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

1. New Ideas – New Medicines – New Hope
www.ithembapharma.com

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. 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. 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. 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 – 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 Current Mtb Therapy Outdated
• 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. 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. 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. 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. 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. Isocitrate Lyase
• Isoniazid and Rifampin like activity
13 www.ithembapharma.com

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. 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. 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. 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. 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. 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. 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. Collaborations
21 www.ithembapharma.com

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. 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. 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. 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. 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. 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. 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. 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. Improving healthcare in Africa and
the developing world
30 www.ithembapharma.com