Tuberculosis is a leading cause of death from infectious disease, second only to human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS). In 2006, there were 9.2 million new cases of tuberculosis and 1.7 million deaths, with the burden of the disease occurring predominantly in the developing world. It is estimated that one third of the world's population is infected with latent Mycobacterium tuberculosis, providing an enormous reservoir for future disease.

Treatment of tuberculosis is protracted and burdensome. Tuberculosis control is further complicated by the synergy between tuberculosis and HIV/AIDS and by the emergence of multidrug-resistant strains of M. tuberculosis. Furthermore, extensively drug-resistant tuberculosis, has recently emerged as a public health threat.

TMC207 (formerly R207910) is an investigational diarylquinoline compound that offers a new mechanism of antituberculosis action by specifically inhibiting mycobacterial ATP synthase.

In vitro, TMC207 potently inhibits drug-sensitive and drug-resistant M. tuberculosis isolates and is also bactericidal against dormant (nonreplicating) tubercle bacilli.

We present here the results of the first stage of this study, which was undertaken to evaluate the safety, adverse-event profile, pharmacokinetics, and antibacterial activity of TMC207 during prolonged administration.

Methods

Patients

In this study, we included patients ranging in age from 18 to 65 years who had newly diagnosed pulmonary tuberculosis. Patients were excluded from participation if their isolates were not susceptible to aminoglycosides (other than streptomycin) and fluoroquinolones or if they had previously been treated for multidrug-resistant tuberculosis, if they had neurologic or severe extrapulmonary manifestations of tuberculosis, if they had tested positive for HIV with a CD4+ count of fewer than 300 cells per microliter or had received antiretroviral or antifungal medication or both in the previous 90 days, or if they had significant cardiac arrhythmia. Standard exclusion criteria concerning drug hypersensitivity, alcohol and drug abuse, concomitant illness, abnormal laboratory results, pregnancy, breast-feeding, and participation in other clinical studies were also applied.

Study Design

This was an 8-week phase 2, multicenter, placebo-controlled study, conducted among hospitalized patients in South Africa who had confirmed multidrug-resistant tuberculosis, to evaluate the safety, tolerability, pharmacokinetics, and antibacterial activity of TMC207.

The study drugs were provided as TMC207 100-mg tablets (Tibotec BVBA) and matching placebo tablets and were taken with water immediately after breakfast. The preferred background regimen, which was initiated at the start of the double-blind treatment phase, was specified before randomization and consisted of kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or terizidone. After completing 8 weeks of double-blind treatment, patients continued their background treatment regimen and were followed up for a total of 96 weeks.

Safety

Of the patients assigned to TMC207 and of those assigned to placebo, against a background regimen of multidrug-resistant tuberculosis therapy, similar proportions completed the 8-week study and there were no premature discontinuations due to adverse events associated with treatment. Overall side-effect profiles were similar in the two treatment groups, with nausea, unilateral deafness, arthralgia, hemoptysis, hyperuricemia, pain in the extremities, rash, and chest pain being the most common adverse events associated with treatment; of these, only nausea occurred in a significantly higher proportion of patients in the TMC207 group than in the placebo group.

Most adverse events were of mild or moderate intensity and of a type known to occur commonly in patients with tuberculosis or in patients undergoing the standard drug regimen for multidrug-resistant tuberculosis. There was no evidence of a difference between the two treatment groups, on the basis of changes from baseline, on laboratory safety assessments. No consistent or clinically relevant changes in heart rate or electrocardiographic QRS or PR interval were observed during the study. Increases in the mean corrected QT interval were observed in both treatment groups but were more pronounced in the TMC207 group.

 
Antimycobacterial Activity

As compared with placebo, the addition of TMC207 to the standard drug regimen for multidrug-resistant tuberculosis resulted in quicker conversion to a negative sputum culture, according to the MGIT culture system. Treatment responses were similar for all trial centers and across all strata of lung cavitation.

Discussion

New drugs for the treatment of drug-resistant tuberculosis are direly needed. The poor therapeutic efficacy of multidrug-resistant tuberculosis regimens means that the treatment effects of investigational agents are more readily detectable in patients with multidrug-resistant tuberculosis than in those with drug-susceptible tuberculosis which allows for smaller-scale clinical trials. Demonstration of antituberculosis activity in patients with multidrug-resistant tuberculosis paves the way for larger-scale trials of first-line antituberculosis combination therapy for patients with drug-susceptible tuberculosis. Our data present evidence that TMC207, in combination with a five-drug second-line regimen, had an acceptable side-effect profile; reduced the time to sputum-culture conversion in patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis; and significantly increased the proportion of patients with negative sputum cultures after 8 weeks.

In conclusion, the safety and efficacy findings from this study clinically validate ATP synthase as a new target for antituberculosis therapy. The findings also confirm the earlier results obtained with TMC207 in the murine model of tuberculosis and show the potential of TMC207 in the treatment of patients with multidrug-resistant tuberculosis.

Source:  the New England Journal of Medicine Volume 360:2397-2405, June 4, 2009, Number 23