PAN-TB Collaboration Announces the Start of a Phase 2 Clinical Trial to Evaluate Two Novel Tuberculosis Treatment Regimens

Public-private partnership launched a first-of-its-kind phase 2b/c trial to evaluate two novel tuberculosis drug regimens with the potential to treat all forms of active pulmonary TB

SEATTLE, Aug. 9, 2023 /PRNewswire/ -- 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:

• DBQS – delamanid, bedaquiline, quabodepistat and sutezolid
• 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. Find out more at: www.pan-tb.org.

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. The Company's 17 sites offer highly synergistic technologies and services and operate as complementary clusters of excellence. For additional information please go to www.evotec.com and follow us on Twitter @Evotec and LinkedIn.

About GSK

GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com/company.

About the Janssen Pharmaceutical Companies of Johnson & Johnson

At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension.

Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenGlobal. Janssen Research & Development, LLC and Janssen Pharmaceutica NV are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

About Otsuka Pharmaceutical Co., Ltd.

Otsuka is a global healthcare company with the corporate philosophy, Otsuka-people creating new products for better health worldwide. Otsuka researches, develops, manufactures and markets innovative products, focusing on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health. In pharmaceuticals, Otsuka is a leader in the challenging area of mental health and also has research programs in several under-addressed diseases including tuberculosis, a significant global public health issue.

About The Global Alliance for TB Drug Development, Inc. (TB Alliance)

TB Alliance is a not-for-profit organization dedicated to finding faster-acting and affordable drug regimens to fight TB. Through innovative science and with partners around the globe, we aim to ensure equitable access to faster, better TB cures that will advance global health and prosperity. TB Alliance operates with support from Australia's Department of Foreign Affairs and Trade, Bill & Melinda Gates Foundation, Cystic Fibrosis Foundation, Foreign, Commonwealth and Development Office (United Kingdom), Germany's Federal Ministry of Education and Research through KfW, Global Disease Eradication Fund (Korea), Global Health Innovative Technology Fund, Indonesia Health Fund, Irish Aid, Korea International Cooperation Agency, Medical Research Council (United Kingdom), National Institute of Allergy and Infectious Diseases, Republic of Korea's Ministry of Foreign Affairs, and the United States Agency for International Development. For more information, visit www.tballiance.org.

About the Bill & Melinda Gates Medical Research Institute (Gates MRI)

The Bill & Melinda Gates Medical Research Institute is a non-profit medical research organization dedicated to the development and effective use of novel biomedical interventions addressing substantial global health concerns, for which investment incentives are limited, including malaria, tuberculosis, enteric and diarrheal diseases, and diseases that impact maternal, newborn, and child health. For further information please visit www.gatesmri.org. 

About the Bill & Melinda Gates Foundation

Guided by the belief that every life has equal value, the Bill & Melinda Gates Foundation works to help all people lead healthy, productive lives. In developing countries, it focuses on improving people's health and giving them the chance to lift themselves out of hunger and extreme poverty. In the United States, it seeks to ensure that all people—especially those with the fewest resources—have access to the opportunities they need to succeed in school and life. Based in Seattle, Washington, the foundation is led by CEO Mark Suzman, under the direction of Co-chairs Bill Gates and Melinda French Gates and the board of trustees. For further information please visit www.gatesfoundation.org.

About Bedaquiline

Bedaquiline, developed by Janssen Pharmaceutica NV, part of the Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen), was the first targeted medicine for TB with a novel mechanism of action to be introduced in over 40 years when it received accelerated approval by the U.S. Food and Drug Administration in 2012. Today, it is recommended by the World Health Organization (WHO) as a core component of all-oral treatment regimens for nearly all DR-TB patients and is included on the WHO Model List of Essential Medicines. It is indicated in the U.S. and European Union for use as part of combination therapy in the treatment of adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary multidrug-resistant tuberculosis (MDR TB). To date, 159 countries are accessing the medicine today, including the 30 countries with the highest burdens of TB, and three out of every four patients with MDR-TB on treatment receive an all-oral bedaquiline-containing regimen. Janssen provided the exclusive rights for developing and marketing bedaquiline for drug-sensitive TB to TB Alliance in 2009. To learn more about how Johnson & Johnson is working to enable access to this medicine, visit JNJ.com/TB.

About Delamanid (Deltyba)

Delamanid is a compound created by Otsuka Pharmaceutical with a mechanism of action showing anti-mycobacterial activity that occurs through inhibition of the synthesis of mycolic acid, an essential component of mycobacterial cell walls. ¹ To date, delamanid (50 mg film-coated tablets) is approved in 47 countries for treatment of patients with MDR-TB. It was added to the WHO Model List of Essential Medicines in 2015 and to date has been used to treat patients with MDR-TB in more than 122 countries.

In 2020, in the European Union, approval was granted for Deltyba 50 mg film-coated tablets to be used in children and adolescents weighing at least 30 kg.² In 2021, a 25 mg dispersible tablet formulation was approved in the European Union for children with pulmonary MDR-TB weighing at least 10 and below 30 kg as part of an appropriate combination regimen, when an effective treatment regimen cannot otherwise be composed for reasons of resistance and tolerability.²

About Quabodepistat

Quabodepistat, previously known as OPC-167832, is an anti-TB compound discovered and currently under investigation by Otsuka. It inhibits the enzyme decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1), which is connected to synthesis involving mycobacterial cell walls. This is a different mechanism of action from other currently available anti-TB drugs. In vivo studies in mice suggest that  quabodepistat plus delamanid-containing regimens have the potential to shorten therapy and improve outcomes in drug-susceptible TB and multidrug-resistant TB (MDR-TB).¹

About Pretomanid

Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. Pretomanid was developed by TB Alliance as an oral tablet formulation for the treatment of tuberculosis in combination with other anti-tuberculosis agents. Pretomanid is recommended by the WHO as part of a combination regimen with bedaquiline and linezolid, with or without moxifloxacin, for the treatment of patients ≥14 years old with MDR-TB or rifampicin-resistant tuberculosis (RR-TB). It is also included in the WHO List of Essential Medicines for MDR-TB. Pretomanid received its first regulatory approval from the US FDA in 2019 followed by EMA approval in 2020.

About Sutezolid

In January 2017, the Medicines Patent Pool (MPP) and Johns Hopkins University (JHU) entered into a license agreement which granted MPP rights to sublicense to third parties the patents owned by JHU relating to sutezolid. In March 2017, MPP and TB Alliance signed a sublicense agreement wherein JHU granted TB Alliance a sublicense to those rights. In October 2019, MPP and Pfizer entered into a license agreement which granted MPP rights to sublicense to third parties the patents and information relating to sutezolid. In December 2020, MPP and Gates MRI signed an agreement to advance the development of this investigational drug from the oxazolidinone class, for use in low- and middle-income countries. Since acquiring rights to develop sutezolid, TB Alliance and Gates MRI have been working together to advance the development of that drug.

¹ The current global and national six-month standard of care treatment regimen for DS-TB consists of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE).
² For example, Philippines National Tuberculosis Control Program Manual of Procedures 6th Edition, Republic of South Africa Department of Health National Tuberculosis Management Guidelines.

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SOURCE The Project to Accelerate New Treatments for Tuberculosis