Research Gap and Neglected Diseases Edith Han February 8, 2007 Access to Essential Medicines (UAEM)

10/90 Gap “Only 10% of the world expenditure on health R&D is spent on health conditions that represent 90% of the global disease burden.” (Global Forum for Health Research)

10/90 Gap “[They] have no purchasing power, no vocal advocacy group is pleading for their needs, and no strategic interests—military or security—are driving concern about these conditions” (BMJ 325: 176–177).

Neglected Disease (ND) Operational Definition (FDA: U.S. Orphan Drug Act, 1983)  Any disease that: affects less than 200,000 persons in the U.S. affects more than 200,000 persons in the U.S. and for which there is no reasonable expectation that the cost of developing and making available in the U.S. a drug for such disease or condition will be recovered from sales in the U.S. of such drug

Neglected Disease (ND)

What NDs have in common:  They affect the world’s poorest people (and are a cause of poverty)  They are often vector-borne or parasitic  Disabling, disfiguring, and stigmatizing  Shortage of safe, effective treatments Resistance is a huge problem  Affected patients represent a low-priority market for Western pharma manufactures.

Neglected Diseases Where does ND research take place?  Universities!  Department of Defense  NIH/NIAID  Research institutes “30 billion dollars of total public spending (that includes government spending for research in institutes, universities, and government facilities), on health research worldwide, only an estimated 100 million dollars was spent annually for four of the most neglected diseases combined.”

Research and Access Gap Pecoul, PLoS Med. 2004

Why? Lack of market-based incentives for the pharmaceutical industry  The pharmaceutical industry in the U.S. derives only 5-7% of its profits from all LMI countries  Latin America, Africa, Asia (excluding Japan), and Australia comprised only 12% of the total worldwide market for pharmaceuticals, including generic drugs

Other Issues Heat-stable formulations Formulation for children Poor diagnostic technology Lack of suitable drug regiments

Malaria $323 million (2004) 49%: NIAID and the Gates Foundation  Account for 80% of growth in funding (’93-’04) 37%: Drugs 24%: Vaccines <1%: Diagnostics “Were malaria research funded at the average rate for all medical conditions, it would receive more than $3 billion in annual R&D funding.” Malaria R&D Alliance

African Trypanosomiasis “African Sleeping Sickness” Between K deaths each year in Africa A local disease – prevalence as high as 20-50% in some areas Symptoms: pain, headaches in first phase, severe neurological disease (confusion, sleep cycle disruption, etc.) Fatal without treatment

African Trypanosomiasis Case Study  Well-studied disease ~13,000 publications (PubMed) Caused by protozoan parasite  Melarsoprol – most widely-used Developed in 1940’s Arsenic-based, administered by injection (extremely painful) Fatal for about 10% of cases Drug resistance

African Trypanosomiasis Case Study (con’t)  Eflornithine – effective, less toxic “Resurrection drug” Developed in 1970’s (Albert Sjoerdsmanot) Approved by FDA in 1990; Aventis discontinued production in 1995  Patent rights and remaining stocks of drug donated to WHO (unsuccessfully tried to secure manufacturer) New use for eflornithine discovered 5 years later and was marketed as Vaniqa  Public-Private Partnership (PPP) formed: Brystol-Myers Squibb, Dow Chemical Co, Akorn Manufacturing Inc, Aventis, WHO, MSF

Case Study: Tuberculosis Mycobacterium Tuberculosis Still a major problem in the world (Also the neglected disease of the week!)

Dye, Christopher, “Global Epidemiology of Tuberculosis” The Lancet Vol. 367

Trajectories of tuberculosis epidemic for nine epidemiologically different regions of the world.

Case Study: Tuberculosis 22 countries account for 80% cases of TB Burden ranking 1. India 2. China 3. Indonesia 4. Nigeria 5. South Africa 6. Bangladesh 7. Pakistan 8. Ethiopia 9. Philippines 10. Kenya 11. Dem Rep of Congo 12. Russian Fed 13. Viet Nam 14. Tanzania 15. Uganda 16. Brazil 17. Afghanistan 18. Thailand 19. Mozambique 20. Zimbabwe 21. Myanmar 22. Cambodia

BCG Vaccination Bacillus Calmette-Guerin  Albert Calmette and Camille Geurin  1921  Live vaccine from Mycobacterium bovis  Variable effectiveness against pulmonary TB 70% protecting in UK study No protecting in India study

Too late? Only have we recently in the past decade or so realize that tuberculosis is a large threat and a big problem in public health.

TB: MDR-TB Resistance to at least isoniazid and rifampicin MDR-TB reveals problems infrastructure  Misuse of antibiotics  Inadequate public health systems  Poor quality “counterfeit” drugs  Default on treatment Challenges to treating MDR-TB  Cost up to 1,400x regular treatment (“second-line”)  Up to 2 years of treatment  No new drugs developed in the past 40 years  HIV co-infection inc proportion of resistant cases 425,000 cases of MDR-TB a year globally

TB: XDR-TB (extensive/extreme) “Virtually untreatable” TB “MDR-TB plus resistance to (i) any flouroquinolone, and (ii) at least 1 or 3 injectable second-line drugs capreomycin, kanamycin, amikacin. Of 17,690 isolates of 49 countries ( ), 20% were MDR-TB, and 2% were XDR-TB

XDR-TB Paul Sommerfield: “XDR-TB is very serious—we are potentially getting close to a bacteria that we have no tools, no weapons against.”