The European Regimen Accelerator for Tuberculosis (ERA4TB) has the explicit goal of developing a new combination therapy to treat all forms of TB starting from ~20 leads and drug candidates provided by EFPIA. Since details of these are as yet unavailable, we will implement an agile drug development algorithm that entails profiling and portfolio construction. Profiling involves characterisation and ranking molecules in preclinical studies comprising in vitro drug combination assays, hollow fiber and single cell analysis, innovative murine and non-human primate models, PK/PD studies, combined with biomarker discovery and non-invasive NIR or PET/CT imaging to monitor disease progression and response to treatment. Modelling, simulation and artificial intelligence tools will help progress compounds from early preclinical to clinical development and to predict drug exposure, human doses and the best combinations. After extensive preclinical profiling, selected compounds will enter portfolio development for first time in human tests and phase I clinical trials in order to ensure that they are safe, well-tolerated and bioavailable with negligible drug-drug interactions. If needed, formulation studies will be conducted to improve pharmacological properties. ERA4TB has assembled the best expertise and resources available in Europe, to build a highly effective and sustainable drug development consortium with a flexible and dynamic management system to execute the profiling and portfolio strategy, aided by clearly defined go/no-go decision points. The expected outcome of ERA4TB is a series of highly active, bactericidal, orally available drugs to constitute two or more new combination regimens with treatment-shortening potential ready for Phase II clinical evaluation. These regimens will be compatible with drugs used to treat common comorbidities, such as HIV-AIDS and diabetes, and should impact UN Sustainable Development Goal 3, namely, ending TB by 2030.

Current anti-tuberculosis (TB) drug regimens face serious limitations at times of increasing antimicrobial drug resistance. Fortunately, for the first time for centuries, several novel anti-TB compounds are available for clinical evaluation. As the traditional approach to testing these in multiple combination regimens is too slow and inefficient new approaches of clinical phase 2 study designs are required if we are to meet the targets of the WHO EndTB strategy to save the lives of millions into the near future. Our consortium brings together a unique group of European and international leaders in TB research and leading industry partners. Together we will provide the necessary comprehensive range of expertise to meet the demands of the UNITE4TB scientific research agenda. Specifically, we will develop a new global standard for phase 2 TB clinical trial designs, utilising simulation tools to identify optimal doses in phase 2A trials and apply a multi-arm multi-stage adaptive randomised controlled 2B/C trial design capable of rapid and simultaneous evaluation of the best candidate regimens. Our innovative phase 2 trials will be performed to the highest regulatory standards, incorporating state-of-the-art microbiology, biomarker investigation and clinical pharmacology. We will take advantage of existing global TB clinical trial networks with the capacity to enrol patients at an unprecedented pace and number across four continents. Artificial intelligence/machine learning technologies will be applied to validate state-of-the art molecular and imaging tools as treatment decision biomarkers with the aim of establishing new, real-time outcome measures. Our consortium will evaluate 3-5 new chemical entities (NCEs) at phase 2A and up to 17 novel combination regimens in phase 2B/C. Our objective is to identify those that have the greatest chance of success in subsequent definitive phase 3 clinical trials and of becoming the global gold-standard TB regimens of the future.

Tuberculosis (TB) remains the leading cause of death due to a single pathogen, Mycobacterium tuberculosis (Mtb; except in 2020-2022, when it was surpassed by the COVID-19 pandemic), with 1.5 million deaths in 2020. The lengthy TB treatment and the numerous adverse events contribute to poor medical adherence and development of antibiotic resistant strains. Thus, novel therapeutic modalities are urgently needed to shorten treatment duration, improve outcomes and control the emergence of drug resistant TB. The ITHEMYC project convenes a multidisciplinary consortium of 11 partners, including two Product Development Partnerships (TBVI, TB-Alliance) and an industrial partner (GSK) involved in vaccine, drug and biomarker R&D for TB. The partners will work jointly to develop innovative adjunctive TB immunotherapies by capitalizing on a promising pipeline and recent developments in the field. The project will combine current and new antibiotic regimens with novel immunotherapies, such as small molecules targeting host pathogen-interactions, including host-directed therapies and virulence inhibitors, immunomodulatory compounds, monoclonal antibodies and therapeutic vaccines. The project will generate robust preclinical safety and efficacy information on compounds and combinations through a set of relevant in vitro, in vivo and in silico models, and progress two of them up to preclinical proof-of-concept in non-human primates within the project duration. The partners are proposing a critical path for characterization and progression of immunotherapies, that will be refined based on knowledge generated in ITHEMYC aiming to increase the understanding and interest for this emerging concept of adjunctive TB immunotherapy. We expect the new combined interventions will improve TB cure rates, reduce the duration and toxicity of current regimens and reduce relapse rates.

EU-PEARL has the ambition of transforming the current approach of conducting single-compound clinical trials into the use of cross-company Integrated Research Platforms (IRPs), taking into consideration both patients’ interests and the opportunities from novel molecules for addressing medical needs. Patient-centric data and knowledge sharing have the potential to accelerate the development of new treatments and reduce the operational costs of clinical trials. EU-PEARL will improve clinical effectiveness, patients’ satisfaction and societal access to timely and affordable medicines and it will shape the clinical trials of the future. This will change the industry paradigm from competition to cooperation in four disease areas and provide the framework for designing IRPs in other disease areas. The main objectives of EU-PEARL are: (1) To create a reusable, accessible and sustainable modular IRP for the design and execution of patient-centric, cross- company IRP in any disease area with unmet needs; (2) To set up the open, dynamic, patient inclusive IRP governance structure that will manage the appropriate regulatory, ethical, legal, statistical and data utilisation requirements of the IRP; (3) To disseminate and exploit the EU-PEARL paradigm through the provision of the necessary common tools, procedures, expertise and operational skills working to the highest scientific, regulatory and ethical standards and best practices, developed jointly by public and industry partners in a consensus-based approach; and (4) To create trial-ready IRP networks in the four disease areas of Major Depressive Disorder (MDD), Tuberculosis (TB), Non-Alcoholic Steatohepatitis (NASH) and Neurofibromatosis (NF).