The tuberculosis (TB) epidemic constitutes a major global health threat. The steady emergence of Mycobacterium tuberculosis strains resistant to current anti-TB drugs, including multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively), as well as the therapeutic obstacles presented by coinfection with HIV and the cumbersome nature of existing treatment protocols all demand the development of new, fast-acting, effective compounds that shorten and simplify the treatment of TB (Arjona, A. and Castaner, R., Drugs Fut 2008, 33(12): 1018).

TMC-207 (R-207910) is a novel diarylquinoline with a unique biological target: the F0 subunit of mycobacterial ATP synthase. The inhibition of mycobacterial ATP synthase function may result in ATP depletion and upset pH homeostasis, thereby slowing the energy production of M. tuberculosis and subsequently reducing its survival. The ATP synthase of mycobacteria has been shown to have a unique sequence, indicating that this is a highly specific target that could be addressed by potentially safer, more potent drugs. TMC-207 exhibits high in vitro activity against a wide range of mycobacterial strains, both susceptible and resistant to all first-line and many second-line anti-TB drugs available. It has also shown remarkable in vivo efficacy against M. tuberculosis and other mycobacterial species in several animal models. Preliminary pharmacokinetic, safety and efficacy analyses in humans have reasserted the potential of this compound for treating TB. TMC-207 is currently undergoing phase II clinical evaluation at Tibotec, a subsidiary of Johnson & Johnson.

Encouraging results from the first part of an ongoing two-stage phase II, randomized, placebo-controlled trial evaluating TMC-207 in the treatment of MDR-TB were published in June. The data show that the addition of TMC-207 for eight weeks to a five-drug background regimen resulted in a significant increase in the proportion of patients achieving a negative sputum culture and a shorter time to sputum culture conversion as compared to the background regimen alone. In the present study, TMC-207 did not appear to be associated with serious adverse events. This study validates APT synthase as a target for tuberculosis (Diacon, A.H. et al., New Engl J Med 2009, 360(23): 2397). The second stage of the study, which will evaluate efficacy following 24 weeks of treatment, is currently ongoing and is actively recruiting patients with MDR-TB in South Africa, Peru, Latvia and Russia. Results from the second stage are expected to be available in 2010.

In late June, Tibotec and the not-for-profit Global Alliance for TB Drug Development (TB Alliance) announced an agreement to collaborate and share their expertise and resources in order to speed the development of TMC-207, potentially the first TB drug with a new mechanism of action in 40 years. Under the terms of the agreement, Tibotec will continue to develop TMC-207 for the treatment of MDR-TB, and on approval, will establish an access program to ensure the compound reaches those in developing countries who are in need. The agreement grants the TB Alliance a royalty-free license for the worldwide development and access to TMC-207 in the field of drug-susceptible TB. In addition, Tibotec will collaborate with the TB Alliance on a discovery research program to identify new compounds for the treatment of TB. The rights for the newly discovered compounds for the treatment of tuberculosis will belong to the TB Alliance under a royalty free license. Costs for the development of TMC-207 will be shared.