TMC207: The First Compound of a New Class of Potent Anti-tuberculosis Drugs

Alberto Matteelli; Anna CC Carvalho; Kelly E Dooley; Afranio Kritski

Disclosures

Future Microbiol. 2010;5(6):849-858. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

Disease caused by Mycobacterium tuberculosis continues as a global epidemic, with more than 9 million new cases each year and nearly 2 million deaths.[1] In addition, over 2 billion people harbor latent TB infection (LTBI), thus representing an enormous reservoir of M. tuberculosis that can subsequently progress to active disease and spread. The directly observed therapy strategy launched in 1993 (consisting of five key elements: government commitment, diagnosis through bacteriology, standardized and supervised treatment, uninterrupted drug supply and regular program monitoring) has greatly contributed to the improvement of global TB control over the last 15 years.[2–4] Standardized treatment for active TB consists of a 2-month intensive phase with four anti-TB drugs, namely rifampicin, isoniazid, pyrazinamide and ethambutol, followed by a 4-month continuation phase with rifampicin and isoniazid. Although capable of achieving a cure rate of 85% or more at a global level,[1] this regimen is lengthy, cumbersome and requires considerable efforts to ensure patient adherence and treatment completion. Similarly, the current therapeutic standard for the treatment of LTBI is isoniazid for 6–9 months, but completion rates are unacceptably low, ranging from 20 to 70%. Of note, the majority of patients with LTBI are healthy individuals who may never experience progression to active disease, even in the absence of LTBI treatment.

The new global STOP-TB strategy, launched in 2006, reiterates the central importance of standardized TB treatment, while recognizing that the emergence of drug resistance constitutes a real threat to TB control and elimination.[101] Multidrug-resistant (MDR)-TB is defined as TB caused by M. tuberculosis strains that are resistant to, at least, the two most powerful first-line anti-TB drugs, isoniazid and rifampicin; extensively drug-resistant (XDR)-TB refers to a form of disease caused by strains of M. tuberculosis that are resistant to isoniazid and rifampicin, in addition to any fluoroquinolone, and to at least one of the three following injectable drugs: capreomycin, kanamycin or amikacin.[5,6] Over 500,000 new cases of MDR-TB occur each year, and prevalent cases are estimated at over 1 million.[1] Although their number is currently unknown, XDR cases are recognized in every setting where there has been the capacity to detect them. Mathematical models show that the MDR- and XDR-TB epidemics have the potential to further expand, thus threatening all gains in TB control over recent decades.[7–9]

The future is therefore in our hands and will depend on our capacity, first, to prevent the emergence of additional drug resistance through sound TB control efforts and, second, to effectively diagnose and cure existing MDR- and XDR-TB cases.[10] Our success will depend on the development of new anti-TB agents designed to achieve four major objectives:

  • Shorten treatment duration

  • Increase adherence by enabling intermittent therapy

  • Introduce agents with novel mechanisms of action to ensure activity against drug-resistant M. tuberculosis

  • Decrease incidence by developing safer, shorter duration treatment regimens for LTBI

For the first time in decades, the pipeline of new anti-TB agents is growing.[11–14] TMC207 is among three new compounds in Phase II studies and is especially promising owing to its novel mechanism of action, activity against drug-sensitive and drug-resistant TB, and potential for treatment shortening in preclinical studies.

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