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Qualifying a human Liver-Chip for predictive toxicology: Performance assessment and economic implications

View ORCID ProfileLorna Ewart, View ORCID ProfileAthanasia Apostolou, Skyler A. Briggs, View ORCID ProfileChristopher V. Carman, Jake T. Chaff, Anthony R. Heng, Sushma Jadalannagari, View ORCID ProfileJeshina Janardhanan, Kyung-Jin Jang, Sannidhi R. Joshipura, Mahika M. Kadam, View ORCID ProfileMarianne Kanellias, View ORCID ProfileVille J. Kujala, View ORCID ProfileGauri Kulkarni, Christopher Y. Le, View ORCID ProfileCarolina Lucchesi, View ORCID ProfileDimitris V. Manatakis, Kairav K. Maniar, Meaghan E. Quinn, View ORCID ProfileJoseph S. Ravan, Ann Catherine Rizos, John F.K. Sauld, Josiah D. Sliz, William Tien-Street, Dennis Ramos Trinidad, James Velez, Max Wendell, Onyi Irrechukwu, View ORCID ProfilePrathap Kumar Mahalingaiah, View ORCID ProfileDonald E. Ingber, Jack W. Scannell, Daniel Levner
doi: https://doi.org/10.1101/2021.12.14.472674
Lorna Ewart
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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  • For correspondence: lorna.ewart@emulatebio.com
Athanasia Apostolou
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Skyler A. Briggs
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Christopher V. Carman
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Jake T. Chaff
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Anthony R. Heng
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Sushma Jadalannagari
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Jeshina Janardhanan
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Kyung-Jin Jang
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Sannidhi R. Joshipura
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Mahika M. Kadam
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Marianne Kanellias
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Ville J. Kujala
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Gauri Kulkarni
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Christopher Y. Le
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Carolina Lucchesi
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Dimitris V. Manatakis
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Kairav K. Maniar
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Meaghan E. Quinn
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Joseph S. Ravan
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Ann Catherine Rizos
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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John F.K. Sauld
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Josiah D. Sliz
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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William Tien-Street
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Dennis Ramos Trinidad
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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James Velez
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Max Wendell
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Onyi Irrechukwu
2Janssen Pharmaceuticals, Spring House, Philadelphia, PA, United States
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Prathap Kumar Mahalingaiah
3Investigative Toxicology and Pathology, Abbvie, North Chicago, IL, United States
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Donald E. Ingber
4Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
5Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United States
6Vascular Biology Program and Department of Surgery, Harvard Medical School and Boston Children’s Hospital, Boston, MA, United States
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Jack W. Scannell
7JW Scannell Analytics LTD, 32 Queens Crescent, Edinburgh, EH9 2BA, United Kingdom
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Daniel Levner
1Emulate Inc., 27 Drydock Avenue, Boston, MA, United States
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Abstract

Human organ-on-a-chip (Organ-Chip) technology has the potential to disrupt preclinical drug discovery and improve success in drug development pipelines as it can recapitulate organ-level pathophysiology and clinical responses. The Innovation and Quality (IQ) consortium formed by multiple pharmaceutical and biotechnology companies to confront this challenge has published guidelines that define criteria for qualifying preclinical models, however, systematic and quantitative evaluation of the predictive value of Organ-Chips has not yet been reported. Here, 870 Liver-Chips were analyzed to determine their ability to predict drug-induced liver injury (DILI) caused by small molecules identified as benchmarks by the IQ consortium. The Liver-Chip met the qualification guidelines across a blinded set of 27 known hepatotoxic and non-toxic drugs with a sensitivity of 87% and a specificity of 100%. A computational economic value analysis suggests that with this performance the Liver-Chip could generate $3 billion annually for the pharmaceutical industry due to increased R&D productivity.

Competing Interest Statement

L.E., D.L., D.V.M., J.D.S., A.A., S.A.B., J.T.C., C.V.C., A.R.H., J.J., S.J., S. R. J., J.F.K.S., M.M.K., M.K., K.K.M., M.E.Q., A.C.R., W.T., M.W., G.K., V.J.K., C.Y.L., C. L., J.S.R., D.R.T., J.V., K-J.J. are employees or former employees of Emulate Inc. and may hold equity; D.E.I. is a founder, board member, SAB chair, and equity holder in Emulate Inc. J.W.S. is a shareholder and director of JW Scannell Analytics LTD and received payment from Emulate Inc. for contributing to this work.

Footnotes

  • Additional data on a third hepatocyte donor has been added as well as additional information regarding the economic model is included. Consequently Jack Scannell has been added as an author.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 02, 2022.
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Qualifying a human Liver-Chip for predictive toxicology: Performance assessment and economic implications
Lorna Ewart, Athanasia Apostolou, Skyler A. Briggs, Christopher V. Carman, Jake T. Chaff, Anthony R. Heng, Sushma Jadalannagari, Jeshina Janardhanan, Kyung-Jin Jang, Sannidhi R. Joshipura, Mahika M. Kadam, Marianne Kanellias, Ville J. Kujala, Gauri Kulkarni, Christopher Y. Le, Carolina Lucchesi, Dimitris V. Manatakis, Kairav K. Maniar, Meaghan E. Quinn, Joseph S. Ravan, Ann Catherine Rizos, John F.K. Sauld, Josiah D. Sliz, William Tien-Street, Dennis Ramos Trinidad, James Velez, Max Wendell, Onyi Irrechukwu, Prathap Kumar Mahalingaiah, Donald E. Ingber, Jack W. Scannell, Daniel Levner
bioRxiv 2021.12.14.472674; doi: https://doi.org/10.1101/2021.12.14.472674
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Qualifying a human Liver-Chip for predictive toxicology: Performance assessment and economic implications
Lorna Ewart, Athanasia Apostolou, Skyler A. Briggs, Christopher V. Carman, Jake T. Chaff, Anthony R. Heng, Sushma Jadalannagari, Jeshina Janardhanan, Kyung-Jin Jang, Sannidhi R. Joshipura, Mahika M. Kadam, Marianne Kanellias, Ville J. Kujala, Gauri Kulkarni, Christopher Y. Le, Carolina Lucchesi, Dimitris V. Manatakis, Kairav K. Maniar, Meaghan E. Quinn, Joseph S. Ravan, Ann Catherine Rizos, John F.K. Sauld, Josiah D. Sliz, William Tien-Street, Dennis Ramos Trinidad, James Velez, Max Wendell, Onyi Irrechukwu, Prathap Kumar Mahalingaiah, Donald E. Ingber, Jack W. Scannell, Daniel Levner
bioRxiv 2021.12.14.472674; doi: https://doi.org/10.1101/2021.12.14.472674

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