DNDi aims to make treatments safer, shorter, and more affordable and effective for all forms of leishmaniasis. In the short term, better treatment regiments are being developed using existing drugs. In the long term, the goal is to develop an entirely new generation of all-oral drugs.

DNDi’s current leishmaniasis portfolio includes:

Discovery

• Screening: DNDi has identified a variety of novel hit series via the screening of new compound libraries to continuously feed the early discovery pipeline for leishmaniasis. Those new starting points originate from both natural product and synthetic compound collections, either accessed through partnerships, acquired via purchase, or obtained as in-kind contributions to DNDi.

• Leishmaniasis hit-to-lead: The process of hit-to-lead optimization is ongoing, with multiple series being progressed based on outputs of the screening programme. A variety of hit-to-lead mechanisms and exploration strategies are being used to progress towards in vivo proof-of-concept studies in pre-clinical efficacy models of leishmaniasis.

• NTD Drug Discovery Booster hit-to-lead: Booster screening activities were placed on temporary hold in early 2019 to focus efforts on transitioning existing hit series into lead optimization projects. Two hit series are currently under further investigation with Takeda, and work is underway to transition additional series for potential lead optimization in 2020.

• Daiichi-Sankyo leishmaniasis hit-to-lead: The frontrunning series that is the current focus of this hit-to-lead project has clear activity against the T. cruzi parasite, which causes Chagas disease. This series will therefore be progressed for Chagas disease.

• DNDI-5421 & DNDI-5610: Further development of these two compounds remains on hold as development of lead compound DNDI-6148 progresses to a Phase I study.

• Aminopyrazoles: Further work on the back-ups from this series is currently on hold; however, new chemical spaces continue to be investigated through the Open Synthesis Network, a collaborative project that engages master’s and undergraduate students in research for neglected diseases.

• CF series: Further optimization of the CF series lead-series has provided compounds displaying promising potency against L. infantum. Further optimization is ongoing to select additional compounds for in vivo testing.

• Leishmaniasis L205 series: Following the assessment of the three lead compounds from this series (DNDI-6588, DNDI-6749, and DNDI-6174), DNDI-6174 was progressed and nominated as a pre-clinical candidate for visceral leishmaniasis.

Translation

• DNDI-6174: Emerging from the leishmaniasis L205 lead optimization series after showing great efficacy in vivo in both mouse and hamster models for visceral leishmaniasis, DNDI-6174 was nominated as a pre-clinical candidate for visceral leishmaniasis in 2019. Planning is underway to start pre-clinical studies in 2020.

• GSK3186899/DDD853651 & GSK3494245/DDD1305143: A Phase I single ascending dose study of GSK3186899/DDD853651 in healthy volunteers was completed in 2019; a Phase I single ascending dose study of GSK3494245/DDD1305143 is planned to start in late 2020.

• CpG-D35 for cutaneous leishmaniasis: Pre-clinical toxicology studies were initiated in 2019 and should be completed by mid-2020. Pending positive results, DNDi hopes to initiate a first-in-human Phase I study by late 2020.

• DNDI-5561: Due to unfavourable safety results in pre-clinical studies, the decision was made to stop development of DNDI-5561 in 2019.

• DNDI-6148: The clinical trial application for this study was approved in November 2019 and the first volunteer was enrolled in a Phase I single ascending dose study in January 2020. Pending study results, a multiple ascending dose study will start in late 2020.

• DNDI-0690: A Phase I single ascending dose study in healthy volunteers was initiated in 2019; a multiple ascending dose study is planned for 2020.

Development

• New cutaneous leishmaniasis combination: Preliminary results of a Phase II study completed in April 2019 show the combination of thermotherapy with a shorter course of oral miltefosine to be significantly better than thermotherapy alone for the treatment of uncomplicated CL in the Americas. A Phase III study is planned to start in the second half of 2020 to compare the non-inferiority of the combination against the current recommended systemic treatments, sodium stibogluconate or miltefosine.

• New treatments for PKDL: A Phase II study to test both liposomal amphotericin B in combination with miltefosine, and paromomycin in combination with miltefosine began in Dooka, Sudan in 2018 and had enrolled 73 patients by January 2020. Results are expected by 2021.In South Asia, patient enrollment in three sites in India (KAMRC and RMRI) and Bangladesh (icddr,b) was completed in January 2019 for DNDi’s Phase II study to assess the safety and efficacy of liposomal amphotericin B monotherapy and a combination of liposomal amphotericin B and miltefosine. Results are expected by mid-2021 following completion of a 24-month follow-up period.In Sudan, work continues at University of Gedaref to establish a sandfly colony in preparation for infectivity studies in PKDL and VL patients. A similar study completed in Bangladesh in 2018 confirmed that PKDL acts as a reservoir for ongoing leishmaniasis infection.
• Miltefosine + paromomycin combination for Africa: By January 2020, a total of 350 patients, both children and adults, were enrolled in the study across seven sites in Ethiopia (Gondar and Abdurafi), Kenya (Kacheliba), Sudan (Dooka, Um el Kher, and Tabarak Allah), and Uganda (Amudat). Completion of patient enrollment is targeted for August 2020.

• New visceral leishmaniasis treatments in Latin America:The Brazilian Ministry of Health is reviewing its treatment policy to consider the adoption of liposomal amphotericin B as the country’s first-line visceral leishmaniasis treatment.

• New treatments for HIV/VL: DNDi and the Rajendra Memorial Research Institute acted as technical partners in a Phase III study sponsored by MSF in India to evaluate currently recommended liposomal amphotericin B (LAmB) therapy and a combination of LAmB and miltefosine for the treatment of VL in patients co-infected with HIV. The last patient follow-up visit for the study was completed in May 2019 and the publication of study results is expected in 2020. Results of this study and the Phase III study on HIV/VL co-infected patients in Ethiopia will be reviewed in early 2020 by a World Health Organization Guideline Development Group evaluating treatment recommendations for people co-infected with VL and HIV.

Photo credit: Maneesh Agnihotri-DNDi