Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen

Natasha Strydom; Jacqueline P. Ernest; Marjorie Imperial; Belén P. Solans; Qianwen Wang; Rokeya Tasneen; Sandeep Tyagi; Heena Soni; Andrew Garcia; Kristina Bigelow; Martin Gengenbacher; Matthew Zimmerman; Min Xie; Jansy P. Sarathy; Tian J. Yang; Véronique Dartois; Eric L. Nuermberger; Radojka M. Savic

doi:10.1038/s41467-024-50781-4

Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen

Natasha Strydom, Jacqueline P. Ernest, Marjorie Imperial, Belén P. Solans, Qianwen Wang, Rokeya Tasneen, Sandeep Tyagi, Heena Soni, Andrew Garcia, Kristina Bigelow, Martin Gengenbacher, Matthew Zimmerman, Min Xie, Jansy P. Sarathy, Tian J. Yang, Véronique Dartois, Eric L. Nuermberger, Radojka M. Savic

Center for Discovery and Innovation

Hackensack Meridian School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid. A translational platform incorporating linezolid and BPaL data from preclinical experiments and 4 clinical trials (NCT00396084, NCT02333799, NCT03086486, NCT00816426) is developed, enabling validation of the framework. TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200–2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.

Original language	English
Article number	7311
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-50781-4
State	Published - Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-024-50781-4

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Strydom, N., Ernest, J. P., Imperial, M., Solans, B. P., Wang, Q., Tasneen, R., Tyagi, S., Soni, H., Garcia, A., Bigelow, K., Gengenbacher, M., Zimmerman, M., Xie, M., Sarathy, J. P., Yang, T. J., Dartois, V., Nuermberger, E. L., & Savic, R. M. (2024). Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen. Nature communications, 15(1), Article 7311. https://doi.org/10.1038/s41467-024-50781-4

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title = "Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen",

abstract = "TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid. A translational platform incorporating linezolid and BPaL data from preclinical experiments and 4 clinical trials (NCT00396084, NCT02333799, NCT03086486, NCT00816426) is developed, enabling validation of the framework. TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200–2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.",

author = "Natasha Strydom and Ernest, {Jacqueline P.} and Marjorie Imperial and Solans, {Bel{\'e}n P.} and Qianwen Wang and Rokeya Tasneen and Sandeep Tyagi and Heena Soni and Andrew Garcia and Kristina Bigelow and Martin Gengenbacher and Matthew Zimmerman and Min Xie and Sarathy, {Jansy P.} and Yang, {Tian J.} and V{\'e}ronique Dartois and Nuermberger, {Eric L.} and Savic, {Radojka M.}",

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doi = "10.1038/s41467-024-50781-4",

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Strydom, N, Ernest, JP, Imperial, M, Solans, BP, Wang, Q, Tasneen, R, Tyagi, S, Soni, H, Garcia, A, Bigelow, K, Gengenbacher, M , Zimmerman, M, Xie, M, Sarathy, JP, Yang, TJ, Dartois, V, Nuermberger, EL & Savic, RM 2024, 'Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen', Nature communications, vol. 15, no. 1, 7311. https://doi.org/10.1038/s41467-024-50781-4

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T1 - Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen

AU - Strydom, Natasha

AU - Ernest, Jacqueline P.

AU - Imperial, Marjorie

AU - Solans, Belén P.

AU - Wang, Qianwen

AU - Tasneen, Rokeya

AU - Tyagi, Sandeep

AU - Soni, Heena

AU - Garcia, Andrew

AU - Bigelow, Kristina

AU - Gengenbacher, Martin

AU - Zimmerman, Matthew

AU - Xie, Min

AU - Sarathy, Jansy P.

AU - Yang, Tian J.

AU - Dartois, Véronique

AU - Nuermberger, Eric L.

AU - Savic, Radojka M.

PY - 2024/12

Y1 - 2024/12

N2 - TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid. A translational platform incorporating linezolid and BPaL data from preclinical experiments and 4 clinical trials (NCT00396084, NCT02333799, NCT03086486, NCT00816426) is developed, enabling validation of the framework. TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200–2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.

AB - TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid. A translational platform incorporating linezolid and BPaL data from preclinical experiments and 4 clinical trials (NCT00396084, NCT02333799, NCT03086486, NCT00816426) is developed, enabling validation of the framework. TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200–2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.

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JF - Nature communications

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ER -

Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen

Abstract

ASJC Scopus subject areas

UN SDGs

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