Periodic Reporting for period 3 - TT4CL (Clinical development of oral oleylphosphocholine as a new drug for the treatment of Old World Cutaneous Leishmaniasis)
Berichtszeitraum: 2022-11-01 bis 2024-07-31
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 bites, lesions form which then develop 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 was to develop a new orally available drug for treatment of CL. Oleylphosphocholine (OlPC), which is structurally related to the anti-leishmanial miltefosine, is being developed as an immediate-release capsule 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 was to complete the pre-clinical package that is essential for the subsequent clinical development of OlPC. The project aimed to optimize the synthesis and formulation of OlPC, including stability testing that is appropriate for tropical climates. It included in vitro drug sensitivity analyses in ex vivo 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 showed efficacy advantages and determined pharmacokinetic-pharmacodynamic relationships for OlPC. The Phase 1 study confirmed tolerability and pharmacokinetics of escalating single doses. 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.
The aim of this project was to develop a new orally available drug for treatment of CL. Oleylphosphocholine (OlPC), which is structurally related to the anti-leishmanial miltefosine, is being developed as an immediate-release capsule 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 was to complete the pre-clinical package that is essential for the subsequent clinical development of OlPC. The project aimed to optimize the synthesis and formulation of OlPC, including stability testing that is appropriate for tropical climates. It included in vitro drug sensitivity analyses in ex vivo 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 showed efficacy advantages and determined pharmacokinetic-pharmacodynamic relationships for OlPC. The Phase 1 study confirmed tolerability and pharmacokinetics of escalating single doses. 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.
TT4CL has successfully delivered a Phase 1 dose-escalation study, in a fed state, conforming to standards of stringent European regulatory authorities. The results are encouraging, demonstrating a safe and tolerated dose of OlPC. Together with the underpinning scientific work including in vitro assays of both reference parasites, patient samples, and animal model studies, we hope to progress the clinical development programme as a matter of urgency.
Drug development and formulation optimisation: Avivia focused on stability testing of the drug substance and the drug product including optimal packaging and storage conditions. An expanded IMPD was prepared for the clinical trial protocol. The drug product is stable for at least 12 months at high temperature and high humidity. Formulation work identified areas where cost savings can be made to improve both stability and affordability of the drug product.
In vivo testing: Partners at the LSHTM, University of York and collaborators have managed to complete the in vivo deliverables focusing on the PK/PD analyses of OlPC.
The Phase I trial in Germany has been completed with the last patient out and pharmacokinetic analyses completed as well as a in depth safety report. The Clinical Study Final Report has been submitted to the German regulatory authority (BfArM).
Work has been completed in Iran; a large number of clinical samples of parasites have been collected and a number assessed for drug susceptibility. This component was impacted by both the COVID19 pandemic, early on in 2020/21 and, more recently, social unrest. However, capacity strengthening 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 since 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 enabled discussions with stakeholders to both promote TT4CL and ascertain needs for therapeutics for CL in their respective fields. We expanded on our social media side of communications to reach a wider audience; both science/industry and the general public.
Drug development and formulation optimisation: Avivia focused on stability testing of the drug substance and the drug product including optimal packaging and storage conditions. An expanded IMPD was prepared for the clinical trial protocol. The drug product is stable for at least 12 months at high temperature and high humidity. Formulation work identified areas where cost savings can be made to improve both stability and affordability of the drug product.
In vivo testing: Partners at the LSHTM, University of York and collaborators have managed to complete the in vivo deliverables focusing on the PK/PD analyses of OlPC.
The Phase I trial in Germany has been completed with the last patient out and pharmacokinetic analyses completed as well as a in depth safety report. The Clinical Study Final Report has been submitted to the German regulatory authority (BfArM).
Work has been completed in Iran; a large number of clinical samples of parasites have been collected and a number assessed for drug susceptibility. This component was impacted by both the COVID19 pandemic, early on in 2020/21 and, more recently, social unrest. However, capacity strengthening 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 since 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 enabled discussions with stakeholders to both promote TT4CL and ascertain needs for therapeutics for CL in their respective fields. We expanded on our social media side of communications to reach a wider audience; both science/industry and the general public.
TT4CL aims to deliver a new, safe, orally available treatment for 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 be a major advancement. No other drugs are at 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 DNDi (Geneva), there are no other systemic drugs considered for monotherapy that are sufficiently advanced to enter Phase 1/2 studies for 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 intended to allow selection of a safe appropriate efficacious dose at the end of the Phase 1 study, so that further trials, including loading dose and multiple dose phase I can be implemented.
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 the Phase I trials will be compiled in an application for stringent regulatory authorities (the American FDA and the EMA). This will have a spill-over to the development of OlPC for new parasitological and/or fungal indications.
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 be a major advancement. No other drugs are at 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 DNDi (Geneva), there are no other systemic drugs considered for monotherapy that are sufficiently advanced to enter Phase 1/2 studies for 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 intended to allow selection of a safe appropriate efficacious dose at the end of the Phase 1 study, so that further trials, including loading dose and multiple dose phase I can be implemented.
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 the Phase I trials will be compiled in an application for stringent regulatory authorities (the American FDA and the EMA). This will have a spill-over to the development of OlPC for new parasitological and/or fungal indications.