MICA: Efficacy and safety evaluation of AZD1236 (Matrix metalloproteinase 9 & 12 inhibitor) in experimental stroke

Lead Research Organisation: University of Sheffield
Department Name: Neurosciences

Abstract

Stroke is a devastating neurological disease for which we have limited treatment options. Most strokes are caused by blockage of a blood vessel in the brain with clot. The clot busting medication, tissue plasminogen activator (t-PA) is only administered to a small select minority of stroke patients because most patients don't arrive in hospital early enough to be eligible for this treatment. In addition, many patients can't receive t-PA because they are taking certain medications or have medical conditions that make them ineligible for this therapy. Despite its beneficial effects overall, t-PA can have dangerous side-effects which can worsen symptoms. There is, therefore, an urgent need for new treatments.

We are proposing a novel solution which entails repurposing a drug called AZD1236 which was originally developed for chronic obstructive pulmonary disease (COPD) by a pharmaceutical company (AstraZeneca). This drug inhibits enzymes called matrix metalloproteinases (MMPs) which have a range of functions in normal health but in diseases such as stroke, these enzymes destroy connective tissue leading to the breakdown of the protective seal around the brain called the blood brain barrier (BBB). This break of the protective seal leads to brain swelling, enhanced brain injury and poorer outcomes. MMP activation can also increase the risk of serious bleeding after t-PA. Inhibition of MMPs using a potent and safe drug could protect the brain from stroke and improve outcomes after stroke.

MMPs are a family of enzymes and not all of them are involved in stroke related brain injury. Considerable work done in our laboratory and in other laboratories around the world using cell and animal models of stroke have shown that MMP-9 is activated during stroke and helps to break down the BBB, promotes injury to the brain and leads to poorer outcomes. In animal and cell models of stroke, inhibiting MMP-9 leads to better outcomes. More recently, MMP-12 has also been shown to promote brain injury after stroke by direct effects of its own and by facilitating MMP-9. Interestingly, inhibition of MMP-12 reduces brain injury in animal models of stroke.

AZD1236 is a unique drug in that it is a potent inhibitor of both MMP-9 and MMP-12 and has not been tested for efficacy in stroke models. A big advantage of AZD1236 is that it has no side-effects when used short-term which also opens up the possibility that it could be administered by the ambulance service before the patient is transferred to hospital. Since 'time is brain' early treatment could result in saving more brain from stroke injury.

In the series of experiments proposed in this application, we will test AZD1236 for efficacy in several stroke models. We will initially test in young male mice for proof of concept. If those experiments show efficacy and safety, we will then test in old and female animals since stroke also affects women and elderly individuals. Since many stroke patients are overweight, we will also test the drug in obese mice. Moreover, we will evaluate the effect of combining AZD1236 with t-PA, looking for synergy or any adverse effects. Using MRI and histology tests we will also assess the influence of AZD1236 on the BBB.

The series of experiments that we have proposed will generate the needed data that will allow us to evaluate whether AZD1236 should be progressed along the pathway of development which will ultimately lead to testing in humans.

Technical Summary

An urgent need exists for new acute stroke therapies. The only approved treatment for ischaemic stroke is recombinant tissue plasminogen activator (t-PA), but the benefits of t-PA are limited by a short treatment time window, low rates of reperfusion, and the potential for haemorrhagic transformation. We, and others, have shown that matrix metalloproteinases (MMPs), especially MMP-9 play a key role in the cascade of pathological processes that are activated by cerebral ischaemia. These processes include disruption of the blood brain barrier (BBB). This exacerbates brain oedema and potentiates ischaemic cell injury leading to widespread cell death. Moreover, MMP-9 increases risk of haemorrhagic transformation after thrombolysis resulting in poorer outcomes. Published data have shown that inhibition of MMP-9 is highly protective in experimental stroke.

Recent studies also suggest that MMP-12 may play a deleterious role in stroke directly, and by also enhancing MMP-9 activity. Since both MMP-9 and MMP-12 play important (and potentially synergistic) roles in stroke, inhibition of both MMPs could be a powerful treatment for acute stroke.

In collaboration with AstraZeneca, we advance a series of proof of concept studies to evaluate the efficacy and safety in experimental stroke of a novel MMP-9 and MMP-12 inhibitor, AZD1236 which was originally developed for the treatment of chronic obstructive pulmonary disease and is a phase 2-ready compound for an acute indication such is stroke.

Using mouse middle cerebral artery occlusion (MCAO) models, we will:
1. Determine the pharmacokinetics, efficacy and safety of AZD1236 in a number of experimental models of stroke
2. Determine the effect of AZD1236 on MMP expression and activity in brain and serum
3. Determine the effect of AZD1236 on BBB integrity using histology and 7-T MRI

Successful completion of these studies will establish whether further preclinical development of this compound is warranted.

Planned Impact

The ultimate aim of this research project is to repurpose an AstraZeneca small molecule (AZD1236) for potential use in acute ischaemic stroke treatment. There is an urgent medical need for new drugs and therapies for stroke that are more efficacious and/or have a longer therapeutic window for treatment.

In this preclinical proposal, we will generate relevant efficacy and safety data of the compound in various animal models of ischaemic stroke that will allow us to evaluate whether this drug should be developed further for treating stroke.

This research has the potential to impact on stroke patients, relatives (caregivers), healthcare providers, health service payers as well as the general scientific and medical communities.

The main beneficiary group from this research will be the patient population who suffer strokes. An effective agent for stroke therapy could be used to prevent and/or reduce neurological damage during stroke which otherwise would result in disability or even fatality.

The translational and medical research communities will also benefit from the training and knowledge that this project will generate by enhancing our understanding of an important pathological pathway that causes injury to the brain during stroke.

If the drug is approved for use in patients, the NHS and other health care providers around the world will benefit from the significant economic impact relating to the anticipated reduction in healthcare costs due to reduction in disability. This will result in less time spent in hospitals to rehabilitate, an earlier return to work and economic productivity, which will help the wider economy in general.

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