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

2. 2 Contents 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? DNDi’s origin, vision, and Founding Partners

3. 3 The DND i 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. 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. 5 DND i ’s Founding Partners Kenya Medical Research Institute WHO/TDR (permanent observer) Medecins Sans Frontieres Malaysian Ministry of Health Institut Pasteur, France Oswaldo Cruz Foundation, Brazil Indian Council for Medical Research

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

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

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

9. 9 Only 1% of new drugs developed are for neglected diseases Tropical diseases: 13 Tuberculosis: 3 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. 10 A significant medical need exists, but :  These diseases are 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 Neglected diseases attract negligible R&D

11. 11 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 Validated candidate drugs do not enter clinical development because of strategic company choices. New or existing drugs do not reach patients: registration problems, lack of production, high prices, or not adapted to the local conditions of use mainly public sector mainly industry (in North) Availability to patients Development Pre Clinical Discovery GAP2GAP3GAP1

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

13. 13 DND i ’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 awareness about the need for R&D for neglected diseases Use DNDi projects to strengthen existing capacity in disease-endemic countries.

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

15. 15 DND i ’s approach 1.Give top priority to patients’ needs 2.Use innovative development models 3.Adhere to international standards for drug development and registration 4.Build regional networks

16. 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. 17 Business Plan projections 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

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

19. 19 DND i 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. 20 DNDi projects 2005 Combination therapy for VL Benzofuroxan comps for Chagas disease Nitro comps for HAT Protease inhibitor for Chagas Nifurtimox - Eflornithine for HAT Protease inhibitors for HAT Artesunate- Amodiaquine for malaria Artesunate- Mefloquine for malaria Imiquimod for cutaneous leish Paromomycin for VL in Africa Protein farnesyl- transferase inhibitors for trypanosomes Trypanothione reductase inhibitors for leish + tryps Whole cell African trypanosome screen Target validation of dihydrofolate reductase for leish & tryps HAT: Human African trypanosomiasis VL: Visceral leishmaniasis Leish: Leishmaniasis Tryp: Trypanosomiasis Ascofuranone for HAT Ongoing 2005 approved projects Availability to patients Development Pre Clinical Discovery

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

22. 22 DND i 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. 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 ETHIOPIA SUDAN KENYA Addis Ababa University DACA Ministry of Health University of Khartoum Federal Ministry of Health MSF- Holland Ministry of Health KEMRI + DNDi IOWH- India IDA WHO/TDR

24. 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. 25 LEAP’s inaugural project 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 Paromomycin for Africa Clinical trials have begun in 5 east African sites

26. 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 -not necessary for KEMRI studies

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

28. 28 Paromomycin project timetable Trial Design phase: completed July 31 st 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 18 th November ’04 –Sudan Current status: 116 of 705 planned patients entered into trial

29. 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 2 nd supportive, comparative trial vs amphotericin B completion May 2005 by IOWH in India

30. 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