Phase II anti-inflammatory and immune-modulating drugs for acute ischaemic stroke

Abstract

Introduction: Stroke is the second leading cause of death worldwide and the leading cause of adult neurological disability. Despite advances in stroke unit care, and increasing use of thrombolysis, there remains an urgent need for safe and effective treatments for acute ischaemic stroke. However, this is against a backdrop of multiple failures in translational drug development. Cerebral ischaemia initiates a complex cascade of immune and inflammatory pathways in the brain microvasculature and periphery, which contribute to the evolution of cerebral injury, resolution and repair. Targeting specific inflammatory or immune pathways, therefore, represents an attractive treatment strategy in acute ischaemic stroke. Although anti-inflammatory drugs have already failed in clinical trial development, several are currently at the Phase II developmental stage.

Areas covered: The authors highlight several candidate drugs, which modulate a range of inflammatory and immune pathways, and have been investigated in pre-clinical and Phase II studies to date.

Expert opinion: Drugs targeting inflammatory and immune pathways offer theoretical advantages including potentially longer therapeutic time windows and effects complementary to thrombolysis (ameliorating reperfusion injury). Fundamental changes in the approach to pre-clinical and clinical drug development are required to facilitate successful translation of promising candidate drugs into clinical practice.

Keywords:

• acute ischaemic stroke
• anti-inflammatory
• cerebral ischaemia
• inflammation
• translational research

Declaration of interest

CJ Smith is supported by Salford Royal NHS Foundation Trust; PJ Tyrrell is supported by the University of Manchester; A Denes is supported by OTKA K 109743, TÁMOP-4.2.4.A/2-11/1-2012-0001 and the Hungarian Brain Research Program KTIA_13_NAP-A-I/2. M Di Napoli is supported by the Italian National Health Service. PJ Tyrell was chief investigator, and CJ Smith a co- investigator, in the IV IL-1Ra stroke study (funded by Research into Ageing, provided by the UK Community Fund); PJ Tyrrell is the lead investigator, and CJ Smith a co-investigator in the SCIL-STROKE study (funded by the Stroke Association). The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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