CYSTIC FIBROSIS (CF): THE CHALLENGE OF EARLY, SYSTEMIC PROGRESSION

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1 CYSTIC FIBROSIS (CF): THE CHALLENGE OF EARLY, SYSTEMIC PROGRESSION A Program for the CF Center Care Team Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA Vertex and the Vertex triangle logo are registered trademarks for Vertex Pharmaceuticals Incorporated Vertex Pharmaceuticals Incorporated VXR-US / Vertex Pharmaceuticals Incorporated

2 Program Objectives Improve your understanding of: What causes CF and its cellular effects How CF progresses in different organs of the body The importance of monitoring disease progression throughout a patient s life Vertex Pharmaceuticals Incorporated

3 CF and its Progression A challenge throughout the patient s care journey Vertex Pharmaceuticals Incorporated

4 In CF, mutations in the CFTR gene affect CFTR protein production 281 known CFTR mutations can result in CF due to too few and/or defective CFTR proteins 1-3 A person needs 2 CF-causing mutations to have CF 2 With too few and/or defective CFTR proteins, the balance of water and salt at epithelial cell surfaces is disrupted 2,4-6 Mucus becomes thick and sticky in organs throughout the body, and it can clog small passages 2,4-6 This interferes with the proper function of the lungs, pancreas, gastrointestinal system, sinuses, liver, and reproductive system CFTR, cystic fibrosis transmembrane conductance regulator. References: 1. Castellani C et al. J Cyst Fibros. 2008;7(3): Zielenski J. Respiration. 2000;67(2): The Clinical and Functional TRanslation of CFTR (CFTR2); available at List of CFTR2 mutations. Accessed July 31, Davis PB. Am J Respir Crit Care Med. 2006;173(5): Welsh MJ et al. Membrane transport disorders: cystic fibrosis. In: Valle D, Beaudet A, Vogelstein B, et al, eds. The Online Metabolic & Molecular Bases of Inherited Disease. The McGraw-Hill Companies, Inc.; 2004:part 21, chap O Sullivan BP, Freedman SD. Lancet. 2009;373(9678): Vertex Pharmaceuticals Incorporated

5 CFTR proteins: An important regulator of fluid and ion balance in organs throughout the body CFTR proteins are found on epithelial cell surfaces in organs throughout the body 1-4 Normally, CFTR protein channels transport ions, such as chloride and bicarbonate, through the epithelial cell surface in these organs 1-4 Maintaining water and salt balance at the epithelial cell surface requires an adequate quantity and function of CFTR proteins 1,5 References: 1. Zielenski J. Respiration. 2000;67(2): O Sullivan BP, Freedman SD. Lancet. 2009;373(9678): MacDonald KD et al. Pediatr Drugs. 2007;9(1): Derichs N. Eur Respir Rev. 2013;22(127): Ward CL, Kopito RR. J Biol Chem. 1994;269(41): Vertex Pharmaceuticals Incorporated

6 If the quantity and/or function of CFTR proteins are reduced significantly, the result can be CF Reduced CFTR quantity 1-4 Reduced CFTR function 1-4 References: 1. Castellani C et al. J Cyst Fibros. 2008;7(3): Sheppard DN et al. Nature. 1993;362(6416): Zielenski J. Respiration. 2000;67(2): Derichs N. Eur Respir Rev. 2013;22(127): Vertex Pharmaceuticals Incorporated

7 Too few or defective CFTR proteins means a cascade of disease and lung damage The cascade of CF in the lungs can result in inflammation, infection, and lung damage, even before the loss of lung function is detected by spirometry 1-4 Damage can be cumulative over time 1,2,5,6 A similar cascade of events with CFTR dysfunction causes thickening of secretions, blocking of small passages, inflammation, and damage in other organs 1,2,7-9 THE CFTR DYSFUNCTION CASCADE IN THE LUNGS 2 References: 1. O Sullivan BP, Freedman SD. Lancet. 2009;373(9678): Elborn JS. Lancet. 2016;388(10059): Rao S, Grigg J. Arch Dis Child. 2006;91: Levy H et al. Pediatr Pulmonol. 2007;42(3): Farrell PM et al. Radiology. 2009;252(2): Smith L et al. Am J Respir Crit Care Med doi: /rccm le. [Epub ahead of print.] 7. Cunningham JC, Taussig LM. An introduction to cystic fibrosis for patients and their families. Cystic Fibrosis Foundation Orenstein DM et al. Cystic fibrosis: a guide for patient and family. 4th Ed. Philadelphia, PA: Lippincott Williams & Wilkins; Ooi CY, Durie PR. J Cyst Fibros. 2012;11(5): Vertex Pharmaceuticals Incorporated

8 CF and its Progression Affects many of the patient s organs, throughout their lifetime Vertex Pharmaceuticals Incorporated

9 CFTR protein dysfunction affects multiple organ systems with progressive signs and symptoms 1-4 Sinuses Lungs Pancreas Skin/sweat glands Gastrointestinal system Reproductive system Many problems with CF may be present at birth and persist and progress throughout a patient s life 1,4 Onset and progression of CF symptoms can occur in different organs at different ages 1,5 References: 1. Zielenski J. Respiration. 2000;67(2): Davis PB. Am J Respir Crit Care Med. 2006;173(5): Welsh MJ et al. Membrane transport disorders: cystic fibrosis. In: Valle D, Beaudet A, Vogelstein B, et al, eds. The Online Metabolic & Molecular Bases of Inherited Disease. The McGraw-Hill Companies, Inc.; 2004:part 21, chap O Sullivan BP, Freedman SD. Lancet. 2009;373(9678): Elborn JS. Lancet. 2016;388(10059): Vertex Pharmaceuticals Incorporated

10 Potentially irreversible lung damage can begin early in life Mucus plugging and thickening of airways (bronchiectasis) often occurs in infants and young children (age 0-5 years) 1,2 Bronchiectasis advances as children age and is typically established before age 20 years 1 Pulmonary exacerbations become more common (age 6-10 years) 2,3 Small airway damage has been seen in infants and children, often despite normal-appearing lung function 2,4,5 The predominant infection in small children is Staphylococcus aureus, but increasingly becomes Pseudomonas aeruginosa beginning in adolescence 1 In adult patients, established bronchiectasis with hemoptysis and pneumothorax may occur 1 Eventually, patients develop progressive respiratory failure and may need lung transplant 1 Childhood Adolescence Adulthood Lifelong Mucus plugging, infections, beginning lung damage 1 Progressive lung disease 1 Eventual lung failure 1 Pulmonary exacerbations 2,3 References: 1. Elborn JS. Lancet. 2016;388(10059): Sly PD et al. N Engl J Med. 2013;368(21): Byrnes CA et al. Thorax. 2013;68(7): Kraemer R et al. Am J Respir Crit Care Med. 2005;171(4): Rowan SA et al. Am J Respir Crit Care Med. 2014;189(5): Vertex Pharmaceuticals Incorporated

11 Patients may experience structural lung damage before a decline in FEV 1 is detected HRCT scan below shows pulmonary abnormalities in the lungs of a 13-year-old boy with normal pulmonary function tests and a ppfev 1 of 99% 1 1. Bronchiectasis 2. Bronchiectasis 5. Peripheral cysts 3. Peripheral cysts 4. Mucus-plugged bronchus This was a retrospective study in 25 children with CF with a mean age of 10.7 years and a mean FEV 1 of 76. The purpose of the study was to show correlation of CT score with pulmonary disease. The study was able to show correlation of CT score with pulmonary function tests. The image above was 1 instance where CT scan was shown to be more sensitive. 1 Adapted with permission from de Jong et al. FEV 1, forced expiratory volume in 1 second; HRCT, high-resolution computed tomography; ppfev 1, percent predicted FEV 1. Reference: 1. de Jong PA et al. Radiology. 2004;231(2): Vertex Pharmaceuticals Incorporated

12 LCI is sensitive at detecting early CF airway disease LCI shows a strong correlation with CT scan for verification of early disease 1 In the same study, FEV 1 did not detect the presence of abnormalities observed on CT scan 1 LCI is more sensitive to damage to the small peripheral airways than FEV 1 2 LCI is still considered an exploratory endpoint in clinical trials 3 LCI z-score vs CT score 1 A significant linear correlation was observed between CT score and LCI score 1 * Reprinted from Respir Med, 104(12), Ellemunter H, Fuchs SI, Unsinn KM, et al, Sensitivity of lung clearance index and chest computed tomography in early CF lung disease, , Copyright 2010, with permission from Elsevier. *138 patients from the Medical University of Innsbruck were screened to identify patients with normal FEV 1, defined as the annual average >80% predicted normal value at a minimum of 4 lung function measurements per year. Forty-one patients were asked to participate. Thirty-four patients age 6-26 years (mean age 14 years) with early lung disease shown on CT scan were assessed; 59% were F508del homozygous and 35% were F508del heterozygous. 1 LCI, lung clearance index. References: 1. Ellemunter H et al. Respir Med. 2010;104(12): Davies JC et al. Thorax. 2008;63(2): Kent L et al. J Cyst Fibros. 2014;13(2): Vertex Pharmaceuticals Incorporated

13 Sinusitis can be a lifelong problem The sinuses may be a reservoir for lung pathogens The sinuses are considered to be a major reservoir for bacteria that later infect the lungs 1 Chronic rhinosinusitis and increased incidence of nasal polyps occur in almost all patients with CF due to increased mucus viscosity Sinusitis often precedes the development of progressive lung disease in CF Lifelong Chronic rhinosinusitis, nasal polyps 1 Reference: 1. Illing EA, Woodworth BA. Curr Opin Pulm Med. 2014;20(6): Vertex Pharmaceuticals Incorporated

14 Pancreatic problems are very common and progressive As many as 90% of people with CF have impaired pancreatic function (pancreatic insufficiency) at birth or shortly afterward 1,2 The rest are considered pancreatic sufficient 3 In pancreatic insufficiency, mucus obstructs pancreatic ducts, impedes function, and leads to progressive damage 2 Such obstruction can begin even before birth 1 These patients with pancreatic insufficiency have a hard time digesting and absorbing food, resulting in poor growth and health 2 Over time, the pancreas undergoes autolysis (destruction) with replacement of the body of the pancreas with fat 2 Up to 40% of adults with CF will develop CF-related diabetes mellitus 1 Insulin insufficiency and carbohydrate intolerance follow autolysis, marking the development of CF-related diabetes mellitus 2 Among the rest (patients with CF who are pancreatic sufficient), 15% develop pancreatitis by age 20 years 3 By age 35 years, as many as 30% have pancreatitis Childhood Adolescence Adulthood Pancreatic insufficiency, poor nutrition and growth 1-3 Progressive pancreatic damage 1,3 CF-related diabetes, pancreatitis 1,3 References: 1. Elborn JS. Lancet. 2016;388(10059): O Sullivan BP, Freedman SD. Lancet. 2009;373(9678): Ooi CY, Durie PR. J Cyst Fibros. 2012;11(5): Vertex Pharmaceuticals Incorporated

15 Difficulties in the gastrointestinal tract can affect nutrition Gastrointestinal consequences in adults with CF include 1 : Thickened intestinal secretions Decreased motility of food through the gut Nutrient malabsorption DIOS or chronic constipation in older patients can occur 1 Nutrient malabsorption especially of fat-soluble vitamins can lead to 1 : Acrodermatitis Anemia Neuropathy Night blindness Osteoporosis Bleeding disorders There is also a risk of focal biliary cirrhosis caused by obstruction of intrahepatic bile ducts 1 Childhood Later in life Poor gut motility and absorption of nutrients 1 DIOS, focal biliary cirrhosis 1 DIOS, distal intestinal obstruction syndrome. Reference: 1. O Sullivan BP, Freedman SD. Lancet. 2009;373(9678): Vertex Pharmaceuticals Incorporated

16 Poor nutrition in younger children is correlated with reduced lung function Low weight at age 3 years predicts lower FEV 1 at age 6 years 1 Mean ppfev 1 at Age 6 Years by WFA Percentile at Age 3 Years (N=931) Adapted from Konstan et al. WFA, weight for age. Reference: 1. Konstan et al. J Pediatr. 2003;142: Vertex Pharmaceuticals Incorporated

17 In the liver, progressive biliary plugging and eventual liver damage can occur Dysfunctional or absent CFTR proteins appear to alter bile viscosity and cause mucosal obstruction of bile ducts 1,2 This can result in progressive biliary plugging and chronic cholestasis, biliary obstruction, inflammation, and structural damage 2 As early as age 10 years, patients may have abnormal liver function test results 3 5% of patients may develop biliary cirrhosis by age 15 years 1,3 As patients become adults, 5% to 10% additionally develop portal hypertension 3 Liver transplant may be required in some patients (typically age >35 years) Childhood Adulthood Abnormal liver function tests 3 Portal hypertension 3 References: 1. O Sullivan BP, Freedman SD. Lancet. 2009;373(9678): Cañas T et al. Biomed Res Int. 2015;2015: doi: /2015/ [Epub ahead of print.] 3. Elborn JS. Lancet. 2016;388(10059): Vertex Pharmaceuticals Incorporated

18 CF can cause fertility problems in both sexes 97% of males with CF have congenital bilateral absence of the vas deferens (CBAVD) and azoospermia 1 CBAVD can occur in men who do not have clinical CF but have a CFTR mutation Women can experience fertility impairment related to thick cervical mucus that fails to undergo the usual mid-cycle thinning 2 Lifelong (males) Adulthood (females) Infertility 1,3 Difficulty conceiving 2 References: 1. Alves MG et al. Curr Drug Targets. 2015;16(9): Davis PB. Am J Respir Crit Care Med. 2006;173(5): Elborn JS. Lancet. 2016;388(10059): Vertex Pharmaceuticals Incorporated

19 CF may impact important regulators of bone metabolism CFTR is expressed in bone, and CFTR dysfunction affects bone metabolism 1,2 Emergence of bone disease increases as patients get older 3 Between the ages of 20 and 35 years, patients with CF may demonstrate arthropathy and CF-related bone disease (osteoporosis) 3 Patients with CF are at increased risk of low bone density related trauma fractures 2,4 Nutritional status and chronic inflammation due to other CF-related effects may compound the problem 2,4 Adulthood Arthropathy, osteoporosis, fractures 2-4 References: 1. Marquette M, Haworth CS et al. Paediatr Respir Rev. 2016;20(suppl 2-5). doi: /j.prrv Jacquot J et al. Osteoporos Int. 2016;27(4): Elborn JS. Lancet. 2016;388(10059): O Sullivan BP, Freedman DS. Lancet. 2009;373(9678): Vertex Pharmaceuticals Incorporated

20 All Patients with CF Experience Progression Monitoring plays a critical role in disease management Vertex Pharmaceuticals Incorporated

21 Everyone with CF faces progression, and progression shortens lives Age of onset and rate of CF progression vary between and within the genetic mutations known to cause CF 1 However, the range of systemic effects and eventual progression is typically similar across all CF-causing genotypes 1 Mortality by CFTR genotype classification 2 In a separate analysis of registry data, the median age of death in people with CF was approximately 29 years 3 Adapted from McKone et al. Patients were grouped by genotype, classified as high risk or lower risk of early lung function decline based on the primary functional class of their CFTR mutations, or unclassified if 1 or both alleles were unidentified. 2 References: 1. Castellani C et al. J Cyst Fibros. 2008;7(3): McKone EF et al. J Cyst Fibros. 2015;14(5): Cystic Fibrosis Foundation. Patient Registry Annual Data Report Bethesda, MD Cystic Fibrosis Foundation Vertex Pharmaceuticals Incorporated

22 Lung assessments remain fundamental to helping monitor disease progression Considerations when choosing lung assessments HRCT Radiation burden with frequent imaging may be a concern, especially in young children 1 Magnetic resonance imaging Similar accuracy to CT without radiation risk 2 Relatively new technology; unproven in clinical practice 2 Spirometry (eg, FEV 1, FVC) 3-5 Standard assessment of lung function, specifically large airways Young children (<6 years) may find it difficult to perform May be normal despite underlying small airway structural damage LCI 3,6-8 May be easier for young children (<6 years), requiring only passive breathing Can detect underlying small airway lung damage even with normal FEV 1 LCI is still considered an exploratory endpoint in clinical trials FVC, forced vital capacity. References: 1. Davies JC et al. Thorax. 2008;63(2): Roach DJ et al. Ann Am Thorac Soc. 2016;13(11): Lahiri T et al. Pediatrics Apr;137(4). pii: e doi: /peds Epub 2016 Mar Jat KR. Prim Care Respir J. 2013;22(2): Mall MA et al. Pediatr Pulmonol. 2016;51(S44):S49-S Benseler A. Respirology. 2015;20(3): doi: /resp Epub 2015 Jan Aurora P et al. Thorax. 2004;59: Kent L et al. J Cyst Fibros. 2014;13(2): Vertex Pharmaceuticals Incorporated

23 A wide range of tests can help assess CF progression across organ systems Organ Commonly used measures Considerations Body mass index Standard assessment for the nutritional impact of CF, along with weight and height measurements 1 Pancreas Immunoreactive trypsinogen Increasingly used in neonatal screening for CF 2,3 Fecal elastase-1 Easy to use for all ages 4 Liver Gastrointestinal Sinus Transaminase levels Signs and symptoms (dysmotility, constipation, etc) Nasal endoscopy CT radiographic imaging Transaminases vary over time in patients with CF-related liver disease 5 Consistently high transaminase levels occur only with advanced liver disease 6,7 Monitoring may help avoid effects that may compound malnourishment due to pancreatic insufficiency 8 Useful for detecting chronic rhinosinusitis and polyps, which occur in almost all patients and may precede development of CF lung disease 9,10 Bone Dual-energy x-ray absorptiometry Radiation burden may be a concern 11 References: 1. Lahiri T et al. Pediatrics Apr;137(4). pii: e doi: /peds Epub 2016 Mar Tardelli ACS et al. J Pediatr Gastroenterol Nutr. 2013;56(2): Daftary A et al. J Cystic Fibros. 2006;5(2): Paracchini V et al. JIMD Rep. 2012;4: doi: /8904_2011_55. Epub 2011 Nov Cañas T et al. Biomed Res Int. 2015;2015: doi: /2015/ Epub 2015 Nov Woodruff SA et al. J Cyst Fibros. 7. Stonebraker JR et al. Clin Gastroenterol Hepatol. 2016;14(8): ;16(1): Sathe MN, Freeman AJ. Pediatr Clin North Am. 2016;63(4): Illing EA et al. Curr Opin Pulm Med. 2014;20(6): Savastano V et al. Eur Rev Med Pharmacol Sci. 2014;18(14): Stalvey MS, Clines GA. Curr Opin Endocrinol Diabetes Obes. 2013;20(6): Vertex Pharmaceuticals Incorporated

24 Milestones in the management of CF Pancreatic enzyme replacement therapy Sweat test developed Antibiotics for CF pathogens Airway clearance CF center care Tobramycin inhalation solution CFTR discovered Dornase alpha Azithromycin Hypertonic saline Aztreonam solution for inhalation CFTR modulation As advances in detection and management have emerged, median predicted survival has increased 1-4 From approximately 6 months in 1938 to 42 years in 2015 References: 1. Clancy JP, Jain M. Am J Respir Crit Care Med. 2012;186(7): Davis PB. Am J Respir Crit Care Med. 2006;173(5): Cystic Fibrosis Foundation. Patient Registry Annual Data Report Bethesda, MD Cystic Fibrosis Foundation. 4. Cystic Fibrosis Foundation. Patient Registry Annual Data Report Bethesda, MD Cystic Fibrosis Foundation Vertex Pharmaceuticals Incorporated

25 Summary Vertex Pharmaceuticals Incorporated

26 CF progression: Understanding the cause and its impact on your patients CF is a multi-organ, progressive, genetic disease that affects the whole body, and many problems with CF may be present at birth 1,2 Onset and progression of CF symptoms can occur in different organs at different ages Multisystemic damage can occur before symptoms emerge 3 Our ability to detect and monitor CF progression in different organs has increased over time with improved understanding of the disease 4 All patients with CF experience progression; however, CF management has improved over time in concert with scientific and medical discoveries 1,5 References: 1. Elborn JS. Lancet. 2016;388(10059): Zielenski J. Respiration. 2000;67(2): Schram CA. Can Fam Physician. 2012;58: Clancy JP, Jain M. Am J Respir Crit Care Med. 2012;186(7): McKone EF et al. J Cyst Fibros. 2014;14(5): Vertex Pharmaceuticals Incorporated