Manifesto to encourage R&D of rapid tests for cutaneous leishmaniasis is released in WorldLeish 7

Through the Manifesto, researchers commit to contribute by creating a common strategic agenda aimed at producing, validating, implementing and accessing new diagnostic tools suitable for CL

The Network of Researchers and Collaborators in Leishmaniasis (redeLEISH) launched during WorldLEISH 7, the most important event on leishmaniasis in the world, a Manifesto that addresses the urgent need to develop simple diagnostic techniques for cutaneous leishmaniasis (CL). The document, which is aimed at the scientific community, health authorities and funders, highlights the challenging environment of endemic countries and the urgent need for more incentives for research and development (R&D) of diagnostic tests for CL. The Manifesto may be signed by any member of the scientific community. The document will circulate during the ChagasLeish meetings, a satellite event that will be held simultaneously with the Congress of the Brazilian Society of Tropical Medicine (MEDTROP), which will take place from November 13 to 16 in Belém (PA).

Leishmaniasis in all its clinical forms are included in the list of neglected tropical diseases of the World Health Organization (WHO) because they are closely linked to poverty and the low rate of pharmaceutical and biotechnological innovation. Around one million people are affected by cutaneous leishmaniasis every year in the world. Although it causes disfiguring and sometimes disabling injuries, the disease still arouses very little interest from governments, the pharmaceutical industry and decision makers. According to the G-Finder report, by 2020 only $0,1 million had been invested in R&D for the diagnosis of leishmaniasis, representing less than 0,5% of total R&D funding for the disease ($(45 million).

It is expected that this Manifesto can draw the attention of the scientific community, funding agents and health authorities to the need for greater incentives for R&D of rapid diagnostic tests for CL, which present high performance, and can be easily carried out in primary care, from samples collected in a minimally invasive way, says Dr. Joelle Rode, from the Drugs for Neglected Diseases Initiative (DNDi). Also according to her, when signing the Manifesto, the researchers present at the RedeLEISH meeting, held during the WL7 Congress in Cartagena de Indias, committed themselves to contribute to creating a common strategic agenda aimed at the production, validation, implementation and access to new diagnostic tools suitable for CL, in line with the Critical Actions of the who 2030 roadmap for Neglected Tropical Diseases.

Cutaneous leishmaniasis is considered one of the most stigmatizing diseases among Neglected Tropical Diseases (NTDs), however the psychosocial aspects that surround it still tend to be underestimated by governments, public policy makers and even health professionals. Studies carried out in several countries indicate that people living with CL have impaired self-esteem, high rates of depression and anxiety disorders. The injuries and scars resulting from the disease compromise the quality of life and psychological health of patients, who suffer from moral condemnation and consequent economic vulnerability.

Currently, efforts in the search for new treatments and available resources are largely directed to visceral leishmaniasis. Asked why very little is directed at the cutaneous form, Dr. Rode explains that in general resources for leishmaniasis are scarce. “Because it is not a fatal disease, CL receives even less attention in terms of R&D and effective intervention strategies, although it has a wide geographical distribution, with an estimated 600 to 1 million new cases occurring annually, and is responsible for causing chronic and disfiguring skin lesions, resulting in a significant burden of morbidity, social stigma, and psychological problems, aspects that are often also neglected,” she regrets. Dr. Rode also emphasizes that CL mainly affects poor populations in low- and middle-income countries, which, with limited resources, still need to fight other diseases with a high impact on public health. “As a result, efforts dedicated to the diagnosis, treatment and control of CL remain insufficient,” she adds.

Challenge of LC diagnosis

The availability of adequate tools for the diagnosis of CL is a prerequisite for achieving the disease control goals established by who in the Roadmap for NTDs 2021-2030, that 85% of all CL cases are detected and 95% of those reported treated. However, the currently available methods have several limitations, such as a limited sensitivity that may vary due to several factors, including the species of Leishmania, the method of collecting the samples and the duration of the lesion; the need for trained professionals or infrastructure, or the complexity and high cost. Dr. Rode details that the minimum criteria necessary for the development of an ideal rapid test have already been agreed in a base document (Target-Product-Profile – TPP), developed by the Foundation for New Innovative Diagnostics (FIND), together with specialists, which was recently approved by the who Technical Advisory Group for the Diagnosis of Unattended Tropical Diseases (who DTAG).

In this way, the development and validation of a diagnostic test based on these defined minimum parameters should be a priority strategy for all actors involved in the fight against the disease. This will require greater investments, which is a major challenge, considering the scarcity of resources. There is still a long way to reach an ideal test, especially if we consider the diversity of the Leishmania species involved and the clinical manifestations of the disease. In this sense, we hope that the Manifesto can alert to this unmet need and contribute to accelerate the process, she highlights.

She also notes that, due to the complexity of the transmission cycle of LC, involving human or animal hosts, several species of the parasite Leishmania, and different species of insect phlebotomines, disease control strategies should include several interventions, carried out in an integrated and collaborative manner. According to Dr. Rode, one of the most important is the early diagnosis and appropriate treatment, which reduces the transmission of the disease, as well as the risks of morbidity and disabilities. The lack of appropriate and accessible rapid diagnostic tests hinders timely detection and early treatment, increasing the suffering of people affected by the disease.

Work developed by DNDi for CL

The goal of DNDi is to develop short-term, effective, safe, affordable, and adapted treatments for all forms of the disease, including oral, topical, and immunomodulatory treatments. For this, the institution works with short- and long-term strategies. In the short term, DNDi seeks to improve existing treatments, combining therapeutic options, in order to improve efficacy and safety and reduce the time of administration of treatments. In this axis, the Initiative completed a multicenter phase II clinical trial to evaluate the efficacy and safety of a combination of a single heat therapy session with a 21-day cycle of miltefosine, the only existing oral drug to treat leishmaniasis. The final results of this study showing a cure rate in D90 of 80.3% for the combination, guided the decision to proceed to a randomized, open, multicenter phase III clinical trial, which aims to evaluate this combination of thermotherapy with 21 days of miltefosine for the treatment of uncomplicated cutaneous leishmaniasis in the New World. This clinical study is currently being conducted with partner institutions in four countries (Brazil, Peru, Panama and Bolivia), with expected results for early 2024.

In the long term, DNDi aims to develop an oral treatment that is adapted to the contexts of the affected populations, from new chemical entities. Since 2015 screening and compound discovery efforts for visceral leishmaniasis (VL) have been expanded and included species of Leishmania that cause CL. Currently, with the participation of several research groups around the world and pharmaceutical companies, five new candidates for oral drugs, with different mechanisms of action and leishmanicidal activity against both species causing VL and CL are in clinical development.

Another approach includes the development, together with several partners, of an immunomodulator, CpG-D35, to stimulate the elimination of parasites by strengthening the hosts immune responses. The use of an immunomodulator in combination with an antiparasitic agent is one of the pillars of the DNDi strategy to improve the treatment of complicated forms of LC. A first ascending single dose Phase I clinical trial with CpG-D35, conducted in the UK in healthy volunteers, ended in November 2021. Based on preliminary results, which indicate that CpG-D35 is safe and elicits the expected immunological effects, an ascending multiple dose study is being prepared in patients with uncomplicated cutaneous leishmaniasis in the New World.

RedeLEISH

DNDi also coordinates RedeLEISH, a network of researchers and collaborators in Leishmaniasis, which aims to support the implementation of clinical trials aimed at CL, promote the exchange of technical and scientific information, the realization of collaborative research projects and the harmonization of criteria for conducting clinical trials, as well as identify research priorities. In this perspective, the development of diagnostic tests for CL was identified as a priority of collaboration by the members of the network, which led to the launch of the Manifesto. The initiative operates through a virtual forum, to facilitate technical-scientific exchange; the publication of annual newsletters; and face-to-face meetings, which allow the identification of research priorities and the articulation of collaborative projects. Founded in 2014, the network currently brings together more than 200 experts from more than 91 institutions in 28 countries.