Periodic Reporting for period 3 - UNITE4TB (ACADEMIA AND INDUSTRY UNITED INNOVATION AND TREATMENT FOR TUBERCULOSIS)
Okres sprawozdawczy: 2023-06-01 do 2024-05-31
The UNITE4TB consortium aims to accelerate and improve the clinical evaluation of novel compounds and combinations of drugs to develop new and highly active anti-tuberculosis (TB) treatment regimens for drug-resistant (DR) and drug-sensitive (DS) TB. Together with EFPIA and Associated Partners, UNITE4TB gained access to the majority of the most innovative TB compounds, currently in late pre-clinical, clinical phase 1 and early 2 stages. The consortium will deliver an efficient, global clinical trials (CTs) network equipped to implement phase 2A and 2B/C trials that conform to the highest regulatory standards. We will integrate state-of-the-art adaptive trial designs with conventional and new biomarkers of treatment success and employ advanced pharmacokinetic (PK) and pharmacodynamic (PD) modelling techniques and artificial intelligence (AI) and machine learning (ML) techniques to select, test and deliver novel combination regimens with a high probability of success in subsequent phase 3 CTs. Thus, UNITE4TB aims to set a new standard for anti-TB regimen development, upgrading current CT methodology and enhancing the efficiency with which new regimens are delivered to the world.
-The phase 2B/C trials, PARADIGM4TB and DECISION, have been designed and prepared in years 1&2, and launched in year 3 in South Africa. A protocol amendment for a 2nd wave of phase 2B combination regimens in PARADIGM4TB has been initiated.
-The DECISION AND PARADIGM4TB trial teams continue to implement the trials. Currently 30 sites in 12 countries have been internally approved for PARADIGM4TB and four sites in two countries for DECISION. The first ethical and/or regulatory submissions have been completed in six and two countries for PARADIGM4TB and DECISION, respectively.
-For PARADIGM4TB a statistical Analysis Plan has been developed for the Phase 2B (regimen selection) and Phase 2C (duration ranging) parts of the trial. Furthermore, the determination of Minimal Inhibitory Concentrations distribution for ganfeborole and BTZ-043 has been completed in line with the trial protocol. A Mycobacteriology Laboratory Manual for PARADIGM4TB was developed. Training on the manual was provided at sites in South Africa, Tanzania and Uganda.
-In the area of machine learning/AI, the first models to enhance tuberculosis treatment outcome predictions and to predict Mycobacteria Growth Indicator Tube outcomes have been developed.
-Bioassay validation covering the control regimen in PARADIGM4TB has been finalized. The validation of a ganfeborole assay has been completed, for BTZ-043 this is ongoing. As part of the PARADIGM4TB wave 2 preparation, validation of a quabodepistat assay has been initiated.
-Early and late-stage biomarker Target Product Profiles have been developed in years 1&2. In year 3, four regional laboratories have been identified to analyse samples of selected biomarkers (TB-22, MBLA and LAM).
-Digital Adherence Technologies (DAT) have been selected in year 2 and activities are ongoing to implement the DATs in the trials. In year 3, a DAT training module was developed providing guidance for staff to use the DATs.
-The first phase 2A clinical trial, ENABLE, is being prepared and planned to start in Q4 2024. Based on the investigational medicinal product characteristics of alpibectir, TASK (sponsor) and GSK (asset owner) have led the trial design of ENABLE. The trial will be an alpibectir dose-ranging clinical trial and study to assess the safety of alpibectir/ethionamide in combination with a rifamycin containing regimen (RZE), including two biomarkers (MBLA and LAM). -
-In year 3 the Data Collaboration Platform (DCP) has transitioned from a prototype to a production DCP and is available for UNITE4TB partner online access requests. As a result of the Data Contribution Agreements executed in years 1 and 2, background data or in-kind contributions for six clinical trial studies are currently being integrated in the DCP.
-The UNITE4TB Community Advisory Group, Ethics Advisory Board and Scientific Advisory Board have been fully integrated into the UNITE4TB consortium governance in years 1&2. These advisory bodies continue to meet regularly, and representatives attend the UNITE4TB Annual meetings.
-To raise awareness and stimulate cross-learning, a continuous and growing flow of dissemination and exploitation, including engagement with key stakeholders and other TB research consortia has been continued.
-The DECISION AND PARADIGM4TB trial teams continue to implement the trials. Currently 30 sites in 12 countries have been internally approved for PARADIGM4TB and four sites in two countries for DECISION. The first ethical and/or regulatory submissions have been completed in six and two countries for PARADIGM4TB and DECISION, respectively.
-For PARADIGM4TB a statistical Analysis Plan has been developed for the Phase 2B (regimen selection) and Phase 2C (duration ranging) parts of the trial. Furthermore, the determination of Minimal Inhibitory Concentrations distribution for ganfeborole and BTZ-043 has been completed in line with the trial protocol. A Mycobacteriology Laboratory Manual for PARADIGM4TB was developed. Training on the manual was provided at sites in South Africa, Tanzania and Uganda.
-In the area of machine learning/AI, the first models to enhance tuberculosis treatment outcome predictions and to predict Mycobacteria Growth Indicator Tube outcomes have been developed.
-Bioassay validation covering the control regimen in PARADIGM4TB has been finalized. The validation of a ganfeborole assay has been completed, for BTZ-043 this is ongoing. As part of the PARADIGM4TB wave 2 preparation, validation of a quabodepistat assay has been initiated.
-Early and late-stage biomarker Target Product Profiles have been developed in years 1&2. In year 3, four regional laboratories have been identified to analyse samples of selected biomarkers (TB-22, MBLA and LAM).
-Digital Adherence Technologies (DAT) have been selected in year 2 and activities are ongoing to implement the DATs in the trials. In year 3, a DAT training module was developed providing guidance for staff to use the DATs.
-The first phase 2A clinical trial, ENABLE, is being prepared and planned to start in Q4 2024. Based on the investigational medicinal product characteristics of alpibectir, TASK (sponsor) and GSK (asset owner) have led the trial design of ENABLE. The trial will be an alpibectir dose-ranging clinical trial and study to assess the safety of alpibectir/ethionamide in combination with a rifamycin containing regimen (RZE), including two biomarkers (MBLA and LAM). -
-In year 3 the Data Collaboration Platform (DCP) has transitioned from a prototype to a production DCP and is available for UNITE4TB partner online access requests. As a result of the Data Contribution Agreements executed in years 1 and 2, background data or in-kind contributions for six clinical trial studies are currently being integrated in the DCP.
-The UNITE4TB Community Advisory Group, Ethics Advisory Board and Scientific Advisory Board have been fully integrated into the UNITE4TB consortium governance in years 1&2. These advisory bodies continue to meet regularly, and representatives attend the UNITE4TB Annual meetings.
-To raise awareness and stimulate cross-learning, a continuous and growing flow of dissemination and exploitation, including engagement with key stakeholders and other TB research consortia has been continued.
Expected results:
-New regimen(s) selected for phase 3 trials.
-Innovative multi-arm multi-stage (MAMS) trial design, with analyses-driven decision-making throughout the process and including stratification for disease severity.
-New endpoints in phase 2A trials to quantify change in bacterial load.
-Investigation of truncated treatment regimens with an early relapse endpoint
-Exploration of biomarkers for the predication of relapse-free cure.
-PK modelling to explore DDIs for novel drug combinations and PK/PD modelling in 2A and 2B/C trials, to investigate possible exposure-response relationships, and exposure-safety relationships (if required) to help optimise selection of safe and efficacious dosing regimens, complementing the primary outcome analysis of early relapse.
-Investigation of application of AI/ML methodologies to predict relapse-free cure, prioritise treatment regimens and optimise design for phase 2C or 3 clinical trials.
Expected impact:
-Providing new tools and understanding on how to progress TB science for the discovery and development of new clinical candidates and combinations thereof across the TB R&D landscape with special emphasis on innovative clinical trial design and development of novel biomarkers.
-Contributing to the EU’s ambition of being a ‘best practice region’ for addressing AMR, and profit from its medical capacity to individualize and implement into medical practice combination therapies addressing MDR/XDR.
-Developing new knowledge and tools, innovative clinical trial designs, imaging technology, biomarkers and pharmacogenomics diagnostics and exploiting artificial intelligence for the development of new clinical candidates and combinations.
-Enabling the progression of potential new safe, efficacious, shorter, and affordable treatment solutions for people with TB worldwide, with the intent to improve quality of life and life expectancy.
-Contributing to the development of a vibrant TB research environment in the EU, fostering private-public collaboration across EFPIA, Academia, NGOs and SMEs and strengthening the competitiveness and industrial leadership of Europe
-Providing a legal frame and agreement on IP terms and exploitation, as paradigm of public and private international collaboration in the development of combination regimens.
-Implementing agreements with other consortia facilitating prompt data exploitation, including data sharing with the external TB research community to accelerate future TB drug regimen development.
-To continue to act as a platform for TB drug development breakthroughs beyond the lifetime of the project and set-up of smaller partnerships specifically designed to progress individual compounds/regimens, so-called spin-offs.
-Increased awareness of regulators, policy makers, and future procurers on the UNITE4TB project, goals and findings in support of future policy development.
-New regimen(s) selected for phase 3 trials.
-Innovative multi-arm multi-stage (MAMS) trial design, with analyses-driven decision-making throughout the process and including stratification for disease severity.
-New endpoints in phase 2A trials to quantify change in bacterial load.
-Investigation of truncated treatment regimens with an early relapse endpoint
-Exploration of biomarkers for the predication of relapse-free cure.
-PK modelling to explore DDIs for novel drug combinations and PK/PD modelling in 2A and 2B/C trials, to investigate possible exposure-response relationships, and exposure-safety relationships (if required) to help optimise selection of safe and efficacious dosing regimens, complementing the primary outcome analysis of early relapse.
-Investigation of application of AI/ML methodologies to predict relapse-free cure, prioritise treatment regimens and optimise design for phase 2C or 3 clinical trials.
Expected impact:
-Providing new tools and understanding on how to progress TB science for the discovery and development of new clinical candidates and combinations thereof across the TB R&D landscape with special emphasis on innovative clinical trial design and development of novel biomarkers.
-Contributing to the EU’s ambition of being a ‘best practice region’ for addressing AMR, and profit from its medical capacity to individualize and implement into medical practice combination therapies addressing MDR/XDR.
-Developing new knowledge and tools, innovative clinical trial designs, imaging technology, biomarkers and pharmacogenomics diagnostics and exploiting artificial intelligence for the development of new clinical candidates and combinations.
-Enabling the progression of potential new safe, efficacious, shorter, and affordable treatment solutions for people with TB worldwide, with the intent to improve quality of life and life expectancy.
-Contributing to the development of a vibrant TB research environment in the EU, fostering private-public collaboration across EFPIA, Academia, NGOs and SMEs and strengthening the competitiveness and industrial leadership of Europe
-Providing a legal frame and agreement on IP terms and exploitation, as paradigm of public and private international collaboration in the development of combination regimens.
-Implementing agreements with other consortia facilitating prompt data exploitation, including data sharing with the external TB research community to accelerate future TB drug regimen development.
-To continue to act as a platform for TB drug development breakthroughs beyond the lifetime of the project and set-up of smaller partnerships specifically designed to progress individual compounds/regimens, so-called spin-offs.
-Increased awareness of regulators, policy makers, and future procurers on the UNITE4TB project, goals and findings in support of future policy development.