iThemba overview

www.ithembapharma.com

New Ideas – New Medicines – New Hope


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

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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

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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

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Drug Discovery

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Disease Focus

Medicinal Chemistry

Drug Discovery

Malaria300-500 million infected p.a. 1-2 million deaths p.a. mostly children

HIV6 million HIV+ in SA alone4 million new infections p.a.Over 30 million HIV+ in Africa

TB8 million infections and 2 million deaths p.a. Mortality growing at 20% p.aResistance

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www.ithembapharma.com7

Pipeline

Proposal Screening Hit to LeadLead

OptimisationProcess

Optimisation

TB/ICL

Malaria hits

Set 1

(12k, Malaria)

Set 1

(7k, TB)Abacavir

IF – TB Nitroimidazoles

Malaria proposals

TB Hits

(NIH/TB CoC)

TB selective macrophage accumulation


Current Mtb Therapy Outdated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


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

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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.

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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’

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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

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Isocitrate Lyase

• Isoniazid and Rifampin like activity


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


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

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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

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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

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• 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

iThemba Approach

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• 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

iThemba Screening Solution

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Screening Progress

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• 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


Collaborations

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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 optimization22


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

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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)

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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

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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

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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

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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

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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: [email protected]

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Improving healthcare in Africa and the developing world

iThemba overview

Health & Medicine

Transcript of iThemba overview