Disease caused by Mycobacterium tuberculosis continues as a global epidemic: over 2 billion people harbor latent TB
infection, and more than 9 million new TB cases, of whom 500,000 are multidrug-resistant (MDR), and nearly 2 million deaths are estimated to occur each year. New drugs are required to shorten
treatment duration of
drug-sensitive TB and for the treatment of MDR-TB.
TMC207 is a first-in-class
diarylquinoline compound with a novel mechanism of action, the inhibition of bacterial
ATP synthase, and potent activity against
drug-sensitive and
drug-resistant TB. It has bactericidal and sterilizing activity against M.
tuberculosis and other mycobacterial species, but little activity against other bacteria. In a Phase II efficacy study conducted in patients with MDR-TB taking
TMC207 plus a standard background regimen, the
drug appeared to be safe and well tolerated, and showed significant efficacy after 2 months of treatment with conversion rates of sputum culture of 48% (vs 9% in the placebo group). Given the product development partnership between Tibotec and the TB Alliance, the strategies of using
TMC207 in shorter first-line regimens or using it in second-line regimens for
drug-resistant M.
tuberculosis infections are both being pursued. No clinical data of
TMC207 in TB patients with
HIV coinfection have been published;
drug-drug interaction studies with antiretrovirals are being conducted. Finally, the remarkable sterilizing capacity of
TMC207 also makes it an attractive
drug in the strategy of TB elimination. Current and future studies will determine the role of
TMC207 in a shortened treatment regimen for
drug-sensitive TB, a more effective and better-tolerated regimen for MDR-TB, the treatment of latent TB
infection, and intermittent-TB treatment regimens.