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The Pharmacogenetics of Asthma Therapy

Explore the role of genetics in asthma therapy, including examples of pharmacogenetic responses to leukotriene modifiers, glucocorticoids, and beta agonists. Discuss the future impact on drug discovery and clinical practice.

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The Pharmacogenetics of Asthma Therapy

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  1. The Pharmacogenetics of Asthma Therapy Wayne Anderson, Ph.D. Therapeutic Area Head, Respiratory Translational Medicine and Genetics GlaxoSmithKline

  2. Outline • Introduction • Some Genetics Basics • What is Pharmacogenetics • Respiratory Pharmacogenetic Examples • Leukotriene Modifiers • Glucocorticoids • Beta Agonists • The Future Impact of Pharmacogenetics • How does this affect drug discovery • How will this affect clinical practice

  3. Sir Archibald E. Garrod 1858-1936Coined the term “Chemical Instability” “Even against chemical poisons taken by mouth, or by other channels, there are some means of defense. Every active drug is a poison, when taken in large enough doses; and in some subjects a dose which is innocuous to the majority of people has toxic effects, whereas others show exceptional tolerance of the same drug. Some chemical poisons are destroyed in the tissues, provided that the dose given be not too large, and others are combined up with substances to hand, and so rendered innocuous and got rid of.”

  4. Protein Amino Acid DNA to proteins Information in DNA leads to the production of proteins that do the body’s work

  5. Genes: DNA to RNA to Protein (35,000 genes in total) GENE (DNA) intron transcription precursor RNA splicing mRNA translation protein

  6. Anatomy of a Gene Coding Region Promoter Exons Intron DNA Start Transcription RNA transcript Processing mRNA AAAAAAAAA

  7. Genetic Variation …G G T A A C T G… Human Genome has 3 billion DNA base-pairs Polymorphic …G G C A A C T G... Some people have a different base at a given location: This is a Single Nucleotide Polymorphism or SNP

  8. Genetic differences among patients Interactions with concomitant drugs Compliance Dose Factors That Influence Medicine Response Patient’s responseto drug Diagnosis

  9. Sources of Drug Variability at the Target • Removal • Metabolism • Elimination • Delivery • Absorption • Distribution Other molecules that determine the biological context in which drug-target interactions occur Other Molecules with which the drug interacts DM Roden et al: Nature Reviews, Drug Discovery, 1, 37-43, 2002

  10. Pharmacogenetics and the concept of Personalize Medicine

  11. No Medicine Is Perfect! • People do not respond to medicines in the same way • Adverse events may occur in some people, not in others • Doses can be different • Efficacy can vary • Variable responses to medicines are known to occur in some populations • Variable responses (particularly rare adverse events) are often difficult to predict Spear (2001) Trends Mol Medicine 7:201-206

  12. Despite Testing, ADRs are Public Health Concern Table: Selected Adverse Drug Reactions Leading to Market Withdrawal Source:http://online.wsj.com/article/0,,SB110960218490965860,00.html

  13. “Classic” Pharmacogenetics (CYP2D6) Meyer (2004) Nat Rev Genetics 5:669-76

  14. Frequency Response: Leukotriene Receptor Antagonists <30 0 <20 30-39 40-49 <10 0-9 20-29 10-19 Change in FEV1 (% of Predicted) Data on file, GlaxoSmithKline: FAS40023 and SAS40020-21.

  15. BAL LTC4 Concentrations After Segmental Antigen Challenge 10000 LTC4 p=0.0003 1000 LTC4 Concentration (pg / ml) 100 10 1 Low LT High LT Adapted from Hasday, JD et al. AJRCCM 161; 1229-1236, 2000

  16. 5-Lipoxygenase Gene Polymorphisms Location: Chromosome 10 3,4,5,6 Tandem SP1 Repeats G-1761A G-1708A C21T G270A A1728G -88 to -212 -1,557 to -1,844 -854 to -931 -292 to -727 -88 to -212 1 2 3 4 5 6 7 8 9 10 11 12 13 14 ATG Transcription Factor Binding Region Negative Regulatory Regions Positive Regulatory Region

  17. Pharmacogenetic Association Between ALOX5 Promoter Genotype and the Response to the ALOX5 Inhibitor ABT-761 • Randomized, double-blind, parallel-group trial of ABT-761 (n=221) • 84-day treatment period • Clinically stable asthma patients, using 2-agonists only • FEV1 = 40%-75% predicted • ABT-761 150 and 300 mg/day • ~6% of patients without wild-type allele * * Significantly different from 5,5 P< 0.0001 Drazen et al. Nat Genet. 1999;22:168-170.

  18. Effect of 5-Lipoxygenase Genotype on Response to Fluticasone Propionate and Zafirlukast 2 0 1 5 Change From Baseline 1 0 (% predicted) F P 8 8 Z a f i r l u k a s t 5 44 44 31 5 19 0 5 , , 5 , 5 X X X 5 - 5 (59.5%) (33.8%) (6.8%) Anderson et al. European Respiratory Society, 2000.

  19. Combined ALOX5 and LTC4 Polymorphisms P= 0.003 P= 0.038 Group 1: ALOX5 Sp-1 X,X; ALOX5 (1728G), 1,2 or 2,2 or LTC4 S (-444) 2,2 Group 2: All others

  20. Variability in Steroid Response in Asthma KG Tantisira et al: Human Molecular Genetics, 13(13), 1353-1359, 2004

  21. Association of CRHR1 with Response to Inhaled Corticosteroid KG Tantisira et al: Human Molecular Genetics, 13(13), 1353-1359, 2004

  22. Association of CRHR1 Haplotype with Response to Inhaled Corticosteroid KG Tantisira et al: Human Molecular Genetics, 13(13), 1353-1359, 2004

  23. 2-Adrenergic Receptor Polymorphisms Reihsaus etal. Am J Respir Cell Mol Biol. 1993;8:334-339.

  24. BARGE: Results Israel (2004) Lancet 364:1505-12

  25. AM PEF Response to Salbutamol and Salmeterol by Genotype Salmeterol Salbutamol Adapted from: Taylor DR et al. Thorax 55; 762-767: 2000

  26. - 1023 - 709 - 654 - 468 - 406 - 367 - 47 - 20 Beta Receptor Haplotypes 46 79 252 491 523 G/A C/G G/A C/T C/A G/A C/A G/A C/G C/T T/C T/C T/C Codon 16 Arg/Gly Codon 27 Glu/Gln Codon 164 Thr/Ile 19 AA Cys/Arg 20 - 17 - 14 - 11 - 8 - 5 - Change % FEV1 30.6% 20.7% 6.6% 18.2% 11.6% 2/4 2/2 2/6 4/4 4/6 Haplotype Pair Drysdale, CM et al PNAS 97; 10483, 2000

  27. 25 20 15 Change from baseline FEV1 percent predicted 10 5 Arg/Arg (n=15) Arg/Gly (n=42) Gly/Gly (n=29) 0 0 0.5 1 2 3 4 6 8 10 12 Time (hour) 25 20 15 Change from baseline FEV1 percent predicted 10 5 Arg/Arg (n=13) Arg/Gly (n=43) Gly/Gly (n=48) 0 0 0.5 1 2 3 4 6 8 10 12 Time (hour) Asthma PGx: Response to Salmeterol & Advair Salmeterol Week 12 Advair Week 12 Combined studies SAS 30001, SAS 30003, SAS 30004

  28. Personalized Medicine New Drugs New Diagnostic Tests 2005 The Genomic Opportunity 2001

  29. The Paradigm of Personalized Medicine Better Diagnosis More Effective Therapy Earlier Intervention More Efficient Drug Development Personalized Medicine Collation: www.personalizedmedicinecollation.org

  30. When and Why Industry is Applying Pharmacogenetics Data from CMR International Institute for Regulatory Science 2003

  31. Public Policy Issues • Intellectual Property • Regulatory Oversight • Privacy and Ethics • Reimbursement • Genetic Discrimination (Insurance, employment) • Patient Education • Physician Education • Hospital system infrastructure • R&D Incentives

  32. Begin Colonoscopy @ 40 yrs of age • Avoid high fat in diet • Drug dose selected by drug metabolism genetic profile • Targeted gene-based therapy with improved efficacy and decreased AEs Personalized Medicine: The Right Drug, for the Right Patient, at the Right Time Risk Prediction Pharmacogenomics New Therapies

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