1. DNDi Briefing Dr Catherine Royce Senior Project Manager, DNDi Geneva 6th Global Forum on Bioethics in Research Blantyre, Malawi 17 March 2005

2. Contents DNDi’s origin, vision, and Founding Partners • What are neglected diseases? Why are we interested in them? • What are DNDi’s objectives? How will we achieve them? • How will DNDi obtain funds to cover costs? • Where are we today?

3. The DNDi idea • Several NGOs and MSF raised the issue of access to drugs amongst neglected populations in developing countries • DNDi established in July 2003 as a not for profit organisation to meet the specific needs of these neglected patients • DNDi partners with experts in disease-endemic countries in its work

4. DNDi’s Vision • Develop new drugs for people suffering from neglected diseases • Ensure equitable access to new and field- relevant health tools • Raise awareness of the need to develop drugs for neglected diseases • Build public responsibility and leadership in addressing needs of these patients

5. DNDi’sFounding Partners Medecins Sans Frontieres WHO/TDR (permanent observer) Institut Pasteur, France Malaysian Ministry of Health Oswaldo Cruz Foundation, Brazil Indian Council for Medical Research Kenya Medical Research Institute

6. DNDi structure • Board of Directors • Scientific Advisory Committee • Coordinating/Executive team • Project Managers • Regional Liaisons • Financial & Administration Officers • Advocacy & Fundraising Officers

7. Contents • DNDi’s origin, vision and Founding Partners What are neglected diseases? Why are we interested in them? • What are DNDi’s objectives? How will we achieve them? • How will DNDi obtain funds to cover costs? • Where are we today?

8. World Pharmaceutical Market, 2002 SE Asia + China Rest of the world North America Latin America Japan EU Total $406 billion Source: IMS Health

9. Tropical diseases: 13 Tuberculosis: 3 Only 1% of new drugs developed are for neglected diseases • 10/90 disequilibrium in health research spending • 1975-1999: 1,393 new chemical entities marketed • 68·7% registered products presented little or no therapeutic gain

10. Neglected diseases attract negligible R&D • A significant medical need exists, but : • These diseasesare of no strategic (military, security) interest • Patients have • No purchasing power • No advocacy group to lobby for them • Thus there is no drug innovation for neglected diseases

11. Pre Clinical Development Availability to patients Discovery GAP2 GAP3 GAP1 Gaps exist in the R&D process for neglected diseases New knowledge on drug targets and lead compounds is published but pre-clinical research does not begin mainly industry (in North) mainly public sector New or existing drugs do not reach patients: registration problems, lack of production, high prices, or not adapted to the local conditions of use Validated candidate drugs do not enter clinical development because of strategic company choices.

12. Contents • DNDi’s origin, vision and Founding Partners • What are neglected diseases? Why are we interested in them? What are DNDi’s objectives? How will we achieve them? • How will DNDi obtain funds to cover costs? • Where are we today?

13. DNDi’s objective to develop new drugs is threefold • Develop a portfolio to address needs • Short and medium-term projects making better use of existing drugs • Long-term projects that will identify new compounds • Raise awarenessabout the need for R&D for neglected diseases • Use DNDi projects to strengthen existing capacityin disease-endemic countries.

14. Pre Clinical Development Availability to patients Discovery New chemical or bio-chemical compounds Fixed dose combinations;New indications of existing drugs Completing registration dossier;Reformulation Long-term projects Medium-term projects Short-term projects GAP3 GAP1 GAP2 DNDi’s portfolio will fill R&D gaps

15. Give top priority to patients’ needs Use innovative development models Adhere to international standards for drug development and registration Build regional networks DNDi’s approach

16. Contents • DNDi’s origin, vision and Founding Partners • What are neglected diseases? Why are we interested in them? • What are DNDi’s objectives? How will we achieve them? How will DNDi obtain funds to cover costs?Where are we today?

17. US$255 million over 12 years to achieve registration of 6 to 7 drugs and a balanced portfolio of projects Funding principle To obtain a mix of public and private funding aiming to increase involvement and responsibility of governments and international organizations in R&D for neglected diseases Business Plan projections

18. Funding projection (USD million) Public Funding Private Funding Founding Partners

19. DNDi today • A mix of 9 short, medium and long-term projects in 2004 portfolio • 6 more projects selected for 2005 portfolio • Regional research network operational and growing • Kenya (Nairobi) • Brazil (Rio de Janeiro) • Malaysia (Penang) • India (Delhi)

20. Pre Clinical Development Availability to patients Discovery DNDi projects 2005 Target validation of dihydrofolate reductase for leish & tryps Combination therapy for VL Nifurtimox - Eflornithine for HAT Protease inhibitor for Chagas Artesunate-Amodiaquine for malaria Whole cell African trypanosome screen Trypanothione reductase inhibitors for leish + tryps Artesunate-Mefloquine for malaria Protein farnesyl-transferase inhibitors for trypanosomes Paromomycin for VL in Africa Protease inhibitors for HAT Imiquimod for cutaneous leish Nitro comps for HAT Benzofuroxan comps for Chagas disease HAT: Human African trypanosomiasis VL: Visceral leishmaniasis Leish: Leishmaniasis Tryp: Trypanosomiasis Ascofuranone for HAT

21. Capacity building • Identify new scientific partners • Tap existing research facilities and scientific knowledge • Transfer technology and strengthen existing capacity in developing countries

22. DNDi rooted in networks • DNDi is a “virtual” organisation based on networks of scientists and scientific institutions • DNDi founding partner institutions have national and/or international networks • DNDi projects also work with other public and private organisations

23. Leishmania East Africa Platform (LEAP) LEAP: A group of scientists and institutions working on developing clinical trial capacity to bring new treatments to patients • University of Khartoum • Federal Ministry of Health • MSF- Holland SUDAN • Addis Ababa University • DACA • Ministry of Health ETHIOPIA + DNDi IOWH- India IDA WHO/TDR • Ministry of Health • KEMRI KENYA

24. Role of LEAP • Facilitate clinical testing and registration of new treatments for VL in the region • Evaluate, validate and register improved options that address regional needs for leishmaniasis • Provide capacity strengthening for drug evaluation and clinical studies in the region (Ethiopia, Kenya and Sudan)

25. LEAP’s inaugural project Paromomycinfor Africa • To register paromomycin (PM) as a new alternative treatment for VL in East Africa (Sudan, Ethiopia and Kenya) • To confirm efficacy and safety of paromomycin (and SSG) • To confirm efficacy and safety of a shorter combination course of PM/SSG Clinical trials have begun in 5 east African sites

26. Regulatory approval for trial • Institutional Ethics Committees • MSF International Ethics Committee • WHO-TDR Ethics Committee • National Authority in each country -Sudan -Federal Ministry of Health -Ethiopia -Drug Adminstration & Control Agency -Kenya -notnecessary for KEMRI studies

27. GCP training 2004 Investigators inEthiopia, Kenya, Sudan TDR-WHO Monitors Clinical Trial Consulting, Basel DSMB Drug Research & Safety Unit, London

28. Paromomycin project timetable Trial Design phase: completed July 31st 2004 Trial Preparation phase: in progress • approved in Sudan and Kenya • in progress in Ethiopia, now expected early March ’05 • includes trial site needs assessment and facility refurbishments/re-training e.g. new lab at Kassab First site started recruitment 18th November ’04 –Sudan Current status: 116 of 705 planned patients entered into trial

29. Paromomycin project timetable contd. Implementation phase • Patient recruitment; 9-12 months • Follow up six months • Earliest finish date (last patient, last visit) end2Q06 Reporting phase • Earliest data analysis and report end3Q06 • Earliest dossier submission end4Q06 • 2nd supportive, comparative trial vs amphotericin B completion May 2005 by IOWH in India

30. LEAP 0104 trial design • Multicentre, prospective, randomised, parallel group trial 1) SSG 30 days (20mg/kg/day) im injection vs 2) PM 21 days (15mg/kg/day) im injection vs 3) SSG/PM 17 days (dosages as above) im injection • Primary end-point: 6 month cure rate • Secondary end point: initial cure rate (test of cure at end of treatment) • Sample size: n=705 • Powered to show similarity in efficacy of all 3 regimens • Safety parameters; ECG, audiometry, LFTs, U&E, FBC • Good Clinical research Practice (pivotal for registration) • Data management and analysis by KEMRI