MICA: Potential of P2X7 receptor antagonism to attenuate the adverse consequences of neurotrauma (PROTECT)

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Traumatic brain injury (TBI) is commonly associated with falls, road traffic and assaults and has a massive impact upon the community; it is the leading cause of death and disability in the first four decades of life, costing the UK economy an estimated £8 billion per year.Current standard care centers upon neurosurgical intervention and stabilization, yet mortality is relatively high and many that survive suffer life-time disability. Despite the obvious unmet clinical need, there are no approved drugs available in the clinic to reduce the impact of TBI on the patient. Whilst it would be difficult for a drug to reduce the consequences of the initial injury, it is well recognised that the dead and dying brain tissue associated with the initial trauma gives rise to inflammation that spreads to surrounding brain tissue that may be damaged but not irreversibly. However, the added stress of inflammation to this adjacent brain tissue expands the volume of brain damage. This secondary non-mechanical brain damage begins over hours to days after the initial TBI event and is hence considered amenable to potential treatment with drugs. It is well recognized in the scientific literature that a drug target called the P2X7 receptor is involved in the physiological processes that stress brain tissue and can lead to brain cell death - indeed the term 'death receptor' has been coined for the P2X7 receptor. Initial activation of the P2X7 receptor causes excitation of brain cells resulting in their secretion of chemicals that increase inflammation, adding to the stress upon brain cells from the inflammatory environment post-TBI. With more prolonged activation of the P2X7 receptor, the receptor changes shape such that it forms relatively large pores in the cell membrane, which further stresses the cells and can lead to cell death. We believe that blocking the P2X7 receptor with a drug will put a brake on the processes contributing to stressing the brain cells and so help reduce the secondary brain damage subsequent to TBI. We predict this will improve the clinical outcomes for patients following TBI allowing more patients to survive and reduce disability. It is fortunate that, through a collaboration with the pharmaceutical company Pfizer, we will be able to use a drug, code name CE-224,535, that is selective in its ability to block the P2X7 receptor. In addition, clinical studies to date using CE-224,535 in healthy volunteers and patients with arthritis have shown that the drug is well tolerated following oral administration.Our studies will take a step-wise approach. We will first use small pieces of brain tissue from TBI patients undergoing neurosurgery - this brain tissue comes away from the brain during standard neurosurgical techniques and hence its collection does not change the outcome for the patient. Results from experiments with these cells will enable a prediction concerning the concentrations of CE-224,535 that need to get into the brain of patients with TBI to block the P2X7 receptor, which we predict will be beneficial for the patient.We will then perform a clinical trial with CE-224,535 given to TBI patients with the primary purpose of the clinical trial to assess whether CE-224,535 is well tolerated and reaches concentrations in the injured part of the brain that will block the P2X7 receptor. We will also monitor any effect of the drug on biological chemicals that act as markers for cell damage and inflammation and monitor the clinical condition of the patient and follow up the patient after 28 days. Importantly, even if benefit for the patients is not overt possibly due to the relatively small number of patients studied, the outcomes will better inform the design of larger clinical trials that directly assess the potential of CE-224,535 (and other drugs that also block the P2X7 receptor) to benefit patients with TBI.