37th European Cystic Fibrosis Conference
Scientific Coverage
Gothenburg, Sweden
11-14 June 2014
© 2014 Vertex Pharmaceuticals Incorporated │ VXR-EU-02-00091 │ 09/2014
Scientific Coverage Contributors
• Contributors to this scientific coverage include:
– Jacqueline Rendall, MD
Centre Director, Northern Ireland Regional Adult
Cystic Fibrosis Centre, Belfast HSC Trust
Honorary Lecturer, Queen’s University, Belfast
Northern Ireland
 Dr. Rendall attended and interpreted select sessions during the
conference. Her perspective is noted by the blue stethoscope icon
– Scientific staff at Fallon Medica LLC
Tinton Falls, US
 Christine Park
Senior Medical Writer/Editor
 Judi Greif, RN, MS, APNC
Senior Medical Writer/Editor
 Kelly Ludwinski
Account Executive
The summaries and opinions expressed by the contributors whose input is included in this scientific coverage are their own and are
not meant to represent those of the European Cystic Fibrosis Society, Vertex Pharmaceuticals Incorporated, or Fallon Medica LLC.
This presentation is produced for educational purposes only and is intended to be a synopsis of highlights of the conference.
2
Table of Contents
Navigation Instructions:
You may access the presentations by clicking on the hyperlinked double arrows (»).
To return to the Table of Contents, click on Table of Contents located at the bottom of each slide.
• Screening and Diagnosis »
– CF 2014: New Diagnostic Challenges »
– Screening and Diagnosis »
• Management of CF »
–
–
–
–
–
How to Progress With CFTR Modulators? »
Fixing Basic Defects – New Therapies »
New Antibacterial Therapies »
The Therapeutic Pipeline 2014 »
Airway Controversies »
CF=cystic fibrosis.
3
Table of Contents (cont)
• Evaluating the Lung and Intestines »
– Indexing the Lung »
– New Insights in Lung Disease »
– Functional Intestinal Outcome Measures in CF in the Era of Correctors
and Potentiators »
– Multiple Breath Inert Gas Washout (MBW)—An Introduction »
– Utility of MBW in CF and Other Paediatric Respiratory Disorders »
• Standards of Care and Clinical Practice Guidelines »
– The New ECFS Standards of Care »
– ECFS Clinical Practice Guideline: Exercise Testing in CF »
• Clinical Care Considerations »
–
–
–
–
Adherence »
FEV1 and Nutritional Status: Chicken or the Egg? »
Nutritional Challenges in Adults »
Multidisciplinary Aspects of CFRD »
4
Table of Contents (cont)
• Case Studies in CF »
– Psychosocial/Nursing Complex Case Presentations »
– Interactive Case Studies »
• Registry Data »
– Using Registries to Identify New Challenges »
– Pharmacovigilance/Phase 4 Studies Using Registries »
• Clinical Trials »
– Exploring New Endpoints in Clinical Trials »
– AHP Research Symposium: Changing Clinical Practice
Through Research With Minimal or No Funding »
– Clinical Trials in Preschool Children »
5
Table of Contents (cont)
• Science of CF »
–
–
–
–
–
–
Stem Cell-Based Airway Modelling and Regenerative Medicine for CF »
Late-Breaking Science »
CFTR Genetics and Function »
Epithelial Cell Biology »
The “Epithelial” Channeltome and Options for Rescue »
Translational Value of Ex Vivo CFTR Biomarker »
• Plenary Session »
• Posters »
– Best Poster Awards »
– Abstracts Online »
6
Table of Contents (cont)
• Satellite Symposia »
–
–
–
–
Changing Faces, Changing Solutions (Gilead) »
CFTR Modulation in CF (Vertex) »
CF Treatment: Past, Present, and Future (Roche) »
Changing Antibiotic Delivery to Improve CF Patients’ Lives:
Challenges and Opportunities (Novartis) »
• Acknowledgements »
7
Screening and Diagnosis
• CF 2014: New Diagnostic Challenges
• Screening and Diagnosis »
»
Table of Contents
8
CF 2014: New Diagnostic Challenges
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9
12 June Thursday, Symposium 10
CF 2014:
New Diagnostic Challenges
Faculty Perspective – Dr. Jacqueline Rendall, UK
“This symposium highlighted some of the challenges
seen in clinical practice with the wide range of CFTR
mutations and making sense of these in relevance to
phenotype. The work of both CFTR2 and CFTR3 groups
was outlined, and how they are working in collaboration.
This has important clinical relevance.”
CFTR=cystic fibrosis transmembrane conductance regulator.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 10.
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10
12 June Thursday, Symposium 10
CF 2014:
New Diagnostic Challenges (cont)
• CFTR2: Defining the most common CF-causing mutations –
Patrick Sosnay, Baltimore, US
– Goal of CFTR2.org is to accurately document the most common
CFTR mutations
– In 2014, CFTR2 contains disease liability information on 206 mutations
– The website is being redesigned and updated with different languages
for next year
– Ongoing efforts include accurate information of the most common CFTR
mutations in CF patients, including more rare and ethnically/geographically
diverse mutations
 Unpublished California Public Health records indicate n=2520, with most
common mutations in Hispanic population
 CFTR mutations identified in infertile men in China, Japan, Iran, India,
Mexico, North Africa, Poland, and Turkey
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 10.
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12 June Thursday, Symposium 10
CF 2014:
New Diagnostic Challenges (cont)
• CFTR3: Personalised characterisation of rare CF genotypes –
Nico Derichs, Berlin, DE
– CFTR3.eu is an open-access genotype/phenotype database on individual
and clinical consequences of rare CFTR mutations
– CFTR3 is directly linked from CF centres and will collaborate with CFTR2
– Goal is to phenotype patients with a rare (non-CFTR2) mutation on a
personalised basis
– Several CFTR biomarkers will be used, including sweat test, NPD, ICM,
organoids, and clinical data
– Benefit for patients is direct diagnostic help in questionable CF and
personalised characterisation
– CFTR3 is supported by the VIA programme
NPD=nasal potential difference; ICM=intestinal current measurement; VIA=Vertex Innovation Award.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 10.
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12 June Thursday, Symposium 10
CF 2014:
New Diagnostic Challenges (cont)
• Experience of using the term CRMS in the US –
Clement L. Ren, Rochester, US
– CRMS occurs in 17% of new infants identified by NBS in the registry
 F508del/R117H is a common genotype
 Misclassification of CRMS in the CF patient registry is common
– CRMS outcomes at 1 year include: normal nutritional indices,
higher-than-expected P aeruginosa positive cultures
– Next steps discussed:
 Educate CF clinicians on CRMS definition
 Obtain more complete data for polyT status for R117H patients,
sweat test results, and faecal elastase
 Obtain longer term CRMS outcome data
 Identify risk factors for CF disease in CRMS infants
(genotype, sweat chloride)
CRMS=CFTR-related metabolic syndrome, defined as sweat chloride concentration 30-59 mmol/L (40-59 mmol/L
if age ≥6 months) and <2 CF-causing mutations; or, sweat chloride concentrations <30 mmol/L (<40 mmol/L if
age ≥6 months) and 2 CFTR mutations of which no more than 1 is known to be CF-causing; sweat chloride confirmed
on ≥2 occasions)1; NBS=newborn screening.
1. Cystic Fibrosis Foundation, Borowitz D, Parad RB, et al. J Pediatr. 2009;155(6 suppl):S106-S116.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 10.
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12 June Thursday, Symposium 10
CF 2014:
New Diagnostic Challenges (cont)
• CF diagnostic guidelines: How to classify intermediate phenotypes? –
Anne Munck, Paris, FR
– Classification of
intermediate phenotypes
is an ongoing process
since the year 2000
– Tool box (clinical
manifestations,
sweat testing,
genotype [CFTR2]
and CFTR bioassays)
with collaboration with
ECFS/US working groups
allowed construction
of algorithms
– Diagnostic algorithms
should not be
considered as dogma
EU=European Union.
1. Reproduced from De Boeck K et al. Thorax. 2006;61(7):627-635 with permission from BMJ Publishing Group Ltd.
2. Reprinted from Mayell SJ et al. J Cyst Fibros. 2009;8(1):71-78 with permission from Elsevier.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 10.
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Screening and Diagnosis
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12 June Thursday, Workshop 11
Screening and Diagnosis
• Age-related cut-off levels for immunoreactive trypsin (IRT)
in healthy newborns in the first 2 months of life –
Toni Torresani, Zurich, CH
– Found a significant decrease of IRT levels in healthy babies during
the first 2 months of life
– When performing NBS for CF using repeated IRT measurements,
the decline of IRT in relation to the age at time of sampling must be
accounted for when interpreting results
– Obtaining a second IRT measure is helpful when sweat testing fails
or is not possible
IRT=immunoreactive trypsin; NBS=newborn screening.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 11.
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12 June Thursday, Workshop 11
Screening and Diagnosis (cont)
• Development of a comprehensive workflow for the analysis of
CFTR gene using next generation sequencing technology –
Iveta Valaskova, Brno, CZ
– Evaluated the multiplex PCR strategy (CFTR MASTER, Multiplicon) to
generate patient’s library followed by pyrosequencing using an NGS
platform (454 GS Junior, Roche) and subsequent bioinformatics analysis
based on the software Sequence Pilot (JSI Medical Systems)
– Common and rare CF mutations and coding SNPs were detected;
3 novel sequence changes were identified
– NGS is changing genetic diagnosis because of its large sequencing
capacity, cost effectiveness, fast and accurate results
CFTR=cystic fibrosis transmembrane conductance regulator; PCR=polymerase chain reaction;
NGS=next generation sequencing; SNP=single nucleotide polymorphism.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 11.
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12 June Thursday, Workshop 11
Screening and Diagnosis (cont)
• Development of a comprehensive workflow for the analysis of
CFTR gene using next generation sequencing technology –
Iveta Valaskova, Brno, CZ (cont)
Reproduced with
permission from
the presenter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 11.
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12 June Thursday, Workshop 11
Screening and Diagnosis (cont)
• Change of algorithm in the CF centres influences the amount of equivocal
CF diagnoses in the newborn screening programme in Switzerland –
Jürg Barben, St. Gallen, CH
– Goal to detect all children with CF but not ECF
 All children with positive screening referred for ST
 Changed algorithm to perform FE before extensive DNA analysis when ST
not possible or inconclusive
 When FE was negative, repeated ST when weight >4000 g
– Algorithms can strongly affect ratio of CF vs ECF cases
• Uptake of cascade testing in CF families: preliminary results from the
experience of western Brittany, France –
Ingrid Duguépéroux, Brest, FR
– Cascade carrier testing enables detection of new 1-in-4 risk couples
– Study aimed to report uptake of carrier testing where CF is frequent
– First reporting of uptake of family testing in Europe
 Preliminary results revealed higher uptake than previously reported in Australia
ECF=equivocal cystic fibrosis; ST=sweat test; FE=faecal elastase.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 11.
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12 June Thursday, Workshop 11
Screening and Diagnosis (cont)
• Newborn screening for CF in Norway –
Emma Lundman, Oslo, NO
– Norway introduced NBS in March 2012 using 3-tier IRT/DNA/DNA
protocol with CFTR mutation included
– Found fewer children with a clear CF genotype than expected
– Suggests reviewing IRT cut-off level; continued reporting of
p.R117H variants; extending 2nd tier mutation panel
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 11.
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12 June Thursday, Workshop 11
Screening and Diagnosis (cont)
• Interpretation of nasal potential difference (nPD) measurements in
difficult cases of possible CF and the role of published equations –
Rishi Pabary, London, UK
– Retrospective analysis of nPD traces from patients difficult to diagnose
 Equations derived that may accurately differentiate CF from non-CF
[Wilschanski (eqW) and Sermet (eqS)]
 Examined agreement between 2 equations and clinician’s interpretation
– Both equations work well in classic CF patients and controls
 There was perfect agreement between all 3 analysis methods for healthy
controls and DF508/DF508
 In difficult CF diagnosis patients, the clinical interpretation of nPD results included:
o Non-CF: n=44 (68.2%)
»
eqS was concordant with clinical interpretation; eqW led to 2 subjects being classified
as CF; neither had an identified CFTR mutation
o Variant/atypical CF: n=9 (13.6%)
»
6 were labelled CF by eqS and 3 with eqW
– Agreement poor between equations in complex patients; in those with
equivocal traces, or in those affected by inflammation
nPD=nasal potential difference.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 11.
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Management of CF
•
•
•
•
•
How to Progress With CFTR Modulators?
Fixing Basic Defects – New Therapies »
New Antibacterial Therapies
»
The Therapeutic Pipeline 2014
»
Airway Controversies »
Table of Contents
»
22
How to Progress With CFTR Modulators?
Table of Contents
23
12 June Thursday, Symposium 1
How to Progress With CFTR Modulators?
Faculty Perspective – Dr. Jacqueline Rendall, UK
“This symposium was an excellent overview of
CFTR modulators highlighting the progress made to date
and the priorities for the future. The speakers were able to
review the science behind modulator therapy and translate
that to the clinic, clearly showing that the way forward
should be individual—specifically based on genetic profile.”
CFTR=cystic fibrosis transmembrane conductance regulator.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 1.
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12 June Thursday, Symposium 1
How to Progress With CFTR Modulators? (cont)
• The way forward in drug testing is mutation-specific –
Katja Conrath, Mechelen, BE
– Feasibility of several strategies to address the cause of CF based on
mutation class
– Optimal combination of treatment for each genetic background may vary
– Room for different modulators (potentiators and correctors) with different
characteristics to be developed for treatment of CF patients
– Need for technologies to assess optimal combinations for each patient
(eg, organoids)—steps for personalised medicine are set
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 1.
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12 June Thursday, Symposium 1
How to Progress With CFTR Modulators? (cont)
• The way forward in drug testing is phenotype-specific –
Isabelle Sermet, Paris, FR
– The phenotypic response, as
assessed by sweat test and FEV1
change, can be mapped onto
CFTR modulation
– Patients carrying G551D mutation or
other gating mutations and treated with
ivacaftor have the highest response
– Patients with mutations with residual
function are also responsive, although
to a lesser degree than G551D
– For the F508del mutation, ivacaftor
alone does not rescue

Association with correctors (VX-809
or VX-661) is more potent on FEV1
(although again to a lesser degree
than effect of ivacaftor on G551D)
– Adjunction of a corrector to ivacaftor in
F508del/G551D compound heterozygotes
further increase efficacy
Reproduced with permission from the presenter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 1.
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12 June Thursday, Symposium 1
How to Progress With CFTR Modulators? (cont)
• Design-based vs high throughput screening –
Luis Galietta, Genoa, IT
– AATs are interesting molecules for possible development of dual-acting compounds
(ie, potentiator and corrector properties)

However, the dual activity may arise from separate mechanisms

FC G is the compound with the best dual activity

Some AATs have potentiator activity only
– Wet screenings may still be useful to find novel pharmacological modulators of mutant CFTR
• Topical vs systemic modulators –
Jane Davies, London, UK
– Topical delivery device and inhalation techniques include nebulizer, dry powder,
and slow-release; systemic modulators include oral therapies
– Benefit of topical vs systemic modulators depends on the drug and patient
– Topical modulators have more benefits if they are safe with few side effects, easy to
take/absorb, have limited DDI, and reach the airways successfully
– Systemic modulators have more benefits if they are easy, likely more consistent in
levels, and have potential for benefits outside the lung
AAT=aminoarylthiazole; DDI=drug-drug interaction.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 1.
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Fixing Basic Defects – New Therapies
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12 June Thursday, Workshop 1
Fixing Basic Defects – New Therapies
• Vardenafil promotes relocalisation of F508del-CFTR in
human and mouse airways –
Barbara Dhooghe, Brussels, BE
– Vardenafil is a clinically-approved cGMP-dependent PDE5i that
normalises defective F508del-CFTR chloride transport across the
nasal mucosa of mice carrying the F508del mutation
– Results indicate that vardenafil in cell cultures of mouse and human
bronchial epithelial cells stimulates the relocalisation of the CFTR
protein towards the apical compartment, suggesting that the cGMP
pathway might be a therapeutic target for CF pharmacotherapy
CFTR=cystic fibrosis transmembrane conductance regulator; cGMP=Cyclic guanosine monophosphate;
PDE5i=phosphodiesterase type 5 inhibitor.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 1.
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12 June Thursday, Workshop 1
Fixing Basic Defects – New Therapies (cont)
• The effect of ivacaftor, a CFTR potentiator, in patients with CF and a
non-G551D-CFTR gating mutation, the KONNECTION study –
Kris De Boeck, Leuven, BE
– Part 1: 8 weeks of ivacaftor treatment significantly
improved lung function (% predicted FEV1),
BMI, sweat chloride, and CFQ-R in patients
with CF and a non-G551D gating mutation
– Part 2: Improvements previously reported were
maintained through 24 weeks with a mean absolute
improvement from baseline in lung function (FEV1)
of 13.5 percentage points (n=18)
– In patients with CF and a non-G551D-CFTR
gating mutation (G178R, G551S, S549N, S549R,
G970R, G1244E, S1251N, S1255P, and G1349D),
treatment with ivacaftor leads to a marked and
sustained improvement in FEV1 (see figure)
– Safety and tolerability results observed through
24 weeks consistent with those during Part 1
Observed (raw) mean changes from baseline
FEV1 are plotted at each time point.
Reproduced with permission from the presenter
and Vertex Pharmaceuticals Incorporated.
CFTR=cystic fibrosis transmembrane conductance regulator; KONNECTION=Study of Ivacaftor in Subjects With Cystic
Fibrosis Who Have a Non-G551D CFTR Gating Mutation; FEV1=forced expiratory volume in 1 second; BMI=body mass
index; CFQ-R=Cystic Fibrosis Questionnaire-Revised; BL=baseline; SE=standard error.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 1.
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12 June Thursday, Workshop 1
Fixing Basic Defects – New Therapies (cont)
• Enhanced correction of F508del CFTR using drug-like small
molecules in combination with correctors and potentiators –
Markus Haeberlein, Cambridge, US
– A high-throughput screen of small molecules that affect the protein
homeostasis network (which improves the folding, trafficking, and
function of F508del CFTR) was conducted in primary human bronchial
epithelial cells
– Series B was found to have robust activity and, when combined with
known correctors and a potentiator, doubled the F508del CFTR
functional rescue of these agents, thereby strengthening drug
discovery efforts to develop additional CF pharmacotherapies
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 1.
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12 June Thursday, Workshop 1
Fixing Basic Defects – New Therapies (cont)
• A rAAV2/5 based gene therapy model for CF airway disease –
Marianne Carlon, Leuven, BE
– Perinatal administration and readministration (at 3 months) of rAAV2/5 using reporter
genes to foetal and neonatal mouse airways resulted in long-term (at 6 months)
gene expression
– Conclusions: Efficient transduction of nasal respiratory epithelium and restoration of
chloride conductance in CF dF/dF mice 1 month after rAAV2/5-CFTRΔR gene therapy
Reproduced with
permission from
the presenter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 1.
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12 June Thursday, Workshop 1
Fixing Basic Defects – New Therapies (cont)
• Restoration of the CFTR function by antisense oligonucleotide splicing modulation –
Batsheva Kerem, Jerusalem, IL
– 10-15% of mutations in
the CFTR gene influence
its correct splicing

Among patients carrying
such mutations, disease
severity varies widely,
correlating with the
quantity of incorrectly
spliced CFTR genes
– Results indicated that
AOs can promote the
correct splicing of the
CFTR gene

However, additional
studies will be needed
to determine whether
AOs can restore CFTR
function and improve
patients’ clinical status
Reproduced with permission from the presenter.
AO=antisense oligonucleotide.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 1.
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12 June Thursday, Workshop 1
Fixing Basic Defects – New Therapies (cont)
• OligoG normalises the CF mucus phenotype –
Anna Ermund, Gothenburg, SE
– OligoG CF-5/20, a natural product derived from alginate and comprised of
mostly guluronate oligomers, was tested on ileum mucus from mice with CF
– Higher OligoG concentrations normalised the mucus phenotype without
increasing mucus thickness, and indicated that OligoG might work by
normalising mucus layers in the gut and the lungs of humans
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 1.
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New Antibacterial Therapies
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12 June Thursday, Workshop 7
New Antibacterial Therapies
Faculty Perspective – Dr. Jacqueline Rendall, UK
“This is an important workshop looking at new antibacterial
therapies in CF. The workshop highlighted real-world data
of multiple centres of inhaled aztreonam lysine, the
most recently licensed inhaled antibiotic in CF.
The benefit of this was outlined in moving forward
with the licencing of the new agents.”
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 7.
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12 June Thursday, Workshop 7
New Antibacterial Therapies (cont)
• Antibacterial activity of RTD-1
against clinical isolates of
Pseudomonas aeruginosa –
Paul Beringer, Los Angeles, US
RTD-1 Bactericidal Activity
– The macrocyclic peptide
RTD-1 exhibits broadspectrum antibacterial and
anti-inflammatory activities
– Results indicate RTD-1 holds
therapeutic promise with its
highly stable, selective, and
potent antibacterial activity
against multidrug-resistant
P aeruginosa isolates from
CF patients
RTD-1 exhibits rapid concentration-dependent
bactericidal activity P. aeruginosa (PAO1, MIC=2 μg/mL).
Reproduced with permission from the presenter.
RTD-1=rhesus theta defensin-1; MIC=minimum inhibitory concentration.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 7.
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12 June Thursday, Workshop 7
New Antibacterial Therapies (cont)
• Once-daily liposomal amikacin for inhalation is noninferior to twice-daily
tobramycin inhalation solution in improving pulmonary function in
CF patients with chronic infection due to Pseudomonas aeruginosa –
Diana Bilton, London, UK
– Patients were randomized to LAI 590 mg via eFlow® nebulizer system or TIS 300 mg via a
PARI LC® PLUS nebulizer (received 3 cycles of treatment) and were stratified by age and
FEV1 percent predicted
– There were no unexpected AEs, and treatment-emergent AEs were consistent with
underlying CF disease
– LAI was noninferior to TIS with respect to the relative change from baseline to
end-of-study FEV1
– Reduction in P aeruginosa sputum density was comparable during all on-treatment periods
– Treatment burden on the CFQ-R improved with LAI. Clinically meaningful improvements on
the CFQ-R respiratory symptoms score were also observed for those on LAI
– These data provide further understanding of a new antibiotic to treat chronic
P aeruginosa lung infection in CF patients
LAI=liposomal amikacin for inhalation; TIS=tobramycin inhalation solution; FEV1=forced expiratory volume in 1 second;
AE=adverse event; CFQ-R=Cystic Fibrosis Questionnaire-Revised.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 7.
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12 June Thursday, Workshop 7
New Antibacterial Therapies (cont)
• Pre-clinical evaluation of novel antibiotic POL7001 against Pseudomonas
aeruginosa in lung infection models –
Alessandra Bragonzi, Milan, IT
– Pre-clinical evaluation of novel antibiotic POL7001 against P aeruginosa in lung infection
models showed superior efficacy compared to ciprofloxacin
Reproduced with
permission from
the presenter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 7.
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12 June Thursday, Workshop 7
New Antibacterial Therapies (cont)
• Inhaled aztreonam lysine (Cayston) therapy significantly improves lung function,
weight, hospitalisations and exacerbation rates prospectively—an Irish and UK
real-world experience –
Barry Plant, Cork, IE
– Developed an online Cayston Treatment Evaluator to assess its effectiveness in routine practice
– Data were extracted for 1 year pre- and 1 year post-inhaled aztreonam lysine treatment
– The median (IQR) FEV1 % predicted deteriorated from pre 6-12 months to pre 0-6 months but
improved from pre 0-6 to post 0-6 months
– In subjects with complete 2-year FEV1 data, the rate of deterioration in median (IQR) FEV1%
predicted across the 2 consecutive 6-month intervals post-Inhaled aztreonam lysine was
substantially lower than pre-treatment
– Median (IQR) body weight deteriorated from pre 6-12 to pre 0-6 months, but increased from
pre 0-6 to post 0-6 months
– Pre rates significantly decreased, with median (IQR) for hospital bed days/year: 19 vs. 5.5,
P=0.001 and for total and home IV antibiotic days per year 55.5 vs. 31.7, P<0.001 and 21.0 vs.
13.5, P<0.001, respectively
– This real-world evaluator showed, in a deteriorating cohort, the introduction of inhaled aztreonam
lysine significantly improved lung function, weight, hospitalisation and exacerbation rates
– This study highlighted the need for additional real-world studies due to the limitations of
translating clinical data into the real world
IQR=interquartile range; PA=Pseudomonas aeruginosa.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 7.
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12 June Thursday, Workshop 7
New Antibacterial Therapies (cont)
• Prolonged improvement in lung function and quality of life in CF:
A 24-week extension study of levofloxacin nebulisation solution
(APT-1026) versus tobramycin nebulisation solution in stable
CF patients with chronic P. aeruginosa infection –
Stuart Elborn, Belfast, UK
– This was a non-randomised, single-arm 24-week extension study to a
randomised, open-label Phase 3 study comparing levofloxacin nebulisation
solution with tobramycin nebulisation solution over three 28-day on/28-day off
cycles in CF patients with chronic PA lung infection
 Patients either continued cyclic treatment with APT-1026 or switched from TNS to
APT-1026 following prior cyclic TNS for 3 additional cycles
– Efficacy endpoints included spirometry and CFQ-R respiratory domain; safety
was assessed at 28-day intervals
– APT-1026 was well tolerated and no new significant AEs were identified during
the extension
– Levofloxacin inhalation solution is safe and effective for long-term management
of chronic lung infection due to PA
PA=Pseudomonas aeruginosa.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 7.
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12 June Thursday, Workshop 7
New Antibacterial Therapies (cont)
• Incorporation of a third inhaled antipseudomonal antibiotic class into the
management of patients at an adult CF care centre –
Donald Vandevanter, Cleveland, US
– There is evidence of increasing incorporation of a third inhaled antipseudomonal antibiotic
class for treating adult patients


Increase in 2 or 3 inhaled antibiotics from 2009 to 2012, with significant increase in 2012
Need for addressing standard of care
2009
2012
Reproduced with
permission from
the presenter.
Proportions of patients from the Cleveland Adult CF center treated with >1 class of inhaled antibiotics
during the year significantly increased from 2009 to 2012 due to introduction of inhaled aztreonam
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 7.
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42
The Therapeutic Pipeline 2014
Table of Contents
43
13 June Friday, Symposium 20
The Therapeutic Pipeline 2014
Faculty Perspective – Dr. Jacqueline Rendall, UK
“The focus of this symposium was on the future of 2014
and beyond in regard to correctors, potentiators, and
what we are doing to further improve current
symptomatic therapies. The work in this
field—particularly in regard to modulators—is
moving fast and far. It’s an exciting time to be
involved in this field.”
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 20.
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44
13 June Friday, Symposium 20
The Therapeutic Pipeline 2014 (cont)
• ECFS-CTN overview –
Isabelle Fajac, Paris, FR
– ECFS-CTN, active since 2008,
provides access to 30 large and
experienced CF centres located in
11 different countries in the EU
– Ongoing/completed studies:
https://www.ecfs.eu/ctn/clinical-trials
Reproduced with permission from the presenter.
Reproduced with permission from the presenter.
ECFS-CTN=ECFS-Clinical Trial Network; EU=European Union.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 20.
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45
13 June Friday, Symposium 20
The Therapeutic Pipeline 2014 (cont)
• Where do we stand with correctors –
Michael Boyle, Baltimore, US
– Different classes of correctors based on CFTR domain target
 Class I stabilises the NBD1-MSD1/2 interface: VX-809, VX-661, C18 (VRT-534), C3
 Class II targets NBD2: C4, Core-corr II
 Class III (chemical chaperones) stabilises the NBD1: Glycerol, Myo-inositol
– Correctors in the pipeline include:




VX-809/VX-770 combination (Phase 3 study)—results expected this summer
VX-661/VX-770 combination (Phase 2 study)
N91115, an oral GSNOR inhibitor (Phase 1 study)—results expected this summer
Organisations developing correctors: Novartis, Pfizer, Galapagos/Abbvie, Reata, Bayer,
Genzyme, Hospital for Sick Children, Cystic Fibrosis Foundation, McGill University
– The future of correctors
 Synergy of CFTR correctors with potentiators
 Studies of ivacaftor in children ages 2-5
 Further study of R117H in combination with poly 5T
CFTR=cystic fibrosis transmembrane conductance regulator; NBD=nucleotide binding domain;
MSD=membrane-spanning domain; GSNOR=S-nitrosoglutathione reductase.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 20.
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46
13 June Friday, Symposium 20
The Therapeutic Pipeline 2014 (cont)
• Broadening the spectrum of potentiators –
Kris De Boeck, Leuven, BE
– Potentiators: What more can we learn?
 Insight in basic CFTR defect
 Reliability of ex vivo prediction of efficacy
 Relative response to potentiators in gut, sweat, lung
o Potentiator-specific
o Mutation-specific
o Person/disease severity-specific
 Long-term impact on disease progression
o FEV1 rate of decline, Pseudomonas acquisition
o Prevention of complications, treatment burden
– Conclusions
 They are proof of concept that ‘small molecule approach’ in CF works
 There is still room for improvement as sweat chloride is not normalised
 Wide applicability in combination trials should help to contain long-term
drug cost
FEV1=forced expiratory volume in 1 second.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 20.
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47
13 June Friday, Symposium 20
The Therapeutic Pipeline 2014 (cont)
• Can we further improve symptomatic therapies –
Patrick Flume, Charleston, US
– Be better at determining best therapeutic regimen for each patient
 Registry data show a high variance in use of therapies
o Some patients are not on therapies that could prove beneficial
 We cannot assume that all patients should be on all recommended therapies
o Are there patients on therapies inappropriately?
 To be better, we must rigorously assess and document effects
(good, bad, or indifferent) as we add (or subtract) a therapy
– Look for ways to improve adherence
 Education alone will be insufficient (not typically an intellectual issue)
 Make therapies become routine
 Create incentives, remove disincentives
o Shorten time for therapy (eg, dry powder)
o Make it easier to do (eg, increase portability)
o Make it more fun (eg, exercise as airway clearance)
– Consider earlier intervention
– Optimise use of inhaled antibiotics
 Identify optimum regimen for suppression of Pseudomonas
 Evaluate whether same strategy will be effective for other pathogens
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 20.
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48
Airway Controversies
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49
13 June Friday, Symposium 19
Airway Controversies
• Upper airway: Surgery is the answer for sinus symptoms in CF - PRO –
Kasper Aanaes, Copenhagen, DK
– Removal of pus and polyps from the frontal sinuses are the main reasons for surgery
 Sinus symptoms have a severe impact on QoL
– Medical therapies (eg, nasal irrigation) are not as effective in CF population
– Surgery is safe in CF and paediatric patients
• Upper airway: Surgery is the answer for sinus symptoms in CF - CON –
Jochen Mainz, Jena, DE
– CFTR defect persists postsurgery, requiring repeated procedures (≥20 in 1 patient
for relapses)
– More radical surgery with resection of sinonasal landmarks can lead to functional
defects
– Perioperative and postoperative colonisation of bacteria may occur in wound area
 Surgery alone does not eradicate Pseudomonas aeruginosa
– By contrast to surgery, favours conservative treatment (nasal lavage; decongestants;
topical and systemic antibiotics; and topical corticosteroids)
QoL=quality of life; CFTR=cystic fibrosis transmembrane conductance regulator.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 19.
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50
13 June Friday, Symposium 19
Airway Controversies (cont)
• Airways should be kept sterile - PRO –
Barry Plant, Cork, IE
– No environment is sterile; issue is in attempting sterility
– Must balance concerns of toxicity and resistance with eradicating bacteria
– Long-term suppressive therapy keeps airway “clean” and avoids intravenous
antibiotic therapy
– Studies reveal that more infectious exacerbations lead to more morbidity
and mortality
– Suppressive therapy with targeted regimens improves survival, but there
are consequences and challenges
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 19.
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51
13 June Friday, Symposium 19
Airway Controversies (cont)
Prevalence of major organisms in lungs
• Airways should be kept sterile - CON –
Scott Bell, Brisbane, AU
–
–
–
–
Sterile – What do we really mean?
Definitions of infection are unclear?
Do we go after everything?
What are the costs of this approach?




Patient months
drug recruitments
Patient engagement
Long-term (downstream costs)
Does Rx beget more Rx?
Longitudinal studies are urgently
required (such as the observational
EPIC study, ARESTcf, ACFBAL, etc)
– Yes “give it a crack” but consider limits,
especially as we are not sure how
sterile, sterile airways should be?
Reprinted with permission from Australian Cystic Fibrosis
Foundation Data Registry 2012. Baulkham Hills, Australia; 2013.
Patient allergy profile
Reproduced with permission
from the presenter.
Reproduced with permission
from the presenter.
EPIC=Longitudinal Assessment of Risk Factors For and Impact of Pseudomonas Aeruginosa Acquisition and Early
Anti-Pseudomonal Treatment in Children With CF; ARESTcf=Australian Respiratory Early Surveillance Team for CF;
ACFBAL=Australasian CF bronchoalveolar lavage study.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 19.
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52
Evaluating the Lung and Intestines
• Indexing the Lung
»
• New Insights in Lung Disease »
• Functional Intestinal Outcome Measures in CF in the Era
of Correctors and Potentiators »
• Multiple Breath Inert Gas Washout (MBW)—An Introduction »
• Utility of MBW in CF and Other Paediatric Respiratory Disorders »
Table of Contents
53
Indexing the Lung
Table of Contents
54
13 June Friday, Workshop 20
Indexing the Lung
Faculty Perspective – Dr. Jacqueline Rendall, UK
“This was an interesting workshop analysing the usefulness
of LCI in assessing the lungs of individuals with CF. It was
concluded that LCI does play an important role—particularly
in measuring more subtle changes in mild and early
lung disease. It continues to be of interest in
paediatrics—especially in preschool age when
there is both limited disease and difficulty in
carrying out spirometry.”
LCI=lung clearance index.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 20.
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55
13 June Friday, Workshop 20
Indexing the Lung (cont)
• Are pre-school lung clearance index (LCI) measurements
a predictor for later structural lung disease? –
Krista Gerbrands, Rotterdam, NL
– This retrospective, cohort trial in preschool-aged CF patients sought to
validate whether LCI is a promising tool to monitor early CF disease
– LCI MBWN2 proved to be a strong indicator of chronic lung changes—far
superior to conventional spirometry outcomes; CT abnormalities do not
necessarily reflect disease in preschool children
– Findings suggested that high LCI (score >3.6) in preschool age predicts
faster progression of trapped air, but not for bronchiectasis
– LCI may be a useful tool for monitoring ivacaftor therapy effectiveness,
especially in those with normal FEV1 measurements
MBW N2=multiple breath washout with N2; CT=computed tomography; FEV1=forced expiratory volume in 1 second.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 20.
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56
13 June Friday, Workshop 20
Indexing the Lung (cont)
• Difference between multiple breath washout with N2 (MBWN2)
vs SF6 (MBWSF6) in 12 months follow up in children with CF –
Anders Lindblad, Gothenburg, SE
– Although MBWSF6 has been utilised for many years at the Gothenburg CF
centre, a switch to MBWN2 is now planned
– In this study, multiple breath washout with both MBWN2 vs MBWSF6
correlated well with FEV1 and with one another
 Median LCIN2 and LCISF6 at start were 9.12 and 8.12, respectively (p<0.001)
but correlated well
 Both methods correlated similarly well with FEV1
 At follow-up, only LCIF6 had increased significantly (8.45, p=0.008)
– Magnitude of the difference in change LCIN2 and LCISF6 over 1 year may
be due to the starting LCI level
MBWSF6=multiple breath washout with sulphur hexafluoride; LCIN2= lung clearance index with nitrogen;
LCISF6=lung clearance index with sulphur hexafluoride.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 20.
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13 June Friday, Workshop 20
Indexing the Lung (cont)
• Lung clearance index and Aspergillus colonisation are clinical
markers of chronic lung changes by spirometry controlled CT in
children with CF –
Thomas Kongstad, Copenhagen, DK
– CT is a highly sensitive tool for detecting chronic lung changes, and spirometry
during the procedure standardises breathing and improves image accuracy
– Using spirometry-controlled CT, researchers identified a closer correlation
between LCI and CFCT score than previously recorded
– The clinical parameter with the strongest correlation to CFCT score was LCI
derived from MBW
 Multiple regression analysis adjusted for LCI showed that Aspergillus colonization
was a significant predictor of chronic lung changes, using percentage positive
growth the previous year and Aspergillus IgG levels as variables for analysis
(p=0.038 and p=0.003, respectively)
– These findings may have application to managing both intermittent and chronic
Aspergillus colonisation
CFCT=cystic fibrosis computed tomography.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 20.
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58
13 June Friday, Workshop 20
Indexing the Lung (cont)
• Is lung clearance index (LCI) affected by the severity of lung disease in CF? –
Elpida Hatziagorou, Thessaloniki, GR
– Data from this trial
involving children and
adolescents with CF
suggested that LCI is
a very useful tool for
detecting lung disease
early in the disease
course, and that LCI5
and FEV1 are more
useful tools for the
detection of lung
disease when the
disease is moderate
Reproduced with permission from the presenter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 20.
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59
13 June Friday, Workshop 20
Indexing the Lung (cont)
• The use of LCI as an effective tool for monitoring clinical response
to ivacaftor therapy in CF patients with at least one G551D-allele –
Laura Jenkins, Belfast, UK
– In this study, mean LCI improved in adults and children subsequent to
1 month on ivacaftor treatment and was sustained in children at 6 months
 Mean baseline LCI: adults 11.15; children 9.07
 Mean LCI after 1 month of treatment: adults 10.93; children 7.68
 Mean LCI after 6 months of treatment: children 7.8
– Drop in LCI correlated with increase in FEV1: Many of the children had normal
or near normal % predicted FEV1 with a mean FEV1 of 84.1% at baseline,
101.5% at 1 month, and 96.3% at 6 months
– A significant reduction in IV treatment days in both children and adults followed
the introduction of ivacaftor compared with the previous year
– Results suggested that LCI may be a useful tool for monitoring ivacaftor
effectiveness, particularly in those with normal FEV1
IV=intravenous.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 20.
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60
New Insights in Lung Disease
Table of Contents
61
13 June Friday, Workshop 13
New Insights in Lung Disease
• Patients with mutations that permit 3% or more of wild-type
CFTR function are associated with higher FEV1 –
Patrick Sosnay, Baltimore, US
– Clinical and genetic data collected on 39,696 patients
– Patients with 2 mutations each having <1% wild-type CFTR function
(includes F508del and PTC mutations) and patients with at least one
mutation of ≥3% CFTR function have a significant difference in FEV1
– Patients with ≥3% CFTR function had a clinically relevant difference
in FEV1 along with decreased sweat chloride concentrations and rates
of pancreatic insufficiency (which decreased linearly)
– Milder mutations are associated with older patients
CFTR=cystic fibrosis transmembrane conductance regulator; FEV1=forced expiratory volume in 1 second;
PTC=premature termination codon.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 13.
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62
13 June Friday, Workshop 13
New Insights in Lung Disease (cont)
• Change in FEV1 % predicted in one year in patients with
nonsense mutations and patients homozygous for F508del –
Kris De Boeck, Leuven, BE
– Used ECFS registry data to evaluate change in FEV1 in 1 year in subjects
≥6 years (without lung transplant) and baseline lung function between
40% and 90% predicted
– Compared change in FEV1 in subjects with ≥1 nonsense mutation and
in subjects homozygous for F508del
– There is no evidence for a worse course of lung function in subjects
with nonsense mutations compared with F508del homozygous or
Class 3 mutations
– There is high variability in FEV1 from year to year
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 13.
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63
13 June Friday, Workshop 13
New Insights in Lung Disease (cont)
• Magnetic resonance imaging
detects changes in structure
and perfusion, and response to
therapy in early CF lung disease –
Mark Wielpuetz, Heidelberg, DE
– Evaluated potential of MRI to detect
abnormal lung structure and perfusion
in 50 infants and young children with
CF; monitored therapeutic response
to exacerbations
– MRI is sensitive to detect early CF
lung disease, including morphologic
and perfusion abnormalities and is
non-invasive
 May depict potentially reversible
abnormalities, exacerbations,
and therapeutic response
Top row: MRI of acute exacerbation in early CF of a
6-year-old patient, which revealed extensive contrastenhancing airway wall thickening, and mucus plugging with
high signal intensity on T2-weighted sequences of upper and
lower lung lobes. Consolidations were present in both upper
lobes. Wedge-shaped perfusion abnormalities can be
identified on the subtracted perfusion map
Bottom row: Repeat study 1 month after IV antibiotic
therapy. Airway wall thickening and enhancement, mucus
plugging, and consolidations were substantially reduced.
Most perfusion defects resolved and a more homogeneous
perfusion was restored
MRI=magnetic resonance imaging; IV=intravenous.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 13.
Reprinted with permission of the American Thoracic Society. Copyright © 2014 American Thoracic Society.
Wielpütz MO et al. Am J Respir Crit Care Med. 2014;189(8):956-965. Official Journal of the American Thoracic Society.
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64
13 June Friday, Workshop 13
New Insights in Lung Disease (cont)
• Small-airway disease in CF studied with multidetector CT and
microCT –
Barbara Bosch, Leuven, BE
– CF lungs had significantly more visible airways on MDCT than controls
(mean total 606 vs 316, p=0.02)
– Found dilatation and obstruction of airways from generation 5-6 onwards;
(75% of total airways or approximately 40% of airways per generation were
obstructed) as well as narrowing and disappearance of terminal bronchioles
 microCT showed a significant reduction in the number (2.9 vs 5.6/mL; p<0.001),
diameter (212 vs 363 µm; p<0.001) and cross-sectional area of terminal
bronchioles (92 vs 177 µm2; p<0.001) in CF versus control
MDCT=multidetector computed tomography.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 13.
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65
13 June Friday, Workshop 13
New Insights in Lung Disease (cont)
• Visualising ventilation heterogeneity in mild CF using hyperpolarised
3He MRI, and comparison with lung clearance index (LCI) –
Alexander Horsley, Manchester, UK
– Investigated and
compared sensitivity
of 3He MRI and LCI
to detect ventilation
changes in children
with mild CF (n=11)
– Preliminary results
suggest helium MRI
more sensitive to early
ventilation changes
than LCI or conventional
lung function tests

Show a range of
ventilation defect
patterns (typically
diffuse and patchy
heterogeneity)
Reproduced with permission from the presenter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 13.
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66
13 June Friday, Workshop 13
New Insights in Lung Disease (cont)
• Structural alterations in the end-stage CF lung:
Comparing histopathology to microCT –
Elise Lammertyn, Leuven, BE
– Compared structural alterations of airways,
blood vessels, and parenchyma in end-stage CF
using histology matched with microCT (allows
3D morphometry of terminal bronchioles)
– End-stage CF lung disease characterised
by remodelling of small airways and
reorganisation of end-terminal airways
– Panel A shows a mucus-filled bronchiectatic
small airway (red arrow) with thickened wall.
The blue arrow marks the accompanying
blood vessel
– More distally, the airway lumen progressively
narrows (Panel B), until it is no longer
Reproduced with permission from the presenter.
discernible and is replaced by scar tissue (Panel C)
– This entity reorganises into an airway more downstream (red arrow in Panel D)
– After branching (Panel E), one side branch (green arrow) stays obstructed whereas
the other opens up again in an airway with normal appearance (red arrow in Panel F)
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 13.
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67
Functional Intestinal Outcome
Measures in CF in the Era of
Correctors and Potentiators
Table of Contents
68
Functional Intestinal Outcome
Measures in CF in the Era of
Correctors and Potentiators
14 June Saturday, Symposium 28
• Intestine-derived organoids: Tools to predict the restoration of the
intestinal CFTR function? –
Jeffrey Beekman, Utrecht, NL
– May be able to predict individual treatment of CFTR-targeted therapy using organoids from
rectal biopsies of CF patients
– Two new assays have demonstrated efficacy in detecting CFTR function in organoids: FIS and SLS


FIS able to discriminate between mild and severe CF phenotypes
SLS can discriminate between WT and mild CF
– Using FIS, potential drug response rates with potentiator and corrector have been investigated


F508del homozygous and F508del/A455E mutations showed good response to VX-809/VX-770,
while F508del/S1251N and F508del/G1249R demonstrated good response to VX-770
R117H, A455E were in the green area, but N1303K had no response and behaved as a nonsense mutation
– Using these assays, it may be possible to classify CFTR mutations for drug responsiveness, and
samples can serve as biobanks for testing several agents
• Gastrointestinal outcome measures for clinical CF trials:
Opportunities and challenges –
Frank Bodewes, Groningen, NL
– Select GI parameters via intestinal current measurements are important markers for CFTR function

Fat (mal)absorption (based on tricyclic absorption) and bile acid synthesis/loss
CFTR=cystic fibrosis transmembrane conductance regulator; FIS=forskolin induced swelling; SLS=steady-state lumen;
WT=wild-type; VX=Vertex; GI=gastrointestinal.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 28.
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69
Functional Intestinal Outcome
Measures in CF in the Era of
Correctors and Potentiators (cont)
14 June Saturday, Symposium 28
• Video endoscopy for the assessment of intestinal CFTR function –
Michael Wilschanski, Jerusalem, IL
– Via use of a “pill cam,” bowel pathology is readily identified (including tumour, oedema,
petechiae, denudation of folds, mucous overproduction and other non-CF-related pathology)
– Discussed a possible mechanism for communication between the gut and airway,
and how they may not be as isolated from one another as previously thought

A number of factors could impact this communication (environment, nutrient injection,
among others)
• Smart pills for intestinal CF: Treatment effects and future possibilities –
Drucy Borowitz, Buffalo, US
– HCO3 in the GI tract important in relation to: neutralisation of acids, as a driver for
fluid secretion, its ability to unfold/hydrate mucin, and promotion of bacterial killing
– CF patients often have delayed normalisation of gastric acid
– “pH pill” is a modality that checks pH, temperature, and pressure within GI tract

GOAL study used this type of device and reported that gastric acid normalised with ivacaftor use
– For future use, modification can be made to allow for expanded use of metrics and indications
to assess CF activity
HCO3=bicarbonate; GOAL=G551D Observational Study-Expanded to Additional Genotypes and Extended
for Long Term Follow up.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 28.
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70
Multiple Breath Inert Gas
Washout (MBW)—An Introduction
Table of Contents
71
Meet the Experts—P Gustafsson
Multiple Breath Inert
Gas Washout (MBW)—An Introduction
• Early diagnosis of inflammation and structural abnormalities of small
airways important in progressive diseases such as CF
– Leads to improved management and assessment of novel therapies
• Small airways may be a “silent zone” for spirometry
• Inert gas washout tests (MBW and SBW) measure ventilation distribution
efficiency and is feasible in all age groups
– MBW useful for infants and toddlers (does not require active engagement)
– Is an open circuit (minimal rebreathing) test measuring clearance rate of an
inert marker gas (nitrogen)
• New analytical approach=normalised slope (SnIII) analysis
– “Typical fingerprints of different diseases”
– Offers mechanistic insight and potential for airway remodelling
• International guidelines for MBW have been published
MBW=multiple breath washout; SBW=single breath washout.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Meet the Experts.
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72
Utility of MBW in CF and Other
Paediatric Respiratory Disorders
Table of Contents
73
Meet the Experts—P Gustafsson
Utility of MBW in CF and Other
Paediatric Respiratory Disorders
• LCI is a measure of abnormal ventilation distribution derived from MBW
• LCI correlates with school-age LCI and predicts abnormalities in
school-age FEV1
• MBW may be a suitable tool to assess early intervention strategies
(eg, hypertonic saline; dornase alpha) and pulmonary exacerbations in CF
• MBW may be used clinically to demonstrate early CF lung disease when
spirometry is normal
• May also be useful in non-CF bronchiectasis and obliterative bronchiolitis;
usefulness in asthma, in identifying pulmonary issues in premature babies,
and in bronchopulmonary dysplasia less clear
LCI=lung clearance index; MBW=multiple breath washout; FEV1=forced expiratory volume in 1 second.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Meet the Experts.
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74
Standards of Care
and Clinical Practice Guidelines
• The New ECFS Standards of Care
»
• ECFS Clinical Practice Guideline: Exercise Testing in CF »
Table of Contents
75
The New ECFS Standards of Care
Table of Contents
76
13 June Friday, Symposium 13
The New ECFS Standards of Care
Faculty Perspective – Dr. Jacqueline Rendall, UK
“This important project was reviewed in detail.
It is relevant to all CF centres—paediatric and
adult—and will be the framework on which centres will be
built or developed. It provides up-to-date standards
upon which services can be reviewed and
negotiations with funders around required
resources can be focussed.”
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 13.
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13 June Friday, Symposium 13
The New ECFS Standards of Care (cont)
• The new ECFS standards of care:
Why and how –
Carlo Castellani, Verona, IT
– Why? Much has changed since the last
guidelines published in 2005

More newborn screening (including 2
national programmes in Austria and France)

More patients are living to age 40;
treatment focus is shifting

Preconception counselling now offered

Mutation-specific therapeutic approach
now possible

CF centres have established a clinical
trial network
– How? Special project group established
to review original guidelines

Will focus on centre framework;
best practice; quality improvement

Published report in 2014 supplement
to the Journal of Cystic Fibrosis
We strongly believe that all
European nations should strive
to achieve a model of CF care in
accordance with the ECFS
recommendations.
Standards of Care for CF
Ten Years Later JCF 2014
Optimal care may not be an easily
achievable target and in some less
advantaged countries, a stepwise
approach may be the only deliverable
approach. However, the present
standards should remain as a goal.
Standards of Care for CF
Ten Years Later JCF 2014
Reproduced with permission from the presenter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 13.
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13 June Friday, Symposium 13
The New ECFS Standards of Care (cont)
• The new ECFS standards of care: Centre framework –
Steven Conway, Leeds, UK
– Provides a framework for organisation of the CF Centre to meet medical and
psychosocial challenges
– Delineates centre structure, staff, roles, facilities, hardware/software, including how
these may be adapted to the heterogeneous care organisations in Europe

Regions should adapt; not compromise
– Emphasises need for adequate resources and patients (≥100) to meet standards



Expert-led, multidisciplinary team, but each discipline should establish its own rigorous framework
Collaboration between paediatric and adult services necessary to assure effective transition
Provide direct access 24 hours per day
• The new ECFS standards of care: Best practice –
Alan Smyth, Nottingham, UK
– Main chapters concern:







Neonatal screening and access to specialist care from early life
Diagnosis
Prevention of lung disease progression by access to effective therapies
Optimal nutrition and management of metabolic complications
Treatment of other complications in a timely and effective way
Lung transplantation and appropriate management of end-of-life issues
Psychosocial support
– See figure on next slide
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 13.
Table of Contents
79
13 June Friday, Symposium 13
The New ECFS Standards of Care (cont)
• The new ECFS standards of care: Best practice –
Alan Smyth, Nottingham, UK (cont)
Evolution of Standards of Care for CF 2005 to 2014
Journal of Cystic Fibrosis 4 (2005) 7-26
2005
Standards of care for patients with cystic fibrosis: a European consensus
Eitan Kerem, Steven Conway, Stuart Elborn, Harry Heijerman
For the Consensus Committee
Department of Pediatrics and CF center, Mount Scopus, Jerusalem 91240, Israel
Journal of Cystic Fibrosis 13 (2014) S3-S22
Journal of Cystic Fibrosis 13 (2014) S43-S59
Review
European Cystic Fibrosis Society Standards of Care: Framework
for the Cystic Fibrosis Centre
Review
European Cystic Fibrosis Society Standards of Care:
Quality Management in cystic fibrosis
Steven Conway, Ian M. Balfour-Lynn, Karleen De Rijcke, Pavel Drevinek,
Juliet Foweraker, Trudy Havermans, Harry Jeijerman, Louise Lannefors, Anders Lindblad,
Milan Macek, Sue Madge, Maeve Moran, Lisa Morrison, Alison Morton,
Jacquelien Noordhoek, Dorota Sands, Anneke Vertommen, Dnaiel Packham
Martin Stern, Dominique Pougheon Bertrand, Elisabetta Bignamini, Mary Corey
Birgit Dembski, Christopher H. Goss, Tunja Pressler, Gilles Rault, Laura Viviani,
J. Stuart Elborn, Carlo Castellani
Journal of Cystic Fibrosis 13 (2014) S23-S42
Review
European Cystic Fibrosis Society Standards of Care: Best
Practice guidelines
Alan R. Smyth, Scott C. Bell, Snezana Bojcin, Mandy Bryon, Alistair Duff
Patrick Flume, Nataliya Kashirskaya, Anne Munck, Felix Ratjen
Sarah Jane Schwarzenberg, Isabelle Sermet-Gaudelus, Kevin W. Southern
Giovanni Taccetti, Gerald Ullrich, Sue Wolfe
Reproduced with
permission from
the presenter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 13.
Table of Contents
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13 June Friday, Symposium 13
The New ECFS Standards of Care (cont)
• The new ECFS standards of care: Quality improvement –
Martin Stern, Tübingen, DE
– Suggests quality control strategies and explores potential for peer
review and accreditation procedures (eg, with ECFS Registry)
 QI may be implemented on all tiers, including at the patient, centre,
regional, national, and international levels
– Must consider the heterogeneous structures and services available
in Europe that may not make optimal care immediately feasible in
some regions
 Gradual steps for improvement suggested for less advantaged areas
QI=quality improvement.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 13.
Table of Contents
81
ECFS Clinical Practice Guideline:
Exercise Testing in CF
Table of Contents
82
CFTR Educational Suite Expert Session
–H. Hebestreit
ECFS Clinical Practice Guideline:
Exercise Testing in CF
• Exercise tolerance and physical fitness are important data for disease management
• The ECFS and NACFC collaborated to provide expert consensus guidelines for
exercise testing (endorsed by ECFS March 2014)
• Indications for exercise testing include assessing exercise capacity; understanding
limitations to exercise; obtaining prognostic information; screening for exercise-related
adverse reactions; and reducing anxiety/increase motivation towards exercise
• Guidelines specify the preferred test and provide details for specific exercise tests
and measurements
• Addresses:
–
–
–
–
Who should be tested and when
Which test protocol should be used
Which measures should be taken
How to interpret results
• Standardised testing may allow exercise capacity to be introduced as an outcome in
patient registries
NACFC=North American Cystic Fibrosis Conference.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
CFTR Educational Suite Expert Session.
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83
Clinical Care Considerations
•
•
•
•
Adherence »
FEV1 and Nutritional Status: Chicken or the Egg? »
Nutritional Challenges in Adults »
Multidisciplinary Aspects of CFRD »
Table of Contents
84
Adherence
Table of Contents
85
12 June Thursday, Workshop 10
Adherence
• Can home drug audit prevent oversupply and indicate adherence? –
Caroline Whitton, Plymouth, UK
– Data from this study suggested home drug audits that identify oversupply and wastage
and assess adherence with high-cost nebulised drugs offer no cost savings, but may identify
patients who are nonadherent due to low drug supplies
• Adherence to study drugs in clinical trials –
Thea Pugatsch, Jerusalem, IL
– Results indicated that CF patients are generally more adherent with drug protocols when
enrolled in a clinical trial
– Factors that negatively affected adherence in clinical trials were: self-preparation of drug,
timing according to holidays and vacations, and length of study. These should be considered
when planning a clinical trial to optimise adherence
• Adherence with ivacaftor in CF patients with the G551D mutation –
Jade Fox, Liverpool, UK
– Results suggested that 20% of eligible CF patients do not take ivacaftor routinely
– Nonadherent CF patients had poorer baseline health indicators and chaotic lifestyles,
which impacted their CF management
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 10.
Table of Contents
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12 June Thursday, Workshop 10
Adherence (cont)
• Pharmacist intervention to influence beliefs about medication in an adult CF clinic –
Patrick Wilson, Leicester, UK
– In this study, CF patients prescribed inhaled antibiotic therapy completed the CF Quality of Life
and Beliefs about Medicines questionnaires and engaged in a discussion with the pharmacist
about their treatment and barriers to adherence
– Pharmacist intervention improved scores on the Beliefs about Medicines questionnaire, a finding
that has been associated with higher adherence in other disease states
– CF patients have a greater appreciation of their need for pharmacotherapy; they also have
less concern regarding harm from their pharmacotherapy treatments compared with patients
with other chronic diseases
• Objective predictors of self-report of adherence in adults with CF –
Daniel Peckham, Leeds, UK
– This study, involving completion of a CF self-report of adherence (CFQ-R), revealed that
3 objective factors account for 20% of adherence aetiology
– Odds of achieving greater adherence increased as age increased, as CoV FEV1 decreased,
and as additional medication was added to the treatment regimen
CFQ-R= Cystic Fibrosis Questionnaire-Revised; CoV=coefficient of variation; FEV1=forced expiratory volume in 1 second.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 10.
Table of Contents
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12 June Thursday, Workshop 10
Adherence (cont)
• Objective predictors of self-report of adherence in adults with CF –
Daniel Peckham, Leeds, UK (cont)
– Self-reported adherence and CoV FEV1 were inversely related (r=-0.16, p<0.001),
suggesting that less variation is apparent as adherence improves
Reproduced with
permission from
the presenter.
CRP=C-reactive protein; PERT=pancreatic enzyme replacement therapy.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 10.
Table of Contents
88
12 June Thursday, Workshop 10
Adherence (cont)
• Social support, self-esteem and treatment barriers in adolescents
with CF: The LINFA study –
Carla Colombo, Milan, IT
– Results suggested a relationship between CF patients’ self-esteem and family
support, psychological well-being, treatment issues, and adherence barriers
– Shared decision making and open family communication were associated
with greater support from family and self-esteem in CF patients
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 10.
Table of Contents
89
FEV1 and Nutritional Status:
Chicken or the Egg?
Table of Contents
90
12 June Thursday, Symposium 6
FEV1 and Nutritional Status:
Chicken or the Egg?
• Nutritional status: Should we aim for the 50th percentile? PRO –
Marci Sontag, Aurora, US
– Children with WFA percentiles <10th percentile at age 6 have poorer lung function than
children with WFA at 50th percentile at age 3 (who demonstrate FEV1=100% at age 6)
– At 50th percentile, FEV1 >90% predicted
recommendation to maintain BMI
at ≥50th percentile
– >50th percentile also associated with increased survival
– BMI may not be best measurement because children may not have met their height
potential; need to look at other measures of nutritional status
• Nutritional status: Should we aim for the 50th percentile? CON –
Willie Woestenenk, Utrecht, NL
– Children with CF may be misclassified based on standard growth charts

Z-scores may underestimate height delay
– Children with CF may have bone maturation delay of ~1 year in bone age
– Children with height growth <5th percentile (age 5-7) 6 times more likely to die
– Nutritional status assessments must be tailored to the individual patient,
and may fall below or above 50th percentile
WFA=weight for age; FEV1=forced expiratory volume in 1 second; BMI=body mass index.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 6.
Table of Contents
91
12 June Thursday, Symposium 6
FEV1 and Nutritional Status:
Chicken or the Egg? (cont)
• Longitudinal data on FEV1 –
Laura Viviani, Milan, IT
– Studied 795 patients over 30 years (1982-2012) for association between
malnutrition (height, weight, BMI) and lung function (FEV1 SDS)
– Mean FEV1 SDS loss 14% over 8 years (loss of -1.1 FEV1 SDS per year);
BMI stayed stable
– Patients diagnosed in more recent years have better FEV1 SDS than
patients diagnosed before the 1990s; no gender differences
• Influence of early stage CFRD on lung function and nutritional status –
Renske van der Meer, The Hague, NL
– Decline in lung function is proportional to degree of glucose intolerance
– Early detection and treatment may prevent lung disease progression
– Effect on lung function may also be from anti-inflammatory effects
of insulin
SDS=standard deviation score; CFRD=cystic fibrosis-related diabetes.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 6.
Table of Contents
92
Nutritional Challenges in Adults
Table of Contents
93
12 June Thursday, Symposium 12
Nutritional Challenges in Adults
• Prevention and treatment of obesity in CF: Is it time to revise our guidelines? –
Susannah King, Melbourne, AU
– Median BMI increasing in CF population by 1 BMI unit per year through major focus on nutrition

Need to focus on obese as well as malnourished CF patients

5% are obese; metabolic syndrome is more common; may have sleep apnoea;
may be excluded from lung transplant (BMI >29)
– BMIs >25 do not confer benefit in patients (eg, no increase in FEV1)
– Must achieve negative energy balance and focus on decreasing fat mass in overweight
CF patients via interdisciplinary approach
• Pregnancy outcomes for the mother and child: The nutritional challenges
faced in CF –
Christine Etherington, Leeds, UK
– Pre-pregnancy FEV1 determines survival of mother, as does nutritional status (BMI)
and presence of diabetes
– Pre-pregnancy planning and prenatal care to assure optimal BMI important to maternal
survival and foetal outcomes

Better weight gain through maximising fat intake, oral supplements, and enteral tube
feeding (as needed) will improve likelihood of healthy mothers and babies
– In general, outcomes for babies are better than those for mothers
BMI=body mass index; FEV1=forced expiratory volume in 1 second.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 12.
Table of Contents
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12 June Thursday, Symposium 12
Nutritional Challenges in Adults (cont)
• Nutritional challenges pre- and post-transplantation –
Francis Hollander, Utrecht, NL
– Nutritional status important predictor of survival post-transplant
 Low BMI (FFMI) appears to impair survival
– Management plan should include enteral tube feeding, good glucose control via
insulin pump, and improved physical fitness/muscle mass via physiotherapy
– Mortality higher if CF lung transplant patients have diabetes (44% vs 6%);
however, 80% of patients develop diabetes (possibly due to post-transplant
immunosuppressive therapies)
FFMI=fat-free mass index.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 12.
Table of Contents
95
12 June Thursday, Symposium 12
Nutritional Challenges in Adults (cont)
• Post ivacaftor –
Drucy Borowitz, Buffalo, US
– Pivotal trial demonstrated significant weight gain (mean 2.7 kg; p<0.001) for treatment
population

Various MOAs may be responsible, including increased GI bicarbonate leading to improved fat
digestion and absorption; increased fluid flow through the GI tract; increased appetite; reduced
bacterial overgrowth, and respiratory tract effects including more efficient use of ATP; decreased sinus
mucus and airway obstruction
– Clinicians should not alter nutritional counselling for the patient on ivacaftor because:


Needs to be taken with a fatty meal
Weight gain stabilises over time (after 16 weeks)
Small bowel
pH changes
(mean pH
readings
every minute)
pH
pH
Gastric acid neutralisation is normalised in subjects with CF taking ivacaftor
Small bowel pH changes (1min means)
Small bowel pH changes (1min means)
Pre VX-770
Post
Pre VX-770
Post VX-770
8
8
7
7
6
6
5
5
4
4
3
03
00
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120
0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120
p< 0.05
p< 0.05
8
8
24
24
gastric emtpying
MinutesMinutes
fromfromgastric
emptying
Minutes from gastric emtpying
Adapted with permission of the American
Thoracic Society. Copyright © 2014
American Thoracic Society. Rowe SM et al. Am J Respir Crit Care Med.
2014;190(2):175-184. Official Journal of the American Thoracic Society.
Adapted from Gelfond D et al. Dig Dis Sci.
2013;58(8):2275-2281. With kind permission of
Springer Science+Business Media.
MOA=mechanism of action; GI=gastrointestinal; ATP=adenosine triphosphate.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 12.
Table of Contents
96
Multidisciplinary Aspects of CFRD
Table of Contents
97
13 June Friday, Symposium 16
Multidisciplinary Aspects of CFRD
• Insulin and the lung –
Nicola Bridges, London, UK
– There is no clear cut-off (OGTT, CGMS, HbA1c) when to start treatment

Data from the UK CF registry showed a 3-fold increased mortality risk in CFRD patients with HbA1c levels >6.5%
(the clinical defined target for HbA1c ), suggesting that the treatment target remains unclear in this population
– Team approach from CF team and patient is pivotal
– Three main problems of CFRD: (i) low anabolic effect of insulin;
(ii) glucose level in the lung; (iii) microvascular complications
– Insulin deficiency correlates with lower lung function and lower
survival rate in CF patients
– Decline in lung function and BMI precedes the CFRD for 12 months
– OGTT after 2 h can be normal, but in between very high levels
reached; therefore, samples at 30, 60, and 90 minutes are necessary
– After starting treatment with insulin, lung function and BMI both increase

Presenter recommended once daily long-acting insulin starting with a
low dose and titrating upward
– Summary





“We know that insulin
deficiency in CF has an
adverse effect on lung
function and clinical status,
and that treatment with
insulin results in improved
clinical status.
Conventional definitions of
the diagnosis of diabetes are
unhelpful because there is
evidence of benefit for
individuals who do not meet
the criteria for a diagnosis of
diabetes.”
–Nicola Bridges
Insulin deficiency in CF has an adverse effect on clinical status and survival
Insulin treatment improves clinical status
Conventional definitions for diabetes are unhelpful; there is an adverse effect
for glucose levels which do not meet the criteria for diabetes
Glycaemic targets for treatment are unclear
Very long-term benefits of screening and early treatment have not been demonstrated
OGTT=oral glucose tolerance test; CGMS=continuous glucose monitoring system; HbA1c=hemoglobin A1c; CFRD=cystic
fibrosis-related diabetes; BMI=body mass index.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 16.
Table of Contents
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13 June Friday, Symposium 16
Multidisciplinary Aspects of CFRD (cont)
• Endocrine pancreas function at birth: Lessons from the ferret –
John Engelhardt, Iowa City, US
– Three main hypotheses for development of CFRD:



Endocrine cells are destroyed after the exocrine cells
CFTR primary function in the pancreas is altered
Possible CFTR effects outside the islet cells
– Prior to major exocrine pancreas disease, newborn
CF ferret kits demonstrated significantly abnormal
insulin regulation and glucose tolerance
– Insulin defects included impaired first phase insulin
secretion, delayed insulin peak in response to
glucose and/or L-arginine, and widely variant and
elevated insulin (Panel A) and C-peptide levels in
the non-fasted state (Panel B)
Reproduced with permission from the presenter. Panel C adapted
– Under non-fasted conditions, a positive relationship
with permission of American Society for Clinical Investigation.
Olivier AK et al. J Clin Invest. 2012;122(10):3755-3768.
between blood glucose and insulin levels is expected
– Indeed, blood glucose and insulin levels were positively correlated in nursing non-CF kits
– However, blood glucose and insulin levels were negatively correlated in nursing CF kits,
suggestive of poorly regulated insulin (Panel C)
– Currently no available ferret/pig models to check the effects of ivacaftor on insulin secretion
CFTR=cystic fibrosis transmembrane conductance regulator.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 16.
Table of Contents
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13 June Friday, Symposium 16
Multidisciplinary Aspects of CFRD (cont)
• Nutritional approach to the different stages of CFRD –
Hila Elyashar-Earon, Jerusalem, IL
– Annual OGTT is recommended
– Optimal basal insulin therapy can lead to an increase in lung function
and weight score (Hameed, Arch Dis Child, 2012)
– ISPAD recommendation: screen for microvascular complications
– Educate patients regarding the effect of carbohydrates on blood glucose
levels and about the importance of daily glucose level checks
• Coping with CFRD diagnosis –
Maya Kirszenbaum, Paris, FR
– Trauma, grief, and coping are steps the patient and the CF clinic team
have to address
– CF patients see 2 distinct diseases harming their lives: CF and diabetes
– Perfect adherence should not be assumed
ISPAD=International Society for Pediatric and Adolescent Diabetes.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 16.
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100
Case Studies in CF
• Psychosocial/Nursing Complex Case Presentations »
• Interactive Case Studies »
Table of Contents
101
Psychosocial/Nursing
Complex Case Presentations
Table of Contents
102
13 June Friday, Workshop 22
Psychosocial/Nursing
Complex Case Presentations
• Seeing through the Kalydeco: When a potentially life-saving treatment
fails to bring focus –
Beverly Govin, Liverpool, UK
– 23-year-old male diagnosed with CF at age 12 after being misdiagnosed with asthma

Complicated social history (spent time in foster care and in juvenile justice system for drugs and
petty crime)

Parents not supportive; brother has tried to help to no avail; girlfriend is pregnant
– “Chaotic” CF care:

Rarely attends outpatient clinic visits or comes late; nonadherent to treatment

As a result, requires 5-7 emergency hospital admissions per year
o
When hospitalised, is “rude”; does not cooperate with staff or therapies

FEV1 ranges from 23%-40%; occasionally 50%

Identified as a candidate for ivacaftor, but required to attend clinic every 2 weeks to receive medication;
inconsistently keeps appointments or takes medication, resulting in continued poor clinical condition
– Discussion:

Was it realistic to expect this patient to attend clinic every 2 weeks?
o

The staff wanted to compel the patient to be physically present
Should the clinic refuse to continue treating a patient who is rude and aggressive?
o
Must balance patient and staff safety/cohesiveness with acquiescing to patient’s goal
of being discharged from care—potentially without follow-up elsewhere
FEV1=forced expiratory volume in 1 second.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 22.
Table of Contents
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13 June Friday, Workshop 22
Psychosocial/Nursing
Complex Case Presentations (cont)
• Psychological care of a teenager with CF undergoing a double
lung transplantation and 10 years later a re-transplantation –
Trudy Havermans, Leuven, BE
– Followed by psychologist between
ages 18 and 32 years
– Supportive parents; sister died of
CF complications at age 16
– Medical history:
 Underwent double lung transplantation
Reproduced with permission from the presenter.
at age 18; acute rejection at age 29,
requiring re-transplantation (FEV1
dropped from 100% to 20%)
 Developed renal insufficiency at age 30, requiring critical care; nearly died
– Psychosocial issues:
 At age 18, expressed that she wanted to “die and be with her sister”
 After first transplant surgery was “happy” to be home but “scared” about
transitioning to adult life (school, work, friends, romantic relationships were all
issues she struggled with; felt “isolated”)
 After rapid deterioration (age 29), felt despair, anger, guilt, feared death
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 22.
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13 June Friday, Workshop 22
Psychosocial/Nursing
Complex Case Presentations (cont)
• Psychological care of a teenager with CF
undergoing a double lung transplantation
and 10 years later a re-transplantation –
Trudy Havermans, Leuven, BE (cont)
– Discussion:
 Main issue for psychologist: how to balance
“a professional closeness while maintaining a
personal distance”
 Psychologist also experienced doubt and
insecurity; relied on her colleagues for support
o Needed to help patient find support from those
she is closest to while being empathetic but
setting boundaries
– The challenge in a long-term professional
relationship of maintaining the boundaries
between professional closeness and
personal distance
Professional closeness
• Know the patient
–
–
–
–
–
Know the family
Know their history
Know their life interests
Know their goals and aspirations
Know their weaknesses and strengths
• Openness, available
• Empathy, real caring
Personal distance
• Professional relationship
–
–
–
–
Know the illness and treatments
Listen (encourage stories)
Analyse the process
Acceptance Commitment Therapy, dual
process, positive psychology, grief and
bereavement, social skills training
• Discuss/define boundaries
– When (not) available?
– Disclosure
• Know your weaknesses and strengths
• Work in the team
Reproduced with permission from the presenter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 22.
Table of Contents
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13 June Friday, Workshop 22
Psychosocial/Nursing
Complex Case Presentations (cont)
• Use of insulin to treat hypoglycaemia: An unusual presentation of
CF-related diabetes in a teenage girl –
Katie Dick, London, UK
– 14-year-old female with complaint of feeling dizzy, missing school;
symptoms causing stress in the family
– Medical history:
 Underwent CGM; determined patient’s glucose levels not completely normal;
however, no initial evidence of hypoglycaemia
 Admitted for Mycobacterium abscessus eradication; condition worsened
 Ultimately diagnosed with rebound hypoglycaemia
– Management plan:
 Dietician provided nutritional counselling; continued to experience symptoms
 Started on insulin and patient’s symptoms improved
o Insulin adjustment required after developing M abscessus
– Discussion:
 CGM allows more frequent diagnosis of CFRD
 Should more effort have been directed toward dietary and school interventions?
 Adolescence is a stressful time for a young body without CF and diabetes
CGM=continuous glucose monitoring; CFRD=cystic fibrosis-related diabetes.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 22.
Table of Contents
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13 June Friday, Workshop 22
Psychosocial/Nursing
Complex Case Presentations (cont)
• Using behaviour change techniques to improve adherence to
inhaled therapy and create habits –
Rachael Curley, Sheffield, UK
– Highlighted 2 cases utilising a 3-month behaviour change intervention based
on 3 conditions: capability, opportunity, and motivation forming a behaviour
change wheel developed by Michie et al
– Case 1: “Can’t”
 32-year-old male computer professional with treatment adherence ~60%;
believed he needed to separate nebuliser treatments by 30 minutes
 Counselled this was unnecessary and advised to connect his treatment to
bells in school where he works, resulting in improved adherence
– Case 2: “Won’t”
 27-year-old female college student with treatment adherence ~16% due to lack
of motivation
 Team implemented positive reinforcement and adherence increased to 29%
– Adherence is challenging for patients and team, but can be improved by
linking nebuliser treatments to daily activities and identifying ways to reduce
treatment burden
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 22.
Table of Contents
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13 June Friday, Workshop 22
Psychosocial/Nursing
Complex Case Presentations (cont)
• An attempt to eradicate Mycobacterium abscessus in a patient with CF –
Kairen Griffiths, Aberdeen, UK
– 34-year-old female regularly treated for Pseudomonas aeruginosa contracted
M abscessus while living in Indonesia
– Has a brother with CF who has undergone lung transplantation
– Medical history:
 Patient underwent treatment to eradicate infection due to extensive lung disease
(M abscessus contraindication for lung transplant); fear of infecting brother
 Utilised 3 intravenous antibiotics for 6-7 hours per day for 1 month, then transitioned
to maintenance therapy
 Cultures remained positive for P aeruginosa; cleared of M abscessus
 Lung function has declined (FEV1= 40%)
– Discussion:
 Although the mycobacterium infection has been cleared, lung function and QoL
have declined, challenging whether treating has “done the patient any good”
 Further research and development of formal guidelines is urgently needed
QoL=quality of life.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 22.
Table of Contents
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13 June Friday, Workshop 22
Psychosocial/Nursing
Complex Case Presentations (cont)
• An attempt to eradicate Mycobacterium abscessus in a patient with CF –
Kairen Griffiths, Aberdeen, UK (cont)
Plan for eradication therapy
1
2
3
1-month
Induction
Therapy
4
Beginning of
week 4 –
2-year
maintenance
therapy
Imipenem
500 mg 4 x day IV
Tigecycline
50 mg 2 x day IV
Amikacin
15 mg/kg in 2 divided doses IV
Azithromycin
500 mg daily oral
Amikacin
500 mg bd nebulised
Meropenem
250 mg bd nebulised
Azithromycin
250 mg daily oral
Minocycline
100 mg 2 x day oral
Reproduced with permission from the presenter.
IV=intravenous.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 22.
Table of Contents
109
Interactive Case Studies
Table of Contents
110
13 June Friday, Symposium 14
Interactive Case Studies
• Chronic progressive hypoxemia in a 14-year-old CF patient with a
mild pulmonary disease: Work up, diagnosis, and treatment –
Oded Breuer, Jerusalem, IL
–
–
–
–
14-year-old male CF patient
Genotype: F508del/G542X
Patient presented with mild pulmonary disease
Interactive discussions included:




Reason for patient’s hypoxemia: secondary to liver disease
Contrast-enhanced echo as the next step for patient’s workup
Diagnosis of HPS
Liver transplant as the definitive treatment for this condition
– Prevalence of HPS is 4%-47% with chronic liver disease
– Patient outcome: Received a successful liver transplant with improvement
in O2 saturation, repeat echocardiogram was normal
– HPS with hypoxemia is an absolute indication for liver transplantation
– General recommendation: Screen every patient with liver disease for HPS
HPS=hepatopulmonary syndrome.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 14.
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13 June Friday, Symposium 14
Interactive Case Studies (cont)
• Clinical deterioration during pregnancy, leading to abortion and acute lung
transplantation with fatal outcome –
Ulrika Lindberg, Lund, SE
–
–
–
–
31-year-old female CF patient
Genotype: F508del/2183AA-G
Patient is pancreatic insufficient, diabetic, Pseudomonas aeruginosa colonised at young age
1st IVF: Although initially advised against pregnancy due to low lung function, she wanted
to proceed and had a successful IVF at age 29



Followed by pulmonology CF team and specialist obstetrician
FEV1 fell to 22%, several pulmonary exacerbations stabilised with antibiotics
At gestation week 34, she had a planned C-section and gave birth to a daughter
– 2nd IVF: 2 years later, she proceeded with her 2nd IVF


During week 15, she was hospitalised, put on ventilator, pregnancy terminated with a hysterectomy
20 days later received a lung transplant that became complicated and she did not survive
– Interactive discussions included the ethical nature of the following:


Letting the patient carry out the 1st and 2nd IVF treatments
Accepting the patient for lung transplantation
– Summary: This case demonstrates the ethical issues related to pregnancy in a CF
patient who experiences deterioration of health and eventual abortion and death from
complications of the pregnancy
IVF=in vitro fertilization; FEV1=forced expiratory volume in 1 second.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 14.
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13 June Friday, Symposium 14
Interactive Case Studies (cont)
• A binge-drinking girl with recurrent pancreatitis –
Barbara Bosch, Leuven, BE
Total chloride response of the patient
compared to controls and patients with CF
– A 15-year-old girl with a Sri Lankan mother and
Belgian father presented with a second episode of
idiopathic pancreatitis

Her further medical and family history were negative
– Two CFTR mutations: G542X (Class I mutation) from
her dad; S1251N (Class III mutation) from her mom
– Further investigations showed:




Normal chest x-ray
FEV1 102% predicted and FVC 105% predicted
Borderline sweat chloride concentration (47 mmol/L)
An intermediate NPD
– This unexpected finding raised 2 major questions:


Reproduced with permission from the presenter.
How can the mild phenotype be explained given the severe genotype?
Why is the prevalence of CF so low in Asians?
– Interactive discussion included possible gene modifiers; influence of Asian diet on the CF phenotype;
value of CFTR biomarkers (sweat chloride, NPD, organoids) in atypical cases; whether and when to
start ivacaftor in this patient (ivacaftor has FDA approval for patients with the S1251N mutation)
– Summary: This case reveals that CF is a heterogeneous disease, which may explain the genetic
modifiers. The value of CFTR biomarkers and considerations for ivacaftor were discussed
CFTR=cystic fibrosis transmembrane conductance regulator; FVC=forced vital capacity;
NPD=nasal potential difference; FDA=Food and Drug Administration.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 14.
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13 June Friday, Symposium 14
Interactive Case Studies (cont)
• Mundane mutations? To treat or not to treat? –
Julie Duncan, London, UK
–
–
–
–
–
–
Male second child of well parents
Genotype: F508del/R117H
Based on a mild phenotype, patient has a possible risk of CF
EU guidelines should be consulted for next steps
Patient should be followed up with surveillance for now
Interactive discussions included the following:
 Description that best fits the child
 Initial management considerations
 Change in diagnosis, if any
– Summary: This case study of a patient with the genotype
F508del/R117H confirms the difficulties of managing this
group with a mild phenotype
EU=European Union.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 14.
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Registry Data
• Using Registries to Identify New Challenges
»
• Pharmacovigilance/Phase 4 Studies Using Registries »
Table of Contents
115
Using Registries to
Identify New Challenges
Table of Contents
116
12 June Thursday, Workshop 4
Using Registries to
Identify New Challenges
Faculty Perspective – Dr. Jacqueline Rendall, UK
“This excellent workshop was particularly clinically relevant.
It demonstrated how completion and analysis of national
registries can inform us in so many ways. It is fast
becoming an efficient way to answer numerous
clinically challenging questions in this population.
The information acquired is, however, only as good as the
data entered—accuracy remaining the key.”
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 4.
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12 June Thursday, Workshop 4
Using Registries to
Identify New Challenges (cont)
• Treatment burden in patients with CF and at least one class 4 or 5 mutation –
Jonas Dewulf, Leuven, BE
– Used the Belgian CF Registry to compare disease severity and treatment burden
between these patients and those with two class 1, 2, or 3 mutations
– Results confirmed that milder phenotype and lower treatment burden are seen
in patients with ≥1 class 4 or 5 mutation
– This knowledge can help provide better individually tailored counselling at the time
of diagnosis
• How different is the cohort of young CF children included in national
registries of countries with and without newborn screening? –
Muriel Thomas, Brussels, BE
– Compared the demographic and clinical characteristics of young children in
countries with and without NBS programmes
– NBS permitted diagnosis <2 months of age
– NBS changes the characteristics of young children included in CF registries;
the effect reflects the screening strategy utilised
NBS=newborn screening.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 4.
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12 June Thursday, Workshop 4
Using Registries to
Identify New Challenges (cont)
• Modelling airway infections in CF –
Ann Granchelli, Salt Lake City, US
– Used data from the CFFPR to study >1 million cultures from >28,000 patients
– Found strong interactions between specific infections
 MSSA has a negative association with development of PA
 MRSA has a positive association with development of PA
 B cepacia strongly discourages growth of other organisms
– Models can demonstrate which infections can influence acquiring other
infections in the future and whether there is an association between
diabetes, lung function, and various infections
– Understanding these effects may help predict future health outcomes
and identify transitions between infections to target interventions
CFFPR=Cystic Fibrosis Foundation Patient Registry; MSSA=methicillin-sensitive Staphylococcus aureus;
PA=Pseudomonas aeruginosa; MRSA=methicillin-resistant Staphylococcus aureus.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 4.
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12 June Thursday, Workshop 4
Using Registries to
Identify New Challenges (cont)
• Multicentre prevalence study of nontuberculous mycobacteria
in patients with CF in Scandinavia –
Tavs Qvist, Copenhagen, DK
– Between 2000 and 2012, NTM was cultured 1187 times from 162 CF
patients (12%)
 MABSC was the most common NTM (56% of patients), followed by MAC
(48% of patients)
– In 118/162 patients from whom clinical data was available from the time of first
NTM, median FEV1 of predicted was 75%; 45% had a concurrent chronic
infection with other bacteria, most frequently with P. aeruginosa (34%)
– The annual NTM incidence (particularly MABSC and MAC) increased in
Scandinavia from an average of 8/1000 in 2000–2006 to 13/1000 in 2006–2012
 Presently 1 in 9 CF patients have been NTM culture positive at least once
 Geographic variations exist; may be due to different reporting methods
– M abscessus patients are younger and have more pancreatic insufficiency
than M avium complex patients
NTM=nontuberculosis mycobacteria; MABSC=Mycobacteria abscessus complex; MAC=mycobacterium avium complex.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 4.
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12 June Thursday, Workshop 4
Using Registries to
Identify New Challenges (cont)
• CF mutations and survival –
Theodore Liou, Salt Lake City, US
–
–
–
–
–
–
Used CFFPR registry data to evaluate risks (hazard ratio) both in severe and mild mutations
Survival mediated by different clinical characteristics
There were 9 Class IV or V mutations with better survivorship than F508del
Two Class I mutations were more severe than F508del and one Class I mutation was less severe
G551D and I507del had survivorship effects similar to F508del
Variable courses of disease associated with mutations of the same class indicate different
molecular mechanisms of disease
• Cancer in patients with CF –
Carsten Schwarz, Berlin, DE
– Prospective data collected in Germany to evaluate a difference in tumour incidence among CF
patients compared with general population

Compared with the general population (0.93%), female patients with CF (aged 25-49 years)
were more likely to have cancer (4.32%)

In male patients with CF (2.17%), the incidence rate was also higher than in the general
population (0.56%)
– Earlier routine screening may be needed to detect cancer in this population
CFFPR=CF Foundation Patient Registry.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 4.
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Pharmacovigilance/Phase 4 Studies
Using Registries
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122
14 June Saturday, Symposium 29
Pharmacovigilance/Phase 4 Studies
Using Registries
• UK example –
Diana Bilton, London, UK
– FDA and EMA are recognising the benefits of registry data


Want to evaluate exposed vs non-exposed populations to track safety data
Risk vs benefit of new therapies
o
Example: evaluating whether inhaled product caused hemoptysis or whether it was a symptom of CF
– UK Registry includes 59 centres with ≥10,000 patients in 90 clinics

All patients give informed consent; data is shared with trusted third parties and is anonymous—not
individualised
o

Partners include CF Trust, pharmaceutical companies, EMA, and academia
Source of revenue for registries
• Examples from the USA –
Bruce Marshall, Bethesda, US
– Using registries to ascertain real-world data; limited exposure in trials


Clinical trials=safety/efficacy
Clinical experience=safety/effectiveness
– Provides control group for open-label trials; also useful for conducting retrospective,
observational studies and Phase 4 studies
– Source of revenue for registries
– FDA recognises conflict of pharmaceutical companies as stakeholders; however,
patients are ultimate stakeholders and registry does not “hide data”
FDA=Food and Drug Administration; EMA=European Medicines Agency.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 29.
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14 June Saturday, Symposium 29
Pharmacovigilance/Phase 4 Studies
Using Registries (cont)
• Perspectives from pharma –
Sini Eskola, Brussels, BE
– EFPIA represents pharmaceutical industry in Europe
– Uses registries for post-authorisation studies (real-world data)


PASS and PAES (clinical and observational)
o
PASS obtains further information on a medicine's safety, or to measure the effectiveness of
risk-management measures
o
PAES carried out if concerns relating to some aspects of efficacy of the medicinal product are identified
and can be resolved only after the medicinal product has been marketed, or if the understanding of the
diseases, the clinical methodology, or the use of the medicinal product under real-life conditions indicate
that previous efficacy evaluations might have to be revised significantly
To further study previously identified potential risks; to gather information where safety information is
limited or missing (eg, pregnant women); to identify patterns of drug utilisation; to evaluate
effectiveness of risk minimisation programmes
– Pros and cons

No interference from investigator; tool toward balanced risk assessment; real-world setting; can use
social media to collect data

Cannot randomise sample; false positives; under-reporting or differential reporting; QC issues
– Current challenges:

EU Data Protection Regulation and complex US privacy regulations
EFPIA=European Federation of Pharmaceutical Industries and Associations; PASS=post-authorisation safety study;
PAES=post-authorisation efficacy study; QC=quality control; EU=European Union.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 29.
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14 June Saturday, Symposium 29
Pharmacovigilance/Phase 4 Studies
Using Registries (cont)
• Opportunities for the European Registry –
Edward McKone, Dublin, IE
– Highlighted the potential uses of CF patient
registries beyond epidemiology including
improving care and monitoring the safety
and efficacy of new CF treatments
– Registries are used to evaluate Phase 4 data
 Pharmacoeconomic, long-term use,
drug–drug interactions, real-world
monitoring
– ECFS Tracker
 Data collection platform developed
to collect real-time demographic and
clinical data on >35,000 patients from
28 countries, 13 national registries,
and 60 CF centres
 Can be customised to generate graphs;
evaluate comparative outcomes; link to EMR
Reproduced with permission from the presenter.
 QC measures in place to ensure data accuracy
EMR=electronic medical record.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 29.
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Clinical Trials
• Exploring New Endpoints in Clinical Trials »
• AHP Research Symposium: Changing Clinical Practice
Through Research With Minimal or No Funding »
• Clinical Trials in Preschool Children »
Table of Contents
126
Exploring New Endpoints
in Clinical Trials
Table of Contents
127
12 June Thursday, Workshop 3
Exploring New Endpoints
in Clinical Trials
• The effect of ivacaftor treatment on lung ventilation defects,
as measured by hyperpolarised helium-3 MRI, on patients with CF
and a G551D-CFTR mutation –
Talissa Altes, Charlottesville, US
– Phase 2 study of patients with a G551D-CFTR mutation and % predicted FEV1 ≥40%
– Part A was a single-blind, placebo-controlled study comprising 4 weeks of ivacaftor
treatment; Part B was an open-label, 48-week study
– In Part A, 3He-MRI revealed that ivacaftor treatment reduced the TVD by a mean
of 8.2 percentage points (P=0.0547) and the mean TDV by 0.48 L (P=0.0313)
– In Part B, the mean decrease in TVD was 6.3 percentage points (P=0.1953)
and the mean decrease in TDV was 0.31 L (P=0.2656)
– There was a 12.8-point increase (P=0.0078) in mean % predicted FEV 1 in Part A
and a 5.2-point increase in Part B (P=0.1953)
– TVD was responsive to ivacaftor therapy, and 3He-MRI may be useful for assessing
ventilation defects that may not be captured using traditional spirometry
FEV1=forced expiratory volume in 1 second; MRI=magnetic resonance imaging; TVD=proportion of total ventilation defect
volume to total lung volume; TDV=total defect volume.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 3.
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12 June Thursday, Workshop 3
Exploring New Endpoints
in Clinical Trials (cont)
• The effect of ivacaftor on the rate of lung function decline
in CF patients with a G551D-CFTR mutation –
Edward McKone, Dublin, IE
– Ivacaftor is known to improve lung function in CF patients with a
G551D mutation, but it is unknown whether treatment impacts FEV1
rates of decline
– A propensity score was used to match CF patients with a G551D
mutation who received ivacaftor in clinical trials for up to 144 weeks
(n=192) in a 1:5 ratio with patients in the US CFPR homozygous for the
F508del mutation
 Matching was based on measures such as age, gender, % predicted FEV1,
and P. aeruginosa infection
– Estimated annualised rate of decline in % predicted FEV1 (± SE) in
ivacaftor-treated patients is -0.81 ± 0.36
US CFPR= United States Cystic Fibrosis Patient Registry.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 3.
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12 June Thursday, Workshop 3
Exploring New Endpoints
in Clinical Trials (cont)
• MRI-based pulmonary blood flow and lung function in CF patients –
flow changes with pulmonary decline –
John Clancy, Cincinnati, US
– This trial investigated relationships between pulmonary blood flow
and FEV1 in CF patients with a range of disease severity
– APCBF was within the normal range in CF subjects with mild lung disease,
but rapidly increased as FEV1 % dropped below 100%
– A significant increase in the APCBF compared with controls was measured
in patients with moderate-severe CF lung disease
– Results indicate that APCBF might function as a novel biomarker of early CF
pulmonary disease
APCBF=aorto-pulmonary collateral blood flow.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 3.
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12 June Thursday, Workshop 3
Exploring New Endpoints
in Clinical Trials (cont)
• Lack of correlation between sputum Pseudomonas aeruginosa density
and FEV1 changes among CF patients treated with inhaled antibiotics –
Donald Vandevanter, Cleveland, US
– In this 24-week randomised
comparison of LNS and TNS,
beneficial FEV1 changes
subsequent to inhalation or
withdrawal from an antibiotic
for 28 days did not correlate
with expected changes in Pa
concentrations in sputum
TNS
– Results suggest that sputum
Pa density changes inadequately
reflect the effect of inhaled
antibiotics on the airways of
CF patients
Change in FEV1 does not correlate with change in
sputum Pa density among CF patients treated with
inhaled antibiotics
Reproduced with permission from the presenter.
LNS=levofloxacin nebuliser solution; TNS=tobramycin nebuliser solution; Pa=Pseudomonas aeruginosa.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 3.
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12 June Thursday, Workshop 3
Exploring New Endpoints
in Clinical Trials (cont)
• Inhaled 7% hypertonic saline treatment in preschool children with CF –
Silvia Palacio, Buenos Aires, AR
– In a two-centre, parallel-group, open-label study in CF patients aged 3 to
6 years, 7% hypertonic saline nebulised twice daily resulted in a slight, but
not statistically significant, improvement in pulmonary function compared
with 0.9% isotonic saline
• The effect of inhaled dry powder mannitol (IDPM) on ventilation
inhomogeneity (VI) in adults with CF –
Krystyna Poplawska, Mainz, DE
– Results from this pilot, prospective, observational study in which adults
with CF underwent 4 weeks of treatment with IDPM indicated that IDPM
improved ventilation inhomogeneity (measured as LCI) in CF patients
with well-preserved lung function
– Results support the need for larger cross-over trials in adults and
children with CF
LCI=lung clearance index.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 3.
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AHP Research Symposium:
Changing Clinical Practice Through
Research With Minimal or No Funding
Table of Contents
133
AHP Research Symposium:
Changing Clinical Practice Through
Research With Minimal or No Funding
13 June Friday, Special Symposium
• Clinical questions that can be answered with small scale studies –
Susannah King, Melbourne, AU
–
–
–
–
Clinical practice in CF is very conducive to small studies within and across disciplines
Many questions from clinical practice are suitable for investigating in small studies
Small studies should still conform to principles of good research design and conduct
Support and collaboration are keys to successful clinical research
AHP=allied health professional.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Special Symposium.
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13 June Friday, Special Symposium
AHP Research Symposium:
Changing Clinical Practice Through
Research With Minimal or No Funding (cont)
• Simple studies can determine the smallest worthwhile effect –
Ruth Dentice, Sydney, AU
– “The smallest amount of patient-valued benefit that an intervention would require
in order to justify associated costs, risks, and other harms.” –Barrett 2005
– The benefit–harm trade-off method involves first presenting respondents with
summaries of benefits and harms associated with a particular intervention
– The benefit–harm trade-off method has merit because:
 The estimate must be derived exclusively from the patient: They must not be
influenced by a researcher or clinician
 The estimate must be generated with respect to a specific intervention:
Decisions about whether an intervention’s effect is worthwhile must
consider whether the benefit of the intervention outweighs its costs,
risks and inconveniences (Barrett 2005)
 The estimate must be expressed in terms of an effect, not an outcome:
The effect of an intervention is the difference in outcomes that would
occur with and without that intervention. The overall outcome that occurs
without intervention can be influenced by natural recovery, regression to
the mean, and placebo effects (Herbert 2011)
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Special Symposium.
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13 June Friday, Special Symposium
AHP Research Symposium:
Changing Clinical Practice Through
Research With Minimal or No Funding (cont)
• Low cost ways to reduce bias and improve clarity in clinical studies –
Eleanor Main, London, UK
– Choose an outcome measure that matters to patients and HCPs
– Enrol enough participants to answer your question
– Beware of short-term intervention studies: Do not over-interpret safety
or effectiveness
– Compare changes between groups, not within groups
– Report confidence intervals, not just P values, to indicate clinically versus
statistically important changes
– Register the trial—any kind of trial—prospectively
– Crossover design can control for variability associated with diverse clinical
circumstances but only useful in short-term trials
– Only choose RCT if strong preferences unlikely, you can conceal allocation,
and intervention is not effortful, demanding, or long term
– If using randomisation, do it properly—independent and immediately
before intervention
– Use ITT analysis—understand and explain dropouts
HCP=healthcare provider; RCT=randomised clinical trial; ITT=intention-to-treat
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Special Symposium.
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13 June Friday, Special Symposium
AHP Research Symposium:
Changing Clinical Practice Through
Research With Minimal or No Funding (cont)
• Minimal requirements for any clinical research study –
Kate Blakeley, London, UK
– Identify a research area based on personal interest, recurrent issues
in clinical practice, service developments, and critical evaluation of
everyday practice
– Prioritised research areas for AHPs and nurses by European working group:
adherence, exercise/physical activity, airway clearance techniques and
interventions for newborn with CF, evaluation of outcome measures for use
in AHP and nursing research
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Special Symposium.
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Clinical Trials
in Preschool Children
Table of Contents
138
14 June Saturday, Symposium 25
Clinical Trials in Preschool Children
• How to do an interventional trial in infants and toddlers – Adam Jaffe, Randwick, AU
• We must urgently try out novel drugs in early childhood - PRO – Margaret Rosenfeld,
Seattle, US
• We must urgently try out novel drugs in early childhood - CON – Michael Fayon,
Bordeaux, FR
• Regulatory challenges in trials with preschool children – Irmgard Eichler, London, UK
– An international consensus is needed on how trials are conducted in young children
– Studies need to demonstrate efficacy and safety; EMA guidelines need to be eased
– PRO:




Extending life expectancy will require early intervention prior to onset of irreversible lung damage
This is an opportunity afforded by newborn screening
Traditional clinical endpoints not sensitive enough; newer, sensitive physiologic endpoints necessary
Novel drugs should be tried. Structural airway damage begins early, even though clinical signs are not
evident; must arrest CF
o
Bronchiectasis seen in one-third of 4-year-olds and half of 6-year-olds in Australia and London
– CON:

There are risks involved in treating very young children, including anaesthesia related to CT scans
(MRI is excellent at showing bronchiectasis and is preferable); antibiotics may be toxic; dexamethasone
in neonates may cause neurotoxicity later in life
o
Nonpharmacologic interventions are preferable
EMA=European Medicines Agency; CT=computed tomography; MRI=magnetic resonance imaging.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 25.
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Science of CF
•
•
•
•
•
•
Stem Cell-Based Airway Modelling and Regenerative Medicine for CF »
Late-Breaking Science »
CFTR Genetics and Function »
Epithelial Cell Biology »
The “Epithelial” Channeltome and Options for Rescue »
Translational Value of Ex Vivo CFTR Biomarker »
Table of Contents
140
Stem Cell-Based Airway Modelling
and Regenerative Medicine for CF
Table of Contents
141
12 June Thursday, Symposium 11
Stem Cell-Based Airway Modelling
and Regenerative Medicine for CF
• Lung injury and repair in CF, prospects for cell therapy and
regenerative medicine –
Bob Scholte, Rotterdam, NL
– By age 3, 50% of CF
patients have lung disease
– How much CFTR for rescue
is a “tricky question”
 100% CFTR in 10% of
cells = 10% CFTR in
100% of cells
– Gene therapy: adenoviral
therapy has several AEs
– In the lung: committed
progenitor cell niches in
the airway epithelium
Reproduced with permission from the presenter.
CFTR=cystic fibrosis transmembrane conductance regulator; AEs=adverse events.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 11.
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12 June Thursday, Symposium 11
Stem Cell-Based Airway Modelling
and Regenerative Medicine for CF (cont)
• Generation of lung epithelium from pluripotent stem cells –
Amy P. Wong, Toronto, CA
– Study focussed on cell reprogramming by induced pluripotent stem cells to
provide a renewable source of epithelial cells
– Process: skin fibroblast (viral transduction) leads to reprogrammed cells
– Lung is endoderm-derived organ
 Can obtain differentiated epithelia from technique but produces heterogenous
population of cells (non-airway endoderm lineage)
– Transplantation of new epithelia “very unlikely” in our times
• Growing stem cell-based lung organoids –
Robert Vries, Utrecht, NL
– LGR5 cells ideal multipotent stem cells; unlimitedly expansive; genetically stable
– Applications of human organoids: disease model, drug testing, and screening
in CF
 Organoids of intestine and liver easier to realise; next goal is to establish human
lung organoids
LGR5=leucine-rich repeat-containing G-protein-coupled receptor 5.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 11.
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12 June Thursday, Symposium 11
Stem Cell-Based Airway Modelling
and Regenerative Medicine for CF (cont)
• Stem cell therapy for CF –
Ulrich Martin, Hannover, DE
– Very difficult to produce hiPSC because of differentiation problems
– Focus on Clara cells (also known as “nonciliated bronchiolar secretory cells”)
from iPSC-derived endoderm and differentiate with glucocorticoids and KGF to
produce a tubular structure
Personalised therapies for CF:
patient-specific induced pluripotent stem cells for disease modelling,
drug screening, and cellular therapies
Reproduced with permission from the presenter.
hiPSC=human induced pluripotent stem cells; iPSC=induced pluripotent stem cells; KGF=keratinocyte growth factor.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 11.
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Late-Breaking Science
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145
13 June Friday, Workshop 18
Late-Breaking Science
• 407 compound, a new corrector for ΔF508CFTR: state of art –
Aleksander Edelman, Paris, FR
– In silico screening to interrupt unwanted interaction between housekeeping proteins and
F508del CFTR preventing delivery to plasma membrane
– Keratin 8 is an intermediate filament expressed in simple epithelia. Keratin 8 interaction
with F508del NBD1 prevents delivery of F508del to cell surface
– 407 compound prevents F508del from proteasomal and proteolysis degradation and
lengthens half-life of F508del
– 407 may mask CFTR R553 amino acid of F508del, and acts through a nonconventional pathway
– Functional test was done in mice with NPD measurements. One set of experiments
involved 3 daily intraperitoneal injections of 407
– Similar stabilising effect of 407 seen with AAT mutZ protein

40% of AAT secreted when treated with 407; thus, this agent is not a specific CFTR corrector
– Challenges:

407 is easy to synthesise, but it is first generation, so needs improvement in activity

Animal toxicity needs to be done, but it has been difficult to find investors
CFTR=cystic fibrosis transmembrane conductance regulator; NBD=nucleotide binding domain;
NPD=nasal potential difference; AAT=alpha1-antitrypsin.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 18.
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13 June Friday, Workshop 18
Late-Breaking Science (cont)
• Clinical pharmacodynamics of CTX-4430, a potential new oral
anti-inflammatory treatment for CF –
Stuart Elborn, Belfast, UK
– CTX-440 is a potential new oral anti-inflammatory treatment for CF
 Neutrophils are the first responders to microbial challenges
 A right balance between reducing inflammation and reducing infection is needed
 CTX-4430 is an inhibitor of leukotriene B4, a neutrophil chemoattractant
– Once-daily oral capsule with promising early clinical data
 Good animal toxicity data in rats and dogs
 Dose/response level can be adjusted to identify optimal risk/benefit profile for
treatment of CF
– Phase 1 in healthy volunteers completed. Phase 1b is ongoing in adult CF
and plans to initiate Phase 2 early 2015
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 18.
Table of Contents
147
13 June Friday, Workshop 18
Late-Breaking Science (cont)
• Effect of ciprofloxacin on ivacaftor, a sensitive CYP3A substrate,
in healthy volunteers –
Sarah M. Robertson, Boston, US
– Ciprofloxacin is not an inhibitor of CYP3A when administered at a dose
of 750 mg q12h
– Therefore, no ivacaftor dose adjustment is needed when coadministered
with ciprofloxacin
– The combination of ivacaftor and ciprofloxacin was generally well tolerated
– Question was raised about whether any other drugs were planned to be
studied for DDI with ivacaftor, and whether there was any effect of
ivacaftor on ciprofloxacin
 Dr. Robertson said there is no imminent list of drugs to be studied for DDI
with ivacaftor and effect of ivacaftor on ciprofloxacin is not expected
DDI=drug-drug interaction.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 18.
Table of Contents
148
CFTR Genetics and Function
Table of Contents
149
13 June Friday, Workshop 23
CFTR Genetics and Function
• Models of the 3D structure of CFTR: from the understanding of the
protein functions to the design of correctors –
Brice Hoffmann, Paris, FR
– Molecular dynamics experiments were performed to gain insights into the
structural and functional characteristics of CFTR
– A relevant model of the full open form of the anion channel was obtained
and the stability and conformational variability of the 3D structure of CFTR
was able to be explored
– The models used in these experiments provided insight into molecular
mechanisms related to the correct functioning of the CFTR protein and the
impact of mutations in patients with CF
CFTR=cystic fibrosis transmembrane conductance regulator.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 23.
Table of Contents
150
13 June Friday, Workshop 23
CFTR Genetics and Function (cont)
• Characterisation of the CFTR mutation c.3700 A>G informs strategies for future
medical intervention –
Steven Molinski, Toronto, CA
– This study investigated the consequences of the missense mutation p.Ile1234Val, a relatively
common variant in the Middle East
– Results indicated that the mutation
caused a primary defect in processing,
which was partially ameliorated by
lumacaftor (VX-809), a compound
in clinical trial for CF patients
with p.Phe508del
– CFTR mutation c.3700 A>G
causes aberrant splicing,
leading to deletion of 6 amino
acids and defective CFTR
biosynthesis; however,
lumacaftor (VX-809) can
repair p.Ile1234_Arg1239del-CFTR
to levels comparable to that
Adapted by permission from Macmillan Publishers Ltd:
Molinski SV et al. Genet Med. 2014;16(8):625-632.
of pharmacologically rescued
p.Phe508del-CFTR
NBD=nucleotide binding domain; WT=wild-type.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 23.
Table of Contents
151
13 June Friday, Workshop 23
CFTR Genetics and Function (cont)
• ICM is sensitive to detect potentiation of CFTR-mediated Cl- secretion
in patients with CF and the G551D mutation treated with ivacaftor –
Simon Graeber, Heidelberg, DE
– In this trial, rectal biopsies were obtained from patients carrying
G551D-CFTR mutation before and at least 4 weeks after initiation
of ivacaftor therapy
– Results indicate that ICM may be a useful bioassay for determining
therapeutic responses to ivacaftor
• Rare CF genotype with severe hepatic failure associated with
medium chain acid deficiency (MCAD) in a neonate –
Anne Mornand, Geneva, CH
– This case report documents the case of a baby boy with a CF genotype
never before described (homozygous mutation c.1853_1863del)
– This rare genotype was associated with very early and severe
hepatic dysfunction
– The association between MCAD and CF has never been reported
ICM=intestinal current measurement.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 23.
Table of Contents
152
13 June Friday, Workshop 23
CFTR Genetics and Function (cont)
• Clinical importance of homozygous R117C (c.349C>T) CFTR mutation –
Isabelle de Monestrol, Stockholm, SE
– This case report described the first case of R117C (7T) homozygosity, by UPD,
causing CF and Silver-Russell syndrome in a 17-month-old boy
 17 mo: CFTR dysfunction; sweat Cl- 54 and 64 mmol/L; NPD borderline;
CXR bronchial thickening; PFT Vmax FRC 275; anti-S aureus and P aeruginosa
neg; F-chymotrypsine and -elastase normal
– Clinical picture: intermittent need of inhalation therapy, viscous mucus only
with respiratory tract infections
– R117C (c.349C>T) is a non-classical CFTR mutation with positive sweat test,
borderline NPD, pancreas sufficiency, and intermittent pulmonary symptoms
UPD=uniparental isodisomy; NPD=nasal potential difference; CXR=chest radiogram; PFT=pulmonary function test;
Vmax FRC=maximal flow at functional residual capacity.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 23.
Table of Contents
153
13 June Friday, Workshop 23
CFTR Genetics and Function (cont)
• Ivacaftor treatment in patients with CF who have an R117H-CFTR mutation,
the KONDUCT study –
Richard Moss, Palo Alto, US
– In this Phase 3, randomised, double-blind,
placebo-controlled study, patients received
ivacaftor vs placebo twice daily for 24 weeks
– No new safety concerns were identified;
pulmonary exacerbation was the most
common SAE reported
– Data from this study suggest that ivacaftor
may benefit some patients with R117H-CFTR,
particularly those at least 18 years of age
– Ivacaftor improved lung function over 24 weeks
in CF patients ≥18 years old (n=50, baseline
FEV1 64.5%) with absolute change
% predicted FEV1 treatment effect of 5.0
(P=0.01); relative change treatment effect
(not shown) was 9.1 (P=0.01)
Reproduced with permission from the presenter and
Vertex Pharmaceuticals Incorporated.
Change from baseline
through Week 24
Absolute change in
percent predicted
FEV1 (% points)
Treatment Difference
(P value)
5.0
(P=0.01)
Line graphs plot model-adjusted least squares mean for change from baseline at each time point. Table reports treatment
difference for model-adjusted least squares mean change through Week 24 (overall post-baseline, inclusive of all available data).
KONDUCT=Study of Ivacaftor in Subjects With Cystic Fibrosis Who Have the R117H-CFTR Mutation; SAE=serious adverse effect;
FEV1=forced expiratory volume in 1 second; SE=standard error.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 23.
Table of Contents
154
Epithelial Cell Biology
Table of Contents
155
13 June Friday, Workshop 17
Epithelial Cell Biology
• Hydrostatic pressure induced stretch activates CFTR in native
pulmonary epithelium –
Constanze Vitzthum, Giessen, DE
– In this ex vivo study, hydrostatic pressure activated Cl- secretion in lung tissue that
is CFTR inhibitor sensitive but secretagogue insensitive
– Results suggested that CFTR activity is modulated by membrane stretch and that
CFTR is sensitive to mechanical forces
• Recruitment of CFTR to the enterocyte apical membrane is coordinated
with internalisation of the transmembrane mucin MUC17 and secretion of
the MUC2 mucin from the goblet cells –
Hannah Schneider, Gothenburg, SE
–
–
–
–
Small intestinal mucus consists of the goblet cell secreted gel-forming mucin MUC2
Others include membrane-tethered mucins MUC3, MUC12, and MUC17
These build enterocyte glycocalyx and may protect the brush border membrane
The interaction of PDZ protein PDZK1 with CFTR and MUC17 was studied
by immunofluorescent co-staining and co-immunoprecipitation of native and
mutant constructs
CFTR=cystic fibrosis transmembrane conductance regulator.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 17.
Table of Contents
156
13 June Friday, Workshop 17
Epithelial Cell Biology (cont)
• Recruitment of CFTR to the enterocyte apical membrane is coordinated with
internalisation of the transmembrane mucin MUC17 and secretion of the MUC2
mucin from the goblet cells –
Hannah Schneider, Gothenburg, SE (cont)
– Plasma membrane MUC17 binds to PDZK1 via its cytoplasmic tail, which harbours a
phosphorylation site, and its internalisation is coordinated with recruitment of CFTR to the
enterocyte apical membrane
Reproduced with
permission from
the presenter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 17.
Table of Contents
157
13 June Friday, Workshop 17
Epithelial Cell Biology (cont)
• SLC26A9 channel functionality is characterised in epithelial cells –
Johanna Salomon, Heidelberg, DE
– SLC26A9 is a recently identified epithelial Cl- channel that prevents mucus obstruction
in airway inflammation, which may have an application to CF
– In this ex vivo study, data suggested that the translocation of SLC26A9 to the plasma
membrane and volume-sensing kinases may be important in the
activation of SLC26A9-mediated Cl- conductance
• Expression of ENaC subunits in Fischer Rat Thyroid cells as an investigation tool
of the interaction between CFTR and ENaC and evaluation of ENaC inhibitors –
Stefano Castellani, Foggia, IT
– FRT cells expressed subunits at high level with a cytoplasmic localisation and at
intercellular borders
– FRT transfected with ENaC subunits in a ratio of α:β:γ of 2:1:1 showed a higher fluid
absorption than non-transfected cells but lower than wt CFTR 16HBE14o-cells, even in
the presence of dexamethasone, consistent with low ENaC activity
– Nevertheless, camostat significantly reduced the rate of fluid reabsorption in transfected
cells in a dose-dependent way
– Optimal doses of camostat that inhibit ENaC function were identified
ENaC=epithelial sodium channel; FRT=transfected Fischer rat thyroid; HBE=human bronchial epithelial cells.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 17.
Table of Contents
158
13 June Friday, Workshop 17
Epithelial Cell Biology (cont)
• A new tool for CF diagnosis: short circuit current measurements
in human nasal epithelial cells collected by nasal brushing –
Virginie Pruliere-Escabasse, Créteil, FR
– A new method is necessary to evaluate ion transports in upper airways ex vivo
as an emerging number of CF patients present with an atypical phenotype
who may have normal/intermediate-range sweat chloride levels and no or one
CF-causing mutation; current measures can be problematic in CF patients
with rhinosinusitis
– Short circuit current measurements were identified as a new and reliable tool
for CF diagnosis, which could also allow for the study of new CF therapies
• Colonic mucus formation relies on bicarbonate secretion via apical
Cl-/HCO3--exchange –
Jenny Gustafsson, Gothenburg, SE
– Ex vivo study conducted in colonic tissues of mice
– Results indicated that bicarbonate secretion is important in regulating mucus
formation in the colon, in addition to the ileum, which has been previously shown
– The principal route of bicarbonate secretion appeared to be via apical
Cl-/HCO3--exchange
HCO3=bicarbonate.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Workshop 17.
Table of Contents
159
The “Epithelial” Channeltome
and Options for Rescue
Table of Contents
160
14 June Saturday, Symposium 30
The “Epithelial” Channeltome
and Options for Rescue
• Bicarbonate and its channels –
Paul Quinton, San Diego, US
– There are 4 types of channels: CLCs, anoctamins,
bestrophins, CFTR
– If CFTR is not transporting chloride out of the cell, it is
transporting bicarbonate into the cell via the gradient
difference; this bicarbonate transport can exceed chloride
in the presence of SPAK
– R117H/F508del demonstrates some bicarbonate
conductance, whereas homozygous F508del does not
– Dorschner et al 2006 showed that effective killing of S aureus
requires bicarbonate; subsequent studies have reported
that other bacterial species require bicarbonate as well
– Maintenance of the ASL layer in the lung requires a balance of
fluid absorption and secretion maintained at a particular height;
cells in the lower half of pleats secrete fluid and mucins,
whereas the cells in the upper half of the pleats absorb
Reproduced with permission
from the presenter.
CLC=chloride channel; CFTR=cystic fibrosis transmembrane conductance regulator; SPAK=Ste20-related
proline-alanine-rich kinase; ASL=airway surface liquid; HCO3=bicarbonate.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 30.
Table of Contents
161
14 June Saturday, Symposium 30
The “Epithelial” Channeltome
and Options for Rescue (cont)
• SLC26A9-mediated chloride secretion can prevent lung mucus obstruction –
Marcus Mall, Heidelberg, DE
– Mouse models have shown no influence on CFTR
transcription levels implicating another channel
– SLC29A9 has been shown to be a chloride channel
in HBE cells; in A9 KO mice, chloride transport
is upregulated in the presence of IL13
– SLC26A9 may be very prominent in a “mucus”
phenotype of CF patients; it is essential to prevent
mucus plugging in inflammation-driven mucus
secretion as chloride transport is also increased
through this channel
HBE=human bronchial epithelial; WT=wild-type; KO=knockout.
Source: Anagnostopoulou P et al. J Clin Invest. 2012;122(10):3629-3634.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 30.
Table of Contents
162
14 June Saturday, Symposium 30
The “Epithelial” Channeltome
and Options for Rescue (cont)
• cAMP compartmentation and CFTR regulation –
Manuela Zaccolo, Oxford, UK
– In HBE cells, the subcortical cytoskeleton allows compartmentalisation
of cAMP in the sub-plasma membrane compartment, necessary for
optimal CFTR regulation
– In CFBE cells, the subcortical cytoskeleton is disrupted with loss
of cAMP at the membrane and excessive accumulation of cAMP in
the cytosol
– Overexpression of NHERF in CFBE cells re-establishes the subcortical
cytoskeleton and compartmentalisation of cAMP as well as Cl- efflux
cAMP=cyclic adenosine monophosphate; CFBE=cystic fibrosis bronchial epithelial cell; NHERF=Na +/H+ exchanger
regulatory factor.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 30.
Table of Contents
163
14 June Saturday, Symposium 30
The “Epithelial” Channeltome
and Options for Rescue (cont)
• cAMP compartmentation and CFTR regulation –
Manuela Zaccolo, Oxford, UK (cont)
Adapted with permission from Monterisi S et al. J Cell Sci. 2012;125(Pt 5):1106-1117.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Symposium 30.
Table of Contents
164
Translational Value of
Ex Vivo CFTR Biomarker
Table of Contents
165
CFTR Educational Suite Experts Session
Translational Value of Ex Vivo CFTR Biomarker
• Speaker: Nico Derichs, Berlin, DE
• Ex vivo CFTR biomarkers:
– ICM – human rectal biopsies
– Intestinal organoids derived from rectal
biopsies after ICM
• Advantages of ICM
– Sensible to detect CFTR function in highly
CFTR-expressing tissue
– Low variability, high reliability, high
discriminative validity
– Feasible also in young children (no age limits)
– Potential to procure biopsies to organoids after ICM
• Potential and challenges include:
–
–
–
–
–
Highly reproducible outcome parameter
Reproduced with permission from the presenter.
CFTR relevant human tissue
Prediction of clinical effect by preclinical ex vivo treatment
Responsive to in vivo CFTR modulator treatment
Possibility of individualised longitudinal tracking of CFTR function
(ex vivo/in vivo) and clinical phenotype in the same patients
– Long-term correlation CFTR function vs clinical phenotype?
CFTR=cystic fibrosis transmembrane conductance regulator; ICM=intestinal current measurement.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
CFTR Educational Suite Experts Session.
Table of Contents
166
Plenary Session
Table of Contents
167
14 June Saturday, Closing Plenary
Plenary Session
• Mucus: The central problem in CF –
Gunnar C. Hansson, Gothenburg, SE
– Discussed role of mucus in the normal
body compared with pathophysiology
of mucus in patients with CF
 Lack of CFTR, which may contribute
to the lack of HCO3, allows the
attached mucus to trap bacteria
and causes CF disease
Goblet Cell
Attachment
Does not
occur in CF
– Presented research being conducted
in the CF pig in Europe and US
showing that trapped mucus cannot
move out of glands
 Results in problems beginning at
birth with hyper-concentrated mucus
that permits accumulation of bacteria
and suggests the need to begin
treatment early
packed
in
granulae
Goblet Cell
Enzyme
secreted
and
unfolded
Reproduced with permission from the presenter.
CF mucins remain anchored to the epithelium
as bicarbonate necessary for unfolding mucin
to access cleavage site is lacking
CFTR=cystic fibrosis transmembrane conductance regulator; HCO3=bicarbonate.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Closing Plenary.
Table of Contents
168
14 June Saturday, Closing Plenary
Plenary Session (cont)
• Preventing and treating pulmonary exacerbations –
Patrick Flume, Charleston, US
– Data have shown that patients do not return to what is believed
to be their baseline lung function after treatment for a pulmonary
exacerbation
– Hypotheses for why there is incomplete recovery following an
exacerbation include:
 Etiology of the exacerbation
 Host factors
o Underlying disease status
o Chronic therapies
o Acute inflammatory response
 Treatment factors
o Delay in treatment
o Inadequate treatment
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Closing Plenary.
Table of Contents
169
14 June Saturday, Closing Plenary
Plenary Session (cont)
• Preventing and treating pulmonary exacerbations –
Patrick Flume, Charleston, US (cont)
– As optimum treatments for an exacerbation are identified, the figure demonstrates
how much we still do not know when trying to understand what is meant by an
optimal response
Treating to previous baseline: What path did the patient follow from ‘stable’ to ‘unstable’?
Diagnose
exacerbation
Undiagnosed
exacerbation?
worse
Signs and
Symptoms
Previous
(stable)
encounter
New
baseline?
treat
goal
goal
better
Time
Reproduced with permission from the presenter and Dutch VanDevanter.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Closing Plenary.
Table of Contents
170
Posters
• Best Poster Awards »
• Abstracts Online »
Table of Contents
171
Best Poster Awards
CFTR/Cell Biology/Cell Physiology/New Therapies –
Maaike Berkhout, The Hague, The Netherlands
Nursing/Psychosocial Issues –
Frederick Frost, Liverpool, United Kingdom
Genetics/Screening/Diagnosis –
Andrea Holubová, Prague, Czech Republic
Gastrointestinal/Liver Disease/Metabolic
Complications of CF/Nutrition –
Anne Mößeler, Hannover, Germany
Genetics/Screening/Diagnosis: Highly Commended –
Corina Rueegg, Lucerne, Switzerland
Samya Nasr, Ann Arbor, MI United States
Veronika Krulišová, Prague, Czech Republic
Microbiology –
Nina Cramer, Hannover, Germany
Physiotherapy –
Fiona Shaw, London, United Kingdom
Epidemiology – Registry/Delivery of Care –
Emem Ukor, Cambridge, United Kingdom
Immunology/Inflammation/Pulmonology –
Jochen Mainz, Jena, Germany
Table of Contents
172
Abstracts Online
• Abstracts of the oral presentations (workshops) and posters have
been published
– Journal of Cystic Fibrosis. 2014;13(Suppl 2):S1-S136
• Titles of these abstracts are available online
– ECFS website:
https://www.ecfs.eu/meetings/ecfs/37th+ECFS+Conference%2C+
Gothenberg+%2C+Sweden%2C+June+2014/6066
– Journal of Cystic Fibrosis website:
http://www.cysticfibrosisjournal.com/issue/S1569-1993(14)X0005-6
Table of Contents
173
Satellite Symposia
•
•
•
•
Changing Faces Changing Solutions (Gilead) »
CFTR Modulation in CF (Vertex)
»
CF Treatment: Past, Present, and Future (Roche) »
Changing Antibiotic Delivery to Improve CF Patients’ Lives:
Challenges and Opportunities (Novartis)
»
Table of Contents
174
Changing Faces, Changing Solutions
(Gilead)
Table of Contents
175
12 June Thursday, Satellite Symposium (Gilead)
Changing Faces, Changing Solutions
•
Welcome and introduction – Stuart Elborn, Belfast, UK
•
Overview – Barry Plant, Cork, IE
•
The role of international/European registries –
Edward McKone, Dublin, IE
•
Preventing exacerbations – Elizabeth Tullis, Toronto, CA
•
Patient registries are important and provide multiple benefits
(emphasis on ECFS registry)
•
Review of existing CF registries for monitoring of new drug safety
and efficacy compared to the setting up of an industry-sponsored
Phase IV trial
•
•
Discussion of significance of exacerbations, starting with defining
what is an exacerbation through causes of exacerbations, their
impact on morbidity/mortality, and importance of prevention of
exacerbation
Industry
Phase 4 Studies
Ability to monitor
outcome
measures
Good – designed for
this
OK but not for
PROs & some
surrogates
(NPD, LCI, CT)
Ability to detect
adverse drug
reactions
Good – designed for
this
Poor – not
designed for
this
Startup issues
Very costly. Ethical
issues – “seeding
trials”
None – already
in existence
Ownership
Industry
Academia
Data collection
Substantial addition
to, or duplication of
workload
Most data
currently being
collected
Real world
Less so
Yes
Comparative
analysis
No control group
Potential for
research with
concurrent/
historical
controls
Health economic
data
Good
Limited
Future challenges of CF care:
–
–
–
Patients now have increasingly complex issues associated with disease
(comorbidities, resistance, toxicity, mental health complications, etc)
secondary to better, earlier care
Challenges surrounding communications were mentioned (how to respond
to e-mails, texts, social media), as were issues surrounding loss of
personalisation/intimacy with patients as clinic sizes grow (how big is too big)
Costs to the system were also discussed
CF Registry
Reproduced with permission from the presenter.
PROs=patient-reported outcomes; NPD=nasal potential difference; LCI=lung clearance index; CT=computed tomography.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Gilead).
Table of Contents
176
12 June Thursday, Satellite Symposium (Gilead)
Changing Faces, Changing Solutions (cont)
Growth in adult CF population at TPCH
• Understanding future
challenges of clinical care –
Scott Bell, Brisbane, AU
– Numbers increasing
– Complexity increasing
 Patient
 CF team
Reproduced with permission from the presenter.
– New complications emerging
– Impact on psychological, work,
and family life considerable
– Models of care being challenged
– Costs of CF into the future will
challenge the system
Reprinted with permission from Cystic Fibrosis Foundation Patient
Registry, 2012 Annual Data Report, Bethesda, Maryland,
©2013 Cystic Fibrosis Foundation.
TPCH=The Prince Charles Hospital.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Gilead).
Table of Contents
177
CFTR Modulation in CF
(Vertex)
Table of Contents
178
12 June Thursday, Satellite Symposium (Vertex)
CFTR Modulation in CF
Faculty Perspective – Dr. Jacqueline Rendall, UK
“Informative talks were followed by a practical and interactive
discussion led by a panel. Real-life cases and challenges
were discussed. The session generated a lot of interest and
questions from the floor. It highlighted the importance of
real-world monitoring as each new therapeutic option is
introduced to the clinic, and the importance of sharing
experience with the wider CF community.”
CFTR=cystic fibrosis transmembrane conductance regulator.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Vertex).
Table of Contents
179
12 June Thursday, Satellite Symposium (Vertex)
CFTR Modulation in CF (cont)
• CFTR in CF –
Claire Wainwright, Herston, AU
– Worldwide burden: one of most common genetic diseases (70k worldwide); high morbidity/mortality
– Life of a normal CFTR protein channel was reviewed including synthesis, folding and processing,
trafficking, turnover, and function
– The degree to which the molecular defect affects CFTR quantity and function determines total
CFTR activity
– 2,000 mutations identified, but not all are disease-forming (cftr2.org)
– “Our challenge is finding therapy to correct CFTR for all CF mutations” –Dr. Ramsey
What determines CFTR quantity and function?
CFTR
Quantity
Number of CFTR
Channels in
Apical Surface
•
•
•
•
CFTR synthesis
CFTR processing
CFTR splicing
CFTR surface stability
CFTR Function
Channel Open
Probability
• Channel gating
Channel
Conductance
Total CFTR Activity
Total Chloride
Ion Transport
• Transport rate
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Vertex).
Table of Contents
180
12 June Thursday, Satellite Symposium (Vertex)
CFTR Modulation in CF (cont)
• Long-term safety and efficacy of CFTR modulation –
Ernst Rietschel, Cologne, DE
– In PERSIST, patients on ivacaftor showed improvement
in lung function and weight gain
– Lung function:

In STRIVE, patients receiving ivacaftor demonstrated a 10-12% mean
absolute change in FEV1, which persisted for 96 weeks. Patients
formerly on placebo in STRIVE reached the same improvement in
FEV1 when switched to PERSIST

In ENVISION, there was more than 10% mean absolute change from
baseline in percent predicted FEV1. The FEV1 of children coming from
the placebo arm of ENVISION improved more slowly, reached the
same level at week 96, and persisted as well until the end of study
Mean Absolute Change From Baseline
in Percent Predicted FEV1
Adults/Adolescents
Children
– Weight gain:

As in STRIVE, the mean absolute change from baseline in weight
improved by 3 kg and persisted over time for adults and adolescents

The placebo group of children in ENVISION showed slower weight
gain than the ivacaftor group, but after rollover to PERSIST they
reached equal weight gain
– Most common adverse events included pulmonary
exacerbation, cough, and upper respiratory tract infection
Observed (raw) mean changes from baseline in STRIVE and in
ENVISION percent predicted FEV1 are plotted at each time point.
Changes are measured from baseline of the STRIVE and of the
ENVISION study (most recent measure prior to first dose).
Reproduced with permission from the presenter
PERSIST=An Open-Label, Rollover Study to Evaluate the Long Term Safety and Efficacy of VX 770 in
and Vertex Pharmaceuticals Incorporated.
Subjects With Cystic Fibrosis; STRIVE=Study of Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older
With the G551D Mutation; ENVISION=Study of Ivacaftor in Cystic Fibrosis Subjects Aged 6 to 11 Years With
the G551D Mutation; FEV1=forced expiratory volume in 1 second; SE=standard error.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden. Satellite Symposium (Vertex).
McKone E et al. Pediatr Pulmonol. 2013;48 (S36):287.
Table of Contents
181
12 June Thursday, Satellite Symposium (Vertex)
CFTR Modulation in CF (cont)
• How should we evaluate CFTR modulation? Roundtable Panel Discussion –
Gordon MacGregor, Glasgow, UK; Dominique Hubert, Paris, FR; Peter Barry,
Manchester, UK; Jacqueline Rendall, Belfast, UK; Claire Wainwright, Herston, AU;
Ernst Rietschel, Cologne, DE
– Follow up with ivacaftor (4 wks, 6 mo, and 1 yr) includes lung function, weight,
and spirometry to assess effectiveness and adherence
– Exercise tolerance and 6-minute walk test as clinical trial endpoints
– FEV1 is a gold standard, but new potential technologies include: high resolution
CT scan, hyperpolarised 3H-MRI, and LCI for detection of early disease
– Reduction of P aeruginosa with ivacaftor (GOAL study)—longitudinal study necessary
– Adherence issues include obesity
– On GI improvement, in a French cohort, one patient stopped having episodes of
pancreatitis exacerbations post-ivacaftor
– LFT management options include ivacaftor dose reduction

IV antibiotics were mentioned as contributors to LFT abnormalities
– The panel encouraged inclusion of patients with FEV1<40 in trials as they have
seen response with ivacaftor, although improvement was seen after 3 months.
IV antibiotic use is less frequent in patients on ivacaftor treatment
CT=computed tomography; MRI=magnetic resonance imaging; LCI=lung clearance index; GOAL=G551D Observational
Study-Expanded to Additional Genotypes and Extended for Long Term Follow up; GI=gastrointestinal; LFT=liver function
test; IV=intravenous.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Vertex).
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182
CF Treatment:
Past , Present , and Future
(Roche)
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183
12 June Thursday, Satellite Symposium (Roche)
CF Treatment: Past, Present, and Future
• CF treatment in paediatric patients –
Harm Tiddens, Rotterdam, NL
– Past pivotal trials comparing 2 DA doses vs placebo were presented.
These indicated benefits to FEV1 and respiratory tract exacerbations
(DA still used today in 70% of CF patients)
– Currently trying to determine how to optimise efficacy and
“personalise” medicine
 Eg, by using “smart” nebulisers (target small vs large airways)
– In the future, need to explore novel therapies and technologies
 Ivacaftor
 DA in children <6 years; for use in small airway disease
 Bridging studies to smart nebulisers
 Multimodality monitoring
DA=dornase alpha; FEV1=forced expiratory volume in 1 second.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Roche).
Table of Contents
184
12 June Thursday, Satellite Symposium (Roche)
CF Treatment: Past, Present, and Future (cont)
• CF treatment in adult patients –
Christopher Goss, Seattle, US
– Between 1989 and 2013, adult CF centres grew from 20 patients to nearly 300
– In the past, recombinant DNAse showed rapid improvement in lung function
– Currently need to manage chronic illnesses because CF patients are living longer

Adult patients are approaching >50% of the CF population
– Currently have 5 Grade A evidence-based therapies, but patients are spending several
hours per day on regimens
– In the future, need to explore novel therapies (eg, ivacaftor) and technologies to
maximise lung function and personalise treatment
• Rates of adherence, treatment burden, and avenues for intervention –
Alexandra Quittner, Coral Gables, US
– By contrast with the past, adherence is increasingly recognised as important
– Current data reveal that patients comply with ~50% of treatments

Adherence declines over time, and with increasing regimen complexity and costs
– In the future, need electronic measures of adherence (eg, “smart” devices/“apps”),
better patient-provider collaboration, and management of psychosocial issues
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Roche).
Table of Contents
185
Changing Antibiotic Delivery
to Improve CF Patients’ Lives:
Challenges and Opportunities
(Novartis)
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186
Changing Antibiotic Delivery
to Improve CF Patients’ Lives:
Challenges and Opportunities
13 June Friday, Satellite Symposium (Novartis)
Faculty Perspective – Dr. Jacqueline Rendall, UK
“Interesting symposium looking in detail at the
challenges and opportunities we share with inhaled
antibiotics. This is particularly relevant as the number
available to us is likely to increase in the future.
It is important that we consider this issue of resistance
and find the optimal regimen for each patient.
‘Real-world’ evidence may be the best way of
assessing this.”
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Novartis).
Table of Contents
187
Changing Antibiotic Delivery
to Improve CF Patients’ Lives:
Challenges and Opportunities (cont)
13 June Friday, Satellite Symposium (Novartis)
• New modes of antibiotic delivery: Challenges and opportunities –
Harm Tiddens, Rotterdam, NL
– Properties of TIP vs TIS including better deposition (smaller particle size), non-inferiority to
TIS, possibility of treatment of smaller airway/diseased airway as current modality fails to
deliver to these areas, as deposition of TIP not as dependent on airflow
• Novel methods of antibiotic administration: What does real-world
evidence tell us? –
Barry Plant, Cork, IE
– Traditional inhaled therapy had a poor adherence track record (patients often cite
time commitment as major factor—need 20-30 min per administration—as well as
cumbersome device)
 New dry-powder, which is small and takes ~4 min to administer, offers a better option
– Although trials may demonstrate good data, they are limited in real-world application, as
neither patient nor healthcare provider are willing/capable of devoting similar time/resources
 Looked at a real-world reflective trial (MJ Harrison) looking at TIP vs TIS over
15 months
TIP=tobramycin inhalation powder; TIS=tobramycin inhalation solution.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Novartis).
Table of Contents
188
Changing Antibiotic Delivery
to Improve CF Patients’ Lives:
Challenges and Opportunities (cont)
13 June Friday, Satellite Symposium (Novartis)
• Debate introduction and historical overview –
Anders Lindblad, Gothenburg, SE
– The biggest rationale for the concept of 28 days on/28 days off comes from
2 studies from the 1980s that demonstrated improvements in FEV1 over a
30-day time period, but saw little improvement in the subsequent 90 days of
continuous medication
– Discussed reduction in P aeruginosa concentration in the first 28 days, with
no further drop in the following 27 days of continued medication
• Microbiologist’s perspective –
Juliet Foweraker, Cambridge, UK
– The risks of long-term antibiotics and the potential management options to
reduce the risks were discussed, including intermittent drug use, and
alternation of drugs (preferably ones with different MOAs)
– Discussions included resistance development, and how it may come about,
as well as concerns surrounding superinfection
– Continuous use vs cycling of medications was also reviewed
FEV1=forced expiratory volume in 1 second; MOA=mechanism of action.
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Novartis).
Table of Contents
189
Changing Antibiotic Delivery
to Improve CF Patients’ Lives:
Challenges and Opportunities (cont)
13 June Friday, Satellite Symposium (Novartis)
• Clinician’s perspective –
Diana Bilton, London, UK
– Discussed real-world needs of both patients and caregivers in relation to
management of condition and therapy
– Trials do not reflect real-world conditions. Frequently, events/conditions
noted in trials are not tolerated in actual setting, and results often need further
interpretation
• Patient cases discussion –
Juliet Foweraker, Cambridge, UK/Diana Bilton, London, UK
– Two cases illustrated types of patients that may or may not be candidates for new
therapeutic modalities (TIP vs TIS) and offered rationale for treatment decisions
Presented at: 37th European Cystic Fibrosis Conference; 11-14 June 2014; Gothenburg, Sweden.
Satellite Symposium (Novartis).
Table of Contents
190
Acknowledgements
We acknowledge the contributions of
Dr. Jacqueline Rendall for providing her clinical perspective,
and Fallon Medica LLC (Christine Park, Judi Greif, and
Kelly Ludwinski) for providing on-site conference coverage
and developing this summary of the
key highlights of the meeting.
This presentation was funded by Vertex Pharmaceuticals Incorporated.
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