The diarylquinoline TMC207 for multidrug-resistant tuberculosis.

Area of Science:

• Infectious Diseases
• Pharmacology

Background:

• TMC207 is a diarylquinoline with a novel mechanism of action against tuberculosis, inhibiting mycobacterial ATP synthase.
• It demonstrates potent activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis strains in vitro.
• Clinical studies show TMC207 exhibits bactericidal activity in patients with drug-susceptible pulmonary tuberculosis.

Purpose of the Study:

• To evaluate the efficacy and safety of TMC207 in combination with standard second-line therapy for multidrug-resistant pulmonary tuberculosis.
• To determine if TMC207 accelerates sputum culture conversion in patients with multidrug-resistant tuberculosis.

Main Methods:

• A two-stage, phase 2, randomized, controlled trial was conducted.
• 47 patients with newly diagnosed multidrug-resistant pulmonary tuberculosis were randomized to receive either TMC207 or placebo, combined with a standard five-drug regimen.
• The primary endpoint was the time to sputum culture conversion from positive to negative.

Main Results:

• TMC207 significantly reduced the time to sputum culture conversion compared to placebo (HR, 11.8; P=0.003).
• The proportion of patients achieving culture conversion was higher in the TMC207 group (48%) versus the placebo group (9%).
• Adverse events were mostly mild to moderate, with nausea being significantly more frequent in the TMC207 group.

Conclusions:

• The clinical efficacy of TMC207 supports ATP synthase as a validated therapeutic target for tuberculosis treatment.
• TMC207 demonstrates significant clinical activity in patients with multidrug-resistant tuberculosis.
• Further investigation into TMC207 as a treatment for tuberculosis is warranted.