Development of the drug miltefosine for the treatment of leishmaniasis

Over 300 million people in developing countries are at risk of leishmaniasis, a disease caused by around 20 different species of protozoan parasites and transmitted by sandflies.

There are two main types of the disease: cutaneous, with one million cases reported in the last five years; and visceral, with 300,000 cases annually and 20,000 deaths.

In the 1980s Simon Croft, now professor of parasitology at the School, discovered that miltefosine, a novel phospholipid compound, was highly active against Leishmania parasites in experimental models. He carried out further studies on similar drugs and also showed the miltefosine was active against the Leishmania species that cause both visceral and cutaneous leishmaniasis. At the same time, groups in Germany were developing miltefosine as an anti-cancer drug.

Following initial funding from WHO Special Programme for Research and Training in Tropical Diseases, Croft initiated and co-ordinated two programmes, funded by the European Union, with partners from South America and Europe to study the mechanism and action of resistance of the parasite to the drug. Researchers in Spain identified a membrane transporter responsible for conferring drug resistance.

Following clinical trials, miltefosine was registered for the treatment of visceral leishmaniasis in India in 2002, and in 2005, the governments of India, Nepal and Bangladesh agreed a 10-year programme to eliminate leishmaniasis.  Miltefosine was the only drug in the programme, and was used to treat more than 137,000 patients between 2008 and 2013.

The next step in Croft’s research was to look ways to shorten courses of treatment and combat resistance to leishmaniasis therapy. Studies in vitro and in mice identified combinations of miltefosine with other drugs giving significant additional effect. In 2004, Croft was appointed the first Research & Development Director at the Drugs for Neglected Diseases Initiative, Geneva, where he led the development programme for combination therapy.

Phase three and four clinical trials of anti-leishmanial drug combinations were carried out in India in 2009 to 2010 and show that a combination therapy gives a more than 98% cure rate. The combinations could dramatically reduce the length of a course of treatment from 28 to eight days.

In 2010 the World Health Organization (WHO) included miltefosine on its list of essential medicines, a crucial step as many charities working in the developing world will only use drugs on this list. That same year a WHO expert committee published a technical documentwhich has been used by many governments, recommending the use of miltefosine.

In Colombia, miltefosine has become a drug of choice for cutaneous leishmaniasis where it has been shown to have an 84 to 91% cure rate, and Argentina’s ministry of health recommends the drug as a first-line treatment.

In 2014, the US Food and Drug Administration approved miltefosine for any form of leishmaniasis, and it became the first approved drug for cutaneous leishmaniasis.