Periodic Reporting for period 4 - ERA4TB (EUROPEAN REGIMEN ACCELERATOR FOR TUBERCULOSIS)
Período documentado: 2023-01-01 hasta 2023-12-31
Before the pandemic crisis, tuberculosis (TB) was the leading cause of death by an infectious disease worldwide. According to the World Health Organization (WHO), an estimated 10 million people became ill with tuberculosis in 2019, and 1.4 million died. Even though the incidence of tuberculosis is declining, the drug-resistant form constitutes a growing threat to the safety of the world’s population. It is in this spirit that the UN has pledged to end the tuberculosis epidemic by 2030 through joint action of its member states.
TB treatments are long, often associated with side effects that complicate full treatment compliance, especially when treating comorbidities such as HIV/AIDS or diabetes. Poor treatment compliance contributed to the global emergence of antimicrobial resistance (AMR) in TB i.e. multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, which is the largest contributor to AMR in terms of morbidity, mortality and economic loss worldwide. Therefore, and despite the fact that several new drugs and combinations, are being tested in clinical trials to identify better TB regimens, it is still necessary to develop additional anti-TB drugs that offer options for treatment-shortening and control of drug resistant forms.
The absence of suitable reimbursement models for the development of new antimicrobials, including anti-TB agents, has led to the obliteration of the true societal value of these essential pillars of our health, and to a low return on investment for the pharmaceutical sector. A joint public-private effort on the antimicrobial development process has the potential to help rebalance costs and incentives, thereby motivating pharmaceutical companies to re-invest in antimicrobial development. ERA4TB has gathered relevant pharmaceutical companies, NGOs, SMEs and academic partners to accelerate the development of new anti-tubercular treatments that will have a major immediate impact on society by mitigating the effects of TB and antibiotic resistant TB on society. At the same time, the project will contribute to protect the global community by preventing the potential onset of pandemic events associated to M(X)DR TB.
The global objective of ERA4TB is to develop and test combinations of molecules for which there is yet limited or no resistance described in the TB clinical field. To reach this ambitious target, the Consortium will need to complete the preclinical pipeline necessary to progress new drugs all the way to the end of Phase I, and this endeavour will require a cooperative commitment of the public and private partners. New regimes may include recently approved drugs such as bedaquiline, and compounds in late stage development, such as pretomanid.
ERA4TB introduces the concept of a Knowledge Generation Pathway (KGP) that integrates outputs from in vitro, in vivo and imaging studies with modelling activities in the form of a continuous ‘learning system’ in such a way that, once clinical trials are performed, this new knowledge will help in refining studies conducted within the project and beyond, through the identification of better assays, parameters and drug development pathways.
TB treatments are long, often associated with side effects that complicate full treatment compliance, especially when treating comorbidities such as HIV/AIDS or diabetes. Poor treatment compliance contributed to the global emergence of antimicrobial resistance (AMR) in TB i.e. multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, which is the largest contributor to AMR in terms of morbidity, mortality and economic loss worldwide. Therefore, and despite the fact that several new drugs and combinations, are being tested in clinical trials to identify better TB regimens, it is still necessary to develop additional anti-TB drugs that offer options for treatment-shortening and control of drug resistant forms.
The absence of suitable reimbursement models for the development of new antimicrobials, including anti-TB agents, has led to the obliteration of the true societal value of these essential pillars of our health, and to a low return on investment for the pharmaceutical sector. A joint public-private effort on the antimicrobial development process has the potential to help rebalance costs and incentives, thereby motivating pharmaceutical companies to re-invest in antimicrobial development. ERA4TB has gathered relevant pharmaceutical companies, NGOs, SMEs and academic partners to accelerate the development of new anti-tubercular treatments that will have a major immediate impact on society by mitigating the effects of TB and antibiotic resistant TB on society. At the same time, the project will contribute to protect the global community by preventing the potential onset of pandemic events associated to M(X)DR TB.
The global objective of ERA4TB is to develop and test combinations of molecules for which there is yet limited or no resistance described in the TB clinical field. To reach this ambitious target, the Consortium will need to complete the preclinical pipeline necessary to progress new drugs all the way to the end of Phase I, and this endeavour will require a cooperative commitment of the public and private partners. New regimes may include recently approved drugs such as bedaquiline, and compounds in late stage development, such as pretomanid.
ERA4TB introduces the concept of a Knowledge Generation Pathway (KGP) that integrates outputs from in vitro, in vivo and imaging studies with modelling activities in the form of a continuous ‘learning system’ in such a way that, once clinical trials are performed, this new knowledge will help in refining studies conducted within the project and beyond, through the identification of better assays, parameters and drug development pathways.
In its fourth year of activity, ERA4TB has achieved significant milestones in its path toward accelerating the development of new anti-TB regimes.
One of the pivotal achievements of the project is concerned with the core goal of the initiative, to carry out clinical studies with the anti-TB drugs of combinations. In this respect, the past year has been a very significant for the consortium since we were able to successfully complete the first Phase I trials with an asset belonging to one EFPIA partner of the Project. In line with this, ERA4TB has incorporated eight new assets to its drug development pipeline along with six new drug combinations. On the other side, the active research carried out by ERA4TB partners enabled to timely drop four assets from the pipeline after they showed either poor efficacy or safety issues.
ERA4TB, is a private-public initiative fully committed with standardisation and harmonization. In the past year, the Project has implemented epidemiological cut-off (ECOFF) and clinical breakpoints (CBs) using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference method.
In line with the idea of harmonization, ER4TB has recently published a protocol that outlines the process for selecting and validating clinical units to conduct First-Time-in-Human (FTIH) trials in Europe This step is crucial for ensuring safety, efficacy and rapid unit selection in early human testing.
With the purpose of getting the most out of its funding and the research environment in which the Project develops its activity, ERA4TB, has established a framework of collaboration with the UNITE4TB Project. As a result of this initiative, the two projects are currently sharing certain assets and the partners responsible for modelling in both projects are working hand in hand to enhance the overall research outcomes.
In what pertains the scientific and technical domains, in addition to the ongoing research in all areas of activity of the Project, the bioimaging area has seen the development of two new innovations. The first one consists in the development of system to automatically monitor Mycobacterium population growth in time-lapse microscopy experiments using Deep Learning. The other achievement is the development of a protocol for acquiring PET/CT images from mice without having the interfering signal from the heart of the animals.
Overall, all project activities are progressing optimally and at good pace. This positive trajectory was confirmed in the Project Midterm Review, in which ERA4TB received very high evaluations. Surely the later will boost the continuum enthusiasm even more.
One of the pivotal achievements of the project is concerned with the core goal of the initiative, to carry out clinical studies with the anti-TB drugs of combinations. In this respect, the past year has been a very significant for the consortium since we were able to successfully complete the first Phase I trials with an asset belonging to one EFPIA partner of the Project. In line with this, ERA4TB has incorporated eight new assets to its drug development pipeline along with six new drug combinations. On the other side, the active research carried out by ERA4TB partners enabled to timely drop four assets from the pipeline after they showed either poor efficacy or safety issues.
ERA4TB, is a private-public initiative fully committed with standardisation and harmonization. In the past year, the Project has implemented epidemiological cut-off (ECOFF) and clinical breakpoints (CBs) using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference method.
In line with the idea of harmonization, ER4TB has recently published a protocol that outlines the process for selecting and validating clinical units to conduct First-Time-in-Human (FTIH) trials in Europe This step is crucial for ensuring safety, efficacy and rapid unit selection in early human testing.
With the purpose of getting the most out of its funding and the research environment in which the Project develops its activity, ERA4TB, has established a framework of collaboration with the UNITE4TB Project. As a result of this initiative, the two projects are currently sharing certain assets and the partners responsible for modelling in both projects are working hand in hand to enhance the overall research outcomes.
In what pertains the scientific and technical domains, in addition to the ongoing research in all areas of activity of the Project, the bioimaging area has seen the development of two new innovations. The first one consists in the development of system to automatically monitor Mycobacterium population growth in time-lapse microscopy experiments using Deep Learning. The other achievement is the development of a protocol for acquiring PET/CT images from mice without having the interfering signal from the heart of the animals.
Overall, all project activities are progressing optimally and at good pace. This positive trajectory was confirmed in the Project Midterm Review, in which ERA4TB received very high evaluations. Surely the later will boost the continuum enthusiasm even more.
The most important ERA4TB development to date has been the successful completion of the first Phase I trials with a compound belonging to one of the EFPIA partners in the project.
ERA4TB consortium management has developed a modular structure that allows the simultaneous handling of several compounds with different pipeline entry points while ensuring experimental reproducibility, which represents a major advance in the state of the art of antibiotic development and public-private partnerships.
In terms of data management, ERA4TB's main development has been the Drug Development Information Management (DDIM) system, a platform for collecting, organising and disseminating curated, standardised preclinical and clinical TB data that will facilitate collaboration within ERA4TB and also with other TB projects.
In terms of in vivo imaging, a new CT image biomarker was developed to quantify the relative volume of TB lesions in humans, NHPs and mice, and a radiomics biomarker for NHP TB manifestations was developed. In the area of animal models, three protocols for NHP PET/CT imaging were developed and validated, and the experimental setup was prepared.
The implementation of the OPTIKA methodology and the strategy to evaluate new antitubercular combinations will help to prioritise clinical trials for the development of future TB regimens.
The new models developed in the project have taken a significant incremental leap forward by allowing not only the validation of experimental results but also the optimisation of experimental design.
ERA4TB consortium management has developed a modular structure that allows the simultaneous handling of several compounds with different pipeline entry points while ensuring experimental reproducibility, which represents a major advance in the state of the art of antibiotic development and public-private partnerships.
In terms of data management, ERA4TB's main development has been the Drug Development Information Management (DDIM) system, a platform for collecting, organising and disseminating curated, standardised preclinical and clinical TB data that will facilitate collaboration within ERA4TB and also with other TB projects.
In terms of in vivo imaging, a new CT image biomarker was developed to quantify the relative volume of TB lesions in humans, NHPs and mice, and a radiomics biomarker for NHP TB manifestations was developed. In the area of animal models, three protocols for NHP PET/CT imaging were developed and validated, and the experimental setup was prepared.
The implementation of the OPTIKA methodology and the strategy to evaluate new antitubercular combinations will help to prioritise clinical trials for the development of future TB regimens.
The new models developed in the project have taken a significant incremental leap forward by allowing not only the validation of experimental results but also the optimisation of experimental design.