Drug Discovery - The Origin of New Chemical Entity Pharmaceuticals

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Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices

Speaker: Jack Jiang, VP Medicinal and Analytical Chemistry, Ricerca BioSciences

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Drug Discovery - The Origin of New Chemical Entity Pharmaceuticals

  1. 1. Drug Discovery the origin of new chemical entity pharmaceuticals Presented By Jack Jiang, Ph.D. Ricerca Biosciences, LLC 5/23/07 MAR066
  2. 2. Outline What is drug discovery? Current approaches to drug discovery Issues associated with drug discovery How to succeed in drug discovery MAR066
  3. 3. Drug Composition Excipient API Packaging MAR066
  4. 4. Types of New Pharmaceuticals New Chemical Entity (NCE) New active pharmaceutical ingredient (API) New or old formulation New Formulation Old API + new formulation Old API + new delivery system New Brand Old API + old formulation MAR066
  5. 5. Best of the Best New Chemical Entity (NCE) New compounds with new chemical structures Different interactions with biological targets (MOA) Better therapeutic response For patients Better treatment outcome Increased efficacy, reduced side effects May be curative For drug developers Better products Best patent protection More revenue and profit MAR066
  6. 6. What is Drug Discovery and Development? Idea Lock Biological Target Development IND Lead Candidate Candidate Chemical Key Compound NDA Phase I Phase II Phase III To Market MAR066
  7. 7. What is Drug Discovery? Searching for new drugs is like fishing Fish are chemical compounds Bait is the biological assay Fishing requires patience; so does drug discovery MAR066
  8. 8. What is Drug Discovery? The best fish Best chemical compounds provide novel mechanisms Novel mechanisms may exhibit superior efficacy with reduced toxicity Best chemical compounds are druggable and developable The best bait Biological assays that provide the above MAR066
  9. 9. Let’s Go Fishing! How to catch new fish? Go to new fish pond with old bait Go to old fish pond with new bait Go to new fish pond with new bait New fish pond New diverse compound libraries (chemical diversity) New bait New biological assays based on novel biological targets (molecular biology) MAR066
  10. 10. Fish (Compound) Sources Natural products Plants Micro-organisms Animals Synthetic compounds Analogs of existing drugs Combinatorial synthesis (maximizing analogs) Rational drug design Macro molecular structure Small molecular structure Molecular interactions MAR066
  11. 11. From IP to IND – the preclinical process Development Discovery Chemistry Chemistry Biological Target IND Development Lead Candidate Candidate Chemical Discovery Compound Development Biology Biology MAR066
  12. 12. From Lead to Development Candidate Lead optimization SAR guided by bioassays Patentability issues Druggability Bioavailability in vitro and in vivo Permeability and metabolic stability Formulability Injectable vs. solid dosage form Solubility, polymorph, excipient compatibility and stability MAR066
  13. 13. !quot;#$%#&'(%)* '(quot;+#,-$%.'/$%-quot;#$+ help you find the most druggable candidate 012 9)quot;:7 quot;;* 6, #)+$7 '3quot;8 %&%quot;$+ 9:, #<+ !quot;#$%&%'( H, :$#):&%'2&%* $B+ 345( 3$&7 '@A Bquot;C quot;D&Bquot;, ; 4EE quot; &#.'F '/$:$#Bquot;-quot;B. # =%$GE, %C ):&Bquot;, ; 9quot;, &-&quot;:&8 quot;:quot;B. =%$#:quot;;quot;#&:' >5?(1(524 MAR066
  14. 14. You Need a Hand to Guide You from IP to IND to NDA From IP to IND Discovery chemistry and biology Development chemistry and biology Regulatory compliance From IND to NDA Clinical R&D Development chemistry Regulatory compliance MAR066
  15. 15. The Five Fingers Discovery Chemistry Development Chemistry Discovery Biology Development Biology Regulatory Consultation MAR066
  16. 16. Definitions Drug Development Drug Discovery Development No development candidate found candidate identified Studies non- Studies driven by protocol driven protocols Data not regulated Data scrutinized by by FDA FDA Timeline flexible Rigid timeline required MAR066
  17. 17. New Mindset Needed for Discovery Why The average 10-year R&D timeline per NCE unacceptable = $1.25 bill per NCE (2004) Early go-no-go decision saves time and money First-to-market incentives Novel targets require new endpoints How Address development issues early on Expand research scope to cover potential regulatory pitfalls “Discover” new endpoints Remove barrier between discovery and development MAR066
  18. 18. Issues in Discovery Fish pond vs. bait New assays (new bait) may improve the odds. New compound libraries (new fish pond) may provide novel structures. Novel structures (new fish) offer patentability and maybe better therapy. Looking for needles in a haystack Rational drug design is STILL at its infancy. The biological system remains a black box. NCE identification continues to be a numbers game. The need to improve odds is unchanged. MAR066
  19. 19. Issues in Discovery Target selectivity Molecular targets are many Most targets are proteins Small molecule-protein interaction rarely specific Non-selective small molecules produce side- effects Models not predictive of clinical outcome Target relevant assays Target relevant models Disease relevant models Dosing regiment relevant animal models MAR066
  20. 20. Issues in Discovery Therapeutic window Efficacy vs. toxicity All chemicals are toxic Pharmacology is low dose of toxicology Toxicology is high dose of pharmacology Bioavailability Effective drug concentration Plasma concentration Tissue concentration Target concentration Formulability What is your ultimate formulation? Can your compound be formulated? MAR066
  21. 21. Issues in Development Drug Substance (API) Cost to produce Scalability Analytical methods Stability Drug Product (Formulated API) Cost to produce Scalability Analytical methods Stability Packaging and storage MAR066
  22. 22. Issues in Development Toxicology Species relevance Dosing regimen relevance Drug metabolism relevance Acute vs. chronic toxicity Metabolism Inactive and active metabolites Toxic metabolites P450 activity Drug-drug interaction MAR066
  23. 23. New Mindset Needed for Discovery …additional thoughts… Efficacy Selectivity in vitro ! Selectivity in vivo High potency ! Superior efficacy Animal ! Human Toxicity Structure-toxicity-relationship studies (STR) Target toxicity ! Drug toxicity Animal ! Human MAR066
  24. 24. Key to Discovery Success Identify appropriate clinic problems Unmet medical needs Underline mechanisms Select clinically relevant targets Target specificity Rescue mechanisms Establish target relevant assays Easy Fast Non-radioactive Robust (important to SAR studies) MAR066
  25. 25. Key to Discovery Success Prepare for development issues CMC Process Analytical methods Toxicology Anticipate roadblocks Clinical end points Side effects Manufacturing issues Stability MAR066
  26. 26. One Last Reminder…… Non-reg Reg Biological Target IND Development Lead Candidate Candidate Chemical Compound $$$$ $$ MAR066
  27. 27. Let Us Assist YOU…. !43-Acre site !3 Bldgs: 260,000 ft2 !Accessible from major airports MAR066

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