PAN-TB regimens to address growing TB drug resistance

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tuberculosis

By Dr. Charles Wells, head of therapeutics development at Gates Medical Research Institute

As nearly one-quarter of the world’s population is presumed to be infected with Mycobacterium tuberculosis bacteria and are at risk for developing active tuberculosis (TB), the disease represents a major public health challenge globally. 

As reported by the World Health Organization (WHO), more than 10 million cases of TB occur worldwide annually, and in 2021, 1.6 million people died from TB, making it the second-leading infectious killer after COVID-19. The disease burden remains greatest in low-and-middle-income-countries (LMICs), which account for 98% of reported TB cases. 

People living with HIV infection are at greater risk for progressing from infection to active TB and TB remains a leading cause of death for them. Of note, the TB incidence rate was in a slow decline prior to the COVID pandemic, and that decline has now stalled.

Despite new medicines being introduced in recent years, successfully treating TB is complex and challenging. Patients with drug-sensitive TB must first receive a correct diagnosis and then complete a standard course of multiple drugs that lasts for a minimum of six months. 

This places heavy demands on patients, families, and health systems, particularly in LMICs, which face the highest TB burden. 

Growing resistance

Treatment is further complicated by growing resistance to commonly used TB drugs which can occur when patients are mismanaged medically or not well supported through the course of treatment or when drug supplies are unstable, unreliable, or of poor quality. It can be amplified when the diagnostic capacity to identify underlying resistance is not available.

Among resistant forms, multidrug-resistant TB (MDR-TB) – TB resistant to at least isoniazid and rifampin as the two most potent “first-line” TB drugs – is particularly problematic to manage. Though treatment options for this form had improved substantially over the past few years, with treatment durations down to six months from 18 months before the newer agents were available, the agents required to treat it are more expensive, still not widely available, and have more issues with tolerability and toxicity compared to the standard treatment course for drug-sensitive TB. 

Extensively drug-resistant TB (XDR-TB), a less common type of MDR-TB with additional resistance to fluoroquinolones and at least one of the newer treatment agents, bedaquiline or linezolid, is even more difficult to treat with fewer treatment options and lower treatment success for patients.

To hasten the decline of the global TB burden, reduce mortality, override the existing background of resistance among patients, and allow healthcare systems in LMICs to deliver more efficient, shorter and simpler TB treatment with greater success, potent new and novel regimens with a favorable safety profile and limited-to-no drug resistance that could serve as a “pan-TB” regimen to treat all patients are urgently needed. Such a regimen could reduce the need for drug susceptibility testing and clinical monitoring, which would simplify associated therapy adjustments to provide a significant benefit to both patients and health systems.

No single organization 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.

PAN-TB

I am proud to work in support of the Project to Accelerate New Treatments for Tuberculosis (PAN-TB), which is a collaboration among philanthropic, non-profit, and private sector organizations that aims to accelerate the identification of promising pan-TB regimens and advance them through rigorous phase 2b/2c clinical trial evaluation. The PAN-TB collaboration is composed of the following members: Evotec, GSK, Johnson & Johnson, Otsuka Pharmaceutical Co., Ltd., based in Japan, the TB Alliance, the Bill & Melinda Gates Medical Research Institute, and the Bill & Melinda Gates Foundation.

As part of the collaboration, these organizations are leveraging their collective assets, resources, and scientific expertise for the discovery of novel regimens and the use of innovative approaches to identify and evaluate new drug regimens with an acceptable safety profile comprised of medicines to which there is limited or no drug resistance, and that are better-tolerated, shorter in duration and simpler to use than existing options. Collaborative pre-clinical research activities have begun. Clinical trials will be announced as they are planned.

A subgroup of PAN-TB members signed a joint development agreement (JDA) in 2022, supporting the progression of two investigational TB combination treatment regimens into phase 2 clinical development. The collaboration 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 new JDA, and the organizations contributing them, include:

• Bedaquiline; 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 Alliance1

• Delamanid; registered product, Otsuka Pharmaceutical Co., Ltd.

• Pretomanid; registered product, TB Alliance

• OPC-167832; NCE, Otsuka

• Sutezolid; NCE, TB Alliance, Medicines Patent Pool, Bill & Melinda Gates Medical Research Institute

The two investigational drug regimen combinations to be evaluated include:

• DBOS – delamanid, bedaquiline, OPC-167832 and sutezolid

• PBOS – pretomanid, bedaquiline, OPC-167832 and sutezolid

A pan-TB regimen for more resources

A pan-TB regimen that is expected to be significantly shorter than current standard TB treatments (2-3 months) would allow more TB patients to be cured, resulting in less transmission of infection and a reduced burden on health systems that treat TB. In turn, this would permit more resources to be focused on finding the estimated 3 million cases of active TB that are often underreported and go undiagnosed and untreated every year.

This work could result in a significant global health impact, with an accelerated decline in TB disease burden that ultimately paves the path to eliminating TB. TB can be prevented and curable with the right investments and resources.

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