The objectives of this Call Topic are to develop and implement innovative, state of the art adaptive clinical trial designs for the field of TB regimen development able to define the therapeutic dose for existing experimental New Chemical Entities (NCE’s) within treatment combinations. The funded action will define the duration and composition of novel treatment combinations that will shorten or simplify the standard of care, as well as prospectively validating biomarkers against the relapse endpoint. In addition, the funded action is expected to develop clinical trial simulations, evaluate new technologies to monitor and enhance treatment adherence, and develop an understanding of population pharmacogenomics.
The funded action will develop innovative trial designs able to define optimal treatment duration against endpoints that better predict the current Phase 3 endpoint of relapse and will improve efficiency by comparing multiple regimens in parallel within the same study. Early interims will stop failing/futile arms, resulting in even greater efficiencies.
The funded action should also prospectively validate biomarkers against a relapse endpoint. The primary objectives of the biomarker work is to validate i) biomarkers able to accurately prioritise regimens for evaluation in phase 3, ii) biomarkers that are able to predict sterilizing cure/relapse at the individual patient level, and iii); a third, more ambitious objective, is to identify biomarkers that permit the building of a clinical trial simulation platform.
Tuberculosis (TB) is the leading infectious cause of death worldwide.1 To achieve the target of TB elimination by 2035, the WHO estimates that there is a funding shortfall of over USD1 billion per year in TB research. The treatment of drug-sensitive TB is an onerous regimen of four drugs for two months followed by two drugs for four months (six-months total), and multidrug-resistant TB may require treatment for up to two years. Many patients find adherence difficult, and the current drugs are associated with significant tolerability issues. Shorter and safer treatment regimens are urgently needed. Tuberculosis has a low or negative expected return on investment and therefore fails to attract funding: this call addresses this high unmet medical and public health need.
Currently, TB drug development involves 14-day monotherapy trials for early bactericidal activity (EBA) to identify the maximally efficacious dose for a new chemical entity (NCE). The standard trial design contains no option to change doses or de-escalate in-stream in response to emerging Pharmacokinetic-pharmacodynamic (PKPD) or safety data, resulting in a flat dose-respose.2 In Phase 2B, the efficacy of treatment combinations is then studied in eight weeks of dosing, with time-to-sputum-culture-conversion as the primary endpoint. This paradigm has multiple weaknesses: inadequate exploration of dose response; lack of innovative study designs to empirically determine optimal duration of therapy as well as inability to study multiple regimens in parallel. Moreover, there is a lack of Phase 2 biomarkers that adequately predict phase 3 outcome (relapse-free cure).3,4,5
Therefore, there is a critical need for innovative trial designs in TB. Efficient adaptive trial designs would accelerate clinical development in Phase 2, but cannot be implemented currently due to the lack of in-stream biomarkers for sterilising cure/relapse. Several RNA expression, cytokine, bacterial and radiological biomarkers have been proposed in the literature, but to date there has been neither comparison nor prospective validation of these biomarkers. A biomarker that predicts relapse at an individual level may further create opportunities for individualised medicine, or even permit creation/validation of trial simulations. These trial simulations could help optimise trial design, and facilitate in-stream decision-making in adaptive trials.
The objectives, deliverables and impact of the resulting action are well aligned with the mission and goals of IMI2 JU to deliver increased success rate of biomarkers and priority medicines in innovative clinical trials. The expected impact of the funded action will also help attain 2030 UN Strategic Development Goals and 2035 End TB Targets by:
- 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 TB patients worldwide, with the intent to improve the quality of life and life expectancy of TB patients;
- contributing to the development of a vibrant TB research environment in the EU, fostering private-public collaboration across EFPIA, Academia, NGO’s and SME’s 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 regimes.
- Implementing agreement with other consortia facilitating prompt data sharing and data exploitation to accelerate TB drug regimen development.