A Quick Guide to the I507del 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 1,2 Total CFTR % of Normal 100% No CF Disease CFTR-related Disorders Some CFTR mutations result in residual or partial CFTR activity 3-5 0% 100% Some CFTR mutations result in little to no CFTR activity 3-5 0% 100% People with 2 CFTR mutations resulting in loss of CFTR activity generally have a CF phenotype, which may include 1-3,6 Elevated sweat chloride (>60 mmol/l) Pancreatic insufficiency CBAVD a Lung function decline over time Pseudomonas aeruginosa colonization 0% Cystic Fibrosis Total CFTR Total CFTR a CBAVD, congenital bilateral absence of the vas deferens. 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 CF 1 Survival Probability Survival Curves by CFTR During a 10-Year Follow-Up (1993-2002) of Patients From the US CFF Registry a 1.00 0.75 0.50 0.25 0.00 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 10 20 Risk Time (Age) n=1126 n=14,525 30 40 50 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. a Data 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. Life expectancy in Western countries (general population born in 2000) is ~79 years 2 Between 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 I507del mutation (Class II) were part of the severely reduced CFTR activity group More recent US data (2000-2010) suggest median survival across genotypes continues to improve 3 3
Country registries listing the I507del mutation report 1% prevalence among patients with CF1-6 Prevalence of the I507del Mutation in Patients With Cystic Fibrosis (% of Patients With at Least 1 Allele) I n the CFTR2 global database, ~0.7% of patients with CF have at least 1 copy of the I507del mutation7 Additional sources report frequency of the I507del mutation on CF alleles US1: 0.8% Country Mexico8 3% Uruguay9 1% Spain 1% 10 Aus6: 0.3% Europe: Germany2: 0.1% UK3: 0.9% Belgium4: 0.9% France5: 0.7% References: 1. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2013 Annual Data Report. Bethesda, MD. 2014; Cystic Fibrosis Foundation. 2. Mukoviszidose e.v. und Mukoviszidose Institut gemeinnützige Gesselschaft für Forschung und Therapienntwicklung mbh. Beriichtsband Qualitätssicherung Mukoviszidose 2012. 2013, Bonn, Germany. 3. Cystic Fibrosis Trust. UK Cystic Fibrosis Registry Annual Data Report 2014. 2015; Cystic Fibrosis Trust; London, UK. 4. 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. 5. French Cystic Fibrosis Registry. Annual Report 2013. Vaincre la Mucoviscidose and Ined, 2015; Paris, France. 6. Cystic Fibrosis Australia. Australian Cystic Fibrosis Data Registry 2013 16th Annual Report. 2015; Cystic Fibrosis Australia; Baulkham Hills NSW, Australia. 7. 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. 8. Bobadilla JL et al. Hum Mutat. 2002;19(2):575-606. 9. World Health Organization. The molecular genetic epidemiology of cystic fibrosis: report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS; June 19, 2002; Genoa, Italy. World Health Organization; 2004. 10. Alonso MJ et al. Ann Hum Genet. 2006;71(Pt 2):194-201. % of Alleles Ireland9 0.8% Greece 0.7% 8 Italy8 Canada 0.7% 9 0.7% 4
The I507del mutation results in defective processing and trafficking of the CFTR protein 1-3 CFTR Turnover CFTR Function CFTR Trafficking CFTR Processing Illustrative Example of Class II Defect Golgi complex Posttranslational modification Immature CFTR Proteosome Translation I507del has a severe defect in CFTR processing and trafficking with degradation of immature CFTR proteins in the endoplasmic reticulum, typical of a Class II mutation 1-3 Few to no CFTR channels are present at the apical cell surface 1-3 mrna CFTR Synthesis mrna Transcription DNA Endoplasmic reticulum References: 1. Welsh MJ, Smith AE. Cell. 1993;73(7):1251-1254. 2. Zielenski J. Respiration. 2000;67(2):117-133. 3. Wilschanski M et al. J Pediatr. 1995;127(5):705-710. 5
The I507del allele results in little to no total CFTR activity 1-4 1 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 I507del allele results in few to no CFTR channels at apical surface Defective Processing and Trafficking (Class II) CFTR Function CFTR Channel-open Quantity x x Conductance = Probability x x Channel-open Conductance: N/A Probability: N/A = 2 Total CFTR 3 Little to No I507del-CFTR 1 Significantly reduced I507del-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 N/A, not applicable. References: 1. Welsh MJ, Smith AE. Cell. 1993;73(7):1251-1254. 2. Zielenski J. Respiration. 2000;67(2):117-133. 3. Wilschanski M et al. J Pediatr. 1995;127(5):705-710. 4. Sheppard DN et al. Nature. 1993;362(6416):160-164. 6
Both CFTR alleles play a role in determining phenotype or disease severity 1-5 100% No CF Disease Normal individuals and CF carriers Total CFTR CFTR-related Disorder Clinical entities associated with CFTR dysfunction that do not fulfill diagnostic criteria for CF Cystic Fibrosis An I507del allele results in little to no CFTR activity. The phenotype of a particular patient is also influenced by the mutation on the other allele 1-5 I507del typically results in the indicated phenotypes 0% Allele 1 Total CFTR Normal Normal Normal Residual Residual Little to None Allele 2 Total CFTR Normal Residual Little to None Residual Little to None Little to None 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. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196. 4. Zielenski J. Respiration. 2000;67(2):117-133. 5. Davis PB et al. Am J Respir Crit Care Med. 1996;154(5):1229-1256. 7
I507del in combination with another allele that produces little to no CFTR activity usually results in a CF phenotype 1-5 CFTR Genotype Allele #1: I507del Little to No CFTR Protein Allele #2 Little to No CFTR Protein CF Phenotype In patients registered in the CFTR2 database with an I507del mutation on 1 allele and a pancreatic insufficient mutation on the second allele 1 Modifier Genes Little to No Total CFTR Environmental Factors Elevated sweat chloride (average):102 mmol/l Lung function decline over time 2 Pseudomonas colonization: 62% 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. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196. 4. Zielenski J. Respiration. 2000;67(2):117-133. 5. Davis PB et al. Am J Respir Crit Care Med. 1996;154(5):1229-1256. 8
Summary Loss of CFTR activity is the underlying cause of CF Levels of CFTR activity affect survival in CF Country registries listing the I507del mutation report 1% prevalence among patients with CF T he I507del mutation results in defective processing and trafficking of the CFTR protein The I507del allele results in little to no total CFTR activity B oth CFTR alleles play a role in determining phenotype or disease severity I 507del in combination with another allele that produces little to no CFTR activity usually results in a CF phenotype 9