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 2024 includes:
Discovery
Screening: DNDi has completed its high-throughput screening (HTS) programme testing compounds for activity against Leishmania donovani in collaboration with University of Tokyo and with support from the Global Health Innovative Technology (GHIT) Fund. A total of 11 hits belonging to seven chemical series were identified. The three most attractive scaffolds were followed up via the purchase and testing of 88 chemical analogues at the Swiss Tropical and Public Health Institute and the University of Tokyo. Unfortunately, none of the compounds showed significant activity against Leishmania donovani.
Open Synthesis Network: Optimization of compounds from project P7 is currently underway. Completion of projects P5 and P1Tc are currently under review. Three scientific manuscripts resulting from OSN projects have been published. The team at the University of Munster, led by Prof. Bernhard Wünsch, authored two publications focused on medicinal chemistry and compound optimization for leishmaniasis. The team at the University of Washington at Tacoma, led by Prof. Kelly Kim, authored a paper investigating the regioselectivity of certain reactions employed in project P6.
Translation
LXE408 Novartis for visceral leishmaniasis: Recruitment in India progressed well, with 88 adult patients enrolled by the end of 2024. Following an interim analysis conducted in April, the Independent Data Monitoring Committee recommended continuing the study and expanding it to include ten adolescents. The first adolescent was included in November. In parallel, the first patient in the Ethiopia study was enrolled in April, and 36 patients had been recruited by the end of the year. Both studies are planned to be completed in 2025, with results expected to be available in early 2026. DNDi and partners are also preparing for a Phase II, randomized, multicentre, observer-blinded study, to evaluate the safety, efficacy, and pharmacokinetic profile of two oral LXE408 regimens compared with oral miltefosine as active control in patients with localized cutaneous leishmaniasis in the region of the Americas.
DNDI-8526 (S07 series): The nominated pre-clinical candidate for visceral leishmaniasis, DNDI-8526, has shown promise, but several challenges and risks (such as solubility, pharmacokinetics, and species variability) have been identified that need to be addressed before advancing to pre-clinical studies. Given that this compound is positioned as a backup new chemical entity in the leishmaniasis portfolio as a proteasome inhibitor (behind two other compounds, LXE408 and GSK245), the project was placed on hold pending the availability of resources for further development and testing. The project is considered successful thus far, with a clearly defined plan in place for its next steps.
DNDI-6899 (GSK899/DDD853651): The clinical trial application for Phase I evaluation in healthy volunteers, including food effect and multiple ascending dose studies, was approved on 5 July 2024 by the Research Ethics Committee and the UK Medicines and Healthcare Products Regulatory Agency (MHRA). Further start-up activities progressed and funding for the trial was granted by Wellcome in November 2024. Anticipated to start in early 2025, the Phase I study will be performed at the MHRA-accredited NHS Phase I unit at the Royal Liverpool University Hospital, UK, in partnership with the University of Liverpool and the Liverpool University Hospitals NHS Foundation Trust.
DNDI-6174: The pre-clinical programme was successfully completed and DNDI-6174 was nominated as a clinical candidate. The pivotal 28-day toxicity studies support the administration of DNDI-6174 up to 14 consecutive days in humans – the maximum acceptable duration in the target product profile. Target organs and potential risks to humans, non-observed adverse effect level (NOAEL), safety margin, first-in-human starting dose, and stopping criteria were defined. Acceptable stability of the GMP material up to 18 months was demonstrated, and the tablet Phase I candidate formulation was shown to be stable under long-term conditions for at least 12 months and under accelerated conditions for 6 months. The excellent pharmacological profile of DNDI-6174 was reinforced by showing its potential to approach sterile cure for visceral leishmaniasis, and for the additional indication of cutaneous leishmaniasis.
CpG-D35 (DNDI-2319): The multiple ascending dose study was stopped due to futility after the enrolment of six participants. Four participants received CpG-D35; two received miltefosine. All adverse events reported were mild or moderate and did not require the interruption of treatment. Recruitment difficulties were related to the need for hospitalization and particularly narrow inclusion and exclusion criteria. Ongoing efforts aim to simplify the study protocol and procedures and expand the pool of potential participants.
GSK245 (DDD1305143): GSK is the sponsor of a Phase I study in healthy volunteers in the UK that was completed in 2024. This drug candidate shares a similar mode of action with LXE408, the frontrunner in DNDi’s portfolio of NCEs under development for leishmaniasis.
DNDI-6148: Activities related to the clinical development of DNDI-6148 remain on hold.
DNDI-0690: Activities related to the clinical development of DNDI-0690 remain on hold.
Development
Miltefosine + thermotherapy for cutaneous leishmaniasis: Enrolment in the Phase III study was completed, with 127 participants included: 64 in the miltefosine monotherapy arm, and 63 in the miltefosine + thermotherapy arm. Patient demographics and baseline characteristics were similar across both treatment arms. Most adverse events reported were mild and aligned with the expected safety profile of the study interventions. The combination arm was shown to be non-inferior to standard miltefosine monotherapy in the per-protocol analysis at day 90 (65.5% vs. 75.0%, respectively). However, the combination treatment appears to be more efficacious than miltefosine alone for lesions due to L. braziliensis.
Miltefosine + Paromomycin for visceral leishmaniasis (Africa): The World Health Organization (WHO) review of study results and proposed treatment guideline changes is ongoing. Countries have indicated that they will await WHO approval before implementing modifications to national treatment guidelines. The process of updating guidelines has begun in Uganda and Kenya alongside the WHO review process in order to shorten the timeline between the release of WHO recommendations and their adoption by ministries of health. DNDi joined the Leishmaniasis Technical Advisory Group Sub-Committee that was newly formed in Kenya and convened in September and November to work on the draft guidelines. The Kenyan guidelines review process remains pending, awaiting WHO recommendations.
New treatments for PKDL (Eastern Africa): The WHO 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 2025. In parallel, the ministries of health in the endemic countries in the region are reviewing the evidence and are expected to release revised national treatment guidelines following the release of WHO recommendations.
New treatments for PKDL (South Asia): The WHO 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 2025. 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): Following the recommendation of the WHO mission on the kala-azar elimination programme in 2019, DNDi partnered with the India Ministry of Health and ICMR RMRI to establish a reference Centre of Excellence for the management of patients with leishmaniasis to bring diagnostic and treatment facilities closer to affected communities, build health provider expertise, and give effect to new guidelines for the treatment of visceral leishmaniasis and post-kala-azar dermal leishmaniasis (PKDL). In collaboration with the Ministry of Health of Bangladesh, the successful model was expanded to the country with the establishment of a Centre of Excellence at the Infectious Diseases Hospital, Dhaka in 2024 with the aim of building on the country’s success in eliminating VL as a public health problem and achieving zero new cases and zero transmission by 2030. With support from DNDi, the Centre of Excellence hosted a two-day training in April to enhance the clinical skills of frontline doctors, nurses, and laboratory technicians in visceral leishmaniasis and PKDL diagnosis and treatment. This included advanced laboratory techniques and emerging diagnostic and treatment protocols that will contribute to strengthening national efforts to reach its 2030 goals. Preparations to establish a Centre of Excellence in Nepal are ongoing.
New treatments for VL/HIV: Twenty-six people living with both visceral leishmaniasis (VL) and HIV were treated at the DNDi-supported Leishmaniasis Research and Treatment Centre in Gondar, Ethiopia. Of these, 25 (96%) were treated with the newly recommended liposomal amphotericin B and miltefosine combination (LAmB + MF) therapy. In addition, rollout of LAmB + MF began in two hospitals in Ethiopia. Located in the Amhara and Tigray regions, these hospitals were selected based on the local prevalence of VL/HIV.
Photo credit: Lameck Ododo-DNDi
