Peptidyl arginine deiminase (PAD) inhibitors and methods of using the same

Abstract

Described herein are compositions for treating human patients exhibiting hyperactivity of PAD enzymes, hypercitrullination and / or a neurodegenerative disease exhibiting a demyelinating condition, or treating multiple sclerosis in human patients in need thereof. Also described herein are methods of treating a human patient exhibiting hyperactivity of PAD enzymes, hypercitrullination and / or a neurodegenerative disease exhibiting a demyelinating condition, or multiple sclerosis in human patients in need thereof, including orally administering to the patient once or twice daily a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Description

PEPTIDYL ARGININE DEIMINASE (PAD) INHIBITORS AND METHODS OF USING THE SAMECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 587,370, filed October 2, 2023, and of U.S. Provisional Application No. 63 / 587,855, filed October 4, 2023.FIELD OF THE INVENTION

[0002] The present disclosure generally relates to peptidyl arginine deiminase 2 (PAD2) inhibitors, compositions containing the same, and methods of treating multiple sclerosis, hyperactivity of PAD enzymes, hypercitrullination and / or neurodegenerative diseases exhibiting demyelinating conditions in human patients with the same.BACKGROUND

[0003] Multiple sclerosis (MS) is a disease of the central nervous system (CNS) affecting more than 2.8 million people worldwide. It is the most common cause of disability in young adults in temperate climates. It commences with a relapsing-remitting phase (RRMS) in 85% of individuals which in the majority will become secondary progressive (SPMS) around 15 years later. In 15%, it will be primary progressive (PPMS) from the onset. Progressive disability is a major individual, healthcare and societal burden. Domains affected include motor, sphincter, visual and cognitive function.

[0004] The early clinical symptoms of MS are thought to occur through an invasion of immune cells in the white matter of the CNS as part of an autoimmune process. Dormant myelin-specific T cells infiltrate the CNS and are subsequently activated by microglia and / or perivascular dendritic cells presenting myelin antigens. The activated T cells in turn release chemokines and initiate the inflammatory responses that lead to myelin sheath degradation and demyelinating lesions. It is thought that this inflammatory response is accountable for demyelination and axon injury in acute white matter lesions and is a triggerfor secondary neurodegeneration in MS. Accordingly, the initial drugs developed to treat MS have immunomodulatory mechanisms of action.

[0005] Several drugs, termed disease modifying therapies (DMTs), are successful in decreasing the frequency and severity of inflammatory demyelinating attacks in the brain and spinal cord in RRMS. Although DMTs are effective in controlling the inflammatory demyelinating attacks, they have proven less efficacious in stopping disease progression.

[0006] Ocrelizumab and siponimod, the only DMTs with clinical efficacy in progressive MS, exhibit only moderate efficacy in stopping disease progression. The clinical efficacy of ocrelizumab was evaluated in clinical trials which included a younger patient population with progressive MS, a population which represents a more active phenotype with more ongoing immune-based lesion activity, and may not be representative of classical PPMS or SPMS.

[0007] The limitations of the effects of DMTs on MS progression has led to an increasing focus on neuroprotective and myelinoprotective therapies as potential therapeutic targets. Myelinoprotective therapies focus on regulating myelin decompaction, reducing pathogenic hypercitrullination, and degenerating myelin debris to prevent the onset and exacerbation of inflammatory demyelination in MS. Developing agents that promote remyelination of axons is also an approach under consideration in the art.

[0008] The myelin sheath is involved in neural insulation and conduction of nerve impulses. Therefore, it is crucial to maintain myelin sheath integrity, as destruction or instability leads to saltatory conduction failure. The stability and maintenance of the myelin sheath are partly dependent on the balance of citrullinated and non-citrullinated myelin basic protein (MBP). Upregulation of citrullination (the conversion of peptidyl arginine residues to peptidyl citrulline) or hypercitrullination of MBP has been shown to have a destabilizing effect on myelin integrity and has been linked to the pathophysiology of MS in non-clinical and clinical studies.

[0009] The citrullination of peptidyl arginine residue by peptidyl arginine deiminase (PAD) enzymes is illustrated in Reaction Scheme I, below.Peptidyl Arg residue Peptidyl Cit residueReaction Scheme I.

[0010] 2-Chloroacetamidine (2CA) is a covalent PAD inhibitor and has demonstrated efficacy in the EAE inflammatory mouse models of MS. However, despite its efficacy, 2CA exhibits unfavorable properties, including covalent reactivity and a lack of selectivity for PAD2, which may lead to toxicities and produce off target effects due to inhibition of other PAD enzymes. A significant increase, compared with controls, in citrullinated proteins in myelin of MS cases has been observed. Luchicchi A, Hart B, Frigerio I, van Dam AM, Perna L, Offerhaus HL, et al. Axon-Myelin Unit Blistering as Early Event in MS Normal Appearing White Matter. Ann. Neurol. 2021, 89(4), 711-25.). MBP citrullination has been found to precede and trigger autoimmune inflammatory demyelination. Id:, Caprariello AV, Rogers JA, Morgan ML, et al., Biochemically altered myelin triggers autoimmune demyelination, Proc Natl Acad Set USA 2018;l 15:5528- 5533.SUMMARY OF THE INVENTION

[0011] A first aspect of the disclosure is directed to a method of treating multiple sclerosis in a human patient in need thereof comprising orally administering to the patient once or twice daily about 200 to about 500 mg (on a free base basis), alternatively about 200 to about 400 mg (on a free base basis), alternatively about 200 to about 350 mg (on a free base basis), or alternatively about 250 to about 300 mg (on a free base basis) of a compound of Formula (I):or a pharmaceutically acceptable salt thereof. In some instances, the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers (alternatively referred to compound Formula (I) racemate). In some instances, the compound of Formula (I) is in the (R)- enantiomer form. In some instances, the compound of Formula (I) is in the (S)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (R)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (S)-enantiomer form.

[0012] A second aspect of the disclosure is directed to a method of treating a human patient exhibiting hyperactivity of PAD enzymes, hypercitrullination and / or a neurodegenerative disease exhibiting a demyelinating condition, comprising orally administering to the patient once or twice daily about 200 to about 500 mg (on a free base basis), alternatively about 200 to about 400 mg (on a free base basis), alternatively about 200 to about 350 mg (on a free base basis), or alternatively about 250 to about 300 mg (on a free base basis) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some instances, the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers. In some instances, the compound of Formula (I) is in the (R)-enantiomer form. In some instances, the compound of Formula (I) is in the (S)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (R)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and(S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (S)- enantiomer form.

[0013] A third aspect of the disclosure is directed to a method of treating multiple sclerosis, hyperactivity of PAD enzymes, hypercitrullination and / or a neurodegenerative disease exhibiting a demyelinating condition in a human patient in need thereof comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to provide (i) an area under the curve (AUCo-48hrs) of the compound of Formula (I) of 7.4 to 19.4 hr pg / mL once or twice daily and / or (ii) a maximum concentration (Cmax) of the compound of Formula (I) of 3.1 to 6.9 pg / mL. In some instances, the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers (alternatively referred to compound Formula (I) racemate). In some instances, the compound of Formula (I) is in the (R)- enantiomer form. In some instances, the compound of Formula (I) is in the (S)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (R)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (S)-enantiomer form.

[0014] A fourth aspect of the disclosure is directed to a method of treating multiple sclerosis, hyperactivity of PAD enzymes, hypercitrullination and / or a neurodegenerative disease exhibiting a demyelinating condition a human patient in need thereof comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to provide a plasma concentration of the compound of Formula (I) of at least 1.5 pg / mL for at least 1.5 hours a day, such that the patient also has a plasma concentration of the compound of Formula (I) of no more than 6 pg / mL for at least 1.0 hours a day. In some instances, the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers. In some instances, the compound of Formula (I) is in the (R)-enantiomer form. In some instances, the compound of Formula (I) is in the (S)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (R)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and(S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (S)- enantiomer form.

[0015] A fifth aspect of the disclosure is directed to a method according to the third or fourth aspects, wherein the method comprises orally administering once or twice daily about 200 to about 500 mg (on a free base basis), alternatively about 200 to about 400 mg (on a free base basis), alternatively about 200 to about 350 mg (on a free base basis), or alternatively about 250 to about 300 mg (on a free base basis) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0016] A sixth aspect of the disclosure is directed to a method to according to any one of the first through fifth aspects, wherein the method comprises orally administering once or twice daily about 200 to about 350 mg (on a free base basis) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0017] A seventh aspect of the disclosure is directed to a method according to any one of the first through fifth aspects, wherein the method comprises orally administering once or twice daily about 250 to about 300 mg (on a free base basis) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0018] An eighth aspect of the disclosure is directed to a method according to any one of the first through seventh aspects, wherein the compound of Formula (I) is administered once daily.

[0019] A ninth aspect of the disclosure is directed to a method according to any one of the first through seventh aspects, wherein the compound of Formula (I) is administered twice daily.

[0020] A tenth aspect of the disclosure is directed to a method according to any one of the first through ninth aspects, wherein the compound of Formula (I) is in one or more immediate release dosage forms (e.g., immediate release oral dosage forms).

[0021] An eleventh aspect of the disclosure is directed to a method according to any one of the first, second and fourth through tenth aspects, wherein in vivo area under the curve (AUCo-48hrs) of the compound of Formula (I) after administration is 7.4 to 19.4 hr- pg / mL.

[0022] A twelfth aspect of the disclosure is directed to a method according to any one of the first through eleventh aspects, wherein in vivo area under the curve (AUCo-48hrs) of the compound of Formula (I) after administration is 10.4 to 16.4 hr pg / mL.

[0023] A thirteenth aspect of the disclosure is directed to a method according to any one of the first, second and fourth through twelfth aspects, wherein the maximum concentration (Cmax) of the compound of Formula (I) after administration is 3.1 to 6.9 pg / mL.

[0024] A fourteenth aspect of the disclosure is directed to a method according to any one of the first, second and fourth through thirteenth aspects, wherein the maximum concentration (Cmax) of the compound of Formula (I) after administration is 4.0 to 6.0 pg / mL.

[0025] A fifteenth aspect of the disclosure is directed to a method according to any one of the first, second and fourth through fourteenth aspects, wherein the time to maximum concentration (Tmax) of the compound of Formula (I) after administration is from about 0.5 to 1.5 hours.

[0026] A sixteenth aspect of the disclosure is directed to a method according to any one of the first, second and fourth through fifteenth aspects, wherein the compound of Formula (I) is administered in the form of a tablet or capsule.

[0027] A seventeenth aspect of the disclosure is directed to a method according to the sixteenth aspect, wherein the tablet or capsule further comprises one or more of a diluent, a disintegrant, a binder, a wetting agent, a solubility enhancer, an anti-adherent, a glidant, and a lubricant.

[0028] An eighteenth aspect of the disclosure is directed to a method according to the seventeenth aspect, wherein the diluent includes one or more of a microcrystalline cellulose, a silicified microcrystalline cellulose, a starch, a pregelatinized starch, isomalt, dextrose, a dextrate, lactose anhydrous, lactose monohydrate, sorbitol, a gelatin, mannitol, a maltodextrin, calcium carbonate, calcium phosphate dibasic dihydrate, calcium phosphate dibasic anhydrous, calcium phosphate dibasic trihydrate, magnesium carbonate, and magnesium oxide.

[0029] A nineteenth aspect of the disclosure is directed to a method according to the seventeenth or eighteenth aspect, wherein the diluent is present in a concentration ranging from about 5 to about 90 w / w% in the tablet or capsule.

[0030] A twentieth aspect of the disclosure is directed to a method according to any one of the seventeenth through nineteenth aspects, wherein the binder includes one or more of a carbomer, a microcrystalline cellulose, a silicified microcrystalline cellulose, corn syrup,ethylcellulose, hydroxypropylmethylcellulose, guar gum, hydroxypropylcellulose, a polycarbophil, a povidone, corn starch, and a pregelatinized starch.

[0031] A twenty-first aspect of the disclosure is directed to a method according to any one of the seventeenth through twentieth aspects, wherein the binder is present in a concentration ranging from about 0.01 to about 15 w / w% in the tablet or capsule.

[0032] A twenty-second aspect of the disclosure is directed to a method according to any one of the seventeenth through twenty-first aspects, wherein the disintegrant includes one or more of sodium starch glycolate, a crospovidone, croscarmellose sodium, a microcrystalline cellulose, croscarmellose calcium, a starch, and a colloidal silicon dioxide.

[0033] A twenty-third aspect of the disclosure is directed to a method according to any one of the seventeenth through twenty-second aspects, wherein the disintegrant is present in a concentration ranging from about 0.01 to about 15 w / w% in the tablet or capsule.

[0034] A twenty-fourth aspect of the disclosure is directed to a method according to any one of the seventeenth through twenty-third aspects, wherein the glidant includes one or more of a colloidal silicon dioxide, silicon dioxide, sodium stearate, and talc.

[0035] A twenty-fifth aspect of the disclosure is directed to a method to any one of the seventeenth through twenty-fourth aspects, wherein the glidant is present in a concentration ranging from about 0.01 to about 5 w / w% in the tablet or capsule.

[0036] A twenty-sixth aspect of the disclosure is directed to a method according to any one of the seventeenth through twenty-fifth aspects, wherein the lubricant includes one or more of magnesium stearate, a behenoyl polyoxylglyceride, calcium stearate, castor oil, hydrogenated coconut oil, hydrogenated glyceryl behenate, glyceryl dibehenate, glyceryl behenate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprylocaprate, glyceryl dicaprylocaprate, fumaric acid, glyceryl monostearate, a polysorbate, sodium lauryl sulfate (SLS), sodium stearyl fumarate, sorbitan monolaurate, mineral oil, zinc stearate, stearic acid, sorbitan monostearate, sorbitan monooleate, sorbitan monopalmitate, and talc.

[0037] A twenty-seventh aspect of the disclosure is directed to a method according to any one of the seventeenth through twenty-sixth aspects, wherein the lubricant is present in a concentration ranging from about 0.01 to about 5 w / w% in the tablet or capsule.

[0038] A twenty-eighth aspect of the disclosure is directed to a capsule comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the dosage form is substantially free of pharmaceutically acceptable excipients. In some instances, the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers. In some instances, the compound of Formula (I) is in the (R)-enantiomer form. In some instances, the compound of Formula (I) is in the (S)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (R)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)- enantiomer form, wherein the majority of the compound of Formula (I) is the (S)- enantiomer form.

[0039] A twenty-ninth aspect of the disclosure is directed to a capsule consisting essentially of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some instances, the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers. In some instances, the compound of Formula (I) is in the (R)-enantiomer form. In some instances, the compound of Formula (I) is in the (S)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (R)- enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)- enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (S)-enantiomer form.

[0040] A thirtieth aspect of the disclosure is directed to a capsule according to the twentyninth aspect, wherein the capsule consists essentially of the compound of Formula (I) in free base form.

[0041] A thirty-first aspect of the disclosure is directed to a capsule according to the twenty -ninth or thirtieth aspect, wherein the capsule consists essentially of (i) 50 mg of the compound of Formula (I) in free base form in a size 0 capsule, (ii) 100 mg of the compound of Formula (I) in free base form in a size 0 capsule, (iii) 150 mg of the compound of Formula (I) in free base form in a size 0 capsule, or (iv) 300 mg of the compound of Formula (I) in free base form in a size 00 or 000 capsule or in more than one size 0 capsule (for example, two size 0 capsules or two size 0 capsules each with 150 mg).

[0042] A thirty-second aspect of the disclosure is directed to a capsule consisting of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some instances, the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers. In some instances, the compound of Formula (I) is in the (R)-enantiomer form. In some instances, the compound of Formula (I) is in the (S)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (R)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)- enantiomer form, wherein the majority of the compound of Formula (I) is the (S)- enantiomer form.

[0043] A thirty-third aspect of the disclosure is directed to a capsule according to the thirty- second aspect, wherein the capsule consists of the compound of Formula (I) in free base form.

[0044] A thirty-fourth aspect of the disclosure is directed to a capsule according to the thirty-second or thirty -third aspect, wherein the capsule consists of (i) 50 mg of the compound of Formula (I) in free base form in a size 0 capsule, (ii) 100 mg of the compound of Formula (I) in free base form in a size 0 capsule, (iii) 150 mg of the compound of Formula (I) in free base form in a size 0 capsule, or (iv) 300 mg of the compound of Formula (I) in free base form in a size 00 or 000 capsule or in more than one size 0 capsule (for example, two size 0 capsules or two size 0 capsules each with 150mg).BRIEF DESCRIPTION OF THE DRAWINGS

[0045] In order that the present disclosure may be readily understood, aspects of the invention are illustrated by way of examples in the accompanying drawings, in which like parts are referred to with like reference numerals throughout.

[0046] FIG. 1 is graphical display showing plasma concentration (with ± standard deviation bars) of compound Formula (I) over time in human clinical trial cohorts 1-4.

[0047] FIG. 2 is a graphical display showing the Cmax (circle data points with ± standard deviation bars) and AUCo-48hrs (square data points with ± standard deviation bars) relative to the dosage amount of compound Formula (I) in human clinical trial cohorts 1-4.

[0048] FIG. 3 is a graphical display comparing the Cmax (geometric mean ± 95% C.I.) of compound Formula (I) in human clinical trial cohort 5 (participants in fed / fasted states).

[0049] FIG. 4 is a graphical display comparing the AUCo-48hrs (geometric mean ± 95% C.I.) of compound Formula (I) in human clinical trial cohort 5 (participants in fed / fasted states).DETAILED DESCRIPTION

[0050] The following description of the embodiments is merely exemplary in nature and is in no way intended to limit the subject matter of the present disclosure, their application, or uses.

[0051] As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. Unless otherwise specified, all percentages and amounts expressed herein and elsewhere in the specification should be understood to refer to percentages by weight.

[0052] For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” The use of the term “about” applies to all numeric values, whether or not explicitly indicated. This term generally refers to a range of numbers that one of ordinary skill in the art would consider as a reasonable amount of deviation to the recited numeric values (i.e., having the equivalent function or result). For example, this term can be construed as including a deviation of ±10 percent, alternatively ±5 percent, alternatively ±1 percent, alternatively ±0.5 percent, and alternatively ±0.1 percent of the given numeric value provided such a deviation does not alter the end function or result of the value. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the present invention.

[0053] It is noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the,” include plural references unless expressly and unequivocally limited to one referent. As used herein, the term “include” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion ofother like items that can be substituted or added to the listed items. For example, as used in this specification and the following claims, the terms “comprise” (as well as forms, derivatives, or variations thereof, such as “comprising” and “comprises”), “include” (as well as forms, derivatives, or variations thereof, such as “including” and “includes”) and “has” (as well as forms, derivatives, or variations thereof, such as “having” and “have”) are inclusive (i.e., open-ended) and do not exclude additional elements or steps. Accordingly, these terms are intended to not only cover the recited element(s) or step(s), but may also include other elements or steps not expressly recited. Furthermore, as used herein, the use of the terms “a” or “an” when used in conjunction with an element may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” Therefore, an element preceded by “a” or “an” does not, without more constraints, preclude the existence of additional identical elements.

[0054] Various aspects of the present disclosure are directed oral dosage forms comprising, consisting essentially of, or consisting of a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

[0055] The compound of Formula (I) is a non-covalent inhibitor of peptidyl arginine deiminase 2 (PAD2). The (S)-enantiomer of compound Formula (I) has demonstrated efficacy in an experimental autoimmune encephalomyelitis (EAE) mouse model (Tejeda et al., “Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis”, J. Med. Chem., 2017; 60(21):8876-87) and cuprizone autoimmune encephalitis (CAE) (Caprariello AV, Rogers JA, Morgan ML,Hoghooghi V, Plemel JR, Koebel A, Tsutsui S, Dunn JF, Kotra LP, Ousman SS, Wee Yong V, Stys PK. Biochemically altered myelin triggers autoimmune demyelination. Proc. Natl. Acad. Set. USA, 2018, 115(21), 5528-33). Compound of Formula (I) (racemate and enantiomeric excess compounds) treatment improved clinical scores significantly with functional recovery, reduced T cell and macrophage infiltration into CNS, reduced activated astrocytes and microglia, and prevented demyelination with subsequent myelin recovery in the CNS. GLP toxicology studies (28-days) demonstrated that compound Formula (I) racemate was well tolerated in both rats and dogs. The Compound of Formula (I) treatment did not show any evidence for eliciting traditional immunomodulatory effects. It inhibited myelin hypercitrullination, protected myelin, reduced axonal loss and reduced secondary inflammation in both EAE and CAE mouse models.

[0056] In some instances, the compound of Formula (I) is in free base form. The inventors have surprisingly discovered that oral dosage forms consisting of the compound of Formula (I) in free base form exhibit surprisingly high bioavailability. Specifically, the inventors have surprisingly discovered that oral dosage forms consisting of the compound of Formula (I) in free base form as a powder in a capsule exhibit surprisingly high bioavailability.

[0057] In some instances, the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers (alternatively referred to as compound Formula (I) racemate). In some instances, the compound of Formula (I) is in the (R)-enantiomer form. In some instances, the compound of Formula (I) is in the (S)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (R)-enantiomer form. In some instances, the compound of Formula (I) is a mixture of the (R)-enantiomer form and (S)- enantiomer form, wherein the majority of the compound of Formula (I) is the (S)- enantiomer form. As described herein, the compound of Formula (I) may be in free base form in some instances and in the form of a pharmaceutically acceptable salt thereof in some instances. In free base form or in the form of a pharmaceutically acceptable salt, the compound of formula (I) can be in the form of a racemate, a non-racemic mixture of (R)- and (S) enantiomers, only the (R)-enantiomer, or only the (S)-enantiomer.

[0058] In some instances, the compound of Formula (I), whether as a racemate, a non- racemic mixture of a non-racemic mixture of (R)- and (S) enantiomers, only the (R)-enantiomer, or only the (S)-enantiomer can be produced according to modified procedures for the synthesis of compound Formula (I) as described in U.S. Patent No. 10,716,791, the entire contents of which are incorporated herein by reference.

[0059] In some instances, the compound of Formula (I) is in the form a pharmaceutically acceptable salt. In some instances, the pharmaceutically acceptable salt of the compound of Formula (I) is a hydrochloride salt. In some instances, the pharmaceutically acceptable salt of the compound of Formula (I) can be, for example, a chloride salt, sulfate salt, a methylsulfate salt, an acetate salt, a phosphate salt, a diphosphate salt, a citrate salt, a nitrate salt, a mesylate salt, a tartrate salt, a lactate salt, an iodide salt, a salicylate salt, a bromide salt, a carbonate salt, a bicarbonate salt, a propionate salt, a glycolate salt, or a gluconate salt.

[0060] In some instances, oral dosages forms comprising, consisting essentially of, or consisting of the compound of Formula (I) can be used in methods of treating human patients exhibiting hypercitrullination. Methods of treating a human patient exhibiting hypercitrullination can comprise orally administering to the patient a pharmaceutically effective amount of the compound of Formula (I). In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 50 mg to about 500 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 50 mg to about 400 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 100 mg to about 400 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 150 mg to about 400 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 150 mg to about 350 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 200 mg to about 350 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 250 mg to about 300 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can be orally administered to the patient once daily. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can be orally administered to the patienttwice daily. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can be orally administered in an immediate release oral dosage form.

[0061] In some instances, oral dosages forms comprising, consisting essentially of, or consisting of the compound of Formula (I) can be used in methods of treating human patients that exhibit indications of, or have been diagnosed with, multiple sclerosis. Methods of treating a human patient that exhibits indications of, or has been diagnosed with, multiple sclerosis can comprise orally administering to the patient a pharmaceutically effective amount of the compound of Formula (I). In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 50 mg to about 500 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 50 mg to about 400 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 100 mg to about 400 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 150 mg to about 400 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 150 mg to about 350 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 200 mg to about 350 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can range from about 250 mg to about 300 mg on a free base basis. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can be orally administered to the patient once daily. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can be orally administered to the patient twice daily. In some instances, the pharmaceutically effective amount of the compound of Formula (I) can be orally administered in an immediate release oral dosage form.Excipients

[0062] In some instances, oral dosage forms comprising the compound of Formula (I) may further include one or more pharmaceutically acceptable excipients. Suitable excipients include, but are not limited to, diluents, disintegrant, binders, wetting agents, solubility enhancers, anti-adherents, glidant, and lubricant.

[0063] In some instances, oral dosage forms comprising the compound of Formula (I) may include one or more diluents. Suitable diluents include, but are not limited to microcrystalline celluloses, silicified microcrystalline celluloses, starches, pregelatinized starches, isomalt, dextrose, dextrates, lactose anhydrous, lactose monohydrate, sorbitol, gelatins, mannitol, maltodextrins, calcium carbonate, calcium phosphate dibasic dihydrate, calcium phosphate dibasic anhydrous, calcium phosphate dibasic trihydrate, magnesium carbonate, and magnesium oxide. When present in an oral dosage form comprising the compound of Formula (I), the combined amount of the one or more diluents may range from about 5 to about 90 w / w% of the oral dosage form.

[0064] In some instances, oral dosage forms comprising the compound of Formula (I) may include one or more binders. Suitable binders include, but are not limited to carbomers, microcrystalline celluloses, silicified microcrystalline celluloses, corn syrup, ethylcellulose, hydroxypropylmethylcellulose, guar gum, hydroxypropylcellulose, polycarbophils, povidones, corn starch, and pregelatinized starches. When present in an oral dosage form comprising the compound of Formula (I), the combined amount of the one or more binders may range from about 0.01 to about 15 w / w% of the oral dosage form.

[0065] In some instances, oral dosage forms comprising the compound of Formula (I) may include one or more disintegrants. Suitable disintegrants include, but are not limited to sodium starch glycolate, crospovidones, croscarmellose sodium, microcrystalline celluloses, croscarmellose calcium, starches, and colloidal silicon dioxides. When present in an oral dosage form comprising the compound of Formula (I), the combined amount of the one or more disintegrants may range from about 0.01 to about 15 w / w% of the oral dosage form.

[0066] In some instances, oral dosage forms comprising the compound of Formula (I) may include one or more glidants. Suitable glidants include, but are not limited to, colloidal silicon dioxides, silicon dioxide, sodium stearate, and talc. When present in an oral dosage form comprising the compound of Formula (I), the combined amount of the one or more glidants may range from about 0.01 to about 5 w / w% of the oral dosage form.

[0067] In some instances, oral dosage forms comprising the compound of Formula (I) may include one or more lubricants. Suitable lubricants include, but are not limited to, magnesium stearate, behenoyl polyoxylglycerides, calcium stearate, castor oil,hydrogenated coconut oil, hydrogenated glyceryl behenate, glyceryl dibehenate, glyceryl behenate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprylocaprate, glyceryl dicaprylocaprate, fumaric acid, glyceryl monostearate, polysorbates, sodium lauryl sulfate (SLS), sodium stearyl fumarate, sorbitan monolaurate, mineral oil, zinc stearate, stearic acid, sorbitan monostearate, sorbitan monooleate, sorbitan monopalmitate, and talc. When present in an oral dosage form comprising the compound of Formula (I), the combined amount of the one or more lubricants may range from about 0.01 to about 5 w / w% of the oral dosage form.

[0068] In some instances, oral dosage forms comprising the compound of Formula (I) are substantially free of pharmaceutically acceptable excipients. As discussed above, the inventors have surprisingly discovered that oral dosage forms consisting of the compound of Formula (I) in free base form exhibit surprisingly high bioavailability. Specifically, the inventors have surprisingly discovered that oral dosage forms consisting of the compound of Formula (I) in free base form as a powder in a capsule exhibit surprisingly high bioavailability.Modes of Oral Dosage Form Administration

[0069] Oral dosage forms of the compound of Formula (I) can be formulated for various modes of oral administration. In some instances, oral dosage forms can include the compound of Formula (I) as a racemic mixture of (R)- and (S)- enantiomers (alternatively referred to as compound Formula (I) racemate). In some instances, oral dosage forms can include the compound of Formula (I) in the (R)-enantiomer form. In some instances, oral dosage forms can include the compound of Formula (I) in the (S)-enantiomer form. In some instances, oral dosage forms can include the compound of Formula (I) as a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (R)-enantiomer form. In some instances, oral dosage forms can include the compound of Formula (I) as a mixture of the (R)-enantiomer form and (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (S)-enantiomer form. In some instances, oral dosage forms can include the compound of Formula (I) in free base form. In some instances, oral dosage forms can include the compound of Formula (I) in the form of a pharmaceutically acceptable salt. While various modes of oral delivery are discussed below, one of ordinary skill in the art may envision additional modes.

[0070] In some instances, suitable oral dosage forms can be in the form of a tablet. In some instances, such a tablet can consist of the compound of Formula (I) in free base form or as a pharmaceutically acceptable salt thereof. In some instances, such a tablet can consist essentially of the compound of Formula (I) in free base form or as a pharmaceutically acceptable salt thereof. In some instances, such a tablet can comprise the compound of Formula (I), in free base form or as a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Tablets can be prepared for the oral delivery of about 50 mg to about 500 mg, alternatively from about 50 mg to about 400 mg, alternatively from about 100 mg to about 350 mg, alternatively from about 150 mg to about 350 mg, alternatively from about 200 mg to about 350 mg, and alternatively from about 250 mg to about 300 mg of the compound of Formula (I) on a free base basis. Tablets comprising, consisting essentially of, or consisting of the compound of Formula (I) can be formed by processes that include wet or dry granulation of predetermined amount(s) of the component(s) to be included in the tablets followed by compression. In some instances, the tablets may be coated with a pharmaceutically acceptable coating. In some instances, the tablets may be scored to facilitate breaking a single table into more than one dosage.

[0071] In some instances, suitable oral dosage forms can be in the form of a capsule. In some instances, such a capsule can consist of the compound of Formula (I), in free base form or as a pharmaceutically acceptable salt thereof, contained therein. In some instances, such a capsule can consist essentially of the compound of Formula (I), in free base form or as a pharmaceutically acceptable salt thereof, contained therein. In some instances, such a capsule can comprise the compound of Formula (I), in free base form or as a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients contained therein. Capsules can be prepared for the oral delivery of about 50 mg to about 500 mg, alternatively from about 50 mg to about 400 mg, alternatively from about 100 mg to about 350 mg, alternatively from about 150 mg to about 350 mg, alternatively from about 200 mg to about 350 mg, and alternatively from about 250 mg to about 300 mg of the compound of Formula (I) on a free base basis.

[0072] In some instances, suitable oral dosage forms can be in the form of an aqueous suspension or dispersion. In some instances, such an aqueous suspension or dispersion can consist of water and the compound of Formula (I), in free base form or as apharmaceutically acceptable salt thereof, suspended or dispersed therein. In some instances, such an aqueous suspension or dispersion can consist essentially of water and the compound of Formula (I), in free base form or as a pharmaceutically acceptable salt thereof, suspended or dispersed therein. In some instances, such an aqueous suspension or dispersion can comprise water with the compound of Formula (I), in free base form or as a pharmaceutically acceptable salt thereof, suspended or dispersed therein, and one or more pharmaceutically acceptable excipients. Aqueous suspensions or dispersions can be prepared for the oral delivery of about 50 mg to about 500 mg, alternatively from about 50 mg to about 400 mg, alternatively from about 100 mg to about 350 mg, alternatively from about 150 mg to about 350 mg, alternatively from about 200 mg to about 350 mg, and alternatively from about 250 mg to about 300 mg of the compound of Formula (I), on free base basis, per unit volume of the aqueous suspension or dispersion. In some instances, aqueous suspensions or dispersions can be formulated for the oral administration of a single dose of the compound of Formula (I) in free base form or as a pharmaceutically acceptable salt thereof. In some instances, aqueous suspensions or dispersions can be formulated for the oral administration of two doses of the compound of Formula (I) in free base form or as a pharmaceutically acceptable salt thereof. In some instances, aqueous suspensions or dispersions can be formulated for the oral administration of more than two doses of the compound of Formula (I) in free base form or as a pharmaceutically acceptable salt thereof.

[0073] In some instances, suitable oral dosage forms can be in the form of syrup. In some instances, the syrup can consist of a pharmaceutically acceptable syrup composition and the compound of Formula (I), in free base form or as a pharmaceutically acceptable salt thereof, suspended or dispersed therein. In some instances, the syrup can consist essentially of a pharmaceutically acceptable syrup composition and the compound of Formula (I), in free base form or as a pharmaceutically acceptable salt thereof, suspended or dispersed therein. In some instances, the syrup can comprise a pharmaceutically acceptable syrup composition with the compound of Formula (I), in free base form or as a pharmaceutically acceptable salt thereof, suspended or dispersed therein, and one or more pharmaceutically acceptable excipients. Syrups can be prepared for the oral delivery of about 50 mg to about 500 mg, alternatively from about 50 mg to about 400 mg, alternatively from about 100 mg to about 350 mg, alternatively from about 150 mg to about 350 mg, alternatively fromabout 200 mg to about 350 mg, and alternatively from about 250 mg to about 300 mg of the compound of Formula (I), on a free base basis, per unit volume of the syrup. In some instances, syrups can be formulated for the oral administration of a single dose of the compound of Formula (I) in free base form or as a pharmaceutically acceptable salt thereof. In some instances, syrups can be formulated for the oral administration of two doses of the compound of Formula (I) in free base form or as a pharmaceutically acceptable salt thereof. In some instances, syrups can be formulated for the oral administration of more than two doses of the compound of Formula (I) in free base form or as a pharmaceutically acceptable salt thereof.Examples

[0074] Solubility Testing of Compound Formula (I). The solubility of compound Formula (I) racemate was evaluated in various solvents and under varying pH conditions. The results of the solubility testing is provided in Table 1 below.

[0075] In view of the above, it appears the solubility of compound Formula (I) racemate in organic solvents generally increases as a function of increasing solvent polarity. In aqueous systems, the solubility of compound Formula (I) racemate increases as a function of decreasing pH.

[0076] Compound Formula (I) - Human Clinical Trials. A single center, randomized, double-blind, placebo-controlled, single ascending dose (SAD) study directed toward oral administration of compound Formula (I) racemate or placebo to humans (ages 18-60 years)was conducted. The SAD study consisted of five cohorts. Each of the cohorts 1 -4 included eight participants, six of which were orally administered compound Formula (I) racemate and two of which were orally administered a placebo. In cohort 1, 50 mg of compound Formula (I) racemate was administered orally once daily. In cohort 2, 100 mg of compound Formula (I) racemate was administered orally once daily. In cohort 3, 150 mg of compound Formula (I) racemate was administered orally once daily. In cohort 4, 300 mg of compound Formula (I) racemate was administered orally once daily. In cohort 5, all eight participants were orally administered 50 mg of compound Formula (1) racemate once daily during fed and fasted states to evaluate the effects of food (fed / fast cohort) on pharmacokinetics. As used herein, the term “Cmax” means the maximum (or peak) plasma concentration of the compound of Formula (I) racemate after administration to a patient. As used herein, the term “area under the curve” or “AUC” means the definite integral of the concentration of the compound Formula (I) racemate in plasma as a function of time. As used herein, the term “Tmax” means the time at which the Cmax is observed.

[0077] FIG. 1 is a graphical display illustrating the plasma concentration of compound Formula (I) racemate vs. time in each of cohorts 1-4, and Table 2 shows the pharmacokinetic parameters for these cohorts based upon plasma concentration levels.Table 2.

[0078] In cohorts 1-4, the pharmacokinetic parameters (Cmax and AUCo-48hrs) were proportional to the orally administered dose (FIG. 2). As illustrated in the bar graphs of FIGS. 3 and 4, there was little to no difference in pharmacokinetics parameters Cmax and AUCo-48hrs between the fed and fasted states.

[0079] Human Clinical Trial Data vs. Non-Clinical Studies. In previous rat models, the bioavailability (F) of compound Formula 1 was found to be 79%. The bioavailability of compound Formula (I) in human clinical trials has yet to be determined. It is noted,however, the AUCo-48hrs for cohort 4 was several fold below the corresponding “no observed adverse effects level” (NOAEL) in rats and dogs, and is comparable to the AUCo- 48hrs in efficacy studies performed on experimental autoimmune encephalomyelitis (EAE) mice (See Tejeda et al., “Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis”, J. Med. Chem., 2017; 60(21):8876- 87) (Table 2).Table 3. ^NOAEL values;2Tejeda et al.;3cohort 4)

[0080] The safety and tolerability of compound Formula (I) racemate was also evaluated in patients of cohorts 1-5. A summary of the safety and tolerability data is provided below in Table 4.Table 4. ('Defined per ICH E3B guidelines)

[0081] As shown in Table 4, a total of 13 adverse events (AEs) were reported by eight of the 40 participants who received compound Formula (I) racemate or placebo. Most of the AEs were graded a mild in quality; 11 of the AEs were graded mild while one was graded moderate in participants who received any amount of the active study drug. There were no AEs that graded as severe and no serious adverse events (SAEs) were reported.

[0082] While certain implementations have been described in terms of what may be considered to be specific aspects, the present disclosure is not limited to the disclosed aspects. Additional modifications and improvements to the aforementioned 3D printed structures may be apparent to those skilled in the art. Moreover, the many features and advantages of the disclosure are apparent from the detailed specification, and thus, it is intended by the appended claims to cover all such features and advantages of the present disclosure which fall within the spirit and scope of the disclosure.

Claims

CLAIMSWhat is claimed is:

1. A method of treating multiple sclerosis in a human patient in need thereof comprising orally administering to the patient once or twice daily about 200 to about 350 mg (on a free base basis) of a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

2. A method of treating a human patient exhibiting hyperactivity of PAD enzymes, hypercitrullination and / or a neurodegenerative disease exhibiting a demyelinating condition, comprising orally administering to the patient once or twice daily about 200 to about 350 mg (on a free base basis) of a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

3. A method of treating multiple sclerosis, hyperactivity of PAD enzymes, hypercitrullination and / or a neurodegenerative disease exhibiting a demyelinatingcondition in a human patient in need thereof comprising administering a compound of Formula (I):or a pharmaceutically acceptable salt thereof to provide (i) an area under the curve (AUCo- 48hrs) of the compound of Formula (I) of 7.4 to 19.4 hr pg / mL once or twice daily or (ii) a maximum concentration (Cmax) of the compound of Formula (I) of 3.1 to 6.9 pg / mL.

4. A method of treating multiple sclerosis, hyperactivity of PAD enzymes, hypercitrullination and / or a neurodegenerative disease exhibiting a demyelinating condition in a human patient in need thereof comprising administering a compound of Formula (I):or a pharmaceutically acceptable salt thereof to provide a plasma concentration of the compound of Formula (I) of at least 1.5 pg / mL for at least 1.5 hours a day, such that the patient also has a plasma concentration of the compound of Formula (I) of no more than 6 pg / mL for at least 1.0 hours a day.

5. The method of claim 3 or 4, wherein the method comprises orally administering once or twice daily about 200 to about 350 mg (on a free base basis) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

6. The method of any one of the preceding claims, wherein the method comprises orally administering once or twice daily about 250 mg to about 300 mg (on a free base basis) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

7. The method of any one of the preceding claims, wherein the compound of Formula (I) is administered once daily.

8. The method of any one of claims 1 to 6, wherein the compound of Formula (I) is administered twice daily.

9. The method of any one of claims 1-8, wherein the compound of Formula (I) is in one or more immediate release dosage forms (e.g., immediate release oral dosage forms).

10. The method of any one of claims 1 , 2, and 4-9, wherein in vivo area under the curve (AUCo-48hrs) of the compound of Formula (I) after administration is 7.4 to 19.4 hr- pg / mL.

11. The method of any one of the preceding claims, wherein in vivo area under the curve (AUCo-48hrs) of the compound of Formula (I) after administration is 10.4 to 16.4 hr- pg / mL.

12. The method of any one of claims 1, 2, and 4-11, wherein the maximum concentration (Cmax) of the compound of Formula (I) after administration is 3.1 to 6.9 pg / mL.

13. The method of any one of the preceding claims, wherein the maximum concentration (Cmax) of the compound of Formula (I) after administration is 4.0 to 6.0 pg / mL.

14. The method of any one of the preceding claims, wherein the time to maximum concentration (Tmax) of the compound of Formula (I) after administration is from about 0.5 to 1.5 hours.

15. The method of any one of the preceding claims, wherein the compound of Formula (I) is administered in the form of a tablet or capsule.

16. The method of claim 15, wherein the tablet or capsule further comprises one or more of a diluent, a disintegrant, a binder, a wetting agent, a solubility enhancer, an antiadherent, a glidant, and a lubricant.

17. The method of claim 16, wherein the diluent includes one or more of a microcrystalline cellulose, a silicified microcrystalline cellulose, a starch, a pregelatinized starch, isomalt, dextrose, a dextrate, lactose anhydrous, lactose monohydrate, sorbitol, a gelatin, mannitol, a maltodextrin, calcium carbonate, calcium phosphate dibasic dihydrate, calcium phosphate dibasic anhydrous, calcium phosphate dibasic trihydrate, magnesium carbonate, and magnesium oxide.

18. The method of claim 16 or 17, wherein the diluent is present in a concentration ranging from about 5 to about 90 w / w% in the tablet or capsule.

19. The method of any one of claims 16 to 18, wherein the binder includes one or more of a carbomer, a microcrystalline cellulose, a silicified microcrystalline cellulose, corn syrup, ethylcellulose, hydroxypropylmethylcellulose, guar gum, hydroxypropylcellulose, a polycarbophil, a povidone, corn starch, and a pregelatinized starch.

20. The method of any one of claims 16 to 19, wherein the binder is present in a concentration ranging from about 0.01 to about 15 w / w% in the tablet or capsule.

21. The method of any one of claims 16 to 20, wherein the disintegrant includes one or more of sodium starch glycolate, a crospovidone, croscarmellose sodium, a microcrystalline cellulose, croscarmellose calcium, a starch, and a colloidal silicon dioxide.

22. The method of any one of claims 16 to 21, wherein the disintegrant is present in a concentration ranging from about 0.01 to about 15 w / w% in the tablet or capsule.

23. The method of any one of claims 16 to 22, wherein the glidant includes one or more of a colloidal silicon dioxide, silicon dioxide, sodium stearate, and talc.

24. The method of any one of claims 16 to 23, wherein the glidant is present in a concentration ranging from about 0.01 to about 5 w / w% in the tablet or capsule.

25. The method of any one of claims 16 to 24, wherein the lubricant includes one or more of magnesium stearate, a behenoyl polyoxylglyceride, calcium stearate, castor oil, hydrogenated coconut oil, hydrogenated glyceryl behenate, glyceryl dibehenate, glyceryl behenate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprylocaprate, glyceryl dicaprylocaprate, fumaric acid, glyceryl monostearate, a polysorbate, sodium lauryl sulfate (SLS), sodium stearyl fumarate, sorbitan monolaurate, mineral oil, zinc stearate, stearic acid, sorbitan monostearate, sorbitan monooleate, sorbitan monopalmitate, and talc.

26. The method of any one of claims 16 to 25, wherein the lubricant is present in a concentration ranging from about 0.01 to about 5 w / w% in the tablet or capsule.

27. The method of any one of claims 1 to 26, wherein the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers.

28. The method of any one of claims 1 to 26, wherein the compound of Formula (I) is in the (R)-enantiomer form.

29. The method of any one of claims 1 to 26, wherein the compound of Formula (I) is in the (S)-enantiomer form.

30. The method of any one of claims 1 to 26, wherein the compound of Formula (I) is a mixture of the (R)-enantiomer form and the (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (R)-enantiomer form.

31. The method of any one of claims 1 to 26, wherein the compound of Formula (I) is a mixture of the (R)-enantiomer form and the (S)-enantiomer form, wherein the majority of the compound of Formula (I) is the (S)-enantiomer form.

32. An oral dosage form comprising a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the dosage form is substantially free of pharmaceutically acceptable excipients.

33. The capsule of claim 32, wherein the compound of Formula (I) in free base form.

34. The oral dosage form of claim 32 or 33, wherein the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers.

35. A capsule consisting essentially of a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

36. The capsule of claim 35, wherein the capsule consists essentially of the compound of Formula (I) in free base form.

37. The oral dosage form of claim 35 or 36, wherein the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers.

38. The capsule of any one of claims 35 to 37, wherein the capsule consists essentially of (i) 50 mg of the compound of Formula (I) in free base form in a size 0 capsule, (ii) 100 mg of the compound of Formula (I) in free base form in a size 0 capsule, (iii) 150 mg of the compound of Formula (I) in free base form in a size 0 capsule, or (iv) 300 mg of the compound of Formula (I) in free base form in a size 00 or 000 capsule or in more than one size 0 capsule or two size 0 capsules each with 150 mg.

39. A capsule consisting of a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

40. The capsule of claim 39, wherein the capsule consists of the compound of Formula (I) in free base form.

41. The oral dosage form of claim 39 or 40, wherein the compound of Formula (I) is a racemic mixture of (R)- and (S)- enantiomers.

42. The capsule of any one of claims 39 to 41, wherein the capsule consists of (i) 50 mg of the compound of Formula (I) in free base form in a size 0 capsule, (ii) 100 mg of the compound of Formula (I) in free base form in a size 0 capsule, (iii) 150 mg of the compoundof Formula (I) in free base form in a size 0 capsule, or (iv) 300 mg of the compound of Formula (I) in free base form in a size 00 or 000 capsule or in more than one size 0 capsule or two size 0 capsules each with 150 mg.

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