UNDERSTANDING HOW CYSTIC FIBROSIS (CF) PROGRESSES AND ITS IMPACT ON YOUR PATIENTS

2

Lungs Pancreas Liver

Early mucinous plugging and bronchiectasis1

Pancreatic exocrine insufficiency; up to 71% of patients with CF are pancreatic insufficient at birth1,2

Abnormal liver function test results1

Advancing bronchiectasis and pulmonary exacerbations2

Ongoing degradation, as thickened secretions clog more ducts3

Bronchiectasis with recurrent exacerbations, requiring nutritional support, supplementary oxygen, and noninvasive ventilatory support1

CF-related diabetes mellitus in approximately 25% of adolescents4

Cirrhosis1

Bronchiectasis with hemoptysis, pneumothorax; progressive respiratory failure; lung transplant1

CF-related diabetes mellitus in up to 40% of adults1

Portal hypertension (5%-10%); liver transplant1

Potentially irreversible damage as early as 2 months of age; eventual pulmonary insufficiency responsible for ~80% of CF-related deaths3

Nutritional/caloric deficiency issue (growth impairment)5

CF can be associated with biliary cirrhosis (<10%)1

CF IS A MULTI-ORGAN, PROGRESSIVE, GENETIC DISEASE

Many problems with CF may be present at birth and persist and progress throughout the patient’s life

Age 0-5 years

Age 20+years

Age 11-20years

Age 6-10 years

AdditionalConsiderations

Not all patients with CF experience all these symptoms or follow this timeline.

3

CF IS A MULTI-ORGAN, PROGRESSIVE, GENETIC DISEASE (cont)

Many problems with CF may be present at birth and persist and progress throughout the patient’s life

Gastrointestinal Other Symptoms

Meconium ileus1 Chronic rhinosinusitis; nasal polyp; absence of vas deferens1,3

Constant vigilance regarding malnutrition3

Decreased motility may lead to chronic constipation3

Arthropathy; CF-related bone disease (osteoporosis); female infertility1,6

Distal intestinal obstruction syndrome1

Gastrointestinal abnormalities often evident before birth2

Potential for renal dysfunction in diabetic patients1

Age 0-5 years

Age 20+years

Age 11-20years

Age 6-10 years

AdditionalConsiderations

Not all patients with CF experience all these symptoms or follow this timeline.

4

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 CF8

• However, the range of systemic effects and eventual progression is typically similar across all CF-causing genotypes8

• In a separate analysis of registry data, the median age of death in people with CF was approximately 29 years9

MORTALITY BY CFTR GENOTYPE CLASSIFICATION7

9 17 25 33 41 49 57 651

Age at Death or Discontinuation (years)

GenotypeUnclassifiedLower RiskHigher Risk

100

75

50

25

0

Perc

enta

ge o

f pati

ents

stil

l liv

ing

Some genotypes are associated with longer survival than others, but CF remains a life-shortening disease7

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.7

CFTR, cystic fibrosis transmembrane conductance regulator.

Adapted from McKone et al.

5

PEOPLE NEED AN ADEQUATE QUANTITYOF WELL-FUNCTIONING CFTR PROTEINS TO STAY HEALTHY

Maintaining water and salt balance at the epithelial cell surface requires an adequate quantity and function of CFTR proteins 10,11

A

Nucleus

Cell surfaceNormalCFTR protein

• CFTR proteins are an important regulator of fluid and ion balance in epithelial tissues in organs throughout the body3,10,12,13

• Normally, CFTR protein channels transport ions, such as chloride and bicarbonate, through the epithelial cell surface in these organs3,10,12,13

– In normal cells, CFTR proteins are open about 40% of the time14

• This controlled movement of ions helps to regulate water and electrolyte (salt) balance at the cell surface to keep mucus thin and watery3,10,12,13

– Thin, watery mucus is easily moved through organ passages and helps ensure normal organ function

6

CF IS CAUSED BY DEFECTIVE OR A REDUCED QUANTITY OF CFTR PROTEINS RESULTING FROM MUTATIONS IN THE CFTR GENE

Nucleus

CFTR protein

B

Cell surface

Defective synthesisDefective processing

Nucleus

Cell surface CFTR protein

C

Defective gatingDefective conductance

REDUCED CFTR QUANTITY8,10,13,19 • 281 known CFTR mutations can result in CF due to too few and/or

defective CFTR8,10,15

• With too few and/or defective CFTR proteins, water and salt balance at epithelial cell surfaces is disrupted3,6,10,16

• Mucus becomes thick and sticky in organs throughout the body, and it can clog small passages3,6,10,16

– This interferes with the proper function of the lungs, pancreas, gastrointestinal system, sinuses, liver, and reproductive system

• This can lead to potentially irreversible lung damage even before loss of function is detected by spirometry1,3,17,18

– Damage can be cumulative over time

A defect in quantity and/or function of CFTR is the underlying cause of CF8,19

REDUCED CFTR FUNCTION8,10,13,19

713

CF-CAUSING CFTR MUTATIONS CAN REDUCE TOTAL CFTR ACTIVITY TO VARYING DEGREES

It depends on how the mutations affect the quantity and/or function of CFTR proteins

With little to no CFTR activity, CF appears early and progresses rapidly10,20-22

With some CFTR activity, CF can appear later in life, but remains progressive10,20

Regardless of whether

they have only some or little to no CFTR

activity, people with

2 CF-causing mutations experience progressive CF disease7

LITTLE TO NO QUANTITY LITTLE TO NO FUNCTION

SOME QUANTITY SOME FUNCTION

Nucleus

CFTR protein

B

Cell surface

Defective synthesisDefective processingD

Nucleus

Cell surface Normal CFTR protein

E

Nucleus

Cell surface Abnormal CFTR protein

Nucleus

Cell surface CFTR protein

C

Defective gatingDefective conductance

8

TOO FEW OR DEFECTIVE CFTR PROTEINS MEANS A CASCADE OF DISEASE AND LUNG DAMAGE

THE CFTR DYSFUNCTION CASCADE IN THE LUNGS1

• The cascade of CF in the lungs can result in inflammation, infection, and lung damage, even before loss of lung function is detected by spirometry1,3,23,24

CFTRdysfunction

Ionimbalance

Mucusthickening

Plugging ofbronchial ductsand passages

Susceptibilityto infection

Inflammation,infection,

lung damage

9

A SIMILAR CASCADE OF EFFECTS OCCURS IN OTHER ORGAN SYSTEMS

• This cascade results in thickening of secretions, blocking of small passages, inflammation, and organ damage3,6,10,16

• As a consequence, CFTR protein dysfunction affects multiple organ systems with progressive signs and symptoms1,3,25-27

Sinuses

Lungs

Pancreas

Gastrointestinal system Skin/sweat

glands

Reproductive system

10

1. Bronchiectasis 2. Peripheral cysts 3. Bronchiectasis 4. Mucus-plugged bronchus

5. Peripheral cysts

PATIENTS MAY EXPERIENCE STRUCTURAL LUNG DAMAGEBEFORE A DECLINE IN FEV1 IS DETECTED

HRCT scan shows pulmonary abnormalities in the lungs of a 13-year-old boy with normal pulmonary function tests and a ppFEV1 of 99%28

This was a retrospective study in 25 children with CF with a mean age of 10.7 years and a mean FEV1 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 the only instance where CT scan was shown to be more sensitive.28

CT, computed tomography; FEV1, forced expiratory volume in 1 second; HRCT, high-resolution computed tomography; ppFEV1, percent predicted FEV1.

Adapted from de Jong et al.

11

PULMONARY EXACERBATIONS ARE A HARMFUL FEATURE OF CF AND CONTRIBUTE TO LUNG DAMAGE

Pulmonary exacerbations begin early in life and increase in incidence with age29,30

* Source of data: Patients with CF treated at Cystic Fibrosis Foundation (CFF)–accredited care centers in the US who consented to have their data entered in 2015 in the CFF Registry.

• Damaging pulmonary exacerbations can occur early in life30

– Although the incidence of exacerbations is relatively low in young children with CF, it increases as the children age29,30

– By age 12 years, as many as 30% of patients will have at least 1 pulmonary exacerbation per year9*

• Pulmonary exacerbations are a major cause of irreversible lung damage and can have devastating effects, including increased risk of mortality, hospitalizations, and use of intravenous antibiotics; reduced quality of life; and a rapid decline in pulmonary function9,31

PULMONARY EXACERBATIONS BY AGE IN YEARS, 20159*

Num

ber o

f ind

ivid

uals

900800700600500400300200100

0<1 10 20 30 40 50 60 70

Age (years)

Total individuals with or without exacerbations

Individuals with 1 or more pulmonary exacerbations

Individuals with 2 or more pulmonary exacerbations

Perc

enta

ge o

f ind

ivid

uals 100%

90%80%70%60%50%40%30%20%10%

0<1 10 20 30 40 50 60 70

Age (years)

Individuals with one or more pulmonary exacerbationsIndividuals with two or more pulmonary exacerbations

Adapted from CFF Registry 2015.

12

WFA percentile at age 3

<5thn=105

5-9thn=83

Patients with CF below the 10th WFA percentile are generally regarded as having poor growth

10-24thn=216

25-49thn=259

50-74thn=155

>75thn=113

100

95

90

85

80

105

Mea

n pp

FEV

1 pre

dict

ed

at a

ge 6

MEAN ppFEV1 AT AGE 6 BY WFA PERCENTILE AT AGE 3 (N=931)32

Adapted from Konstan et al. WFA, weight for age.

POOR NUTRITION IN YOUNGER CHILDREN IS CORRELATED WITH REDUCED LUNG FUNCTION

• When young children are below weight for their age, there is a correlation with reduced future lung function32

• In a study of preschool children, it was found that low weight for age at age 3 was associated with a lower ppFEV1 at age 632

Nutritional deficits due to CF-related pancreatic and digestive problems are associated with decreased lung function

13

MILESTONES IN THE MANAGEMENT OF CF

As advances in detection and management have emerged, median predicted survival has increased from approximately 6 months in 1938 to 42 years in 20156,9,33,34

Pancreatic enzyme replacement therapy

Dornase alpha

Sweat testdeveloped

Antibiotics for CF pathogensAirway clearance

CF center care

19801970196019501940

CFTR discovered

CFTR modulation

Tobramycin inhalation solution Azithromycin Hypertonic salineAztreonam solution for inhalation

1990 2000 2010 Present

14

A WIDE RANGE OF TESTS CAN HELP ASSESS CF PROGRESSION ACROSS ORGAN SYSTEMS

Consideration should be given to a method’s effectiveness, age-based ease of use, and impact/burden on the patient

Lung Pancreas

Commonly Used Assessment Tools

Imaging with HRCT

Spirometry (eg, FEV1, FVC)

Magnetic resonance imaging

Lung clearance index (LCI)

Body mass index

Immunoreactive trypsinogen

Fecal elastase-1

Considerations

Radiation burden with frequent imaging may be a concern, especially in young children35

Standard assessment of lung function, specifically large airways5

Young children (<6 years) may find it difficult to perform36

May be normal despite underlying small airway structural damage37

Similar accuracy to CT without radiation risk38

Relatively new technology; unproven in clinical practice38

Can detect underlying small airway lung damage even with normal FEV1

5,39

May be easier for young children (<6 years)40

LCI is still considered an exploratory endpoint in clinical trials41

Standard assessment for the nutritional impact of CF, along with weight and height measurements5

Increasingly used in neonatal screening for CF42,43

Easy to use for all ages44

FVC, forced vital capacity.

15

A WIDE RANGE OF TESTS CAN HELP ASSESS CF PROGRESSION ACROSS ORGAN SYSTEMS (cont)

Consideration should be given to a method’s effectiveness, age-based ease of use, and impact/burden on the patient

Liver Gastrointestinal Sinus Bone

Commonly Used Assessment Tools

Transaminase levels

Signs and symptoms (dysmotility, constipation, etc)

Nasal endoscopy

CT radiographic imaging

Dual-energy x-ray absorptiometry

Considerations

Transaminases vary over time in patients with CF-related liver disease45

Consistently high transaminase levels occur only with advanced liver disease46,47

Monitoring may help avoid effects that may compound malnourishment due to pancreatic insufficiency48

Useful for detecting chronic rhinosinusitis and polyps, which occur in almost all patients and may precede development of CF lung disease49,50

Radiation burden may be a concern51

16

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 birth1,10

– Onset and progression of CF symptoms can occur in different organs at different ages

• Multisystemic damage often occurs before symptoms emerge52

• Our ability to detect and monitor CF progression in different organs has increased over time with improved understanding of the disease33

• All patients with CF experience progression; however, CF management has improved over time in concert with scientific and medical discoveries1,7

BROUGHT TO YOU BY VERTEX, because we believe that knowledge empowers you and your patients. More resources are available for you at CFSourceHCP.com, and for your patients at CFSource.com.

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Association of sweat chloride concentration at time of diagnosis and CFTR genotype with mortality and cystic fibrosis phenotype. J Cyst Fibros. 2015;14(5):580-586. doi:10.1016/j.jcf.2015.01.005. Epub 2015 Feb 3. 8.Castellani C, Cuppens H, Macek M Jr, et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008;7(3):179-196.9. Cystic Fibrosis Foundation. Patient Registry Annual Data Report 2015. Bethesda, MD. Cystic Fibrosis Foundation; 2016. 10. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117-133. 11. Ward CL, Kopito RR. Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild-type and mutant proteins. J Biol Chem. 1994;269(41):25710-25718. 12.MacDonald KD, McKenzie KR, Zeitlin PL. Cystic fibrosis transmembrane regulator protein mutations: ‘class’ opportunity for novel drug innovation. 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Longitudinal assessment of children with mild CF using hyperpolarised gas lung MRI and LCI. Am J Respir Crit Care Med. 2017. doi:10.1164/rccm.201705-0894LE. [Epub ahead of print]. 19. Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl-channels with altered pore properties. Nature 1993;362(6416):160-164. 20. Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med. 1996;154(5):1229-1256.21. Green DM, McDougal KE, Blackman SM, et al. Mutations that permit CFTR function delay acquisition of multiple respiratory pathogens in CF patients. Respir Res. 2010;11:140. 22. Griesenbach U, Geddes DM, Alton EWFW. The pathogenic consequences of a single mutated CFTR gene. Thorax. 1999;54(suppl 2):S19-S23. 23. Rao S, Grigg J. New insights into pulmonary inflammation in cystic fibrosis. Arch Dis Child. 2006;91:786–788. 24. Levy H, Kalish LA, Huntington I, et al. Inflammatory markers of lung disease in adult patients with cystic fibrosis. Pediatr Pulmonol. 2007;42(3):256-262. 25. Cunningham JC, Taussig LM. An introduction to cystic fibrosis for patients and their families. Cystic Fibrosis Foundation. 2013. 26. Orenstein DM, Spahr JE, Weiner DJ. Cystic fibrosis: a guide for patient and family. 4th Ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. 27. Ooi CY, Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012;11(5):355-362. 28. de Jong PA, Ottink MD, Robben SG, et al. Pulmonary disease assessment in cystic fibrosis: comparison of CT scoring systems and value of bronchial and arterial dimension measurements. Radiology. 2004;231(2):434-439. 29. Goss CH, Burns JL. Exacerbations in cystic fibrosis. 1: epidemiology and pathogenesis. Thorax. 2007;62(4):360-367. 30. Byrnes CA, Vidmar S, Cheney JL, et al. Prospective evaluation of respiratory exacerbations in children with cystic fibrosis from newborn screening to 5 years of age. Thorax. 2013;68(7):643-651. 31. Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to recover baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med. 2010;182(5):627-632. 32. Konstan MW, Butler SM, Wohl MEB, et al. Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. J Pediatr. 2003;142(6):624-630. 33. Clancy JP, Jain M. Personalized medicine in cystic fibrosis: dawning of a new era. Am J Respir Crit Care Med. 2012;186(7):593-597. 34. Cystic Fibrosis Foundation. Patient Registry Annual Data Report 2012. Bethesda, MD. Cystic Fibrosis Foundation; 2016. 35. Davies JC, Cunningham S, Alton EWFW, Innes JA. Lung clearance index in CF: a sensitive marker of lung disease severity. Thorax. 2008;63(2):96-97. 36. Jat KR. Spirometry in children. Prim Care Respir J. 2013;22(2):221-229. 37. Mall MA, Stahl M, Graeber SY, Sommerburg O, Kauczor HU, Wielpütz MO. Early detection and sensitive monitoring of CF lung disease: prospects of improved and safer imaging. Pediatr Pulmol. 2016;51(S44):S49-S60. 38. Roach DJ, Crémillieux Y, Fleck RJ, et al. Ultrashort echo-time magnetic resonance imaging is a sensitive method for the evaluation of early cystic fibrosis lung disease. Ann Am Thorac Soc. 2016;13(11):1923-1931. 39. Benseler A, Stanojevic S, Jensen R, Gustafsson P, Ratjen F. The effect of equipment dead space on multiple breath washout measures. Respirology. 2015;20(3):459-466. 40. Aurora P, Gustafsson P, Bush A, et al. Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis. Thorax. 2004;59(12):1068-1073. 41. Kent L, Reix P, Innes JA, et al. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros. 2014;13(2):123-138. 42. Daftary A, Acton J, Heubi J, Amin R. Fecal elastase-1: utility in pancreatic function in cystic fibrosis. J Cystic Fibros. 2006;5(2):71-76. 43. Paracchini V, Seia M, Raimondi S, et al. Cystic fibrosis newborn screening: distribution of blood immunoreactive trypsinogen concentrations in hypertrypsinemic neonates. JIMD Rep. 2012;4:17-23. 44.Tardelli ACS, Camargos PAM, Penna FJ, Sarkis PFB, Guimarães EV. Comparison of diagnostic methods for pancreatic insufficiency in infants with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2013;56(2):178–181. 45. Cañas T, Maciá A, Muñoz-Codoceo RA, et al. Hepatic and splenic acoustic radiation force impulse shear wave velocity elastography in children with liver disease associated with cystic fibrosis. Biomed Res Int. 2015;2015:517369. 46. Woodruff SA, Sontag MK, Accurso FJ, Sokol RJ, Narkewicz MR. Prevalence of elevated liver enzymes in children with cystic fibrosis diagnosed by newborn screen. J Cyst Fibros. 2017;16(1):139-145. 47. Stonebraker JR, Ooi CY, Pace RG, et al. Features of severe liver disease with portal hypertension in patients with cystic fibrosis. Clin Gastroenterol Hepatol. 2016;14(8):1207-1215. 48. Sathe MN, Freeman AJ. Gastrointestinal, pancreatic, and hepatobiliary manifestations of cystic fibrosis. Pediatr Clin North Am. 2016;63(4):679–698. 49. Illing EA, Woodworth BA. Management of the upper airway in cystic fibrosis. Curr Opin Pulm Med. 2014;20(6):623-631. 50. Savastano V, Bertin S, Vittori T, Tripodi C, Magliulo G. Evaluation of chronic rhinosinusitis management using the SNOT-22 in adult cystic fibrosis patients. Eur Rev Med Pharmacol Sci. 2014;18(14):1985-1989. 51. Stalvey MS, Clines GA. Cystic fibrosis-related bone disease: insights into a growing problem. Curr Opin Endocrinol Diabetes Obes. 2013;20(6):547-552. 52. Schram CA. Atypical cystic fibrosis: identification in the primary care setting. Can Fam Physician. 2012;58(12):1341-1345.

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