Introduction and Background of the Project

Introduction

Schistosomiasis, also known as bilharzia and endemic in 78 developing countries, is a chronic inflammatory neglected tropical disease caused by parasitic worms. The disease affects more than 258 million people, including 100 million children, globally. It is one of the most prevalent tropical diseases in the world after malaria, and represents an important health burden in developing countries, especially in Africa where more than 90% of the infections occur.

 The current gold standard recommended treatment for schistosomiasis, praziquantel (PZQ), is available in oral tablets for adults and children, but younger children under 4 years cannot be treated due to missing clinical data. In addition, a pediatric formulation of praziquantel that would be appropriate for preschool age children, infants and toddlers, and would permit accurate dosing and enhanced compliance in these patients is non-existent and highly needed. The development of a new pediatric formulation of praziquantel is to be seen in the context of the WHO’s 2020 Roadmap and with respect to the initiative of “Uniting to combat Neglected Tropical Diseases” under which the global community agreed on control and elimination of schistosomiasis.

Project objective

The Pediatric Praziquantel Consortium is an international not-for-profit partnership that aims to reduce the global disease burden of schistosomiasis by addressing the medical need of infected preschool-age children. Its mission is to develop, register and provide access to a suitable pediatric praziquantel formulation for treating schistosomiasis in this age group. The pediatric formulation under investigation has been designed to be smaller, exhibit an improved palatability and be orally dispersible compared to the current commercial formulation.

Project design

The Consortium was established in July 2012 by Merck KGaA, Darmstadt, Germany (Merck KGaA), Astellas Pharma Inc. (Astellas), Swiss Tropical and Public Health Institute (Swiss TPH) and Lygature (formerly TI Pharma). At the beginning of 2014, Farmanguinhos and Simcyp, a Certara company, joined the Consortium as full partners. The Schistosomiasis Control Initiative (SCI), part of Imperial College London, joined in 2016.

 All partners are bound by a Consortium agreement, which arranges their roles and responsibilities and includes a formal governance structure with a Consortium Board as the highest decision-making body, and Lygature as independent Coordinator. An external expert panel is called by the Consortium prior to each clinical development stage to provide an independent evaluation of the project. The partners have formed a core project team, led by Merck KGaA, comprising one representative of each partner and/or expertise area that meets every month. The core project team is supported by various subteams focusing on specific technical and operational aspects to implement the consortium’s program.

How can your partnership (project) address global health challenges?

In order to tackle the important public health problem of schistosomiasis, the non-profit Pediatric Praziquantel Consortium has been formed in July 2012 to develop a pediatric formulation of praziquantel. The project will contribute to the overall goal of control and elimination of schistosomiasis by developing a product urgently required for the treatment of preschool-age children, infants and toddlers, a population that is currently being considered by WHO to be included in treatment campaigns. The development and registration of a new pediatric formulation of praziquantel is regarded by the Consortium as a cornerstone to fulfill the 2020 WHO commitment to address the health burden that schistosomiasis represents and the importance of controlling disease-related morbidities. To achieve this commitment, several measures need to be integrated among which making chemotherapy treatment available to all age groups is an important part of.

What sort of innovation are you bringing in your project?

The Pediatric Praziquantel Consortium combines the best science and most experienced public and private partners to develop and register a new pediatric formulation of praziquantel, the current gold standard treatment for schistosomiasis. It has developed new oral dispersible formulations of praziquantel that can be easily administered to preschool-aged children, infants and toddlers, exhibit improved taste, and are able to withstand the challenges presented by a tropical climate. The Consortium is currently conducting the clinical phase II in Ivory Coast, and in the second quarter of 2017 the project will move into the clinical development phase III.

Role and Responsibility of Each Partner

Merck KGaA (Darmstadt, Germany) leads the program and brings expertise and support related to praziquantel, including resources from different areas (drug product manufacturing, pre-clinical, clinical, regulatory) needed for clinical development and to efficiently execute the project. Astellas contributes by providing its innovative pharmaceutical technologies in the area of pediatric drug formulation development as well as clinical development in children. Swiss TPH brings extensive experience in helminths biological and pharmacological research, epidemiology and clinical research in endemic regions. The governance is facilitated by Lygature, a Dutch non-profit organization and independent party with an extensive portfolio of international public-private partnerships in drug research and development, including in the area of neglected diseases. Farmanguinhos, the federal governmental pharmaceutical laboratory of the Fiocruz Foundation in Brazil, brings unique expertise to produce and distribute the new pediatric formulations product in endemic countries. Simcyp, a Certara company, brings expertise in pharmacokinetic modelling for better predicting the appropriate dosage for use in the pediatric clinical trials. SCI, part of Imperial College London, provides the necessary expertise to define and execute the access strategy and plan as well as to initiate and implement NTD control and elimination programs in Sub-Saharan Africa.

Others (including references if necessary)

For more detailed information on the Pediatric Praziquantel Consortium, the project team and the development program, please feel free to visit the Consortium website:

• www.pediatricpraziquantelconsortium.org.
• To receive regular updates on the progress and activities of the program, feel free to sign-up for the bi-annual Consortium Newsletter:

http://www.pediatricpraziquantelconsortium.org/nieuwsbrief.html.

Final Report

1.Project objective
The Pediatric Praziquantel Consortium is an international not-for-profit partnership that aims to reduce the global disease burden of schistosomiasis by addressing the medical need of infected preschool-age children. Its mission is to develop, register and provide access to a suitable pediatric praziquantel treatment for treating schistosomiasis in this age group. The pediatric formulation (arpraziquantel), successfully evaluated in a Phase III clinical trial, has been designed to be smaller, exhibit an improved palatability and be orally dispersible compared to the current commercial formulation. Apart from registration, the next steps focus on establishing optimal arpraziquantel access and delivery strategies for different endemic settings in Africa.

2.Project design
The Consortium was established in July 2012 and currently consists of Merck KGaA, Darmstadt, Germany, Astellas Pharma Inc., Swiss Tropical and Public Health Institute, Lygature, Farmanguinhos, Schistosomiasis Control Initiative Foundation, Université Félix Houphouët Boigny, Kenya Medical Research Institute, Technical University of Munich, African Institute for Health and Development, and Ministry of Health of Côte d’Ivoire. Additional support is provided by the Ministries of Health in Kenya and Uganda and Makerere University School of Public Health Since the start, all partners have been efficiently working together to progress the project and achieve the pre-clinical, clinical phase I-III, registration and access objectives.

3. Results, lessons learned
In January 2022, the Consortium successfully completed the project and the key results of the Phase III program were:

CLINICAL) The confirmatory phase III study in Cote d’Ivoire and Kenya has been completed successfully. The aim of the trial was to demonstrate the efficacy and safety of a single dose of arpraziquantel in children age 3 months to 6 years infected with Schistosoma mansoni and Schistosoma haematobium. It was initiated in September 2019 and put on hold in Mar 2020 due to the Covid-19 pandemic measures. Recruitment was restarted in Nov 2020 and in August 2021 the trial was completed, and the trial key results became available in November 2021.

PRODUCT DEVELOPMENT) The Active Pharmaceutical Ingredient (API) process technology transfer from Merck KGaA to Valiant (China) was completed in 2019. The Process Performance Qualification of the API manufacturing process at commercial scale and validation of the analytical methods have been completed successfully in 2021. The Drug Product (DP) manufacturing process was successfully established at Farmanguinhos (Brazil) and analytical methods for Phase III were validated and demonstrated by successful manufacture and release of the Phase III Clinical Trial Supply batch. Apart from Farmanguinhos, the Consortium selected (2018), and contracted (2021) Universal (Kenya) as 2nd local DP manufacturing site.

REGULATORY) The Regulatory Strategy and plan was put in place, and the dossier generation process has progressed under the guidance of a Submission Task Force since 2019. Based on the successful outcome of the Phase III study, the project has entered the regulatory filing stage in November 2021. On behalf of the Consortium, Merck aims to submit the Marketing Authorization Application to the EMA (EU-M4all procedure) end of 2022 and to have the product available for launch in the first endemic country in Africa in 2024.

ACCESS) Together with relevant stakeholders, the Consortium examined ways of providing access to arpraziquantel in an affordable and sustainable manner. Using the collective feedback, it secured funding from GHIT and EDCTP in support of its 5-year pilot and district-level implementation programme in Kenya, Cote d’Ivoire and Uganda (ADOPT).