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. New Ideas β New Medicines β New Hope www.ithembapharma.com
- 2. iThemba β at a glance β’ Mission: To become the premier medicinal chemistry driven drug discovery organization in Africa and to improve African healthcare through, novel, affordable small molecule drugs β’ 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. Business Model β’ Offset discovery βcash-burnβ by building world class collaborative service business β’ Invest profits from above into in-house projects β’ Identify, funded, IP generating collaborations β’ License products at suitable point β’ Retain marketing rights in Africa 3 www.ithembapharma.com
- 4. Board of Scientific Advisors β’ Prof. Dennis Liotta - Emory University, Atlanta, USA β’ Prof. James Bull - University of Cape Town, South Africa β’ Prof. Anthony G. M. Barrett - Imperial College, London, United Kingdom β’ Prof. Erick Carreira - ETH, Zurich β’ Prof. Steven V. Ley - Cambridge University, England β’ Dr. George R. Painter - Chimerix Inc., NC, USA 4 www.ithembapharma.com
- 5. Drug Discovery 5 www.ithembapharma.com
- 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. Pipeline Lead Process Proposal Screening Hit to Lead Optimisation Optimisation Malaria Set 1 TB/ICL Abacavir proposals (7k, TB) IF β TB TB selective Nitroimidazoles macrophage accumulation Malaria hits TB Hits (NIH/TB CoC) Set 1 (12k, Malaria) 7 www.ithembapharma.com
- 8. Current Mtb Therapy Outdated β’ About 1/3 of the global population is infected with Mycobacterium tuberculosis (Mtb) β’ Annually, nearly 8 million of the infected people develop active TB β’ Current therapy takes too long to administer β’ Current regimen from 1960βs β’ 6 β 9 months to complete therapy β’ Non-compliance results in drug-resistant strains β’ Some resistant strains untreatable www.ithembapharma.com
- 9. TB adapts β’ Like all pathogens TB adapts to its environment β’ Mycobacteria mobilize the glyoxylate shunt for catabolism of fatty acids in order to sustain infection in an immune competent host β’ The glyoxylate shunt is unique to bacteria and lower eukaryotes β’ IsoCitrate Lyase (ICL) and Maleate Synthase (MS) are key enzymes in this process 9 www.ithembapharma.com
- 10. Isocitrate Lyase β’ ICL (plus MS) allows MTB to bypass the CO2- generating steps of the tricarboxylic acid (TCA) cycle β The metabolic pathway by which acetate is oxidized to generate ATP. β’ The shunt consumes two molecules of acetyl CoA to generate one molecule of succinate. β Lipids are a source of acetyl CoA, and succinate is a precursor for the synthesis of glucose. β’ The net effect is that the glyoxylate shunt allows MTB to synthesize carbohydrates from fatty acids. β Thus, disruption of this pathway is a viable treatment for latent tuberculosis infections. 10 www.ithembapharma.com
- 11. Target Validation β’ ICL promotes bacterial survival in infected macrophages β McKinney et al. Nature, 2000 β’ Gene deletion results in impaired growth β McKinney et al. Nat. Med, 2005 β’ Glyoxylate cycle is essential for TB growth and persistence in macrophages and mice ο ICL Previously deemed βun-druggableβ 11 www.ithembapharma.com
- 12. Solution β’ Screen a focused set of small molecules against ICL β 2 x small molecule inhibitors identified (IC50 <50nM) β Program designed and initiated to address liabilities β Promising efficacy against Mtb οTechnology licensed from Emory University 12 www.ithembapharma.com
- 13. Isocitrate Lyase β’ Isoniazid and Rifampin like activity 13 www.ithembapharma.com
- 14. Novel iThemba Nitroimidazoles β’ In-house program to discover new nitroimidazoles β’ Favourable IP position β’ Short synthetic routes using readily available reagents, and established synthetic protocols β’ No chiral centres β’ Incorporate solubilizing groups, overcoming associated solubility and bioavailability problems β’ No structural alerts β’ Increased molecular flexibility 14 www.ithembapharma.com
- 15. HIV Massive Problem in SA β’ South Africa is currently experiencing one of the most severe AIDS epidemics in the world β’ 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 β’ TB co-infection probably largest killer of HIV positive patients 15 www.ithembapharma.com
- 16. iThemba Solution β’ Take existing drug and produce for less β’ New process for anti-retroviral drug β 2007 global sales $220 million β Off patent 2009 β Current synthetic route 15 steps, low yield β iThemba has licensed technology from Emory university for 7 step process 16 www.ithembapharma.com
- 17. Short-circuiting Drug Discovery β’ Traditional drug discovery approach not viable in South Africa β Cost and lack of infrastructure β Too many hurdles β’ Solution to target whole organisms β Take away major hurdles β Identify efficacious hits immediately 17 www.ithembapharma.com
- 18. iThemba Approach β’ Negotiate use of other companies screening collections β Requires no target/disease conflicts β’ Leverage neglected disease angle β’ Requires no capital investment in library purchase and storage 18 www.ithembapharma.com
- 19. iThemba Screening Solution β’ Novel screening collaborations in place for Malaria (MMV sponsored) β’ Medical Research Council Technology β’ 45k compounds β’ Constructed from commercial sources β’ Historically good hit rate β’ Chimerix compound collection β’ 7k compounds β’ Acquired from Dr Leroy Townsend (University of Michigan) β’ Contains numerous unique nucleoside analogues as well as a diverse set of heterocycles 19 www.ithembapharma.com
- 20. Screening Progress β’ Chimerix collection of nucleoside analogues β 131 cpds with activity IC50<1Β΅M β High toxicity attrition β Mitochondrial toxicity flag β Highly novel structures β’ MRCT library diverse heterocyclic structures β Low molecular weight (<300) β No toxicophores or potential reactive functional groups β 30 cpds with activity IC50<1Β΅M β MMV proposal submitted β Solids re-ordered 20 www.ithembapharma.com
- 21. Collaborations 21 www.ithembapharma.com
- 22. Chemistry Services β’ Services β FTE contracts β Custom Medicinal Chemistry β Custom synthesis/arrays β Individual compound synthesis β Scale up β’ Cost-effective and alternative synthetic routes β’ Design and synthesis of molecules with drug- like properties β’ Hit-to-lead optimization 22 www.ithembapharma.com
- 23. Capabilities β’ Provide synthesis on milligram to 50+ gram scale on single or multistep routes β’ Follow established synthetic routes, design new synthetic routes, or trouble-shoot existing synthetic routes β’ Provide custom intermediate/template or monomer/reagent synthesis β’ Prepare analog synthesis β’ Produce synthesis of metabolites or standards 23 www.ithembapharma.com
- 24. Capabilities β’ Pharmaceutical standard chemistry β Fully functional synthesis labs β ~750m2 of useable laboratory space β’ Microwave synthesiser β’ Automated prep and analytical HPLC β’ Parallel sysnthesis and evaporation β’ Pharma-standard analytical capability β State-of-the-art LC/MS and NMR (400MHz) 24 www.ithembapharma.com
- 25. Collaborations, example 1 β’ Brief: Synthesis of a number of functionalised steroid analogues as potential anti-cancer agents β’ Solution: iThemba leveraged expertise on itβs SAB to devise novel routes to desired tool compounds β’ Deliverables: 15 synthetic steps, 11 test compounds (>95% purity, β₯25mg) in 5 weeks β’ Preliminary Results: 3 examples inhibit cell proliferation in the metaphase with <20nM EC50βs 25 www.ithembapharma.com
- 26. Collaborations, example 2 β’ Brief: Take computational derived fragments from marketed drugs and design library β’ Solution: Using in-silico techniques and RO3 100 component library deisgned β’ Deliverables: 10, 10 component fragment sets with >95% purity and β₯100mg β’ Time frame: 3 months from project initiation 26 www.ithembapharma.com
- 27. Why iThemba? β’ Competitive cost base β’ Strong IP laws in South Africa β’ Access to superlative Scientific Advisory Board β’ Good cultural fit β’ Moral leverage β all profits re-invested into neglected disease research β’ Governmental support 27 www.ithembapharma.com
- 28. Customer Needs! β’ Communication β Dedicated and accessible project leader β’ Confidentiality β Dedicated, backed up server , ELN, β’ Quality β’ Safety & Environment β Comply with global standards, PPE culture β’ Competitive pricing with flexible terms 28 www.ithembapharma.com
- 29. Rates & Contact Information β’ Competitive rates β’ Flexible pricing model β Per FTE β Bid per project β Bid per compound β Bid per chemical step β’ Contact: Dr. Chris Edlin β Tel (dir) +27 11 605 2635 β Cell +27 82 350 4313 β E-mail: cedlin@ithembapharma.com 29 www.ithembapharma.com
- 30. Improving healthcare in Africa and the developing world 30 www.ithembapharma.com