Advancing precision medicine for acute respiratory distress syndrome

Jeremy R Beitler, B Taylor Thompson, Rebecca M Baron, Julie A Bastarache, Loren C Denlinger, Laura Esserman, Michelle N Gong, Lisa M LaVange, Roger J Lewis, John C Marshall, Thomas R Martin, Daniel F McAuley, Nuala J Meyer, Marc Moss, Lora A Reineck, Eileen Rubin, Eric P Schmidt, Theodore J Standiford, Lorraine B Ware, Hector R Wong, Neil R Aggarwal, Carolyn S Calfee, Jeremy R Beitler, B Taylor Thompson, Rebecca M Baron, Julie A Bastarache, Loren C Denlinger, Laura Esserman, Michelle N Gong, Lisa M LaVange, Roger J Lewis, John C Marshall, Thomas R Martin, Daniel F McAuley, Nuala J Meyer, Marc Moss, Lora A Reineck, Eileen Rubin, Eric P Schmidt, Theodore J Standiford, Lorraine B Ware, Hector R Wong, Neil R Aggarwal, Carolyn S Calfee

Abstract

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.

Conflict of interest statement

Declaration of interests JRB reports grants from the US National Institutes of Health (NIH) and Quantum Leap Healthcare Collaborative and personal fees from Sedana Medical and Hamilton Medical, outside of the submitted work. BTT reports grants from NIH and personal fees from Bayer, Novartis, and Thetis, outside of the submitted work. RMB reports grants from NIH and personal fees from Merck and Genentech, outside of the submitted work. JAB reports grants from NIH, outside of the submitted work. LCD reports grants from NIH, grants and personal fees from AstraZeneca, and personal fees from Sanofi-Regeneron, outside of the submitted work. LE reports being an uncompensated board member of Quantum Leap Healthcare Collaborative. MNG reports grants from NIH and the Agency for Healthcare Research and Quality, outside of the submitted work. RJL is the senior medical scientist at Berry Consultants, a statistical consulting firm that specialises in innovative clinical trial design, including Bayesian adaptive and platform trial designs. JCM is chair of the International Forum for Acute Care Trialists, and reports personal fees from AM Pharma, Gilead Pharmaceuticals, and the Society of Critical Care Medicine, outside of the submitted work. TRM reports personal fees from Novartis Pharmaceuticals, Translate Bio, NIH, the Gates Foundation, and TVM Capital Life Science, outside of the submitted work. DFM reports personal fees for consultancy from GlaxoSmithKline, Boehringer Ingelheim, Bayer, and Novartis, and he holds a patent issued to his institution for a treatment for acute respiratory distress syndrome (ARDS), outside of the submitted work. NJM reports grants from NIH, Athersys, the Marcus Foundation, BioMarck, and Quantum Leap Healthcare Collaborative, outside of the submitted work. MM reports grants from NIH, outside of the submitted work. ER is the president of the ARDS Foundation. EPS reports grants from NIH and equity interest in IHP Therapeutics, outside of the submitted work. LBW reports personal fees from Merck, Bayer, Boehringer Ingelheim, CSL Behring, Quark, Foresee Pharmaceuticals, and Citius, and grants from CSL Behring and Genentech, outside of the submitted work. HRW reports grants from NIH and holds a patent for sepsis biomarkers for prognostic and predictive enrichment. CSC reports grants from NIH and Quantum Leap Healthcare Collaborative, grants and personal fees from Genentech and Bayer, and personal fees from Quark Pharmaceuticals, Prometric, Gen1e Life Sciences, and Vasomune, outside of the submitted work. The other authors declared no conflicts of interest.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Figures

Figure
Figure
Proposed research schema to advance precision medicine pharmacotherapy in acute respiratory distress syndrome *Phase 2 and 3 trials might use a platform design if multiple candidate therapies are deemed ready for testing and amenable to a platform. Other trial designs might also be considered. The number of simultaneous arms need not be constant and might depend on resources, enrolment rate, and number and priority of candidate treatments, among other factors. †Biomarker signatures are denoted by coloured arrows.

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