Transcript presentation here

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)


Cardiotoxicity


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% )
(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
Percentage Cure Rate
100
10 mg/Kg
80
20 mg/Kg
60
40
20
0
70s
80s
Years
92-93
94-97
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