Tuberculosis

Telacebec (Q203), a New Antituberculosis Agent

To the Editor:

Shortly after the discovery of streptomycin in 1943, it became clear that successful treatment of tuberculosis and prevention of drug resistance required a combination of at least three effective drugs. What followed in the 1950s was the introduction of triple therapy with streptomycin, aminosalicylic acid, and isoniazid, the so-called 100% effective regimen and a major milestone on the path to modern antimicrobial therapy.1,2

After the stepwise introduction of more potent agents and massive efforts toward tuberculosis control, the disease that once killed one in four persons became a seemingly distant threat in many countries. However, an increasing prevalence of drug resistance has made the goal of global elimination of tuberculosis a far-removed prospect once more. New drugs and regimens are needed to ensure continued progress toward this goal.

Telacebec (Q203) is a novel first-in-class antituberculosis drug that targets Mycobacterium tuberculosis cellular energy production through inhibition of the mycobacterial cytochrome bc1 complex. In vitro, depletion of ATP synthesis resulted in cell death regardless of the replication status of the bacteria.3 For proof of concept in humans, we conducted a phase 2, prospective, randomized, open-label trial involving 61 patients with newly diagnosed, rifampin- and isoniazid-susceptible pulmonary tuberculosis (ClinicalTrials.gov number, NCT03563599). Patients were assigned to receive 14 days of oral telacebec at a dose of 100 mg, 200 mg, or 300 mg once daily or combination therapy with rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). Serial (16-hour) sputum samples were collected daily, and time to positivity for microbial growth in liquid culture was measured in hours (BACTEC MGIT 960 System, Becton Dickinson). We created a linear mixed-effects model of the daily change in log10 time to positivity to determine bactericidal activity. (The protocol is available with the full text of this letter at NEJM.org.)

Early Bactericidal Activity of Telacebec at Increasing Doses.

Shown is the 14-day early bactericidal activity of telacebec (Q203) at a dose of 100 mg, 200 mg, or 300 mg once daily and of combination therapy with rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE) (Rifafour e-275, Sanofi-Aventis), expressed as the rate of change in the log10 time to positivity for microbial growth in liquid culture. For each group, the darker blue line represents the mean, and the lighter blue bands represent the 95% confidence interval. The figure shows the on-treatment findings, from day 1, with the pretreatment values for time to positivity included as covariates in the model. The four groups had similar pretreatment values for time to positivity.

Increasing doses of telacebec were associated with greater reductions in viable mycobacterial sputum load (Figure 1). We found a daily increase in log10 time to positivity of 0.0036 (95% confidence interval [CI], 0.0013 to 0.0060), 0.0087 (95% CI, 0.0064 to 0.0110), and 0.0135 (95% CI, 0.0112 to 0.0158) for telacebec at a dose of 100 mg, 200 mg, and 300 mg, respectively. The RHZE group validated the quantitative culture methods with an increase of 0.0207 (95% CI, 0.0176 to 0.0284). Telacebec was associated with acceptable adverse-event rates, and adverse events were equally distributed among all groups. There were no serious adverse drug reactions and no adverse drug reactions that resulted in early withdrawal from the study.

After the diarylquinoline bedaquiline4 and the nitroimidazoles delamanid5 and pretomanid, telacebec is the third modern new drug class with proven antituberculosis activity in humans. This opens the door to a new era of clinical trials working toward the first all-new pan-tuberculosis regimen of the 21st century, making the distinction between drug-susceptible and drug-resistant tuberculosis obsolete. The findings from this study support further development of telacebec and continued research into its role as part of a novel tuberculosis regimen.

Veronique R. de Jager, M.B., Ch.B., M.P.H.
TASK Applied Science, Cape Town, South Africa
[email protected]

Rodney Dawson, M.B., Ch.B.
University of Cape Town Lung Institute, Cape Town, South Africa

Christo van Niekerk, M.B., Ch.B.
Jane Hutchings, B.Pharm.
Jeongjun Kim, M.Pharm.
Qurient, Seongnam, South Korea

Naadira Vanker, M.B., Ch.B.
TASK Laboratory, Cape Town, South Africa

Lize van der Merwe, Ph.D.
TASK Applied Science, Cape Town, South Africa

Jinho Choi, M.Pharm.
Kiyean Nam, Ph.D.
Qurient, Seongnam, South Korea

Andreas H. Diacon, M.D., Ph.D.
Stellenbosch University, Cape Town, South Africa

Supported by a grant from the Korea Drug Development Fund.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

  1. 1. Fox W. The chemotherapy of pulmonary tuberculosis: a review. Chest 1979;76:Suppl:785796.

  2. 2. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999;3:Suppl 2:S231S279.

  3. 3. Pethe K, Bifani P, Jang J, et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 2013;19:11571160.

  4. 4. Rustomjee R, Diacon AH, Allen J, et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob Agents Chemother 2008;52:28312835.

  5. 5. Diacon AH, Dawson R, Hanekom M, et al. Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients. Int J Tuberc Lung Dis 2011;15:949954.

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