1. Patient’s needs driven R & D Agenda

2. Increasing Devastation of Leishmaniasis 88 countries in tropical and temperate regions 72 of them developing or least developed Two million cases occur annually About 350 million people are at risk prevalence of 12 million human leishmaniasis is on the increase worldwide —Outbreaks in New areas —Disease moving towards urban areas —Increase in the number of cases in VL & CL —100,000 died of 280,000 in Sudan in 80s

4. Pentavalent Antimony  Pentavalent antimonials (Sb v ) have been the mainstay of all forms of leishmaniasis for seven decades  Branded products and generic products are similar in safety and efficacy  Antimony remains the most important antileishmanial compound in the world for all forms of leishmaniasis  However, toxicity profile of antimony warrants search for safer drugs to replace it as first line drug in other parts of the world as well as least for VL

5. Antimony toxicity  Serious and fatal antimony toxicity not infrequent even with standard products (3-6% deaths in VL)  Ahasan et al 1996, Bangladesh; Thakur et al, 1998; Sundar et al, 2000, India; Moore et al 2001, Kenya; Singh et al; 1989, India; Delgado et al, 1999, Spain 12% )  Cardiotoxicity  ( Thakur et al, 1998, India; Laguna et al, 1999, Spain; Ribiero et al, 1999 Brazil; Sundar et al, 2000, India)  Pancreatitis especially in HIV co-infected  (Aronson et al 1998, US military, Delgado et al, 1999, Spain, Gasser et al, 1994 [CL]Peru; )

6. Drug Failure in India  Indian Epidemic is unique where large scale primary antimony & pentamidine failure has occurred  Once the resistance is established, it escalates rapidly due to anthroponotic nature of transmission  Evidences suggest emergence of antimony refractory strains in India

7. Response to Antimony Therapy in Indian Kala-azar 0 20 40 60 80 100 70s80s92-9394-97 Years Percentage Cure Rate 10 mg/Kg 20 mg/Kg

8. Impact of Antimony Resistance  Sb was the only affordable drug in India (Cost for 50 kg Patient – US $ 35)  Very few can afford anything priced above  Delayed or no cure leading to increased morbidity and mortality

9. Amphotericin B  Effective but toxic drug  Use restricted to hospitals  Prolonged hospitalisation of 5-6 weeks  Expensive (Drug cost – 5 thousand)  Clinical & lab. Monitoring is required  Not affordable for most patients

11. Lipid Associated Amphotericin B in Kala-azar  Important advance in chemotherapy  Deoxycholate replace by other lipids  Drug accumulates in RE system, no organ toxicity  Extremely attractive, few side-effects  High dose over short period can be given  Shorter courses  Reduce the hospitalization cost  Possible to treat larger number of patients

12. Lipid Amphotericin B  Not much to choose in terms of efficacy  AmBisome is safest, nearly free of adverse events and followed by Abelcet > Amphocil  Can be used in presence of renal or hepatic insufficiency, in very sick patients  Commercial formulations (cost for a 15 mg/kg dose for 50 kg person) – Market retail price  AmBisome, Gilead, USA (US $ 3000.00)  Abelcet, Liposome co, USA(US $ 1700.00)  Amphocil, Intermune, USA (US $ 2200.00)

13. Paramomycin (Aminosidine) An aminoglycoside (parenteral) Good antileishmanial activity, earlier used for bacterial & Parasitic infections In several phase II studies 16 mg/kg for 3 weeks cured 93% VL patients Will be licensed after the ongoing multicenter Phase III trial results ( dose 15 mg/kg x 21 days) Safe, Good alternative to antimony as first line Tt Likely to be produced in India Could be the cheapest antileishmanial drug (~ 10-15 US$)

14. Miltefosine - First oral drug for leishmaniasis Approved in India, Germany & Colombia Dose: 100 mg (>25 kg); 50 mg (<25 kg); Children 2.5mg/kg, Duration: Four weeks Long term cure rates 94% Side – effects: Vomiting occurs in ~40%, diarrhea in ~20%. Skin allergy, nephrotoxicity are occasionally seen Can not be used in pregnant females [teratogenic], and those refusing contraception (for the treatment period and another two months) Cost – US$ 145.00, Freely available over the counter in India

15. Future Needs  Limited therapeutic options available  More drugs (better, safer & cheaper) are needed  Cheaper lipid amphotericin B needed preferably AmBisome  Combination multidrug treatment urgently needed especially for Indian subcontinent, eventually globally  Short duration therapy to improve compliance & prevent resistance  Access is important – Drug should be free to patients  Miltefosine is an example – No access to poor patients