Patient’s needs driven R & D Agenda

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

Pentavalent Antimony Pentavalent antimonials (Sbv) 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

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;)

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

Response to Antimony Therapy in Indian Kala-azar

0

20

40

60

80

100

70s 80s 92-93 94-97Years

Perc

enta

ge C

ure

Rate

10 mg/Kg20 mg/Kg

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

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

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

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)

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$)

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

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