Administration methods for reducing intracranial pressure

Abstract

Disclosed are therapeutic methods comprising the delivery of particular substituted pyridine based compounds for lowering intracranial pressure (ICP) and / or lowering neurogenic inflammation in treating substance P mediated pathways in the brain such as, but not limited to concussion, post-concussive (or post-concussion) syndrome (PCS), traumatic brain injury (TBI) and stroke.

Description

ADMINISTRATION METHODS FOR REDUCING INTRACRANIAL PRESSURE

[0001] This application claims priority to Australian Provisional Patent Application No.2024902254 entitled "Administration Methods for Reducing Intracranial Pressure" fded 19 July 2024, the contents of which are incorporated herein by reference in their entirety.FIELD

[0002] This invention relates generally to therapeutic methods comprising the delivery of particular substituted pyridine based compounds for lowering intracranial pressure (ICP) and / or lowering neurogenic inflammation in treating substance P mediated pathways in the brain such as, but not limited to concussion, post-concussive (or post-concussion) syndrome (PCS), traumatic brain injury (TBI) and stroke.BACKGROUND

[0003] Traumatic brain injury (TBI) is a leading cause of death and disability globally, especially in children and young adults. As well as the devastating effects on victims and their families, the condition places a huge economic burden on society. Brain trauma occurs as a consequence of a sudden acceleration or deceleration within the cranium or by a complex combination of both movement and sudden impact. In addition to the damage caused at the moment of injury, a variety of events in the minutes to days following the injury may result in secondary injury. These processes include alterations in cerebral blood flow and the pressure within the skull.

[0004] TBI, also known as intracranial injury, occurs when an external force injures the brain. TBI can be classified based on severity, mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area). TBI can result in physical, cognitive, social, emotional, and behavioural symptoms, and the outcome can range from complete recovery to permanent disability or death.

[0005] The most common causes of TBI include violence, transportation accidents, construction, and sports. Motor bikes are major causes, increasing in significance in developing countries as other causes reduce. It is estimated that between 1.6 and 3.8 million traumatic brain injuries each year are a result of sports and recreation activities in the US. In children aged two to four, falls are the most common cause of TBI, while in older childrentraffic accidents compete with falls for this position. TBI is the third most common injury to result from child abuse. Abuse causes 19% of cases of paediatric brain trauma, and the death rate is higher among these cases.

[0006] A common complication of moderate to severe TBI is raised intracranial pressure(raised ICP or intracranial hypertension). The rise in intracranial pressure (ICP) usually develops within 24 hours after injury but it may commence or worsen 2 or 3 days, or even up to 7 or 8 days and later, after the injury. The intracranial hypertension frequently leads to cerebral ischemia due to a reduction in cerebral perfusion pressure (CPP). In most studies, this is associated with poor outcome including increased mortality. This may be due to intracranial hematomas or contusions, but is frequently due to vasogenic edema. This has led to routine use of ICP monitoring and the use of a range of interventions to reduce ICP. The treatments are generally administered stepwise, starting with head of bed elevation, sedation, analgesia, osmotherapy (hypertonic saline or mannitol to osmotically remove fluid from the brain), followed by removal of cerebrospinal fluid (CSF) through an extraventricular drain (EVD) and decompressive craniectomy. The latter is associated with improved outcome overall in resistant cases, though at the expense of a risk of complications. All of these treatments are symptomatic in nature and do not affect the underlying neurogenic inflammation which leads to the increase in ICP. The pyridinyl based compounds of the present were shown in various animal models to affect the underlying neurogenic inflammation and may, as a causal treatment of elevated ICP, also be combined with any of the symptomatic treatments used currently.

[0007] The current treatments are all associated with unwanted effects e.g., in the case of mannitol (which is commonly used) there is a risk of fluid loss through its diuretic effect and consequent exacerbation of any pre-existent hypotension. None of the medical approaches addresses the underlying cause of the intracranial hypertension which animal studies increasingly suggest is neurogenic inflammation, caused by the release of Substance P followed by plasma extravasation leading to excess liquid transport into the brain which causes vasogenic edema and increase of ICP.

[0008] Substance P is the natural ligand of the NK1 receptor. Administration of certain Neurokinin 1 (NKl) antagonists have been shown to block the effects of Substance P and the associated neurogenic inflammation and serves to reduce such inflammatory responsesafter head injury and prevents or reverses cerebral edema and intracranial hypertension in experimental animals.

[0009] There is a lack of effective medication that can lower elevated ICP in TBI or stroke, neither is there any medication that can prevent the over-expression of hyperphosphorylated tan protein which has been linked to bad clinical outcome in indications such as TBI but also Alzheimer’s disease. Accordingly, there exists a need for treatment regimens that can cure or ameliorate elevated ICP in TBI or stroke or prevent over-expression of hyper-phosphorylated tau protein.

[0010] The issue of the lack of effective medication is further compounded by the fact that patients with TBI are likely to be unconscious or may have difficulties swallowing. Accordingly, there is a limitation on how the medication may be administered.

[0011] Even while an active pharmaceutical ingredient (API) is identified, there are still many obstacles to overcome in formulating and properly delivering a drug. In formulating a drug suitable for human administration, the skilled person would be aware that the formulation art is not predictable. Various factors need to be carefully investigated and tuned to at least maintain (if not enhance) the pharmacokinetic properties of the API, and / or impart stability to the drug such that it can have an acceptable shelf-life. In this sense, the physical characteristics of the API, the mode of delivery, the flow properties of the composition, the excipient compatibility, the uniformity in production and the release profile needs to be carefully studied and investigated.

[0012] The present invention seeks to overcome or ameliorate at least some of the shortcomings of the art in respect to the delivery of specific compounds for lowering ICP.SUMMARY OF THE INVENTION

[0013] In one aspect, the invention provides a method of reducing the intracranial pressure (ICP) in a subject to below about 22 mmHg, the method comprising, consisting or consisting essentially of the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Rj is H or C14alkyl, and wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0014] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or Ci-4 alkyl, in the manufacture of a medicament for reducing intracranial pressure (ICP) to below 22 mmHg in a subject in need thereof, wherein an aqueous preparation of said medicament is to be parenterally administered to said subj ect for a period of at least 2 or more days, wherein the subject is to be administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0015] In a further aspect the invention provides a pharmaceutical composition comprising or consisting essentially of a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or Ci-4 alkyl, for or for use in reducing intracranial pressure (ICP) to below 22 mmHg in a subject in need thereof, comprising, consisting or consisting essentially of parenterally administering an aqueous preparation of said composition to said subject for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0016] In another aspect, the invention provides a method of maintaining the ICP in a subject below about 22 mmHg, the method comprising, consisting or consisting essentially of the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Rj is H or C14alkyl, andwherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0017] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or C1-4 alkyl, in the manufacture of a medicament for maintaining intracranial pressure (ICP) below 22 mmHg in a subject in need thereof, wherein an aqueous preparation of said medicament is to be parenterally administered to said subj ect for a period of at least 2 or more days, wherein the subject is to be administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0018] In a further aspect the invention provides a pharmaceutical composition comprising or consisting essentially of a compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein Ri is H or C1-4 alkyl, for or for use in maintaining intracranial pressure (I CP) below 22 mmHg in a subject in need thereof, comprising, consisting or consisting essentially of parenterally administering an aqueous preparation of said composition to said subject for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0019] In a further aspect, the invention provides a method of maintaining and / or restoring the cognitive function of a subject exposed to a TBI wherein the TBI is characterized by an intracranial pressure (ICP) of about 15 mmHg or above, the method comprising, consisting or consisting essentially of the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Ri is H or C1-4 alkyl, wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 days or more, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime and that the cognitive function of said subj ect is measured at least two times after the 2 or more day treatment period.

[0020] In another aspect, the invention provides a use of a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Ri is H or C1-4 alkyl, in the manufacture of a medicament for maintaining and / or restoring the cognitive function of a subject exposed to a TBI wherein the TBI is characterized by an intracranial pressure (ICP) of about 15 mmHg or above, wherein an aqueous preparation of said medicament is to be parenterally administered to said subject for a period of at least 2 days or more, wherein the subject is to be administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime and the cognitive function of said subject is to be measured at least two times after the 2 or more day treatment period.

[0021] Also provided, in another aspect, is a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Ri is H or C1-4 alkyl, for or for use in maintaining and / or restoring the cognitive function of a subject exposed to a TBI wherein the TBI is characterized by an intracranial pressure (ICP) of about 15 mmHg or above, comprising, consisting or consisting essentially of parenterally administering an aqueous preparation of the compound of formula (I), or a pharmaceutically acceptable saltthereof, wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 days or more, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime and that the cognitive function of said subject is measured at least two times after the 2 or more day treatment period.

[0022] In another aspect, the invention provides a method of preventing or minimizing cerebral hypoperfusion in a subject exposed to a TBI wherein the TBI is characterized by an intracranial pressure (ICP) of about 15 mmHg or above, the method comprising, consisting or consisting essentially of the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Ri is H or C1-4 alkyl, wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0023] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or Ci-4 alkyl, in the manufacture of a medicament for preventing or minimizing cerebral hypoperfusion in a subject exposed to a TBI wherein the TBI is characterized by an intracranial pressure (ICP) of about 15 mmHg or above, wherein an aqueous preparation of said medicament is to be parenterally administered to said subject for a period of at least 2 or more days, wherein the subject is to be administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0024] Also provided, in another aspect, is a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Ri is H or Ci-4 alkyl, for or for use in preventing or minimizing cerebral hypoperfusion in a subject exposed to a TBI wherein the TBI is characterized by an intracranial pressure (ICP) of about 15 mmHg or above, comprising, consisting or consisting essentially of parenterally administering an aqueous preparation of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 days or more, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime and that the cognitive function of said subject is measured at least two times after the 2 or more day treatment period.

[0025] In a further aspect, the invention also provides a method of improving the outcome of a TBI patient on the extended Glasgow Outcome Scale (GOS-E), the methodcomprising, consisting or consisting essentially of the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Ri is H or C1-4 alkyl, wherein the patient is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of 2 or more days, and wherein the patient is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0026] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or C1-4 alkyl, in the manufacture of a medicament for improving the outcome of a TBI patient on the extended Glasgow Outcome Scale (GOS-E), wherein an aqueous preparation of said medicament is to be parenterally administered to said subject for a period of at least 2 ormore days, wherein the subject is to be administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0027] In a further aspect the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or C1-4 alkyl, for or for use in improving the outcome of a TBI patient on the extended Glasgow Outcome Scale (GOS-E), comprising, consisting or consisting essentially of parenterally administering an aqueous preparation of the compound of formula (I), or a pharmaceutically acceptable salt thereof to said subject for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0028] GOS-E is the Glasgow Outcome Scale-Extended used to assess the functional status of a patient after the end of treatment and is thought of as a secondary outcome measurement. In the examples described herein the inventors measured the GOS-E at week 12 after conclusion of treatment. The Glasgow Outcome Scale (GOS-E) is the standard way of assessing functional outcome in a TBI patient. It basically measures how well a patient functions in everyday activity after certain time (e.g. 6 months) after having suffered a TBI. It is a well used test to see if treatment has had any effect.

[0029] This is to be contrasted with the Glasgow coma scale (GCS), in which TBI patients are commonly classified into three subgroups: mild (GCS: 13-15), moderate (GCS:9-12), and severe (GCS:< 8), with mild TBI accounting for more than 85% of cases.

[0030] In certain embodiments, the patient presents with an intracranial pressure (ICP) above 15 mmHg and with a GCS of 9-12.

[0031] In certain embodiments, the patient presents with an intracranial pressure (ICP) above 15 mmHg and with a GCS of 13-15 , 0032] In certain embodiments, the patient presents with an intracranial pressure (ICP) above 15 mmHg and with a GCS of < 8.

[0033] The present invention provides therapeutic methods, uses and compositions that comprise an effective amount of a particular substituted pyridine based compound and other excipients in an aqueous preparation, and more specifically as a parenteral formulation. It advantageously allows administration of the active compound to a subject or patient in need thereof when the subject is unconscious or unable to swallow, for instance, by providing instant relief of substance P mediated processes such as over-expression of hyperphosphorylated tau protein or elevated ICP and accordingly immediately alleviates the condition and / or symptom of indications such as, but not limited to, PCS, CTE, TBI and stroke, and for reducing neurogenic inflammation.

[0034] The active mentioned above is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as represented below:Formula (I) wherein Ri is H or Ci-4 alkyl.

[0035] In certain embodiments and with reference to the above aspects, the compound of Formula (I) is a compound wherein Ri is CH3.

[0036] In certain embodiments and with reference to the above aspects, the compound of Formula (I) is a compound wherein Ri is H (desmethyl).

[0037] In certain embodiments and with reference to the above aspects, the compound of Formula (I) is a 2HC1 salt of the compound wherein Ri is CH3.

[0038] In certain embodiments and with reference to the above aspects, the compound of Formula (I) is a 2HC1 salt of the compound wherein Ri is H (desmethyl).

[0039] Compounds of Formula (I) may be prepared as described in EP 1103546 Bl and WO 2020 / 132716 Al, the entire contents of which are incorporated herein by reference.

[0040] In certain embodiments and with reference to the above aspects, the WAD BID dosage regime is calculated based on the following: (mg) = Body Weight (kg) * 1.58 (mg / kg).

[0041] In certain embodiments and with reference to the above aspects, the WAD BID dosage regime is calculated based on the following:

[0042] It will be appreciated that weight adapted dose twice daily (WAD BID) dosage regime refers to the above mentioned dose amounts administered twice in a single day. It will also be appreciated that the term “weight adapted dose” as used herein refers to a dose that has been calculated (or adjusted) on the basis of the specific weight of the subject or patient.

[0043] The present inventors have shown herein that the methods also serve to reduce neurogenic inflammation, as assessed by the reduction of levels of Glial Fibrillary Acidic Protein (GFAP) to below 0.2 ng / ml within about 2 to 3 days of treatment start.

[0044] GFAP has been identified as a biomarker linked to neurogenic inflammation. Lowering GFAP would therefore be a strong indicator that the compound is reducing inflammation as postulated by the defined mode of action. The present inventors have observed dramatic effects on GFAP in the open-label study when comparing the levels of GFAP in treated patients with known levels in historical controls. Lowering GFAP is seen as positive outcome.

[0045] Neurogenic inflammation is inflammation arising from the local release by afferent neurons of inflammatory mediators such as Substance P, Calcitonin Gene-Related Peptide (CGRP), neurokinin A (NKA), and endothelin-3 (ET-3). In such neurons, release of these pro-inflammatory mediators is thought to be triggered by the activation of ion channels that are the principal detectors of noxious environmental stimuli. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established.

[0046] Neurogenic inflammation is thought to play an important role in the pathogenesis of numerous neurological disease states including migraine. In migraine, stimulation of the trigeminal nerve causes neurogenic inflammation via release of neuropeptides including Substance P, nitric oxide, vasoactive intestinal polypeptide, 5-HT, Neurokinin A and CGRP leading to a "sterile neurogenic inflammation."

[0047] Therefore, according to a further aspect, the invention provides a method of reducing neurogenic inflammation in a subject in need thereof wherein the method comprises, consists or consists essentially of the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein Ri is H or Ci-4 alkyl, wherein a reduction of neurogenic inflammation is assessed by the reduction of levels of GFAP to below 0.2 ng / ml within about 2 to 3 days of treatment start and wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 or more days, and wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0048] Also provided, in another aspect, is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or Ci-4 alkyl, in the manufacture of a medicament for reducing neurogenic inflammation in a subject in need thereof, wherein a reduction of neurogenic inflammation is assessed by the reduction of levels of GFAP to below 0.2 ng / ml within about 2 to 3 days of treatment start, wherein an aqueous preparation of said medicament is to be parenterally administered to said subject for a period of at least 2 or more days, wherein the subject is to be administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0049] In a further aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or C1-4 alkyl, for or for use in reducing neurogenic inflammation in a subject in need thereof, wherein a reduction of neurogenic inflammation is assessed by the reduction of levels of GFAP to below 0.2 ng / ml within about 2 to 3 days of treatment start, comprising, consisting or consisting essentially of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof to said subject for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

[0050] In some embodiments, the reduction of neurogenic inflammation lowers ICP in a subject / patient.

[0051] In some embodiments, the reduction of neurogenic inflammation lowers ICP in a subject / patient who has suffered a TBI.

[0052] In some embodiments, the reduction of neurogenic inflammation treats migraine in the subject.

[0053] In some embodiments, the subject has suffered a TBI, has elevated ICP and / or suffers from migraine.

[0054] In relation to all aspects and in certain embodiments, a patient can have an ICP based Time in the Critical Region (TICR) while using 22 mmHg as the cut-off for the critical range, ranging from 100% (i.e. all time spent above 22 mmHg) to 0 % (i.e. no time spent above 22 mmHg. This TICR can be lowered after administration to reduce levels down to 0% in strong responders or any reduction compared to baseline in others for at least about 4hrs, such as at least about 6 hrs, 8 hrs, 10 hrs, 12 hrs, 14 hrs, 16 hrs, 18 hrs, 20 hrs, 22 hrs, or at least about 24 hrs.

[0055] Using a continuous monitoring software called ICM+ the inventors were able to register the continuous ICP in a patient rather than logging the ICP once an hour. In the classical approach (once an hour) a patients ICP may be at 19 mmHg for 3 or 4 (or more) hours in a row, which appears to be below the critical threshold of 22 (or 20) mmHg. However, with continuous monitoring the inventors show that despite the apparent stable pressure below 22 mmHg, the patient may still have regular peaks above 22 mmHg (or whatever the required cut off is used) and can calculate the fraction of time (in percentage of total time measured) that a patient spends above 22 (or 20) mmHg. This percentage is the TICR, i.e. the time in the critical region, and it has been reported that the longer a patient’s pressure is above 22 mmHg the worse their eventual outcome, in terms of total ICP “dose”. The preliminary data provided herein, shows that treatment with Ex 1 in the defined manner lowers the TICR and hence is predicted to improve the patient’s outcome. The following compound is referred to herein as Ex 1 :

[0056] In relation to all aspects and in certain embodiments, the invention contemplates a specific therapy intensity level (TIL) range from 0 (no treatment for ICP control) to 38 (maximum treatment for ICP control; Zuercher et al., J. Neurotrauma (2016) 33: 1768- 1774). The TIL is a composite score that measures all clinical interventions performed to lower the ICP in a TBI patient, with the exception of the administered active drug (i.e. Compound of Formula (I) or a salt thereof). When the inventors have administered Ex 1 to a TBI patient in the defined manner, the patient also received all current clinical procedures that are used to lower ICP, for example, hypothermia, osmotic treatment such as hypertonic saline or mannitol, sedatives, or the use of an extraventricular drain (EVD). Accordingly, it may often be difficult to quantify if any particular active drug actually lowered the pressure or whether this was the result of the combination of all the other procedures. Thus in orderto understand the effect of Ex 1 of the present invention the inventors calculated the TIL score for each patient which shows how many other treatments a patient needs to receive to keep the ICP below at least 25 mmHg. In the studies, Ex 1 is observed to work well when the TIL score is lowered e.g. from a score of 20 to a score of 6, even when the pressure remains constant at e.g. 18 mmHg. This means that the ICP reduction was mainly caused by the administration of Ex 1 which subsequently removed the need for other procedures. TIL may be calculated by registering all other ICP controlling treatments and calculating a score based on that (using 4-hourly intervals).

[0057] In further embodiments, the invention provides a method of maintaining or reducing the intracranial pressure (ICP) in a subject below about 22 mmHg, the method comprising, consisting or consisting essentially of the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Rj is H or C14alkyl, and wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime, wherein the patient is characterised with the following: reduction of levels of Glial Fibrillary Acidic Protein (GFAP) to below 0.2 ng / ml within about 2 to 3 days of first administration;reduction of ICP based Time in the Critical Region (TICR) above 22 mmHg for at least 4 hrs; an increase of measured average GOS-E score of at least 1 point (on a scale from 1 to 8) at week 12 after first administration; and a reduction in average TIL score of at least 3-5 points during the treatment period and up to at least 2 days after the last dose.

[0058] Also provided, in another aspect, is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or Ci-4 alkyl, in the manufacture of a medicament for maintaining or reducing the intracranial pressure (ICP) in a subject below about 22 mmHg, wherein an aqueous preparation of said medicament is to be parenterally administered to said subject for a period of at least 2 or more days, wherein the subject is to be administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime; wherein the patient is characterised with the following: reduction of levels of Glial Fibrillary Acidic Protein (GFAP) to below 0.2 ng / ml within about 2 to 3 days of first administration; reduction of ICP based Time in the Critical Region (TICR) above 22 mmHg for at least 4 hrs;an increase of measured average GOS-E score of at least 1 point (on a scale from 1 to 8) at week 12 after first administration; and a reduction in average TIL score of at least 3-5 points during the treatment period and up to at least 2 days after the last dose.

[0059] In a further aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or Ci-4 alkyl, for or for use in maintaining or reducing the intracranial pressure (ICP) in a subject below about 22 mmHg, comprising, consisting or consisting essentially of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof to said subject for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime; wherein the patient is characterised with the following: reduction of levels of Glial Fibrillary Acidic Protein (GFAP) to below 0.2 ng / ml within about 2 to 3 days of first administration; reduction of ICP based Time in the Critical Region (TICR) above 22 mmHg for at least 4 hrs; an increase of measured average GOS-E score of at least 1 point (on a scale from 1 to 8) at week 12 after first administration; anda reduction in average TIL score of at least 3-5 points during the treatment period and up to at least 2 days after the last dose.BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 is a graph which depicts intracranial pressure (ICP) (mmHg) vs time (hrs) in relation to the IV administration of a Compound of Formula (I) 2.HC1 (Ri = CH3) - known herein as "Ex 1" (EU-C-001). The line indicates the ICP over time curve; and the vertical arrows indicate the administration of Ex 1 WAD BID.

[0061] Figure 2 is a series of graphs showing the effect of reduction of infusion time ofEx 1 and an increase in Cmax on levels of biomarker GFAP in TBI patients. Figure 2a is a graph showing the GFAP levels in TBI patient 1 after infusion of Ex 1 on days 1 and 2 using a 2 hour infusion; Figure 2b is a graph showing the GFAP levels in TBI patient 2 after infusion of Ex 1 on days 1 and 2 using a 2 hour infusion; and Figure 2c is a graph showing the average GFAP levels in TBI patients (n=8) following infusion of Ex 1 on days 1 and 2 using 15 minute infusions.

[0062] Figure 3 is a graph showing the correlation between body weight and Cmax in TBI patients treated with a dose of 90 mg of Ex 1.

[0063] Figure 4 is a graph showing the ICP and TIL in a patient weighing 45 kg treated with 90 mg of Ex 1.

[0064] Figure 5 is a graph showing the effect of Ex 1 (EU-C-001) treatment on ICP in a sheep model of middle cerebral artery (MCA) occlusion.

[0065] Figure 6 is a schematic showing the dosing schedule for Ex 1 (EU-C-001) in Phase 2, showing the timepoints of administration (15 minutes infusion) at t=0 hrs and t=4 hrs each day. The schedule is repeated up to 4 days in Phase 2.

[0066] Figure 7 is a graph showing the ICP versus time for a TBI patient treated with Ex 1 (EU-C-001) using the BID and WAD dosing schedule. The line indicates the ICP, vertical arrows indicate administration of WAD of Ex 1, and the diagonal arrows indicate an observed reduction in ICP.

[0067] Figure 8 is a graph showing the effect of Ex 1 (EU-C-001) on intracranial pressure in sheep following severe diffuse injury. Sham=non-injured; vehicle=0.9% sterile saline; HTS=hypertonic saline. **p<0.01, ***p<0.001, ****p<0.0001 compared to TBI + vehicle.

[0068] Figure 9 is a graph showing the mean plasma concentration versus time curves ofEx 1 after repeated intravenous administration of different doses ofEx 1 (EU-C-001) after the fifth (last) infusion (semi -logarithmic scale).DETAILED DESCRIPTION OF THE INVENTION

[0069] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. Thus, the use of the term “comprising” and the like indicates that the listed integers are required or mandatory, but that other integers are optional and may or may not be present. By “consisting of’ is meant including, and limited to, whatever follows the phrase “consisting of’. Thus, the phrase “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present. By “consisting essentially of’ is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified for the listed elements. Thus, the phrase “consisting essentially of’ indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

[0070] The term "about" or "approximately" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system (e.g. variance up to about 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1%).

[0071] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (orinformation derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0072] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. For the purposes of the present invention, the following terms are defined below.

[0073] "Subject" and "Patient" are used interchangeably and refer to human subjects / patients which are in need of medical intervention.

[0074] "Alkyl" refers to monovalent alkyl groups which may be straight chained or branched and have from 1 to 4 carbon atoms or more preferably 1 to 3 carbon atoms. As used herein, CM alkyl refers to an alkyl selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. For instance, in an embodiment Ri is H or CH3. In an embodiment Ri is H. In an embodiment, Ri is preferably CH3.

[0075] Parenteral" means a mode of administration that occurs elsewhere in the body other than the mouth and the alimentary canal. Accordingly, parenteral administration is administration by delivery via routes other the gastrointestinal tract. As used herein, "parenteral" refers to modes of administration such as intramuscular, intravenous (bolus and / or infusion), subcutaneous, intravesical, or subgingival. In an embodiment, the mode of administration is intravenous.

[0076] In an embodiment, Ri is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, secbutyl, iso-butyl or tert-butyl. In another embodiment, Ri is H, methyl, ethyl, n-propyl or isopropyl. In another embodiment, Ri is H. In another embodiment, Ri is methyl. In another embodiment, Ri is ethyl. In another embodiment, Ri is n-propyl.

[0077] Accordingly, in some embodiments, and with reference to all above aspects, the pharmaceutical formulation (i.e., aqueous preparation) comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof selected from the following:

[0078] In particular, in some embodiments, the pharmaceutical formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof which is selected from:

[0079] In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is provided as a salt. In another embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is an HC1 salt. In another embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a 2HC1 salt. Accordingly, in some embodiments, the pharmaceutical composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof selected from the following:

[0080] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is Ex 1.

[0081] In the development of the compound of Formula (I) experiments consistently showed strong efficacy of the compound to blocking central NK1 receptors.

[0082] Following Phase 1 and at the start of the treatment of TBI subjects / patients, the rate of infusion of Ex 1 was initially set to 2 hours, in order to avoid any potential safety issues. However, it was found that the lower Cmax values, linked to the slow 2 hour-rate of infusion, did not provide sufficient efficacy in terms of lowering ICP or the biomarker GFAP (Glial Fibrillary Acidic Protein) a biomarker for brain injury and neurogenic inflammation. Based on an analysis of a pharmacodynamic test, an emesis test performed in Phase 1, the rate of infusion in patients was increased to 15 minutes, as was previously done in Phase 1.

[0083] Reported data demonstrates that GFAP is a useful biomarker in severe TBI (e.g. a patient with a GCS of < 8). A report from Lei et al. (Critical Care (2015) 19:362) shows ranges from 0.2 to 3.0 ng / mL which is similar to the reported data of the present inventors (shown in the Examples section below) with a level of about 0 ng / mL for healthy subjects. The present inventors showed that the level was lowered BLQ (below limit of quantification) which should be below any accepted limit.

[0084] Levels of GFAP have been shown to be a differentiator between non-severe and severe TBI and high levels of GFAP at hospital entry a predictor of bad neurological outcome or death. For example, Nylen et al. (Journal of the Neurological Sciences (2006) 240: 85 - 91) report in their study that no survivors were observed in the group of patients with GFAP levels > 15.04 pg / L (=ng / mL) whereas no patients with a favourable outcome were observed with a GFAP level >6.98 ng / mL. Whereas no strict levels of GFAP have been correlated to outcome, patients with lower GFAP levels appear to do better than patients with higher levels (see Lei 2015 above). Overall GFAP is accepted as a biomarker of neurogenic inflammation and levels of GFAP are measured to assess the presence of mild TBI.

[0085] Whereas blood and serum levels of GFAP in a normal patient are in the range of 0.03 - 0.07 ng / mL - patients entering the open-label trial with Ex 1 (first sample on day 2 or 3) show elevated levels in the range of 0.2 - 3.5 ng / mL (refer to Figure 2).

[0086] Accordingly, in a further aspect the invention provides a method of reducing or maintaining the ICP in a subject below about 15 mmHg, the method comprising, consistingor consisting essentially of the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Rj is H or C14alkyl, and wherein the subject presents with a blood or serum level of GFAP above 0.2 ng / mL and is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime in order to achieve a biomarker GFAP level of between 0.03 - 0.07 ng / mL or lower, and preferably BLQ.

[0087] Also provided, in another aspect, is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or C1-4 alkyl, in the manufacture of a medicament for reducing or maintaining the ICP in a subject below about 15 mmHg, wherein the subject presents with a blood or serum level of GFAP above 0.2 ng / mL, and wherein an aqueous preparation of said medicament is to be parenterally administered to said subject for a period of at least 2 or more days, wherein the subject is tobe administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime in order to achieve a biomarker GFAP level of between 0.03 - 0.07 ng / mL or lower, and preferably BLQ.

[0088] In a further aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or Ci-4 alkyl, for or for use in reducing or maintaining the ICP in a subj ect below about 15 mmHg, wherein the subject presents with a blood or serum level of GFAP above 0.2 ng / mL, comprising, consisting or consisting essentially of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof to said subject for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime in order to achieve a biomarker GFAP level of between 0.03 - 0.07 ng / mL or lower, and preferably BLQ.

[0089] It will be appreciated that the methods of the present invention may be automated by infusion systems with integrated computer technology to administer and monitor the patient’s ICP, Cmax values, GFAP levels and so on.

[0090] For instance, in certain other aspects, the invention provides a system for or for use in maintaining the ICP in a subject below about 22 mmHg, the system comprising an infusion device for parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereofFormula (I) wherein Rj is H or C14alkyl, and wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime via said infusion device, and wherein the system also includes a computer implemented monitoring device for monitoring ICP levels in said patient.

[0091] In certain embodiments, the infusion device is a computer programmable infusion pump.

[0092] In certain other embodiments, the infusion device is an infusion pump which is computer programmably linked to the computer implemented monitoring device.Emesis test in Phase 1

[0093] A pharmacodynamic study to assess functional blocking of central NK1 receptors was performed in healthy volunteers during Phase 1. This was done by testing the efficacy of the compound (Ex 1; Compound of Formula (I) 2HC1 (Ri = CEE)) in blocking apomorphine induced emesis. This study indicated the need for a minimum concentration of the Cmax at infusion to obtain efficacious levels, rather than minimal plasma-levels at the time of the apomorphine challenge. These levels are in the range of 1000 - 1300 ng / ml of Cmax when Ex 1 is infused over 15 minutes, whereas the plasma-levels obtained with the 2 hrs infusion schedule were in the range between 400 and 900 ng / ml.

[0094] In the phase 1 apomorphine challenge study the ability of Ex 1 to block emesis induced by apomorphine was tested in healthy volunteers. It was found that when subjects (n=5) were first treated with 90 mg of the compound and then challenged after 2 hours withthe emetogen, apomorphine, an average of 1.4 “retches and vomits” was observed, which indicated full efficacy for NK1 receptor antagonism (efficacy was defined as “reducing the average number of retches and vomits below 3, without the need for rescue, anti-emetic, therapy). Similarly, when the apomorphine challenge was performed 20 hrs after 90 mg of Ex 1 (n=5), the efficacy was only slightly reduced, with an average of 2.6 retches and vomits observed. At neither time-point did subjects require rescue medication to prevent uncontrolled vomiting. On the other hand, when the apomorphine challenge was performed 2 hours after a 30 mg dose (n=5), an average of 4.2 retches and vomits was observed, which would have been even higher had two of five subjects not received rescue medication to block the apomorphine effects. Importantly the plasma concentration of the Compound 2 hours after the 30mg dose was 60% higher than the plasma concentration 20 hours after the 90 mg dose. Nevertheless it showed a lower efficacy.Table 1: Blocking of apomorphine induced emesis with the Compound of Formula (I) 2HC1 (Ri = CH3) - Ex 1.* 2 of 5 subjects required rescue therapy for uncontrolled vomiting, as per protocol.

[0095] These data indicate that a minimum average peak level (Cmax) in the range of at least 1000 ng / ml to 1300 ng / ml are required for central NK1 blockade and the prevention of emesis and that, once blockade is achieved the reduction of the blockade (retches / vomits) lasts up to a minimum of 20 hrs. These levels were obtained using a shorter 15 - 30 minute infusion.

[0096] Based on the emesis test a minimum target Cmax level should be 1000 - 1300 ng / ml to achieve central NK1 blockade. It was noted that the percentage of receptor blockade to prevent emesis may not be identical to the percentage required for blocking neurogenicinflammation, the target in TBI patients. Nevertheless, following the two initial patients in Phase 1, who were treated using a 2-hour infusion, the rate of infusion was reset to 15 minutes in order to target a Cmax of at least 1000 - 1300 ng / ml. Figure 1 demonstrates the ICP over time following IV administration of Ex 1.

[0097] The decision to reduce the infusion time from 2 hours to 15 minutes was subsequently validated by analysis of the biomarker for neurogenic inflammation, GFAP which is elevated in severe TBI patients to levels above 0.2 ng / mL depending on the level of injury and or inflammation. In the two initial patients in which Ex 1 was administered in a 2 hour infusion, GFAP only declined at a slow rate, consistent with the natural decline (see Nylen 2006; Lei 2015 mentioned above), whereas in patients in which Ex 1 was administered with 15 minute infusions, GFAP was reduced to BLQ (Below Limit of Quantification) on day 2 after start of treatment in most patients and on days 3 and 4 in all patients. This is shown in Figure 2.

[0098] Additional to the finding that a minimum level of Cmax is required for efficacy, following treatment of 8 patients in the open-label run-in to Phase 2, it was discovered that the Cmax levels achieved at a given dose were tightly coupled to a patient’s body weight. This is clearly shown in the Figure 3 which shows the body weight corrected dose (in mg / ml) versus Cmax levels.

[0099] The analysis of PK data from TBI patients showed that there was a clear correlation between the Cmax level and the body weight of the patient (correlation coef. 0.91). Moreover, the data suggested a better efficacy in lowering ICP in light weight patients.

[0100] One example of the patient with the lowest body weight is given in Figure 4. The graph shows the ICP (blue line) and ICP-lowering (black arrows) linked to infusion of Ex 1 (red arrows). Moreover, in all patients the TIL was measured (Treatment Intensity Level, red line). Because TBI patients in an ICU (Intensive Care Unit) are treated with multiple therapies to reduce ICP, such as mannitol, hypertonic saline, sedatives, extraventricular drains (EVD) etc., the sum of all treatments, other than Ex 1, was calculated and used as a parameter to assess efficacy. Even though the change in ICP may be difficult to assess due to the co-administration of multiple other treatments, the TIL is postulated to decrease, because Ex 1 should lower the need for these other treatments. In this light-weightpatient a marked decline in TIL was measured (green arrows) after the 3rdand 4thadministration of Ex 1.

[0101] Following an analysis of the weight dependency of PK in patients up to that point, a Weight Adapted Dose (WAD) was developed in which the target Cmax was similar to that observed in light weight patients. Cmax in heavy weight patients was anticipated to be the same as in low weight patients if the dose is corrected using the following formula:WAD (mg) = Body Weight (kg) * 1.58 (mg / kg).

[0102] In order to simplify dosing in the setting of the clinic a dosing table was developed that divides subjects / patients in categories of 10 kg (see below) . Due to the limited amount of data for patients weighing more than 90 kg at the timepoint of the calculation a cap was applied to the dose increase at 90 kg. This cap may be removed and doses increased in future, potentially using the same progression, when more safety data become available in subject with a weight > 90-100 kg.

[0103] The WAD dose levels target Cmax levels in the range of 1800 - 3000 ng / ml.

[0104] This schedule takes into account that for safety reasons Cmax should not exceed levels above 3000 ng / ml, in order to maintain a sufficient safety margin over the No- Observed-Adverse-Effect Level (NOAEL) observed in toxicology studies in animal studies.Table 2: Weight Adapted Dose (WAD) in TBI patients treated with Ex 1

[0105] When comparing Phase 1 (emesis) data with Phase 2 (TBI) data, the results indicate that the dose level required to block an emetic response appears lower than the dose required to block neurogenic inflammation. This may be caused by the fact that the NK1-receptor population involved in the neurogenic inflammation and emetic response are located in different parts of the brain and that different brain penetration of different parts of the brain leads to the requirement of a higher dose for the treatment of neurogenic inflammation than for emesis.

[0106] In some of the pre-clinical studies (a sheep model for stroke, see Figure 5) it was noted that a BID regimen was more effective in terms of lowering ICP if the second dose was administered 4-5 hours after the initial dose rather than after the more conventional 12 hours. In the open-label run-in to Phase 2 it was noted that on several occasions a 4-5 hour drop in ICP followed immediately after infusion of the active compound after which time the ICP started to rise again. This was reminiscent of the observations in the animal model. The finding that the compound had a body weight dependent PK suggested that the first dose functioned as a “loading dose” for the second dose, whereby the first dose fills up a deep compartment (linked to body weight), allowing the second dose to reach a higher Cmax and better brain penetration. The data from the sheep studies in which a 4-5 hour dosing gap was used are shown in Figure 5.

[0107] Based on these data the dosing schedule for Ex 1 was adapted to a BID dosing, whereby the doses are administered att=O hrs and t=4 hrs each day (Figure 6).

[0108] Figure 7 shows the ICP curve of a patient treated using the WAD dosing schedule with a BID dosing regimen as shown above.

[0109] In summary, based on data from Phase 1 and Phase 2 it is concluded for the first time that:• Cmax is the relevant PK parameter for efficacy when Ex 1 is used as an anti-emetic as well as for reducing neurogenic inflammation.• This is further supported by data showing that in TBI patients GFAP is reduced after 15 minute infusions (high Cmax) and not after 2 hour infusions (low Cmax).TBI patients with a lower body weight show higher Cmax levels when given the same dose as patients with a higher body weight (see Figure 3).In order to assure a similar Cmax in all patients a weight adapted dose (WAD) has been calculated and implemented.• The formula for the WAD is: WAD (mg) = Body Weight (kg) * 1.58 (mg / kg).• Data from patients in phase 2 indicate that Cmax levels required for central NK1 blockade for the control of neurogenic inflammation i.e. the control of ICP are higher than those required for anti -emetic activity. This may be explained by different brain penetration of different regions of the brain.• Data from preclinical studies suggested a BID regimen whereby the second dose each day is administered 4-5 hrs after the first dose are more effective. This suggests that the first dose acts as loading dose for the second dose. This observation is consistent with the observed body weight dependent dosing.• Based on these data a BID, WAD has been introduced whereby the second dose is administered 4 hours after the first dose, each day, for up to four days or more.

[0110] The present inventors believe that the need for a high peak concentration to obtain efficacy can be explained by assuming that a minimum peak at Cmax is required to allow passage of a sufficient amount of the compound into the brain. Additionally, because the compound is a non-competitive inhibitor of the NK1 receptor the compound remains active for a longer period of time also when plasma and brain concentrations drop to lower levels. In this model a high initial peak is needed to rapidly enter the brain allowing it to block the receptor both initially and over a longer time after dosing.[oni] An alternative way of administration would be a bolus injection with a lower dose, rather than a 15 or 30 minute infusion, that achieves an equally high initial Cmax, but which will have a lower AUC.

[0112] For efficacy the compound of Formula (I) is preferably administered in a short infusion to allow a minimal peak level or Cmax between 1800 ng / ml and 3000 ng / ml.

[0113] This can be achieved by a short infusion for up to 30 minutes with doses up to 200 mg of the compound of Formula (I) dihydrochloride salt equivalent to about 190 mg of free base when administered via intravenous (IV) administration.

[0114] In another embodiment, this can be achieved by a short infusion for up to 30 minutes with doses up to about 150 mg- 240 mg of the compound of Formula (I) dihydrochloride salt equivalent to about 140-230 mg of free base when administered via IV.

[0115] In another embodiment, this can be achieved by a short infusion for up to 30 minutes with doses up to about 90 mg of the compound of Formula (I) dihydrochloride salt equivalent to about 80 mg of free base when administered via IV. This may be suitable to light weight or paediatric applications.

[0116] In some embodiments, this can be achieved by a short infusion of for up to 30 minutes with doses up to about 90 mg of the compound of Formula (I) dihydrochloride salt equivalent to about 80 mg of free base when administered via IV.

[0117] Alternatively, this can be achieved by an injection, instead of an infusion, of a lower dose, targeting the same Cmax between 1800 and 3000 ng / ml. Such a lower dose can, for example, be in the range of about 1 - 85 mg.

[0118] This can be achieved by injection of doses of about 1 mg to about 85 mg of the compound of Formula (I) dihydrochloride salt (equivalent to about 75 mg / kg of free base). The higher rate of infusion will generate a higher or equally high Cmax while using a lower dose.

[0119] In an embodiment, the parenteral, pharmaceutical composition is an intravenous, pharmaceutical composition. In another embodiment, the composition is an intravenous bolus, pharmaceutical composition. In another embodiment, the composition is an intravenous infusion, pharmaceutical composition. In another embodiment, the composition is an intramuscular, pharmaceutical composition. In another embodiment, the composition is a subcutaneous, pharmaceutical composition. In another embodiment, the composition is an intravesical, pharmaceutical composition. In another embodiment, the composition is a subgingival, pharmaceutical composition.

[0120] In an embodiment, the reconstitutable, parenteral, pharmaceutical composition or parenteral, pharmaceutical composition is subjected to sterilisation. In another embodiment, the composition is subjected to gamma radiation. In another embodiment, the composition is subjected to heat treatment. In another embodiment, the composition issubjected to moist heat treatment. For example, the composition may be heat treated at about 140 °C, about 130 °C, about 120 °C, about 110 °C, about 100 °C, or about 90 °C. The composition may be heat treated for about 5 min, about 10 min, about 15 min, about 20 min, about 30 min, about 40 min, about 50 min, about 60 min or about 120 min.

[0121] In one embodiment, the dosage of the pharmaceutical composition administered to a subject in the various embodiments of the present invention is such that the compound of Formula (I) is administered in the range from about 50 mg to 250 mg (and all mg therebetween) depending on the administration route as discussed above. In one embodiment, the dosage of the pharmaceutical formulation administered to a subject in the various embodiments of the present invention is such that the compound of Formula (I), or pharmaceutically acceptable salt thereof, is administered in an amount of about 50.0 mg, 51.0 mg, 52.0 mg, 53.0 mg, 54.0 mg, 55.0 mg, 56.0 mg, 57.0 mg, 58.0 mg, 59.0 mg, 60.0 mg, 61.0 mg, 62.0 mg, 63.0 mg, 64.0 mg, 65.0 mg, 66.0 mg, 67.0 mg, 68.0 mg, 69.0 mg, 70.0 mg, 71.0 mg, 72.0 mg, 73.0 mg, 74.0 mg, 75.0 mg, 76.0 mg, 77.0 mg, 78.0 mg, 79.0 mg, 80.0 mg, 81.0 mg, 82.0 mg, 83.0 mg, 84.0 mg, 85.0 mg, 86.0 mg, 87.0 mg, 88.0 mg, 89.0 mg, 90.0 mg, 91.0 mg, 92.0 mg, 93.0 mg, 94.0 mg, 95.0 mg, 96.0 mg, 97.0 mg, 98.0 mg, 99.0 mg, 100 mg, 105 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190mg, 200 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg, or any range within the above amounts.

[0122] In the embodiment wherein the administration route is intravenous, the present invention is such that the compound of Formula (I), or pharmaceutically acceptable salt thereof, is administered in an amount of about 60.0 mg, 61.0 mg, 62.0 mg, 63.0 mg, 64.0 mg, 65.0 mg, 66.0 mg, 67.0 mg, 68.0 mg, 69.0 mg, 70.0 mg, 71.0 mg, 72.0 mg, 73.0 mg,74.0 mg, 75.0 mg, 76.0 mg, 77.0 mg, 78.0 mg, 79.0 mg, 80.0 mg, 81.0 mg, 82.0 mg, 83.0 mg, 84.0 mg, 85.0 mg, 86.0 mg, 87.0 mg, 88.0 mg, 89.0 mg, 90.0 mg, 91.0 mg, 92.0 mg,93.0 mg, 94.0 mg, 95.0 mg, 96.0 mg, 97.0 mg, 98.0 mg, 99.0 mg, 100 mg, 105 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg, or any range within the above amounts.

[0123] In the embodiment wherein the administration route is bolus injection, the present invention is such that the compound of Formula (I), or pharmaceutically acceptable salt thereof, is administered in an amount of about 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg,316.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 11.0 mg, 12.0 mg, 13.0 mg, 14.0 mg, 15.0 mg, 16.0 mg, 17.0 mg, 18.0 mg, 19.0 mg, 20.0 mg, 21.0 mg, 22.0 mg, 23.0 mg, 24.0 mg, 25.0 mg, 26.0 mg, 27.0 mg, 28.0 mg, 29.0 mg, 30.0 mg, 31.0 mg, 32.0 mg, 33.0 mg, 34.0 mg, 35.0 mg, 36.0 mg, 37.0 mg, 38.0 mg, 39.0 mg, or 40.0 mg, or any range within the above amounts.

[0124] In an embodiment, the effective amount is administered as a single or multiple dose. In an embodiment, the effective amount is administered as a single or multiple intravenous dose.

[0125] In an embodiment, the effective amount is administered as a single or multiple injection dose.

[0126] In certain embodiments, the administration involves at least 2 days of WAD BID dosing.

[0127] In certain embodiments, the administration involves at least 3 days of WAD BID dosing.

[0128] In certain embodiments, the administration involves at least 4 days of WAD BID dosing.

[0129] In certain embodiments, the administration involves at least 4 days of WAD BID doing totalling at least 8 infusions.

[0130] In certain embodiments, the administration method as disclosed herein is repeated at least 1 more time about from 2-6 hours from first administration.

[0131] In certain embodiments, the administration method is repeated at least 1 more time about 4 hours from first administration.

[0132] In certain embodiments, the administration method is repeated at least 2 more times about 2-8 hours from first administration.

[0133] In certain embodiments, the administration method is repeated at least 2 more times at about 4 and 8 hours from first administration.

[0134] In certain embodiments, the administration method is repeated at least 3 more times about from 3-18 hours from first administration.

[0135] In certain embodiments the administration method is repeated at least 3 more times at about 4, 8 and 12 hours from first administration.

[0136] In certain embodiments, the administration method is repeated at least 3 more times at about 4, 8 and 12 hours from first administration.

[0137] In certain embodiments, the administration method is repeated at least 1 more time at about 4 hours from the first administration for two to four consecutive days.

[0138] In certain embodiments, the subject receives the administration method within 1-72 hrs after being involved in a TBI or having a stroke, or any other incident or disease condition which elevates the subject’s ICP levels above 15 mmHg. Without wishing to be bound by any particular theory, the present inventors believe that the ability of the present compound to block the effect of a rise in substance P (and therefore reduce ICP in an effective manner) may be compromised if the patient does not receive the first administration dose within the first 72 hrs after being involved in a TBI or having a stroke, or any other incident or disease condition which elevates the subjects ICP levels above 15 mmHg.

[0139] In certain embodiments, the subject receives the administration method within 1-72 hrs after being involved in a TBI or having a stroke, or any other incident or disease condition to prevent increase of ICP. Without wishing to be bound by any particular theory the present inventors believe that the ability of the present compound to block the effect of an increase in substance P (and therefore reduce ICP in an effective manner) may be compromised if the patient does not receive the first administration dose within the first 72 hrs after being involved in a TBI or having a stroke, or any other incident or disease condition which elevates the subjects ICP levels.

[0140] The skilled person would appreciate that the aim of the present administration regime is to provide effective stabilisation of ICP of the subject in need thereof. In this regard, effective stabilisation is deemed to have been achieved once an ICP level of below 15 mmHg is established from 5 to over 10 hrs after the last administration dose is providedto said subject (patient), for instance, over 5 hrs, over 6 hrs, over 7h rs, over 8 hrs, over 9 hrs, or over 10 hrs.

[0141] In an embodiment, the method for treating elevated intracranial pressure is also a method for treating traumatic brain injury, as ICP is a critical symptom associated with TBI. In fact, the main reason why TBI patients are treated in the intensive care unit (ICU) is to control their ICP.

[0142] In another embodiment, the method for treating elevated intracranial pressure is also a method for treating stroke, as ICP is a symptom associated with stroke

[0143] In an embodiment, the pharmaceutical formulation is to be administered as a treatment for injury associated with concussion post the injury event which is associated with an increase in ICP.

[0144] Thus the terms “treat,” “treatment,” and “treating” also refers to one or more of the following:(a) relieving or alleviating at least one symptom of a disorder in a subject, including reducing intracranial pressure in a TBI patient;(b) relieving or alleviating the intensity and / or duration of a manifestation of a disorder experienced by a subject including, but not limited to, those that are in response to a given stimulus (e.g., pressure, tissue injury, cold temperature, etc.); and(c) arresting, delaying the onset (i.e., the period prior to clinical manifestation of a disorder) and / or reducing the risk of developing or worsening a disorder.

[0145] A subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human.

[0146] In certain embodiments the human subject (patient) is selected with a presented ICP of above 15 mmHg, such as above 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, 20 mmHg, such as above 21 mmHg, above 22 mmHg, above 23 mmHg, above 24 mmHg, above 25 mmHg, above 26 mmHg, above 27 mmHg, above 28 mmHg, above 29 mmHg, above 30 mmHg, above 31 mmHg, above 32 mmHg, above 33 mmHg, above 34mmHg, above 35 mmHg, above 36 mmHg, above 37 mmHg, above 38 mmHg, above 39 mmHg, above 40 mmHg, above 41 mmHg, above 42 mmHg, above 43 mmHg, or above 44 mmHg.

[0147] In certain embodiments the subject (patient) presents with a Glascow Coma Scale of 3-12.

[0148] Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of a compound with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts can be prepared by reacting a compound with the appropriate base via a variety of known methods. The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2 -hydroxy -ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3 -phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.

[0149] The parental formulations may contain any other suitable carriers, diluents or excipients. These include all conventional solvents, dispersion media, fdlers, solid carriers, coatings, antifungal and antibacterial agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents.

[0150] For example, the pharmaceutical formulation may further comprise a preservative, a buffer, stabiliser and / or a viscosity enhancing agent. Examples of suitable preservatives are benzoic acid esters of para-hydroxybenzoic acid, phenols, phenylethyl alchohol or benzyl alcohol. Examples of suitable buffers are sodium phosphate salts, citric acid, tartaric acid and the like. Examples of suitable stabilisers are, antioxidants such as alpha-tocopherol acetate, alpha-thioglycerin, sodium metabisulphite, ascorbic acid, acetylcysteine, 8-hydroxy quinoline, chelating agents such as disodium edentate. Examples of suitable viscosity enhancing agents, suspending or dispersing agents are substituted cellulose ethers, substituted cellulose esters, polyvinyl alchohol, polyvinylpyrrolidone, carbomer, polyoxypropylene glycols, and sorbitan sesquioleate.

[0151] For example, the pharmaceutical formulation may further comprise a pH controller. Examples of suitable pH controllers include hydrochloric acid, sodium hydroxide and the like.

[0152] In certain embodiments the pharmaceutical formulation comprises a stock solution of Ex 1 in an aqueous solution comprising propylene glycol (solubilizer) and sodium hydroxide (pH adjustment), which is subsequently diluted in a 5% glucose solution for infusion.

[0153] It will be appreciated that any compound that is a prodrug of a compound of formula (I) is also within the scope and spirit of the invention. The term “pro-drug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, phosphonic acid derivatives.

[0154] It will be appreciated that any compound that is a metabolite of a compound of formula (I) and which has demonstrable pharmacological properties similar to the compound of formula (I) is also within the scope and spirit of the invention. Specifically, the main metabolite is the desmethyl version of the compound and is pharmacologically very similar to Ex 1. It has a longer half-life than Ex 1 and may in fact contribute to efficacy when dosed for 3-4 days.

[0155] Those skilled in the art will appreciate that the invention described herein in susceptible to variations and modifications other than those specifically described. It is to beunderstood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

[0156] Certain embodiments of the invention will now be described with reference to the following examples which are intended for the purpose of illustration only and are not intended to limit the scope of the generality hereinbefore described.EXAMPLES

[0157] Compound of Formula (I), in particular compound (la) as shown below, is used in all examples, and in particular the 2HC1 salt of compound (la) (Compound (la) HC1).(Designated herein as “Ex 1”)Pharmacology of Ex 1

[0158] Ex 1 is a potent antagonist at the human NK1 receptor, with a half maximal inhibitory concentration (IC50) of 0.76 nM. The affinity of NK1 receptors for the rat NK1 receptor is lower than that for human receptors due to differences in their protein structures. For this reason, the gerbil and sheep, whose NK1 receptors are similar to those in human, have been used in addition to the rat to test functional effects of Ex 1 in vivo.

[0159] Intracerebroventricular administration of the NK1 agonist GR73632 (3.0 pmol / 5 pl) in gerbils leads to a characteristic foot tapping behaviour which can be quantified. The behaviour is blocked by pre-treatment with NK1 -antagonists. In gerbils, pre-treatment withEx 1 dose dependently blocked the foot tapping behaviour induced by GR73632, with an ED50of 0.7 mg intraperitoneal (IP) and an ED80of 1.8 mg / kg IP.

[0160] Reduction of extravasation of Evans Blue in rats undeigoing head injury was observed in a dose dependent manner after administration of Ex 1 , with a maximal effect at an intravenous (IV) dose of around 3 mg / kg.

[0161] A sheep TBI model has been developed, which is considered more predictive of response in humans than the traditional rat models. In this model, a pronounced and sustained reduction in ICP was observed after IV administration of Ex 1 at a dose of 1 mg / kg, as shown in Figure 8.Administered Formulation

[0162] Ex 1 was formulated as a stock solution consisting of 15 mg / ml Ex 1 in 80% propylene glycol and 20% water for injection set to pH 4.5-5.5 with sodium hydroxide. Placebo stock solution was identical without the active substance. The stock solution was filled into vials containing 7.5 ml. For administration 5.6 to 9.3 ml of stock solution (85 to 140 mg of WAD) was infused in 200 ml of commercially available 5% glucose solution. The solution was infused over 15 minutes by IV. Administration of Ex 1 was done at t = 0 hrs , t = 4 hrs, t = 24 hrs and t = 28 hrs and at t=0 and t=4 for every extra day thereafter (up to 4 days).Non-Clinical Safety Studies

[0163] Safety pharmacology studies have been conducted according to regulatory guidelines. No clinically relevant changes were observed in the hERG assay, in cardiovascular assessments in dogs, or in respiratory or central nervous system function assessed in rats.

[0164] There was no evidence for genotoxicity in vitro in the Ames test or chromosome aberration test or in vivo in the mouse micronucleus test. There were no significant findings in embryofetal toxicity studies in rats and rabbits. No safety concerns were identified in 14- day oral and IV toxicity studies in rats and dogs.Cytochrome P450 Inhibition

[0165] Based on in vitro studies, no clinically relevant interactions involving the cytochrome P450 system are expected at plasma concentrations predicted to occur in the plarmed clinical study.Human Studies

[0166] Single and multiple dose studies of Ex 1 have been conducted by the oral and IV routes in healthy male volunteers.First Study with Ex 1

[0167] A combined single and multiple ascending dose study (oral and IV dosing). The study included 4 groups:• Group 1 (single oral doses), 6 cohorts of 6 subjects received ascending single oral doses of 5 mg to 180 mg of Ex 1 (each cohort consisted of 4 subjects on Ex 1 and 2 subjects on placebo).• Group 2 (single IV doses), 5 cohorts of 6 subjects received ascending IV doses from 5 mg to 90 mg Ex 1 (each cohort consisted of 4 subjects on Ex 1 and 2 subjects on placebo).• Group 3 (multiple oral doses), 4 cohorts of 6 subjects received ascending IV doses, from 15 mg to 180 mg Ex 1, once daily (OD) for 5 days (each cohort consisted of 4 subjects on Ex 1 and 2 subjects on placebo).• Group 4 (multiple IV doses), 4 cohorts of 6 subjects received ascending IV doses, from 5 mg to 90 mg Ex 1, OD for 5 days (each cohort consisted of 5 subjects on Ex 1 and 2 subjects on placebo).

[0168] Ex 1 at all administered doses was well tolerated. No serious adverse events (SAEs) were reported. Most of the adverse events (AEs) reported were mild in intensity and were not regarded as related to study medication.

[0169] Following single and repeated IV administration of Ex 1 or placebo, the study medication was generally well tolerated with no notable differences between the treatment groups.

[0170] Pharmacokinetic (PK) analysis (Table 3 and Figure 9) indicated a dose proportional PK profde with an estimated terminal half-life of approximately 11.5 hours after repeated administration at the highest IV dose (90 mg). An active metabolite (desmethyl Ex 1) wa formed with levels increasing 12 hours after administration. As the concentration of the active metabolite was relatively low on Day 1 and increased to higher steady state levels on Day 2 and Day 3, it could not be predicted if an OD regimen, particularly on Day 1 would be sufficient to control ICP. Hence, the study was designed to start with an open-label pilot phase in which the dosing regimen and safety of a BID regimen is assessed, followed by a double- blind phase to assess safety and efficacy.Table 3: Main Pharmacokinetic Parameters (Median; Range) of Ex 1 after Repeated Intravenous Doses of Ex 1.AUC0-24h, area under the plasma concentration-time curve within 1 dosing interval; Cmax, maximum plasma concentration observed, taken from the plasma-concentration-time profile; N, number; Tl / 2, apparent terminal half-life; Tmax, time taken to reach maximum plasma concentration observed, taken from the plasma concentration- time profile.Second Study of Ex 1

[0171] In the second study, apomorphine challenge tests were performed in healthy male volunteers in Group 1 of the study. Results from Group 1 concerning emesis at the 90 mg (test after 2 hours), 90 mg (test after 20 hours), and 30 mg (test after 2 hours) doses.

[0172] In Group 2, the safety, tolerability, and PK of seven 30 minute IV infusions of 90 mg Ex 1 at 12-hour intervals were tested. To address the local tolerability issues observed in study 1, the glucose concentration of the infusion solution was reduced from 5% to 1%, thereby bringing the osmolality of the solution into the physiological range. Additionally, the infusion time was extended from 15 minutes to 30 minutes. General tolerability was good; however, drug administration was stopped after the second administration in the first 3 subjects due to the observation of intravascular hemolysis in all 3 subjects. The effect commenced after the first dose in 1 subject and after the second dose in the other 2 subjects. Hemolysis was evidenced by hemoglobinuria with an increase in serum lactate dehydrogenase (LDH) and reduced serum haptoglobin. There were no accompanying clinical signs and the biochemical changes were short lasting; the patients recovered spontaneously without sequelae.

[0173] The reason for this transient phenomenon may be related to the reduction in the glucose concentration of the infusion solution. It has been reported that glucose concentrations >4% have a protective effect against hemolysis. Therefore, it is likely that the 5% glucose used as the infusion solution provided protection against transient hemolysis, particularly in the initial seconds after infusion when local concentrations mixing with blood in a small peripheral vein are highest. The risk of hemolysis is also considered to be higher when the compound is administered in a peripheral vein rather than into a large vein through a central line as planned in the clinical study. TBI patients in the ICU routinely get their medication administered through a central line. In the initial 15 patients in the open-label run-in of the Phase 2 study neither any local irritation nor any hemolysis was observed in any of the patients, because the substance was administered through a central line into a large vein rather than through a small peripheral line into a narrow and small vein. It is commonly observed that substances with a higher osmolarity are not well tolerated when administered through a small vein but are well tolerated when administered into a large veinas is done in the ICU setting. The results from the Phase 2 study indicate that the local tolerability issue is not relevant for TBI patients in the ICU.Third study of Ex 1

[0174] In this study Ex 1 PK, tolerability, and safety in healthy females were assessed. Each subject received two single 30-minute infusions with a washout phase of 1 week inbetween. The first dose was 15 mg dissolved in 1% glucose and the second one was 90 mg dissolved in 1% glucose. Ex 1 was well tolerated at all administered doses. No SAEs were reported. Most of the AEs reported were mild to moderate in intensity and were not regarded as related to study medication. One case of transient hemolysis was observed at the 90 mg dose. As in study Ex 1, this was observed when using 1% glucose for infusion. As described above, solutions of glucose below 4% show an increase the risk of hemolysis. No episodes of hemolysis have been observed to date in the subjects in whom the compound has been administered in 5% glucose.

[0175] As a consequence of the Phase 1 and Phase 2 findings all future administrations, in the clinical setting, a BID WAD dose will be administered using 5% glucose as infusion solution.

[0176] In this Phase 1 study, PK assessments were made up to 72 hours allowing an accurate assessment of initial and terminal half-life.

[0177] It was found that Ex 1 at dose levels of 15 mg and 90 mg, had an initial half-life of less than 1.0 hour and a terminal half-life of 20 hours and 38 hours, respectively. All parameters, except time to reach maximum plasma concentration observed (tmax), increased with dose, maximum plasma concentration observed (Cmax) and area under the plasma concentration -time curve (AUC) nearly 10-fold and apparent terminal half-life(P) nearly 2- fold.Dose RationalePreclinical Studies

[0178] Ex 1 has been tested in multiple preclinical studies. The key studies regarding dose level are:In vitro binding• Gerbil foot tapping experiment• Rodent study on BBB restoration using Evan’s blue• Rodent and sheep TBI studiesIn Vitro Binding

[0179] In an in vitro binding assay Ex 1 was shown to have an IC50of 0.76 nM on the human NK1 receptor. This is considered to represent a high affinity predicting a low clinical dose, depending on variables such as brain penetration and PK properties.Gerbils

[0180] In this animal model fortesting central binding of NK1 receptors, the ED50was 0.7 mg / kg (IP dosing) or 0.9 mg / kg (oral dosing); ED80values were 1.8 mg / kg and 2.1 mg / kg for IP and oral dosing, respectively.Dose Ranging in Rats

[0181] Using the Evan’s blue extravasation to determine the restoration of blood brain barrier (BBB) integrity following a TBI in rats, the maximal effect was achieved at an IV dose of approximately 3 mg / kg. The higher dose observed for rats compared to gerbils is not surprising as it is established that the gerbil NK1 receptor is more closely related to the human NK1 receptor than the rat receptor. Due to structural features, the gerbil NK1 receptor was found to be more similar to human NK1 receptors in its responses to various antagonists than the rat receptor.Traumatic Brain Injury Studies in Sheep

[0182] The sheep studies demonstrating significant effects on ICP, CPP, and brain oxygenation were all carried out at a dose of 1 mg / kg. For sheep weighing ~50 kg, no conversion factor was applied, which would hence equate to a human dose of 1 mg / kg or 60 mg in a 60 kg individual. No dose ranging was performed in the sheep model.Rationale for Dose Selection

[0183] Data concerning efficacious dose ranges from preclinical studies, the apomorphine challenge study as well as ICP control in TBI patients are presented in Table 4.Table 4: Efficacious Dose Ranges from Preclinical Studies the Apomorphine Challenge Phase 1 Study and TBI control in Phase 2.

[0184] Using both the BID regimen as optimised by the sheep studies, in which the compound is administered BID with the second dose 4 hours after the first dose, as well as the WAD, all patients in Phase 2 will receive a BID; WAD regimen for four days.

[0185] The initial data from an open label run in to the double blind part of the Phase 2 study indicate that Cmax for patients on the BID, WAD regimen is 1964 ng / ml, which is within the targeted Cmax range.

[0186] The 2 dose groups to be tested in the first study double blind Phase 2 study are:1. 4 days of BID treatment consisting of Ex 1 WAD at time points 0 hours (Dose1), 4 hours (Dose 2), 24 hours (Dose 3), 28 hours (Dose 4), 48 hours (Dose 5), 52 hours (Dose 6), 72 hours (Dose 7) and 76 hours (Dose 8), administered as single IV infusions over 15 minutes... BID treatment consisting of matching placebo at time points 0 hours (Dose 1), at 4 hours (Dose 2), at 24 hours (Dose 3), at 28 hours (Dose 4), at 48 hours (Dose 5), at 52 hours (Dose 6), at 72 hours (Dose 7) and at 76 hours (Dose 8), administered as single IV infusions over 15 minutes.Benefits

[0187] Ex 1 has the potential to decrease ICP with less long-term unwanted side effects than current treatments which means that patients with TBI could have a better chance of survival with a better long- term quality of life (QoL).Phase 2 Study Trial Protocol

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A method of reducing and / or maintaining the intracranial pressure (ICP) in a subject below about 22 mmHg, the method comprising the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof:Formula (I) wherein R is H or C|_4alkyl, and wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

2. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or C1-4 alkyl, in the manufacture of a medicament for reducing and / or maintaining intracranial pressure (ICP) below 22 mmHg in a subject in need thereof, wherein an aqueous preparation of saidmedicament is to be parenterally administered to said subject for a period of at least 2 or more days, wherein the subject is to be administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

3. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein Ri is H or C1-4 alkyl, for reducing and / or maintaining intracranial pressure (ICP) below 22 mmHg in a subject in need thereof, comprising parenterally administering an aqueous preparation of said composition to said subject for a period of at least 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

4. A method of maintaining and / or restoring the cognitive function of a subject exposed to a traumatic brain injury (TBI) wherein the TBI is characterized by an intracranial pressure (ICP) of about 15 mmHg or above, the method comprising the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof:Formula (I) wherein Ri is H or C1-4 alkyl, wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 days or more, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime and that the cognitive function of said subject is measured at least two times after the 2 or more day treatment period.

5. A method of preventing or minimizing cerebral hypoperfusion in a subject exposed to a traumatic brain injury (TBI) wherein the TBI is characterized by an intracranial pressure (ICP) of about 15 mmHg or above, the method comprising the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof:Formula (I) wherein Ri is H or Ci-4 alkyl, wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of 2 or more days, wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

6. A method of improving the outcome of a traumatic brain injury (TBI) patient on the extended Glasgow Outcome Scale (GOS-E), the method comprising the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof:Formula (I) wherein Ri is H or C1-4 alkyl, wherein the patient is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of 2 or more days, and wherein the subject is administrated multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

7. A method according to claim 6, wherein the patient presents with an intracranial pressure (ICP) above 15 mmHg and with a GCS of 9-12.

8. A method according to claim 6, wherein the patient presents with an intracranial pressure (ICP) above 15 mmHg and with a GCS of 13-15.

9. A method according to claim 6, wherein the patient presents with an intracranial pressure (ICP) above 15 mmHg and with a GCS of < 8.

10. A method of reducing neurogenic inflammation in a subject in need thereof wherein the method comprises the step of parenterally administering an aqueous preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof:Formula (I)wherein Ri is H or Ci-4 alkyl, wherein reducing of neurogenic inflammation is assessed by the reduction of levels of GFAP to below 0.2 ng / ml within about 2 to 3 days of treatment start and wherein the subject is treated with the compound of formula (I), or a pharmaceutically acceptable salt thereof, for a period of at least 2 or more days, and wherein the subject is administered multiple doses based on a weight adapted dose twice daily (WAD BID) dosage regime.

11. A method according to claim 10, wherein the reduction of neurogenic inflammation lowers ICP in a subject.

12. A method according to claim 10, wherein the reduction of neurogenic inflammation lowers ICP in a subject who has suffered a TBI.

13. A method according to claim 10, wherein the reduction of neurogenic inflammation neurogenic inflammation treats migraine in the subject.

14. A method, use or composition according to any one of claims 1 to 13, wherein the WAD BID dosage regime is calculated based on the following: (mg) = Body Weight (kg) * 1.58 (mg / kg).

15. A method, use or composition according to any one of claims 1 to 13, wherein the WAD BID dosage regime is calculated based on the following:

16. A method, use or composition according to any one of claims 1 to 15, which reduces neurogenic inflammation, as assessed by the reduction of levels of Glial Fibrillary Acidic Protein (GFAP) to below 0.2 ng / ml within about 2 to 3 days of treatment start.

17. A method, use or composition according to any one of claims 1 to 16, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is as represented belowFormula (I) wherein Ri is CH3 or H.

18. A method, use or composition according to any one of claims 1 to 16, wherein the compound of Formula (I), is the 2HC1 salt, as represented below:Formula (I) wherein Ri is CH3 or H.

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