R&D MODEL & PORTFOLIO
What are the current treatments and their limitations?
Existing drugs have serious drawbacks in terms of safety, resistance, stability, and cost. They have low tolerability, long treatment duration, and are difficult to administer. These drugs are used either as monotherapy or in combination for the various forms of leishmaniasis. Pentavalent antimonials (sodium stibogluconate – SSG – and meglumine antimoniate): used for VL and CL for over 60 years. Acquired resistance in areas of high prevalence and high transmission has been reported. Serious cardiotoxicity leading to death is well documented. In monotherapy, they require a 30-day parenteral treatment for VL. For CL: intramuscular injections for 21 days; in the Old World, generally 1-2 intralesional applications per week for 3-7 weeks, sometimes alternating with cryotherapy (not used in the New World). Registered in South East Asia, Latin America, and some Mediterranean and African countries. Amphotericin B deoxycholate: only an alternative treatment for VL in areas with high rates of unresponsiveness to antimonials where no other options are available. Need for hospitalization, constant renal monitoring of patients, 28-day duration of treatment, and infusion-related adverse events are notable drawbacks. Amphotericin B displays doselimiting toxicity. Registered in South Asian countries and some countries in Africa and Latin America. AmBisome®: a liposomal formulation of amphotericin B, which is comparatively much safer and highly efficacious. A single infusion of 10mg/kg has shown a 96.4% cure rate in Asia. However, high cost and the need for a cold chain limit widespread use. Registered for VL in India, USA, and Europe and used as a second-line drug for the treatment of VL in East Africa at higher doses than in India and for VL in Brazil. It is also used to treat PKDL cases in Sudan. A donation to WHO facilitates free distribution of AmBisome® to the three countries involved in the elimination strategy in South Asia for primary VL patients, and as a rescue treatment for African VL. It is not properly evaluated for cutaneous leishmaniasis (CL). Miltefosine: an oral drug administered twice daily, registered for use in India for VL, and requires 28-day treatment. Major limitations include low compliance, risk of resistance, contraindication in pregnancy, and mandatory contraception for women of child-bearing age for the duration of therapy and three months beyond. A recent study in Asia indicated an emerging lack of efficacy of monotherapy in the region, probably associated with drug underexposure in children, and the same has been observed in Africa. For CL, currently approved for lesions caused by three Leishmania species. Miltefosine is not registered in many endemic countries and is consequently not available. Paromomycin: a low-cost parenteral formulation that requires three weeks of painful intramuscular administration is also highly efficacious in Asia but is associated with some degree of renal and ototoxicity; limited efficacy as monotherapy in East Africa.
at risk in
million cases of CL annually
although with a marked reduction in the number of cases observed in the Indian subcontinent
million cases of VL annually,
Cutaneous and mucocutaneous leishmaniasis Cutaneous leishmaniasis
DNDi Annual Report 2015 › 27