Fingolimod

Fingolimod (FTY720, brand name Gilenya®, Novartis, Basel, Switzerland) is a sphingosine 1-phosphate (S1P) analogue used for the treatment of multiple sclerosis. S1P is a bioactive lipid released from activated platelets, erythrocytes, and endothelium. S1P binds the S1P receptors, which are G protein-coupled receptors (GPCRs) linked to immune responses, vascular integrity, cell differentiation, and cellular trafficking. Fingolimod has been shown to reduce stroke injury and improve outcomes in multiple models of experimental stroke in mice and rats. It has been tested in different therapeutic windows including pre-stroke (prophylactic treatment) and post-stroke with varying days of treatment (up to day 7).  At least fourteen studies have reported a brain protective effect evidenced by a reduction of infarct size after fingolimod administration. However, some groups have reported no benefit of fingolimod treatment. Moreover, it appears that fingolimod testing has been limited in female mice, aging, and with other key biological variables known to impact stroke outcomes and inflammatory responses after stroke.  Fingolimod has also been tested in a few small pilot studies in patients with acute ischemic stroke with positive findings.  These include trials with patients presenting greater than 4.5 hours from onset randomized to standard care versus the addition of fingolimod 0.5 mg daily for three days (NCT02002390), patients within three hours of onset randomized to tPA or tPA + fingolimod 0.5 mg daily for three days (NCT02002390), and patients 4.5-6 hours from onset randomized to tPA or tPA + fingolimod 0.5 mg daily for three days.

Fingolimod is an optimal candidate for testing through the SPAN network since (1) it is a FDA approved medication for multiple sclerosis, with extensive human safety experience and data, (2) it has shown benefit in multiple models of cerebral ischemia by different investigators worldwide, (3) multiple mechanisms of action likely to provide neuroprotection, including enhanced reperfusion, modulation of inflammatory responses, neuronal resistance to ischemia, and reduction in astrogliosis and white matter injury, (4) clear need to rigorously test in models that incorporate key biological variables including aging, female sex, and other stroke comorbidities, and (5) suitability for rapid translation to larger randomized, blinded, placebo-controlled trials in patients.

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