Periodic Reporting for period 4 - UNITE4TB (ACADEMIA AND INDUSTRY UNITED INNOVATION AND TREATMENT FOR TUBERCULOSIS)
Berichtszeitraum: 2024-06-01 bis 2025-05-31
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 has access to the majority of the most innovative TB compounds, currently in late pre-clinical, clinical phase 1 and early 2 stages. The consortium is delivering an efficient, global clinical trials (CTs) network equipped to implement phase 2A and 2B/C trials that conform to the highest regulatory standards. Our work integrates state-of-the-art adaptive trial designs with conventional and new biomarkers of treatment success and employ advanced pharmacokinetic-pharmacodynamic (PK-PD) modelling techniques and artificial intelligence (AI) and machine learning (ML) approaches 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 full Phase 2 trial programme for UNITE4TB is now established, encompassing 6 new chemical entities (NCEs) and over 20 novel treatment regimens. The Phase 2B DECISION trial (dose-optimizing the DprE1 inhibitor BTZ-043) has been completed in South Africa and Tanzania; results will be released in Year 5. The multi-arm, multi-stage platform PARADIGM4TB trial, launched in January 2024, will complete recruitment in July 2025 (400 participants at 14 sites in 5 countries on 3 continents) for the first regimen-selection (2B) phase of 10 experimental regimens including BTZ-043 and/or the leucyl-tRNA synthetase inhibitor ganfeborole. Interim analysis in late 2025/early 2026 will select the best regimens for the duration-randomisation (2C) phase.
In parallel, a second regimen-selection (2B) phase will begin in Q3/Q4 2025, adding 4 new regimens and 2 NCEs (quabodepistat and delpazolid). Additional trial sites in Asia, Europe and South America will join this largest TB platform trial ever conducted. One more Phase 2B/C study—Stage 3 of the PanACEA-STEP2C platform trial—is in preparation to assess treatments for isoniazid-monoresistant and extensively (including bedaquiline)-resistant TB; enrolment will begin in Q3/Q4 2025.
The Phase 2A programme is progressing. ENABLE, a dose-selection study for the transcription regulator alpibectir plus ethionamide, was initiated in Year 4; >60% of participants were recruited by July 2025. SYNERGY, an innovative two-stage evaluation of the diarylquinolone TBAJ-587 in 8-week combinations with four other NCEs, will start in 2026.
Tools to improve trial conduct are advancing. Pharmacokinetic assays for BTZ-043 and ganfeborole are complete, while assays for quabodepistat and alpibectir/ethionamide are ongoing. Epidemiological cut-off values for BTZ-043 and ganfeborole have been defined, with future experiments planned for other drugs. Sample collection and analyses for PK-PD and host/bacterial biomarkers continue across trials. Digital Adherence Technology (Wisepill boxes and AARDEX software) is being rolled out across PARADIGM4TB and will be implemented in SYNERGY. Machine Learning/AI evaluations using TB-PACTS datasets have identified multi-factorial models predicting outcomes including recurrence post-treatment.
The C-Path Data Archive, which houses the Data Collaboration Platform, was user-tested and updated in November 2024. The Data Management Plan was revised, and procedures for safe and sustainable data access are being finalised.
The Community Advisory Group, Ethics Advisory Board and Scientific Advisory Board meet regularly, attend annual meetings, and have reviewed four trial protocols (SYNERGY pending). Communication and dissemination efforts have produced 19 scientific papers, 302 dissemination activities (targeting policymakers, funders and national TB programmes), and 12 poster/conference presentations. Capacity-building has included 12 webinars, 3 seminars for healthcare professionals and 7 educational articles (22 training materials total). The Young Investigators Group has expanded its activities, and the consortium has co-organised 4 webinars and an Interactive Education session for healthcare professionals.
In parallel, a second regimen-selection (2B) phase will begin in Q3/Q4 2025, adding 4 new regimens and 2 NCEs (quabodepistat and delpazolid). Additional trial sites in Asia, Europe and South America will join this largest TB platform trial ever conducted. One more Phase 2B/C study—Stage 3 of the PanACEA-STEP2C platform trial—is in preparation to assess treatments for isoniazid-monoresistant and extensively (including bedaquiline)-resistant TB; enrolment will begin in Q3/Q4 2025.
The Phase 2A programme is progressing. ENABLE, a dose-selection study for the transcription regulator alpibectir plus ethionamide, was initiated in Year 4; >60% of participants were recruited by July 2025. SYNERGY, an innovative two-stage evaluation of the diarylquinolone TBAJ-587 in 8-week combinations with four other NCEs, will start in 2026.
Tools to improve trial conduct are advancing. Pharmacokinetic assays for BTZ-043 and ganfeborole are complete, while assays for quabodepistat and alpibectir/ethionamide are ongoing. Epidemiological cut-off values for BTZ-043 and ganfeborole have been defined, with future experiments planned for other drugs. Sample collection and analyses for PK-PD and host/bacterial biomarkers continue across trials. Digital Adherence Technology (Wisepill boxes and AARDEX software) is being rolled out across PARADIGM4TB and will be implemented in SYNERGY. Machine Learning/AI evaluations using TB-PACTS datasets have identified multi-factorial models predicting outcomes including recurrence post-treatment.
The C-Path Data Archive, which houses the Data Collaboration Platform, was user-tested and updated in November 2024. The Data Management Plan was revised, and procedures for safe and sustainable data access are being finalised.
The Community Advisory Group, Ethics Advisory Board and Scientific Advisory Board meet regularly, attend annual meetings, and have reviewed four trial protocols (SYNERGY pending). Communication and dissemination efforts have produced 19 scientific papers, 302 dissemination activities (targeting policymakers, funders and national TB programmes), and 12 poster/conference presentations. Capacity-building has included 12 webinars, 3 seminars for healthcare professionals and 7 educational articles (22 training materials total). The Young Investigators Group has expanded its activities, and the consortium has co-organised 4 webinars and an Interactive Education session for healthcare professionals.
The Global Plan to End TB 2023–2030 stresses the urgent need for highly effective regimens to control the pandemic. UNITE4TB aims to accelerate TB drug development by running innovative Phase 2A and 2B/C trials, ensuring regimens advance to Phase 3 with high success probability, regulatory approval and availability for DR- and DS-TB patients. The project directly supports End TB Strategy and Sustainable Development Goals (SDGs), addressing drug-resistant TB with new treatments.
Expected results:
• New regimen(s) selected for Phase 3 trials
• Innovative multi-arm, multi-stage designs with decision-making based on interim analyses, including stratification by disease severity
• New endpoints in Phase 2A trials to measure bacterial load reduction
• Investigation of shortened regimens with early-relapse endpoints
• Biomarkers predicting relapse-free cure
• PK modelling for drug-drug interactions and PK-PD modelling across trials to optimise safe and efficacious dosing regimens
• AI/ML methodologies to predict relapse-free cure, prioritise regimens and optimise Phase 2C/3 designs
Expected impact:
• New tools and methodologies to accelerate TB drug development and enable innovative trial designs and biomarker use
• Contribution to EU goals to combat AMR and strengthen implementation of MDR/XDR therapies
• Advancement of imaging, diagnostics, AI tools and pharmacogenomics for candidate selection
• Safer, shorter and more affordable TB treatment options improving patient outcomes worldwide
• Enhanced TB research environment in Europe via strong public-private collaboration (EFPIA, academia, NGOs, SMEs)
• Clear legal/IP frameworks as models of international cooperation on combination regimens
• Agreements for data sharing with other consortia and the TB research community to fast-track future development
• Establishment of a sustainable platform for TB drug breakthroughs beyond the project’s lifetime, with spin-off partnerships for compound/regimen advancement
• Increased awareness among regulators, policymakers and procurers on UNITE4TB findings to shape future policy
These outcomes will usher in a new era of TB drug development, validating combinations of novel compounds more rapidly and reliably using early-relapse endpoints and validated biomarkers. All non-confidential deliverables will be published on the CORDIS website.
Expected results:
• New regimen(s) selected for Phase 3 trials
• Innovative multi-arm, multi-stage designs with decision-making based on interim analyses, including stratification by disease severity
• New endpoints in Phase 2A trials to measure bacterial load reduction
• Investigation of shortened regimens with early-relapse endpoints
• Biomarkers predicting relapse-free cure
• PK modelling for drug-drug interactions and PK-PD modelling across trials to optimise safe and efficacious dosing regimens
• AI/ML methodologies to predict relapse-free cure, prioritise regimens and optimise Phase 2C/3 designs
Expected impact:
• New tools and methodologies to accelerate TB drug development and enable innovative trial designs and biomarker use
• Contribution to EU goals to combat AMR and strengthen implementation of MDR/XDR therapies
• Advancement of imaging, diagnostics, AI tools and pharmacogenomics for candidate selection
• Safer, shorter and more affordable TB treatment options improving patient outcomes worldwide
• Enhanced TB research environment in Europe via strong public-private collaboration (EFPIA, academia, NGOs, SMEs)
• Clear legal/IP frameworks as models of international cooperation on combination regimens
• Agreements for data sharing with other consortia and the TB research community to fast-track future development
• Establishment of a sustainable platform for TB drug breakthroughs beyond the project’s lifetime, with spin-off partnerships for compound/regimen advancement
• Increased awareness among regulators, policymakers and procurers on UNITE4TB findings to shape future policy
These outcomes will usher in a new era of TB drug development, validating combinations of novel compounds more rapidly and reliably using early-relapse endpoints and validated biomarkers. All non-confidential deliverables will be published on the CORDIS website.