Diese Präsentation wurde erfolgreich gemeldet.
Die SlideShare-Präsentation wird heruntergeladen. ×

Target Validation Academy Of Medical Sciences 1 Dec 2006

Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Wird geladen in …3
×

Hier ansehen

1 von 29 Anzeige

Target Validation Academy Of Medical Sciences 1 Dec 2006

An overview of the issues and approaches in selecting the best targets for drug discovery and validating them. Given at the Drug Discovery Forum held at the Royal Society, London and organised by the Academy of Medical Sciences

An overview of the issues and approaches in selecting the best targets for drug discovery and validating them. Given at the Drug Discovery Forum held at the Royal Society, London and organised by the Academy of Medical Sciences

Anzeige
Anzeige

Weitere Verwandte Inhalte

Diashows für Sie (19)

Andere mochten auch (13)

Anzeige

Ähnlich wie Target Validation Academy Of Medical Sciences 1 Dec 2006 (20)

Aktuellste (20)

Anzeige

Target Validation Academy Of Medical Sciences 1 Dec 2006

  1. 1. Target Validation Academy of Medical Sciences London 1 st Dec 2006 Mike Romanos VP Discovery Technology GlaxoSmithKline R&D Stevenage
  2. 2. Drug Discovery Challenges <ul><li>Drug discovery has uniquely long cycle times (>15 years) and very high attrition </li></ul><ul><li>In basic terms the process consists of </li></ul><ul><ul><li>Identifying the right target </li></ul></ul><ul><ul><li>Getting the right compound </li></ul></ul><ul><li>Attrition of unprecedented targets unacceptably high (>95% of targets) </li></ul><ul><ul><li>Targets not validated until Ph2/3 – major cost in the industry impacting innovation </li></ul></ul>
  3. 3. What is Target Validation? <ul><li>Ultimately </li></ul><ul><li>Demonstration that a particular therapeutic modality for a given target can meet the desired Product Profile in the human patient population </li></ul><ul><li>But generally Ongoing process of providing increasing confidence at multiple stages that a target can deliver the desired PP, allowing investment to the next stage of drug discovery </li></ul>Process different for each disease and target, consists of iteratively testing hypotheses
  4. 4. Drug Discovery Process and Target Validation Continuum Gene to target Target to Lead Lead to candidate Candidate to FTIH FTIH to PoC PoC to Commit to Phase III Phase III File & Launch Lifecycle mgt Target selection Lead validation Compound on/off target effects Refined validation vs product profile TARGET VALIDATION Translational medicine
  5. 5. Essential Tools: Biological Systems Animal models of disease Human tissues Disease-relevant cell models Humans
  6. 6. Essential Tools: Target Modulation Transgenics RNAi Tool compounds Biopharmaceutical tools TT TT
  7. 7. Essential Tools: Analytical Methods Genetics Transcriptomics Quantitative PCR Histology Proteomics Bioinformatics
  8. 8. FXR: Cholestasis and Diabetes Target <ul><li>Compound-driven disease association </li></ul><ul><li>Role of transcriptomics </li></ul><ul><li>Serendipity </li></ul>
  9. 9. FXR is a Bile Acid Receptor <ul><li>Part of 48 member family of nuclear receptors: ligand-regulated transcription factors </li></ul><ul><li>FXR primarily in liver and intestinal ileum </li></ul><ul><li>Natural ligand screen identified bile acids as receptors </li></ul><ul><li>Combichem identified GW4064 as selective tool agonist </li></ul>Normalized Luciferase 0 1000 2000 3000 1E-9 1E-8 1E-7 1E-6 1E-5 Concentration (M) GW4064 EC 50 = 80nM 0 20 40 60 80 100 10 -9 10 -8 10 -7 10 -6 Concentration (M) 10 -5 10 -4 % Max CDCA EC 50 = 30  M Lithocholic acid (LCA) Cholic acid (CA ) Deoxycholic acid (DCA) Chenodeoxycholic acid (CDCA)
  10. 10. Compound-based Functional Characterisation of FXR Vehicle + GW4064 Mouse liver Primary human hepatocytes Vehicle + GW4064 or CDCA FXR transcriptome
  11. 11. FXR: Master Regulator of Bile Acid Homeostasis cholesterol Liver Intestine blood bile acid bile bile acid RXR FXR bile acid RXR FXR bile acid
  12. 12. Efficacy of GW4064 in Cholestasis Model # p<0.05 cw Normal * p<0.05 cw ANIT Bile Acids Bilirubin 0 200 400 600 800 Bile acid (µmol/L) 0 1 2 3 4 5 6 Total bilirubin (mg/dL) * # # Enzyme activity (U/L) 0 500 1000 1500 2000 ALT AST # # * * Liu et al., JCI , 112 , 1678 (2003) Normal ANIT ANIT+GW4064 ANIT+TUDCA
  13. 13. Efficacy of GW4064 in Diabetes Model HFD Vehicle HFD 30mg/kg GW4064 bid Intraperitoneal Glucose Tolerance Test 100 150 200 250 300 350 0 60 120 180 Time (min) Serum Glucose (mg/dL) <ul><li>FGF19 most prominent transcriptome change </li></ul><ul><li>FGF19 transgenic mice have improved glucose tolerance on HFD, increased metabolic rate, etc </li></ul><ul><li>Further studies: FXR role in glucose and lipid metabolism </li></ul><ul><li>GW4064 active in High Fat Diet mouse model </li></ul>* * * * * * * * * * p<0.05 cw HFD Vehicle
  14. 14. Vanilloid Receptor in Pain <ul><li>From ligand to target to clinic </li></ul><ul><li>Mouse knock-out for validation </li></ul><ul><li>Compound-based validation in animal models </li></ul><ul><li>PD biomarker for translational studies </li></ul>
  15. 15. Vanilloid Receptor/Pain <ul><li>Capsaicin receptor cloned from Dorsal Root Ganglion cDNA library </li></ul><ul><li>Specific localisation to DRG supports role in pain </li></ul><ul><li>VR1 integrator of pain stimuli </li></ul><ul><li>VR1 expression levels altered in specific DRG sensory neurons following chronic inflammation or nerve injury </li></ul><ul><li>Proposed target in multiple pain states </li></ul>
  16. 16. Mouse VR1 Knockout No response to capsaicin – no overt pathology No hyperalgaesia induced by inflammatory insult (but no effect on mechanical hypersensitivity) -8.0 -7.0 -6.0 -5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 2.0 Capsaicin (KO) Vehicle (KO) Capsaicin (Het) Vehicle (Het) Capsaicin (WT) Vehicle (WT) Mean Maximum Temp Change (Centigrade )
  17. 17. VR1 Antagonists Active in Multiple Pain Models <ul><li>Antagonists active in several pain models (most not predicted from KOs), e.g.: </li></ul><ul><ul><li>Thermal hyperalgesia </li></ul></ul><ul><ul><li>Mechanical hypersensitivity </li></ul></ul><ul><ul><li>Neuropathic pain </li></ul></ul><ul><ul><li>Visceral pain </li></ul></ul>
  18. 18. VR1 expression is up-regulated in chronic inflamed rectum A proliferation of VR1 positive nerve terminals is seen in chronic inflamed gut (oesophagus) C22, 1:5000 Human Disease Tissue: VR1 in Visceral Pain rectal mucosa Normal Hyper 0.0 0.1 0.2 0.3 0.4 0.5 0.6 VR1 immunoreactivity % area p = 0.0286 Mann Whitney U
  19. 19. VR1 Studies in Man Pre-dose Placebo SB705498 <ul><li>VR1 antagonists being pursued by multiple companies for multiple pain states </li></ul><ul><li>Predictivity of pain models an issue </li></ul><ul><li>SB705498 in phase 2/PoC for migraine and dental pain </li></ul><ul><li>Capsaicin Evoked Flare acts as pharmacodynamic biomarker to confirm proof of mechanism </li></ul>
  20. 20. Novel Inflammation Targets from Functional Screens <ul><li>Early use of primary human cell models with RNAi </li></ul><ul><li>Validation in human disease tissue </li></ul>
  21. 21. siRNA Target Identification in Inflammatory Diseases Assays selected to reflect key disease mechanisms Mast Cells: IgER mediated histamine release (Rhinitis) Dendritic Cells: CD40 mediated IL-12 release (Asthma) Macrophages: IC mediated TNF  release (RA) Epithelial Cells: Oxidative stress mediated cytokine release/apoptosis (COPD) T Cells: CD3/CD28 mediated IL-5 and IL-13 release (Asthma) siRNA
  22. 22. siRNA for High Throughput Screen BioFocus Collaboration: Biology-driven Target Discovery
  23. 23. Validation of Target A and B in Primary Human CD4+ Cells Using siRNA Target A (TCR response) Target B (antigen response) Profound inhibition of key cytokines in Rheumatoid Arthritis (TNF  ) and Asthma (IL13) * Selective inhibition of Asthma ‘pathological’ cytokine production 0 1000 2000 3000 4000 5000 6000 7000 TNFa IL13 pg/ml Control T Target A IL13 Control Target B 0 1000 2000 3000 4000 5000 pg/ml
  24. 24. Target Validation in Human Disease Tissue Targeting Allergen Specific T Cell Responses in Asthma Effect of drug on secretion of Cytokines and other Mediators Supernatant allergic asthmatic biopsy material Allergen ± Drug p=0.02 Unchallenged allergen challenged allergen challenged +drug Effect of tool compound to Target A on IL-5 release
  25. 25. Conclusion: What Are the Issues and What Can We Do Better? <ul><li>Novel targets from the genome have been progressed very rapidly and with less information than previously </li></ul><ul><li>More systematic and integrated use of orthogonal approaches should improve success in target and compound selection </li></ul><ul><li>Single targets may not offer required efficacy </li></ul><ul><li>Increased use of compound screening in cellular phenotypic or pathway assays </li></ul><ul><li>Use RNAi to identify potentiators </li></ul>
  26. 26. <ul><li>The available tools have not been used consistently, and the toolbox has had major gaps </li></ul><ul><li>New approaches including RNAi in vitro and in vivo, and genetics, should make an impact </li></ul><ul><li>Preclinical animal models are frequently not predictive of clinical efficacy </li></ul><ul><li>Reduce reliance on these where possible and use human tissues and primary cells as early as possible </li></ul><ul><li>Invest more in linking preclinical to clinical models </li></ul>Conclusion: What Are the Issues and What Can We Do Better?
  27. 27. <ul><li>Clinical PoC studies may fail to detect efficacy </li></ul><ul><li>Stratify patient population where possible </li></ul><ul><li>Ensure all studies are controlled in terms of pharmacodynamic biomarkers </li></ul>Conclusion: What Are the Issues and What Can We Do Better?
  28. 28. Clinical improvement Clinical decline Model-adjusted mean Change from baseline in ADAS-cog by ApoE4 status Pharmacogenetic Stratification Enables Observation of Clinical Efficacy: Roziglitazone in AD
  29. 29. Acknowledgements <ul><li>Particular thanks to: </li></ul><ul><ul><li>Andy Blanchard </li></ul></ul><ul><ul><li>John Davis </li></ul></ul><ul><ul><li>Stacey Jones </li></ul></ul><ul><ul><li>Mark Edbrooke </li></ul></ul><ul><ul><li>Jill Richardson </li></ul></ul>

Hinweis der Redaktion

×