The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) collaboration announced today the start of a phase 2b/c clinical trial, sponsored by the Bill & Melinda Gates Medical Research Institute (Gates MRI). The trial will evaluate whether novel regimens that combine registered products and new chemical entities have the potential to effectively treat drug-sensitive TB (DS-TB) and inform the development of a "pan-TB" regimen capable of treating all forms of active pulmonary TB.
The regimens under evaluation are designed to explore shorter treatment durations compared to existing drug regimens, without the need for accompanying drug-resistance testing for individuals. The goal is to identify a candidate regimen suitable for phase 3 development.
Trial sites are being hosted in countries with a high burden of TB. The trial has started in South Africa with the first participant screened in the last week of July. Subsequent trial sites are expected to launch in the Philippines in August and in Peru in 2024, pending national approvals.
The collaboration is evaluating two novel drug regimens comprising five antibacterial agents—bedaquiline, delamanid, pretomanid, quabodepistat (formerly known as OPC-167832), and sutezolid
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DBQS – delamanid, bedaquiline, quabodepistat and sutezolid
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PBQS – pretomanid, bedaquiline, quabodepistat and sutezolid
The trial employs an innovative design that consists of two stages to assess the efficacy of the regimens and evaluate the potential to shorten treatment duration. In the initial stage, the trial will enroll approximately 129 participants. The safety, tolerability, efficacy, and pharmacokinetics of the complete DBQS and PBQS regimens, with each drug administered daily for four months (17 weeks), will be evaluated in participants 18 to 65 years old with DS pulmonary TB. Approximately 43 participants will receive the six-month (26 weeks) standard-of-care treatment for DS-TB1 in the countries where trial sites are located.2
If successful, the second stage will enroll approximately 400 participants to test the selected regimen at shorter treatment durations, ranging from two to four months, across five arms. An additional 30-40 participants will be enrolled in the standard-of-care arm for the second stage of this trial.
To support participants during their treatment, the trial integrates a Stop Treatment and Watch (STrAW) Concilium, a group made up of expert clinical consultants that will evaluate trial participants' treatment response, blinded to the specific regimen they receive, and advise trial investigators on patient management.
The trial will utilize the best available tools including regular engagement with treatment support workers, direct observation of therapy with video technology, and medication reminder monitors. A novel Biomarkers Strategy will inform promising new biomarkers with the aim of enabling faster access to data to monitor treatment outcomes for future trials.
The need for novel TB treatment regimens
Despite the introduction of new medicines in recent years, treatment remains a long, complex, and demanding process for people diagnosed with TB and can place significant costs on households and the health system. The most used drug regimen for the treatment of DS-TB requires people to take multiple drugs for at least six months, often with routine monitoring.
TB treatment can place unmanageable financial strain on individuals and their households. The World Health Organization (WHO) estimates that nearly half of TB-affected households face catastrophic total costs associated with treatment, including costs of travel to clinics, loss of income during treatment, and more, fueling cycles of poverty in vulnerable communities.
Further, accurate, rapid drug resistance testing is essential for early diagnosis of both drug-sensitive and drug-resistant TB, but access to testing can be limited due to high costs, technical challenges, and other barriers.
Emilio Emini, PhD, CEO, the Bill & Melinda Gates Medical Research Institute, said: "The Bill & Melinda Gates Medical Research Institute is committed to developing biomedical interventions that address global health concerns for those in the greatest need. The team at the Gates MRI looks forward to working with our partners across the PAN-TB collaboration, to evaluate the potential of these novel TB treatment regimens, in the hope that it may offer a potentially easier pathway for all people diagnosed with pulmonary TB by offering well-tolerated, shorter and simpler treatment options."
Masanori Kawasaki, Global TB Project Leader, Otsuka Pharmaceutical Co. Ltd, said: "We are immensely proud to be part of this remarkable, trailblazing, collaboration which is now launching a clinical trial for a new, and shorter, pan-TB treatment regimen. We are excited too to be working closely with key partners to bring new treatment options to patients. Otsuka is dedicated to life-saving research and development as demonstrated by our sustained hard work and investment in developing a new chemical entity called quabodepistat. We are most grateful to the Bill & Melinda Gates Medical Research Institute for bringing together leaders in the field of TB, towards the goal of ending TB for good."
Ruxandra Draghia-Akli, MD, PhD, Global Head of Global Public Health R&D, Janssen Research & Development, LLC, said: "Our medicine for multidrug-resistant TB has reshaped TB treatment regimens over the past decade, but more must be done to develop the even shorter, simpler regimens needed to treat all forms of the disease and end TB once and for all. Today's milestone is another step in this direction, and we look forward to seeing the results of this important study."
Mel Spigelman, MD, President and CEO of TB Alliance, said: "Sincere thanks and congratulations to all who have made this innovative and exciting new journey a reality. Bringing revolutionary, highly impactful new treatments to all TB patients around the world is a goal that deserves and requires all our concerted dedicated efforts."
About the Project to Accelerate New Treatments for Tuberculosis
The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) is a first-of-its-kind collaboration among philanthropic, non-profit and private sectors that aims to accelerate the development of an investigational drug regimen capable of treating all forms of tuberculosis.
The PAN-TB collaboration leverages members' collective assets, resources and scientific expertise to identify and evaluate new drug regimens with an acceptable safety profile, that have the potential to treat both drug-sensitive and drug-resistant TB and are well-tolerated, shorter in duration and simpler to use than existing options. The collaboration focuses on advancing research through phase 2 clinical efficacy studies to identify promising regimens for further development.
The PAN-TB collaboration plans to work closely and transparently with the European Regimen Accelerator for Tuberculosis (ERA4TB), which was launched in January 2020. New molecular entities identified by ERA4TB that show promise in initial human studies could later be incorporated into the PAN-TB collaboration's later-stage, clinical research. Several organizations, including Evotec, GSK, TB Alliance and Janssen Pharmaceutica NV, are members of both projects, which will help to ensure coordination across collaborations toward the common goal of advancing TB drug and regimen development.
The members of the PAN-TB collaboration are Evotec, GSK, Janssen Pharmaceutica NV, Otsuka Pharmaceutical Co., Ltd., based in Japan, TB Alliance, the Bill & Melinda Gates Medical Research Institute and the Bill & Melinda Gates Foundation. Additional members may be announced in the future.
About Evotec SE
Evotec is a life science company with a unique business model that delivers on its mission to discover and develop highly effective therapeutics and make them available to the patients. The Company's multimodality platform comprises a unique combination of innovative technologies, data and science for the discovery, development, and production of first-in-class and best-in-class pharmaceutical products. Evotec leverages this "Data-driven R&D Autobahn to Cures" for proprietary projects and within a network of partners including all Top 20 Pharma and over 800 biotechnology companies, academic institutions, as well as other healthcare stakeholders. Evotec has strategic activities in a broad range of currently underserved therapeutic areas, including e.g., neurology, oncology, as well as metabolic and infectious diseases. Within these areas of expertise, Evotec aims to create the world-leading co-owned pipeline for innovative therapeutics and has to-date established a portfolio of more than 200 proprietary and co-owned R&D projects from early discovery to clinical development. Evotec operates globally with more than 4,900 highly qualified people.