Fl ELD OF THE I NVENTI ON

The present invention relates to (S) -cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis. I n particular, the present invention relates to the use of (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, in a novel dose and dosage regimen for the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis. The present invention is further directed to pharmaceutical compositions comprising said compound for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis by said novel dose or dosage regimen. The present invention further relates to methods of treating a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis through administration of (S)-cyclopentyl 2- cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl ) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, under a novel dose and dosage regimen.

BACKGROUN D TO TH E I NVENTI ON

Rheumatoid arthritis is a chronic inflammatory joint disease that affects approximately 1 % of the population in the industrialised world. I t affects approximately 3 times more women than men and onset is generally between 40 - 60 years of age. Rheumatoid arthritis is characterised by hyperplasia and inflammation of the synovial membrane, inflammation within the synovial fluid, and progressive destruction of the surrounding bone and cartilage. I t is a painful and debilitating condition , which can result in severe disability and ultimately affects a sufferer's ability to perform simple everyday tasks. Effects of rheumatoid arthritis vary between individuals, but the disease can progress very rapidly, causing swelling and damaging cartilage and bone around the joints. Any joint may be affected but most commonly the hands, feet and wrists.

I n rheumatoid arthritis, macrophages and monocytes become activated and infiltrate the synovial membranes, secreting inflammatory cytokines such as tumour necrosis factor alpha (TNFa) and interleukins, such as I L-1 , I L-6 and I L-8 (Li, 2013) . These cytokines activate fibroblast-like synoviocytes which produce enzymes that damage the bones and cartilage.

Disease-modifying antirheumatic drugs ( DMARDS) are the fundamental treatment for patients with rheumatoid arthritis. Methotrexate (MTX) is the current gold standard treatment and it effectively reduces clinical disease measures in a large population of patients. However, only 30% of RA patients will have low disease activity with MTX alone and in the population failing to respond, combination treatment with biological DMARDS targeted to cytokines, B-cells or T-cells, is the preferred treatment option (O'Dell, 2013) . A subset of these patients will still fail to achieve meaningful responses to treatment, or experience adverse events, and will continue to experience severely debilitating symptoms (Rubbert-Roth , 2009) . Histone deacetylase (HDAC) inhibitors have been shown to be active in various models of inflammation (Lin, 2007; Nishida, 2004; Joosten , 201 1 ; Gauben , 2008) . The role of HDAC inhibitors in cancer, neurological diseases and immune disorders has been reviewed ( Falkenberg KJ et al, Nat Rev Drug Discov, 13, 673-691 , (2014) . However, there is a concern that, because of the pleiotropic activity, it may be challenging to obtain a therapeutic window wide enough to allow their extensive use in the treatment of chronic inflammatory diseases, such as rheumatoid arthritis.

The most studied HDAC inhibitor is the hydroxamic acid based compound vorinostat and this was approved in 2006 by the Food and Drug Association (FDA) for use in the treatment of cutaneous T-cell lymphoma (CTCL) . No HDAC inhibitor, however, including vorinostat, has been approved for use in the treatment of a chronic inflammatory or autoimmune disease, such as rheumatoid arthritis.

I nternational Patent Application Publication Number WO 2008/040934 discloses a series of HDAC inhibitors, one of which is (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate.

I n light of the above, it is clear that there is a current unmet need for more effective treatments for chronic inflammatory and/or autoimmune diseases, such as rheumatoid arthritis. I n particular, there exists a need for an efficacious treatment for chronic inflammatory and/or autoimmune diseases, such as rheumatoid arthritis that has a suitable safety profile.

SUMMARY OF TH E I NVENTI ON

I n a first aspect, the present invention provides (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate , or a pharmaceutically acceptable salt thereof, for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, in a human or animal subject, by administration in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day.

I n a further aspect, the present invention provides a pharmaceutical composition for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein the pharmaceutical composition comprises from about 10 mg to about 40 mg of (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for administration twice a week, three times a week, or every other day.

I n a further aspect, the present invention provides a pharmaceutical composition comprising (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg, and a pharmaceutically acceptable excipient.

I n yet a further aspect, the present invention provides a method of treating a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, which method comprises administering to a human or animal subject in need thereof (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate , or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg twice a week, three times a week, or every other day.

DESCRI PTI ON OF DRAW I NGS/ Fl GURES

FI G. 1 (a)— (f) Data from a clinical study evaluating (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate in healthy volunteers. Figure 1 shows the absolute monocyte counts over time obtained under the single ascending dose part of the study ( Part A) .

FI G. 2 (a)-(e) Data from a clinical study evaluating (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate in healthy volunteers. Figure 2 shows the absolute monocyte counts over time obtained under the multiple ascending dose part of the study ( Part B)

FI G. 3 Data from a clinical study evaluating (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)- 3-oxopropyl)pyridin-3-yl) methyl)amino)acetate in healthy volunteers. Figure 3 shows the concentration of acid in monocytes and non-monocytes obtained under the single ascending dose part of the study ( Part A)

FI G. 4 Data from a clinical study evaluating (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)- 3-oxopropyl)pyridin-3-yl) methyl)amino)acetate in healthy volunteers. Figure 4 shows the concentration of acid in monocytes and non-monocytes on Day 1 and Day 7 obtained under the multiple ascending dose part of the study (Part B)

FI G. 5 Data from a clinical study evaluating (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)- 3-oxopropyl)pyridin-3-yl) methyl)amino)acetate in healthy volunteers. Figure 5 shows the mean % change in acetylation of monocytes and non-monocytes obtained under the single ascending dose part of the study (Part A)

FI G. 6 Data from a clinical study evaluating (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)- 3-oxopropyl)pyridin-3-yl) methyl)amino)acetate in healthy volunteers. Figure 6 shows thMean % Change in Acetylation of Monocytes and No n- Monocytes obtained under the multiple ascending dose part of the study (Part B)

FI G. 7A/B: Monocyte Count Profiling by K-PD Modelling. Medians (solid and dashed lines) and their 80% prediction intervals (grey ribbons) from 300 simulations considering inter-subject variability, when administering three every other day doses of 20 and 40 mg of the compound of the invention .

FI G. 7C: Medians (solid and dashed lines) and their 80% prediction intervals (grey ribbons) from 300 simulations considering inter-subject variability, when administering three every day doses of 20 and

40 mg of the compound of the invention .

FI G. 7D: Medians (solid and dashed lines) and their 80% prediction intervals (grey ribbons) from 300 simulations considering inter-subject variability, when administering two doses of 20 and 40 mg of the compound of the invention , each one every three days (Q3D strategy) . DETAI LED DESCRI PTI ON OF THE I NVENTI ON

DEFI NI TI ONS

As used herein , the term "DMARD" refers to "Disease-Modifying Anti-Rheumatic Drugs" and includes among others hydroxycloroquine, sulfasalazine, methotrexate, leflunomide, azathioprine, D- penicillamine, gold salts (oral) , gold salts (intramuscular) , minocycline, cyclosporine including cyclosporine A and topical cyclosporine, and TNF-inhibitors (e.g. etanercept ( ENBREL) , infliximab ( REM I CADE) , adalimumab (HUMI RA) , certolizumab pegol (CI MZI A) , and golimumab (SI MPONI ^® )) , including salts, variants, and derivatives thereof . Exemplary DMARDs herein are non-biological, i.e. classic DMARDs, including azathioprine, chloroquine, hydroxychloroquine, leflunomide, methotrexate and sulfasalazine. I n one embodiment, the DMARD is methotrexate.

As used herein, the phrase "every other day" means on alternate days and thus in the context of a drug administration regime, there is a day when the dose is not administered between each day when a dose is administered. An example of an "every other day" dosing regimen would be dosing on Day 1 , Day 3, Day 5, Day 7, with no dosing on the days inbetween (i.e. Day 2, Day 4, Day 6, Day 8 etc) .

As used herein, the phrase "twice a week" means that in a typical week consisting of seven days, there are two days when a subject is administered a dose of the compound of the invention and five days when the subject is not administered a dose of the compound of the invention. An example of a "twice a week" dosing regimen would be dosing on a Monday (e.g. Day 1 ) and Thursday (e.g. Day 4) .

As used herein , the phrase "three times a week" means that in a typical week consisting of seven days, there are three days when a subject is administered a dose of the compound of the invention and four days when the subject is not administered a dose of the compound of the invention. An example of a "three times a week" dosing regimen would be dosing on a Monday (e.g. Day 1 ) , Wednesday (e.g. Day 3) and Friday (e.g. Day 5) .

As used herein , the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compound in question and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. Furthermore, pharmaceutically-acceptable salts of the compound in question , (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate, may be prepared during further processing of the free acid or base form, for example in situ during manufacture into a pharmaceutical composition.

As used herein, the term "treatment" refers to ameliorating or stabilising the specified condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject. As used herein, the term "subject" refers to an animal or human body.

References herein to "compound of the invention" mean (S)-cyclopentyl 2-cyclohexyl-2-(((6- (3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof.

(S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, may be in crystalline or amorphous form , each of which are included within the scope of the present invention. The most thermodynamically stable crystalline form is of particular interest. Crystalline forms may be characterised and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD) , infrared spectroscopy ( I R) , Raman spectroscopy, differential scanning calorimetry ( DSC) , thermogravimetric analysis (TGA) and solid-state nuclear magnetic resonance (ssNMR) .

I n one embodiment, there is provided a crystalline solid state form of (S)-cyclopentyl 2- cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl ) methyl)amino)acetate. I n a further embodiment, there is provided an amorphous form of (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl) amino)acetate.

STATEMENT OF THE I NVENTI ON

I n a first aspect, the present invention provides (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate , or a pharmaceutically acceptable salt thereof, for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, in a human or animal subject, by administration in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day. I n one embodiment, administration is every other day.

I n a further aspect, the present invention provides a pharmaceutical composition for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein the pharmaceutical composition comprises from about 10 mg to about 40 mg of (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for administration twice a week, three times a week, or every other day. I n one embodiment, administration is every other day.

I n a further aspect, the present invention provides a pharmaceutical composition comprising (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg, and a pharmaceutically acceptable excipient.

I n a further aspect, the present invention provides a method of treating a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, which method comprises administering to a human or animal subject in need thereof (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate , or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg twice a week, three times a week, or every other day. I n one embodiment, administration is every other day.

I n yet a further aspect, the present invention provides the use of (S)-cyclopentyl 2- cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl ) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate is for administration in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day.

(S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate is an inhibitor of histone deacetylase (HDAC) enzymes and is disclosed in I nternational Patent Application Publication Number WO 2008/040934 as Example 62. This compound has the following chemical structure:

(S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate is also known by the chemical name cyclopentyl (2S)-cyclohexyl[ ({ 6-[3- (hydroxyamino)-3-oxopropyl] pyridine-3-yl} methyl)amino] acetate.

This compound comprises an alpha amino acid ester moiety that facilitates delivery of the compound into the cell. The molecule comprising the alpha amino acid ester is not charged and is freely transported through the cell wall. Once inside the cell, the alpha amino acid ester undergoes hydrolysis by intracellular carboxylesterases, particularly hCE-1 , to the corresponding carboxylic acid, (S)-2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridi n-3-yl)methyl)amino)acetic acid, shown below. Being charged, the acid is not readily transported out of the cell and thus the intracellular concentration of the inhibitor increases, leading to an increase in cellular potency and duration of action . The acid which is disclosed in I nternational Patent Application Publication Number WO 2008/040934 as Example 103 has the following chemical structure:

(S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino) -3-oxopropyl)pyridin-3- yl) methyl)amino)acetate has been the subject of an initial, Phase 1 clinical study in healthy human volunteers. I n this first clinical study, cohorts of healthy male volunteers received doses of the compound either as single ascending doses up to 60 mg (Part A of the study) or as multiple ascending doses of up to 40 mg once daily for a period of 7 days (Part B of the study) . A decision was made to not complete the final planned cohort at 60 mg in order to further investigate an unexpected pharmacodynamic observation. Following both single and multiple doses, the study team observed a significant reduction in the levels of circulating monocytes. I n Part A, from Cohort 2 ( 10 mg) onwards there was a decrease in the monocyte count observed at 4 hours and which showed a greater decrease at 24 hours post dosing. I n Part B, in both cohorts (20 mg and 40 mg, each once daily) , rapid depletion of monocytes was observed which then plateaued around Day 2.

The clinical significance of depleting circulating monocytes is poorly understood given the diverse functions of monocytes in the body and the complimentary roles of other immune cell types. However, it is thought that selective depletion of circulating monocytes (which may also be known by the term "isolated-monocytopaenia") may, for example, decrease a person's immunological defence mechanisms and thus make them more susceptible to infection.

Monocytes are a subset of circulating white blood cells and bloodstream monocytes are derived from the precursors in the bone marrow. Human monocytes are divided into subsets on the basis of surface CD14 and CD16 expression. The classical monocytes, CD14 ⁺⁺ CD16 ^" monocytes, are the most prevalent subset in human blood. The CD16 ⁺ monocytes comprises two subsets, CD14 ⁺ CD16 ⁺⁺ (non-classical) and CD14 ^{+ +} CD16 ⁺ (intermediate) .

Monocytes are part of the host anti-microbial defence system . Recruitment of monocytes has been shown to contribute to the control and clearance of multiple infective agents by trafficking to sites of infections where they secrete cytokines and chemokines, by differentiation into cells such as macrophages and dendritic cells and by direct killing of microbes (Serbina, N.V. , Jia, T. , Hohl, T. M. & Pamer, E. G. , Monocyte-mediated defense against microbial pathogens. Annu. Rev. Immunol. 26, 421 - 452 (2008)) . Examples of pathogens controlled by monocytes include, but are not limited to, bacteria such as Listeria monocytogenes (Pamer, E.G. I mmune responses to Listeria monocytogenes. Nature Rev. Immunol. 4, 812-823 (2004) and Mycobacterium tuberculosis ( Peters, W. et al. Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 98, 7958-7963 (2001 )) , viruses such as Herpes simplex virus and West Nile virus (Lim, J. K. et al. Chemokine receptor Ccr2 is critical for monocyte accumulation and survival in west nile virus encephalitis. J. Immunol. 1 86 , 471 -478 (201 1 )) , fungi such as Cryptococcus neoformans (Traynor, T. R. , Kuziel, W. A. , Toews, G. B. & Huffnagle, G. B. CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection. J. Immunol. 1 64 , 2021 -2027 (2000)) and protozoan parasites such as Toxoplasma gondii ( Dunay, I . R. et al. Gr1 + inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity 29, 306-317 (2008)) and Leishmania major ( Leon, B. , Lopez-Bravo, M. Ardavin, C. Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity 2 , 519-531 (2007)) .

Following completion of the clinical study, we conducted a number of mechanistic studies to investigate the observed depletion of circulating monocytes.

We have now surprisingly found that (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate or a pharmaceutically acceptable salt thereof administered via a particular dosage regimen disclosed herein has the potential to provide an efficacious and safe treatment for a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis. I n particular, in a first aspect the present invention provides (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, in a human or animal subject, by administration in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day.

I n a further aspect, the present invention provides (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, in a human or animal subject, by administration for at least 7 days in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day.

I n a further aspect the present invention provides (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-

(hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, in a human or animal subject, by administration every other day in an amount of about 10 mg to about 40 mg.

I n a further aspect, the present invention provides a pharmaceutical composition for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein the pharmaceutical composition comprises from about 10 mg to about 40 mg of (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for administration twice a week, three times a week, or every other day.

I n a further aspect, the present invention provides a pharmaceutical composition for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein the pharmaceutical composition comprises from about 10 mg to about 40 mg of (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for administration twice a week, three times a week, or every other day for at least 7 days.

I n a further aspect, the present invention provides a pharmaceutical composition for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein the pharmaceutical composition comprises from about 10 mg to about 40 mg of (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for administration every other day.

I n a further aspect, the present invention provides a pharmaceutical composition comprising (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg, and a pharmaceutically acceptable excipient.

I n yet a further aspect, the present invention provides the use of (S)-cyclopentyl 2- cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl ) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate is for administration in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day.

I n yet a further aspect, the present invention provides a method of a chronic inflammatory and/or autoimmune disease, such as treating rheumatoid arthritis, which method comprises administering to a human or animal subject in need thereof (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate , or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day.

I n yet a further aspect, the present invention provides a method of a chronic inflammatory and/or autoimmune disease, such as treating rheumatoid arthritis, which method comprises administering to a human or animal subject in need thereof (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate , or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day for at least 7 days.

I n yet a further aspect, the present invention provides a method of a chronic inflammatory and/or autoimmune disease, such as treating rheumatoid arthritis, which method comprises administering to a human or animal subject in need thereof (S) -cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate , or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg every other day.

I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, is administered in an amount of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg.

I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, is administered every other day in an amount of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg.

I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, is administered twice a week in an amount of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg.

I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, is administered three times a week in an amount of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg.

I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, is administered in an amount of between 10 mg and 20 mg, between 20 mg and 30 mg, or between 30 mg and 40 mg.

I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, is administered every other day in an amount between 10 mg and 20 mg, between 20 mg and 30 mg, or between 30 mg and 40 mg.

I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, is administered twice a week in an amount between 10 mg and 20 mg, between 20 mg and 30 mg, between 30 mg and 40 mg, between 40 mg and 50 mg, or between 50 mg and 60 mg.

I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, is administered three times a week in an amount between 10 mg and 20 mg, between 20 mg and 30 mg, or between 30 mg and 40 mg.

I n a further embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof, is administered every other day in an amount of about 40 mg.

I n particular, in one embodiment the present invention provides (S)-cyclopentyl 2- cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl ) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, in a human or animal subject, by administration every other day in an amount of about 40 mg.

I n a further embodiment, the present invention provides a pharmaceutical composition for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein the pharmaceutical composition comprises about 40 mg of (S)-cyclopentyl 2- cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl ) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for administration every other day.

I n a further embodiment, the present invention provides a pharmaceutical composition comprising (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 40 mg, and a pharmaceutically acceptable excipient.

I n yet a further aspect, the present invention provides a method of treating a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, which method comprises administering to a human or animal subject in need thereof (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 40 mg every other day.

Our data suggests that dosing the compound of the invention according to a regimen as described herein (e.g. every other day dosing) within the dose range specified permits monocyte recovery during each dosing interval. Thus, not only is the monocyte depletion reversible but that levels can recover either fully or partially to an acceptable level within the interval between doses and hence prior to administration of a subsequent dose. Thus, dosing according to a regimen described herein (e.g. every other day dosing) within the specified range disclosed herein prevents prolonged depletion of this population of leukocytes. The dosage regimens of the present invention thus aim to minimise the potentially adverse effects of sustained monocyte depletion, while advantageously maintaining therapeutic efficacy with the compound of the invention.

I ncomplete or partial recovery of monocytes under a dosing strategy according to the present invention (i.e. such that there remains a degree of monocyte depletion but the levels of monocytes remain above that which may trigger adverse effects of sustained monocyte depletion) may enhance the therapeutic benefit in the treatment of a chronic inflammatory and/or autoimmune disease, in particular rheumatoid arthritis. Monocytes are central to the pathophysiology of rheumatoid arthritis. They are present in large numbers in inflamed joints and contribute to pathology through the release of cytokines and chemokines which drive inflammation and also via maturation into inflammatory macrophages and osteoclasts (C. A. Roberts et al, Frontiers in I mmunology, Vol. 6, Article 571 , (2015)) . Monocytes in the circulation of rheumatoid arthritis patients have also been shown to have an activated phenotype.

I n one embodiment, administration of a compound of the invention according to a dosing regimen described herein in an amount of about 10 mg to about 40 mg permits recovery of circulating monocytes prior to administration of the next dose, wherein recovery is between 30% and 100% (e.g. greater than 30% , 40% , 50% , 60% , 70% , 80% , or 90% ) of the normal baseline level prior to treatment with a compound of the invention .

I n a further embodiment, administration of a compound of the invention every other day in an amount of about 20 mg to about 40 mg permits recovery of circulating monocytes prior to administration of the next dose, wherein recovery is between 50% and 80% (e.g. greater than 50% , 60% , or 70% ) of the normal baseline level prior to treatment with a compound of the invention.

I n a further embodiment, administration of a compound of the invention every other day in an amount of about 20 mg permits recovery of circulating monocytes prior to administration of the next dose, wherein recovery is between 60% and 80% (e.g. greater than 60% , or 70% ) of the normal baseline level pre-treatment with a compound of the invention.

I n a further embodiment, administration of a compound of the invention every other day in an amount of about 40 mg permits recovery of circulating monocytes prior to administration of the next dose, wherein recovery is between 50% and 70% (e.g. greater than 50% or 60%) of the normal baseline level prior to treatment with a compound of the invention.

Furthermore, we have also surprisingly found from a mechanistic study in a mouse model that the effect observed, i.e. partial or complete recovery of monocyte levels before subsequent dosing, is reproducible following multiple doses. Therefore, prolonged use of (S)-cyclopentyl 2- cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl ) methyl)amino)acetate in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis according to a dosage regimen described herein is not likely to result in cumulative monocytopaenia, in which the magnitude of monocyte recovery diminishes over time and with each subsequent dose.

Whilst the administration of (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day may provide a safer therapy for the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, this administration strategy may also maintain or enhance efficacy.

MEDI CAL USE

The dosage regimens described herein are for use in the treatment of inflammatory and/or autoimmune diseases in a human or animal subject. I n one embodiment, the dosage regimens described herein are for use in the treatment of chronic inflammatory and/or autoimmune diseases in a human or animal subject. I n one embodiment, the subject is a human.

Autoimmune and/or inflammatory conditions (e.g. chronic autoimmune and/or inflammatory conditions) include rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupus erythematosus, pulmonary arterial hypertension (PAH) , multiple sclerosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis) , asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis (including atopic dermatitis) , alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, hypercholesterolemia, atherosclerosis, Alzheimer's disease, depression, Sjogren's syndrome, sialoadenitis, central retinal vein occlusion, branched retinal vein occlusion , I rvine-Gass syndrome (post cataract and post-surgical) , retinitis pigmentosa, pars planitis, birdshot retinochoroidopathy, epiretinal membrane, cystic macular odema, parafoveal telengiectasis, tractional maculopathies, vitreomacular traction syndromes, retinal detachment, neuroretinitis, idiopathic macular odema, retinitis, dry eye (keratoconjunctivitis Sicca) , vernal keratoconjunctivitis, atopic keratoconjunctivitis, uveitis (such as anterior uveitis, pan uveitis, posterior uveitis, uveitis- associated macular odema) , scleritis, diabetic retinopathy, diabetic macula odema, age-related macular dystrophy, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, pyoderma gangrenosum, vasculitis with organ involvement, acute rejection of transplanted organs, and juvenile idiopathic arthritis (e.g. systemic-onset, persistent or extended oligoarthritis, RF- negative polyarthritis, RF-positive polyarthritis, psoriatic, enthesitis-related, and undifferentiated) .

I n another embodiment, the chronic autoimmune and/or inflammatory condition is a systemic inflammatory disorder such as rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupus erythematosus, multiple sclerosis or inflammatory bowel disease (Crohn's disease and ulcerative colitis) .

The dose and dosage regimens described herein may further find use in the treatment of viral infections and cancer. Viral infections include herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus (HPV) , human immunodeficiency virus (HI V) , cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus. I n one embodiment, the viral infection is HI V infection. Cancers include haematological (such as leukaemia, lymphoma and multiple myeloma) , epithelial including lung, breast and colon carcinomas, midline carcinomas, mesenchymal, hepatic, renal and neurological tumours. Also brain cancer (gliomas) , glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, colorectal cancer, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma cancer, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukaemia, chronic myelogenous leukaemia, chronic lymphocytic leukaemia, hairy-cell leukaemia, acute lymphoblastic leukaemia, acute myelogenous leukaemia, chronic neutrophilic leukaemia, acute lymphoblastic T-cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia, multiple myeloma, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, mixed lineage leukaaemia, erythroleukaemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GI ST (gastrointestinal stromal tumor) , NUT-midline carcinoma and testicular cancer.

I n one embodiment, the cancer is a leukaemia, for example a leukaemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukaemia (MLL) .

The use of a compound of the invention via a novel dosage regimen in the treatment of rheumatoid arthritis is of particular interest. Rheumatoid arthritis is an autoimmune disease characterised by chronic inflammation of synovial tissue, leading to destruction of the joint architecture. I t is a painful and debilitating condition, which can result in severe disability and ultimately affects a sufferer's ability to perform simple everyday tasks. Effects of rheumatoid arthritis vary between individuals, but the disease can progress very rapidly, causing swelling and damaging cartilage and bone around the joints. Any joint may be affected but most commonly the hands, feet and wrists.

I n rheumatoid arthritis, macrophages and monocytes become activated and infiltrate the synovial membranes, secreting inflammatory cytokines such as tumour necrosis factor alpha (TNFa) and interleukins, such as I L-1 , I L-6 and I L-8 (Li, 2013) . These cytokines activate fibroblast-like synoviocytes which produce enzymes that damage the bones and cartilage.

I n one embodiment, the dosage regimens described herein are for use in the treatment of moderate to severe rheumatoid arthritis. A commonly used method for classifiying disease activity in rheumatoid arthritis patients is Disease Activity Score of 28 joints (DAS 28). A DAS28 of <3.2 is classified as inactive. A DAS28 of > 3.2 but < 5.1 is classified as moderate rheumatoid arthritis. A DAS28 of > 5.1 is classified as severe.

I n a further embodiment, the dosage regimens described herein are for use in the treatment of severe rheumatoid arthritis. I n a further embodiment, the dosage regimens described herein are for use in the treatment of severe rheumatoid arthritis, i.e. wherein the patient has a DAS28 of > 5.1 . I n yet a futher embodiment, the dosage regimens described herein are for use in the treatment of subjects with severe rheumatoid arthritis despite treatment with existing therapies, such as conventional and biological disease modifying anti-rheumatic drugs ( DMARDs) .

I n a separate and further aspect of the invention, there is provided the compound of the invention for use in the treatment of autoimmune and/or inflammatory conditions. I n a further aspect of the present invention, there is provided a method of treatment of an autoimmune and/or inflammatory condition , which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention . I n yet a further aspect, the present invention is directed to the use of a compound of the invention in the manufacture of a medicament for use in the treatment of an autoimmune and/or inflammatory condition.

I n one embodiment, there is provided the compound of the invention for use in the treatment of arthritis, for example rheumatoid arthritis (e.g. severe rheumatoid arthritis) .

I n a further aspect of the present invention, there is provided a method of treatment of arthritis (for example rheumatoid arthritis (e.g. severe rheumatoid arthritis) , which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention. I n yet a further aspect, the present invention is directed to the use of a compound of the invention in the manufacture of a medicament for use in the treatment of arthritis (for example rheumatoid arthritis (e.g. severe rheumatoid arthritis)) .

Moreover, data disclosed herein (e.g. Example 2) demonstrate that the compound of the invention possesses monocyte-depletion activity (e.g. depletion of circulating blood monocytes) separate from an HDAC inhibitory effect, and thus may be used to effectively deplete circulating blood monocytes. This property may be exploited in the treatment or prevention of diseases (e.g. autoimmune and/or inflammatory diseases, and cancers) where monocytes are known to play an important role in the development and progression of the disease. I n one embodiment,

administration of the compound of the invention results in depletion of circulating blood monocytes. Mechanistic studies reported herein demonstrate that the surprising monocyte-depleting activity of the compound of the invention is not observed with non-targeted HDAC inhibitors (SAHA was used in Example 3, Study 3) . This effect was, however, observed for an analogue of the compound of the invention.

I n one aspect, there is provided an HDAC inhibitor comprising a carboxylesterase sensitive motif for use in the treatment of prevention of an autoimmune and/or inflammatory condition , wherein the HDAC inhibitor is administered at a dose which results in depletion of circulating blood monocytes. As used herein the term "HDAC inhibitor comprising a carboxylesterase sensitive motif" refers to a covalent conjugate of an HDAC inhibitor and an alpha amino acid ester, wherein the ester group of the alpha amino acid ester is hydrolysable by one or more intracellular carboxylesterases to the corresponding carboxylic acid. Covalent conjugates of an HDAC inhibitor and an alpha amino acid ester are disclosed in, for example, WO2006/ 1 17567, WO2006/ 1 17549, WO2008/040934, WO2008/053131 , WO2009/ 106848, WO2006/ 1 17548, WO2008/053131 , WO2008/040934, WO2010/097586, WO2012/025701 , , and each of these covalent conjugates (e.g. tefinostat, which is also known as CHR-2845, or a pharmaceutically acceptable salt thereof) are incorporated herein by reference and may be utilised in the methods of treatment/medical uses described herein below.

I n one aspect of the invention, there is provided the compound of the invention for use in the treatment or prevention of an autoimmune and/or inflammatory disease, wherein the compound of the invention is administered at a dose which results in depletion of circulating blood monocytes. I n a further aspect of the present invention, there is provided a method of treatment or prevention of an autoimmune and/or inflammatory condition, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention , wherein the compound of the invention is administered at a dose which results in depletion of circulating blood monocytes. I n yet a further aspect, the present invention is directed to the use of a compound of the invention in the manufacture of a medicament for use in the treatment or prevention of an autoimmune and/or inflammatory condition, wherein the compound of the invention is administered at a dose which results in depletion of circulating blood monocytes. I n a further embodiment, depletion of circulating blood monocytes may be prolonged depletion, i.e. for at least the duration of the treatment period with the compound of the invention . I n a further embodiment, administration of a compound of the invention results in depletion of circulating monocytes to between 10% and 90% (e.g. between 10% and 30% , or less than 20% , 30% , 40% , 50% , 60% , 70% , or 80% ) of the normal baseline level prior to treatment with a compound of the invention. I n a further embodiment, administration of a compound of the invention results in depletion of circulating monocytes to between 10% and 30% of the normal baseline level prior to treatment with a compound of the invention .

I n a further aspect of the invention, there is provided a method of modulating monocytes (e.g. circulating blood monocytes) and/or macrophages and/or dendritic cells in a subject comprising administration to the subject in need thereof a therapeutically effective amount of an HDAC inhibitor comprising a carboxylesterase sensitive motif. I n a further aspect of the invention, there is provided a method of modulating monocytes (e.g. circulating blood monocytes) and/or macrophages and/or dendritic cells in a subject comprising administration to the subject in need thereof a therapeutically effective amount of a compound of the invention. I n one embodiment, the subject has been diagnosed with an autoimmune and/or inflammatory disease and/or cancer. I n a further embodiment, the present invention provides a method of modulating monocytes (e.g. circulating blood monocytes) and/or macrophages and/or dendritic cells in a subject comprising administration to the subject in need thereof a therapeutically effective amount of a compound of the invention, wherein the subject has been diagnosed with an autoimmune and/or inflammatory disease, and wherein the method decreases, reduces, suppresses, limits, or inhibits an undesired or aberrant immune or inflammatory component of an autoimmune and/or inflammatory disease.

I n a further aspect of the invention, there is provided a method of modulating monocytes (e.g. circulating blood monocytes) in a subject comprising administration to the subject in need thereof a therapeutically effective amount of an HDAC inhibitor comprising a carboxylesterase sensitive motif. I n a further aspect of the invention, there is provided a method of modulating monocytes (e.g. circulating blood monocytes) in a subject comprising administration to the subject in need thereof a therapeutically effective amount of a compound of the invention . I n one embodiment, the subject has been diagnosed with an autoimmune and/or inflammatory disease and/or cancer. I n a further embodiment, the present invention provides a method of modulating monocytes (e.g. circulating blood monocytes) in a subject comprising administration to the subject in need thereof a therapeutically effective amount of a compound of the invention , wherein the subject has been diagnosed with an autoimmune and/or inflammatory disease, and wherein the method decreases, reduces, suppresses, limits, or inhibits an undesired or aberrant immune or inflammatory component of an autoimmune and/or inflammatory disease.

I n a further aspect, the present invention provides a compound of the invention for use in a method of modulating monocytes (e.g. circulating blood monocytes) and/or macrophages and/or dendritic cells in a subject. I n one embodiment, the subject has been diagnosed with an autoimmune and/or inflammatory disease and/or cancer. I n a further embodiment, the present invention provides a compound of the invention for use in a method of modulating monocytes (e.g. circulating blood monocytes)and/or macrophages and/or dendritic cells in a subject who has been diagnosed with an autoimmune and/or inflammatory disease and/or cancer. I n a further embodiment, the present invention provides a compound of the invention for use in a method of modulating monocytes (e.g. circulating blood monocytes) and/or macrophages and/or dendritic cells in a subject, wherein the method decreases, reduces, suppresses, limits, or inhibits an undesired or aberrant immune or inflammatory component of an autoimmune and/or inflammatory disease. I n one embodiment, the subject whose monocytes and/or macrophages and/or dendritic cells will be modulated following administration of a compound of the invention is at risk of developing or has been diagnosed with an autoimmune and/or inflammatory condition as set forth herein.

I n a further aspect, the present invention provides a compound of the invention for use in a method of modulating monocytes (e.g. circulating blood monocytes) in a subject. I n one embodiment, the subject has been diagnosed with an autoimmune and/or inflammatory disease and/or cancer. I n a further embodiment, the present invention provides a compound of the invention for use in a method of modulating monocytes (e.g. circulating blood monocytes) in a subject who has been diagnosed with an autoimmune and/or inflammatory disease and/or cancer. I n a further embodiment, the present invention provides a compound of the invention for use in a method of modulating monocytes (e.g. circulating blood monocytes) in a subject, wherein the method decreases, reduces, suppresses, limits, or inhibits an undesired or aberrant immune or inflammatory component of an autoimmune and/or inflammatory disease. I n one embodiment, the subject whose monocytes will be modulated following administration of a compound of the invention is at risk of developing or has been diagnosed with an autoimmune and/or inflammatory condition as set forth herein.

The present invention is further directed to a method for attenuating monocyte hyperactivity in a subject (e.g. a human subject) comprising administering to the subject in need thereof a therapeutically effective amount of an HDAC inhibitor comprising a carboxylesterase sensitive motif, wherein monocyte hyperactivity is attenuated. The present invention is further directed to a method for attenuating monocyte hyperactivity in a subject (e.g. a human subject) comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the invention, wherein monocyte hyperactivity is attenuated. I n a further aspect, the present invention provides a compound of the invention for use in attenuating monocyte hyperactivity in a subject (e.g. a human subject) . I n one embodiment, the subject with monocyte hyperactivity is at risk of developing or has been diagnosed with an autoimmune and/or inflammatory disease as set forth herein .

I n one embodiment, the subject is a human subject.

As used herein, the term "at risk" refers to those subjects who have a high probability of developing a disease, determined by, for example, genetic predisposition (i.e. family history and/or detection of one or more genetic polymorphisms or mutations) , biomarker analysis and/or imaging.

As used herein, the term "modulating, depleting or attenuating" refers to decreasing or reducing (e.g. the amount of circulating blood monocytes) either permanently (e.g. apoptosis) or transiently (e.g. margination or retention in tissues and/or decreased production) . Monocyte levels, unless otherwise specified, may be decreased or reduced to between 10% and 90% (e.g. less than 20% , 30% , 40% , 50% , 60% , 70% , or 80% ) of the normal baseline level prior to treatment with a compound of the invention . The normal baseline level may be determined by performing a Full Blood Count ( FBC) test. FBC is a well-known, standard test that provides information about the types of cells in a subject's blood, for example cell count for each cell type. I n one embodiment, the monocyte level, unless otherwise specified, may be decreased or reduced to between 10% and 90% (e.g. between 10% and 30% , or less than 20% , 30% , 40% , 50% , 60% , 70% , or 80% ) of the normal monocyte range of 0.2 - 1 .5 x 10 ⁹ cells/L. Depletion or reduction of monocytes refers to depletion or reduction of one or more of the three recognised subsets of monocytes: classical, non-classical and intermediate. I n one embodiment, all subsets of monocytes are depleted/reduced/modulated/ attenuated.

Many autoimmune and inflammatory diseases have been linked to over-activation of the immune system , and the dysregulation of monocyte and macrophage functions (see, for example, S T Gren et al, Role of Monocytes and I ntestinal Macrophages in Crohn's Disease and Ulcerative Colitis, I nflamm Bowel Dis, Vol 22, No. 8, August 2016) . Furthermore, inflammation has been suggested to play a key role in the pathogenesis of atrial fibrillation (AF) with one study investigating whether peripheral monocyte TLR expression was associated with AF presence, and recurrence of AF after cryoablation, as a reflection of inflammatory status (see K M Gurses et al, Monocyte Toll-Like Receptor Expression in Patients with Atrial Fibrillation, Am J Cardiol, 2016, 1 17, p1463-1467) .

I n one embodiment, autoimmune and/or inflammatory diseases that may be treated or prevented with a compound of the invention, via depletion/modulation/reduction/attenuation of monocytes (e.g. circulating blood monocytes) include inflammatory bowel disease (Crohn's disease and ulcerative colitis) , non-alcoholic steato hepatitis (NASH) , and primary biliary cirrhosis ( PBC) . I n a further embodiment, autoimmune and/or inflammatory diseases that may be treated with a compound of the invention, via depletion/modulation/reduction/attenuation of monocytes (e.g. circulating blood monocytes) include psoriatic arthritis ( PsA) , ankylosing spondylitis (AS) , atrial fibrillation, and juvenile idiopathic arthritis (e.g. systemic-onset, persistent or extended oligoarthritis, RF-negative polyarthritis, RF-positive polyarthritis, psoriatic, enthesitis-related, and undifferentiated) . I n a further embodiment, the autoimmune and/or inflammatory disease that may be treated with a compound of the invention, via depletion/modulation/reduction/attenuation of monocytes is rheumatoid arthritis. I n a further embodiment, the autoimmune and/or inflammatory disease that may be treated with a compound of the invention, via depletion/modulation/reduction/attenuation of monocytes is multiple sclerosis. I n a further embodiment, the autoimmune and/or inflammatory disease that may be treated with a compound of the invention , via depletion/modulation/reduction/attenuation of monocytes is atherosclerosis. I n a further embodiment, the compound of the invention, via depletion/modulation/reduction/attenuation of monocytes (e.g. circulating blood monocytes) may be useful in the treatment of monocytosis.

I n a further aspect of the present invention, the capability of the compound of the invention to deplete monocytes may be useful for the treatment of monocytosis. Monocytosis, which occurs during chronic inflammation , is an increase in the number of monocytes circulating in the blood. I n one embodiment, a monocyte count above 950/μΙ_ is regarded as monocytosis. I n one embodiment, there is provided a compound of the invention for use in the treatment of monocytosis. I n a further embodiment, there is provided a compound of the invention for use in the treatment of monocytosis wherein the compound of the invention results in the depletion of monocytes (e.g. circulating blood monocytes) . I n a further aspect of the present invention, there is provided a method of treatment of monocytosis, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention . I n a further aspect of the present invention , there is provided a method of treatment of monocytosis, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention, wherein the compound of the invention is administered at a dose which results in depletion of circulating blood monocytes. I n yet a further aspect, the present invention is directed to the use of a compound of the invention in the manufacture of a medicament for use in the treatment of monocytosis. I n yet a further aspect, the present invention is directed to the use of a compound of the invention in the manufacture of a medicament for use in the treatment of monocytosis, wherein the compound of the invention is administered at a dose which results in depletion of circulating blood monocytes. A subject (e.g. a human subject) diagnosed with monocytosis may have an autoimmune and/or inflammatory condition.

Embodiment 1 : The compound of the invention for use in the treatment or prevention of an autoimmune and/or inflammatory disease and/or cancer in a subject, wherein the compound of the invention is administered at a dose which results in depletion of circulating blood monocytes and/or macrophages and/or dendritic cells.

Embodiment 2: The compound for use according to Embodiment 1 , wherein depletion of circulating blood monocytes may be prolonged depletion, i.e. for at least the duration of the treatment period with the compound of the invention .

Embodiment 3: The compound for use according to Embodiment 1 or 2, wherein administration of the compound of the invention results in depletion of circulating monocytes to between 10% and 90% (e.g. between 10% and 30% , or less than 20% , 30% , 40% , 50% , 60% , 70% , or 80% ) of the normal baseline level (optionally determined by performing a Full Blood Count) determined prior to treatment with a compound of the invention .

Embodiment 4: The compound for use according to Embodiment 3, wherein administration of the compound of the invention results in depletion of circulating monocytes to between 10% and 30% of the normal baseline level (optionally determined by performing a Full Blood Count) determined prior to treatment with the compound of the invention.

Embodiment 5: The compound for use according to any of Embodiments 1 to 4, wherein the autoimmune and/or inflammatory disease is selected from the group consisting of : inflammatory bowel disease (Crohn's disease and ulcerative colitis) , non-alcoholic steato hepatitis (NASH) , primary biliary cirrhosis ( PBC) , psoriatic arthritis ( PsA) , ankylosing spondylitis (AS) , atrial fibrillation, juvenile idiopathic arthritis (e.g. systemic-onset, persistent or extended oligoarthritis, RF-negative polyarthritis, RF-positive polyarthritis, psoriatic, enthesitis-related, and undifferentiated) , rheumatoid arthritis, multiple sclerosis and atherosclerosis.

Embodiment 6: The compound for use according to any of Embodiments 1 to 5, wherein the subject is a human subject.

Embodiment 7: The compound for use according to any of Embodiments 1 to 6, wherein the compound of the invention is (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate.

Embodiment 8: The compound for use according to any of Embodiments 1 to 7, wherein the use is for the treatment of an autoimmune and/or inflammatory disease. Embodiment 9: The compound for use according to any of Embodiments 1 to 8, wherein the compound of the invention results in depletion of one or more subsets (classical, non-classical and intermediate) of circulating blood monocytes.

Embodiment 10: The compound for use according to any of Embodiments 1 to 9, wherein the compound of the invention results in depletion of all subsets (classical, non-classical and intermediate) of circulating blood monocytes.

Embodiment 1 1 : The compound of the invention for use in a method of modulating monocytes (e.g. circulating blood monocytes) and/or macrophages and/or dendritic cells in a subject.

Embodiment 12: The compound for use according to Embodiment 1 1 , wherein the monocyte (e.g. circulating blood monocytes) level is decreased or reduced to between 10% and 90% (e.g. less than 20% , 30% , 40% , 50% , 60% , 70% , or 80% ) of the normal baseline level (optionally determined by performing a Full Blood Count) determined prior to treatment with the compound of the invention.

Embodiment 13: The compound for use according to Embodiment 12, wherein administration of the compound of the invention results in depletion of circulating monocytes to between 10% and 30% of the normal baseline level (optionally determined by performing a Full Blood Count) determined prior to treatment with the compound of the invention .

Embodiment 14: The compound for use according to any of Embodiments 1 1 to 13, wherein the subject is a human subject.

Embodiment 15: The compound for use according to any of Embodiments 1 1 to 14, wherein the subject has been diagnosed with an autoimmune and/or inflammatory disease and/or cancer.

Embodiment 16: The compound for use according to any of Embodiments 1 1 to 15, wherein the subject has been diagnosed with an autoimmune and/or inflammatory disease and the compound of the invention is for the treatment of said disease.

Embodiment 17: The compound for use according to Embodiment 15 or 16, wherein the autoimmune and/or inflammatory disease is selected from the group consisting of : inflammatory bowel disease (Crohn's disease and ulcerative colitis) , non-alcoholic steato hepatitis (NASH) , primary biliary cirrhosis (PBC) , psoriatic arthritis (PsA) , ankylosing spondylitis (AS) , atrial fibrillation , juvenile idiopathic arthritis (e.g. systemic-onset, persistent or extended oligoarthritis, RF-negative polyarthritis, RF-positive polyarthritis, psoriatic, enthesitis-related, and undifferentiated) , rheumatoid arthritis, multiple sclerosis and atherosclerosis.

Embodiment 18: The compound for use according to any of Embodiments 1 1 to 17, wherein the compound of the invention is (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate.

Embodiment 19: The compound for use according to any of Embodiments 1 1 to 18, wherein the compound of the invention results in modulation of one or more subsets (classical, non-classical and intermediate) of circulating blood monocytes. Embodiment 20: The compound for use according to any of Embodiments 1 1 to 19, wherein the compound of the invention results in depletion of all subsets (classical, non-classical and intermediate) of circulating blood monocytes.

Embodiment 21 : A method of treatment or prevention of an autoimmune and/or inflammatory condition and/or cancer, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention, wherein the compound of the invention is administered at a dose which results in depletion of circulating blood monocytes.

Embodiment 22: A method of treatment according to Embodiment 21 , wherein depletion of circulating blood monocytes may be prolonged depletion, i.e. for at least the duration of the treatment period with the compound of the invention .

Embodiment 23: A method of treatment according to Embodiment 21 or 22, wherein administration of the compound of the invention results in depletion of circulating monocytes to between 10% and 90% (e.g. between 10% and 30% , or less than 20% , 30% , 40% , 50% , 60% , 70% , or 80% ) of the normal baseline level (optionally determined by performing a Full Blood Count) determined prior to treatment with a compound of the invention .

Embodiment 24: A method of treatment according to Embodiment 23, wherein administration of the compound of the invention results in depletion of circulating monocytes to between 10% and 30% of the normal baseline level (optionally determined by performing a Full Blood Count) determined prior to treatment with the compound of the invention.

Embodiment 25: A method of treatment according to any of Embodiments 21 to 24, wherein the autoimmune and/or inflammatory disease is selected from the group consisting of : inflammatory bowel disease (Crohn's disease and ulcerative colitis) , non-alcoholic steato hepatitis (NASH) , primary biliary cirrhosis ( PBC) , psoriatic arthritis ( PsA) , ankylosing spondylitis (AS) , atrial fibrillation, juvenile idiopathic arthritis (e.g. systemic-onset, persistent or extended oligoarthritis, RF-negative polyarthritis, RF-positive polyarthritis, psoriatic, enthesitis-related, and undifferentiated) , rheumatoid arthritis, multiple sclerosis and atherosclerosis.

Embodiment 26: A method of treatment according to any of Embodiments 21 to 25, wherein the subject is a human subject.

Embodiment 27: A method of treatment according to any of Embodiments 21 to 26, wherein the compound of the invention is (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate.

Embodiment 28: A method of treatment according to any of Embodiments 21 to 27, wherein the method of treatment is of an autoimmune and/or inflammatory disease.

Embodiment 29: A method of treatment according to any of Embodiments 21 to 28, wherein the compound of the invention results in depletion of one or more subsets (classical, non-classical and intermediate) of circulating blood monocytes. Embodiment 30: A method of treatment according to any of Embodiments 21 to 29, wherein the compound of the invention results in depletion of all subsets (classical, non-classical and intermediate) of circulating blood monocytes.

Embodiment 31 : A method of modulating monocytes (e.g. circulating blood monocytes) and/or macrophages and/or dendritic cells in a subject comprising administration to the subject in need thereof a therapeutically effective amount of a compound of the invention.

Embodiment 32: A method of modulating according to Embodiment 31 , wherein the monocyte (e.g. circulating blood monocytes) level in a subject is decreased or reduced to between 10% and 90% (e.g. less than 20% , 30% , 40% , 50% , 60% , 70% , or 80% ) of the normal baseline level (optionally determined by performing a Full Blood Count) determined prior to treatment with the compound of the invention.

Embodiment 33: A method of modulating according to Embodiment 32, wherein administration of the compound of the invention results in depletion of circulating monocytes to between 10% and 30% of the normal baseline level (optionally determined by performing a Full Blood Count) determined prior to treatment with the compound of the invention .

Embodiment 34: A method of modulating according to any of Embodiments 31 to 33, wherein the subject is a human subject.

Embodiment 35: A method of modulating according to any of Embodiments 31 to 34, wherein the subject has been diagnosed with an autoimmune and/or inflammatory disease and/or cancer.

Embodiment 36: A method of modulating according to any of Embodiments 31 to 35, wherein the subject has been diagnosed with an autoimmune and/or inflammatory disease and the compound of the invention is for the treatment of said disease.

Embodiment 37: A method of modulating according to Embodiment 35 or 36, wherein the autoimmune and/or inflammatory disease is selected from the group consisting of : inflammatory bowel disease (Crohn's disease and ulcerative colitis) , non-alcoholic steato hepatitis (NASH) , primary biliary cirrhosis ( PBC) , psoriatic arthritis ( PsA) , ankylosing spondylitis (AS) , atrial fibrillation, juvenile idiopathic arthritis (e.g. systemic-onset, persistent or extended oligoarthritis, RF-negative polyarthritis,

RF-positive polyarthritis, psoriatic, enthesitis-related, and undifferentiated) , rheumatoid arthritis, multiple sclerosis and atherosclerosis.

Embodiment 38: A method of modulating according to any of Embodiments 31 to 37, wherein the compound of the invention is (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate.

Embodiment 39: A method of modulating according to any of Embodiments 31 to 38, wherein the compound of the invention results in modulation of one or more subsets (classical, non-classical and intermediate) of circulating blood monocytes. Embodiment 40: A method of modulating according to any of Embodiments 31 to 39, wherein the compound of the invention results in depletion of all subsets (classical, non-classical and intermediate) of circulating blood monocytes.

PHARMACEUTI CAL COMPOSI TI ONS/ ROUTES OF ADMI Nl STRATI ON/ DOSAGES

While it is possible that for use in therapy a compound of the invention may be administered as the raw chemical, it is common to present the active ingredient as a pharmaceutical composition. I n one embodiment, the pharmaceutical composition comprising a compound of the invention further comprises a pharmaceutically acceptable excipient. I n a further embodiment, the pharmaceutical composition comprises a compound of the invention and one or more pharmaceutically acceptable excipient(s) .

I n one embodiment, there is provided a pharmaceutical composition comprising (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg, and a pharmaceutically acceptable excipient. I n a further embodiment, there is provided a pharmaceutical composition comprising (S) -cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin- 3-yl)methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg, and a pharmaceutically acceptable excipient.

I n one embodiment, the pharmaceutical composition comprises (S)-cyclopentyl 2-cyclohexyl- 2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)ami no)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 40 mg.

As would be expected, any excipients utilised must be pharmaceutically acceptable and be compatible with the other components (other excipients and the active ingredient) of the composition. I n accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical composition including admixing (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate , or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg, with a pharmaceutically acceptable excipient.

Since (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, is intended for use in pharmaceutical compositions it will be readily understood that the compound is preferably provided in substantially pure form , for example, at least 85% pure, especially at least 98% pure (% in a weight for weight basis) .

Pharmaceutical compositions for use in the treatment of rheumatoid arthritis according to the present invention may be administered orally. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the excipient(s) . Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as tablets or capsules, powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, edible foams or whips, or oil-in-water liquid emulsions or water-in-oil liquid emulsions. I n one embodiment, the pharmaceutical composition is adapted for oral administration.

I n one embodiment, the present invention provides (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, in a human or animal subject, by oral administration in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day.

I n one embodiment, the present invention provides (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate , or a pharmaceutically acceptable salt thereof, for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, in a human or animal subject, by oral administration every other day in an amount of about 10 mg to about 40 mg. I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate is administered orally in an amount of about 40 mg. I n another embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate is administered orally in an amount of about 20 mg.

I n a further embodiment, the present invention provides a pharmaceutical composition for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein the pharmaceutical composition comprises from about 10 mg to about 40 mg of (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for oral administration twice a week, three times a week, or every other day.

I n a further embodiment, the present invention provides a pharmaceutical composition for use in the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein the pharmaceutical composition comprises from about 10 mg to about 40 mg of (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for oral administration every other day. I n another embodiment, the pharmaceutical composition comprises about 40 mg of (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof. I n another embodiment, the pharmaceutical composition comprises about 20 mg of (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof.

I n a further embodiment, the present invention provides a pharmaceutical composition comprising (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for oral administration. I n another embodiment, the pharmaceutical composition comprises about 40 mg of (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof. I n another embodiment, the pharmaceutical composition comprises about 20 mg of (S)-cyclopentyl 2- cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl ) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof.

I n yet a further embodiment, the present invention provides the use of (S)-cyclopentyl 2- cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl ) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, wherein (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate is for oral administration in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day.

I n yet a further embodiment, the present invention provides a method of treating a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, which method comprises orally administering to a human or animal subject in need thereof (S)-cyclopentyl 2-cyclohexyl-2-(((6- (3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day.

I n yet a further embodiment, the present invention provides a method of treating a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, which method comprises orally administering to a human or animal subject in need thereof (S)-cyclopentyl 2-cyclohexyl-2-(((6- (3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acet ate, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg every other day.

I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate is administered orally in an amount of about 40 mg. I n another embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate is administered orally in an amount of about 20 mg.

I n yet a further embodiment, the present invention provides a method of treating a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, which method comprises orally administering to a human or animal subject in need thereof (S)-cyclopentyl 2-cyclohexyl-2-(((6- (3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acet ate, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg at a frequency of twice a week, three times a week, or every other day, wherein (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, is in the form of a pharmaceutical composition. I n yet a further embodiment, the present invention provides a method of treating a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis, which method comprises orally administering to a human or animal subject in need thereof (S)-cyclopentyl 2-cyclohexyl-2-(((6- (3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 40 mg every other day, wherein (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, or a pharmaceutically acceptable salt thereof, is in the form of a pharmaceutical composition . I n one embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate is administered orally in an amount of about 40 mg. I n another embodiment, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate is administered orally in an amount of about 20 mg.

Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage compositions are those containing the dose for an entire day or sub-dose, or an appropriate fraction thereof, of an active ingredient. Unit doses that contain a sub-dose of the recommended dose for a day may therefore be administered more than once in order to make up the total dose for a day. For example, if a dose on a particular day is 40 mg, this may be contained in one unit or in multiple units (e.g. 4 units each comprising 10 mg of active ingredient) , wherein a unit may for example be a tablet or capsule. I n one embodiment, the pharmaceutical composition is in unit dosage form . I n a further embodiment, the unit dosage form is a tablet or a capsule.

Powders suitable for incorporating into tablets or capsules may be prepared by reducing a compound of the invention to a suitable fine size (e.g. by micronisation) and mixing with a similarly prepared pharmaceutical excipient such as an edible carbohydrate, for example, starch or mannitol. Flavouring, preservative, dispersing and colouring agents, for example, may also be present.

Capsules may be made by preparing a powder mixture and filling formed gelatin sheaths.

Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, sodium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride and the like, or solid polyethylene glycol can be added to the powder mixture before the filling operation . A diluent, such as microcrystalline cellulose can also be added. A disintegrating or solubilising agent such as agar- agar, starch, methyl cellulose, bentonite, xanthan gum , calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Moreover, suitable binders, sweetening agents, flavours, and colouring agents can also be incorporated into the mixture. Suitable binders include starch (e.g. pregelatinised starch) , gelatin , natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.

I n one embodiment, each capsule comprises a compound of the invention, pregelatinised starch, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate. I n a further embodiment, each capsule comprises 10 to 40 mg of a compound of the invention , pregelatinised starch, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate. I n a further embodiment, each capsule comprises 20 mg of a compound of the invention, pregelatinised starch, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate. I n a further embodiment, each capsule comprises 40 mg of a compound of the invention, pregelatinised starch, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate.

Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin , a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. A compound of the invention can also be combined with a free flowing inert excipient and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

I n one embodiment, a tablet formulation may comprise a compound of the invention and microcrystalline cellulose, mannitol, croscarmellose sodium , hypromellose and magnesium stearate.

Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilisers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavour additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit compositions for oral administration can be microencapsulated.

COMBI NATI ON THERAPY

I n certain embodiments, (S) -cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3- oxopropyl)pyridin-3-yl) methyl)amino)acetate or a pharmaceutically acceptable salt thereof for use according to the present invention may be administered in combination with one or more (e.g. two) other therapeutic agents that treat a chronic inflammatory and/or autoimmune disease, such as rheumatoid arthritis.

For the treatment of rheumatoid arthritis, the additional therapeutic agent(s) include, for example, immunosuppressive agents, non-steroidal anti-inflammatory drugs (NSAI Ds) , disease modifying anti-rheumatic drugs (DMARDs) , such as methotrexate (MTX) , anti-B-cell surface marker antibodies, such as anti-CD20 antibodies (e.g. rituximab) , TNF-alpha-inhibitors (e.g. infliximab, adalimumab, certolizumab pegol, golimumab, or etanercept) , anti-I L-6 antibodies (e.g. tocilizumab, sirukumab) , anti-GM-CSF antibodies (e.g. an antibody having amino acid sequence and DNA sequence as provided in Figure 1 of WO 2014/044768) , corticosteroids (e.g. prednisone,

prednisolone, methylprednisolone, or dexamethasone) , and co-stimulatory modifiers, or any combination thereof. I n one embodiment, the additional therapeutic agent(s) is selected from the group consisting of non- biological DMARDs, NSAI DS, and corticosteroids.

These additional therapeutic agents may be administered via the same or a different administration route as (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin- 3-yl) methyl)amino)acetate according to the present invention. Furthermore, they may be

administered in the same dosage/dosage regimen as (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)acetate according to the present invention.

I f additional therapeutic agents are utilised, in one embodiment, the combined action of (S)- cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate and the additional therapeutic agent(s) is greater than the sum or each acting separately. The combination of two or more therapeutic agents may, thus, provide a synergistic effect.

Combination therapy with one or more additional therapeutic agents includes coadministration (simultaneous administration) and sequential or consecutive administration . Agents intended for use in combination may be formulated in separate compositions or, if the same dosage regimen can be used for all agents, a single pharmaceutical composition .

I t will be clear to a person skilled in the art that, where appropriate, the other therapeutic agent(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or as solvates, for example hydrates, to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic agent. I t will be clear also that, where appropriate, the therapeutic agents may be used in optically pure form .

EXAM PLES

Exam ple 1 : Pharmaceut ical Com positions

The following are example capsule compositions for use in therapy as described herein. References in the Examples to "the compound" or "compound" refer to (S)-cyclopentyl 2-cyclohexyl- 2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)ami no)acetate as the free base.

Table 1 : Example Capsule Composition ( 1 ) Capsules are white, opaque, hard gelatine capsules for oral administration. The capsules may be packed into high-density polyethylene (HDPE) bottles with child resistant closures and also may include a dessicant.

Exam ple 2 : Clinical St udy in Healt hy Volunteers

I n a first clinical study of the compound, cohorts of healthy male volunteers received doses of the compound either as single ascending doses up to 60 mg ( Part A: 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, and 60 mg doses) or as multiple ascending doses of up to 40 mg once daily for 7 days ( Part B: 20 mg and 40 mg doses) . This study was to determine the safety and tolerability of the compound and characterised the pharmacokinetics of the compound and its acid (the corresponding acid product is produced from hydrolysis of the ester by the intracellular esterase, carboxy-esterase- 1 (hCE-1 )) . The study also explored the pharmacodynamic profile of the compound.

The compound was found to be well tolerated ; however, a decision was made to not complete the final planned cohort at 60 mg in order to investigate the emergence of an unexpected pharmacodynamic observation : marked depletion of circulating monocytes.

Pharmacodynamics

Monocyte Counts

I n Part A, from Cohort 2 (10 mg) onwards there was a decrease in the monocyte count observed at 4 hours and which showed a greater decrease at 24 hours post dosing. I n the post-dose sample collected at post-study physical examination (performed between 4 to 7 days after the last study treatment) the decrease in monocytes had reversed (see Figure 1 ) . I n Part B, in both cohorts (20 mg and 40 mg) , rapid depletion in monocytes was seen which then plateaued around Day 2. I n the post-dose sample collected at post-study physical examination (performed between 4 to 7 days after the last study treatment) the monocyte count had returned to baseline (see Figure 2) .

Acid Retention in Monocytes

The concentration of the acid hydrolysis product in monocytes and non-monocyte cell populations was determined as part of the study.

I n Part A, the peak mean concentration of the acid in monocytes and

non-monocytes tended to occur at approximately 1 hour post-dose across all treatment groups (see Figure 3) . The mean concentration of the acid in monocytes (negatively selected from PBMCs) and in non-monocytes (remaining PBMCs) tended to increase with dose at all timepoints. Overall, concentrations of the acid tended to be higher in monocytes than in non-monocytes and remained detectable 12 hours post dose, well beyond plasma concentrations. Concentration above I C90 was maintained for up to 1 .8 hours at 20 mg and up to 7.6 hours at 40 mg after one single dose.

I n Part B, the peak mean concentration of acid in monocytes and non-monocytes tended to occur at 1 hour post-dose across both active treatment groups on Day 1 and on Day 7 (see Figure 4) . The mean concentration of acid in monocytes and non-monocytes tended to increase with dose at 1 and 4 hours post-dose at Day 1 , but not at Day 7. Concentrations of the acid tended to be much higher in monocytes than in non-monocytes from 1 hour to 12 hours post-dose. Pre-dose levels of the acid on Day 7 in monocytes were similar to levels on Day 1 , 12 hours post-dose.

Change in Acetylation Levels of Monocytes, Lymphocytes and Granulocytes Over Time

I n Part A, the level of acetylation of monocytes was greater than non-monocytes

(granulocytes and lymphocytes) from 1 hour to 12 hours post-dose from 10 mg to 60 mg, inclusive (See Figure 5) .

I n Part B, the level of acetylation of monocytes was greater than non-monocytes

(granulocytes and lymphocytes) from 1 hour to 12 hours post-dose in Cohort 1 (20 mg) and Cohort 2 (40 mg) (See Figure 6) . Monocyte acetylation was maintained beyond plasma concentrations. There was increased acetylation on Day 7 pre-dose (24 hours post-6 ^th dose) , which was further increased upon administration of a further dose of the compound.

Cytokine I nhibition

Cytokines levels were measured in fasted state. In general, for all cytokines (TNFa, IL-6, I L- 10, I FN-γ and IL- Ιβ) some degree of inhibition of LPS-induced production was observed.

I n Part A, mean percentage levels of LPS-induced TNFa and LPS-induced I L-6 were below 50% of baseline levels in Cohort 3 (20 mg, fasted) , Cohort 4 (40 mg, fasted) , Cohort 5 (60 mg) and Cohort 6 (50 mg) , and these levels remained below 50% up to 12 hours post-dose. Levels of LPS- induced I L-10 were also below 50% of baseline levels in Cohort 2 (10 mg) , Cohort 3 (20 mg, fasted) , Cohort 4 (40 mg, fasted) , Cohort 5 (60 mg) and Cohort 6 (50 mg) with levels remaining below 50% of baseline levels in Cohorts 4, 5 and 6 up to 12 hours post-dose. Mean percentage levels of LPS-induced I L- Ιβ of Cohort 4 (40 mg, fasted) , Cohort 5 (60 mg) and Cohort 6 (50 mg) , remained below 50% of baseline levels up to 12 hours post-dose.

I n Part B, mean percentage levels of LPS-induced TNFa, IL-6, I L-10, I FN-γ and IL-Ιβ were less than 50% from baseline on Day 1 , and remained below 50% of baseline levels at 12 hours post-dose on Day 7 for both cohorts. For all cytokine levels across the 2 treatment groups, there was a difference between placebo and active treatments.

[Exam ple 3 : Leukocyte Profiling Study

To investigate the reductions in monocytes observed in the Phase 1 healthy volunteer clinical study discussed above, a series of mechanistic studies were carried out, all in male hCE-1/ Es1 e mice (since rodent monocytes do not contain a homologue of hCE-1 , these transgenic mice were generated with the human hCE-1 gene under the control of the human CD68 promoter to drive expression in monocytes and macrophages [Gough et al, I mmunology, 103(3) , 351 -361 , (2001 )] . Given the high levels of plasma esterase activity in mouse blood, these transgenic mice were also crossed with an esterase-deficient ( Es1 e) mice to generate hCE-1 / Es1 e strain.) . Since rodent monocytes do not contain a homologue of hCE-1 , these transgenic mice were

generated with the human hCE-1 gene under the control of the human CD68 promoter to drive expression in monocytes and macrophages [Gough, 2001 ] . Given the high levels of plasma esterase activity in mouse blood, these transgenic mice were also crossed with an esterase-deficient ( Es1 e) mice to generate hCE-1 / Es1 e strain. The compound at 10 mg/kg/day by intraperitoneal ( I P) injection was selected as a standard dose and 6 hours was selected as the standard timepoint across all studies.

Study 1

A study was designed to evaluate effect of a single dose of the compound on leukocyte populations in the blood of male hCE1 / Es1 e mice at 1 h , 6h and 24h post dose. I n two separate experiments cardiac bleeds were taken and flow cytometry analysis showed that circulating monocytes were significantly decreased by 78 and 67% after 6h. This was confirmed by additional blood smear analysis and automated cell counting. I n summary, these studies illustrate that treatment of hCE1 / Es1 e mice with the compound administered by intraperitoneal ( I P) injection at 1 0 mg/kg resulted in a selective and significant decrease in circulating monocytes at 6h .

Study 2

This study was designed to evaluate the effects of two intraperitoneal doses of 10 mg/kg compound, (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate, on leukocyte populations in the blood of male hCE1 / Es1 e mice. Mice were dosed at 0 and 24h and circulating leukocyte levels were assessed by flow cytometry and blood smear analysis at 6h , 24h and 30h (i.e. 6h post second dose) . Flow cytometric analysis of blood showed a significant decrease in circulating monocytes at the 6h timepoint (82% ) followed by a return to levels comparable to vehicle control animals by 24h. Following a second administration of the compound at 24h there was an 84% decrease in circulating monocytes at 30h, which is a similar magnitude to that seen at 6h, indicating reproducible effects of multiple dosing. The percentage of B cells, T cells and neutrophils were unaffected.

Study 3

This study was designed to compare the effects of a single intaperitoneal dose of two targeted HDAC inhibitors ((S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate and (S)-cyclopentyl 2-cyclohexyl-2-((4-(3-(hydroxyamino)-3- oxopropyl)benzyl)amino)acetate) and the non-targeted HDAC inhibitor SAHA (vorinostat) on leukocyte populations in the blood of male hCE1 / Es1 e mice at 6h post dose. Both targeted compounds were dosed at 10 mg/kg and SAHA was dosed at 100 mg/kg. Flow cytometric analysis of CD45 ⁺ leukocytes revealed a significant decrease in monocytes by both targeted HDAC inhibitors at 6h which was not seen with SAHA. However, SAHA caused an increase in circulating granulocytes. I n order to exclude the possibility that this influx might be impacting the analysis of monocytes (when expressed as % CD45 ⁺ leukocytes) the data were re-analysed excluding granulocytes. Upon reanalysis the specific effects of the targeted HDAC compounds on monocytes were confirmed. Both analysis methods revealed that all monocyte subsets were significantly reduced with the targeted HDAC compounds, with a more substantial decrease in the Ly6C ^int and Ly6C'° subsets.

Study 4

This study investigated the effects of (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-

3-oxopropyl)pyridin-3-yl)methyl) amino)acetate and a non-hydrolysable t-butyl ester control ((S)-tert- butyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3- yl) methyl)amino)acetate) on leukocytes at 6h post intraperitoneal dosing of male hCE1 / Es1 e mice. Leukocyte populations were assessed by flow cytometry phenotyping and the study was designed to determine the effects of the non-hydrolysable t-butyl control molecule dosed at 10 mg/kg on circulating leukocytes, and to evaluate the effects of 3 mg/kg and 10 mg/kg (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3-(hydroxyamino)- 3-oxopropyl)pyridin-3-yl)methyl) amino)acetate on circulating leukocytes compared to vehicle-treated animals.

When the t-butyl ester control was dosed at 10 mg/kg no effect on circulating monocytes was observed. Furthermore, a 10 mg/kg dose of the t-butyl ester control molecule did not alter B cell, T cell or neutrophil populations in the blood.

A significant decrease in circulating monocytes was seen in animals treated with 3 mg/kg (59% decrease) or 10 mg/kg (78% decrease) of (S)-cyclopentyl 2-cyclohexyl-2-(((6-(3- (hydroxyamino)-3-oxopropyl)pyridin-3-yl) methyl)amino)acetate, when data were analysed as percentage of CD45 ⁺ cells. Absolute cell counts confirmed this observation. Although the decrease in monocytes was greater with the 10 mg/kg dose, this was not statistically different from 3 mg/kg. Similarly, all monocyte subsets were decreased by both 3 and 10 mg/kg (S)-cyclopentyl 2-cyclohexyl- 2-(((6-(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)ami no)acetate, with the Ly6C ^int and Ly6C ¹⁰ monocyte subsets being more substantially decreased.

Exam ple 4 : Anti-Collagen Antibody I nduced Arthritis Studies

These studies have been included to support the use of the compound of the invention in the treatment of arthritis.

Four studies were performed to evaluate the efficacy of the compound in the murine Anti- Collagen Antibody I nduced Arthritis (ACAI A) model; two in which the drug was administered by intaperitoneal ( I P) injection and two using the oral route. The model was run in transgenic mice over-expressing human carboxyesterase-1 (hCE-1 ) .

I n the two I P administration studies, arthritis was induced in hCE1 transgenic and wild type mice by administering 4 mg of a monoclonal antibody (mAb) cocktail intravenously on study day 0. Three days post the single mAb administrations, all animals were subjected to a single

intraperitoneal injection of LPS (50 μς/ηηοιιεΘ). hCEl transgenic or wild type mice were treated with vehicle control or compound at 30 mg/kg, 10 mg/kg or 3mg/kg intraperitoneal^ on days 0-1 1 . All mice were monitored for the development of arthritis and clinical signs, and were weighed, on days 0 and 3-12.

The endpoints evaluated were incidence of arthritis, clinical score (front paws, rear paws and total) , paw thickness (front and rear) and body weight. I n the strain of mice used, the severity of the disease is less evident in the rear paws.

Treatment of hCE1 transgenic mice with the compound, (S)-cyclopentyl 2-cyclohexyl-2-(((6-

(3-(hydroxyamino)-3-oxopropyl)pyridin-3-yl)methyl)amino)a cetate, administered by intaperitoneal ( I P) injection at 10 mg/kg or 3 mg/kg (Study A) significantly inhibited the development of arthritis with sustained reductions in total paw score, fore paw score and fore paw thickness. I n addition, a sustained reduction in rear paw score was observed, however, this was not significant. To a lesser extent, treatment with the compound at 1 mg/kg also resulted in reductions in total arthritis scores, fore paw scores and fore paw thickness, however, this was not significant.

Treatment of hCE1 transgenic mice with the compound administered by intaperitoneal ( I P) injection at 30 mg/kg or 10 mg/kg (Study B) significantly inhibited the development of arthritis with sustained reductions in total paw score, fore paw score and fore paw thickness. I n addition, a sustained reduction in rear paw score was observed, although this was not significant. Treatment with the compound at 3mg/kg also significantly inhibited the development of arthritis with reductions in total arthritis scores and fore paw scores. Treatment of wild type mice with the compound at 30 mg/kg or 10 mg/kg also reduced the development of arthritis, however, this was not significant.

I n two further studies, the compound was evaluated by oral administration at 0, 10, 30 and

100 mg/kg/day. At 100 mg/kg/day there was a reduction in the severity of arthritis, with statistically significant reductions in total, fore and rear paw scores, and fore paw thickness. Example 5 : Monocyte Count Profiling

A K-PD model (Jacqmin et al, J Pharmacokineti Pharmacodyn, 2007, 34(1 ) , pages 57-85) was fitted to Part A and Part B monocyte count data at Example 2 using NONMEM® (http://www.iconplc.com/innovation/solutions/nonmem/) , I CON'S non-linear, mixed effects modeling tool for Population Pharmacokinetic/ Pharmacodynamic ( PK/PD) data analysis, version 7.2 and Perl- speaks-NONMEM (PsN) version 3.4.2 (http://psn.sourceforge.net ) . The fitted model was subsequently utilized to simulate the monocyte count profile after every day, every other day and every three days dosing of 20mg and 40mg of the compound. The simulations were performed using R software environment, version 3.0.1 (https://www.r-project.org/about.html) . Figures 7A/B: Medians (solid and dashed lines) and their 80% prediction intervals (grey ribbons) from 300 simulations considering inter-subject variability, when administering three every other day doses of 20 and 40 mg of compound. Figures 7C: Medians (solid and dashed lines) and their 80% prediction intervals (grey ribbons) from 300 simulations considering inter-subject variability, when administering three every day doses of 20 and 40 mg of compound. . Figures 7D: Medians (solid and dashed lines) and their 80% prediction intervals (grey ribbons) from 300 simulations considering inter-subject variability, when administering two doses of 20 and 40 mg of compound, each one every three days (Q3D strategy) .

Example 6 : Clinical Study in Patients

This study will evaluate the efficacy, safety and tolerability of the compound at a dose of 40 mg orally every other day in subjects with severe rheumatoid arthritis despite treatment with disease- modifying anti-rheumatic drugs (DMARDs) . This study as a secondary objective, will also investigate the monocyte numbers after every other day dosing with the compound.

This is a randomised, double-blind (sponsor open) , multicentre, placebo-controlled, parallel group study to evaluate the efficacy, safety and tolerability, PK and PD of the compound in subjects with RA resistant to DMARD therapy.

The total maximum study duration is approximately 10 weeks (not including any rescreen) . Following a screening period of up to 28 days, subjects will be randomised ( 1 : 1 ) to placebo or 40 mg of the compound orally-administered every other day for a period of 28 days (14 doses) . Subjects will be followed up for 7-14 days post final dose.

Approximately 40 subjects with severe RA despite treatment with DMARDs will be randomised into the study. Subjects in this study are not currently benefiting from DMARD therapy therefore such DMARD therapies will be excluded for the duration of the study. Any subject currently deriving benefit from DMARD therapy will not be included in this study.

I nclusion Criteria: Type of subject and diagnosis including disease severity

The subject must have a diagnosis of RA according to the 2010 ACR/ EULAR classification criteria for RA. Functional class I , I I or I I I defined by the 1992 ACR Classification of Functional Status in RA. The subject must have a EULAR DAS 28-CRP of greater than 5.1 at screening. Disease duration of > 6 months (time from onset of patient-reported symptoms of either pain or stiff ness or swelling in hands, feet or wrists). Swollen joint count of >6 (66-joint count) and tender joint count of >8 (68- joint count) at screening and at day 1 . The subject must have a CRP serum level of > 5 mg/L at screening. The subject has had an inadequate response or intolerance of DMARDs (due to lack of efficacy or toxicity, after at least 8 weeks treatment) .