
AJRCCM 2005
Coch Data Syst Rev 2012

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Azithromycin in PSA positive patients
JAMA 2003

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Macrolides (chronic)
• Mechanism may involve antibacterial effects and/or anti-
inflammatory effects
• In non-PSA infected patients: reduction in pulmonary
exacerbations and weight gain
• Recommended for all patients with evidence of airways
inflammation: cough, reduced FEV1
• Can be dosed 250 mg daily, or 250 mg thrice weekly if
intolerant or < 40 Kg
JAMA 2010
Thorax 2002

21. Other Anti-inflammatory Agents
Inhaled corticosteroids (age > 6 yo)
■ No asthma, no ABPA
■ Five RCT, two RCO, Cochrane review (2006)
■ Total n = 388
■ Recommendation = D (level of evidence fair, net benefit zero)
Oral/systemic corticosteroids (age 6–18 yrs)
■ No asthma, no ABPA
■ Three RCT, Cochrane review (2006)
■ Total n = 354
■ Recommendation = D (level of evidence good, net benefit negative)
Oral/systemic corticosteroids (adults)
■ No asthma, no ABPA
■ One RCT (Total n = 20)
■ Recommendation = I (level of evidence poor, net benefit zero)
Lancet 1985
J Ped 1995
AJRCCM 2006

22. Anti-inflammatory
Agents (cont’d)
Oral nonsteroidal anti-inflammatory
drugs (NSAIDS)
■ Three RCT, Cochrane review (2005)
■ Total n = 145
■ Recommendation = B (level of evidence fair, net benefit moderate) for
children < 13 years old
Leukotriene modifiers
■ Two RCO, one controlled trial
■ Total n = 64
■ Recommendation = I (level of evidence poor, net benefit none)
Cromolyn
■ Two RCT, one clinical trial
■ Total n = 44
■ Recommendation = I (level of evidence poor, net benefit none)
AJRCCM 2007
AJRCCM 2006

23. Bronchodilators
Patients > 6 yo
b2 adrenergic agonists
■ Fourteen RCO (mix of nebulized/MDI)
■ Total n = 257
■ Recommendation = B (level of evidence good,
net benefit moderate)
Anticholinergics
■ Five RCO
■ Total n = 79
■ Recommendation = I (level of evidence poor, net
benefit none)

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• Prior to airway clearance sessions
• Prior to nebulized saline, nebulized antibiotics, or DNase
• Rescue medication for those with positive response
Bronchodilators: clinic use

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A story of progress…

26. CF: A Story of Progress
1950 1989 2015

27. CF respiratory disease pathways

28. Therapies that treat downstream
effects

30. What the future present holds

31. 2012: CFTR modulators: Ivacaftor
Age 2 and older
Small molecular compound
Designed to treat G551D mutation
Drug is a “potentiator”
Treats “gating mutation”
43

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NEJM
2011
Ivacaftor: improved lung function

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NEJM
2011
Ivacaftor: fewer exacerbations

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Ivacaftor: better quality of life
NEJM
2011

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Ivacaftor: weight gain
NEJM
2011

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Ivacaftor Label: January 31, 2012

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Ivacaftor approved for additional gating
mutations
G1244E
G1349D
G178R
G551D
G551S
R117H
S1251N
S1255P
S549N
S549R

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Ivacaftor Label: December 29, 2014

39. A1067T E193K L206W R74W
A455E E56K P67L S945L
D110E E831X R1070Q S977F
D110H F1052V R1070W 2789+5GA
D1152H F1074L R117C 3272-26AG
D1270N G1069R R347H 3849+10kbCT
D579G K1060T R352Q 711+3AG
51
Ivacaftor approved for residual function
mutations

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FDA opens the door to use of in-vitro testing to
assess rare mutations modulator response
FDA Press Release,
May 17, 2017

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Ivacaftor Label: May 17, 2017

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FDA decision opens a
new era of personalized CF medicine,
allowing laboratory evaluation
of rare CFTR mutations
unable to be studied in clinical trials.

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2015: Lumacaftor-ivacaftor for F508del
Age 6 and older
TRAFFIC and TRANSPORT studies
Modest improvement in lung function
Reduces risk of pulmonary exacerbation
Trend towards increased BMI
(PROGRESS STUDY) NEJM 2015
Lanc Resp 2017

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Lumacaftor-ivacaftor for F508del
NEJM
2015

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NEJM
2015
Lumacaftor-ivacaftor for F508del

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A “typical CF patient”?

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CF patient with lumacaftor-ivacaftor

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2017: Tezacaftor-ivacaftor
Age 12 and older
EVOLVE trial
F508del homozygotes
Improvement in lung function
Reduced risk of pulmonary exacerbation
Slightly better than lumacaftor/ivacaftor
NEJM 2017

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2017: Tezacaftor-ivacaftor
F508del/residual function heterozygotes
Improvement in lung function
Reduced risk of pulmonary exacerbation
Better improvements than in homozygotes
Better than ivacaftor alone

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2017: Tezacaftor-ivacaftor
Residual function mutations (independent of
second mutation): FDA-approved based on
in vitro studies showing equal or better
efficacy compared to ivacaftor alone

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Theratyping for Rare Mutations
HIGHLY-EFFECTIVE
MODULATOR THERAPY
RARE MUTATIONS
(THAT MAKE PROTEIN)
TWO CLASS I MUTATIONS
(NO PROTEIN)
90%
5%5%

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CF Foundation, 2018
CF Research Pipeline

53. Patients with CF
CFF Patient Registry, 2014
0
3000
6000
9000
12000
15000
86 90 94 98 02 06 10 14
Children Adults
NumberofPatients
Year
50.7%
29.2%

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CF Centers and CF Foundation
More than 120 CF
Foundation Accredited
Centers
CF Foundation Patient
Registry
Multidisciplinary Patient
Care Model

55. 70
0
20
40
60
80
100
120
140
160
180
2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
Total Pts Seen
Reported to Registry
Spectrum Health Adult CF Center

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57. Researchers are the
unsung heroes – the
engine that pushes us
toward the finish line.
Cystic fibrosis is no
longer a childhood
disease, and so much
of this accomplishment
is a direct result of
their hard work
and dedication.”
– Brandon Erhart,
adult with CF, 26
“

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