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Scientific Coverage Gothenburg, Sweden 11-14 June 2014 37th European Cystic Fibrosis Conference © 2014 Vertex Pharmaceuticals Incorporated │ VXR-EU-02-00091.

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Presentation on theme: "Scientific Coverage Gothenburg, Sweden 11-14 June 2014 37th European Cystic Fibrosis Conference © 2014 Vertex Pharmaceuticals Incorporated │ VXR-EU-02-00091."— Presentation transcript:

1 Scientific Coverage Gothenburg, Sweden June th European Cystic Fibrosis Conference © 2014 Vertex Pharmaceuticals Incorporated │ VXR-EU │ 09/2014

2 2 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 Scientific Coverage Contributors 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.

3 3 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 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. Table of Contents

4 4 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 »» –FEV 1 and Nutritional Status: Chicken or the Egg? »» –Nutritional Challenges in Adults »» –Multidisciplinary Aspects of CFRD »»

5 5 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 »»

6 6 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 »»

7 7 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 »»

8 8 Screening and Diagnosis CF 2014: New Diagnostic Challenges »» Screening and Diagnosis »» Table of Contents

9 9 CF 2014: New Diagnostic Challenges Table of Contents

10 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; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 10 Table of Contents

11 11 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; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 10 Table of Contents

12 12 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; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 10 Table of Contents

13 13 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 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; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 10 Table of Contents

14 14 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): 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; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 10 Table of Contents

15 15 Screening and Diagnosis Table of Contents

16 16 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 11 Table of Contents

17 17 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 11 Table of Contents

18 18 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) Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop 11. Reproduced with permission from the presenter. 12 June Thursday, Workshop 11 Table of Contents

19 19 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 11 Table of Contents

20 20 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 11 Table of Contents

21 21 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 11 Table of Contents

22 22 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

23 23 How to Progress With CFTR Modulators? Table of Contents

24 24 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; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 1 Table of Contents

25 25 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; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 1 Table of Contents

26 26 The way forward in drug testing is phenotype-specific – Isabelle Sermet, Paris, FR –The phenotypic response, as assessed by sweat test and FEV 1 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 FEV 1 (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 How to Progress With CFTR Modulators? (cont) Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 1 Reproduced with permission from the presenter. Table of Contents

27 27 AAT=aminoarylthiazole; DDI=drug-drug interaction. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. 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 12 June Thursday, Symposium 1 Table of Contents

28 28 Fixing Basic Defects – New Therapies Table of Contents

29 29 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 1 Table of Contents

30 30 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 FEV 1 ), 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 (FEV 1 ) 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 FEV 1 (see figure) – Safety and tolerability results observed through 24 weeks consistent with those during Part 1 Fixing Basic Defects – New Therapies (cont) CFTR=cystic fibrosis transmembrane conductance regulator; KONNECTION=Study of Ivacaftor in Subjects With Cystic Fibrosis Who Have a Non-G551D CFTR Gating Mutation; FEV 1 =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; June 2014; Gothenburg, Sweden. Workshop 1. Observed (raw) mean changes from baseline FEV 1 are plotted at each time point. Reproduced with permission from the presenter and Vertex Pharmaceuticals Incorporated. 12 June Thursday, Workshop 1 Table of Contents

31 31 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 1 Table of Contents

32 32 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 Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop 1. Reproduced with permission from the presenter. 12 June Thursday, Workshop 1 Table of Contents

33 33 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 AO=antisense oligonucleotide. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 1 Reproduced with permission from the presenter. Table of Contents

34 34 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 1 Table of Contents

35 35 New Antibacterial Therapies Table of Contents

36 36 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 7 Table of Contents

37 37 New Antibacterial Therapies (cont) Antibacterial activity of RTD-1 against clinical isolates of Pseudomonas aeruginosa – Paul Beringer, Los Angeles, US –The macrocyclic peptide RTD-1 exhibits broad- spectrum 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=rhesus theta defensin-1; MIC=minimum inhibitory concentration. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 7 RTD-1 exhibits rapid concentration-dependent bactericidal activity P. aeruginosa (PAO1, MIC=2 μg/mL). RTD-1 Bactericidal Activity Reproduced with permission from the presenter. Table of Contents

38 38 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 FEV 1 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 FEV 1 –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; FEV 1 =forced expiratory volume in 1 second; AE=adverse event; CFQ-R=Cystic Fibrosis Questionnaire-Revised. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 7 Table of Contents

39 39 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 Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 7 Reproduced with permission from the presenter. Table of Contents

40 40 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) FEV 1 % 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 FEV 1 data, the rate of deterioration in median (IQR) FEV 1 % 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 7 Table of Contents

41 41 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 7 Table of Contents

42 42 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 Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 7 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 Reproduced with permission from the presenter. Table of Contents

43 43 The Therapeutic Pipeline 2014 Table of Contents

44 44 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 20 Table of Contents

45 45 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 https://www.ecfs.eu/ctn/clinical-trials ECFS-CTN=ECFS-Clinical Trial Network; EU=European Union. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 20 Reproduced with permission from the presenter. Table of Contents

46 46 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 20 Table of Contents

47 47 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 FEV 1 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 FEV 1 =forced expiratory volume in 1 second. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 20 Table of Contents

48 48 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 20 Table of Contents

49 49 Airway Controversies Table of Contents

50 50 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 19 Table of Contents

51 51 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 19 Table of Contents

52 52 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 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? Airway Controversies (cont) 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; June 2014; Gothenburg, Sweden. Symposium 19. Patient allergy profile Patient months drug recruitments 13 June Friday, Symposium 19 Reproduced with permission from the presenter. Reprinted with permission from Australian Cystic Fibrosis Foundation Data Registry Baulkham Hills, Australia; Reproduced with permission from the presenter. Prevalence of major organisms in lungs Table of Contents

53 53 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

54 54 Indexing the Lung Table of Contents

55 55 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 20 Table of Contents

56 56 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 FEV 1 measurements MBW N2=multiple breath washout with N 2 ; CT=computed tomography; FEV 1 =forced expiratory volume in 1 second. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 20 Table of Contents

57 57 Indexing the Lung (cont) Difference between multiple breath washout with N 2 (MBWN2) vs SF 6 (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 FEV 1 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 FEV 1  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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 20 Table of Contents

58 58 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 20 Table of Contents

59 59 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 LCI 5 and FEV 1 are more useful tools for the detection of lung disease when the disease is moderate Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 20 Reproduced with permission from the presenter. Table of Contents

60 60 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 FEV 1 : Many of the children had normal or near normal % predicted FEV 1 with a mean FEV 1 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 FEV 1 IV=intravenous. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 20 Table of Contents

61 61 New Insights in Lung Disease Table of Contents

62 62 New Insights in Lung Disease Patients with mutations that permit 3% or more of wild-type CFTR function are associated with higher FEV 1 – 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 FEV 1 –Patients with ≥3% CFTR function had a clinically relevant difference in FEV 1 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; FEV 1 =forced expiratory volume in 1 second; PTC=premature termination codon. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 13 Table of Contents

63 63 New Insights in Lung Disease (cont) Change in FEV 1 % 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 FEV 1 in 1 year in subjects ≥6 years (without lung transplant) and baseline lung function between 40% and 90% predicted –Compared change in FEV 1 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 FEV 1 from year to year Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 13 Table of Contents

64 64 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 New Insights in Lung Disease (cont) MRI=magnetic resonance imaging; IV=intravenous. Presented at: 37th European Cystic Fibrosis Conference; 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): Official Journal of the American Thoracic Society. Top row: MRI of acute exacerbation in early CF of a 6-year-old patient, which revealed extensive contrast- enhancing 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 13 June Friday, Workshop 13 Table of Contents

65 65 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 µm 2 ; p<0.001) in CF versus control MDCT=multidetector computed tomography. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 13 Table of Contents

66 66 New Insights in Lung Disease (cont) Visualising ventilation heterogeneity in mild CF using hyperpolarised 3 He MRI, and comparison with lung clearance index (LCI) – Alexander Horsley, Manchester, UK –Investigated and compared sensitivity of 3 He 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) Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 13 Reproduced with permission from the presenter. Table of Contents

67 67 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 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 13 Reproduced with permission from the presenter. Table of Contents

68 68 Functional Intestinal Outcome Measures in CF in the Era of Correctors and Potentiators Table of Contents

69 69 Functional Intestinal Outcome Measures in CF in the Era of Correctors and Potentiators 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; June 2014; Gothenburg, Sweden. Symposium June Saturday, Symposium 28 Table of Contents

70 70 Functional Intestinal Outcome Measures in CF in the Era of Correctors and Potentiators (cont) 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 –HCO 3 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 HCO 3 =bicarbonate; GOAL=G551D Observational Study-Expanded to Additional Genotypes and Extended for Long Term Follow up. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Saturday, Symposium 28 Table of Contents

71 71 Multiple Breath Inert Gas Washout (MBW)—An Introduction Table of Contents

72 72 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 (Sn III ) 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; June 2014; Gothenburg, Sweden. Meet the Experts. Meet the Experts—P Gustafsson Table of Contents

73 73 Utility of MBW in CF and Other Paediatric Respiratory Disorders Table of Contents

74 74 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 FEV 1 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; FEV 1 =forced expiratory volume in 1 second. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Meet the Experts. Meet the Experts—P Gustafsson Table of Contents

75 75 Standards of Care and Clinical Practice Guidelines The New ECFS Standards of Care »» ECFS Clinical Practice Guideline: Exercise Testing in CF »» Table of Contents

76 76 The New ECFS Standards of Care Table of Contents

77 77 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 13 Table of Contents

78 78 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 Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 13 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 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 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. Table of Contents

79 79 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 13 Table of Contents

80 80 The New ECFS Standards of Care (cont) The new ECFS standards of care: Best practice – Alan Smyth, Nottingham, UK (cont) Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium Evolution of Standards of Care for CF 2005 to June Friday, Symposium 13 Journal of Cystic Fibrosis 4 (2005) 7-26 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 Review European Cystic Fibrosis Society Standards of Care: Framework for the Cystic Fibrosis Centre 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 Journal of Cystic Fibrosis 13 (2014) S43-S59 Review European Cystic Fibrosis Society Standards of Care: Quality Management in cystic fibrosis 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. Table of Contents

81 81 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 13 Table of Contents

82 82 ECFS Clinical Practice Guideline: Exercise Testing in CF Table of Contents

83 83 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; June 2014; Gothenburg, Sweden. CFTR Educational Suite Expert Session. CFTR Educational Suite Expert Session –H. Hebestreit Table of Contents

84 84 Clinical Care Considerations Adherence »» FEV 1 and Nutritional Status: Chicken or the Egg? »» Nutritional Challenges in Adults »» Multidisciplinary Aspects of CFRD »» Table of Contents

85 85 Adherence Table of Contents

86 86 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 10 Table of Contents

87 87 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 FEV 1 decreased, and as additional medication was added to the treatment regimen CFQ-R= Cystic Fibrosis Questionnaire-Revised; CoV=coefficient of variation; FEV 1 =forced expiratory volume in 1 second. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 10 Table of Contents

88 88 Adherence (cont) Objective predictors of self-report of adherence in adults with CF – Daniel Peckham, Leeds, UK (cont) –Self-reported adherence and CoV FEV 1 were inversely related (r=-0.16, p<0.001), suggesting that less variation is apparent as adherence improves CRP=C-reactive protein; PERT=pancreatic enzyme replacement therapy. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 10 Reproduced with permission from the presenter. Table of Contents

89 89 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 10 Table of Contents

90 90 FEV 1 and Nutritional Status: Chicken or the Egg? Table of Contents

91 91 FEV 1 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 FEV 1 =100% at age 6) –At 50th percentile, FEV 1 >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; FEV 1 =forced expiratory volume in 1 second; BMI=body mass index. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 6 Table of Contents

92 92 FEV 1 and Nutritional Status: Chicken or the Egg? (cont) Longitudinal data on FEV 1 – Laura Viviani, Milan, IT –Studied 795 patients over 30 years ( ) for association between malnutrition (height, weight, BMI) and lung function (FEV 1 SDS) –Mean FEV 1 SDS loss 14% over 8 years (loss of -1.1 FEV 1 SDS per year); BMI stayed stable –Patients diagnosed in more recent years have better FEV 1 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; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 6 Table of Contents

93 93 Nutritional Challenges in Adults Table of Contents

94 94 BMI=body mass index; FEV 1 =forced expiratory volume in 1 second. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. 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 FEV 1 ) –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 FEV 1 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 12 June Thursday, Symposium 12 Table of Contents

95 95 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; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 12 Table of Contents

96 96 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) MOA=mechanism of action; GI=gastrointestinal; ATP=adenosine triphosphate. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 12 Gastric acid neutralisation is normalised in subjects with CF taking ivacaftor 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): Official Journal of the American Thoracic Society. Adapted from Gelfond D et al. Dig Dis Sci. 2013;58(8): With kind permission of Springer Science+Business Media. Minutes from gastric emptying Small bowel pH changes (mean pH readings every minute) Table of Contents

97 97 Multidisciplinary Aspects of CFRD Table of Contents

98 98 Multidisciplinary Aspects of CFRD Insulin and the lung – Nicola Bridges, London, UK –There is no clear cut-off (OGTT, CGMS, HbA 1c ) when to start treatment  Data from the UK CF registry showed a 3-fold increased mortality risk in CFRD patients with HbA 1c levels >6.5% (the clinical defined target for HbA 1c ), 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  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; HbA 1c =hemoglobin A 1c ; CFRD=cystic fibrosis-related diabetes; BMI=body mass index. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 16 “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 “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 Table of Contents

99 99 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) –Under non-fasted conditions, a positive relationship 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 13 June Friday, Symposium 16 Reproduced with permission from the presenter. Panel C adapted with permission of American Society for Clinical Investigation. Olivier AK et al. J Clin Invest. 2012;122(10): CFTR=cystic fibrosis transmembrane conductance regulator. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium 16. Table of Contents

100 100 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 16 Table of Contents

101 101 Case Studies in CF Psychosocial/Nursing Complex Case Presentations »» Interactive Case Studies »» Table of Contents

102 102 Psychosocial/Nursing Complex Case Presentations Table of Contents

103 103 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  FEV 1 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 FEV 1 =forced expiratory volume in 1 second. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 22 Table of Contents

104 104 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 at age 18; acute rejection at age 29, requiring re-transplantation (FEV 1 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 22 Reproduced with permission from the presenter. Table of Contents

105 105 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 Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop 22. 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 13 June Friday, Workshop 22 Reproduced with permission from the presenter. Table of Contents

106 106 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 22 Table of Contents

107 107 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 22 Table of Contents

108 108 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 (FEV 1 = 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 22 Table of Contents

109 109 Psychosocial/Nursing Complex Case Presentations (cont) An attempt to eradicate Mycobacterium abscessus in a patient with CF – Kairen Griffiths, Aberdeen, UK (cont) IV=intravenous. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop 22. Plan for eradication therapy 1 1-month Induction Therapy Imipenem500 mg 4 x day IV 2Tigecycline50 mg 2 x day IV 3Amikacin15 mg/kg in 2 divided doses IV 4Azithromycin500 mg daily oral Beginning of week 4 – 2-year maintenance therapy Amikacin500 mg bd nebulised Meropenem250 mg bd nebulised Azithromycin250 mg daily oral Minocycline100 mg 2 x day oral 13 June Friday, Workshop 22 Reproduced with permission from the presenter. Table of Contents

110 110 Interactive Case Studies Table of Contents

111 111 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 O 2 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 14 Table of Contents

112 112 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  FEV 1 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; FEV 1 =forced expiratory volume in 1 second. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 14 Table of Contents

113 113 Interactive Case Studies (cont) A binge-drinking girl with recurrent pancreatitis – Barbara Bosch, Leuven, BE –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  FEV 1 102% predicted and FVC 105% predicted  Borderline sweat chloride concentration (47 mmol/L)  An intermediate NPD –This unexpected finding raised 2 major questions:  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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 14 Reproduced with permission from the presenter. Total chloride response of the patient compared to controls and patients with CF Table of Contents

114 114 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; June 2014; Gothenburg, Sweden. Symposium June Friday, Symposium 14 Table of Contents

115 115 Registry Data Using Registries to Identify New Challenges »» Pharmacovigilance/Phase 4 Studies Using Registries »» Table of Contents

116 116 Using Registries to Identify New Challenges Table of Contents

117 117 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 4 Table of Contents

118 118 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 4 Table of Contents

119 119 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 4 Table of Contents

120 120 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 FEV 1 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 4 Table of Contents

121 121 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 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 4 Table of Contents

122 122 Pharmacovigilance/Phase 4 Studies Using Registries Table of Contents

123 123 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; June 2014; Gothenburg, Sweden. Symposium June Saturday, Symposium 29 Table of Contents

124 124 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; June 2014; Gothenburg, Sweden. Symposium June Saturday, Symposium 29 Pharmacovigilance/Phase 4 Studies Using Registries (cont) Table of Contents

125 125 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  QC measures in place to ensure data accuracy EMR=electronic medical record. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Saturday, Symposium 29 Pharmacovigilance/Phase 4 Studies Using Registries (cont) Reproduced with permission from the presenter. Table of Contents

126 126 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

127 127 Exploring New Endpoints in Clinical Trials Table of Contents

128 128 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 FEV 1 ≥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, 3 He-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 3 He-MRI may be useful for assessing ventilation defects that may not be captured using traditional spirometry FEV 1 =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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 3 Table of Contents

129 129 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 FEV 1 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 FEV 1, and P. aeruginosa infection –Estimated annualised rate of decline in % predicted FEV 1 (± SE) in ivacaftor-treated patients is ± 0.36 US CFPR= United States Cystic Fibrosis Patient Registry. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 3 Table of Contents

130 130 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 FEV 1 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 FEV 1 % 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 3 Table of Contents

131 131 Exploring New Endpoints in Clinical Trials (cont) Lack of correlation between sputum Pseudomonas aeruginosa density and FEV 1 changes among CF patients treated with inhaled antibiotics – Donald Vandevanter, Cleveland, US –In this 24-week randomised comparison of LNS and TNS, beneficial FEV 1 changes subsequent to inhalation or withdrawal from an antibiotic for 28 days did not correlate with expected changes in Pa concentrations in sputum –Results suggest that sputum Pa density changes inadequately reflect the effect of inhaled antibiotics on the airways of CF patients LNS=levofloxacin nebuliser solution; TNS=tobramycin nebuliser solution; Pa=Pseudomonas aeruginosa. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop 3. Change in FEV 1 does not correlate with change in sputum Pa density among CF patients treated with inhaled antibiotics 12 June Thursday, Workshop 3 Reproduced with permission from the presenter. TNS Table of Contents

132 132 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; June 2014; Gothenburg, Sweden. Workshop June Thursday, Workshop 3 Table of Contents

133 133 AHP Research Symposium: Changing Clinical Practice Through Research With Minimal or No Funding Table of Contents

134 134 AHP Research Symposium: Changing Clinical Practice Through Research With Minimal or No Funding 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; June 2014; Gothenburg, Sweden. Special Symposium. 13 June Friday, Special Symposium Table of Contents

135 135 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; June 2014; Gothenburg, Sweden. Special Symposium. 13 June Friday, Special Symposium Table of Contents

136 136 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; June 2014; Gothenburg, Sweden. Special Symposium. 13 June Friday, Special Symposium Table of Contents

137 137 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; June 2014; Gothenburg, Sweden. Special Symposium. 13 June Friday, Special Symposium Table of Contents

138 138 Clinical Trials in Preschool Children Table of Contents

139 139 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; June 2014; Gothenburg, Sweden. Symposium June Saturday, Symposium 25 Table of Contents

140 140 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

141 141 Stem Cell-Based Airway Modelling and Regenerative Medicine for CF Table of Contents

142 142 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 CFTR=cystic fibrosis transmembrane conductance regulator; AEs=adverse events. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 11 Reproduced with permission from the presenter. Table of Contents

143 143 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; June 2014; Gothenburg, Sweden. Symposium June Thursday, Symposium 11 Table of Contents

144 144 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 hiPSC=human induced pluripotent stem cells; iPSC=induced pluripotent stem cells; KGF=keratinocyte growth factor. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium 11. Personalised therapies for CF: patient-specific induced pluripotent stem cells for disease modelling, drug screening, and cellular therapies 12 June Thursday, Symposium 11 Reproduced with permission from the presenter. Table of Contents

145 145 Late-Breaking Science Table of Contents

146 146 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 non- conventional 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 18 Table of Contents

147 147 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 18 Table of Contents

148 148 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 18 Table of Contents

149 149 CFTR Genetics and Function Table of Contents

150 150 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 23 Table of Contents

151 151 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 of pharmacologically rescued p.Phe508del-CFTR NBD=nucleotide binding domain; WT=wild-type. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 23 Adapted by permission from Macmillan Publishers Ltd: Molinski SV et al. Genet Med. 2014;16(8): Table of Contents

152 152 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 23 Table of Contents

153 153 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 V max 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; V max FRC=maximal flow at functional residual capacity. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 23 Table of Contents

154 154 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 FEV %) with absolute change % predicted FEV 1 treatment effect of 5.0 (P=0.01); relative change treatment effect (not shown) was 9.1 (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; FEV 1 =forced expiratory volume in 1 second; SE=standard error. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop 23. Change from baseline through Week 24 Treatment Difference (P value) Absolute change in percent predicted FEV 1 (% points) 5.0 (P=0.01) 13 June Friday, Workshop 23 Reproduced with permission from the presenter and Vertex Pharmaceuticals Incorporated. Table of Contents

155 155 Epithelial Cell Biology Table of Contents

156 156 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 17 Table of Contents

157 157 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 Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 17 Reproduced with permission from the presenter. Table of Contents

158 158 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; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 17 Table of Contents

159 159 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 - /HCO 3 - -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 - /HCO 3 - -exchange HCO 3 =bicarbonate. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Workshop June Friday, Workshop 17 Table of Contents

160 160 The “Epithelial” Channeltome and Options for Rescue Table of Contents

161 161 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 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; June 2014; Gothenburg, Sweden. Symposium June Saturday, Symposium 30 Reproduced with permission from the presenter. Table of Contents

162 162 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 The “Epithelial” Channeltome and Options for Rescue (cont) HBE=human bronchial epithelial; WT=wild-type; KO=knockout. Source: Anagnostopoulou P et al. J Clin Invest. 2012;122(10): Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Saturday, Symposium 30 Table of Contents

163 163 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; June 2014; Gothenburg, Sweden. Symposium June Saturday, Symposium 30 Table of Contents

164 164 The “Epithelial” Channeltome and Options for Rescue (cont) cAMP compartmentation and CFTR regulation – Manuela Zaccolo, Oxford, UK (cont) Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Symposium June Saturday, Symposium 30 Adapted with permission from Monterisi S et al. J Cell Sci. 2012;125(Pt 5): Table of Contents

165 165 Translational Value of Ex Vivo CFTR Biomarker Table of Contents

166 166 Translational Value of Ex Vivo CFTR Biomarker CFTR=cystic fibrosis transmembrane conductance regulator; ICM=intestinal current measurement. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. CFTR Educational Suite Experts Session. CFTR Educational Suite Experts Session Reproduced with permission from the presenter. 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 –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? Table of Contents

167 167 Plenary Session Table of Contents

168 168 Goblet Cell Does not occur in CF Enzyme Attachment packed in granulae secreted and unfolded 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 HCO 3, allows the attached mucus to trap bacteria and causes CF disease –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 CFTR=cystic fibrosis transmembrane conductance regulator; HCO 3 =bicarbonate. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Closing Plenary. CF mucins remain anchored to the epithelium as bicarbonate necessary for unfolding mucin to access cleavage site is lacking Reproduced with permission from the presenter. 14 June Saturday, Closing Plenary Table of Contents

169 169 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; June 2014; Gothenburg, Sweden. Closing Plenary. 14 June Saturday, Closing Plenary Table of Contents

170 170 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 Reproduced with permission from the presenter and Dutch VanDevanter. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Closing Plenary. Signs and Symptoms worse better Diagnose exacerbation treat Time Previous (stable) encounter Treating to previous baseline: What path did the patient follow from ‘stable’ to ‘unstable’? Undiagnosed exacerbation? New baseline? goal 14 June Saturday, Closing Plenary Table of Contents

171 171 Posters Best Poster Awards »» Abstracts Online »» Table of Contents

172 172 Best Poster Awards CFTR/Cell Biology/Cell Physiology/New Therapies – Maaike Berkhout, The Hague, The Netherlands Genetics/Screening/Diagnosis – Andrea Holubová, Prague, Czech Republic 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 Immunology/Inflammation/Pulmonology – Jochen Mainz, Jena, Germany Nursing/Psychosocial Issues – Frederick Frost, Liverpool, United Kingdom Gastrointestinal/Liver Disease/Metabolic Complications of CF/Nutrition – Anne Mößeler, Hannover, Germany Physiotherapy – Fiona Shaw, London, United Kingdom Epidemiology – Registry/Delivery of Care – Emem Ukor, Cambridge, United Kingdom Table of Contents

173 173 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 https://www.ecfs.eu/meetings/ecfs/37th+ECFS+Conference%2C+ Gothenberg+%2C+Sweden%2C+June+2014/6066 –Journal of Cystic Fibrosis website: Table of Contents

174 174 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

175 175 Changing Faces Changing Solutions (Gilead) Table of Contents,

176 176 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 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 s, 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 PROs=patient-reported outcomes; NPD=nasal potential difference; LCI=lung clearance index; CT=computed tomography. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Satellite Symposium (Gilead). 12 June Thursday, Satellite Symposium (Gilead) Industry Phase 4 StudiesCF Registry 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 OwnershipIndustryAcademia Data collection Substantial addition to, or duplication of workload Most data currently being collected Real worldLess soYes Comparative analysis No control group Potential for research with concurrent/ historical controls Health economic data GoodLimited Reproduced with permission from the presenter. Table of Contents

177 177 Changing Faces, Changing Solutions (cont) Understanding future challenges of clinical care – Scott Bell, Brisbane, AU –Numbers increasing –Complexity increasing  Patient  CF team –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 TPCH=The Prince Charles Hospital. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Satellite Symposium (Gilead). Growth in adult CF population at TPCH 12 June Thursday, Satellite Symposium (Gilead) Reproduced with permission from the presenter. Reprinted with permission from Cystic Fibrosis Foundation Patient Registry, 2012 Annual Data Report, Bethesda, Maryland, ©2013 Cystic Fibrosis Foundation. Table of Contents

178 178 CFTR Modulation in CF (Vertex) Table of Contents

179 179 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; June 2014; Gothenburg, Sweden. Satellite Symposium (Vertex). 12 June Thursday, Satellite Symposium (Vertex) Table of Contents

180 180 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 Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Satellite Symposium (Vertex). 12 June Thursday, Satellite Symposium (Vertex) What determines CFTR quantity and function? Total CFTR Activity Total Chloride Ion Transport Total CFTR Activity Total Chloride Ion Transport Number of CFTR Channels in Apical Surface CFTR synthesis CFTR processing CFTR splicing CFTR surface stability Channel Open Probability Channel Conductance Channel gating Transport rate CFTR Quantity CFTR Function Table of Contents

181 181 CFTR Modulation in CF (cont) 12 June Thursday, Satellite Symposium (Vertex) Mean Absolute Change From Baseline in Percent Predicted FEV 1 Adults/Adolescents Children Observed (raw) mean changes from baseline in STRIVE and in ENVISION percent predicted FEV 1 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). 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 FEV 1, which persisted for 96 weeks. Patients formerly on placebo in STRIVE reached the same improvement in FEV 1 when switched to PERSIST  In ENVISION, there was more than 10% mean absolute change from baseline in percent predicted FEV 1. The FEV 1 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 –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 PERSIST=An Open-Label, Rollover Study to Evaluate the Long Term Safety and Efficacy of VX 770 in 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; FEV 1 =forced expiratory volume in 1 second; SE=standard error. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Satellite Symposium (Vertex). McKone E et al. Pediatr Pulmonol. 2013;48 (S36):287. Reproduced with permission from the presenter and Vertex Pharmaceuticals Incorporated. Table of Contents

182 182 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 –FEV 1 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 FEV 1 <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; June 2014; Gothenburg, Sweden. Satellite Symposium (Vertex). 12 June Thursday, Satellite Symposium (Vertex) Table of Contents

183 183 CF Treatment: Past Present and Future (Roche) Table of Contents,,

184 184 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 FEV 1 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; FEV 1 =forced expiratory volume in 1 second. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Satellite Symposium (Roche). 12 June Thursday, Satellite Symposium (Roche) Table of Contents

185 185 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; June 2014; Gothenburg, Sweden. Satellite Symposium (Roche). 12 June Thursday, Satellite Symposium (Roche) Table of Contents

186 186 Changing Antibiotic Delivery to Improve CF Patients’ Lives: Challenges and Opportunities (Novartis) Table of Contents

187 187 Changing Antibiotic Delivery to Improve CF Patients’ Lives: Challenges and Opportunities 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; June 2014; Gothenburg, Sweden. Satellite Symposium (Novartis). 13 June Friday, Satellite Symposium (Novartis) Table of Contents

188 188 Changing Antibiotic Delivery to Improve CF Patients’ Lives: Challenges and Opportunities (cont) 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 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; June 2014; Gothenburg, Sweden. Satellite Symposium (Novartis). 13 June Friday, Satellite Symposium (Novartis) Table of Contents

189 189 Changing Antibiotic Delivery to Improve CF Patients’ Lives: Challenges and Opportunities (cont) 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 FEV 1 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 FEV 1 =forced expiratory volume in 1 second; MOA=mechanism of action. Presented at: 37th European Cystic Fibrosis Conference; June 2014; Gothenburg, Sweden. Satellite Symposium (Novartis). 13 June Friday, Satellite Symposium (Novartis) Table of Contents

190 190 Changing Antibiotic Delivery to Improve CF Patients’ Lives: Challenges and Opportunities (cont) 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; June 2014; Gothenburg, Sweden. Satellite Symposium (Novartis). 13 June Friday, Satellite Symposium (Novartis) Table of Contents

191 191 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. Table of Contents


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