The UK charitable foundation Wellcome has awarded a €5.7 million grant to the non-profit medical research organization Drugs for Neglected Diseases initiative (DNDi) to continue the development of promising oral new chemical entities to treat leishmaniasis, one of the world’s most devastating parasitic diseases.
Leishmaniasis is the deadliest parasitic killer after malaria. It is endemic in 98 countries with over one billion people at risk globally and between 700,000 and 1 million new cases estimated annually. The most severe form, visceral leishmaniasis, is fatal if untreated. Its cutaneous form can cause disfigurement and permanent scarring, leading to social stigmatization and mental health issues, especially for women. Half of people affected are children under 15.
‘Leishmaniasis is a deeply neglected disease that affects the poorest communities. Existing treatments are not good enough: most are outdated, require painful injections, and have serious toxicities and variable efficacy. Patients deserve better. That is why we are excited to renew our collaboration with Wellcome, which will allow us to continue to develop promising molecules for safe, effective and easy-to-administer oral drugs,’ said Dr Fabiana Alves, Director of NTDs (Neglected Tropical Diseases) Leishmaniasis and Mycetoma at DNDi.
DNDi, in partnership with Wellcome and others, has developed in recent years a large and unique portfolio of new chemical entities (NCEs) that includes a total of five NCEs advancing to pre-clinical and Phase I clinical trials, and the lead compound LXE408 which is advancing to Phase II trials. LXE408 was discovered at pharmaceutical company Novartis with financial support from Wellcome and is being developed jointly by DNDi and Novartis.
The renewed partnership will build on a successful project by Wellcome and DNDi entitled ‘21st century treatments for sustainable elimination of leishmaniasis’ that started in 2018. The renewed project aims at continuing the development of the new drugs, including progressing LXE408 to Phase II clinical trials. The long-term objective is to develop up to five oral therapies for visceral leishmaniasis and cutaneous leishmaniasis in Asia, Africa, and Latin America: the most promising candidates will progress towards Phase III clinical studies, with industrial scale-up and registration in disease-endemic regions.
‘Our intent is that the future treatments that we are developing will cater to the needs of these neglected patients, especially children who represent half of visceral leishmaniasis cases. If they are oral and well-tolerated, they could be deployed within primary healthcare systems, which will allow a higher number of people to receive early treatment,’ said Dr Alves. ‘That will contribute to the sustainable elimination efforts against VL in Asia, as well as disease control in Africa and Latin America, and will contribute to control of cutaneous leishmaniasis worldwide.’
Leishmaniasis is strongly associated with poverty, poor access to healthcare, and conflict. The forced displacement of non-immune migrants to endemic areas caused visceral leishmaniasis epidemics during conflict in South Sudan in the 1990s and in 2010, as well the more recent outbreak of cutaneous leishmaniasis in Syria. The COVID-19 pandemic has disrupted visceral leishmaniasis control efforts.
Moreover, leishmaniasis is a climate-sensitive disease. Changes in temperatures and rain patterns impact the survival and distribution of sandflies that transmit the disease, which in turn will facilitate the parasite’s transmission in previously non-endemic areas. Health systems need to be prepared and a simple oral treatment would be better adapted to meet these upcoming challenges.
The new treatments developed thanks to this grant could also benefit patients presenting with complex forms of leishmaniasis, such as visceral leishmaniasis and HIV co-infected individuals, muco-cutaneous and post-kala-azar dermal leishmaniasis (PKDL). The programme contributes actively to the World Health Organization Roadmap for NTDs, calling for user-friendly, safe, and highly efficacious treatments.
Wellcome supports science to solve the urgent health challenges facing everyone. We support discovery research into life, health and wellbeing, and we’re taking on three worldwide health challenges: mental health, infectious disease and climate and health.
A not-for-profit research and development organization, DNDi works to deliver new treatments for neglected patients, those living with Chagas disease, sleeping sickness (human African trypanosomiasis), leishmaniasis, filarial infections, mycetoma, paediatric HIV, and hepatitis C. DNDi is also coordinating the ANTICOV clinical trial to find treatments for mild-to-moderate COVID-19 cases in Africa. Since its inception in 2003, DNDi has delivered twelve new treatments to date, including new drug combinations for kala-azar, two fixed-dose antimalarials, and DNDi’s first successfully developed new chemical entity, fexinidazole, approved in 2018 for the treatment of both stages of sleeping sickness. dndi.org
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Photo credit: Maneesh Agnihotri-DNDi