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 aim to build 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, our longer-term goal is to develop all-new treatments with new chemical entities that are safe, effective, and easier to manage at the primary healthcare level.
Our progress in 2023 includes:
Discovery
Screening: DNDi maintained a similar strategy of decreased leishmaniasis screening activities in 2023. However, the fully funded collaboration with University of Tokyo to establish high-throughput screening (HTS) for leishmaniasis in Japan continued with ongoing screening of the Drug Discovery Initiative collection of 220,000 compounds. The HTS programme was completed in March 2023, and a four-month funding extension was obtained from the Global Health Innovative Technology (GHIT) Fund to confirm the activity of and further characterize the three most promising chemical series identified through the project.
S07 series: Exploratory toxicology studies for the two selected optimized leads were performed and finalized at Accelera. While a no-observed-adverse-effect level (NOAEL) for one of the leads could not be determined, the second optimized lead fulfills the criteria of the target candidate profile for visceral leishmaniasis. The putative mechanism of action of parasite proteasome inhibition and selectivity against the human target were also confirmed for both S07 series compounds.
Translation
DNDI-6174: Our teams and partners focused on extending our knowledge of DNDI-6174’s nonclinical profile and progressing on the path to a first-in-human clinical trial. From a pharmaceutical development perspective, all ongoing stability studies were successful. This includes confirmation of the six-month stability of the GMP material and studies of the 5 and 50 mg tablets to establish storage and packaging conditions. The outcomes of our work with GSK and Dundee University on the discovery and preclinical development of DNDI-6174 that lead to its nomination as a drug candidate for visceral leishmaniasis were published in Science Translational Medicine.
DNDI-6148: The development of DNDI-6148 for leishmaniasis has been deprioritized due to pre-clinical reproductive toxicity signals that could necessitate the use of contraceptives for women of childbearing potential.
DNDI-0690: Additional in vitro investigations were conducted to understand the underlying mechanism causing temporary biological abnormalities in some Phase I multiple-ascending dose study participants, but the mechanism was not fully elucidated. Reliably predicting the frequency of occurrence and potential severity of these abnormalities in leishmaniasis patients remains challenging. With other compounds currently under investigation for leishmaniasis in the DNDi portfolio presenting superior safety profiles, activities related to the clinical development of DNDI-0690 were placed on hold.
DNDI-6899 (GSK899/DDD853651): Following a positive meeting with health authorities in the UK in early 2023, DNDi restarted the development of DNDi-6899 and advanced preparations for a clinical Phase I multiple ascending dose study. The active pharmaceutical ingredient stored by GSK at WuXi AppTech was successfully reprocessed and formulated to support the initiation of a multiple ascending dose study in 2024.
CpG-D35 (DNDI-2319): The Phase I multiple ascending dose study protocol was approved by the Colombian regulatory authorities in June 2023, allowing for the importation of study drugs and organization of the study site initiation visit, which was held in July 2023. The screening of potential participants started in September. Although 42 potential participants were pre-screened by the end of December, the number of subjects meeting enrolment criteria was below expectations. An amendment to the study protocol that aims to expedite enrolment and complete the study by the end of 2024 is under development.
GSK245 (DDD1305143): The development of GSK245 continues and GSK is the sponsor of a Phase I clinical study in healthy volunteers in the UK. The single ascending dose part of the study has been completed. This drug candidate shares a similar mode of action with LXE408, the frontrunner in DNDi’s portfolio of NCEs under development for leishmaniasis.
LXE408 Novartis: The second site for the Phase II study in India was initiated at Rajendra Memorial Research Institute of Medical Sciences (RMRIMS) in Patna in August. By the end of 2023, 39 patients were enrolled across the two study sites and 17 patients had completed the study. In parallel, institutional ethics committee and regulatory approvals were obtained for the Phase II study in Ethiopia, where the study site initiation visit was conducted in February 2024. The first patient in Ethiopia is expected to be enrolled in Q1 2024.
Development
Miltefosine + thermotherapy for cutaneous leishmaniasis: The last patient in the Phase III study was enrolled in August. A total of 182 patients were enrolled, including 63 in the miltefosine monotherapy arm, 63 in the combination thermotherapy and miltefosine arm, and 56 in the meglumine antimoniate arm prior to its removal from the protocol. A new protocol amendment was made to address WHO recommendations for the prevention, early detection, and management of ocular adverse events in patients exposed to miltefosine and submitted to all ethics committees in early March.
New treatments for PKDL: Phase II clinical trials in South Asia and Sudan were completed, both demonstrating the suitably of safe and efficacious shorter treatments for PKDL as alternatives to current long-course treatments that present toxicity risks. Findings from the Phase II trial in Sudan were published in November 2023; the manuscript prepared following the Phase II trial in South Asia is under review. It is expected that these alternative therapies will be recommended for patients with PKDL.
Miltefosine + Paromomycin for VL (Africa): The WHO Guideline Development Group began a review of the evidence generated in DNDi’s Phase III trial, which we hope will inform revised treatment guidelines for visceral leishmaniasis in eastern Africa. DNDi disseminated trial results to leishmaniasis technical and advisory groups in the region, as well as to communities where the studies were conducted.
Implementation
New VL treatments (South Asia): In October 2023, the World Health Organization announced that Bangladesh has eliminated visceral leishmaniasis (VL) as a public health problem – the first country in the world to achieve elimination status, reporting fewer than 1 case per 10,000 people over three consecutive years. Research conducted by DNDi and partners from 2012-2015 provided key evidence to support VL treatment policy change in Bangladesh, India, and Nepal, including the recommendation of single-dose liposomal amphotericin B as the first treatment option and a combination of paromomycin and miltefosine as the second option. The new options shortened the length of treatment, reduced the risk of resistance, and made it easier for people to complete their full course of treatment.
New treatments for HIV/VL: Following the adoption of the new recommendations for the treatment of visceral leishmaniasis in people living with HIV in Ethiopia, training was provided to 27 health workers caring for this patient population across eight health facilities in the Amhara Region, Oromia Region, and Southern Nations, Nationalities, and Peoples’ Region of Ethiopia. Forty-nine people living with HIV and visceral leishmaniasis were treated with the newly recommended liposomal amphotericin B and miltefosine combination therapy in the DNDi-supported Leishmaniasis Research and Treatment Center in Gondar, Ethiopia.
Photo credit: Sydelle Willow Smith-DNDi
