The parasite that causes leishmaniasis is transmitted by the bite of a sandfly. Leishmaniasis is a complex group of diseases with over a million new cases occurring every year and 350 million people living at risk worldwide in 98 countries. The most common forms of the disease are visceral leishmaniasis (VL), which is fatal without treatment, and cutaneous leishmaniasis (CL).

India, Bangladesh, Ethiopia, South Sudan, Sudan, and Brazil account for 90% of all reported cases of VL. Existing treatments are either difficult to administer, toxic, or costly. Drug resistance is also an increasing problem. PKDL is a skin lesions disease which mostly affects individuals after treatment for VL. Up to 50% of all VL patients in Sudan and 5-10% patients in India and Bangladesh develop PKDL, which may play a major role in disease transmission between epidemics. The WHO Roadmap (2012) and the Indian revised National Kala-Azar Elimination Roadmap have set the objective to eliminate VL from the Indian subcontinent.

DNDi’s current leishmaniasis portfolio includes:

Research

Four projects in the research phase:

• Nitroimidazoles: This project aims to identify nitroimidazole backups to compounds that are currently in translation phase. DNDi-0690, a nitroimidazole for the treatment of VL and possibly CL, was selected for preclinical development on 1 September 2015 and may have improved properties compared to earlier compounds of the same class
• Oxaleish: The most advanced oxaboroles for treating VL and possibly CL (‘oxaleish’) are nearing completion of the lead optimization and profiling phases. The aim is to select the most promising compound from this class during the next twelve months.
• Aminopyrazoles: The aminopyrazole class of compounds has shown promising early profiles for the treatment of both VL and CL. Lead optimization is ongoing to identify a pre-clinical candidate from this class.
• Leish H2L: This project continues to evaluate hits identified from screening and to begin the process of optimizing these new chemical series. If promising activity can be demonstrated in in vivo models of leishmaniasis, the series will be advanced into full lead optimization. This process of ‘hit to lead’ optimization is ongoing with multiple series from several pharmaceutical companies.

Translation

Five projects in the translation phase:

• Fexinidazole/miltefosine combination: Fexinidazole and miltefosine are foreseen as the first combination of two oral drugs for VL, under development in East Africa. Before proceeding to a proof-of-concept (PoC) study in patients, a drug-drug interaction (DDI) study to assess pharmacokinetics and safety of the combination will be conducted in up to 60 healthy volunteers.  A pharmacokinetic and safety study of miltefosine in 30 children completed recruitment in August 2015. A previous study carried out in Africa showed that dose adjustment was required for children, as results indicated under-exposure in this group compared to adults. Adjusted doses of fexinidazole will be also be assessed (increasing efficacy within safety limits). If the DDI study shows the combination is safe, a PoC study will be initiated in patients to assess its efficacy and safety in primary VL cases.

• Fexi-sulfone: Fexinidazole is converted extensively in vivo to an active metabolite called fexinidazole sulfone. This compound may offer some advantages for the treatment of VL compared to fexinidazole, such as reaching effective blood concentrations in patients more quickly and with less variability, or improving side-effects. DNDi has evaluated fexinidazole sulfone in an in vivo efficacy model and an assessment of the overall strategy for its development will be considered along with other candidate molecules before deciding to proceed to clinical trials.

• CpG-D35 for CL: Having been taken up in DNDi’s portfolio in 2014, this project aims at producing an immunomodulator to stimulate the innate immune system to fight the parasitic infection as an adjunct to drug therapy. The project has made progress and non-GMP batches were produced to start toxicological and immunological studies.

• New CL combinations: The safety and efficacy profiles of the current CL treatments (antimonials, miltefosine, and thermotherapy) when administrated alone are very well established. Using a combination of therapeutic approaches may both improve efficacy rates, reduce treatment duration, and improve the rate of adverse events. DNDi will soon begin to test a combination of one single application of thermotherapy at 50 degrees Celsius for 30 minutes combined with a short course (3 weeks) of oral miltefosine.

• Anfoleish for CL: A Phase II study with Anfoleish, a topical cream containing amphotericin B started in 2014 at one site in Colombia to assess the safety, pharmacokinetics (PK), and efficacy of the cream in patients with CL caused by L. braziliensis and L. panamensis (since 2015). Following the safety data of the first 30 subjects enrolled in the study, recommendation was made to continue the study. Forty additional patients have been enrolled since then.

Two projects were interrupted:

• In 2013, VL-2098 was identified among the nitroimidazoles as a very potent molecule and was expected to enter into Phase I after positive results of the toxicology/safety analysis. However, after following comprehensive review of the VL-2098 testicular toxicity data in in vivo models, the decision was taken to stop the study.

• The Phase II proof-of-concept study with fexinidazole for the treatment of adult primary VL patients in Sudan, which aimed to evaluate drug efficacy and establish safety and pharmacokinetic/pharmacodynamic (PK/PD) profiles, was interrupted. The doses selected for the study were identical to those of the Phase II/III Human African Trypanosomiasis trial. Enrolment began in November 2013 and ended in May 2014, with a total of 164 patients screened and 14 enrolled in the study. Treatment was very well tolerated. Majority of patients had an initial good clinical response with a negative test of cure by microscopy at the end of treatment. However, this response was not sustained, and relapses were observed in the follow-up period. New regimens including fexinidazole are currently being explored to improve efficacy, within safety limits (see fexinidazole/miltefosine combination).

Development

 Four projects in the development phase:

• A Phase III study of treatments for HIV/VL co-infection (132 patients), testing a combination treatment (AmBisome and miltefosine, and monotherapy with AmBisome at a higher dose than current practice) had started in 2014 at two sites in Ethiopia. Neither treatment regimen was able to achieve the targeted efficacy rate thus the decision was taken to interrupt the study.

• A Phase II study of two treatments, AmBisome monotherapy and in combination with miltefosine, for Post-Kala-Azar Dermal Leishmaniasis (PKDL) to assess the safety and efficacy for treatments of patients in India and Bangladesh, is currently under development.

• A Phase III study (sponsored by the Brazilian Ministry of Health) with new VL treatments based on combination therapies^[1]for the treatment of VL patients in Brazil started in 2011 at five sites and recruited 380 patients. The national guidelines for VL were revised in 2013 based on the interim safety data from the trial. Glucantime remains the first-line treatment, while AmBisome replaced Amphotericin B deoxycholate as second-line treatment. Final results of this trial are under analysis.

• MSF, in collaboration with DNDi and the Rajendra Memorial Research Institute of Medical Sciences (RMRI), is planning to initiate a Phase III study testing AmBisome monotherapy and the combination of AmBisome and miltefosine to treat HIV/VL in India.

Implementation

 Implementation and access to treatments:

• DNDi also continues to support the implementation of SSG&PM, a combination VL treatment for Africa delivered in 2010 by DNDi and the Leishmaniasis East Africa Platform (LEAP). Whereas this combination was recommended as first-line therapy for VL patients in East Africa by the WHO Expert Committee on the Control of Leishmaniases in 2010 and by the most affected countries, DNDi continues to support registration efforts, notably of paromomycin (PM), and treatment availability to VL patients in the region. PM is registered in Kenya and Uganda. In Sudan and Ethiopia, the registration dossier is still under submission to the regulatory authorities. SSG is registered in Kenya, Uganda, and Sudan, and a dossier was submitted in Ethiopia. In Ethiopia (SSG and PM) and Sudan (SSG), the drugs can be imported, as they were included in the national essential medicines lists.

• In Asia, DNDi and partners, working closely with the Indian government, have provided data from an implementation study (1761 enrolled patients) to support policy change expressed in the revised National Kala-Azar Elimination Roadmap, which recommends the use of AmBisome single infusion in areas of high prevalence and paromomycin/miltefosine combination as appropriate in low prevalence districts. Follow-up visits continue to assess long-term efficacy and identify development of PKDL.

Among its activities, DNDi joined in 2015 the Consortium for the Control and Elimination of Visceral Leishmaniasis, known as KalaCORE, a new partnership between DNDi, the London School of Hygiene and Tropical Medicine (LSHTM), Médecins Sans Frontières (MSF), and Mott MacDonald. The consortium has been appointed by the Department for International Development (DFID) to deliver its programme over the next four years in six countries (India, Bangladesh, Nepal, Ethiopia, Sudan, and South Sudan) supporting national efforts and coordinating with national VL control programmes.