Gates Medical Research Institute as an integrator – our partnerships to help address the public health challenges posed by tuberculosis
24 March 2022
– By Charles Wells, M.D., Head of Therapeutics Development at the Bill & Melinda Gates Medical Research Institute
Tuberculosis (TB) is a major cause of ill health and one of the leading causes of death worldwide. Prior to the advent of the COVID-19 pandemic, TB was the leading cause of death from a single infectious agent. The COVID-19 pandemic and the resulting strain on health service delivery has accentuated the TB burden with access to care and case notifications decreasing sharply in 2020, and the number of TB deaths increasing (WHO Global TB Report, 2021). Approximately 50% of TB patients and their families face catastrophic costs that exceed 20% of their annual household income. Without proper treatment, 45% of HIV-negative people with TB, on average, and nearly all people living with HIV who are coinfected with TB will die. Globally, low- and middle-income countries (LMICs) accounted for 98% of reported TB cases in 2020
TB is caused by the bacillus Mycobacterium tuberculosis (Mtb), which is spread when people who are sick with TB expel bacteria into the air (e.g., by coughing or breathing). The disease typically affects the lungs (pulmonary TB) but can affect other sites. Most people (about 90%) who develop the disease are adults, with more cases among men than women (WHO Global TB Report, 2021).
Infection most often results in the establishment of a “latent” infection status, which can convert to active TB disease at any time during the latently infected individual’s lifetime. When a person develops active TB disease, the symptoms (such as cough, fever, night sweats, or weight loss) may be mild for many months. This can lead to delays in seeking treatment, thereby prolonging the period of transmissibility which occurs during active TB disease.
The biological complexity of the bacterium and the efficacy of existing TB drugs requires that they be administered in a multi-drug regimen for at least six months. This long duration of treatment results in poor adherence and may lead to the development of drug-resistant TB (DR-TB). DR-TB is even more difficult to treat (3-5 drugs for up to 12-15 months) and can have significantly higher mortality. Decades of misuse of existing antibiotics and limited health system infrastructure to support patients through the long course of treatment, have created an epidemic of drug resistance that threatens TB-control programs worldwide. New drugs and treatment regimens with activity against drug-susceptible and drug-resistant TB that can also greatly reduce the duration of treatment to achieve a cure are desperately needed to manage this public health crisis.
The Bill & Melinda Gates Medical Research Institute (Gates MRI) is pleased to be a member of the Project to Accelerate New Treatments for Tuberculosis (PAN-TB) collaboration. The collaboration aims to identify novel regimens that could treat both drug-susceptible and drug-resistant forms of TB in a much shorter duration than the currently used treatment regimens. The novel regimen would ideally have a safety profile that would require little to no monitoring, be easy to administer (once daily), and will be affordable for patients in LMICs.
The hope is that these attributes will lead to greater treatment adherence and improved treatment success among millions of TB patients, and perhaps also lead to lessened transmission of infection. With less treatment support needed for patients, in half the time of current standard of care, the novel treatment regimen could allow for enhanced active TB case-finding due to increased availability of resources. These aspirational characteristics should result in greater epidemiologic impact with accelerated decline in disease burden on the path to eliminate TB.
This global collaboration of philanthropic, non-profit and private sector organisations is working together to expedite the development of novel TB treatment regimens for all TB patients, to enable a simpler “test and treat” paradigm. The “Collaboration” consists of Evotec, GSK, Janssen, Bill & Melinda Gates Foundation, Gates MRI, Otsuka and the TB Alliance. The Gates MRI is responsible for the execution within the Collaboration of phase 2 clinical trials intended to de-risk promising new and novel treatment regimens for phase 3 evaluation, in close coordination and joint governance with PAN-TB partners.
A key drug in the proposed regimen is sutezolid (formerly known as PNU-100480), a promising antibiotic drug candidate. In October 2019, The Medicines Patent Pool (MPP) and Pfizer entered into a licence agreement which granted MPP rights to sublicense to third parties the patents and know-how relating to sutezolid. In December 2020, MPP and Gates MRI signed an agreement to advance the development of this investigational drug, for use in LMICs. Sutezolid, in combination with other drugs, could potentially be used as an all-oral, shortened regimen for all forms of TB, including DR-TB.
Sutezolid is an oxazolidinone (see structure below) that has demonstrated a potentially acceptable safety profile and antimycobacterial activity, making it a promising candidate for further evaluation.
From my perspective as a clinician, I am excited to further study this drug candidate, with a view to contributing to our goal of accelerating the end of TB and bringing hope to those who suffer from this infectious disease. With our partners in the PAN-TB collaboration, we are keen to pursue development of a novel TB regimen that may include sutezolid.
It is our hope that this work may contribute to ending the TB epidemic by 2030, one of the health targets of the United Nations Sustainable Development Goals.