Sphingosine 1-Phosphate Receptor Modulators as a Potential Treatment Option in COVID-19 Induced Acute Respiratory Distress Syndrome: Mechanistic Insights and Benefit-Risk Assessment

ABSTRACT

Introduction: Coronavirus disease 2019 (COVID-19) is a viral infection caused by a newly emergent coronavirus, SARS-CoV-2, primarily affecting the respiratory tract. Maladjusted immune responses, e.g. cytokine release syndrome, may result in immunopathology and acute respiratory distress syndrome (ARDS). Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, is crucial in maintaining endothelial cell chemotaxis and barrier integrity (Table 1). An industry- independent clinical study is currently underway in China investigating the efficacy of oral fingolimod 0.5 mg (a non selective S1P receptor modulator) taken once-daily, for three consecutive days in patients with COVID-19. Methods: Here we review the potential mechanisms by which fingolimod may regulate the inflammatory response to SARS-CoV-2 and assess the potential benefit-risk of short-term treatment with fingolimod in patients with COVID- 19 experiencing ARDS. Results: The key hypotheses through which beneficial effects manifest are (1) attenuation of cytokine release via activation of serine/threonine protein phosphatase 2A (PP2A);(2) inhibition of Th17-mediated pathway;and (3) enhancement of the pulmonary endothelial barrier via c-Abl tyrosine kinase pathway (Table 2). The short-term intervention with fingolimod might rapidly attenuate maladjusted immune responses while sparing memory immune responses and thus has relatively low risk of infections. Any potential effects on heart rate and cardiac rhythm could be managed under the intensive care treatment setting. Furthermore, simulations from a PKPD model of lymphocyte count data with short-term fingolimod treatment will be presented. Conclusions: S1P receptor modulators, such as fingolimod, may represent a potential treatment option to ameliorate immune responses against SARS-CoV-2 and merit further investigation following careful benefit-risk evaluation in this setting. (Table Presented) .