The evolution of TB innovation: insights, breakthroughs, and future paths

On World TB Day, we delve into our Infectious Disease R&D Tracker to identify the novel vaccines, groundbreaking drugs, and cutting-edge diagnostics in development for TB. We look at how things have changed since 2015 and examine the technologies that will help us say 'Yes, we can end TB'.

There is reason to hope. Progress has been made but more research and investment are needed in all product areas to address remaining gaps with vulnerabilities in the vaccine pipeline in particular. Only then will we see improved outcomes for people infected with TB.

Research and innovation – the third pillar of End TB Strategy

The End TB Strategy?aims for a 90% reduction in TB deaths and an 80% drop in TB incidence by 2030. To achieve this, new tools (diagnostics, drugs, and vaccines) are vital. This includes point-of-care (POC) tests for TB detection, shorter and safer drugs for treating all types of TB; including drug sensitive (DS-)- and drug resistant (DR-)-TB; and a vaccine preventing TB before and after exposure for all ages.

As of December 2023, at least 114 different TB countermeasures are in development. Anti-tubercular drugs, including regimens, make up nearly half of the pipeline, diagnostics account for just under a third, and the remaining pipeline comprises vaccines (18%) and biologics (4%). But what progress have we made since 2015?

Safer, shorter, pan-TB regimens

When looking at the changes over time, the total number of TB drugs in development in 2023 is slightly higher (up by four) than in 2015. Compared with 2017 and 2019, the current pipeline has significantly contracted – from 54 in 2017 to 34 in 2019. However, the drop is due to the completion of regimen trials of repurposed drugs.

When comparing new chemical entities (NCEs) in clinical development, the pipeline has increased more than three times since 2015. Of the 20 NCEs currently in clinical development, at least eight belong to novel chemical classes with diverse mechanisms of action. The front-running candidates include quabodepistat, which is being investigated as part of a regimen for shortening DS-TB treatment from six months to two to four months. The interim analysis from an ongoing clinical trial showed a high cure rate among participants taking quabodepistat-based regimens.

Next-generation TB vaccine: preventing infection and disease among all age groups

The effectiveness of BCG, the only licensed TB vaccine available, is limited to protecting infants and young children from severe forms of TB and is ineffective among adolescents and adults, the age group with the highest burden. The lack of a next-generation TB vaccine with the ability to prevent all forms of TB, including infection and disease, among all age groups is recognised as the biggest obstacle in achieving the goals set in the End TB strategy.

Despite this significant unmet need, TB vaccine development has seen dismal progress compared to drugs and diagnostics. The clinical pipeline has consistently shrunk with multiple candidates moving out of the pipeline, primarily due to numerous unsuccessful clinical trials. There are now significantly fewer candidates in phase II, a proxy for future successful licensure of a new vaccine, compared to 2017. M72/AS01E-4, the only investigational vaccine to successfully complete a phase IIb efficacy trial. A phase 3 clinical trial is now underway at University of the Witwatersrand, Johannesburg, South Africa, the first of up to 60 sites in seven countries to assess the safety and efficacy of the M72/AS01E vaccine candidate.

More recently, the first-ever mRNA-based vaccine started a phase I trial. A relatively small number of pipeline candidates based on a limited pool of target antigens is problematic. More early-stage research, potentially translating into a more diverse clinical pipeline, is urgently needed.

New diagnostics tool for screening, detecting and treatment monitoring

Diagnostics remain the weakest link in the TB cascade of care. In 2022, close to 30% of people with TB were never diagnosed and therefore left untreated. New tools appropriate for resource-limited settings for screening, diagnosing (including drug resistance), and monitoring treatment response are critical to reap the benefits of newer and shorter treatments. To treat TB, first, we need to find TB cases.

The diagnostics pipeline has decreased since 2015 but a big part of the decrease is explained by how the data was curated. The most recent review presents diagnostics by technology type; so all similar tests ('me toos') are grouped to avoid overestimating novel products.

Close to two-thirds of the tests currently in development are based on molecular platforms, and all but one of the remaining are immunoassays. In terms of diversity of use-case, the current TB diagnostic pipeline is the healthiest it has ever been. Confirmatory tests with the ability to test drug resistance make up close to a third (29%) of the pipeline, followed by POC diagnosis (26%), triage and screening tests (21%) and treatment monitoring (12%).

Conclusion

The 2023 United Nations high-level meeting on the fight against tuberculosis emphasised the crucial role research will play in ending TB. After years of neglect with no significant results, the TB product development pipeline shows signs of improvement. But some product areas are performing better than others. Multiple novel drugs are either closer to or already undergoing TB treatment regimen trials. The current drug pipeline is expected to deliver shorter, easy-to-administer TB treatment in the next five years. The TB diagnostics pipeline has diversified at a fast pace, and it now seems possible that sputum smear microscopy will be wholly replaced with POC molecular tests in the near future. Vaccine research is one area that needs urgent attention; more pre-clinical candidates with diverse antigen profiles are required to bolster and replenish the pipeline and replace unsuccessful clinical candidates. The establishment of the TB Vaccine Accelerator Council by World Health Organisation, which will enable high-level coordination, is a step in the right direction for rejuvenating TB vaccine R&D.

As we mark World TB Day, it becomes imperative to acknowledge the dynamic landscape of TB research and innovation. The development of innovative tools stands out as a cornerstone to achieve the ambitious goals outlined in the End TB strategy. So 'Yes, we can end TB', if we uphold the remarkable research strides witnessed in therapeutics and diagnostics over recent years, coupled with a coordinated global effort to expand the TB vaccine pipeline’s number and diversity.

To explore more of the neglected disease approved products, see our Infectious Disease R&D Tracker.

The tracker is part of our Evidence for Impact project which seeks to evaluate the health and economic outcomes of 20 years of neglected disease R&D, alongside assessing ROI from past investments and projecting impacts of products in the pipeline until 2040. To receive updates about the project, including its launch on May 28th 2024, as well as other Policy Cures Research insights and data, sign up here.