P38 map kinase inhibitor for use in the treatment of inflammation

Abstract

A method of treating or preventing inflammation in a human patient in need thereof, comprising administering to the patient a therapeutically or prophylactically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. Also related methods, uses and products.

Description

[0001] P38 MAP KINASE INHIBITOR FOR USE IN THE TREATMENT OF INFLAMMATION

[0002] FIELD OF THE DISCLOSURE

[0003] The present invention concerns methods of treating or preventing inflammation 5 in a human patient and compounds for use in such methods.

[0004] SUMMARY OF THE DISCLOSURE

[0005] In a first aspect of the present disclosure, there is provided a method of treating or preventing inflammation in a human patient in need thereof, comprising0 administering to the patient a therapeutically or prophylactically effective amount of a compound of Formula I:

[0006] Formula I or a pharmaceutically acceptable salt or solvate thereof. 5

[0007] In a second aspect of the present disclosure, there is provided a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in a method according to the first aspect of the disclosure. 0 In a third aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in a method according to the first aspect of the disclosure.

[0008] In a fourth aspect, the present disclosure provides the use of a compound of5 Formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in a method according to the first aspect of the disclosure. Also provided, in a fifth aspect, is the use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in a method according to the first aspect of the disclosure.

[0009] It will be appreciated that features described in relation to one aspect of the present disclosure may be incorporated into other aspects of the present disclosure.

[0010] DESCRIPTION OF THE DRAWINGS

[0011] Embodiments of the present disclosure are now described by way of example only with reference to the accompanying drawings in which:

[0012] Figure 1 illustrates schematically the design of the study described in the Examples.

[0013] Figure 2 illustrates mean body temperature in human volunteers 3 hours post intravenous lipopolysaccharide (LPS) challenge.

[0014] Figure 3 illustrates the rise in heart rate produced in human volunteers by intravenous LPS challenge.

[0015] Figure 4 illustrates the mean concentration of C-reactive protein in blood plasma (mg / L) in human volunteers 24 hours post intravenous LPS challenge.

[0016] Figures 5A to 5C illustrate the concentration of cytokines TNF- a, IL-6 and IL- 8 in blood plasma (pg / ml) of human volunteers pre and post intravenous LPS challenge.

[0017] Figure 6 shows TNF-a amounts (pg / ml) in skin blister extrudate of human volunteers post intradermal LPS challenge. Figure 7 shows laser speckle contrast (LCS) images of blood perfusion into tissues in an LPS-induced skin blister for a human volunteer administered placebo, compared to an LPS-induced skin blister for a volunteer dosed with 150 mg of the compound of Formula I.

[0018] Figure 8 shows the concentration of the compound of Formula I in blood serum (ng / mL) of human volunteers pre and post intravenous LPS challenge.

[0019] Figure 9 shows p38 MAPK phosphorylation in CD14+ monocytes of human volunteers pre and post intravenous LPS challenge.

[0020] DETAILED DESCRIPTION

[0021] While the subject-matter of the present disclosure is described and illustrated below with reference to particular embodiments, it will be appreciated by those skilled in the art that the subject-matter lends itself to many different variations not specifically illustrated herein. By way of example only, certain possible variations will now be described.

[0022] As disclosed above, in a first aspect of the present disclosure, there is provided a method of treating or preventing inflammation in a human patient in need thereof, comprising administering to the patient a therapeutically or prophylactically effective amount of a compound of Formula I:

[0023] Formula I or a pharmaceutically acceptable salt or solvate thereof. In a second aspect of the present disclosure, there is provided a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in a method according to the first aspect of the disclosure.

[0024] As used herein, the term “inflammation” has its normal meaning in the art, referring to the response of the mammalian immune system (including, for example, cells such as lymphocytes, neutrophils, and monocytes) to one or more stimuli, especially infection. Inflammation may be mediated by cytokines, such as those described herein, including for example IL-ip, IL-6, IL-8, IL-10, TNFa and COX-2.

[0025] Inflammation may be local. Local inflammation may, for example, be or comprise dermal inflammation. The compound of Formula I may be effective to reduce local inflammation such, for example, as dermal inflammation, especially dermal inflammation involving one or more of neutrophils, classical monocytes, myeloid dendritic cells and TNF.

[0026] Inflammation may be systemic.

[0027] In some embodiments, inflammation may be characteristic of a condition involving both local and systemic inflammation.

[0028] The inflammation disclosed herein may typically be p38 mitogen activated protein kinase (MAPK) mediated inflammation. The p38 MAP kinases comprise a mitogen-activated protein kinase subfamily that regulates a variety of cellular processes including cell growth processes, cell differentiation, apoptosis and cellular responses to inflammation. The p38 MAP kinases are regulated by cytokine receptors and can be activated in response to bacterial or viral pathogens, or substances produced thereby, such as lipopolysaccharide (LPS). The compound of Formula I is a p38 MAPK inhibitor (as are its pharmaceutically acceptable salts and solvates). The compound of Formula I may treat or prevent inflammation via inhibiting p38 MAPK. The inflammation disclosed herein may be associated with an infection or syndrome, such, for example, as those described in WO 2018 / 007788 Al (PCT / GB2017 / 051865; HVIVO SERVICES LIMITED) and WO 2019 / 122909 Al (PCT / GB2018 / 053732; HVIVO SERVICES LIMITED), the contents of which are incorporated herein by reference as if set forth in their entirety.

[0029] The inflammation may be or comprise hypercytokinemia. As used herein, the term hypercytokinemia has its normal meaning in the art, referring to a sudden surge in the circulating levels of pro-inflammatory cytokines, such as IL-1, IL-6 and TNF. Hypercytokinemia (or “cytokine storm”, or “cytokine cascade”) is associated with various conditions including infectious diseases, non-infectious diseases, autoimmune reactions and adverse drug reactions. The high levels of pro-inflammatory cytokines released in hypercytokinemia can lead to damage of the blood vessels in the lung and other tissues resulting in liquid leaking into tissues (oedema). Rather than being protective, the inflammatory response becomes destructive. The hypercytokinemia may be associated with one or more of the following: severe influenza virus infection; graft- versus-host disease (GVHD); acute respiratory distress syndrome (ARDS); sepsis; Ebola; smallpox; systemic inflammatory response syndrome (SIRS); bacterial infection; and cancer.

[0030] The inflammation may be caused for example by exposure to a pathogen, or may be caused by cancer, or may be caused by an autoimmune response.

[0031] The inflammation may be or comprise inflammation associated with severe influenza (which is also known in the art as complicated influenza).

[0032] Uncomplicated influenza is a mild inflammation of the upper respiratory tract. In uncomplicated influenza, the inflammation is short lived and repair to the damaged epithelial cell lining of the upper airways starts about 2-3 days after onset of symptoms. In contrast to uncomplicated influenza, the inflammatory response in severe (i.e., complicated) influenza is exaggerated or extended. Rather than being protective, the response becomes destructive. Accumulation of fluid and immune cells in the lungs can lead to pneumonia, acute lung injury and ARDS and respiratory failure in severe cases. The exaggerated inflammatory response in severe (i.e., complicated) influenza can be viewed as a non-linear process where there is a critical point - a phase transition, or tipping point - when the normal inflammatory response becomes an abnormal or more destructive response. In severe influenza, rather than going down a resolution path after peak symptoms at around day 3 after infection, patients progress to develop other respiratory complications, a process driven by an exaggerated inflammatory response.

[0033] The severe (i.e., complicated) influenza may suitably be characterized by symptoms that persist or recur for more than 2, 3, 4, 5 or more days without signs of resolution.

[0034] Especially when the inflammation is or comprises inflammation associated with severe (i.e., complicated) influenza, the compound of Formula I may inhibit both the release of pro-inflammatory cytokines from endothelial cells and the release of pro- inflammatory cytokines from immune cells.

[0035] The symptoms of severe (i.e., complicated) influenza may be symptoms selected from fever (a temperature greater than 100 °F / 38 °C), lethargy, achiness, congestion, cough, sinus congestion, sinus drainage or upper respiratory congestion or inflammation.

[0036] Severe (i.e., complicated) influenza may, in some embodiments, be characterised by hypercytokinemia.

[0037] Severe (i.e., complicated) influenza may involve: clinical and / or radiological signs of lower respiratory tract disease, central nervous system (CNS) involvement, severe dehydration, or secondary complications selected from renal failure, multi-organ failure, septic shock, rhabdomyolysis and myocarditis; exacerbation of underlying chronic disease; any other condition or clinical presentation that requires hospital admission for clinical management; or signs and symptoms of progressive disease selected from symptoms and signs suggesting oxygen impairment or cardiopulmonary insufficiency, symptoms and signs suggesting CNS complications, evidence of sustained or spreading virus replication or invasive secondary bacterial infection based on laboratory testing or clinical signs, or severe dehydration, manifested as decreased physical or mental activity, dizziness, decreased urine output, and lethargy. (See WHO Guidelines for Pharmacological Management of Pandemic Influenza A(H1N1) 2009 and other Influenza Viruses, Revised February 2010, Part I Recommendations, p. 5.)

[0038] Severe (i.e., complicated) influenza may involve hypoxemia or cardiopulmonary insufficiency.

[0039] Severe (i.e., complicated) influenza may require hospitalization of the patient. Thus, in some embodiments, the patient may be hospitalized.

[0040] The patient may have one or more underlying comorbidities that predispose the patient to severe (i.e., complicated) influenza. For example, the patient may be immunocompromised, or may suffer from COPD, severe genetic anaemia, asthma or diabetes, chronic hepatic or renal insufficiency, obesity or a cardiovascular disorder or condition.

[0041] The patient may be an infant (i.e. less than one year old) or elderly (i.e. 65 years old or more) or may be a pregnant woman.

[0042] In some embodiments, the inflammation may be or comprise cancer immunotherapy-induced cytokine release syndrome. The term “cancer immunotherapy-induced cytokine release syndrome” (“CRS”), as used herein, refers to an uncontrolled systemic inflammatory response that is triggered by cancer immunotherapy.

[0043] Cancer immunotherapy, such, for example, as CAR T cell therapy or infusion of T cell-engaging agents, may result in significant toxi cities including CRS. CRS may clinically manifest from a few (e.g., about 4, about 5 or about 6) hours to several weeks after administration of the cancer immunotherapy. CRS may present with a variety of symptoms ranging from mild, flu-like symptoms to severe, life-threatening manifestations of an exaggerated systemic inflammatory response. In severe cases, and despite therapeutic intervention, CRS may lead to death.

[0044] As used herein, the term “cancer immunotherapy” refers to therapeutic stimulation of the immune system to treat cancer. Cancer immunotherapy is thought to enhance the natural capacity of the immune system to recognise and destroy cancer cells and may enhance immune cell memory functions, thereby preventing or reducing the risk of cancer recurrence.

[0045] Cancer immunotherapy may be administered to a patient in need thereof by an intravenous infusion (which may be referred to herein simply as an infusion). The time taken for the infusion may be about 1 minute to about 24 hours. Infusion may occur continuously or intermittently (preferably, continuously, until the whole dose of cancer immunotherapy has been delivered). One dose of cancer immunotherapy may be administered as a single infusion. The compound of Formula I may be administered before the infusion begins. The compound of Formula I may be administered during the infusion. The compound of Formula I may be administered after the infusion ends. Preferably, the compound of Formula I is administered at least before the infusion begins; if so, the compound of Formula I may be administered during the infusion and / or after the infusion (up to a time point after the infusion ends; i.e., administration of the compound of Formula I may then be stopped).

[0046] As the term is used herein, cancer immunotherapy may especially comprehend one or more of: therapies which employ genetically engineered (or otherwise modified or cultured) T cells; immune cell-engaging therapies (especially BiTEs and other bispecific antibodies); and other therapies such as natural killer (“NK”) cell therapy, cancer vaccines and T cell checkpoint modulators (especially, T cell checkpoint inhibitors).

[0047] Cancer immunotherapy may preferably comprise or consist of adoptive T cells or otherwise implicate T cells. It will be appreciated that a cancer immunotherapy which is said to “otherwise implicate T cells” may not necessarily be limited to a T cellengaging therapy (such as BiTE, CiTE, SMITe or TriKE) but rather may comprehend any cancer immunotherapy wherein T cells are implicated.

[0048] Cancer immunotherapy may comprehend a therapy mediated by T cell effector functions and memory; especially, therapies with engineered T cells (such, for example, as CAR T cell therapy and TCR therapy), with otherwise modified or cultured T cells (such, for example, as TIL therapy), or with T cell checkpoint modulators.

[0049] Cancer immunotherapy of the present disclosure may be a therapy mediated by T cell effector functions (but not, however, especially dependent on T cell memory); such, for example, as a T cell-engaging therapy, such as bispecific T-cell engager (BiTE) therapy, therapy with other bispecific antibodies, bifunctional checkpoint- inhibitory T cell engager (CiTE) therapy, simultaneous multiple interaction T cell engager (SMITe) therapy or trispecific killer engager (TriKE) therapy, or therapy with other immunostimulatory molecules able to induce cytokine release; especially BiTE therapy.

[0050] Cancer immunotherapy may be a therapy which is not obviously dependent on T cell effector functions; nor on T cell memory. Nevertheless, improvement of T cell function may benefit. For example, the cancer immunotherapy may comprise CARNK therapy, or a cancer vaccine.

[0051] Especially, cancer immunotherapy may be a T cell-engaging therapy, especially a bispecific T-cell engager (BiTE) therapy (or therapy with another bispecific antibody), a CAR NK therapy, a cancer vaccine, or a T cell checkpoint modulator; or a therapy with engineered T cells (such, for example, as CAR T cell therapy and TCR therapy) or with otherwise modified or cultured T cells (such, for example, as TIL therapy).

[0052] Cancer immunotherapy may especially be therapy comprising the administration of genetically engineered (or otherwise modified or cultured) T cells. As used herein, depending on the context, the term “therapy comprising the administration of genetically engineered T cells” may refer to one or both of CAR T cell therapy and TCR therapy; or to a broader group of therapies encompassing CAR T cell therapy and TCR therapy. Meanwhile, “therapy comprising the administration of otherwise modified or cultured T cells” may refer to tumour-infiltrating lymphocyte (“TIL”) therapy, or to a broader group of therapies encompassing TIL therapy.

[0053] The T cells described herein may be PD-1, CTLA4, TIM-3, TIGIT, CD3- or CD28-expressing T cells. CD28 may provide co-stimulatory signals for T cell activation and survival. CD28 may play a role in signals 1, 2, 3 and / or 4, described herein. CD28 may play a role in the CRS described herein.

[0054] Optionally, the cancer immunotherapy may be combination cancer immunotherapy, for example by means of CAR T cell therapy in combination with one or more checkpoint inhibitors, such as one or more anti -PD-1 antibodies.

[0055] By “CAR T cell therapy” herein is meant therapy for the treatment of a cancer patient in which T cells, having been harvested (optionally although not necessarily harvested from the same cancer patient, as T cells may be harvested from a healthy donor) and genetically engineered in vitro to express CARs with specificity for relevant cancer cell antigens (and, optionally although not necessarily, proliferated in vitro are administered to the cancer patient by adoptive transfer. Suitably, CAR T cell therapy may be implemented in treatment of a CD19-expressing malignancy or a BCMA- expressing malignancy. Thus, CAR T cell therapy may be autologous (in that the T cells are harvested from the same cancer patient). Alternatively, CAR T cell therapy may be allogeneic (“off the shelf’) using T cells harvested from a healthy donor and modified to express CARs. In allogeneic CAR T cell therapy, the T cells may optionally be further modified, for example via genome editing technologies such as CRISPR / Cas9 or base editing, to prevent graft-vs.-host disease and host allorej ection.

[0056] Similarly, TCR therapy involves genetic engineering of T cells, followed by their adoptive transfer to a patient in need thereof. While CAR T cells are capable of recognising and binding to naturally occurring antigens on the surface of cancer cells, in TCR therapy T cells are genetically engineered to express receptors which bind to major histocompatibility complex (MHC) proteins. However, the manufacturing process for T cells for use in TCR therapy may otherwise be analogous to that described hereinabove in respect of CAR T cells.

[0057] TCR therapy may thus be used herein to refer to therapy for the treatment of a cancer patient in which T cells, having been harvested (optionally although not necessarily harvested from the same cancer patient, as T cells may be harvested from a healthy donor) and genetically engineered in vitro to express engineered T cell receptors configured to recognise MHC -presented polypeptide fragments molecules (and, optionally although not necessarily, proliferated in vitro are administered to the cancer patient by adoptive transfer.

[0058] In certain preferred embodiments, the inflammation is or comprises CRS associated with CAR T cell therapy or TCR therapy; most preferably, the inflammation is or comprises CRS associated with CAR T cell therapy.

[0059] By “tumour-infiltrating lymphocytes” (“TILs”) herein is meant white blood cells that leave the bloodstream and migrate towards a solid tumour. TILs may be found within a tumour, as well as within the tumour stroma. The abundance and phenotype of TILs may vary with tumour type and stage. TILs may especially include T cells.

[0060] By “TIL therapy” herein is meant adoptive T cell transfer therapy of a patient in need thereof, wherein TILs, especially T cells, which may have originated from the patient or from another individual, are administered to the patient. Typically, therefore, TILs from a resected tumour are expanded in vitro. Several TIL cultures may be established separately before being assayed for satisfactory tumour recognition function. Once selected, the satisfactory TILs may be expanded over the course of a few weeks; typically using IL-2 as a general growth factor. Following a further TIL cell selection step, TIL lines having the best tumour recognition may be further expanded in a "rapid expansion protocol" (REP), which uses anti-CD3 activation for a period of a few weeks. Finally, the post-REP TILs are infused into the patient.

[0061] For some uses of the p38 MAP kinase inhibitor in accordance with the present disclosure, the cancer immunotherapy may be a T cell-engaging therapy, such for example as bispecific T-cell engager (BiTE) therapy or therapy with another bispecific antibody, bifunctional checkpoint-inhibitory T cell engager (CiTE) therapy, simultaneous multiple interaction T cell engager (SMITe) therapy or trispecific killer engager (TriKE) therapy.

[0062] The term “BiTE” as used herein means a bispecific monoclonal antibody for use as an anti -cancer drug. Particularly, a BiTE may be a fusion protein comprising two single-chain variable fragments (“scFvs”) of different antibodies, or amino acid sequences from four different genes, on a single peptide chain. One of the scFvs may be configured to bind to T cells (especially, via a CD3 receptor); the other may be configured to bind to a tumour cell.

[0063] The term bispecific antibody as used herein means an antibody that can bind to two different types of antigen simultaneously. Various bispecific antibodies are known in the art, including BiTEs.

[0064] For some uses of the p38 MAP kinase inhibitor in accordance with the present disclosure, the cancer immunotherapy may be natural killer (“NK”) cell therapy, a cancer vaccine or a T cell checkpoint modulatory therapy.

[0065] The term “NK cell therapy” may be used herein interchangeably with “CAR NK cell therapy”. Like CAR T cells, CAR NK cells are genetically engineered to encode CARs that recognise tumour antigens. The manufacturing process for CARNK cells is broadly analogous to that described hereinabove for CAR T cells.

[0066] By “CAR NK cell therapy” herein is meant therapy for the treatment of a cancer patient in which natural killer cells, having been harvested (optionally although not necessarily harvested from the same cancer patient, as NK cells may be harvested from a healthy donor) and genetically engineered in vitro to express CARs (and, optionally although not necessarily, proliferated in vitro are administered to the cancer patient by adoptive transfer.

[0067] The term “cancer vaccine”, as used herein, means one or more tumour antigen vaccines, whether autologous or allogeneic. A cancer vaccine may, for example, comprise: one or more cancer cell proteins and / or one or more fragments (peptide) thereof; one or more whole cells (such as tumour cells or dendritic cells); one or more nucleic acids; and / or one or more virus-based vaccines (encompassing oncolytic viruses).

[0068] As used herein, the term “T cell checkpoint modulator” has its normal meaning in the medical arts and means a T cell checkpoint inhibitor that is configured to block or otherwise antagonise tumour cell inhibitory immune checkpoint proteins from binding with partner proteins, or a T cell checkpoint stimulator, that is configured to enhance signalling for otherwise agonise tumour cell costimulatory checkpoint proteins.

[0069] Treatment of CRS may typically involve administration of tocilizumab, steroids or anakinra. Thus, in some embodiments, the patient administered the compound of Formula I may also be administered one or more compounds selected from the group consisting of tocilizumab, one or more steroids, and anakinra.

[0070] In some embodiments, the therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 20 to about 200 mg BID (especially, about 30 to about 150 mg BID, more especially about 60 to about 150 mg BID, yet more especially about 75 to about 120 mg BID), optionally provided that the amount is not 30 mg BID, 70 mg BID or 150 mg BID. The therapeutically or prophylactically effective amount of the compound of Formula I may suitably be in a range of from about 31 to about 149 mg BID, optionally provided that the amount is not 70 mg BID. The therapeutically or prophylactically effective amount of the compound of Formula I may suitably be in a range of from about 31 to about 69 mg, administered BID (i.e., twice daily). Optionally, the therapeutically or prophylactically effective amount is in a range of from about 41 to about 69 mg, administered BID. Suitably, the therapeutically or prophylactically effective amount may be in a range of from about 45 to about 65 mg BID.

[0071] The therapeutically or prophylactically effective amount may be in a range of from about 71 to about 149 mg, administered BID. Preferably, the therapeutically or prophylactically effective amount is in a range of from about 75 to about 120 mg, administered BID.

[0072] Administration of an amount of the compound of Formula I in a range as described herein (such as in a range of from about 31 to about 69 mg BID; especially, about 45 to about 65 mg BID; or in a range of from about 71 to about 149 mg BID; especially, about 75 to about 120 mg BID), may provide pharmacological benefits effective to treat or prevent inflammation, while minimising unwanted side effects. Pharmacological benefits include inhibiting the release of one or more pro- inflammatory cytokines (such as IL-ip, IL-6, IL-8, IL- 10, TNFa and COX-2); reducing the level of phosphorylated p38 MAP kinase in circulating monocytes (advantageously, by about 30% to about 97%); reducing the blood plasma concentration of one or more of IL-6, IL-8, IL-10, and TNFa; and / or reducing the blood plasma concentration of C- reactive protein (advantageously, by at least about 25%). Surprisingly, it has been found that dosing in the ranges described herein may achieve suitable pharmacological benefits. Higher doses may lead to unwanted side effects without significantly better results. The dosage ranges described herein may therefore be especially beneficial for their provision of pharmacological benefits without risk of significant unwanted side effects. As used herein, the term “significant unwanted side effects” encompasses moderate and serious adverse events. It is not intended to refer to mild or very mild signs or symptoms, especially where there is doubt whether these are caused by the compound of Formula I. Accordingly, it is thought that optimal dosing of the compound of Formula I (obtaining pharmacological benefits without unwanted side effects) may be achieved by administration in a range of from about 31 to about 69 mg BID (especially, about 41 to about 69 mg BID), or in a range of from about 71 to about 149 mg BID.

[0073] Most preferred may be a range of about 71 to about 149 mg BID, especially about 75 to about 120 mg BID. Especially noticeable anti-inflammatory pharmacological benefits may be obtainable in this range (for example, because a greater amount of the compound of Formula I is administered, compared to dosing in the range of about 31 to about 69 mg BID); while continuing to minimise the risk of unwanted side effects. Thus, such a range may meet the need for an effective amount of the compound to prevent or treat inflammation, without significant unwanted side effects.

[0074] As shown in Figure 8, the concentration of the compound of Formula I in blood serum at steady state (on Day 6 of the study described in the Examples) increases when the dose of the compound administered is increased from 70 mg BID to 150 mg BID. Yet in the study described in the Examples, the pharmacological benefits observed in patients administered 70 mg BID of the compound of Formula I are surprisingly similar to those observed in patients administered 150 mg BID. Notably, Figures 3 and 4 show similar reductions in systemic inflammation (as evidenced by reduced heart rate and reduced circulating C-reactive protein, respectively) at 70 mg BID and 150 mg BID. Continuing, Figures 5A-C show reductions in pro-inflammatory cytokines at 70 mg BID very similar to those observed at 150 mg BID. Figure 6 shows similar reductions in TNF-a in blister extrudate (a proxy for local inflammation) at 70 mg BID and 150 mg BID. Meanwhile, Figure 9 shows similar reductions in p38 MAPK phosphorylation in CD14+ monocytes at 70 mg BID and 150 mg BID.

[0075] Accordingly, although the effects of the compound of Formula I appear to be dose-dependent, its beneficial effects on local and / or systemic inflammation may plateau at doses in a range between 70 mg BID and 150 mg BID. Therefore, the preferred range of about 71 to about 149 mg BID, especially about 75 to about 120 mg BID, may provide an optimised dosage range, wherein the minimum effective dose is administered. Administering a maximally effective dose which is nevertheless the minimum dose required is advantageous to minimise the risk of significant unwanted side effects.

[0076] Thus, the therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 71 to about 149 mg BID, especially about 75 to about 120 mg BID, or even about 105 to about 120 mg BID; such as about 110 mg BID. The pharmacological benefits (in vivo) of the compound of Formula I are thought to be reliably obtainable at about 110 mg BID, as evidenced by the Examples hereinbelow. 110 mg BID and similar amounts may, therefore, be effective to treat or prevent inflammation. As described herein, pharmacological benefits (in vivo) may include inhibiting the release of one or more pro-inflammatory cytokines (such as IL- ip, IL-6, IL-8, IL- 10, TNFa and COX-2); reducing the level of phosphorylated p38 MAP kinase in circulating monocytes (advantageously, by about 30% to about 97%); reducing the blood plasma concentration of one or more of IL-6, IL-8, IL-10, and TNFa; and / or reducing the blood plasma concentration of C-reactive protein (advantageously, by at least about 25%).

[0077] Doses in a range of from about 71 to about 149 mg BID, especially about 75 to about 120 mg BID (or even about 105 to about 120 mg BID; such as about 110 mg BID) may better mitigate against unforeseen fluctuations in bioavailability (compared to lower doses). Meanwhile, such doses may carry a comparatively low risk of side effects (compared to higher doses, especially those above about 200 mg BID or above about 250 mg BID). Yet further, such doses may enable a steady-state concentration of the compound of Formula I to be reached, in blood serum, at a quicker rate than would be possible at lower doses. This may enable the compound of Formula I to be administered for a shorter overall period of time, which may minimise the total amount of the compound of Formula I administered to the patient in question, thereby mitigating against the risk of side effects. Doses in a range of from about 71 to about 149 mg BID, especially about 75 to about 120 mg BID (or even about 105 to about 120 mg BID, such as about 110 mg BID) may especially be suitable when a short-term dosing regime is adopted (thus reducing the risk of side effects resulting from long-term dosing regimes).

[0078] Thus, the therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 71 to about 149 mg BID, especially about 75 to about 120 mg BID (or even about 105 to about 120 mg BID, e.g. about 110 mg BID) when the compound of Formula I is administered for about 1 to about 50 days (only; i.e., and then stopped), especially about 7 to about 25 days (only; i.e., and then stopped).

[0079] The therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 71 to about 149 mg BID, especially about 75 to about 120 mg BID (or even about 105 to about 120 mg BID, such as about 110 mg BID) when the compound of Formula I is administered beginning about 1 to about 7 days before the onset of inflammation, especially about 4 to about 7 days before the onset of inflammation, up to about 1 to about 14 days following the onset of inflammation (and then stopped).

[0080] Doses in a range of from about 71 to about 149 mg BID, especially about 75 to about 120 mg BID (or even about 105 to about 120 mg BID, such as about 110 mg BID) may be suitable for oral and / or intravenous administration, especially oral administration.

[0081] Thus, the therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 71 to about 149 mg BID, especially about 75 to about 120 mg BID (or even about 105 to about 120 mg BID, such as about 110 mg BID), when the compound of Formula I is administered orally for about 1 to about 50 days (only; i.e., and then stopped), especially about 7 to about 25 days (only; i.e., and then stopped). The therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 71 to about 149 mg BID, especially about 75 to about 120 mg BID (or even about 105 to about 120 mg BID, such as about 110 mg BID), when the compound of Formula I is administered orally, beginning about 1 to about 7 days before the onset of inflammation, especially about 4 to about 7 days before the onset of inflammation, up to about 1 to about 14 days following the onset of inflammation (and then stopped).

[0082] As described herein, the inflammation may be or comprise cancer immunotherapy-induced cytokine release syndrome. The therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 71 to about 149 mg BID, especially about 75 to about 120 mg BID (or even about 105 to about 120 mg BID, such as about 110 mg BID) when the compound of Formula I is administered (especially, when it is administered orally) beginning about 1 to about 7 days before commencing the cancer immunotherapy (which may be an infusion of cancer immunotherapy), especially about 4 to about 7 days before commencing the cancer immunotherapy, up to about 1 to about 14 days after the end of the cancer immunotherapy (and then stopped).

[0083] The therapeutically or prophylactically effective amount of the compound of Formula I may suitably (even, typically) be higher. Significant anti-inflammatory pharmacological benefits (in vivo) may be more reliably obtainable when the amount is in a range of from about 70 mg BID to about 180 mg BID; such as when the amount is about 150 mg BID. The pharmacological benefits (in vivo) of the compound of Formula I have been found to be reliably obtainable at 150 mg BID, as evidenced by the Examples hereinbelow. 150 mg BID and similar amounts may, therefore, be effective to treat or prevent inflammation. As described herein, pharmacological benefits (in vivo) may include inhibiting the release of one or more pro-inflammatory cytokines (such as IL-ip, IL-6, IL-8, IL- 10, TNFa and COX-2); reducing the level of phosphorylated p38 MAP kinase in circulating monocytes (advantageously, by about 30% to about 97%); reducing the blood plasma concentration of one or more of IL-6, IL-8, IL-10, and TNFa; and / or reducing the blood plasma concentration of C-reactive protein (advantageously, by at least about 25%).

[0084] Thus, the therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 70 mg BID to about 180 mg BID, especially in a range of from about 80 to about 170 mg BID, more especially in a range of from about 100 to about 160 mg BID; such as about 150 mg BID.

[0085] Doses in a range of from about 70 mg BID to about 180 mg BID (such as about 150 mg BID), may better mitigate against unforeseen fluctuations in bioavailability (compared to lower doses). Meanwhile, doses in a range of from about 70 mg BID to about 180 mg BID may carry a comparatively low risk of side effects (compared to higher doses, especially those above about 200 mg BID or above about 250 mg BID). Yet further, doses in a range of from about 70 mg BID to about 180 mg BID may enable a steady-state concentration of the compound of Formula I to be reached, in blood serum, at a quicker rate than would be possible at lower doses. This may enable the compound of Formula I to be administered for a shorter overall period of time, which may minimise the total amount of the compound of Formula I administered to the patient in question, thereby mitigating against the risk of side effects.

[0086] Doses in a range of from about 70 mg BID to about 180 mg BID (such as about 150 mg BID) may be especially suitable when a short-term dosing regime is adopted (thus reducing the risk of side effects resulting from long-term dosing regimes). As set out in the section “Safety and tolerability” of the Examples hereinbelow, no serious adverse events occurred when the compound of Formula I was delivered at 150 mg BID for a number of days (and then stopped).

[0087] Thus, the therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 70 mg BID to about 180 mg BID (such as about 150 mg BID) when the compound of Formula I is administered for about 1 to about 50 days (only; i.e., and then stopped), especially about 7 to about 25 days (only; i.e., and then stopped). The therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 70 mg BID to about 180 mg BID (such as about 150 mg BID) when the compound of Formula I is administered beginning about 1 to about 7 days before the onset of inflammation, especially about 4 to about 7 days before the onset of inflammation, up to about 1 to about 14 days following the onset of inflammation (and then stopped).

[0088] Doses in a range of from about 70 mg BID to about 180 mg BID, especially in a range of from about 80 to about 170 mg BID, more especially in a range of from about 100 to about 160 mg BID (such as about 150 mg BID) may be suitable for oral and / or intravenous administration, especially oral administration.

[0089] Thus, the therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 70 mg BID to about 180 mg BID, especially in a range of from about 80 to about 170 mg BID, more especially in a range of from about 100 to about 160 mg BID (such as about 150 mg BID), when the compound of Formula I is administered orally for about 1 to about 50 days (only; i.e., and then stopped), especially about 7 to about 25 days (only; i.e., and then stopped).

[0090] The therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 70 mg BID to about 180 mg BID, especially in a range of from about 80 to about 170 mg BID, more especially in a range of from about 100 to about 160 mg BID (such as about 150 mg BID), when the compound of Formula I is administered orally, beginning about 1 to about 7 days before the onset of inflammation, especially about 4 to about 7 days before the onset of inflammation, up to about 1 to about 14 days following the onset of inflammation (and then stopped).

[0091] The therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 100 mg BID to about 200 mg BID, especially about 120 mg BID to about 180 mg BID; such, for example, as being about 150 mg BID. Such amounts may provide an appropriate set of pharmacological benefits (in vivo), with low risk of side effects and may mitigate against unforeseen fluctuations in bioavailability.

[0092] As described herein, the inflammation may be or comprise cancer immunotherapy-induced cytokine release syndrome. The therapeutically or prophylactically effective amount of the compound of Formula I may be in a range of from about 70 mg BID to about 180 mg BID (especially in a range of from about 80 to about 170 mg BID, more especially in a range of from about 100 to about 160 mg BID; such as being about 150 mg BID) when the compound of Formula I is administered (especially, when it is administered orally) beginning about 1 to about 7 days before commencing the cancer immunotherapy (which may be an infusion of cancer immunotherapy), especially about 4 to about 7 days before commencing the cancer immunotherapy, up to about 1 to about 14 days after the end of the cancer immunotherapy (and then stopped).

[0093] As described herein, the compound of Formula I may suitable be administered orally and / or intravenously.

[0094] It has been found that the compound of Formula I is suitable for parenteral administration, especially intravenous administration. Thus, the compound of Formula I may be administered parenterally, especially intravenously.

[0095] It has been found that the compound of Formula I is especially suitable for oral or enteral delivery, especially oral delivery. Thus, the compound of Formula I may be administered orally, preferably in the form of a capsule or tablet, especially a tablet. Advantageously, it has been found that the compound of Formula I may be provided in a tablet form that is stable in that it does not degrade or crumble upon storage.

[0096] Advantageously, oral administration may be convenient in an outpatient setting. Oral administration may enable systemic delivery of the compound of Formula I, which may be especially suitable where the inflammation is systemic. The compound of Formula I may be delivered in the form of an oral suspension, such, for example, as an oral suspension prepared extemporaneously. The oral suspension may contain the compound of Formula I at a concentration in a range of from 0.1 to 20 mg / mL, especially from 1 to 10 mg / mL, more especially from 1 to 8 mg / mL. The oral suspension may preferably be in the form of an aqueous suspension. The suspension (such, for example, as when it is aqueous) may be in the form of a syrup or gel.

[0097] The compound of Formula I may suitably be administered for about 1 to about 60 days (only; i.e., and then stopped), more preferably for about 6 to about 40 days (only; i.e., and then stopped). As used herein, the term “a day” has the meaning conventional in the art, i.e., about 24 hours.

[0098] The compound of Formula I may suitably be administered for about 1 to about 16 days (only; i.e., and then stopped). Preferably, the compound of Formula I is administered for about 6 to about 16 days (only; i.e., and then stopped). To do so may be especially preferred when the inflammation is or comprises inflammation associated with severe influenza (i.e. complicated influenza). It may be especially preferred when the inflammation is or comprises hypercytokinemia.

[0099] The compound of Formula I may suitably be administered for about 1 to about 50 days (only; i.e., and then stopped). Preferably, the compound of Formula I is administered for about 7 to about 40 days (only; i.e., and then stopped), or even for about 7 to about 25 days (only; i.e., and then stopped). To do so may be especially preferred when the inflammation is or comprises cancer immunotherapy-induced CRS.

[0100] It has been found that administering the compound of Formula I for the time periods disclosed herein may provide pharmacological benefits as described herein without unwanted side effects, the risk of which might be anticipated to increase when the compound is administered for longer periods of time. The compound of Formula I may suitably be administered beginning about 1 to about 7 days before the onset of inflammation. The compound of Formula I may suitably be administered beginning about 2 to about 7 days before the onset of inflammation. The compound of Formula I may suitably be administered beginning about 3 to about 7 days before the onset of inflammation. Preferably, the compound of Formula I is administered beginning about 4 to about 7 days before the onset of inflammation. This may enable a steady state blood plasma concentration of the compound of Formula I to be established by the onset of inflammation, which may enhance its prophylactic and therapeutic effects as described herein. Such timing may especially be preferred when the compound of Formula I is administered orally or intravenously, most especially orally.

[0101] The compound of Formula I may be administered until up to about 1 to about 14 days following the onset of inflammation, such as up to about 6 to about 14 days following the onset of inflammation (and then stopped). The compound of Formula I may be administered up to about 14 days after the onset of inflammation, especially up to about 9 days after the onset of inflammation, more especially up to about 6 days after the onset of inflammation (and then stopped). Such timing may especially be preferred when the compound of Formula I is administered orally or intravenously, most especially orally.

[0102] The compound of Formula I may be administered beginning about 1 to about 7 days before the onset of inflammation, especially about 4 to about 7 days before the onset of inflammation, until up to about 1 to about 14 days following the onset of inflammation, such as up to about 6 to about 14 days following the onset of inflammation (and then stopped). The compound of Formula I may suitably be administered beginning about 1 to about 7 days before the onset of inflammation (especially, beginning about 4 to about 7 days before the onset of inflammation) up to about 14 days after the onset of inflammation, especially up to about 9 days after the onset of inflammation, more especially up to about 6 days after the onset of inflammation (and then stopped). In a preferred example, the compound of Formula I is administered beginning about 4 days before the onset of inflammation up to about 6 days after the onset of inflammation (and then stopped).

[0103] As described herein, the inflammation may be or comprise cancer immunotherapy -induced cytokine release syndrome. The compound of Formula I may suitably be administered beginning about 1 to about 7 days before commencing the cancer immunotherapy (which may be an infusion of cancer immunotherapy), especially beginning about 2 to about 7 days before commencing the cancer immunotherapy. The compound of Formula I may even be administered beginning about 3 to about 7 days before commencing the cancer immunotherapy, or beginning about 4 to about 7 days before commencing the cancer immunotherapy. Pre-dosing in this way may enable a steady state blood plasma concentration of the compound of Formula I to be established by the onset of inflammation (induced by said cancer immunotherapy), which may enhance its prophylactic and therapeutic effects as described herein. Such timing may especially be preferred when the compound of Formula I is administered orally or intravenously, most especially orally.

[0104] The compound of Formula I may be administered until up to about 1 to about 14 days after the end of the cancer immunotherapy (which may be an infusion of cancer immunotherapy), such as up to about 6 to about 14 days after the end of the cancer immunotherapy (and then stopped). The compound of Formula I may be administered up to about 14 days after the end of the cancer immunotherapy, especially up to about 9 days after the end of the cancer immunotherapy, more especially up to about 6 days after the end of the cancer immunotherapy (and then stopped). Such timing may especially be preferred when the compound of Formula I is administered orally or intravenously, most especially orally.

[0105] The compound of Formula I may be administered beginning about 1 to about 7 days before commencing the cancer immunotherapy (which may be an infusion of cancer immunotherapy), especially beginning about 4 to about 7 days before commencing the cancer immunotherapy, up to about 1 to about 14 days after the end of the cancer immunotherapy, such as up to about 6 to about 14 days after the end of the cancer immunotherapy (and then stopped). The compound of Formula I may suitably be administered beginning about 1 to about 7 days before commencing the cancer immunotherapy (especially, beginning about 4 to about 7 days before commencing the cancer immunotherapy), up to about 14 days after the end of the cancer immunotherapy, especially up to about 9 days after the end of the cancer immunotherapy, more especially up to about 6 days after the end of the cancer immunotherapy (and then stopped). In a preferred example, the compound of Formula I is administered beginning about 4 days before said commencing the cancer immunotherapy up to about 6 days after the end of the cancer immunotherapy (and then stopped).

[0106] The compound of Formula I may be administered before the onset of inflammation such that the concentration of the compound of Formula I in blood serum reaches a steady state at or prior to the onset of inflammation. The compound of Formula I may be administered for a period of time after the onset of inflammation such that the concentration of the compound of Formula I in blood serum remains at a steady state during the inflammation. Administration of the compound of Formula I may be stopped when inflammation, or the risk of inflammation, ends (for example, as determined by a physician). In this way, the beneficial effects of the compound of Formula I may be obtained during a precise period without unnecessary pre-dosing or post-dosing.

[0107] The compound of Formula I may be administered beginning more than one (especially, more than two) half-lives of the compound of Formula I before the onset of inflammation (it will be appreciated this refers to half-lives of the compound of Formula I in vivo, in a human patient). This may aid in the establishment of a steady state plasma concentration of the compound prior to the onset of inflammation. The compound of Formula I may suitably be administered beginning from a time point in a range of about 3 to about 7 half-lives before the onset of inflammation. The compound of Formula I may be administered beginning from a time point in a range of about 4 to about 5 half-lives before the onset of inflammation. In this way, the beneficial effects of the compound of Formula I may be obtained during a precise period without unnecessary pre-dosing or post-dosing. The half-life of the compound of Formula I in vivo in a human patient may refer to an average (such as the mean or median) half-life of the compound of Formula I in vivo in a human patient. This may be determined by a manner routine in the art, such as in the course of a clinical trial. Without wishing to be bound by theory, it is thought that the mean or median half-life of the compound of Formula I in vivo in a human patient may be in a range of from about 5 hours to about 25 hours, particularly about 10 to about 15 hours.

[0108] As described herein, the inflammation may be or comprise cancer immunotherapy -induced cytokine release syndrome. The compound of Formula I may be administered before commencing the cancer immunotherapy (which may be an infusion of cancer immunotherapy), such that the concentration of the compound of Formula I in blood serum reaches a steady state at or prior to commencing the cancer immunotherapy. The compound of Formula I may be administered for a period of time after the end of the cancer immunotherapy such that the concentration of the compound of Formula I in blood serum remains at a steady state during inflammation induced by said cancer immunotherapy. Administration of the compound of Formula I may be stopped when inflammation, or the risk of inflammation, ends (for example, as determined by a physician). In this way, the beneficial effects of the compound of Formula I may be obtained during a precise period without unnecessary pre-dosing or post-dosing.

[0109] The compound of Formula I may be administered beginning more than one (especially, more than two) half-lives of the compound, in vivo in a human patient, before commencing the cancer immunotherapy (which may be an infusion of cancer immunotherapy). This may aid in the establishment of a steady-state plasma concentration prior to the onset of inflammation induced by cancer immunotherapy. The compound of Formula I may suitably be administered beginning from a time period corresponding to about 3 to about 7 half-lives of the compound, in vivo in a human patient, before commencing the cancer immunotherapy. More preferably, the compound of Formula I may suitably be administered beginning from a time period corresponding to about 4 to about 5 half-lives of the compound, in vivo in a human patient, before beginning the cancer immunotherapy. In this way, the beneficial effects of the compound of Formula I may be obtained during a precise period without unnecessary pre-dosing or post-dosing.

[0110] In some embodiments, the compound of Formula I may be administered at or after the onset of inflammation. Optionally in such embodiments it (the compound of Formula I) is administered for about 1 to about 14 days, preferably about 6 to about 10 days (and then stopped). Suitably in such embodiments the compound of Formula I is administered intravenously.

[0111] When the inflammation is induced by cancer immunotherapy, the compound of Formula I may be administered at or after the beginning of the cancer immunotherapy (which may be an infusion of cancer immunotherapy). Optionally in such embodiments it (the compound of Formula I) is administered for about 1 to about 14 days, preferably about 6 to about 10 days (and then stopped). Suitably in such embodiments the compound of Formula I is administered intravenously.

[0112] The compound of Formula I may inhibit the release of one or more pro- inflammatory cytokines. Especially, the compound of Formula I may inhibit the release of one or more pro-inflammatory cytokines from immune cells. The compound of Formula I may inhibit the release of one or more of IL-ip, IL-6, IL-8, IL- 10, TNFa and COX-2 (especially, from immune cells). In certain preferred embodiments, the compound of Formula I inhibits the release of one or more (especially, all) of IL-6, IL- 8 and TNFa (especially, from immune cells).

[0113] The compound of Formula I may reduce the blood plasma concentration of one or more of IL-6, IL-8, IL- 10, and TNFa. In certain preferred embodiments, the compound of Formula I reduces the blood plasma concentration of one or more (especially, all) of IL-6, IL-8 and TNFa. The compound of Formula I may reduce the level of phosphorylated p38 MAP kinase in circulating monocytes. Advantageously, the compound of Formula I may reduce the level of phosphorylated p38 MAP kinase in circulating monocytes by about 30% to about 97%.

[0114] C-reactive protein (“CRP”) is an annular pentameric protein of hepatic origin, found in blood plasma. The concentration of CRP in the blood plasma rises in response to inflammation, especially following IL-6 secretion by immune cells. The compound of Formula I may reduce the concentration of C-reactive protein in blood plasma. Advantageously, the compound of Formula I may reduce the concentration of C- reactive protein in blood plasma by at least about 25%.

[0115] The compound of Formula I may reduce heart rate elevation associated with inflammation.

[0116] Preferably, the method of the first aspect of the present disclosure comprises administering (preferably, orally) about 31 to about 69 mg BID (more preferably, about 41 to about 69 mg BID) or about 71 to about 149 mg BID (especially, about 75 to about 120 mg BID) of the compound of Formula I (or a pharmaceutically acceptable salt or solvate thereof), for about 6 to about 10 days (preferably, beginning about 4 to about 7 days before the onset of inflammation). It has been found that such a method may achieve optimal pharmacological effects (as described herein), advantageous for the prophylactic and / or therapeutic action of the compound of Formula I; without unwanted side effects which may be anticipated if the compound is to be administered at higher doses and / or for a longer time period.

[0117] In a third aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in a method according to the first aspect of the disclosure.

[0118] In preferred embodiments, the pharmaceutical composition may be a pharmaceutical composition suitable for oral administration. Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of the compound of Formula I as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.

[0119] Such dosage forms may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the compound of Formula I into association with a carrier, which constitutes one or more ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately admixing the compound of Formula I with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound of Formula I in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0120] The compound of Formula I may be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. In preparing the pharmaceutical compositions for an oral dosage form, any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents may be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. In some embodiments, tablets may be coated by standard aqueous or non-aqueous techniques.

[0121] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0122] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0123] Disintegrants may be used in the pharmaceutical compositions disclosed herein to provide tablets that disintegrate when exposed to an aqueous environment. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. For example, about 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that may be used to form pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[0124] Lubricants which may be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant may optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0125] When aqueous suspensions and / or elixirs are desired for oral administration, the compound of Formula I therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, for example, emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0126] Tablet dosage forms as disclosed herein may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the compound of Formula I is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the compound of Formula I is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0127] In some embodiments, the pharmaceutical composition may include one or more surfactants. Surfactants which may be used to form the pharmaceutical composition include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. A mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0128] In some embodiments, the pharmaceutical composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound of Formula I and to minimize precipitation of the compound of Formula I. A solubilizer may also be added to increase the solubility of the compound of Formula I and / or other components, such as surfactants, or to maintain the pharmaceutical composition as a stable or homogeneous solution or dispersion.

[0129] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, 8-caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl tri ethyl citrate, acetyl tributyl citrate, tri ethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, s-caprolactone and isomers thereof, 6-valerolactone and isomers thereof, P-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[0130] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. In some embodiments, solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol. The amount of solubilizer that may be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the pharmaceutical composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer may be in a weight ratio of about 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as about 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.

[0131] The pharmaceutical composition may further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, oils, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0132] Exemplary preservatives may include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxy anisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl. In certain embodiments, the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.

[0133] Exemplary oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyl dodecanol, oleyl alcohol, silicone oil, and combinations thereof. In addition, an acid or a base may be incorporated into the pharmaceutical composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate may also be used. When the base is a salt, the cation may be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[0134] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. In some embodiments, provided herein are pharmaceutical compositions for parenteral administration, especially intravenous administration, containing the compound of Formula I as disclosed herein, and a pharmaceutical excipient suitable for parenteral administration.

[0135] The forms in which the disclosed pharmaceutical compositions may be incorporated for intravenous administration include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0136] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention or attenuation of the action of microorganisms may be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0137] A preferred mode of administration according to the present disclosure may be or involve intravenous infusion of a solution or dispersion of the compound of Formula I. Thus, the present disclosure especially comprehends a pharmaceutical composition wherein the compound of Formula I is incorporated in a powder for the preparation of such a solution or dispersion. The powder may be a vacuum-dried or freeze-dried (lyophilized) powder, comprising the compound of Formula I and, optionally, suitable excipients and / or additives. Suitably the powder may contain a sufficient amount of the compound of Formula I that when made up to form a solution for infusion, the concentration of active agent in the solution is suitable to achieve the required dosage amount per hour at an infusion rate of about 500-3000 mL / 24h. Sterile injectable solutions may be prepared by incorporating the compound of Formula I as disclosed herein in the required amount in the appropriate solvent with various other ingredients as enumerated above, as appropriate, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the sterilized compound of Formula I into a sterile vehicle which contains the basic dispersion medium and the appropriate other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the compound of Formula I plus any additional ingredient from a previously sterile- filtered solution thereof.

[0138] The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Injectable compositions may contain from about 0.1 to about 5% w / w of the compound of Formula I as disclosed herein.

[0139] In some embodiments, provided herein are pharmaceutical compositions for controlled release administration containing the compound of Formula I as disclosed herein, and a pharmaceutical excipient suitable for controlled release administration.

[0140] The compound of Formula I may be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Such dosage forms may be used to provide slow or controlled release of the compound of Formula I using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, may be readily selected for use with the compound of Formula I disclosed herein. Thus, the pharmaceutical compositions provided encompass single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled release.

[0141] All controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. In some embodiments, the use of a controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the disease, disorder, or condition in a minimum amount of time. Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled release formulations may be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and may thus affect the occurrence of side (e.g., adverse) effects.

[0142] In some embodiments, controlled release formulations are designed to initially release an amount of the compound of Formula I as disclosed herein that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of the compound of Formula I to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of the compound in the body, the compound of Formula I should be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of the compound of Formula I may be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0143] In certain embodiments, the pharmaceutical composition may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, or other modes of administration. In one embodiment, a pump may be used. In another embodiment, polymeric materials may be used. In yet another embodiment, a controlled release system may be placed in a subject at an appropriate site determined by a practitioner of skill, e.g., thus requiring only a fraction of the systemic dose. In a fourth aspect, the present disclosure provides the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in a method according to the first aspect of the disclosure.

[0144] Also provided, in a fifth aspect, is the use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in a method according to the first aspect of the disclosure.

[0145] EXAMPLES

[0146] Lipopolysaccharide (LPS) is a bacterial product. Isolated LPS may be administered to humans (mammals) to mimic infection and leads to activation of the immune system. Challenging healthy human volunteers with LPS locally or systemically may therefore be used to provide a model for local or systemic inflammation respectively.

[0147] Study design

[0148] Figure 1 illustrates the design of a single-centre, randomized, double blinded, placebo-controlled, multiple dose human challenge study, in which 36 healthy volunteers (without history of inflammatory diseases, use of anti-inflammatory medicine or other inflammatory complications) were orally administered 30, 70 or 150 mg of the compound of Formula I or placebo, twice daily (BID) (3: 1 investigational medicinal product (IMP) to placebo) for 7 days. As shown in Figure 1, each subject was challenged with four doses of intradermal LPS on Day 4 and one dose of intravenous LPS on Day 6 leading, respectively, to local and systemic inflammation. Each intradermal dose of LPS was 5 ng (thus a total of 20 ng across the four doses), injected into a small cut in the skin of the volar forearm. Each intravenous dose of LPS was a bolus of 1 ng / kg. Purified LPS was used, obtained as LPS Escherichia Coir. 113: H10:K negative (U.S. Standard Reference Endotoxin) provided by List Biological Laboratories of 540 Division Street, Campbell, California 95008, US. Each oral dose of the compound of Formula I was in the form of an extemporaneously prepared suspension. The required quantity of the compound of Formula I (30, 70 or 150 mg) was dispersed in 20 mL Syrspend® Cherry SF PH4 Suspending Base in a dosing bottle and mixed until fully dispersed, according to the following protocol.

[0149] 1. Dispense 20 mL of Syrspend® Cherry SF PH4 suspending base.

[0150] 2. Weigh the required amount of the compound of Formula I (30, 70 or 150 mg).

[0151] 3. Mix the compound of Formula I from (2.) with the suspending base until a homogenous dispersion is obtained.

[0152] 4. If required, formulations may be ground using a mortar and pestle, sonicated, homogenized and stirred overnight to assist dispersion of the compound of Formula I in the suspending base.

[0153] Calculated as ae, 100% and free of water

[0154] Syrspend® Cherry SF PH4 Suspending Base is a standard commercial aqueous vehicle for extemporaneous compounding of a wide range of drug molecules as oral liquid formulations and is available from Fagron UK Ltd, Newcastle upon Tyne, UK; it has the appearance of a hazy, white translucent syrup. Physical and chemical stability of the compound of Formula I in Syrspend® Cherry SF PH Suspending Base at 1.5 and 7.5 mg / mL was confirmed by HPLC after 14 days under refrigerated (2-8°C), ambient (15-25 °C), and accelerated (40 °C) storage conditions, protected from light in amber PET bottles. The study aimed to observe the effect of the compound of Formula I on local and systemic inflammatory responses following LPS challenge, including cytokine analysis, pharmacokinetic analysis and the safety and tolerability of the compound of Formula I; including any dose-dependent effects of the compound of Formula I.

[0155] Results

[0156] Reducing systemic inflammation

[0157] Markers of systemic inflammation include mean body temperature, heart rate and the concentration of C-reactive protein in blood plasma.

[0158] Figure 2 illustrates mean body temperature 3 hours post intravenous LPS challenge. Mean body temperature decreases in a dose-dependent fashion with administration of the compound of Formula I. Both the 70 mg and 150 mg groups showed a particularly beneficial reduction in mean body temperature.

[0159] Figure 3 illustrates the rise in heart rate produced by intravenous LPS challenge (as shown in Figure 3, LPS was administered at Day 6 0 hours; following which, heart rate was monitored at intervals). The rise is dampened in an initially dose-dependent fashion by administration of the compound of Formula I. However, the reduction in heart rate rise was similar for the 70 mg and 150 mg groups, suggesting this advantageous effect of the compound of Formula I may be maximally obtainable without raising the dose far above 70 mg BID (e.g., without raising it to 150 mg BID).

[0160] Meanwhile, Figure 4 illustrates the mean concentration of C-reactive protein in blood plasma 24 hours post intravenous LPS challenge. This too decreases in an initially dose-dependent fashion with administration of the compound of Formula I. CRP was reduced by 33.1 % for the 70 mg group, in comparison with a CRP reduction of 33.3 % for the 150 mg group, suggesting this advantageous effect of the compound of Formula I may also be obtainable without raising the dose far above 70 mg BID (e.g., without raising it to 150 mg BID). Figures 5A to 5C illustrate the concentration of cytokines TNF-a, IL-6 and IL- 8 in blood plasma (pg / ml) post intravenous LPS challenge (as shown in Figures 5A to 5C, LPS was administered at Day 6 0 hours; following which, the concentration of TNF-a, IL-6 and IL-8 in blood plasma was monitored at intervals). Notably, there were observed: a TNF-a reduction of 73.5% and 56.2% for 70 mg and 150 mg respectively (p = 0.0003); an IL-6 reduction of 57.4% and 63.5% for 70 mg and 150 mg respectively (p = 0.0002); and an IL-8 reduction of 80.7% and 76.7% for 70 mg and 150 mg respectively (p < 0.0001). These results suggest that in terms of the effect on pro- inflammatory cytokines, the 70 mg BID dosage regime may be just as beneficial as the 150 mg BID regime.

[0161] Reducing local inflammation

[0162] The compound of Formula I was found to dampen localised cytokine expression, as shown in Figure 6 which shows TNF-a amounts (pg / ml) in a skin blister following intradermal LPS challenge. The concentration of TNF-a decreases in a dosedependent fashion with administration of the compound of Formula I. Nevertheless, the TNF-a curves shown in Figure 6 for the 70 mg BID and 150 mg BID groups are close, suggesting the benefit may be obtainable without raising the dose far above 70 mg BID (e.g., without raising it to 150 mg BID).

[0163] Figure 7 shows LCS images of blood perfusion into tissues in a blister for a volunteer administered placebo, compared to a volunteer dosed with 150 mg of the compound of Formula I. Inflammation is increased in the blister with placebo, compared to with 150 mg of the compound of Formula I.

[0164] The compound of Formula I was also found to reduce LPS-driven immune cell attraction and cytokine responses in the skin (most notable for neutrophils (72.4-81.5%, P = 0.0091), classical monocytes (68.4-73.6%, P = 0.0036), CD3+ T cells (56.4-65.9%, P = 0.0047), myeloid dendritic cells (59-64.4%, P = 0.0174), and TNF (35.3-65.1%, P = 0.0099)). Pharmacokinetics

[0165] The compound of Formula I was found to achieve a steady state concentration in blood serum on Day 3 of the study. Figure 8 shows the concentration of the compound of Formula I in serum (ng / mL) on Day 6, following first administration (in the BID dosing regime). A dose-dependent increase in Cmax (maximum concentration) and AUC12H (area under curve at 12 hours post-administration) of the compound of Formula I was observed over the investigated dosing range. Peak concentrations occurred at a median Tmax of 3h (range: 2.98-6.00h) on Day 4 for all treatment groups. On Day 6, peak concentrations occurred at a median Tmax of 1.5h (range: 1.00-4.17h) for the 30 mg group, and at a median Tmax of Ih (range: 1.00-1.50h) for the 70 mg and 150 mg groups. At Day 1 for the 150 mg group, peak concentrations occurred at a median Tmax of Ih (range: l.OO-l.OOh). A mean (± SD) Cmax of 1087.9±384.88 ng / mL for the 30 mg group, 2598.9±949.64 ng / mL for the 70 mg group and 3953.3±768.98 ng / mL for the 150 mg group was observed on Day 4. On Day 6, a mean (± SD) Cmax of 1087.1±459.63 ng / mL for 30 mg, 2971.1±1224.96 ng / mL for 70 mg and 5407.8±1977.06 ng / mL for 150 mg was observed.

[0166] Despite the difference in the circulating amount of the compound of Formula I at steady state shown in Figure 8 for 70 mg vs. 150 mg BID dosing, the pharmacological benefits at 70 mg BID and 150 mg BID are surprisingly similar. Notably, Figures 3 and 4 show similar reductions in systemic inflammation (as evidenced by reduced heart rate and reduced circulating C-reactive protein, respectively) at 70 mg BID and 150 mg BID. Figures 5A-C show reductions in pro- inflammatory cytokines at 70 mg BID very similar to those observed at 150 mg BID. Figure 6 shows similar reductions in TNF-a in blister extrudate (a proxy for local inflammation) at 70 mg BID and 150 mg BID. Accordingly, although the effects of the compound of Formula I appear to be dose-dependent, its beneficial effects on local and / or systemic inflammation may plateau at doses in a range between 70 mg BID and 150 mg BID, especially about 75 to about 120 mg. Safety and tolerability

[0167] No deaths or serious adverse events occurred during the study. The most commonly reported adverse event was mild headache, with the highest number of participants and events in the placebo group (8 (88.9%) subjects and 14 events) followed by the 30 mg group (6 (66.7%) subjects and 11 events). Therefore, headache was attributed to LPS and not to the compound of Formula I. Other reported AEs were also mild. These included mild chills (also more frequent in placebo group) and mild dizziness (placebo, 30, 70, 150 mg groups, frequency 22.2%, 11.1%, 33.3%, 22.2%, respectively).

[0168] Summarising, the (orally delivered) compound of Formula I is widely distributed, well-tolerated and safe at the doses tested (30, 70 or 150 mg BID). It reduces the inflammatory response following local and systemic LPS challenge. It is thought to do so by binding and inhibiting p38 mitogen activated protein kinase (MAPK); as shown in Figure 9, p38 MAPK phosphorylation in CD14+ monocytes was significantly reduced across all active treatment groups (by 32.0-60.9%). Surprisingly, while the reduction in p38 MAPK phosphorylation was dose-dependent, the difference between the 70 mg and 150 mg groups was small. This may provide further support for a range of about 71 to about 149 mg BID, especially about 75 to about 120 mg BID, providing a “sweet spot” wherein an effective dose is administered while minimising the risk of significant unwanted side effects.

[0169] Where in the foregoing description, features or limitations are mentioned which have equivalents that are known, evident or foreseeable to those skilled in the art in the light of the present disclosure, then such equivalents are incorporated herein as if particularly set forth. Reference should be made primarily to the claims for determining the scope of the subject-matter of the present disclosure. The scope of protection sought by the present application further encompasses any such equivalents. It will also be appreciated by those skilled in the art that features or limitations of the disclosed subject-matter that are described as preferable, suitable, advantageous, convenient or the like may be optional and may not limit the scope of the independent claim(s) or the protection sought unless explicitly stated otherwise. Moreover, it is to be understood that such optional features or limitations, while of potential benefit in some implementations of the disclosed subject-matter, may be undesirable, and may therefore be absent or omitted in other implementations.

Claims

Claims1. A method of treating or preventing inflammation in a human patient in need thereof, comprising administering to the patient a therapeutically or prophylactically effective amount of a compound of Formula I:Formula I or a pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1, wherein the therapeutically or prophylactically effective amount is in a range of from about 20 to about 200 mg BID.

3. The method of claim 2, wherein the therapeutically or prophylactically effective amount is in a range of from about 70 to about 180 mg BID.

4. The method of claim 3, wherein the therapeutically or prophylactically effective amount is about 110 mg BID or about 150 mg BID.

5. The method of claim 2, wherein the therapeutically or prophylactically effective amount is in a range of from about 60 to about 150 mg BID.

6. The method of claim 5, wherein the therapeutically or prophylactically effective amount is in a range of from about 75 to about 120 mg BID.

7. The method of claim 6, wherein the therapeutically or prophylactically effective amount is about 110 mg BID.

8. The method of any one of the preceding claims, wherein the compound of Formula I is administered for a period in a range of about 1 to about 60 days only.

9. The method of claim 8, wherein the compound of Formula I is administered for a period in a range of about 6 to about 40 days only.

10. The method of any one of the preceding claims, wherein the compound of Formula I is administered beginning about 1 to about 7 days before the onset of inflammation.

11. The method of claim 10, wherein the compound of Formula I is administered beginning about 4 to about 7 days before the onset of inflammation.

12. The method of any one of the preceding claims, wherein the compound of Formula I is administered before the onset of inflammation such the concentration of the compound of Formula I in blood serum reaches a steady state at or prior to the onset of inflammation.

13. The method of any one of the preceding claims, wherein the inflammation is induced by cancer immunotherapy.

14. The method of claim 13, wherein the compound of Formula I is administered beginning about 1 to about 7 days before commencing the cancer immunotherapy.

15. The method of claim 14, wherein the compound of Formula I is administered beginning about 4 to about 7 days before commencing the cancer immunotherapy.

16. The method of any one of claims 12 to 15, wherein the compound of Formula I is administered up to about 1 to about 14 days after the end of the cancer immunotherapy (and then stopped).

17. The method of any one of claims 12 to 16, wherein the compound of Formula I is administered before commencing the cancer immunotherapy such that the concentration of the compound of Formula I in blood serum reaches a steady state at or prior to the onset of inflammation induced by the cancer immunotherapy.

18. The method of any one of the preceding claims, wherein the compound of Formula I is administered orally.

19. The method of any one of the preceding claims, wherein the compound of Formula I is administered intravenously.

20. The method of any one of the preceding claims, wherein the compound of Formula I inhibits the release of one or more pro-inflammatory cytokines from immune cells.

21. The method of claim 20, wherein the compound of Formula I inhibits the release of one or more of IL-ip, IL-6, IL-8, IL-10, TNFa and COX-2 from immune cells.

22. The method of any one of the preceding claims, wherein the compound of Formula I reduces the blood plasma level of one or more of IL-6, IL-8, IL-10, and TNFa.

23. The method of any one of the preceding claims, wherein the compound of Formula I reduces the level of phosphorylated p38 MAP kinase in circulating monocytes.

24. The method of any one of the preceding claims, wherein the compound of Formula I reduces the blood plasma concentration of C-reactive protein.

25. The method of claim 24, wherein the compound of Formula I reduces the blood plasma concentration of C-reactive protein by at least about 25%.

26. The method of any one of the preceding claims, wherein the compound of Formula I reduces heart rate elevation associated with the inflammation.

27. A compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in a method according to any one of the preceding claims.

28. A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in a method according to any one of claims 1 to 26.

29. Use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in a method according to any one of claims 1 to 26.

30. Use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in a method according to any one of claims 1 to 26.

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