DNDi and our partners are working to deliver safer, simpler treatments to save lives, reduce social stigma, and eliminate leishmaniasis as a public health problem. In the short term, we are building on our successes in delivering safer, shorter treatments with existing drugs. To bring prompt diagnosis and treatment closer to patients and help facilitate sustainable disease elimination, we are also making strides toward our longer-term goal: developing all-new treatments with new chemical entities that are safe, effective, and easier to manage at the primary healthcare level.
Our progress in 2025 includes:
Discovery
Open Synthesis Network: Work on projects P1Tc and P5 have been finalized, and a new project, P9, has been added to the OSN portfolio. A manuscript detailing the findings from project P1Tc led by the University of Nottingham was published in the journal ACS Infectious Diseases. In addition, Prof. Pascal Marchand of the Université de Nantes was recognized with the French Society for Medicinal Chemistry’s Camille Wermuth Award 2025 for his work using the OSN in teaching undergraduate medicinal chemistry students.
Translation
LXE408 Novartis for visceral leishmaniasis: The Phase II study in India was completed, with recruitment of 95 adult patients finalized in March and follow-up completed in September. Recruitment of adolescent participants – an exploratory endpoint – faced enrolment challenges and closed in June with six participants, with final visits completed in December 2025. The Phase II study in Ethiopia completed recruitment of 52 participants in May 2025, with final visits completed in November 2025. Results from both trials are expected in 2026.
LXE408 Novartis for cutaneous leishmaniasis: The protocol and supporting documents for the Phase II trial evaluating the safety, efficacy, and pharmacokinetic profile of two oral LXE408 regimens were submitted to the regulatory authorities in Brazil and Panama, and approvals were obtained from both countries. Ethics approvals are expected in the first quarter of 2026; and study initiation is expected to follow in the second quarter. DNDi teams made progress developing key study documents, including the case report form and manual of operations, and these are expected to be finalized by the time ethical approvals are received. In addition, the vendor selection process for data management, interactive response technology, statistics, and central depot has been completed.
DNDI-6899 (GSK899/DDD853651): The Phase I food effect and multiple ascending dose study started in April at the Royal Liverpool University Hospital, UK, in partnership with the University of Liverpool. It aims to evaluate the drug’s safety, tolerability, and pharmacokinetics in healthy volunteers. This research will determine if DNDI-6899 is suitable for later trials in patients with visceral leishmaniasis, with a primary focus on Africa. The study is expected to conclude in May 2026, with results anticipated in the third quarter of 2026.
DNDI-6174: The pre-clinical package and Phase I (single ascending dose and multiple ascending dose) concept sheet was discussed with the UK Medicines and Healthcare products Regulatory Agency (MHRA) through the MHRA Scientific Advice service. The UK MHRA provided positive feedback confirming that the non-clinical data package adequately supports first-in-human trials. There was no objection to the study design and scope, including the proposed safety risk monitoring. The Phase I clinical trial of DNDI-6174 is expected to begin in Q1 2027.
CpG-D35 (DNDI-2319): A new study proposal has been developed integrating, in a sequential design, a multiple ascending dose study followed by a proof of concept trial in patients with complicated forms of CL. The target population for the study includes people presenting with ≥4 lesions, lesions ≥4 cm in diameter, facial involvement, prior failure of standard therapies, or clinical forms such as L. recidivans, diffuse, or disseminated CL. Study site selection was guided by the epidemiological prevalence of these severe phenotypes. The study synopsis underwent review and received endorsement from both SwissMedic and the World Health Organization. A funding application for the study is currently under review with feedback expected later in 2026.
GSK245 (DDD1305143): GSK discontinued development of GSK245 following clinical evaluation in healthy volunteers, which confirmed its profile did not meet the criteria for progression to evaluation in patients affected by visceral leishmaniasis.
DNDI-0690: With other compounds currently under investigation for leishmaniasis in the DNDi portfolio presenting superior safety profiles, the clinical development of DNDI-0690 was terminated.
DNDI-6148: To prioritize more advanced compounds in the leishmaniasis portfolio, activities related to the clinical development of DNDI-6148 remain on hold.
Development
Miltefosine + thermotherapy for cutaneous leishmaniasis: The Phase III combination trial testing miltefosine plus thermotherapy has been finalized, and the study manuscript is under preparation. Although overall cure rates did not differ between miltefosine alone and the combination of miltefosine plus thermotherapy, the combination therapy was significantly more effective than either intervention alone in patients with lesions caused by L. braziliensis. DNDi teams continued to support the Pan American Health Organization (PAHO) in scaling up thermotherapy in Latin America through structured training and device deployment.
Miltefosine + Paromomycin for visceral leishmaniasis (Africa): The WHO guidelines development process continued. New guidelines, including new recommendations for VL in Eastern Africa, are expected in 2026. In parallel, the ministries of health in Kenya, Ethiopia, and Uganda are revising their national guidelines, which are expected to be released following the release of the updated WHO recommendations. DNDi provided technical support for the revision process across these countries to ensure that national policies align with the latest evidence and that adoption is accelerated following the release of the updated WHO guidelines. This collaborative effort aims to shorten the timeline from evidence generation to the implementation of improved treatments in the region.
New treatments for PKDL (Eastern Africa): The WHO guidelines development process is ongoing, with the new guidelines, including new recommendations for PKDL in Eastern Africa, expected by 2026. In parallel, the ministries of health in Kenya, Ethiopia, and Uganda are revising their national guidelines, which are expected to be released following the release of the updated WHO recommendations.
New treatments for PKDL (South Asia): The World Health Organization guideline development group convened to review the evidence for new treatments for visceral leishmaniasis and PKDL in Eastern Africa and South Asia in November 2023. The process is ongoing, with the recommendations expected in 2026. In parallel, the regional technical advisory group for kala-azar and ministries of health of the endemic countries in the region are also expected to review the evidence and release new recommendations for the treatment of PKDL in South Asia.
Implementation
New VL treatments (South Asia): The focus on early diagnosis and treatment of VL and PKDL in rural areas of Bihar continued with 23 training events held over the course of the year for close to 1,600 participants. In India, DNDi supported the Bihar State health teams in preparing an elimination dossier to be submitted to WHO for validation of India’s elimination of VL as a public health problem. The Centres of Excellence (CoEs) in Saran and Purnia continued to treat patients with VL and PKDL. In Nepal, DNDi worked to agree on the requirements for the two new CoEs set to be established in leishmaniasis-endemic areas in Karnali and Madesh provinces. Equipment and reagents for the new CoEs have been procured, and delivery and installation of equipment at the two provincial hospital sites is underway. Completion of memoranda of understanding with the hospitals and handover of the CoEs is expected in early 2026.
New treatments for VL/HIV: Twenty-three people living with both VL and HIV were treated at the DNDi-supported Leishmaniasis Research and Treatment Centre in Gondar, Ethiopia. Each received treatment with the newly recommended liposomal amphotericin B and miltefosine combination (LAmB + MF) therapy. The combination therapy has been included as the recommended first-line treatment option for the treatment of VL in people living with HIV in the draft treatment guidelines for leishmaniasis in Kenya and Uganda.
Photo credit: JDot-DNDi
