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

Lead Research Organisation: University of Birmingham
Department Name: Institute of Clinical Sciences

Abstract

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.

Technical Summary

Traumatic brain injury (TBI) is the leading cause of death and disability in the first four decades of life; despite obvious need, there is no approved drug treatment. Activation of the excitatory P2X7 receptor in the brain by relatively high levels of ATP - as likely occur in TBI - promotes an inflammatory environment that may add to the volume of brain damage above that from the primary insult. Also, animal models of neurotrauma respond favourably to P2X7 receptor antagonists. Hence, our hypothesis is that the inflammation and secondary brain damage that evolves hours/days after the primary insult is reduced by blocking the P2X7 receptor. We propose this will tip the balance away from the pro-inflammatory environment to improve clinical outcome. We will test this hypothesis by evaluating the tolerability of the clinical stage P2X7 receptor antagonist, CE-224,535, in patients with TBI and the ability to reach pharmacologically relevant concentrations in the injured brain (also monitoring any drug impact upon neuroinflammation and clinical outcomes). The project progression will be milestone driven, based upon outcomes from Work Packages (WP) addressing the following questions:

WP1: Do primary microglia from patients with TBI express functional P2X7 receptors that promote the secretion of pro-inflammatory cytokines/chemokines?

WP2: Is oral CE-224,535 well tolerated in TBI patients and does the drug gain sufficient access to the brain to potentially reduce the inflammatory environment and improve clinical outcomes?

Whilst minimal outputs from the project include an enhanced understanding of the role of the P2X7 receptor in the inflammation storm that is associated with TBI, positive clinical data from the project will encourage further development of P2X7 receptor antagonists towards meeting the unmet considerable clinical need for a drug to improve the clinical outcomes following TBI.

Planned Impact

NHS and wider healthcare and social services community: Traumatic brain injury (TBI) is the leading cause of death and disability in the first 4 decades of life. The cost to the UK economy alone is estimated to be £8 billion per year (for comparison this is a greater cost to the economy than stroke). A drug treatment to reduce the detrimental consequences of TBI would be a step-change in the clinical management of patients and help reduce the considerable burden on the healthcare system by reducing acute costs associated with patients requiring longer stays in intensive care and neurological wards, as well as aftercare and welfare services for patients with disability in the community. There would be an additional economic impact due to a reduction of time away from work, travel costs and avoiding redeployment for patients whose disability prevents a return to former professions or employment.

Pharmaceutical industry: The project is aligned with needs of the pharmaceutical industry by a first investigation in clinical TBI of a selective P2X7 receptor antagonist, which has a clear rationale from pre-clinical studies in vitro and in vivo as well as clinical studies in vitro. Hence, with the availability of a suitable clinical candidate CE-224,535, a clinical study of patients with TBI is a logical approach to test the potential of a P2X7 receptor antagonist to reduce the consequences of TBI. The absence of other pharmacological treatments for TBI indicates that, should efficacy be established and a suitable product reaches the market, this will achieve rapid market penetration for the benefit of patients as well as commercial benefit for the pharmaceutical company (companies). This also maps onto government's strategy for life sciences recognizing the strength and track record of this sector to the UK economy and aiming to make the UK a world-leading place for life sciences investment as outlined in the recent Green Paper (January 2017): https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/586626/building-our-industrial-strategy-green-paper.pdf

Economic impact: Enhanced UK competitiveness and prosperity is supported through international commercialization and exploitation alongside the planned programme to build the UK's capacity and research strength to tackle a range of diseases that are a heavy burden to the NHS. Also as mentioned above, building economic impact through commercialization of life sciences is a key government objective, as described in the recent Green Paper (https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/586626/building-our-industrial-strategy-green-paper.pdf).

The general public: Through public engagement, including the voluntary sector, we will continue to deliver information about the progress of our study and the socio-economic impact of TBI on people and communities.

Academia: The potential of a P2X7 receptor antagonist to improve the clinical outcomes for patients following TBI has already raised significant interest in the neuroscience field. We will continue to report our advances in the understanding of the pathology - which will likely also offer benefits to the study of other diseases where some of the underlying pathological mechanisms may be common. Hence, a broad range of basic and clinical neuroscience researchers will benefit from the results of the proposed project, which may further forward the P2X7 receptor as a drug target for other diseases and so broaden the impact of the research.

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