Periodic Reporting for period 2 - TT4CL (Clinical development of oral oleylphosphocholine as a new drug for the treatment of Old World Cutaneous Leishmaniasis) Reporting period: 2021-05-01 to 2022-10-31 Summary of the context and overall objectives of the project Cutaneous leishmaniasis (CL) is a poverty related, neglected tropical disease, caused by leishmania parasites. It is primarily transmitted by the bite of infected, blood feeding, sandflies. At the site of the bite a lesion forms which then develops into ulcers which often become further infected by bacteria. Currently there is no effective and cheap systemic treatment for CL. The parasites and vectors causing the disease are widespread, including south America, around the Mediterranean, parts of sub-Saharan Africa and the Middle East. There is a large human population who are at risk of infection. The WHO estimates that there are between 1-1.5 million cases globally of CL per year (CDC estimation 0.7 -1.2 million cases per year). It is a significant cause of disability adjusted life years to society, as a whole, and on an individual level can be life changing.The aim of this project is to develop a new orally available drug for treatment of CL. Oleylphosphocholine (OlPC), which is structurally related to the anti-leishmanial miltefosine. It is being developed as an immediate-release tablet for the treatment of CL and, currently, is the only systemically delivered drug specifically being developed for this indication. OlPC is active in vitro and in vivo against different CL-causing Leishmania parasite species and shows curative advantage over miltefosine in rodent models of leishmaniasis. The primary objective of this study is to complete the pre-clinical package that is essential for the subsequent clinical development of OlPC. The project will aim to optimize the synthesis and formulation of OlPC, including stability testing that is appropriate for tropical climates. It will include in vitro drug sensitivity analyses in parasites causing CL (Leishmania tropica and L. major) in the Islamic Republic of Iran, with our endemic-country partner. Comparative studies in animal models with existing anti-leishmanial compounds will establish efficacy advantages and determine pharmacokinetic-pharmacodynamic relationships for OlPC. Phase 1 studies will confirm tolerability and pharmacokinetics of single doses and multiple dosing regimens. Results will be used to guide decisions by future partners on the clinical development of OlPC. This proposal directly addresses the priorities highlighted in this H2020 call. To our knowledge, we are the only consortium that is implementing this type of approach, and there is no other interest in the pharmaceutical sector to carry out a development programme for the oral treatment of CL. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The extended COVID19 pandemic has substantially impacted on the project and capacity to meet some of the deliverables. However, TT4CL is poised to deliver a Phase 1 dose ranging study conforming to standards of stringent regulatory authorities. If results from this trial are encouraging, then taken together with underpinning scientific work that includes in vitro assays of patient samples, and animal model studies, we would hope to progress the clinical development programme as a matter of urgency. We are on schedule in some areas and may be up to 13 months behind in other areas but will complete deliverables within this time. Drug development and formulation optimisation: Avivia has been focusing on stability testing of both the drug substance and the drug product including the optimal packaging and storage conditions. In addition to this, an expanded IMPD has been prepared for the now approved submission of the clinical trial protocol. In vivo testing: Partners at the LSHTM, University of York and collaborators have managed to complete the remaining in vivo deliverables focusing on the PK/PD analyses of OlPC. The Phase I trial protocol has been approved following in depth discussions and recommendations from the German regulatory authorities (BfArM), who have been very supportive. The trial is set to start recruiting in Tübingen in January 2023 having now completed their site initiation visit. Work has continued in Iran, although attenuated by both the COVID19 pandemic and, more recently, social unrest. However, capacity strengthening has continued including transfer of standardised protocols, reagent transfer and discussions on data analysis and parasite culture with colleagues across the consortium. Communications: It has been possible for the consortium members to go to international meetings in 2022 and present results of the in vivo studies with OlPC. These meetings include the WorldLeish7 (Columbia), British Society of Parasitology (UK) and the International Congresses of Parasitology (Copenhagen). This has also enabled discussions with stakeholders to both promote TT4CL and ascertain what are their needs for therapeutics for CL in their respective fields. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) This project aims to deliver a new, safe, orally available treatment for cutaneous leishmaniasis (CL) afflicting patients in Africa, Europe and the Middle East. Existing therapies have several drawbacks: a variable efficacy, safety issues, upcoming resistance, stability problems and high cost. Moreover, current drugs on the market exhibit low tolerability and serious toxicities. They have long treatment durations and difficult administration (iv, im, intralesional). Miltefosine is the only oral product on the market and patients have difficulties to access it.A more effective drug with an improved safety profile, more accessible to patients and possibly with a higher patient compliance because of shorter treatment regimen, will deliver a major advancement in the field. There are no other drugs in a comparable stage of clinical development. Our impacts will therefore be on an important aspect of disease control. Despite there being few candidates considered for further development work by agencies such as the Drugs for Neglected Diseases initiative (DNDi, Geneva), there are no other systemic drugs considered for monotherapy that are sufficiently advanced to enter Phase 1/2 studies for the indication of CL. For these reasons, delivery of any effective and safe treatment will result in major advancement in the field and transform local and eventually global management of this disease. Our clinical study will have a positive impact on the health of affected Iranian people by focusing activities and collecting comparative data from their isolates that would not otherwise be available. The TT4CL project puts forward the implementation of a rigorous and progressive study design that is intended to allow safe selection of an appropriate efficacious dosage regimen at the end of Phase 1 studies, so that further trials can be implemented for Phases 2/3.If OlPC shows a better safety and at least a similar efficacy compared with the local standard of care, we intend this product to be implemented in national guidelines for the treatment of CL. By answering an unmet medical need OlPC, as an oral safe drug, has the potential to become the preferred alternative to “no treatment”. Registration for the indication of CL with stringent regulatory authorities will greatly facilitate the subsequent registration of OlPC in endemic, mostly LMICs, so that the drug can be accessed. The results of Phase I trials will be compiled in an application for stringent regulatory authorities (the American FDA and the European Medicines Agency) once data on healthy volunteers are obtained. This will have a spill-over to the development of OlPC for new parasitological and/or fungal indications Related documents TT4CL logo.jpg
