This Week in TB R&D – 19 May 2010

18 May 2010
by Working Group

Global tuberculosis drug development pipeline: the need and the reality
Global tuberculosis drug development pipeline: the need and the reality by Zhenkun Ma, Christian Lienhardt, Helen McIlleron, Andrew J Nunn, Xiexiu Wang

Today, The Lancet published a series of articles on tuberculosis, which highlights the continued devastating global impact of this disease, the ongoing challenges related to HIV co-infection, TB in women and children, and importantly the intensified need for new drugs, vaccines, diagnostics and biomarkers.

Since our blog is a ‘new TB drugs’ related blog, we will focus on one article of this series, ‘Global tuberculosis drug development pipeline: the need and the reality’. Zhenkun Ma and colleagues succinctly present current information regarding the 10 TB drugs undergoing clinical development and their respective drug classes. (Click to view these drugs in the WGND online pipeline.) LL-3858, a Lupin compound, is not included in the review due to a lack of available information.

Latent TB treatment, as discussed in a recent WGND blog post, is also an area of ongoing research investigation. Drugs, such as nitroimidazoles like PA-824, that demonstrates killing activity towards replicating and non-replicating bacteria, may be viable future LTBI drug treatment option.

Introducing a single new drug for TB to the market is not enough. We, as a global community of TB stakeholders, must understand how best to use the new and long-awaited products soon to come out of the pipeline to benefit the greatest number of patients, sustainably. Ma and colleagues stress the examination of drug combination trials of TB drugs, new and old, to evaluate their efficacies compared to standard TB treatment for drug susceptible and drug resistant forms of TB.

Importantly, this article does not shy away from discussing the challenges that exist with treatment for TB and HIV co-infection patients and the lack of available knowledge on how to treat children infected with TB. While it is evident that more studies need to be done regarding dosing and safety for child TB treatment, how to overcome this challenge is unclear. Moreover, the pressing need to increase clinical trial site capacity is mentioned to bring awareness to the fact that without adequate facilities to test and assess new TB drugs, the drug development process and registration of a new drug will be affected.

Above all, perhaps the greatest challenge to TB drug development may not be scientific at all, but a lack of funding that may threaten the rate and scope of global TB drug R&D.

In the end, a sense of hope still persists amid a rising tide of new TB infections, including MDR- and XDR-TB.

Should a timeline be generated for clinical trial capacity expansion to reflect the growing need? What incentives could be devised to encourage more drug companies to get involved in TB drug development since it is expensive and the commercial viability of TB drugs is low? It is obvious that we, as a global community, need to gather more critical information about pediatric TB treatment, but how? How can families be encouraged to enroll their children in drug regimen trials? What steps should be taken?

The following is the press release from the TB Alliance:

Lancet Article Highlights Hope in the
Tuberculosis Drug Development Pipeline

TB Alliance author underscores challenges in
TB drug research and development

New York, May 3, 2010 — According to a paper published today in The Lancet, there is unprecedented progress in the development of the global tuberculosis (TB) drug pipeline with 10 drug candidates currently in clinical development. The paper was written by a team of renowned international experts led by Zhenkun Ma, Ph.D., Chief Scientific Officer for the TB Alliance. The article, published as part of The Lancet’s Series on Tuberculosis, also highlights the significant funding and other challenges associated with the pursuit of life-saving treatment for the nearly 2 million people who die each year from TB.

A decade ago, there were essentially no drugs being developed to treat TB, so there has been tremendous progress in this area
Zhenkun Ma, TB Alliance

Of the 10 compounds in clinical development, three TB drugs are being co-developed by the TB Alliance and its partners. These clinical candidates are basic building blocks for a new generation of novel TB drug regimens that have the potential to greatly reduce the global TB burden by shortening the duration of the current treatment regimen, which currently takes six to 30 months. Results of a recent modeling study in a WHO region suggest that new and improved TB drugs, vaccines, and diagnostics could reduce the global incidence of TB by 71% by 2050. In 2008, there were more than 9 million new cases of TB.

“A decade ago, there were essentially no drugs being developed to treat TB, so there has been tremendous progress in this area,” said Dr. Ma, lead author of the paper “Global Tuberculosis Drug Development Pipeline: The Need and the Reality.” “Still, the global TB drug pipeline must continue to be strengthened to ensure we can deliver the tools to help stop the devastation TB wreaks on patients, families, and countries around the world.”

Dr. Ma notes that access to increased and sustainable funding to bring the next generation of TB treatments to patients is a key challenge to unleashing the hope in the drug pipeline. According to Médecins Sans Frontières, currently, there is a 75 percent funding shortfall to support the necessary TB drug research and development.

“While we’re headed in the right direction, this draws much needed attention to the challenges that lie ahead,” said Dr. Stefan Kaufmann, Director, Department of Immunology at the Max Planck Institute for Infection Biology. “Only together and with a global commitment can we support the development of new TB regimens and dramatically reduce the mortality of TB and its economic impacts.”

Multi-drug combinations are needed to treat drug-sensitive and drug-resistant disease. Until recently, only one new TB drug in a regimen has been tested at a time. However, with the availability of drug candidates, the Critical Path to TB Regimens (CPTR) initiative was recently launched, which is intended to enable several new TB drugs to be tested simultaneously, in combination. This is expected to lead to a dramatic reduction in the time that it takes to develop an innovative TB drug regimen.

TB kills nearly two million people every year, and is second only to HIV/AIDS in mortality among infectious diseases. However, 94% of TB cases and 98% of deaths occur in the developing world, and therefore there is very little market incentive for the private sector to invest in TB drug development.

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