A Quick Guide to the 621+1G T. Mutation CFTR SCIENCE

Transcription

1 Quick uide to the Mutation FR SIENE 2016 Vertex Pharmaceuticals Incorporated VXR-HQ a(1) 03/2016

2 Loss of FR activity is the underlying cause of cystic fibrosis (F) 1 Spectrum of Phenotypes ssociated With otal FR ctivity 1,2 otal FR ctivity % of Normal 100% No F Disease FR-related Disorders Some FR mutations result in residual or partial FR activity 3-5 0% 100% Some FR mutations result in little to no FR activity 3-5 0% 100% People with 2 FR mutations resulting in loss of FR activity generally have a F phenotype, which may include 1-3,6 Elevated sweat chloride (>60 mmol/l) Pancreatic insufficiency BVD a Lung function decline over time Pseudomonas aeruginosa colonization 0% ystic Fibrosis otal FR ctivity otal FR ctivity a BVD, congenital bilateral absence of the vas deferens. References: 1. Davis PB et al. m J Respir rit are Med. 1996;154(5): Rowe SM et al. Proc m horac Soc. 2007;4(4): Zielenski J. Respiration. 2000;67(2): Sheppard DN et al. Nature. 1993;362(6416): Welsh MJ, Smith E. ell. 1993;73(7): astellani et al. J yst Fibros. 2008;7(3):

3 Levels of FR activity affect survival in F 1 Survival Probability Survival urves by FR ctivity During a 10-Year Follow-Up ( ) of Patients From the US FF Registry a Residual FR activity (lass IV, V): R117H, R334W, R347P, Kb, , 455E Severely reduced FR activity (lass I, II, III): 542X, R553X, W1282X, R1162X, 621-I, , 1078del, 3659del, I507del, N1303K, S549N, 85E, F508del, 551D, R Risk ime (ge) n=1126 n=14, dapted with permission from McKone EF et al. hest. 2006;130(5): his 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 ystic Fibrosis Foundation patient registry measuring risk of death over a 10-year observation period from 1993 to Patients were grouped as having a high-risk or low-risk genotype based on the functional effects of their class of FR mutation on phenotype and mortality. Patients having a lass I, II, or III mutation on both alleles were considered high-risk, while patients having at least 1 lass IV or V mutation were categorized as low-risk. total of 15,651 patients had a FR genotype of a known functional class; 14,525 (93%) had a high-risk FR genotype and 1126 (7%) had a low-risk FR genotype.1 References: 1. McKone EF et al. hest. 2006;130(5): he World Bank. ccessed November 12, MacKenzie et al. nn Int Med. 2014;161: 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 FR activity was 36.3 years (95% I, 35.5 to 37.6 years), while median survival for those having genotypes associated with residual FR activity was 50 years (95% I, 47.1 to 55.9 years) 1 In this study, patients with the mutation (lass I) were part of the severely reduced FR activity group More recent US data ( ) suggest median survival across genotypes continues to improve 3 3

4 ountry registries listing the mutation report a 0.2% to 6% prevalence among patients with F1-7 Prevalence of the Mutation in Patients With ystic Fibrosis (% of Patients With at Least 1 llele) I n the FR2 global database, ~2% of patients with F have at least 1 copy of the mutation8 he mutation has an atypically high frequency on F alleles in the isolated Saguenay Lac-Saint-Jean region of northeast Quebec (25%)9 an1: 6% US2: 2% dditional sources report frequency of the mutation on F alleles us : 2% 7 Europe: UK3: 2% Ireland4: 2% France5: 0.2% ermany6: 0.2% References: 1. ystic Fibrosis anada. anadian ystic Fibrosis Registry 2013 nnual Report. oronto, ON: ystic Fibrosis anada; ystic Fibrosis Foundation. ystic Fibrosis Foundation Patient Registry 2013 nnual Data Report. Bethesda, MD. 2014; ystic Fibrosis Foundation. 3. ystic Fibrosis rust. UK ystic Fibrosis Registry nnual Data Report ; ystic Fibrosis rust; London, UK. 4. he ystic Fibrosis Registry of Ireland nnual Report. FRI, 2015; Dublin, Ireland. 5. French ystic Fibrosis Registry. nnual Report Vaincre la Mucoviscidose and Ined, 2015; Paris, France. 6. Mukoviszidose e.v. und Mukoviszidose Institut gemeinnützige esselschaft für Forschung und herapienntwicklung mbh. Beriichtsband Qualitätssicherung Mukoviszidose , Bonn, ermany. 7. ystic Fibrosis ustralia. ustralian ystic Fibrosis Data Registry th nnual Report. 2015; ystic Fibrosis ustralia; Baulkham Hills NSW, ustralia. 8. US F Foundation, Johns Hopkins University, he Hospital for Sick hildren. he linical and Functional Ranslation of FR (FR2). ccessed November 12, Madore M et al. enet Med. 2008;10(3): European ystic Fibrosis Society. EFS Patient Registry 2010 nnual Data Report Bobadilla JL et al. Hum Mutat. 2002;19(6): ountry % of lleles reece10 10% urkey11 3% Macedonia 11 1% Romania11 1% Mexico 1% 11 New Zealand11 1% Denmark 0.6% 11 4

5 he mutation results in defective biosynthesis of the FR protein 1 FR urnover FR Function FR rafficking FR Processing Illustrative Example of lass I Defect olgi complex Endoplasmic reticulum Proteosome FR gene (DN) mrn DN hromosome Rest 7 of FR gene FR gene U U U Endoplasmic Reticulum Splicing defect Pre-mRN RN processing is a splice mutation, which produces a premature stop codon 1-3 he cell cannot synthesize a full-length FR protein, a lass I mutation 1-3 s a result, few to no FR proteins are present at the apical cell surface 1-3 mrn FR Synthesis ranscription DN References: 1. Welsh MJ, Smith E. ell. 1993;73(7): Zielenski J. Respiration. 2000;67(2): Zielenski J et al. Hum Mol enet. 1993;2(6):

6 he allele results in little to no total FR activity otal FR activity can be defined as total ion transport mediated by FR protein channels at the cell surface, depending on FR protein quantity and function allele results in few to no FR channels at apical surface Defective Synthesis (lass I) x hannel-open Probability: N/ FR Function FR hannel-open Quantity x x onductance = Probability x 2 onductance: N/ = otal FR ctivity 3 Little to No FR ctivity 1 virtual absence of FR protein quantity 2 regardless of function since few to no FR proteins reach the surface 3 results in little to no total FR activity N/, not applicable. References: 1. Welsh MJ, Smith E. ell. 1993;73(7): Zielenski J et al. Hum Mol enet. 1993;2(6): Zielenski J et al. enomics. 1991;10: Sheppard DN et al. Nature.1993;362(6416):

7 Both FR alleles play a role in determining phenotype or disease severity % No F Disease Normal individuals and F carriers otal FR ctivity FR-related Disorder linical entities associated with FR dysfunction that do not fulfill diagnostic criteria for F ystic Fibrosis allele results in little to no FR activity. he phenotype of a particular patient is also influenced by the mutation on the other allele typically results in the indicated phenotypes 0% llele 1 otal FR ctivity Normal Normal Normal Residual Residual Little to None llele 2 otal FR ctivity Normal Residual Little to None Residual Little to None Little to None dapted from Zielenski J. Respiration. 2000;67(2): References: 1. US F Foundation, Johns Hopkins University, he Hospital for Sick hildren. he linical and Functional Ranslation of FR (FR2). ccessed November 12, deracia J et al. horax. 2005;60(7): ystic Fibrosis enotype-phenotype onsortium. N Engl J Med. 1993;329(18): Davis PB et al. m J Respir rit are Med. 1996;154(5): astellani et al. J yst Fibros. 2008;7(3): Zielenski J. Respiration. 2000;67(2):

8 621+1 in combination with another allele that produces little to no FR activity usually results in a F phenotype 1-5 FR enotype llele #1: Little to No FR Protein ctivity llele #2 Little to No FR Protein ctivity F Phenotype In patients registered in the FR2 database with a mutation on 1 allele and a pancreatic insufficient mutation on the second allele 1 : Modifier enes Little to No FR ctivity Environmental Factors Elevated sweat chloride (average):104 mmol/l Lung function decline over time 5 Pseudomonas colonization: 69% of patients Pancreatic insufficiency: 99% of patients References: 1. US F Foundation, Johns Hopkins University, he Hospital for Sick hildren. he linical and Functional Ranslation of FR (FR2). ccessed November 12, ystic Fibrosis enotype-phenotype onsortium. N Engl J Med. 1993;329(18): astellani et al. J yst Fibros. 2008;7(3): Zielenski J. Respiration. 2000;67(2): leveland RH et al. Radiology. 2009;253(3):

9 Summary Loss of FR activity is the underlying cause of F Levels of FR activity affect survival in F ountry registries listing the mutation report 0.2% to 6% prevalence among patients with F he mutation results in defective biosynthesis of the FR protein he allele results in little to no total FR activity Both FR alleles play a role in determining phenotype or disease severity in combination with another allele that produces little to no FR activity usually results in a F phenotype 9