About TT4CL

  • Objectives
  • Workplan
  • Advisory Board
  • Executive Board

“Societal Challenges” pillar of Horizon 2020

This project gives an answer to the scope of the “Societal Challenges” pillar of Horizon 2020, under the “Health, demographic change and wellbeing” work programme and specifically under the “Better Health and Care, Economic Growth and Sustainable Health Systems” topic: SC1-BHC-15-2018: New anti-infective agents for prevention and/or treatment of neglected infectious diseases (NID).

Many diseases that are not life-threatening in developing countries do not receive the resources and attention required to investigate control, prevention or treatment. Cutaneous leishmaniasis (CL) is one of the most neglected diseases amongst the neglected tropical diseases (NTD).

Infections are common in low-income populations of developing regions. Producing (sometimes up to 200) ulcers on exposed parts of the body, CL can leave permanent scars that are often the source of major stigma, social prejudice and psychological damage and can have an economic impact.

Existing therapies have several drawbacks

  • a variable efficacy
  • safety issues
  • stability problems
  • high cost.

Moreover the current drugs on the market exhibit low tolerability and serious toxicities. They have long treatment durations and difficult administration (iv, im, intralesional).

The innovation encapsulated in this ambitious project is to deliver a new medication for Old World Cutaneous Leishmaniasis (OWCL) patients that is effective, well tolerated and orally administered, as well as being affordable. That could dramatically change the lives of 1 million people around the world

Therefor oral D121 will be evaluated as a new drug to treat Old World CL (OWCL) and the process of clinical development towards registration with a stringent regulatory authority (EMA/FDA) will be accelerated.

Bridging the gap between preclinical and clinical development

D121 is being developed as an immediate-release tablet for the treatment of CL and is currently the most advanced orally formulated drug specifically being developed for this indication. Production (including stability studies), human tolerability (in limited volunteer studies), efficacy in in vitro studies and safety & efficacy studies in animal models all suggest that D121 is a very promising new, safe, orally available, and affordable new candidate for the treatment for cutaneous leishmaniasis (CL).

The main concept underpinning this project is to examine critically and to the highest standards the acceptability of D121 as a new potential treatment for OWCL. The classical early clinical development route for a new anti-infective will be followed, by accumulating information that is on the critical path for decisions regarding further developments. This work will involve information obtained by the endemic country partner on the susceptibility of clinical isolates to D121, improvements in production and stability of optmised formulations, detailed PK-PD studies in animal models and Phase 1 studies aimed at dose selection for subsequent (not in this programme) Phase 2 clinical trials.

Specific objectives

The specific objectives are to complete all preclinical investigation and optimisation by:

  • refining the manufacture, storage and formulation of D121. See Work package 5 to 7.
  • conducting comparative ex vivo efficacy studies in an endemic country (the Islamic Republic of Iran) using fresh CL-causing isolates from clinical studies already in progress, including L.tropica and L. major. See Work package 1 & 2.
  • carrying out comparative efficacy studies in animal models of CL, including the determination of skin pharmacokinetic-pharmacodynamic relationships. See Work package 3 & 4.
  • conducting pharmacokinetic studies in normal volunteers, investigating the effects of increasing and repeated doses as well as food effects. See Work package 8 to 10.

The work plan has been designed to enable our consortium to evaluate D121, using international expertise and established collaborations to minimise risk.

The project has been split into 16 work packages (WP), under the responsibility of different work package leaders, and will be undertaken over a 4 year period.

WP1/2 will be used for ex vivo efficacy studies in Iran. WP3/4 will be used for efficacy studies in animal models of cutaneous leishmaniasis and provide quality control of the studies in Iran. WP5/6/7 is dedicated to the development and supply of D121 oral tablets in full compliance with cGMP guidelines for the trial (WP8/9/10). WP8/9/10 covers all aspect of the Phase 1 food interaction drug trial, including the pharmacokinetic analysis of D121 taken in multiple doses. The latter will encompass a conventional pharmacokinetic analysis, using previously validated methodologies for measuring plasma drug levels. Previously determined single dose pharmacokinetic date will allow an investigation of in vivo/in vitro model correlations. This will allow in vitro models to be developed to ensure future in vivo performance of the formulation. WP11/12/13 will provide mechanisms for dissemination and exploitation of the proposed studies in WP1 to WP10.Finally, WP14/15/16 will run throughout the project and will ensure that the project runs to schedule, and that the necessary reporting is carried out. This WP includes sponsorship, monitoring and data management components, as well as an Ethics component. The latter will oversee all Ethical aspects of the study as it progresses, with appropriate expertise provided by an Ethicist.

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  • WP 1 & 2 : ex vivo efficacy studies in an endemic country (TUMS)

    Whilst many different species of Leishmania have been examined already for D121, there needs to be a focus on those Old World species that are responsible for cutaneous disease. This is because management of leishmaniasis depends crucially on the causative agent. We will include isolates of two species that cause cutaneous disease in Iran, Leishmania tropica and L. major. Other anti-leishmanial drugs have differing sensitivity profiles when tested against these two species, whose biology also differs.

    Clinical samples from appropriate sites in lesions will be collected (into culture permissive saline) and set up in cultures ex vivo as well as being used in PCR to confirm the species. Cultures will not be continued for more than 6 cycles or 1 month, to minimize changes associated with adaptation to in vitro condition. Cultures will be exposed to D121, miltefosine and amphotericin B to determine comparative sensitivities in standardised assays. All ex vivo studies will be undertaken in Iran, though a number of samples (patient, parasite isolates and parasite DNA) will be sent to the UK for quality control purposes (WP 4).

  • WP 3 & 4 : in vivo studies (LSHTM)

    LSHTM will undertake comparative efficacy studies in animal modes of cutaneous leishmaniaisis including determination of skin pharmacokinetic-pharmacodynamic relationships. Apart from an increased intrinsic potency of D121 over other leishmaniais drugs, there are several other possibilities that may contribute to this comparative curative advantage. These include PK properties as well as concentrations of unbound drug at relevant (lesional) sites and compartments. Recent developments in application of skin microdyalisis techniques can now be applied to address some of these PK/PD questions and generate new knowledge.

  • WP 5 to 7 : Chemistry, manufacturing & Controls (CMC) (Avivia)

    Dafra Pharma R&D developed a D121 drug substance and with the assistance of Avivia an oral drug product. Dafra Pharma R&D and later Oblita Therapeutics performed accelerated and real time stability studies up to 36 months. Within this project the optimalisation of the formulation (the coating) and the packaging of the drug product for zoneIII/IVb will be further investigated by Avivia as well as the robustness of the manufacturing process. That will require additional stability studies of the drug substance and the drug product in order to prepare a cGMP production of a Phase I clinical trial product.

    Avivia wil perform an in vivo-in vitro correlation test (IVIVC) to ensure that the drug product will have a consistent quality and pharmacokinetic profile in the human body throughout the further phases of the clinical trials as later on after registration.

    Together with Oblita Therapeutics the affordability of the drug substance and of the drug product will be investigated as “affordability” is crucial for a neglected tropical disease affecting the most vulnerable people in poor resource settings.

  • WP 8 to 10: Phase I trial (EKUT and SGUL)

    Good tolerance and safety has been shown in an extensive package of preclinical studies. This was confirmed in humans at single dosing.

    EKUT and SGUL have wide experience in PK studies in healthy volunteers of new compounds for parasitic infectious diseases. They will carry out an oral, rising dose study in normal volunteers, including food interaction effects.

  • WP 11 to 13 : Dissemination and exploitation (Oblita Therapeutics)

    The first objective of this work package is is to create awareness of the project development to key stakeholders, on the one hand, and to ensure a wide and targeted dissemination of the knowledge generated by the TT4CL project, on the other hand.

    Dissemination will consist of the following activities:

    • Communicate the knowledge, which is not confidential, produced by the project
    • Participation to targeted international conferences through poster and podium presentations
    • Scientific articles to be published in specialised peer-reviewed scientific journals
    • Cooperation with other projects in the field
    • Keep the contact at EU level and with all relevant stakeholders
    • Communication via the public website and through existing communication platforms on leishmaniasis
    • Preparation of common press releases at major milestone dates of the project
    • Presentation of final results in a consortium organized conference or in an existing conference where cutaneous leishmanias is a main topic

    Exploitation of the results:

    The main priority of the project is to prepare all the results for regulatory purposes as well at EMA as at FDA: update of the Investigational Brochure, and of the Investigational Medicinal Product Dossier, presentation of the phase 1 single and multiple food interaction results. This will allow D121 to move forward to an IND.

    Results of the project will be presented to organisations, companies and funds worldwide interested in moving forward with further clinical trials for D121. D121 has shown good preclinical results as well for Old World as for New world leishmaniasis strains. Aim is to reach the right clinicians for further trials as well as potential (financial) investors. Patent strategy is also crucial for the valorization of D121.

    The affordability question is an integral part of this project as the ambition of this project goes beyond the market authorization: a new drug that actually reaches the patients in need. A business plan for further development and market introduction is part of the project. The phase 1 results can mean a leverage for the development of this compound for other neglected diseases (parasitic or fungal), for which D121 has shown already good activity in in vivo or in animal models.

  • WP 14-16: Project Management (SGUL)

    SGUL has extensive experience as a management and dissemination partner in international collaborative projects, including numerous projects involving clinical trials. SGUL has been involved in many EU-Framework Programmes since FP4 and has supported researchers in numerous EU-funded projects to date.

    The TT4CL project management component will:

    • provide support for individual scientists to ensure that project objectives are achieved;
    • monitor and control the progress of each work package;
    • coordinate project activities;
    • implement quality control mechanisms by defining appropriate project standards;
    • ensure targeted dissemination of knowledge.

    A wide array of activities will be undertaken, including scientific and administrative management, guidance of decision making, contractual management, financial management, supervision of and compliance to ethical standards, management of knowledge and IPR issues, and coordination of communication activities.

  • Work Package leaders
    • WP1&2: Professor Ali Khamesipour, TUMS, Iran
    • WP3: Dr Vanessa Yardley, LSHTM, United Kingdom
    • WP4: Dr Henry Staines, SGUL, United Kingdom
    • WP5 to 7: Mr Hans Platteeuw, Avivia, The Netherlands
    • WP8 to 10: Professor Peter Kremsner, EKUT, Germany
    • WP11 to 13: Mrs Caroline Jansen, Oblita Therapeutics, Belgium
    • WP14 to 16: Professor Sanjeev Krishna, SGUL, United Kingdom

Independent Advisory Board (IAB) and Ethical Board

This board will be appointed and steered by the Executive Board. The IAB shall assist and facilitate the decisions made by the Executive Board. The IAB consists of leaders in the field of:

  • drug development
  • ethics
  • regulatory matters
  • business development & investment strategy
  • infectious diseases

The IAB will consider the multidisciplinary nature of strategic health policy and commercialisation issues raised by our drug development program.

When required, the IAB will facilitate compliance with regulatory and ethical requirements by providing requisite guidance.

The IAB will be a combined Scientific and Ethical Adisory Board.

Executive Board (EB)

The executive board is the decision-making body of the consortium.

Professor Sanjeev Krishna is the Coordinator of the project and will work in close collaboration with the WP Leaders, and thus chair all executive board meetings. Every 6 months the EB will be convened.

Every consortium partner has 1 vote and 2 representatives.