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A Quick Guide to the G542X Mutation CFTR SCIENCE © 2016 Vertex Pharmaceuticals Incorporated | VXR-HQ-02-00045a(1) | 03/2016 Loss of CFTR activity is the underlying cause of cystic fibrosis (CF)1 Spectrum of Phenotypes Associated With Total CFTR Activity1,2 •P eople with 2 CFTR mutations resulting in loss of CFTR activity generally have a CF phenotype, which may include1-3,6 100% Clinical Phenotype No CF Disease –E levated sweat chloride (>60 mmol/L) – Pancreatic insufficiency Individuals with 2 normal alleles and CFTR mutation carriers – CBAVDa – Lung function decline over time Total CFTR Activity CFTR-related Disorders % of Normal Clinical entities associated with CFTR dysfunction that do not fulfill diagnostic criteria for CF, e.g., CBAVD, acute recurrent or chronic pancreatitis and bronchiectasis Some CFTR mutations result in residual or partial CFTR activity3-5 0% Cystic Fibrosis 0% Total CFTR Activity 100% –P seudomonas aeruginosa colonization Some CFTR mutations result in little to no CFTR activity3-5 0% 100% Typical phenotype: sinopulmonary disease, sweat chloride >60 mmol/L, insufficiency, Totalpancreatic CFTR Activity appearing early in life. In some patients, progression of disease is delayed or not all features are present CBAVD, congenital bilateral absence of the vas deferens. a References: 1. Davis PB et al. Am J Respir Crit Care Med. 1996;154(5):1229-1256. 2. Rowe SM et al. Proc Am Thorac Soc. 2007;4(4):387-398. 3. Zielenski J. Respiration. 2000;67(2):117-133. 4. Sheppard DN et al. Nature. 1993;362(6416):160-164. 5. Welsh MJ, Smith AE. Cell. 1993;73(7): 1251-1254. 6. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196. 2 Levels of CFTR activity affect survival in CF1 Survival Curves by CFTR Activity During a 10-Year Follow-Up (1993-2002) of Patients From the US CFF Registrya Survival Probability 1.00 0.75 n=1126 0.50 n=14,525 0.25 Residual CFTR activity (Class IV, V): R117H, R334W, R347P, 3849+10KbC–›T, 2789+5G–›A, A455E Severely reduced CFTR activity (Class I, II, III): G542X, R553X, W1282X, R1162X, 621-IG–›T, 1717-1G–›A, 1078delT, 3659delC, I507del, N1303K, S549N, G85E, F508del, G551D, R560T 0.00 0 10 20 30 40 50 Risk Time (Age) Adapted with permission from McKone EF et al. Chest. 2006;130(5):1441-1447. This survival curve represents population-based outcomes.1 Individual outcomes in cystic fibrosis are variable. aData are from a retrospective study of patients enrolled in the Cystic Fibrosis Foundation patient registry measuring risk of death over a 10-year observation period from 1993 to 2002. Patients were grouped as having a high-risk or low-risk genotype based on the functional effects of their class of CFTR mutation on phenotype and mortality. Patients having a Class I, II, or III mutation on both alleles were considered high-risk, while patients having at least 1 Class IV or V mutation were categorized as low-risk. A total of 15,651 patients had a CFTR genotype of a known functional class; 14,525 (93%) had a high-risk CFTR genotype and 1126 (7%) had a low-risk CFTR genotype.1 References: 1. McKone EF et al. Chest. 2006;130(5):1441-1447. 2. The World Bank. http://data.worldbank.org/indicator/SP.DYN.LE00.IN?page=2. Accessed November 12, 2015. 3. MacKenzie T et al. Ann Int Med. 2014;161:233-241. •L ife expectancy in Western countries (general population born in 2000) is ~79 years2 •B etween 1993 and 2002, median survival for US patients with genotypes associated with little to no CFTR activity was 36.3 years (95% CI, 35.5 to 37.6 years), while median survival for those having genotypes associated with residual CFTR activity was 50 years (95% CI, 47.1 to 55.9 years)1 – In this study, patients with the G542X mutation (Class I) were part of the severely reduced CFTR activity group •M ore recent US data (2000-2010) suggest median survival across genotypes continues to improve3 3 G542X is the second most common CFTR mutation in the world1 Prevalence of the G542X Mutation in Patients With Cystic Fibrosis (% of Patients With at Least 1 Allele) • In the CFTR2 global database, ~4% of patients with CF have at least 1 copy of the G542X mutation1 Additional sources report frequency of the G542X mutation on CF alleles Can2: 4% US3: 5% Brazil4: 4% Europe: Belgium5: 5% UK6: 4% France7: 3% Germany8: 2% Netherlands9: 2% Ireland10: 2% Aus11: 3% New Zealand12: 3% References: 1. US CF Foundation, Johns Hopkins University, The Hospital for Sick Children. The Clinical and Functional TRanslation of CFTR (CFTR2). http://www.cftr2.org. Accessed November 12, 2015. 2. Cystic Fibrosis Canada. Canadian Cystic Fibrosis Registry 2013 Annual Report. Toronto, ON: Cystic Fibrosis Canada; 2015. 3. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2013 Annual Data Report. Bethesda, MD. © 2014; Cystic Fibrosis Foundation. 4. The Brazilian Cystic Fibrosis Study Group. Brazilian Cystic Fibrosis Patient Registry. 2012 Annual Report. 5. Belgisch Mucoviscidose Register – Registre Belge de la Mucoviscidose. The Belgian Cystic Fibrosis Registry. Summary Report 2011.© 2014; Institute of Public Health (WIV-ISP), Brussels, Belgium. 6. Cystic Fibrosis Trust. UK Cystic Fibrosis Registry Annual Data Report 2014. © 2015; Cystic Fibrosis Trust; London, UK. 7. French Cystic Fibrosis. Registry Annual Report 2013. © Vaincre la Mucoviscidose and Ined, 2015; Paris, France. 8. Mukoviszidose e.V. und Mukoviszidose Institut gemeinnützige Gesselschaft für Forschung und Therapienntwicklung mbH. Beriichtsband Qualitätssicherung Mukoviszidose 2012. © 2013, Bonn, Germany. 9. Nederlandse Cystic Fibrosis Stichting. Dutch Cystic Fibrosis Patient Registry. Report on the Year 2014. © 2015; NCFS: Baarn, Netherlands. 10. The Cystic Fibrosis Registry of Ireland. 2013 Annual Report. © CFRI, 2015; Dublin, Ireland. 11. Cystic Fibrosis Australia. Australian Cystic Fibrosis Data Registry 2013–16th Annual Report. © 2015; Cystic Fibrosis Australia; Baulkham Hills NSW, Australia. 12. Cystic Fibrosis Association of New Zealand. PORT CFNZ National Data Registry, 2014 Registry Report. Christchurch, New Zealand. 13. Bobadilla JL et al. Hum Mutat. 2002;19(2):575-606. 14. Casals T et al. Hum Genet. 1993;91(1):66-70. Country % of Alleles Tunisia13 9% Spain13 8% Greece 4% 13 Bulgaria13 4% Austria 3% Italy13 3% 13 •T he G542X mutation was found at a higher frequency in certain regions of Spain, including the Canary Islands (25%), Murcia (21%), Navarra (17%), and Valencia (11%)14 4 The G542X mutation results in defective biosynthesis of the CFTR protein1-3 Illustrative Example of Class I Defect • G 542X is a nonsense mutation, which produces a premature stop codon1-3 CFTR Turnover CFTR Function A T A U G C G C CFTR Trafficking CFTR gene (DNA) Golgi complex Endoplasmic reticulum Proteosome A G C T A A U mRNA strand G C G C G A U T A T A Rest of CFTR gene CFTR Processing A T T C Start codon Premature stop codon • T he cell cannot synthesize a full-length CFTR protein, a Class I mutation1-2 • As a result, few to no CFTR proteins are present at the apical cell surface1-2 Rest of mRNA strand mRNA Transcription CFTR Synthesis DNA References: 1. Zielenski J. Respiration. 2000;67(2):117-133. 2. Welsh MJ, Smith AE. Cell. 1993;73(7):1251-1254. 3. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196. 5 The G542X allele results in little to no total CFTR activity1-4 Total CFTR activity can be defined as total ion transport mediated by CFTR protein channels at the cell surface, depending on CFTR protein quantity and function.4 CFTR Quantity G542X allele results in few to no CFTR channels at apical surface x x 1 CFTR Function Channel-open Probability Channel-open Probability: N/A x x 2 Conductance Conductance: N/A = Total CFTR Activity = Little to No G542X-CFTR Activity 3 1 A virtual absence of G542X-CFTR protein quantity… 2 …regardless of function since few to no CFTR proteins reach the surface… 3 …results in little to no total CFTR activity Defective Synthesis (Class I) N/A, not applicable. References: 1. Zielenski J. Respiration. 2000;67(2):117-133. 2. Welsh MJ, Smith AE. Cell. 1993;73(7):1251-1254. 3. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196. 4. Sheppard DN et al. Nature. 1993;362(3):160-164. 6 Both CFTR alleles play a role in determining phenotype or disease severity1-6 100% No CF Disease Normal individuals and CF carriers CFTR-related Disorder Total CFTR Activity Clinical entities associated with CFTR dysfunction that do not fulfill diagnostic criteria for CF Cystic Fibrosis •A G542X allele results in little to no CFTR activity. The phenotype of a particular patient is also influenced by the mutation on the other allele1-6 •G 542X typically results in the indicated phenotypes 0% Allele 1 Normal Normal Normal Residual Residual Little to None Allele 2 Normal Residual Little to None Residual Little to None Little to None Total CFTR Activity Total CFTR Activity Adapted from Zielenski J. Respiration. 2000;67(2):117-133. References: 1. US CF Foundation, Johns Hopkins University, The Hospital for Sick Children. The Clinical and Functional TRanslation of CFTR (CFTR2). http://www.cftr2.org. Accessed November 12, 2015. 2. deGracia J et al. Thorax. 2005;60(7):558-563. 3. Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med. 1993;329(18):1308-1313. 4. Davis PB et al. Am J Respir Crit Care Med. 1996;154(5):1229-1256. 5. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196. 6. Zielenski J. Respiration. 2000;67(2):117-133. 7 G542X in combination with another allele that produces little to no CFTR activity usually results in a CF phenotype1-5 CFTR Genotype Modifier Genes Allele #1: G542X Allele #2 Little to No CFTR Protein Activity Little to No CFTR Protein Activity Little to No Total CFTR Activity CF Phenotype In patients registered in the CFTR2 database with a G542X mutation on 1 allele and a pancreatic insufficient mutation on the second allele1 Environmental Factors • E levated sweat chloride (average):103 mmol/L • L ung function decline over time • Pseudomonas colonization: 56% of patients • Pancreatic insufficiency: 98% of patients References: 1. US CF Foundation, Johns Hopkins University, The Hospital for Sick Children. The Clinical and Functional TRanslation of CFTR (CFTR2). http://www.cftr2.org. Accessed November 12, 2015. 2. deGracia J et al. Thorax. 2005;60(7):558-563. 3. Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med. 1993;329(18):1308-1313. 4. Davis PB et al. Am J Respir Crit Care Med. 1996;154(5):1229-1256. 5. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196. 8 Summary •Loss of CFTR activity is the underlying cause of CF •Levels of CFTR activity affect survival in CF • G542X is the second most common CFTR mutation in the world •The G542X mutation results in defective biosynthesis of the CFTR protein •The G542X allele results in little to no total CFTR activity •Both CFTR alleles play a role in determining phenotype or disease severity •G542X in combination with another allele that produces little to no CFTR activity usually results in a CF phenotype 9