TBAJ-587-CL-001 is the first Phase 1 trial in humans conducted by TB Alliance through the European Regimen Accelerator for Tuberculosis (ERA4TB) project. Funded by the European Union Innovative Medicines Initiative (IMI) Program, ERA4TB operates as a public-private partnership integrating over 30 organizations including academic institutions, not-for-profit organizations, public research organizations, small-medium enterprises and IMI2 Associated Partners. ERA4TB is among nine projects under the IMI Antimicrobial Resistance (AMR) Accelerator initiative and aims to accelerate the development of new TB treatment regimens. Drug-resistant forms of TB infect half a million people each year and are the leading cause of mortality due to AMR – new, effective regimens are urgently needed.
To offer insight into the project, we interviewed Almari Conradie, Director of Clinical Operations at TB Alliance, who is part of the team overseeing clinical development of TBAJ-587. The following conversation has been condensed and edited for clarity.
Can you describe any recent updates on the development of TBAJ-587?TBAJ-587 is being studied through a trial consisting of a Single Ascending Dose (SAD), Food Effect, and Multiple Ascending Dose (MAD) parts. QPS Netherlands was selected as the clinical trial site and is based in Groningen, the Netherlands. The “First Patient First Visit” for the trial was initially planned for June 2020, but was postponed to November 2020 due to complications from the COVID-19 pandemic.
Recruitment and dosing in the SAD as well as the Food Effect cohorts have now been completed with a small number of participants currently in follow-up. The “Last Subject Last Visit” is expected in February 2022.
The safety and pharmacokinetic results are continuously evaluated by a Dose Escalation Meeting Committee and independent reviewers and we are pleased to be informed that no concerns have been raised to date. Plans to proceed to the MAD part are also currently on track.
What impact does TBAJ-587 have on both the ERA4TB program and TB Alliance?TB Alliance entered TBAJ-587 in the ERA4TB pipeline in support of the project’s vision and mission to accelerate the development of new treatment regimens for TB. This work further strengthens the aim of ERA4TB to establish a network of public-private partnerships and an open platform to continue the consortium’s vision. This Phase 1 study, known as TBAJ-587-CL-001, is one of the first “first-time-in-human” trials undertaken by ERA4TB and provides valuable contributions to other work packages within the consortium such as profiling and modeling. In undertaking this trial, ERA4TB now has the experience in implementing a TB trial in a new setting in the Netherlands as the consortium seeks to implement subsequent Phase 1 trials.
Results from this trial will inform TB Alliance’s strategic approach to advancing treatment-shortening combination regimens for TB. TB Alliance also has the opportunity to develop tools, techniques and standards, PK/PD relationships, clinical trial designs, dose predictions and data, thus increasing R&D capacity in the EU to address the global TB challenge, as well as AMR.
What are some of the advantages to partnering with IMI?As a non-profit organization, we are reliant on grant funding to ensure we fulfil our mission in the discovery, development, and delivery of better, faster-acting, and affordable tuberculosis treatments. Resources for this work have always been scarce, increasingly so since the onset of COVID-19. By participating in IMI, TB Alliance has been able to diversify our funding, which is vital to achieving this mission.
ERA4TB is one of three IMI projects in which TB Alliance is a partner, though these projects are closely aligned. This alignment promotes data exchange and sharing and there is an overall shared goal and commitment to succeed, especially given the EU’s sizeable interest in building TB research capacity.
One of the goals of IMI and the AMR Accelerator is to advance and strengthen European capacity for running TB clinical trials. How is our work with ERA4TB helping to accomplish this goal?Through its partnership with ERA4TB to conduct the Phase 1 TBAJ-587-CL-001 trial in the Netherlands, TB Alliance is making a direct contribution developing the capacity for TB clinical trial sites in Europe. This also contributes to achieving the AMR Accelerator’s goal of delivering up to 10 new preclinical candidates and five Phase 2-ready assets by 2025.
How has the COVID-19 pandemic impacted this project?The COVID-19 pandemic created challenges during the trial set-up as well as the recruitment and follow up phases of the SAD and Food Effect studies. TB Alliance had to be innovative and performed virtual and desk audits to qualify vendors during the set-up phase of the trial. The first patient visit had to be postponed by a number of months due to COVID-19-related visit backlog at the Clinical Trial Unit.
Initially the impact on recruitment was negligible, but from March 2021 the high COVID-19 infection rate, national and institutional restrictions, travel restrictions, limited availability of staff, risk of infection, fear of infection, requirements for social distancing, and closures of institutions all had a negative effect on the recruitment of volunteers for the trial. Mitigation measures included amending the protocol, using alternative recruitment measures, factoring in a high drop-out rate during screening, and implementing a COVID-19-specific protocol and consent form.
Overall, the trial had to be extended by just over half a year – but through close collaboration we were able to adapt and are carrying it out successfully.
Are there any other insights from your work on this study?Innovative funding mechanisms such as IMI are more critical than ever before as the COVID-19 pandemic has brought to light the urgent need for increased R&D to develop drugs, vaccines, and diagnostics to combat emerging and re-emerging diseases. The COVID-19 pandemic resulted in an additional half million TB deaths in 2020 alone, reversing years of hard-won progress against TB. Efforts to control TB and COVID-19 will be inextricably linked in the coming years, requiring continued support from the EU and IMI.
The COVID-19 pandemic has taught us to be resilient throughout challenges, about the strength that lies in close collaboration with vendors and partners, and to be innovative in finding solutions to the toughest global health problems.
This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 853989. The JU receives support from the European Union’s Horizon 2020 Research and Innovation Programme and EFPIA and TB Alliance, Bill & Melinda Gates Foundation, University of Dundee.