TB drug development is to receive a major injection of cash and expertise, the Global Alliance for TB Drug Development announced yesterday. The Alliance, which is funded by the Bill and Melinda Gates Foundation, the Rockefeller Foundation, the Dutch government and USAID, is launching a research partnership with GlaxoSmithKline’s Diseases of the Developing World programme to bring six or seven new drugs targeting novel steps in the life cycle of mycobacterium tuberculosis. Human studies on some of these compounds could begin during 2005.
“The TB drug pipeline has been transformed in the past two or three years,” said Dr Mel Spigelman of the Global Alliance for TB Drug Discovery in a press briefing yesterday. “We have six or seven new drugs that could go into human trials this year, which is a revolutionary development in the TB field.”
TB treatment has remained static for many years, and drug resistance is a major problem in many parts of the world, especially the states of the former Soviet Union. TB regimens are lengthy and cumbersome to administer, with an induction phase of two to three months of daily directly observed treatment, followed by a continuation phase of up to six months. Treatment of latent TB may last for up to one year. Discontinuation in all phases due to non-adherence or poor tolerability is high, and is a major contributor to the emergence of multi-drug resistance. Multi-drug resistant TB may require the use of five or six drugs for at least one year.
The Global Alliance’s goal is to develop an entirely new regimen that will shorten and simplify current TB treatment. There have been no new TB drugs introduced for over 40 years.
The research programme is seeking new targets and products to interfere with m.TB replication. These include:
- pleuromutilins, a class of drugs not cross-resistant with any existing antibiotics, that interfere with bacterial protein synthesis and inhibit m.TB growth in the test tube.
- isocitrate lyase (lcl), a protein that must be present for TB infection to persist in macrophages. Targeting this site may reduce the amount of time that continuation phase treatment must last for, and might also be useful in the treatment of latent TB infection.
- INHA, a protein involved in fatty acid synthesis, is already the target for isoniazid, one of the mainstays of current TB treatment. However, isoniazid must be activated before it can inhibit INHA. “Our idea is to bypass that step and directly inhibit INHA,” explained Dr David Pompliano of GlaxoSmithKline.
- GlaxoSmithKline will also screen its vast library of antimicrobials to find novel compounds that can kill m.TB.
TB is the most common opportunistic infection in HIV-positive individuals in developing countries, and its treatment is complicated by interactions between rifampicin, an essential component of anti-TB regimens, and the antiretrovirals nevirapine and efavirenz, either of which is recommended as the mainstay of anti-HIV treatment.
“We desperately need new drugs for TB that do not interact with first-line antiretrovirals,” said Mark Harrington of the Treatment Action Group, which has just launched funded by the Gates Foundation designed to increase advocacy for a joint approach to TB and HIV in the developing world.