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Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury

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Neurotherapeutics

Abstract

Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain structures, likely contributes to these failures. Biomarkers have been recommended to identify patients with relevant pathology (predictive biomarkers) and confirm target engagement and monitor therapy response (pharmacodynamic biomarkers). Our group focuses on traumatic cerebrovascular injury as an understudied endophenotype of TBI and is validating a predictive and pharmacodynamic imaging biomarker (cerebrovascular reactivity; CVR) in moderate-severe TBI. We aim to extend these studies to milder forms of TBI to determine the optimal dose of sildenafil for maximal improvement in CVR. We will conduct a phase II dose-finding study involving 160 chronic TBI patients (mostly mild) using three doses of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The study measures baseline CVR and evaluates the effect of escalating sildenafil doses on CVR improvement. A 4-week trial of thrice daily sildenafil will assess safety, tolerability, and clinical efficacy. This dual-site 4-year study, funded by the Department of Defense and registered in ClinicalTrials.gov (NCT05782244), plans to launch in June 2023. Biomarker-informed RCTs are essential for developing effective TBI interventions, relying on an understanding of underlying pathomechanisms. Traumatic microvascular injury (TMVI) is an attractive mechanism which can be targeted by vaso-active drugs such as PDE-5 inhibitors. CVR is a potential predictive and pharmacodynamic biomarker for targeted interventions aimed at TMVI. (Trial registration: NCT05782244, ClinicalTrials.gov).

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Data Availability

Data will be available through the Federal Interagency Traumatic Brain Injury Reserarch (FITBIR) database.

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Acknowledgements

We would like to acknowledge funding from the US Army Medical Research and Development Command (USAMRDC)’s Fiscal Year 2021 Clinical Trial Award from the TBI and Psychological Health Research Program (TBIPHRP) TP210611 (W81XWH-22-C-0139).

Funding

We would also like to acknowledge prior funding from the Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences.

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Authors and Affiliations

  1. Department of Neurology, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA, 19104, USA

    Priyanka Kalyani & Ramon Diaz-Arrastia

  2. Walter Reed National Military Medical Center, The National Intrepid Center of Excellence, Palmer Rd S, Bethesda, MD, 20814, USA

    Sara M. Lippa, J. Kent Werner & Franck Amyot

  3. Department of Neuroscience, Uniformed Services University Health Sciences, 4301, Jones Bridge Rd, Bethesda, MD, 20814, USA

    Sara M. Lippa, J. Kent Werner, Carol B. Moore & Kimbra Kenney

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  1. Priyanka Kalyani
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Kalyani, P., Lippa, S.M., Werner, J.K. et al. Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury. Neurotherapeutics 20, 1629–1640 (2023). https://doi.org/10.1007/s13311-023-01430-z

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