Introduction and Background of the Project

Introduction

An estimated 50,000 to 90,000 new cases of visceral leishmaniasis (VL) occur worldwide each year. While not fatal, an estimated 600,000 new cases of cutaneous leishmaniasis (CL) occur every year. As South Asian countries make progress towards eliminating the disease, Eastern Africa now accounts for 73% of global VL cases – half of which occur in children under 15 years old. In 2024, several leishmaniasis-endemic African countries joined with the World Health Organization (WHO) to launch a new strategic framework for the elimination of VL as a public health problem in Eastern Africa to address the gap between regions. Clinical data on available drugs show that due to geographical differences in causative agents and drug resistance, VL is more challenging to treat in Eastern Africa than in South Asia, suggesting a combination therapy may be needed to achieve the target 90% efficacy within a treatment duration of 14 days or less. 

DNDI‑6174 is a first-in-class, oral drug candidate that addresses some of the major shortcomings of current VL treatments – such as safety concerns, cold chain requirements, long regimens, and drug resistance – by offering a novel mechanism of action, oral delivery, and short-course potential. Pre-clinical studies show potent efficacy, including potential sterile cure and a low predicted human efficacious dose with a favourable safety and pharmacokinetic profile, making it well-suited for low-resource, field settings. DNDI-6174 is one of the key compounds that could prove suitable in combination with other new chemical entities (NCEs) in the research pipeline.

Project Objective

The goal of this project is to advance DNDI-6174, a novel, oral therapeutic compound for the treatment of VL, with a unique mode of action and pan-kinetoplastid profile targeting VL, CL, and Chagas disease through a first-in-human clinical trial.

Project Design

Pharmaceutical development efforts will focus manufacturing of the drug products and delivering the clinical trial material (CTM) for the Phase I study. Stability studies for the GMP-1 Drug Substance and the Drug Products will also be continued.

The first‑in‑human Phase I trial will assess the safety and pharmacokinetics of DNDI‑6174 through a single ascending dose (SAD) design. The study will begin once all regulatory and ethics approvals in Malaysia have been obtained and will follow international clinical research and data protection standards. The Phase I trial is proposed to take place at Ampang Hospital, Selangor, Malaysia.

The SAD study will be randomized, double‑blind, and placebo‑controlled, enrolling healthy adult men and women. Seven dose‑escalating cohorts are planned, starting at 5 mg. Each cohort will begin with sentinel dosing.

Participants will undergo intensive safety monitoring, including laboratory tests, vital signs, ECG, Holter monitoring, and assessment of adverse events. A specialized committee will review blinded safety and pharmacokinetic data to determine whether dose escalation can proceed based on predefined stopping rules.

DNDi will use dried blood spot (DBS) as a validated and efficient bioanalytical method well suited for future clinical trials in the field. The development of a skin microdialysis method to assess skin drug exposure will support future therapeutic response assessment for CL and post-kala-azar dermal leishmaniasis (PKDL). Population pharmacokinetic modeling will guide dose selection for later study phases. 

DNDi clinical and safety staff will be based in Malaysia to support trial oversight and ensure high-quality implementation.

Early foetal development studies and initiation of PBPK modelling are included to rapidly allow a go/no-go decision for the inclusion of pregnant women and possibly relax constraints on contraception later in the clinical development and guide combination therapy and co-medication strategies.

How can your partnership (project) address global health challenges?

Visceral leishmaniasis (VL) is a serious parasitic disease that mostly affects people in resource-constrained regions. As South Asian countries continue to reduce the incidence of VL in the region, Eastern Africa now carries 73% of the global burden, with an estimated 50% of new cases occurring in children under the age of 15. Another form of the disease, cutaneous leishmaniasis (CL), affects an estimated 600,000 people each year. In 2024, the World Health Organization (WHO) and several endemic African countries launched a new framework to eliminate VL as a public health threat by 2030.

DNDI‑6174 is a new, experimental oral medicine designed to overcome major challenges with current VL treatments, including safety concerns, prolonged hospitalization, and reliance on cold-chain storage. Early laboratory studies showed that DNDI‑6174 is highly effective, has a favorable safety profile, and may completely clear the parasite. If proven safe and effective, DNDI-6174 shows potential to advance efforts to eliminate leishmaniasis, including post-kala azar dermal leishmaniasis (PKDL) and VL-HIV, by helping to reduce the incidence of post-treatment relapse and disease transmission. As a potential short-course oral treatment, the compound could prove suitable for use remote, resource-limited settings. With a novel mode of action differentiating it from current treatments and other compounds in the leishmaniasis research pipeline, advancing the development of DNDI-6174 helps to address pipeline attrition and could contribute to reaching VL elimination goals in Eastern Africa by providing critical data on combination therapies with improved efficacy in the Eastern African region.

Importantly, the compound also shows promise against CL and Chagas disease. If proven safe and effective for these other indications, the compound could be more attractive for manufacturers to produce at scale.

Additional advantages include its low predicted cost, suitability for outpatient care, and potential use as part of combination therapy. DNDI‑6174 is one of only a few VL drug candidates currently in development and meets key WHO standards.

What sort of innovation are you bringing in your project?

The project introduces several major innovations in the treatment of neglected tropical diseases (NTDs), particularly visceral leishmaniasis (VL):

1. A completely new way of attacking the parasite

DNDI‑6174 uses a novel mechanism of action by targeting the parasite’s cytochrome bc1 complex – a target not used by current VL drugs. This opens the door for shorter, oral combination therapies and has shown signs of achieving a sterile cure in pre-clinical studies, meaning it may fully clear the parasite, help to prevent post‑kala‑azar dermal leishmaniasis (PKDL), and help treat VL in people living with HIV.

2. A single potential drug with activity across multiple diseases

DNDI‑6174 has a pan‑kinetoplastid profile, meaning it could treat several related parasitic diseases, including VL, cutaneous leishmaniasis (CL), and Chagas disease. This potential broad anti-parasitic activity increases the compound’s potential public health impact and makes the product more attractive for sustained manufacturing.

3. Designed specifically for low‑resource settings

The compound is an oral tablet that does not require hospitalization or refrigeration. Its favorable safety and pharmacokinetic profile suggest minimal medical supervision is required. A low predicted dose and short treatment course could also improve patient adherence.

4. Extremely low projected cost

With projected suitability for low-cost manufacturing at scale, DNDI‑6174 would be dramatically cheaper than current options, some of which exceed US$150, if proven safe and effective.

5. Innovation in where and how early trials are conducted

Launching the first‑in‑human study at Ampang Hospital in Selangor, Malaysia marks a strategic shift: conducting early‑stage trials in a middle‑income country, as opposed to exclusively in a high-income country. This strengthens national and regional capacity for early research and advances a new model for equitable global drug development.

Role and Responsibility of Each Partner

DNDi has overall responsibility for leading and managing the project. 

DNDi is also acting as the sponsor of the clinical Phase I study, is accountable for medical governance and activities, and is responsible for drug safety, regulatory, nonclinical, and transversal activities.

Eisai is responsible for the pharmaceutical development of the compound and supplying the investigational medicinal products (including placebo) for the Phase I study.

Others (including references if necessary)

(1) DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1. Science Translational Medicine: Braillard S. et al. DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1. Sci.Transl.Med.;15,eadh9902(2023). DOI: 10.1126/scitranslmed.adh9902

(2) Short-course combination treatment for experimental chronic Chagas disease González S, Wall RJ, Thomas J, et al.. Sci Transl Med. 2023;15(726):eadg8105. doi:10.1126/scitranslmed.adg8105

(3) Quantitative analysis of DNDI-6174 using UPLC-MS/MS: A preclinical target site pharmacokinetic study. Journal of Chromatography B. Schouten WM, Van Bocxlaer K, Rosing H, Huitema ADR, Beijnen JH, Kratz JM, Mowbray CE, Dorlo TPC. 2025 https://doi.org/10.1016/j.jchromb.2025.124652