New Ideas – New Medicines – New Hope




                                www.ithembapharma.com
iThemba – at a glance
    • Mission: To become the premier medicinal
      chemistry driven drug discovery organization in...
Business Model
    • Offset discovery ‘cash-burn’ by building world class
      collaborative service business
    • Inves...
Board of Scientific Advisors
    • Prof. Dennis Liotta
          - Emory University, Atlanta, USA
    • Prof. James Bull
 ...
Drug Discovery




5                    www.ithembapharma.com
Disease Focus
                                                HIV
                                   6 million HIV+ in SA ...
Pipeline
                                                             Lead         Process
     Proposal      Screening   ...
Current Mtb Therapy Outdated
• About 1/3 of the global population is infected
  with Mycobacterium tuberculosis (Mtb)
• An...
TB adapts
    • Like all pathogens TB adapts to its environment
    • Mycobacteria mobilize the glyoxylate shunt for
     ...
Isocitrate Lyase
     • ICL (plus MS) allows MTB to bypass the CO2-
       generating steps of the tricarboxylic acid (TCA...
Target Validation
     • ICL promotes bacterial survival in infected
       macrophages
        – McKinney et al. Nature, ...
Solution
     • Screen a focused set of small molecules
       against ICL
       – 2 x small molecule inhibitors identifi...
Isocitrate Lyase




     • Isoniazid and Rifampin like activity

13                                            www.ithemb...
Novel iThemba Nitroimidazoles
     • In-house program to discover new nitroimidazoles
        • Favourable IP position
   ...
HIV Massive Problem in SA
     • South Africa is currently experiencing one of the
       most severe AIDS epidemics in th...
iThemba Solution
     • Take existing drug and produce for less
     • New process for anti-retroviral drug
       –   200...
Short-circuiting Drug Discovery
     • Traditional drug discovery approach not viable
       in South Africa
       – Cost...
iThemba Approach
     • Negotiate use of other companies screening
       collections
       – Requires no target/disease ...
iThemba Screening Solution

     • Novel screening collaborations in place for
       Malaria (MMV sponsored)
     • Medic...
Screening Progress
     • Chimerix collection of nucleoside analogues
        –   131 cpds with activity IC50<1µM
        ...
Collaborations




21                    www.ithembapharma.com
Chemistry Services
     • Services
       –   FTE contracts
       –   Custom Medicinal Chemistry
       –   Custom synthe...
Capabilities
     • Provide synthesis on milligram to 50+ gram scale on
       single or multistep routes
     • Follow es...
Capabilities
     • Pharmaceutical standard chemistry
         – Fully functional synthesis labs
         – ~750m2 of usea...
Collaborations, example 1
     • Brief: Synthesis of a number of functionalised
       steroid analogues as potential anti...
Collaborations, example 2
     • Brief: Take computational derived fragments
       from marketed drugs and design library...
Why iThemba?
     • Competitive cost base
     • Strong IP laws in South Africa
     • Access to superlative Scientific Ad...
Customer Needs!
     • Communication
       – Dedicated and accessible project leader
     • Confidentiality
       – Dedi...
Rates & Contact Information
     • Competitive rates
     • Flexible pricing model
        – Per FTE
        – Bid per pro...
Improving healthcare in Africa and
           the developing world
30                                 www.ithembapharma.com
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iThemba overview

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Non confidential overview of iThemba Pharmaceuticals mission, drug discovery projects and services

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iThemba overview

  1. 1. New Ideas – New Medicines – New Hope www.ithembapharma.com
  2. 2. iThemba – at a glance • Mission: To become the premier medicinal chemistry driven drug discovery organization in Africa and to improve African healthcare through, novel, affordable small molecule drugs • Strategy: leverage the expertise of founders and SAB, generate IP and partner projects with major pharmaceutical companies, offer world class chemistry services to offset drug discovery cash-burn with novel business model 2 www.ithembapharma.com
  3. 3. Business Model • Offset discovery ‘cash-burn’ by building world class collaborative service business • Invest profits from above into in-house projects • Identify, funded, IP generating collaborations • License products at suitable point • Retain marketing rights in Africa 3 www.ithembapharma.com
  4. 4. Board of Scientific Advisors • Prof. Dennis Liotta - Emory University, Atlanta, USA • Prof. James Bull - University of Cape Town, South Africa • Prof. Anthony G. M. Barrett - Imperial College, London, United Kingdom • Prof. Erick Carreira - ETH, Zurich • Prof. Steven V. Ley - Cambridge University, England • Dr. George R. Painter - Chimerix Inc., NC, USA 4 www.ithembapharma.com
  5. 5. Drug Discovery 5 www.ithembapharma.com
  6. 6. Disease Focus HIV 6 million HIV+ in SA alone 4 million new infections p.a. Over 30 million HIV+ in Africa Drug Medicinal Discovery Chemistry TB 8 million infections and 2 Malaria million deaths p.a. 300-500 million infected p.a. Mortality growing at 20% p.a 1-2 million deaths p.a. mostly Resistance children 6 www.ithembapharma.com
  7. 7. Pipeline Lead Process Proposal Screening Hit to Lead Optimisation Optimisation Malaria Set 1 TB/ICL Abacavir proposals (7k, TB) IF – TB TB selective Nitroimidazoles macrophage accumulation Malaria hits TB Hits (NIH/TB CoC) Set 1 (12k, Malaria) 7 www.ithembapharma.com
  8. 8. Current Mtb Therapy Outdated • About 1/3 of the global population is infected with Mycobacterium tuberculosis (Mtb) • Annually, nearly 8 million of the infected people develop active TB • Current therapy takes too long to administer • Current regimen from 1960’s • 6 – 9 months to complete therapy • Non-compliance results in drug-resistant strains • Some resistant strains untreatable www.ithembapharma.com
  9. 9. TB adapts • Like all pathogens TB adapts to its environment • Mycobacteria mobilize the glyoxylate shunt for catabolism of fatty acids in order to sustain infection in an immune competent host • The glyoxylate shunt is unique to bacteria and lower eukaryotes • IsoCitrate Lyase (ICL) and Maleate Synthase (MS) are key enzymes in this process 9 www.ithembapharma.com
  10. 10. Isocitrate Lyase • ICL (plus MS) allows MTB to bypass the CO2- generating steps of the tricarboxylic acid (TCA) cycle – The metabolic pathway by which acetate is oxidized to generate ATP. • The shunt consumes two molecules of acetyl CoA to generate one molecule of succinate. – Lipids are a source of acetyl CoA, and succinate is a precursor for the synthesis of glucose. • The net effect is that the glyoxylate shunt allows MTB to synthesize carbohydrates from fatty acids. – Thus, disruption of this pathway is a viable treatment for latent tuberculosis infections. 10 www.ithembapharma.com
  11. 11. Target Validation • ICL promotes bacterial survival in infected macrophages – McKinney et al. Nature, 2000 • Gene deletion results in impaired growth – McKinney et al. Nat. Med, 2005 • Glyoxylate cycle is essential for TB growth and persistence in macrophages and mice  ICL Previously deemed ‘un-druggable’ 11 www.ithembapharma.com
  12. 12. Solution • Screen a focused set of small molecules against ICL – 2 x small molecule inhibitors identified (IC50 <50nM) – Program designed and initiated to address liabilities – Promising efficacy against Mtb Technology licensed from Emory University 12 www.ithembapharma.com
  13. 13. Isocitrate Lyase • Isoniazid and Rifampin like activity 13 www.ithembapharma.com
  14. 14. Novel iThemba Nitroimidazoles • In-house program to discover new nitroimidazoles • Favourable IP position • Short synthetic routes using readily available reagents, and established synthetic protocols • No chiral centres • Incorporate solubilizing groups, overcoming associated solubility and bioavailability problems • No structural alerts • Increased molecular flexibility 14 www.ithembapharma.com
  15. 15. HIV Massive Problem in SA • South Africa is currently experiencing one of the most severe AIDS epidemics in the world • At the end of 2007, there were approximately 5.7 million people living with HIV in South Africa, and almost 1,000 AIDS deaths occurring every day • TB co-infection probably largest killer of HIV positive patients 15 www.ithembapharma.com
  16. 16. iThemba Solution • Take existing drug and produce for less • New process for anti-retroviral drug – 2007 global sales $220 million – Off patent 2009 – Current synthetic route 15 steps, low yield – iThemba has licensed technology from Emory university for 7 step process 16 www.ithembapharma.com
  17. 17. Short-circuiting Drug Discovery • Traditional drug discovery approach not viable in South Africa – Cost and lack of infrastructure – Too many hurdles • Solution to target whole organisms – Take away major hurdles – Identify efficacious hits immediately 17 www.ithembapharma.com
  18. 18. iThemba Approach • Negotiate use of other companies screening collections – Requires no target/disease conflicts • Leverage neglected disease angle • Requires no capital investment in library purchase and storage 18 www.ithembapharma.com
  19. 19. iThemba Screening Solution • Novel screening collaborations in place for Malaria (MMV sponsored) • Medical Research Council Technology • 45k compounds • Constructed from commercial sources • Historically good hit rate • Chimerix compound collection • 7k compounds • Acquired from Dr Leroy Townsend (University of Michigan) • Contains numerous unique nucleoside analogues as well as a diverse set of heterocycles 19 www.ithembapharma.com
  20. 20. Screening Progress • Chimerix collection of nucleoside analogues – 131 cpds with activity IC50<1µM – High toxicity attrition – Mitochondrial toxicity flag – Highly novel structures • MRCT library diverse heterocyclic structures – Low molecular weight (<300) – No toxicophores or potential reactive functional groups – 30 cpds with activity IC50<1µM – MMV proposal submitted – Solids re-ordered 20 www.ithembapharma.com
  21. 21. Collaborations 21 www.ithembapharma.com
  22. 22. Chemistry Services • Services – FTE contracts – Custom Medicinal Chemistry – Custom synthesis/arrays – Individual compound synthesis – Scale up • Cost-effective and alternative synthetic routes • Design and synthesis of molecules with drug- like properties • Hit-to-lead optimization 22 www.ithembapharma.com
  23. 23. Capabilities • Provide synthesis on milligram to 50+ gram scale on single or multistep routes • Follow established synthetic routes, design new synthetic routes, or trouble-shoot existing synthetic routes • Provide custom intermediate/template or monomer/reagent synthesis • Prepare analog synthesis • Produce synthesis of metabolites or standards 23 www.ithembapharma.com
  24. 24. Capabilities • Pharmaceutical standard chemistry – Fully functional synthesis labs – ~750m2 of useable laboratory space • Microwave synthesiser • Automated prep and analytical HPLC • Parallel sysnthesis and evaporation • Pharma-standard analytical capability – State-of-the-art LC/MS and NMR (400MHz) 24 www.ithembapharma.com
  25. 25. Collaborations, example 1 • Brief: Synthesis of a number of functionalised steroid analogues as potential anti-cancer agents • Solution: iThemba leveraged expertise on it’s SAB to devise novel routes to desired tool compounds • Deliverables: 15 synthetic steps, 11 test compounds (>95% purity, ≥25mg) in 5 weeks • Preliminary Results: 3 examples inhibit cell proliferation in the metaphase with <20nM EC50’s 25 www.ithembapharma.com
  26. 26. Collaborations, example 2 • Brief: Take computational derived fragments from marketed drugs and design library • Solution: Using in-silico techniques and RO3 100 component library deisgned • Deliverables: 10, 10 component fragment sets with >95% purity and ≥100mg • Time frame: 3 months from project initiation 26 www.ithembapharma.com
  27. 27. Why iThemba? • Competitive cost base • Strong IP laws in South Africa • Access to superlative Scientific Advisory Board • Good cultural fit • Moral leverage – all profits re-invested into neglected disease research • Governmental support 27 www.ithembapharma.com
  28. 28. Customer Needs! • Communication – Dedicated and accessible project leader • Confidentiality – Dedicated, backed up server , ELN, • Quality • Safety & Environment – Comply with global standards, PPE culture • Competitive pricing with flexible terms 28 www.ithembapharma.com
  29. 29. Rates & Contact Information • Competitive rates • Flexible pricing model – Per FTE – Bid per project – Bid per compound – Bid per chemical step • Contact: Dr. Chris Edlin – Tel (dir) +27 11 605 2635 – Cell +27 82 350 4313 – E-mail: cedlin@ithembapharma.com 29 www.ithembapharma.com
  30. 30. Improving healthcare in Africa and the developing world 30 www.ithembapharma.com
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