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Telacebec for ultra-short treatment of Buruli ulcer in a mouse model

Deepak V. Almeida, Paul J. Converse, Till F. Omansen, Sandeep Tyagi, Rokeya Tasneen, Jeongjun Kim, Eric L. Nuermberger
doi: https://doi.org/10.1101/2020.02.10.943175
Deepak V. Almeida
aCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Paul J. Converse
aCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Till F. Omansen
aCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
bInfectious Diseases Unit, Department of Internal Medicine, University of Groningen, Groningen, The Netherlands
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Sandeep Tyagi
aCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Rokeya Tasneen
aCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Jeongjun Kim
cQurient Co. Ltd., Korea
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Eric L. Nuermberger
aCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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  • For correspondence: enuermb@jhmi.edu
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ABSTRACT

Telacebec (Q203) is a new anti-tubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture-negative in 2 weeks. Combining Q203 with rifampin resulted in relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF+clarithromycin, the current standard of care, for 4 weeks.

The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2-10 mg/kg were culture-negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2 and 10 mg/kg were culture-negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics sub-study revealed that Q203 doses of 2-10 mg/kg in mice produce plasma concentrations similar to those produced by 100-300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations.

These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for cure to ≤ 1 week (or 5 doses of 2-10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 12, 2020.
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Telacebec for ultra-short treatment of Buruli ulcer in a mouse model
Deepak V. Almeida, Paul J. Converse, Till F. Omansen, Sandeep Tyagi, Rokeya Tasneen, Jeongjun Kim, Eric L. Nuermberger
bioRxiv 2020.02.10.943175; doi: https://doi.org/10.1101/2020.02.10.943175
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Telacebec for ultra-short treatment of Buruli ulcer in a mouse model
Deepak V. Almeida, Paul J. Converse, Till F. Omansen, Sandeep Tyagi, Rokeya Tasneen, Jeongjun Kim, Eric L. Nuermberger
bioRxiv 2020.02.10.943175; doi: https://doi.org/10.1101/2020.02.10.943175

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