Evaluation of combined anakinra and thrombolysis treatment for ischaemic stroke' to 'Targeting interleukin-1 as a therapy for neurological diseases

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. 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 commenced 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. Therefore, the overall aim of this project is to understand the relationship between rtPA and anakinra treatment in ischaemic stroke, using clinically relevant rodent models of thromboembolic stroke.

The primary objectives are to:
(1) Establish if any postulated interaction between anakinra and rtPA in clinical studies can be replicated in rodent models of thromboembolic stroke
(2) Establish the optimal timings of anakinra and rtPA treatment and if reperfusion is important
(3) Further explore the therapeutic potential of anakinra in other neurological diseases beyond rtPA administration

We will use well-described thromboembolic stroke models in mice with imaging, functional and histopathological outcomes being assessed. In parallel to the in vivo stroke studies we will also determine in vitro whether there is any direct interactions between anakinra and rtPA.

In addressing the objectives we will have identified the need for a specific dosing regimen that is required for combined treatment in future clinical trials of anakinra.