It has been several years since a new tuberculosis (TB) drug advanced into Phase III trials, but momentum in the field is now picking up, with a vaccine and two novel treatments progressing through late-stage studies.
The current standard of care (SoC) vaccine for TB is the Bacillus Calmette-Guérin (BCG) vaccine. It remains the only licensed TB vaccine and is one of the most widely administered globally. However, its protection is largely limited to infants and young children, and there is still no approved vaccine that effectively prevents pulmonary TB in adolescents and adults.
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Regarding treatment, currently regimens include a six-month regimen, which consists of two months of isoniazid, rifampin, pyrazinamide, ethambutol and four months of isoniazid and rifampin (HR). For multi-drug resistant (MDR) TB, recommended treatment is a six-month regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin, alongside other longer or alternative regimens depending on resistance profiles and clinical factors.
There are cases of MDR TB where patients require several years of treatment, causing serious toxicity in some patient groups. This highlights the need for more available therapies to both shorten the treatment period and reduce its toxicity. Resistance to Johnson & Johnson’s Sirturo is also a growing concern in the treatment space.
TB is caused by Mycobacterium tuberculosis and primarily affects the lungs, but can also infect other organ systems. In its 2025 annual report on TB, the World Health Organization (WHO) said that the infection remains a “major global public-health problem” and the leading infectious cause of death.
Today, 24 March, marks World TB Day, and despite calls from the WHO to curb the disease’s spread, GlobalData forecasts that TB incidence will continue to rise from around four million cases across the 16 major markets (16MM: US, France, Germany, Italy, Spain, UK, Japan, Australia, Brazil, Canada, China, India, Mexico, Russia, South Africa, South Korea) in 2024 to nearly 4.5 million new cases by 2033.
A broader vaccine could transform TB prevention
In the vaccine space, the Gates Foundation is running a Phase III trial of the M72/AS01E vaccine (NCT06062238). The M72/AS01E vaccine candidate contains the M72 recombinant fusion protein, derived from two Mycobacterium tuberculosis antigens (Mtb32A and Mtb39A), combined with the Adjuvant System AS01.
The study enrolled 20,080 participants from 54 sites in Indonesia, Kenya, Malawi, South Africa and Zambia who tested negative for TB. Most patients enrolled are also human immunodeficiency virus (HIV) negative; however, there is one cohort enrolled with HIV to see how the drug impacts this population.
The drug was being investigated by GSK, but it was passed to the Gates Foundation in 2020 by the company following a Phase IIb trial (NCT01755598). In the study, conducted in partnership with IAVI, M72/AS01E had an acceptable safety profile and reduced cases of TB in HIV-negative adults with latent TB infections by half.
The primary endpoint is the number of participants with laboratory-confirmed pulmonary TB up to 49 months. Secondary endpoints will investigate adverse events (AEs), potential immune mediated diseases and M72-specific antibodies.
Dr Payam Nahid, executive director of the Institute for Global Health Sciences at the UC San Francisco Institute, says: “As a community, we are inspired by the mRNA platform vaccines that were developed so rapidly and with such great efficacy for the Covid-19 pandemic. While M72 is a different type of vaccine, it has enough evidence of effectiveness and safety that it merited this large trial. If the results are positive, M72 will be assuredly incorporated into guidelines worldwide and used, offering a much better option than the current 100-year-old BCG vaccine.”
GlobalData infectious disease analyst, Stephanie Kurdach, agrees that the success of this vaccine could revolutionise the TB market.
“The BCG vaccine is the only TB vaccine currently on the market, and it is primarily indicated for newborns. This leaves a large gap among adolescents and adults, who are responsible for the majority of TB cases,” says Kurdach. “The vaccine has already shown positive efficacy data among adults 18-50 years of age in the Phase IIb trial. The development of new TB vaccines is a high priority of the WHO, and the potential approval of M72/AS01E would address this unmet need and revolutionise the TB vaccines market.”
Bedaquiline replacement in late-stage trials in China
In China, Cisen Pharmaceutical is running a Phase III trial (NCT05824871) of sudapyridine as a treatment for MDR TB. The study, which is estimated to enrol 450 patients, will investigate sudapyridine or bedaquiline, in combination with a background regimen.
The primary endpoint is sputum culture conversion rate after 24 weeks, with secondary endpoints including time to sputum culture conversion at 72 weeks, treatment success rate at 72 weeks and sputum culture conversion rates at multiple time points.
Kurdach says: “Sudapyridine is being presented as a safer alternative to bedaquiline, with similar activity against drug-susceptible and drug-resistant Mycobacterium tuberculosis as bedaquiline. Bedaquiline was the first WHO-recommended drug for the treatment of rifampicin-resistant TB and MDR TB but has a problematic safety profile. If sudapyridine produces Phase III data that maintain that the drug is safer and equally efficacious as bedaquiline, there could be significant uptake of the drug, reducing the market share of bedaquiline.”
Otsuka aims to shorten treatment regimen
Otsuka has also launched the Phase III QUANTUM-TB trial (NCT07209761) of quabodepistat, a decaprenylphosphoryl-beta-D-ribose 2-oxidase (DprE1) inhibitor, as part of a treatment regimen for MDR TB.
The goal of the study, which will enrol 532 patients, is to see if quabodepistat, when combined with other TB drugs, can shorten treatment duration to four months and be as effective and safer than the current WHO endorsed treatment regimen given for six-months.
Quabodepistat will be dosed in combination with bedaquiline, pretomanid and moxifloxacin in the fluoroquinolone-sensitive arm and bedaquiline and pretomanid in the fluoroquinolone-resistant arm. The trial is due to end in May 2027.
Patrick Phillips, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at the University of California, San Francisco, says: “It’s exciting to see a new drug entering a Phase III trial for TB, and quabodepistat appears to be a promising drug. The value of quabodepistat will be in replacing some of the more toxic drugs in the current first-line regimen for MDR TB. It’ll possibly improve the safety of treatment for MDR TB and shorten the duration. If so, it could be a valuable companion drug alongside bedaquiline, pretomanid and moxifloxacin.”
In the Phase IIb/c trial (NCT05221502), a four-month regimen of quabodepistat, in combination with delamanid and bedaquiline, achieved similar safety and efficacy compared to the six-month, standard-of-care four-drug regimen in participants with drug-susceptible TB.
Nahid adds: “20 years ago, a major focus of TB trials was shortening how long treatment lasts because we knew that long durations were challenging to complete, resulting in suboptimal treatment, residual disease and risk of transition from drug susceptible to drug resistant forms of the disease. More recently, the field has shifted toward balancing duration reductions with optimal tolerability and safety, with a focus on making new regimens easier for patients and providers.”
Multiple regimens including established and repurposed drugs
As well as new candidates, there are studies taking place involving well-established drugs such as bedaquiline to better optimise dosing.
Phillips says: “There is a lot of focus on understanding what the best combinations of drugs are and what the optimal duration is. As a result, there is one study funded by the US State Department called PRISM, which is looking at the standard regimen for MDR TB without any additional new drugs, but it is looking to shorten that regimen by using principles of stratified medicine.”
The study (NCT06441006), which is being run by the University of California, San Francisco, where Phillips is employed, is set to enrol 400 patients. It will use baseline markers to predict treatment periods in patients.
There is also the UNITE4TB programme, which consists of four trials, DECISION, PARADIGM4TB, ENABLE, and STEP2C, which was launched in 2023. The trials are investigating different regimens, including new TB treatments, to determine optimal treatment for MDR TB.
Phillips says: “These regimens include repurposed drugs and new drugs rather than just picking a single drug and taking it forward into Phase III. The trials are looking to see how to put together the best combinations that are safe and efficacious to try and replace some of the more toxic drugs.”
Taken together, these late-stage efforts underscore a field that is beginning to regain momentum after years of limited innovation. With TB incidence projected to rise and treatment challenges -particularly in MDR-TB – remaining significant, the need for more effective vaccines and safer, shorter regimens is becoming increasingly urgent.
The outcome of these Phase III trials will be pivotal: a successful adult vaccine or improved therapeutic backbone could not only reshape clinical practice but also alter the trajectory of the disease globally. As the pipeline advances, the next few years will be critical in determining whether these candidates can deliver the step-change needed to meaningfully reduce the burden of TB.
