Tuberculosis (TB) continues to be a major global public health challenge despite being a disease of antiquity. In fact, up to a quarter of the world’s population is latently infected with TB, 10.6 million fell ill from it in 2021 and 1.6 million people lost their lives to this curable disease, making it the second-leading infectious killer after COVID-19, according to the World Health Organization. The disease burden remains greatest in low- and middle-income countries (LMICs), which account for 98% of reported TB cases.
Despite several new TB medicines and treatment regimens being introduced in recent years after more than 40 years of no new treatment options, successfully treating TB remains complex and challenging. Patients with drug-sensitive TB must first receive a correct diagnosis and then complete a standard course of multiple drugs that typically lasts six months or more. This places heavy demands on patients, families and health systems, particularly in LMICs. TB diagnosis and treatment is further complicated by growing resistance to commonly used TB drugs.
Partnerships help us address public health challenges
TB has been a chronically underfunded and under-resourced disease in terms of diagnostics, therapeutics and vaccine development. It’s expensive and risky, and those who would most benefit are typically among the poorest in the world, living in countries with severely constrained health systems. Thankfully, progress has been made in recent years in identifying new targets and compounds, but science alone is not enough. Developing novel treatment regimens requires significant capital and a continued commitment to collaboration across sectors. We see this as an opportunity for the Bill & Melinda Gates Medical Research Institute (Gates MRI) to serve as an integrator and collaborator, to serve our mission and our belief that all lives have equal value.
The Bill & Melinda Gates Foundation funds much of the work of Gates MRI, and we serve as the product development organisation of the philanthropic body. In turn, the MRI works with collaborating partners and organisations, coordinating and driving the full spectrum of biopharmaceutical activities. A collaboration model between nonprofit medical research organisations, such as Gates MRI, and pharmaceutical companies can help address this need for transformational treatment options. Such work must be anchored in the principle of a Global Access Policy, which ensures that knowledge gained from these efforts can be promptly and broadly disseminated and any resulting products be made available and accessible at an affordable price to the world’s poorest.
Pharma companies have the unique research and development expertise to translate fundamental scientific research into development candidates and ultimately into real products, get those products tested and approved efficiently in dozens of countries, and manufacture them for delivery at scale. However, their operating model sometimes means that products that would primarily benefit people in LMICs are less likely to be developed or be made widely accessible to people in LMICs where diseases such as TB are most common and particularly devastating.
The programmes at Gates MRI exemplify what can be achieved when we combine the institute’s funding model and expertise with the discovery capability of pharmaceutical companies; they hold the promise to address major public health challenges – which could translate the promise of science into tremendous impact.
Recent clinical trials have identified new all-oral combination treatments for drug-resistant TB that must be taken for six months instead of the historical regimens that have significant side effects, high pill burdens, and require 18-24 months of treatment, including daily injections for 6-8 months; however, globally, few patients with drug-resistant TB have received these new treatments to date.
New regimens with little to no drug resistance to their component drugs – known as pan-TB regimens – could create a treatment pathway for all people diagnosed with TB that is simpler to use than existing options. Because the same TB treatment regimen could be given to all patients regardless of whether they have drug-sensitive or drug-resistant TB, a pan-TB regimen could reduce the need for obtaining drug susceptibility testing results before initiation of treatment, especially for patients with drug-resistant TB. Improved potency of new and recently approved drugs holds the promise that a pan-TB regimen with these agents could shorten treatment.
No organisation produces the full range of drugs needed to treat all forms of TB and novel regimens will take many years to develop. Innovative collaborations are therefore needed to accelerate the development of pan-TB treatment regimens. Gates MRI is a member of the Project to Accelerate New Treatments for Tuberculosis (PAN-TB). This first-of-its-kind collaboration among philanthropic, non-profit and private sectors aims to accelerate the development of treatment regimens with little to no drug resistance and are ready for phase 3 development.
In August 2022, four partners from the PAN-TB collaboration – Janssen Pharmaceutica NV, Otsuka, TB Alliance and Gates MRI – executed a joint development agreement (JDA) supporting the progression of two investigational TB combination treatment regimens into phase 2 clinical development. The partnership will evaluate whether the novel regimens, which combine registered products and new chemical entities (NCEs), can effectively treat all forms of active pulmonary TB using substantially shorter treatment durations than existing drug regimens, with the goal of identifying a regimen suitable for phase 3 development. The five antimicrobial agents to be evaluated under the JDA, and the organisations contributing them, include:
1. Bedaquiline – a registered product for multidrug-resistant TB, Janssen Pharmaceutica NV, part of the Janssen Pharmaceutical Companies of Johnson & Johnson, and NCE for drug-sensitive TB, TB Alliance
2. Delamanid – a registered product, Otsuka Pharmaceutical
3. Pretomanid – a registered product, TB Alliance
4. OPC-167832 – NCE, Otsuka
5. Sutezolid – NCE, TB Alliance, Medicines Patent Pool, Gates MRI.
The two investigational drug regimen combinations to be evaluated include:
1. DBOS – delamanid, bedaquiline, OPC-167832 and sutezolid
2. PBOS – pretomanid, bedaquiline, OPC-167832 and sutezolid.
What else is in the pipeline?
We are working with several companies to develop a pipeline of novel TB therapeutic candidates. In 2022, Gates MRI announced a licensing agreement with Merck for two preclinical antibacterial candidates for evaluation as potential components of combination regimens for treating TB. These candidates were discovered by scientists at Merck and the National Institutes of Health as part of the TB Drug Accelerator (TBDA). The TBDA is a collaboration established among biopharmaceutical companies, research organisations and universities to accelerate the discovery and development of novel therapeutic candidates against TB and is supported by the Gates Foundation.
Under the agreement, Merck has granted Gates MRI an exclusive global licence for MK-7762 and MK-3854 for TB treatment. The MRI will conduct non-clinical and clinical studies of these candidates to determine their potential for inclusion in new affordable combination treatment regimens for TB with the aim of shortening the duration of treatment irrespective of resistance to the currently available TB drugs.
Most recently, we announced a strategic licensing agreement with Calibr, a division of Scripps Research, to advance the development of a novel investigational compound for TB treatment. Under the agreement, Calibr has granted Gates MRI an exclusive licence to continue the development of the investigational compound CLB073. This compound was discovered and initially developed by a group of scientists from academia and a non-profit research organisation.
The compound uses a novel mechanism of action to weaken the TB bacteria’s ability to survive within macrophages, an important reservoir of TB bacteria and a primary reason why longer treatment courses are required to cure TB. The drug modulates cholesterol catabolism through adenylyl cyclase activation, which ultimately blocks the TB bacteria’s ability to metabolise cholesterol. With this novel mechanism, CLB073 holds the potential to complement and potentiate the current tuberculosis standard of care, aiming to improve efficacy and shorten the duration of treatment.
Are there any vaccine candidates in development?
The institute’s TB vaccine programme has a workstream focused on the development of a candidate vaccine M72/AS01E-4 (under an exclusive licence with GSK) indicated for the prevention of tuberculosis disease in adolescents and adults. In a phase 2b proof-of-concept clinical study, the investigational vaccine demonstrated potential in preventing TB disease among Mtb-infected individuals. The first clinical trial Gates MRI initiated with M72/AS01E is an ongoing trial in South Africa to evaluate the safety and immunogenicity of the vaccine candidate in people living with HIV, referred to as the MESA-TB trial.
In anticipation of a phase 3 efficacy trial of the investigational vaccine, the institute is conducting a TB epidemiology study to document the prevalence of latent Mtb infection and the incidence of TB in populations with a high TB disease burden. The study is also intended to build the required clinical trial capacity to support the investigational vaccine’s phase 3 trial evaluation.
Another of the institute’s current TB research programmes, the BCG revaccination clinical trial, is underway in South Africa. The BCG vaccine was developed over 100 years ago and is commonly given to babies in the first week of life, protecting children from TB for at least ten years, but protection against TB in adolescents and adults is limited. The study enrolled children and adolescents to assess whether a second dose of BCG vaccine, given at ten to 18 years of age, helps protect against Mtb infection. The study is fully enrolled and is now following participants over four years, with testing for Mtb infection every six months. If results are favourable, the goal is to support policy changes around BCG revaccination in countries with a high TB burden. The study will also examine the immune response to Mtb infection and may help us understand mechanisms of protection and develop new TB vaccines.
What is the way forward to defeat TB?
TB is predominantly a disease of the poor and, unfortunately, TB research has experienced research funding shortfalls for decades. In addition, the biology of TB is complex and our understanding of the organism, TB pathogenesis and immunology remains limited in support of vaccine and drug design and development. These challenges are not easily overcome.
TB is preventable and curable with the right investments and resources. Although there is progress in the development of new TB diagnostics, drugs and vaccines, this is constrained by the overall level of R&D investment. With continued investment and collaboration, both monetary and scientific, I am confident that a world without TB is attainable.