(MRC DTP) Evaluation of combined anakinra and thrombolysis treatment for ischaemic stroke

Stroke is a leading cause of mortality and morbidity worldwide with limited treatment options. The only licensed drug treatment for stroke is recombinant tissue plasminogen activator (rtPA), with endovascular thrombectomy recently being shown as an alternative approach that improves outcome. While these reperfusion strategies can be effective in eligible patients this represents a small percentage (~20%) of the overall stroke population, and they are not applicable in haemorrhagic stroke. New, more widely available treatments, ideally that could be used in all stroke sub-types, are therefore required.

We and others have shown that interleukin-1 (IL-1) is a key mediator of neuronal injury and that blocking IL-1 actions with the IL-1 receptor antagonist (anakinra) is protective in different stroke models and that early stage clinical trials of anakinra in both ischaemic and haemorrhagic stroke are promising. Indeed anakinra has some of the strongest available evidence to support its use in stroke compared to any other drug in current development and a phase III study in subarachnoid haemorrhage commences in October 2018.

Our recent Phase 2 study of anakinra in ischaemic stroke revealed that, compared to placebo, anakinra improved clinical outcome by reducing inflammation. However, analysis also revealed an alternative pathway leading to worse outcome, and we cannot rule out that co-administration of rtPA with anakinra might contribute to this. There is therefore an urgent need to explore any potential interaction between rtPA and anakinra in more detail before anakinra can be further developed as a new treatment in ischaemic stroke. To achieve this we will use rodent models of thromboembolic stroke to identify if the timing of treatment with anakinra in relation to rtPA is key, whether the degree of reperfusion is important or whether any interaction is limited to thrombolysis with rtPA. In addressing these questions we will have identified the need for a specific dosing regimen that is required for combined treatment and/or an alternative thrombolytic to rtPA in future clinical trials of anakinra in ischaemic stroke.

https://www.research.manchester.ac.uk/portal/stuart.allan.html
https://www.research.manchester.ac.uk/portal/craig.smith-2.html

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.