DNDi’s current leishmaniasis portfolio includes:

Discovery

Seven projects in the discovery phase:

• Leish hit-to-lead: The process of hit-to-lead optimization is ongoing, with multiple series provided by several pharmaceutical companies as well as with hits from libraries purchased from commercial vendors and screened by DNDi. If promising activity can be demonstrated in pre-clinical models of leishmaniasis, the series will be advanced into full lead optimization.

• Booster hit-to-lead: Screening by NTD Drug Discovery Booster partners continued at the rate of one new iteration per month. The project conducts multilateral, simultaneous searches of millions of compounds based on an active seed supplied by DNDi and uses computational approaches to refine the search iteratively. Since its creation in 2015, the Booster project has launched 45 iterations around 22 seed compounds, with the result that 13 hit series have been released, of which six have progressed to in vivo proof-of-concept studies for leishmaniasis and/or Chagas.

• Daiichi-Sankyo leishmaniasis hit-to-lead: This project, which ended in September 2018, aimed to identify at least one progressable lead series meeting DNDi lead-stage criteria for visceral leishmaniasis and/or Chagas disease. The project milestone was reached with the identification of a progressable Chagas lead series with proven in vivo.

• DNDI-5421 & DNDI-5610 oxaboroles: These two compounds from the oxaborole class serve as back-ups to DNDI-6148. Their further development is currently on hold and will only recommence should problems be encountered with the development of DNDI-6148.

• Aminopyrazoles: While a pre-clinical trial application studies package composed of toxicology and safety studies should start in early 2019 for the lead compound DNDI-5561, 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.

• Celgene Global Health visceral leishmaniasis series 1: Because of poor pharmacokinetics and a lack of safety margins following extensive exploration, the decision was made to stop this series. A new screen has begun with a new sub-set of the Celgene library of compounds with the goal to identify novel lead series.

• Leishmaniasis L205 series: Lead compound DNDI-6588 showed great efficacy in vivo in both mouse and hamster models for visceral leishmaniasis. Additional 205-series compounds having similar or improved profiles have been added to the candidate shortlist and are currently being assessed.

Translation

Six projects in the translation phase:

 DNDI-6148: The decision was made in 2018 to progress to a Phase I single ascending dose in healthy volunteers in parallel with additional toxicological investigations. A clinical trial application for a first-in-human study (Phase I) was submitted to the French authorities in October.

• DNDI-0690 nitroimidazole: A decision to progress to Phase I single ascending dose in healthy volunteers was agreed in 2018. A clinical trial application for a first-in-human study (Phase I) was submitted to UK authorities in February 2019.

• DNDI-5561: DNDI-5561 is the most advanced compound of the aminopyrazole series. It was nominated as a pre-clinical candidate in 2017. The pre-clinical trial application package studies to enable a first-in-human study (Phase I) should start early 2019 and should be completed by the end of 2019.

• GSK3186899/DDD853651 & GSK3494245/DDD1305143: In 2017, DNDi and GSK entered into an agreement for the pre-clinical development of two compounds for leishmaniasis developed by GSK in collaboration with the Drug Discovery Unit (DDU) at the University of Dundee, following co-funding by the Wellcome Trust. A Phase I study with the compound GSK3186899/DDD853651 is expected to start in April 2019 following appropriate regulatory and ethical approvals and will be conducted by GSK. GSK3494245/DDD1305143 is currently under review to assess the feasibility of proceeding to a Phase I study.

• CpG-D35 for cutaneous leishmaniasis: This project aims to produce an immunomodulator to stimulate the innate immune system to fight parasitic infection, as an adjunct to drug therapy. Final results of the preclinical in vivo efficacy study showed an improved outcome for CpG-D35, either alone or in combination with pentavalent antimony (glucantime). A pre-clinical package enabling a first-in-human study (Phase I) will be performed in 2019. A meeting with the UK Medicines and Healthcare Products Regulatory Agency is scheduled for February 2019 to discuss the pre-clinical development plan and clinical package.

• New cutaneous leishmaniasis combination therapies: Recruitment of patients was completed in Peru (65 patients) and in Colombia (65 patients). The last patient six-month follow-up is expected in early 2019. Interim results supported the preparation of a Phase III study in the Americas comparing the combination therapy (thermotherapy and miltefosine) against the standard treatment (meglumine antimoniate). The study is being planned in four countries in Latin America.

Development

Four projects in the clinical development phase:

• New treatments for HIV/VL: The results of a study of AmBisome and miltefosine combination therapy efficacy in co-infected patients in Ethiopia showed an 88% cure rate with a second round of treatment to clear Leishmania parasites. A scientific paper sharing the results was published in PLOS NTDs in January 2019 and should support discussions with other stakeholders to support a new treatment recommendation for VL in people co-infected with HIV. Preliminary results are promising from a Phase III study sponsored by MSF and testing the same combination regimen in India, where DNDi is a technical partner with the Rajendra Memorial Research Institute (RMRI).
• New treatments for PKDL: Recruitment has been completed with 126 patients enrolled in three clinical sites in India (RMRI in Patna and KAMRC in Muzzafarpur) and Bangladesh in a Phase II study of AmBisome monotherapy and a combination of AmBisome and miltefosine. A Phase II study to test both AmBisome in combination with miltefosine, and paromomycin in combination with miltefosine began in Dooka, Sudan in 2018 and had recruited 39 patients by the end of the year. The results of an infectivity study conducted in Bangladesh in 65 patients confirmed that PKDL acts as a reservoir for ongoing leishmaniasis infection. To assess long-term infectivity and the impact of treatment, the study protocol was amended to repeat xenodiagnosis on PKDL patients after treatment completion. In Sudan, preparation for a similar infectivity study is underway.

• Miltefosine/paromomycin combination for Africa: Clinical sites for a Phase III study to compare two combination regimens of miltefosine and paromomycin with the current standard VL treatment, sodium stibogluconate and paromomycin, in both paediatric and adult patients started with the recruitment of the first patient in Sudan (Dooka) in January 2018. 126 patients were recruited in five sites in Sudan (Doka), Kenya (Kacheliba), Ethiopia (Gondar and Abdurafi) and Uganda (Amudat). An additional site in Sudan (Um El Kher) will be initiated in early 2019.

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

Implementation and Access