Eclitasertib for treating receptor-interacting protein kinase 1 -mediated diseases

Abstract

This disclosure relates to the field of therapeutic tyrosine kinase inhibitor, in particular receptor-interacting serine / threonine-protein kinase 1 (RIPK1) inhibitor, to treat a receptor-interacting protein kinase 1-mediated disease or disorder.

Description

ECLITASERTIB FOR TREATING RECEPTOR-INTERACTING PROTEIN KINASE 1 -MEDIATED DISEASESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 664,881, filed on June 27, 2024, which is incorporated by reference herein in its entirety for any purpose.FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to the field of therapeutic kinase inhibitor, in particular receptor-interacting serine / threonine-protein kinase 1 (RIPK1) inhibitor, to treat receptorinteracting protein kinase 1 -mediated disease.BACKGROUND

[0003] RIPK1 is an intracellular protein with an N-terminal kinase domain, a receptor interacting protein (RIP) homotypic interaction motif, and a C-terminal death domain that can be found in downstream signaling pathways of TNF family receptors, toll-like-receptors (TLR) 3 and 4 as well as interferon receptors. The biology of RIPK-mediated cell signaling is complex, but the two main functions are executed via 1) scaffolding properties important in the (NF-kB) signaling pathway to promote cell survival and inflammation, and 2) kinase function, which is heavily involved in regulating the necroptotic cell death pathway after various stimuli. These stimuli include TNFR1 activation by TNF a, as well as cytokine release from macrophages via TLR activation after pathogen sensing events. Necroptosis and RIPK1 activity have been investigated in a number of disease settings tied to immune-dysregulation. Several preclinical studies have demonstrated a role for RIPK1 / RIPK3 activation in the pathogenesis of severe shock or sepsis and inflammatory diseases. Importantly, RIPK1 kinase-dead (KD) and RIPK3 knockout (KO) mice have been shown to be resistant to lethal SIRS induced by TNFa. Given the important role of RIPK1 in cell death signaling, selectively targeting the kinase activity of this molecule as a new treatment modality for immuno-inflammatory disease has been of great interest over the past decades. Inhibiting RIPK1 kinase activity might block necroptosis & inflammatory cytokine induction via multiple pathways including TNF receptor, TLR, and interferon receptors.

[0004] Recently released clinical data from a RIPK1 competitor in psoriasis patients (Clin Pharmacol Ther. 2020;108(4):808-816), suggest that very high levels of RIPKl kinaseactivity inhibition are required to have a clinical effect and that the exposure needed to reach this high level of inhibition is higher in patients with chronic inflammatory diseases than in healthy humans. Thus, there exists a need for RIPK1 inhibitor and methods of use thereof, which can achieve levels of RIPK1 inhibition to achieve target engagement while maintaining an adequate safety and tolerability profile.BRIEF DESCRIPTION

[0005] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of 5-benzyl-N-[(3S)-5-methyl-4- oxo-2,3-dihydropyrido[3,2-b][l,4]oxazepin-3-yl]-4H-l,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0006] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder, comprising administering to a patient in need thereof a dose of about 10 to 800 mg (measured as the equivalent amount of free base) per day of 5-benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydropyrido[3,2- b][l,4]oxazepin-3-yl]-4H-l,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0007] In one embodiment, the present disclosure provides 5-benzyl-N-[(3S)-5-methyl-4- oxo-2,3-dihydropyrido[3,2-b][l,4]oxazepin-3-yl]-4H-l,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof for use in the treatment of a receptor-interacting protein kinase 1 -mediated disease or disorder at a dose of about 10 to 800 mg (measured as the equivalent amount of free base) per day.

[0008] In one embodiment, the present disclosure provides an article of manufacture, a packaging, or an administration unit, comprising: a packaging material; a pharmaceutical composition; and a label or package insert contained within said packaging material, indicating that said pharmaceutical composition is administered to a patient for the treatment of a receptor-interacting protein kinase 1 -mediated disease or disorder, at a dose of about 10 to 800 mg (measured as the equivalent amount of free base) per day of 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazepin-3-yl]-4H-l,2,4- triazole-3 -carboxamide or a pharmaceutically acceptable salt thereof.

[0009] In one embodiment, the present disclosure provides a dose of about 10 to 800 mg (measured as the equivalent amount of free base) per day of 5-benzyl-N-[(3S)-5-methyl-4- oxo-2,3-dihydropyrido[3,2-b][l,4]oxazepin-3-yl]-4H-l,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating a receptor-interacting protein kinase 1 -mediated disease or disorder.

[0010] In another embodiment, herein is provided a dose of about 10 to 800 mg of compound (1), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating a receptor-interacting protein kinase 1 -mediated disease or disorder.BRIEF DESCRIPTION OF FIGURES

[0011] Figure 1 : Plasma concentration versus time following single oral administration of 10-800 mg eclitasertib (semi-log scale)

[0012] Figure 2: Plasma concentration versus time profiles after single administration of 100 mg eclitasertib as CFE formulation in fasted or fed conditions and as DS formulation in fasted conditions (semi-log scale)

[0013] Figure 3: Plasma concentration versus time profiles after administration of eclitasertib 50-600 mg on Day 1 (A) and after 14-days of once-daily administration on Day 14 (B) - semi -log scale

[0014] Figure 4: Relative change from baseline in pS166 levels in PBMCs in SAD (A) and MAD (B) part of the studyDETAILED DESCRIPTION

[0015] The section headings used herein are for organizational purposes only and are not to be construed as limiting the desired subject matter in any way. In the event that any literature incorporated by reference contradicts any term defined in this specification, this specification controls. While the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. The present disclosure includes, for example, any one or a combination of the following embodiments.Definitions

[0016] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meaning:

[0017] As used herein, the terms “the RIPK1 inhibitor,” “the RIPK1 inhibitor compound,” “Compound 1,” “the compound,” and “IMP” refer to 5-benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide having the following structure:or a pharmaceutically acceptable salt thereof.

[0018] As used herein, the term "free base" means the compound referenced per se, e.g., not in the form of a salt or prodrug. Reference to, e.g., a "dose of...5 mg " means that there is an amount of compound present, whether in the form of the free base or a salt or prodrug, which corresponds to the same molar amount of 5 mg of the freebase, i.e., the compound in salt form would have a mass of greater than 5 mg. Unless otherwise indicated, an amount of an active compound for administration (whether administered as a free base or as a salt form) refers to or is based on the amount of the compound in free base form.

[0019] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0020] As used herein, the term “pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of a compound. These salts can be prepared in situ during the final isolation and purification of the compounds.

[0021] Before describing the present teachings in detail, it is to be understood that the disclosure is not limited to specific compositions or process steps, as such may vary.

[0022] It should be noted that, as used in this specification and the appended claims, the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “a conjugate” includes a plurality of conjugates and reference to “a cell” includes a plurality of cells and the like.

[0023] Unless specifically stated or obvious from the context, as used herein, the term "about" refers to a value that is within an acceptable error range for a particular value determined by a person of ordinary skill, a portion of which will depend on how the measurement or determination is made. For example, "about" may mean a range of up to 10% (z.e., ±10%). Therefore, "about" can be understood as greater than or less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1 %, 0.05%, 0.01%, or 0.001%. When a specific value is provided in this disclosure, unless otherwise stated, the meaning of "about" should be assumed to be within an acceptable error range for that specific value.

[0024] Numeric ranges are inclusive of the numbers defining the range. Measured and measurable values are understood to be approximate, taking into account significant digits and the error associated with the measurement. Also, the use of “comprise,” “comprises,” “comprising,” “contain,” “contains,” “containing,” “include,” “includes,” and “including” are not intended to be limiting. It is to be understood that both the foregoing general description and detailed description are exemplary and explanatory only and are not restrictive of the teachings.

[0025] Unless specifically noted in the above specification, embodiments in the specification that recite “comprising” various components are also contemplated as “consisting of’ or “consisting essentially of’ the recited components; embodiments in the specification that recite “consisting of’ various components are also contemplated as “comprising” or “consisting essentially of’ the recited components; and embodiments in the specification that recite “consisting essentially of’ various components are also contemplated as “consisting of’ or “comprising” the recited components (this interchangeability does not apply to the use of these terms in the claims.)

[0026] Unless specifically noted in the above specification, embodiments in the specification that recite “dose” weight described herein refers to the weight of free base of a compound (active moiety).

[0027] The term “or” is used in the inclusive sense, i.e., equivalent to “and / or,” unless the context requires otherwise.

[0028] As used herein, the term “QD” or “OD” refers to every day, once daily, once a day, per day; “BID” refers to twice a day.Administered RIPK1 inhibitor Compound

[0029] In some embodiments, a RIPKl inhibitor compound, 5-benzyl-N-[(3S)-5-methyl-4- oxo-2,3-dihydropyrido[3,2-b][l,4]oxazepin-3-yl]-4H-l,2,4-triazole-3-carboxamide is administered for treating a receptor-interacting protein kinase 1 -mediated disease or disorder in a patient in need thereof.

[0030] In some embodiments, the RIPK1 inhibitor compound is a pharmaceutically acceptable salt of 5-benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazepin- 3 -y 1 ] -4H- 1 , 2, 4 -tri azol e-3 -carb oxami de .

[0031] In some embodiments, a therapeutically effective amount of the RIPK1 inhibitor compound is administered.

[0032] In some embodiments, a dose of about 10 to 800 mg of the RIPK1 inhibitor compound is administered.

[0033] The RIPK1 inhibitor compound can be prepared according to the methods and schemes described in, e.g., U.S. Patent No. 9,896,458, set forth in example 42, which is incorporated herein by reference.Pharmaceutical compositions

[0034] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, also provided herein are pharmaceutical compositions that contain one or more of the compounds described herein or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients. Such compositions are prepared in a manner well known in the pharmaceutical arts.

[0035] The pharmaceutical compositions are comprised of in general, the RIPK1 inhibitor compound and / or a pharmaceutically acceptable salt thereof in combination with apharmaceutically acceptable excipient such as binders, surfactants, diluents, buffering agents, anti adherents, glidants, hydrophilic or hydrophobic polymers, retardants, stabilizing agents or stabilizers, disintegrants or superdisintegrants, antioxidants, antifoaming agents, fillers, flavors, colors, lubricants, sorbents, preservatives, plasticizers, or sweeteners, or mixtures thereof, which facilitate processing of the RIPK1 inhibitor compound and / or a pharmaceutically acceptable salt thereof into preparations which can be used pharmaceutically. Any of the well-known techniques and excipients may be used as suitable and as understood in the art, see for example, Remington: The Science and Practice of Pharmacy, Twenty -first Ed., (Pharmaceutical Press, 2005); Liberman, H. A., Lachman, L., and Schwartz, J.B. Eds., Pharmaceutical Dosage Forms, Vol. 1-2 Taylor & Francis 1990; and R.I. Mahato, Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Second Ed. (Taylor & Francis, 2012).

[0036] In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically- acceptable excipients, such as sodium citrate or dicalcium phosphate and / or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, acetyl alcohol, glycerol monostearate and non-ionic surfactants; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. One example of such composition is powder in capsule (referred herein as SF composition). Example of such composition include, but are not limited to capsule comprising microcrystalline cellulose, mannitol, croscarmellose sodium, polyvinylpyrrolidone, and magnesium stearate (SDF composition).

[0037] One embodiment provided herein is a solid dosage form comprising Compound 1 and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, and magnesium stearate.

[0038] One embodiment provided herein is a pharmaceutical composition comprising Compound 1, at least one water-soluble diluent, at least one water-insoluble diluent, at least one binder, at least one disintegrating agent, and at least one lubricant.

[0039] One embodiment provided herein is a pharmaceutical composition comprising Compound 1, at least one water-soluble diluent, at least one water-insoluble diluent, at least one binder, at least one disintegrating agent, and at least one lubricant, wherein the water- soluble diluent is mannitol, the water-insoluble diluent is microcrystalline cellulose, the disintegrating agent is croscarmellose sodium, the lubricant is magnesium stearate, and the binder is polyvinylpyrrolidone.

[0040] Suitable water- soluble diluents can include, for example, anhydrous lactose, lactose monohydrate, mannitol, sodium chloride, powdered sugar, sorbitol, sucrose, inositol and pregelatinized starch. Suitable water-insoluble diluents can include, for example, microcrystalline cellulose, calcium phosphate and starch. Suitable binders can include, for example, hydroxypropyl cellulose, polyvinylpyrrolidone and sodium laurel sulfate. Suitable disintegrating agents can include, for example, natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch and cross-linked polymer. Suitable lubricants can include, for example, vegetable stearin, magnesium stearate or stearic acid.

[0041] In some embodiments, the pharmaceutical composition comprises about 5-75 percent (w / w), about 10-65 percent (w / w), about 5-10 percent (w / w), about 10-20 percent (w / w), about 20-30 percent (w / w), about 30-40 percent (w / w), about 40-50 percent (w / w), about 50- 60 percent (w / w), about 60-65 percent (w / w), about 60-65 percent (w / w) about 60-70 percent (w / w), or about 65-75 percent (w / w) of Compound 1 on a dry solid basis.

[0042] In some embodiments, the pharmaceutical composition comprises about 10-70 percent (w / w), about 15-60 percent (w / w), about 10-20 percent (w / w), about 20-30 percent (w / w), about 30-40 percent (w / w), about 40-50 percent (w / w), about 50-60 percent (w / w), or about 60-70 percent (w / w) of water- soluble diluents on a dry solid basis.

[0043] In some embodiments, the pharmaceutical composition comprises about 3-30 percent (w / w), about 5-20 percent (w / w), about 3-10 percent (w / w), about 5-10 percent (w / w), about 10-15 percent (w / w), about 15-20 percent (w / w), about 15-25 percent (w / w), about 20-25 percent (w / w), or about 25-30 percent (w / w) of water-insoluble diluent on a dry solid basis.

[0044] In some embodiments, the pharmaceutical composition comprises about 2-10 percent (w / w), about 3-7 percent (w / w) or about 2-6 percent (w / w) of binder on a dry solid basis. The pharmaceutical composition typically comprises about 0.5-5 percent (w / w) or about 0.5-2 percent (w / w) of lubricant on a dry solid basis. In some embodiments, the pharmaceutical composition comprises about 2-10 percent (w / w), about 4-7 percent (w / w), about 3-7 percent (w / w), or about 2-6 percent (w / w) of disintegrating agent on a dry solid basis.

[0045] One embodiment is a solid dosage form comprising about 10-70 percent (w / w) of Compound 1 and pharmaceutical salt thereof, about 10-70 percent (w / w) of water- soluble diluent, about 3-30 percent (w / w) water-insoluble diluents, about 2-10 percent (w / w) of disintegrating agent, about 0.5-5 percent (w / w) of lubricant and 2-10 percent (w / w) of binder.

[0046] One embodiment is a solid dosage form comprising: about 5-35 percent (w / w) of Compound 1; about 45-65 percent (w / w) of mannitol; about 10-25 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate, wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0047] One embodiment is a solid dosage form comprising about 5-35 percent (w / w) of Compound 1 and pharmaceutical salt thereof, about 45-65 percent (w / w) of water- soluble diluent, about 10-25 percent (w / w) water-insoluble diluent, about 2-10 percent (w / w) of disintegrating agent, about 0.5-2 percent (w / w) of lubricant and 2-10 percent (w / w) of binder.

[0048] One embodiment is a solid dosage form comprising: about 50-70 percent (w / w) of Compound 1; about 15-30 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate, wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0049] One embodiment is a solid dosage form comprising: about 60-65 percent (w / w) of Compound 1; about 15-25 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 4-7 percent (w / w) of croscarmellose sodium; about 3-7 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate, wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0050] One embodiment is a solid dosage form comprising about 50-70 percent (w / w) of Compound 1 and pharmaceutical salt thereof, about 15-30 percent (w / w) of water- soluble diluent, about 5-10 percent (w / w) water-insoluble diluent, about 1-10 percent (w / w) of disintegrating agent, about 0.5-2 percent (w / w) of lubricant and 2-10 percent (w / w) of binder.

[0051] One embodiment is a solid dosage form comprising: about 5-70 percent (w / w) of Compound 1; about 15-65 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate, wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0052] One embodiment is a solid dosage form comprising about 10-70 percent (w / w) of Compound 1 and pharmaceutical salt thereof, about 10-70 percent (w / w) of water- soluble diluent, about 3-30 percent (w / w) water-insoluble diluent, about 2-10 percent (w / w) of disintegrating agent, about 0.5-5 percent (w / w) of lubricant and 2-10 percent (w / w) of binder.Therapeutic method

[0053] Provided herein are methods of treating a receptor-interacting protein kinase 1- mediated disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of 5-benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydropyrido[3,2- b][l,4]oxazepin-3-yl]-4H-l,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0054] In certain embodiments, the disease or disorder is inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, cutaneous lupus erythematosus, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcoholsteatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, or peridontitis.

[0055] In certain embodiments, the disease or disorder is trauma, ischemia, stroke, cardiac infarction, infection, lysosomal storage disease, Gaucher's disease, Krabbe disease, Niemann- Pick disease, sepsis, Parkinson's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's Disease), Huntington's disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease.

[0056] In certain embodiments, the disease or disorder is ALS, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, or spinal muscular atrophy.

[0057] In certain embodiments, the disease or disorder is brain injury, spinal cord injury, dementia, stroke, ALS, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, poly glutamine (polyQ) diseases, stroke, Fahr disease, Menke's disease, Wilson's disease, cerebral ischemia, or a prion disorder.

[0058] The receptor-interacting protein kinase 1 inhibitor described herein may be used to treat inflammatory diseases and disorders. Inflammatory diseases and disorders typically exhibit high levels of inflammation in the connective tissues, or degeneration of these tissues.

[0059] Non-limiting examples of inflammatory diseases and disorders include skin inflammatory disease and disorders, ankylosing spondylitis, arthritis including osteoarthritis, rheumatoid arthritis (RA), psoriasis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), cutaneous lupus erythematosus (CLE), systemic lupus erythematous (SLE), nephritis, Parkinson's disease, and ulcerative colitis.

[0060] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof; wherein the compound is administered at a dose of about 10 to 800 mg measured (as the equivalent amount of free base) per day.

[0061] In one embodiment, the present disclosure provides a method of inhibiting a receptorinteracting protein kinase, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof; wherein the compound is administered at a dose of about 10 to 800 mg measured (as the equivalent amount of free base) per day.

[0062] In one embodiment, the present disclosure provides a method of treating an inflammatory diseases and disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof; wherein the compound is administered at a dose of about 10 to 800 mg measured (as the equivalent amount of free base) per day.

[0063] In one embodiment, the present disclosure provides a method of ulcerative colitis, comprising administering to a patient in need thereof a dose of about 10 to 800 mg per day Compound 1, or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment, the present disclosure provides a method of treating an inflammatory diseases and disorder, comprising administering to a patient in need thereof a dose of about 10 to 800 mg (measured as the equivalent amount of free base) per day of Compound 1.

[0065] In one embodiment, the present disclosure provides a method of treating a inflammatory diseases and disorder, comprising administering to a patient in need thereof a dose of about 10 to 800 mg (measured as the equivalent amount of free base) per day of Compound 1.

[0066] In some embodiments, a dose of about 10-50 mg, about 50-100 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350- 400 mg, about 400-450 mg, about 450-500 mg, about 500-550 mg, about 550-600 mg, about 600-650 mg, 650-700 mg, about 700-750 mg, or about 750-800 mg or is administered.

[0067] In some embodiments, the dose is about 10 mg, about 50 mg, about 100 g, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg. In some embodiments, the dose is about 100 mg. In some embodiments, the dose is about 150 mg. In some embodiments, the dose is about 200 mg. In some embodiments, the dose is about 300 mg. In some embodiments, the dose is about 400 mg. In some embodiments, the dose is about 500 mg. In some embodiments, the dose is about 600 mg. In some embodiments, the dose is about 700 mg. In some embodiments, the dose is about 800 mg.

[0068] In some embodiments, the dose is administered daily. The daily dose can be delivered as a single dose or split into multiple parts. For example, in some embodiments, the dose is administered once a day (e.g., about every 24 hours). In some embodiments, the dose is administered twice daily. In some embodiments, the dose is subdivided in two parts to be administered twice per day (e.g., about every 12 hours). In some embodiments, the dose is subdivided in three parts to be administered three times per day (e.g., about every 8 hours).

[0069] In one embodiment, the dose is about 100 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0070] In one embodiment, the dose is about 200 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0071] In one embodiment, the dose is about 300 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment, the dose is about 400 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0073] In one embodiment, the dose is about 500 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0074] In one embodiment, the dose is about 600 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0075] In one embodiment, the dose is about 700 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0076] In one embodiment, the dose is about 800 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0077] In one embodiment, the dose is about 50 mg twice a day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0078] In one embodiment, the dose is about 100 mg twice a day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0079] In one embodiment, the dose is about 150 mg twice a day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment, the dose is about 200 mg twice a day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0081] In one embodiment, the dose is about 250 mg twice a day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0082] In one embodiment, the dose is about 300 mg twice a day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, the dose is about 350 mg twice a day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0084] In one embodiment, the dose is about 400 mg twice a day of Compound 1, or a pharmaceutically acceptable salt thereof.

[0085] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 300 mg twice a day.

[0086] In one embodiment, the present disclosure provides a method of treating an inflammatory disease and disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 300 mg twice a day.

[0087] In one embodiment, the present disclosure provides a method of treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 300 mg twice a day.

[0088] In one embodiment, the present disclosure provides a method of inhibiting of a receptor-interacting protein kinase, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 300 mg twice a day.

[0089] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 200 mg twice a day.

[0090] In one embodiment, the present disclosure provides a method of treating an inflammatory disease and disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 200 mg twice a day.

[0091] In one embodiment, the present disclosure provides a method of inhibiting of a receptor-interacting protein kinase, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 200 mg twice a day.

[0092] In one embodiment, the present disclosure provides a method of treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 200 mg twice a day.

[0093] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 150 mg twice a day.

[0094] In one embodiment, the present disclosure provides a method of treating an inflammatory disease and disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 150 mg twice a day.

[0095] In one embodiment, the present disclosure provides a method of inhibiting of a receptor-interacting protein kinase, comprising administering to a patient in need thereof atherapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 150 mg twice a day.

[0096] In one embodiment, the present disclosure provides a method of treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 150 mg twice a day.

[0097] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 100 mg twice a day.

[0098] In one embodiment, the present disclosure provides a method of treating an inflammatory disease and disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 100 mg twice a day.

[0099] In one embodiment, the present disclosure provides a method of inhibiting of a receptor-interacting protein kinase, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 100 mg twice a day.

[0100] In one embodiment, the present disclosure provides a method of treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 100 mg twice a day.

[0101] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 50 mg twice a day.

[0102] In one embodiment, the present disclosure provides a method of treating an inflammatory disease and disorder, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 50 mg twice a day.

[0103] In one embodiment, the present disclosure provides a method of inhibiting of a receptor-interacting protein kinase, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 50 mg twice a day.

[0104] In one embodiment, the present disclosure provides a method of treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof at a dose of about 50 mg twice a day.

[0105] One embodiment is a method of treating an inflammatory disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition or dosage form disclosed herein.

[0106] One embodiment is a method of treating an inflammatory disease or disorder, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition or dosage form disclosed herein.

[0107] One embodiment is a method of treating an inflammatory disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form, wherein the dosage form comprises: about 50-70 percent (w / w) of Compound 1; about 15-30 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate; wherein the solid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0108] One embodiment is a method of treating an inflammatory disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form, wherein the Compound 1 is present in an amount to provide a daily dose within the range of from about 100 to about 600 mg per day in single or divided doses or multiple doses, wherein the dosage form comprises: about 50-70 percent (w / w) of Compound 1; about 15-30 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate; wherein thesolid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0109] One embodiment is a solid dosage form for use in treating an inflammatory disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form, wherein the Compound 1 is present in an amount to provide a daily dose within the range of from about 100 to about 600 mg per day in single or divided doses or multiple doses, wherein the dosage form comprises: about 50-70 percent (w / w) of Compound 1; about 15-30 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate; wherein the solid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0110] One embodiment is use of a solid dosage form for preparing a medicament for the treatment of an inflammatory disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form, wherein the Compound 1 is present in an amount to provide a daily dose within the range of from about 100 to about 600 mg per day in single or divided doses or multiple doses, wherein the dosage form comprises: about 50-70 percent (w / w) of Compound 1; about 15-30 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate; wherein the solid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.[OHl] One embodiment is a solid dosage form for use in treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form, wherein the Compound 1 is present in an amount to provide a daily dose within the range of from about 100 to about 600 mg per day in single or divided doses or multiple doses, wherein the dosage form comprises: about 50-70 percent (w / w) of Compound 1; about 15-30 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate; wherein the solid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0112] One embodiment is use of a solid dosage form for preparing a medicament for the treatment of ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form, wherein the Compound 1 is present in an amount to provide a daily dose within the range of from about 100 to about 600 mg per day in single or divided doses or multiple doses, wherein the dosage form comprises: about 50-70 percent (w / w) of Compound 1; about 15-30 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate; wherein the solid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0113] One embodiment is a method of treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form, wherein the dosage form comprises: about 50-70 percent (w / w) of Compound 1; about 15-30 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate; wherein the solid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0114] One embodiment is a method of treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form, wherein the Compound 1 is present in an amount to provide a daily dose within the range of from about 100 to about 600 mg per day in single or divided doses or multiple doses, wherein the dosage form comprises: about 50-70 percent (w / w) of Compound 1; about 15-30 percent (w / w) of mannitol; about 5-10 percent (w / w) of microcrystalline cellulose; about 1-10 percent (w / w) of croscarmellose sodium; about 1-10 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate; wherein the solid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0115] One embodiment is a method of treating an inflammatory disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form, wherein the dosage form comprises: about 10-65 percent (w / w) of Compound 1; about 15-60 percent (w / w) of mannitol; about 5-20 percent (w / w) of microcrystalline cellulose; about 3-7 percent (w / w) of croscarmellose sodium; about 3-7 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate;wherein the solid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0116] One embodiment is a method of treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of a solid dosage form, wherein the dosage form comprises: about 10-65 percent (w / w) of Compound 1; about 15-60 percent (w / w) of mannitol; about 5-20 percent (w / w) of microcrystalline cellulose; about 3-7 percent (w / w) of croscarmellose sodium; about 3-7 percent (w / w) of polyvinylpyrrolidone; and about 0.5-2 percent (w / w) of magnesium stearate; wherein the solid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

[0117] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder comprising administering to a patient in need thereof at a dose of about 100-800 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof; wherein said compound is administered in an amount to provide maximum median peripheral pS166-RIPKl inhibition in peripheral blood mononuclear cells (PBMCs) lysates ranged between about 73.8%-95.4% assessed by Meso Scale Discovery (MSD) assay.

[0118] In one embodiment, the present disclosure provides a method of inhibiting of a receptor-interacting protein kinase comprising administering to a patient in need thereof at a dose of about 100-800 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof; wherein said compound is administered in an amount to provide maximum median peripheral pS166-RIPKl inhibition in peripheral blood mononuclear cells (PBMCs) lysates ranged between about 73.8%-95.4% assessed by Meso Scale Discovery (MSD) assay.

[0119] In one embodiment, the present disclosure provides a method of treating ulcerative colitis comprising administering to a patient in need thereof at a dose of about 100-800 mg per day of Compound 1, or a pharmaceutically acceptable salt thereof; wherein said compound is administered in an amount to provide maximum median peripheral pS166- RIPK1 inhibition in peripheral blood mononuclear cells (PBMCs) lysates ranged between about 73.8%-95.4% assessed by Meso Scale Discovery (MSD) assay.

[0120] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, or apharmaceutically acceptable salt thereof at a dose of about 100-800 mg per day wherein said compound is administered to provide absorption with mean tmax reached between 3-4 hours post-administering to the patient in a fasted state.

[0121] In one embodiment, the present disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof is used in the treatment of a receptor-interacting protein kinase 1 -mediated disease or disorder at a dose of about 10 to 800 mg per day.

[0122] In one embodiment, the present disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof is used in the treatment of an inflammatory disease and disorder at a dose of about 10 to 800 mg per day.

[0123] In one embodiment, the present disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof is used in inhibiting of a receptor-interacting protein kinase at a dose of about 10 to 800 mg per day.

[0124] In one embodiment, the present disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof is used in the treatment of ulcerative colitis at a dose of about 300 mg twice a day.

[0125] In one embodiment, the present disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof is used in the treatment of ulcerative colitis at a dose of about 150 mg twice a day.

[0126] In one embodiment, the present disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof is used in the treatment of ulcerative colitis at a dose of about 50 mg twice a day.

[0127] In one embodiment, the present disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of a receptor-interacting protein kinase 1 -mediated disease or disorder at a dose of about 10 to 800 mg per day.

[0128] In one embodiment, the present disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of an inflammatory diseases and disorder at a dose of about 10 to 800 mg per day.

[0129] In one embodiment, the present disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of ulcerative colitis at a dose of about 10 to 800 mg per day.

[0130] In one embodiment, the present disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of ulcerative colitis at a dose of about 300 mg twice a day.

[0131] In one embodiment, the present disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of ulcerative colitis at a dose of about 250 mg twice a day.

[0132] In one embodiment, the present disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of ulcerative colitis at a dose of about 200 mg twice a day.

[0133] In one embodiment, the present disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of ulcerative colitis at a dose of about 150 mg twice a day.

[0134] In one embodiment, the present disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of ulcerative colitis at a dose of about 100 mg twice a day.

[0135] In one embodiment, the present disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment of ulcerative colitis at a dose of about 50 mg twice a day.

[0136] In one embodiment, the present disclosure provides an article of manufacture, a packaging, or an administration unit, comprising: a packaging material; the above defined pharmaceutical composition; and a label or package insert contained within said packaging material, indicating that said pharmaceutical composition is administered to a patient for the treatment of a receptor-interacting protein kinase 1 -mediated disease or disorder, at a dose of about 10 to 800 mg per day of 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazepin-3-yl]-4H-l,2,4-triazole-3-carboxamide or a pharmaceutically acceptable salt thereof.

[0137] In one embodiment, the present disclosure provides a dose of about 10 to 800 mg per day of 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazepin-3-yl]-4H- 1, 2, 4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating a receptor-interacting protein kinase 1- mediated disease or disorder.

[0138] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof; wherein the therapeutically effective amount of the compound is about 10-800 mg of Compound 1, wherein the dose is administered with food.

[0139] In one embodiment, the present disclosure provides a method of treating a receptorinteracting protein kinase 1 -mediated disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof; wherein the therapeutically effective amount of the compound is about 10-800 mg of Compound 1, wherein the dose is administered without food.

[0140] In some embodiments, the dose is administered orally. In some embodiments, the dose is administered in a form of tablets. In some embodiments, the dose is administered in the form of pills, capsules, semisolids, powders, sustained release compositions, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

[0141] In some embodiments, the patient is administered the RIPK1 inhibitor compound for a period of about 4, 8, 12, 16, 20 or 24 weeks. In some embodiments, the patient is administered the RIPK1 inhibitor compound for a period of about 12 weeks.

[0142] In some embodiments, the dose is administered with food. In some embodiments, the dose is administered once daily with food. In some embodiments, the dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg or about 800 mg is administered with food. In some embodiments, the dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg or about 800 mg is administered once daily with food. In some embodiments, the dose of about300 mg is administered twice a day with food. In some embodiments, the dose of about 150 mg is administered twice a day with food. In some embodiments, the dose of about 50 mg is administered twice a day with food.

[0143] In some embodiments, the dose is administered in oral solution or tablets. In some embodiments, the dose is administered in oral solution or tablets with food. In some embodiments, the dose is administered once daily in oral solution or tablets. In some embodiments, the dose is administered once daily in oral solution or tablets with food. In some embodiments, the dose of about 300 mg is administered twice a day in oral solution or tablets. In some embodiments, the dose of about 150 mg is administered twice a day in oral solution or tablets with food. In some embodiments, the dose of about 50 mg is administered twice a day in oral solution or tablets.

[0144] In some embodiments, the dose is administered without food. In some embodiments, the dose is administered once daily without food. In some embodiments, the dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg or about 800 mg is administered without food. In some embodiments, the dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg or about 800 mg is administered once daily without food. In some embodiments, the dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg or about 800 mg is administered once daily with food. In some embodiments, the dose of about 300 mg is administered twice a day without food. In some embodiments, the dose of about 300 mg is administered twice a day with food.

[0145] In some embodiments, the dose is administered in oral solution or tablets. In some embodiments, the dose is administered in oral solution or tablets without food. In some embodiments, the dose is administered once daily in oral solution or tablets without food. In some embodiments, the dose is administered once daily in oral solution or tablets without food. In some embodiments, the dose of about 300 mg is administered once daily in oral solution or tablets. In some embodiments, the dose of about 300 mg is administered twice a day in oral solution or tablets without food. In some embodiments, the dose of about 300 mg is administered twice a day in oral solution or tablets with food. In some embodiments, the dose of about 150 mg is administered twice a day in oral solution or tablets without food. In some embodiments, the dose of about 150 mg is administered twice a day in oral solution or tablets with food. In some embodiments, the dose of about 50 mg is administered twice a dayin oral solution or tablets without food. In some embodiments, the dose of about 50 mg is administered twice a day in oral solution or tablets with food.

[0146] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.AbbreviationsAE: adverse eventAESI: adverse event of special interestALS: amyotrophic lateral sclerosisAUC: area under the plasma concentration versus time curve extrapolated to infinityBID: twice a dayCL / F: apparent total body clearance of a drug from the plasmaCLss / F : apparent total body clearance after repeated extra vascular doses of a drug at steady stateCtrough: concentration observed just before treatment administration during repeated dosingC V : coeffi ci ent of vari ati onCYP: cytochrome P450DEM: dose escalation meetingDMET : drug metabolizing enzymes and transportersDMSO: Dimethyl sulfoxideEGG: electrocardiogram eCRF : electronic case report formGLP: good laboratory practicesIMP: investigational medicinal productLC-MS / MS: liquid chromatography coupled with tandem mass spectrometryLLOQ: low limit of quantificationLOQ: limit of quantificationLTBI: latent tuberculosis infectionLUC: large unstained cellMAD: multiple ascending doseMS: multiple sclerosisNOAEL: no observed adverse event levelPBMCs: peripheral blood mononuclear cellsPBS: Phosphate-buffered salinePCSA: potentially clinically significant abnormalityPD: pharmacodynamicPK: pharmacokineticsQD: once a dayQT : duration of ventricular electrical systoleRIPK1 : receptor interacting serine / threonine kinase 1RR: period between two consecutive ventricular depolarizationsSAD: single ascending doseSAE: serious adverse eventSD: standard deviationSDF : solid dosage formSF : study compositionSOC: system organ class ti / 2Z: half-life associated with the terminal slopeTau: dosage interval tmax time to reach C maxTB: tuberculosisTEAE: treatment emergent adverse eventTLR: toll-like-receptorTNFR: Tumor Necrosis Factor ReceptorTNFa: Tumor Necrosis Factor alphaVz / F: the apparent volume of distributionEXAMPLES

[0147] The following examples are provided to illustrate certain disclosed embodiments and are not to be construed as limiting the scope of this disclosure in any way. In the Examples discussed below, the RIPK1 inhibitor, as defined above, may be also referred as “Compound 1,” “the compound,” or “the drug” interchangeably.Example 1: A randomized, double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of ascending single or repeated oral doses of Compound 1 in healthy adult participants.

[0148] This single-center, first-in-human Phase 1 study conducted in healthy participants in the United States consisted of 3 parts (Part la, Part lb, and Part 2)

[0149] Part la (SAD) was a randomized, double-blind, placebo-controlled study that evaluated 6 sequential ascending single doses cohorts where Compound 1 was administered orally in the morning on Day 1 under fasted conditions at doses of 10 mg, 30 mg, 100 mg, 200 mg, 400 mg and 800 mg (800 mg was an optional dose level cohorts). Participants were fasted overnight for at least 8 hours before the morning dose and 2 hours after dosing.

[0150] Part lb (SAD): Subjects were to receive a single dose of 100 mg study composition (SF) fasted, 100 mg solid dosage form (SDF) fed, and 100 mg SDF fasted across 3 treatment periods. Subjects were randomized to 1 of 3 different sequences. Dose of 100 mg (dose was adapted based on SAD PK results) was used.

[0151] Part 2 (MAD): double-blind, randomized, placebo-controlled, sequential ascending repeated dose study with 3 planned cohorts and one optional cohort, and up to 10 subjects per cohort (8 active and 2 placebo).

[0152] The study duration included a 28-day screening period, a treatment period (1 day each for Parts la and lb; 14 days for Part 2), followed by an observation period (1-4 days for Part la; 1-4 days for Part lb; 1-17 days for Part 2), and a follow up with the end of study (EOS) visit 6 days after dosing in Parts la and lb, and 5-7 days after the last administration in Part 2.

[0153] Eligible participants in both studies were healthy men or women, 18-55 years of age, with body weight between 50-100 kg for men and women, and a body mass index between 18-30 kg / m2.Study endpoints and assessments:

[0154] Safety and tolerability of Compound Iwas assessed by physical examination, neurological examination, monitoring adverse events (AEs) and potentially clinically significant abnormalities (PCSAs) in clinical laboratory tests (hematology, biochemistry, blood sample and urinalysis), vital signs (body temperature, blood pressure and heart rate), and ECG parameters (heart rate, RR, PR, QRS, QT, QTcF, QTcB intervals) measured in the standard 12-lead ECG or ECGs extracted from 24-hour Holter ECG data. An adverse event is considered as treatment emergent if it occurred from the time of the first investigational medicinal product (IMP) administration up to the end of study visit (included). An adverse event is considered severe if the grading is greater or equal 3.PK parameters:

[0155] Plasma concentrations of Compound 1 were analyzed using two validated and crossvalidated liquid chromatography coupled with tandem mass spectrometry (LC-MS / MS) methods with two different calibration ranges, the first one with a low calibration range of 0.2 to 200 ng / mL and the second one with a higher calibration range of 20 to 20 000 ng / mL. The low calibration range assay method was used to assay all predose samples of all cohorts and all samples from the doses 10 to 200 mg, and to assay sample collected around tmax of placebo subjects. The second assay method was developed in order to assay the samples of the last cohorts (from 400 to 800 mg), for which the maximal concentrations were predicted to be higher than the quantifiable concentration with the validated dilution factor of the firstassay method. However, with this high calibration range, most of the concentrations of the last timepoint (72 hours postdose) were below the second limit of quantification (LOQ) (20 ng / mL). In order to assess the elimination phase until 72 hours, these plasma samples were re-assayed with the Low calibration range method (LOQ: 0.2 ng / mL) and previous concentrations were invalidated. Compound 1 concentrations in urine samples were assayed using a qualified LC-MS / MS method with a LOQ of 100 ng / mL.

[0156] The following plasma PK parameters were calculated from plasma Compound 1 concentrations obtained after single (Part la, Part lb) or repeated (Part 2) oral doses: maximum plasma concentration observed (Cmax); time to reach Cmax (tmax); interval between administration time and the sampling time preceding the first concentration above the limit of quantification (tiag); area under the plasma concentration versus time curve from time zero to the real time (AUCiast); area under the plasma concentration versus time curve extrapolated to infinity (AUC); area under the concentration versus time curve during a dosage interval (tau), with tau=12 hours for BID regimen and tau=24 hours for OD regimen terminal (AUCtau); half-life associated with the terminal slope (ti / 2z); apparent total body clearance of a drug from the plasma CL / F; apparent total body clearance after repeated extra vascular doses of a drug at steady state (CLSS / F); the apparent volume of distribution (Vz / F); concentration observed just before treatment administration during repeated dosing (Ctrough).

[0157] In Part la, plasma samples were collected before dosing and at 13 post-dose timepoints on Day 1 (30 minutes, 1 hour, followed by every hour until 12 hours), and samples on Day 2 (at 16 hours and 24 hours), Day 3 (at 48 hours) and Day 4 at 72 hours. In Part lb, timepoints included at least pre-dose and at 13 post-dose timepoints like part la. In Part 2, on Day 1 and Day 14, plasma samples were collected at pre-dose and at 9 post-dose timepoints. In addition, plasma samples were collected on Days 2, 3 and 4.Pharmacodynamic parameters:

[0158] The ability of Compound 1 to inhibit RIPK1 kinase activity, as measured by the inhibition of pS166-RIPKl in prepared PBMC lysates isolated from blood samples, was investigated to assess the peripheral target engagement; pS166-RIPKl levels in human PBMC lysates and percentage of change from baseline were calculated. Levels of SI 66 phosphorylated RIPK1 in unstimulated PBMCs were assessed as described previously, but without TSZ (TNFD, SM-164, Z-VAD-FMK) stimulation. In brief, isolated PBMCs were resuspended in autologous plasma and incubated for 150 mins at 370C, and 5% CO2. PBMCswere lysed in IX CST buffer (Cell Signaling Technologies, Leiden, the Netherlands) and subsequently centrifuged, and the supernatant was frozen at -80°C until assayed (Clin Pharmacol Ther 2020;107:406-14). pS166-RIPKl was detected with a Meso Scale Discovery (MSD) platform-based immunoassay. Each well of a streptavidin small spot 96-well plate coated with biotinylated mouse anti-RIPKl antibody was incubated with PBMC lysate for 2 hours followed by rabbit anti-pS166 RIPK1 for 1 hour. pS166-RIPKl levels were detected with SULFO tagged goat anti -rabbit secondary antibody using a using a Sector S600 plate reader (MSD). In SAD-Part la, four blood samples (on Day 1, Day 2, Day 3 and Day 4) for pS166-RIPKl level were collected per participant. Whole blood was collected, and cell components were separated to isolate PBMCs and prepare cell lysates. Levels of RIPK1 phosphorylation at serine 166 in cell lysates was measured using the Meso Scale Discovery platform (MSD). In MAD-Part 2, blood samples were collected one sample on Day 1, four samples on Day 14, Day 15, Day 16 and Day 17.Statistical analyses:Safety, PK and PD data were summarized with descriptive statistics using SAS version 9.4 (Unix, Version 9 .4, SAS Institute, NC USA).

[0159] Dose proportionality was assessed using empirical power model (pharmacokinetics parameter = a x dosep), along with an “estimation” interpretation, as described by Gough et al (Drug Information Journal, 1995. 29(3): p. 1039-1048). The power model was fit on the log- transformed scale using SAS version 9.4 (Unix, Version 9 .4, SAS Institute, NC USA ): log (parameter) = log (a) + P x log (dose) as described in literatures (Clin Pharmacol Ther, 2020. 107(2): p. 406-414, Clin Transl Sci, 2022. 15(8): p. 2010-2023).

[0160] For estimating the effect of food on PK parameters, Cmax, AUCiast and AUC, the difference between food conditions (including data on subjects receiving CFE only) was assessed on log-transformed parameters with a linear model, a. Log (Parameter) = Sequence + Period + Food + Error with fixed term for sequence, period, and food condition, and with an unstructured 2-by-2 matrix of food condition variances and covariance for subject within sequence.

[0161] For estimating bioavailability differences between DS and CFE formulation in fasted state, Cmax, AUCiast and AUC were assessed on log-transformed parameters with a linear model, i. Log (Parameter) = Sequence + Period + Form + Error with fixed term for sequence, period, formulation DS and formulation CFE, and with an unstructured 2-by-2 matrix of formulation variances and covariance for subject within sequence.

[0162] Reduction in RIPK1 S166 phosphorylation was analyzed as raw values, absolute and percent change from baseline. Results were summarized by cohort using descriptive statistics.Safety:

[0163] Safety population included all participants who received at least one dose of study intervention (Compound or placebo). All safety assessments (AEs, laboratory parameters, vital signs) were based on the review of individual values and were summarized using descriptive statistics. Safety analysis was focused on treatment-emergent period, defined as the time from Compound 1 administration up to the end of study visit (included). AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA, version 23.1 in Part la and Part lb; version 24 in Part 2). Severity was graded from Grade 1 to 4 according to the Food and Drug Administration (FDA) Guidance for Industry. Number (%) of participants experiencing TEAEs and PCSAs in clinical chemistry, vital signs, and ECGs were summarized by dose level group.Pharmacokinetics:

[0164] PK population included all participants exposed to Compound Iwith no major or critical deviations related to Compound 1 and for whom PK data were considered sufficient and interpretable. PK parameters were summarized by descriptive statistics for each dose level group. Distribution of Tmax values was represented by histogram plots for each dose level group. In Part la, for Cmax, AUCiast, and AUC, dose proportionality will be assessed using the empirical power model, along with an “estimation” interpretation, according to the recommendations in Gough et al. (1995). In Part lb, For Cmax, AUCiast and AUC, the difference between food conditions will be assessed on log-transformed parameters with a linear model with fixed term for sequence, period and food condition, and with an unstructured 2-by-2 matrix of food condition variances and covariance for subject withinsequence, using SAS Proc Mixed®. For Cmax, AUCiast, and AUC, estimate and 90% confidence interval for the ratio of food condition geometric means (fed / fasted) will be obtained by computing estimate and 90% confidence interval for the difference between food condition arithmetic means (on log-scale) within the linear model framework, and then converting back to a ratio of geometric means by the antilog transformation. Furthermore, the distribution of tmax values will be represented by histogram plots for each food condition, and a histogram of differences in tmax between food conditions (fed versus fasted) will be provided.

[0165] In Part 2, all PK analyses were performed separately for each regimen (OD and BID). Steady state was assessed on Ctrough using a non-linear model using the SAS Proc Nlmixed® procedure. Accumulation was assessed using a linear model on log-transformed accumulation ratio with dose as fixed effect using SAS Proc Mixed®. Dose proportionality was assessed using a linear model on Cmax and AUCtau on Day 1 and Day 14, separately. Variance components of log-transformed Cmax and AUCtau were estimated using a linear model. In Part lb, 4P-hydroxycholesterol on Day 14 versus Day 1 pre-dose concentration ratios were summarized using descriptive statistics by dose level group and point estimates with 90% confidence interval (90% CI) for the geometric mean of the log-transformed Dayl4 / Dayl ratio was calculated in Part 2. Levels of pS166-RIPKl and percentage of change from baseline were summarized descriptively by dose level group and time point. Scatterplots were provided for pS166-RIPKl data versus PK plasma concentration in the PK / PD population. For each participant, the percent change compared to their baseline was evaluated at multiple timepoints up to 24 hours in Part la and up to 48 hours in Part 2.Pharmacokinetics / pharmacodynamics:

[0166] A PK / PD relationship analysis was performed through a scatterplot by time and pooling all timepoints displaying subject PD parameter: i.e., pS166-RIPKl percentage change from baseline, versus subject PK parameter: i.e., PK plasma concentration. All the analyses were performed on the PK / PD population.

[0167] A Concentration-ECG analysis was based on ECG extracted from 24-hr Holter data. The ECG parameters included heart rate, QTcF, PR, and QRS intervals. Descriptive statistics of change from baseline in ECG parameters and of Compound 1 concentrations were computed by treatment group and time points. All the analyses were performed on the Concentration-ECG population. The relationship between change from baseline andCompound 1 concentrations was explored graphically, in order to investigate any potential delayed or sustained effects and the type of modeling to be done, using plots, by treatment group. In case of direct and linear relationship between concentrations and change from baseline in ECG parameters, a linear mixed effect model was performed.Population PK (popPK)

[0168] The popPK model was established based on phase I rich sampling PK concentrations from two studies (single and multiple escalating dose studies, 78 enrolled healthy subjects and 1868 drug concentrations). The model consisted of a one-compartment model, with first order (Ka) and delayed absorption involving Erlang type multiple transfers. A relative bioavailability parameter was set to 100 % for the lowest dose and a covariate was included in the model with a negative effect of dose (DADM) on F 1.ResultsPopulation characteristics:

[0169] In Part la, a total of 48 subjects were enrolled: 8 subjects were enrolled into each of the 6 cohorts, and treated with 10 mg, 30 mg, 100 mg, 200 mg, 400 mg or 800 mg of Compound 1 (or placebo), respectively. All subjects completed the study and were evaluable for safety assessment, PK and PD parameters.

[0170] In Part lb, a total of 10 subjects were enrolled and all were evaluable for safety assessment: 9 subjects completed all three periods; one subject was discontinued after the first period due to a newly discovered cardiac issue warranting further evaluation by his primary care physician (unrelated to study drug per the Investigator). Thus 9 subjects completed the study. They received a single dose of 100 mg of IMP each dosing period.Pharmacokinetic analysis:

[0171] All samples of placebo subjects assayed only around tmax were below the LLOQ and Compound 1 was quantifiable in all subjects having received Compound 1. Mean Compound 1 PK parameters from Part la (SAD) in heathy subjects are summarized in Table 1.Table 1 - Descriptive statistics of plasma pharmacokinetic parameters following single oral administration of 10 to 800 mg in fasted conditions (PK-Part la)PLASMA Compound 1Mean ± SD(Geometric Mean) [CV%]10 mg 30 mg 100 mg 200 mg 400 mg 800 mgN 6 6 6 6 6 6250 ± 697 ± 1900 ± 3350 ± 5300 ± 6630 ±Cmax24.3 86.9 704 758 2770 2800(249) (692) (1780) (3270) (4760) (6120)(ng / mL)[9.70] [12.5] [37.0] [22.6] [52.4] [42.3] tLmaxa3.00 3.51 3.50 3.52 4.00 4.00(2.00 - (2.02 - (2.00 - (3.00 - (3.00 - (3.02 -(h)4.05) 4.02) 6.00) 8.00) 6.13) 6.02)1810 ± 5670 ± 17500 ± 33000 ± 61700 ± 90500 ±AUCiast206 1200 4730 8110 28500 30300(1800) (5560) (17000) (32000) (57200) (85600)(ng»h / mL)[H.4] [21.2] [27.0] [24.6] [46.3] [33.5]1810 ± 5670 ± 17500 ± 33000 ± 61900 ± 92300 ±AUC206 1200 4730 8100 28500 30900(1800) (5570) (17000) (32100) (57500) (87300)(ng»h / mL)[H.4] [21.2] [27.0] [24.5] [46.0] [33.5]5.86 ± 5.72 ± 6.08 ± 6.38 ± 9.32 ± 9.63 ± tl / 2z0.272 0.766 1.14 0.793 2.73 5.72(5.85) (5-67) (6.00) (6.34) (9.01) (8.47)(h)[4.6] [13.4] [18.8] [12.4] [29.3] [59.4]5.58 ± 5.49 ± 6.05 ± 6.46 ± 7.40 ± 9.79 ±CL / F0.607 1.13 1.54 1.98 2.56 4.09(5.55) (5.39) (5.88) (6.24) (6.96) (9.17)(L / h)[10.9] [20.5] [25.4] [30.6] [34.6] [41.7]47.3 ± 44.9 ± 53.7 ± 61.1 ± 103 ± 121 ±Vz / F6.03 8.56 19.9 27.5 57.4 57.4(46.9) (44.1) (50.9) (57.1) (90.5) (112)[12.8] [19.1] [37.1] [45.1] [55.5] [47.3]40.7 ± 42.9 ± 58.2 ± 66.0 ± 110 ± 146 ±Vss / F5.03 5.81 22.3 20.0 56.4 55.2(40.5) (42.6) (54.7) (63.7) (97.6) (137)[12.3] [13.5] [38.2] [30.3] [51.4] [37.8]aMedian (Min - Max)

[0172] The pharmacokinetic profiles are presented in Figure 3. Pharmacokinetic parameters are summarized in Error! Reference source not found.. One subject was withdrawn after his first period and was included in both pharmacokinetic and statistics analysis since he completed that period, thereby n=10 only for the SDF in fasted state.Table 2 - Descriptive statistics of Compound 1 PK parameters after single dose of 100 mg Compound 1 as SDF composition in fasted or fed conditions and as SF composition in fasted conditions in healthy subjects (PK-Part lb)Mean ± SDPLASMA Compound 1 (Geometric Mean) [CV%]SDF SDF6SFCFasted Fed FastedN 10 9 9Cmax 2490 ± 550 2690 ± 586 1930 ± 594(ng / mL) (2430) [22.1] (2640) [21.8] (1850) [30.8] tmax0 3.00 4.00 3.00(h) (2.00 - 6.00) (2.00 - 6.00) (1.02 - 4.00)ti / 2z 5.73 ± 0.643 5.11 ± 0.446 6.18 ± 0.493(h) (5.70) [11.2] (5.10) [8.7] (6.16) [8.0]AUCiast 21 600 ± 5630 21 900 ± 5730 19 400 ± 6180(ng»h / mL) (21 000) [26.0] (21 400) [26.1] (18 600) [31.9]AUC 21 600 ± 5640 21 900 ± 5730 19 400 ± 6190(ng»h / mL) (21 000) [26.0] (21 400) [26.1] (18 600) [31.9] a Median (Min - Max); b SDF : Composition 2 in Example 5; c SF : power in capsule

[0173] The bioavailability of the SDF and SF compositions are similar in terms of AUCs, and Cmax is slightly increased by 30% for the SDF composition (Table 3).Table 3 - Relative bioavailability: Cmax, AUCiast, AUC point estimate and 90% CI for composition geometric mean ratio: SDF versus SF, in fasted state

[0174] Fasted Concomitant intake of a high fat meal does not modify the bioavailability of the SDF composition. The between subject variability on exposure parameters of the SDF composition (fasted and fed conditions) and SF composition is rather low and similar (Table 4).Table 4 - Food effect: Cmax, AUCiast, AUC point estimate and 90% CI for food effect geometric mean ratio: fed versus fasted, for SDFPharmacokinetic Results for Part la Study:

[0175] Following its administration as single oral doses (10 mg-800 mg) eclitasertib plasma concentration were quantifiable (above LLOQ) up to 48h post dose after 10 mg , up to 48h or 72h after 30 mg (depending of subjects), up to 72h after 100 mg, 400 and 800 mg) (For the NCA , plasma concentrations below the LLOQ are replaced by missing values). Compound 1 in fasted conditions, median tmax was reached between 3.0- and 4.0-hours post dosing with a trend to increase with dose (Figure 1, Table 1).

[0176] When Compound 1 was administered with high fat meal and fasted AUCs and Cmax were similar. In fed conditions, median tmax is slightly increased (4 hours versus 3 hours in fasted conditions), min-max values being similar (2 to 6 hours). The between subject variability on exposure parameters is similar in both conditions.

[0177] Drug excretion in urine is low. The cumulated amounts of unchanged Compound 1 excreted in urine over 24 hours were less than 1% of the administered 800 mg dose.

[0178] AUCs increased without major deviation from dose proportionality from 10 to 200 mg and then increased less than expected from dose proportionality from 200 to 800 mg. Cmax increased less than expected by dose proportionality from 10 to 800 mg. Overall, using the power model from 10 mg to 800 mg, Cmax and AUC increased on average by 1.68-fold and 1.86-fold respectively when dose increased by 2-fold.

[0179] Mean ti / 2z was estimated around 6 hours from 10 to 200 mg doses and around 9 hours from 400 to 800 mg doses. Interindividual variability in Cmax and AUC was low in the 10 and 30 mg groups (<30%) and was moderate in higher dose groups (ranging from 22.6%- 52.4%).

[0180] After once daily administration no significant accumulation occurred, accumulation ratios ranged from 1.01 to 1.13 for Cmax and 1.01 to 1.11 for AUC0-24. Steady state is achieved after the first dose administration.

[0181] From 10 to 200 mg, the between-subject variability of Compound 1 Cmax, AUCs, in fasted conditions are low (CV <30%), except for Cmax of 100 mg dose (CV of 37%). From 400 mg to 800 mg, the between-subject variability of Compound 1 Cmax, AUCs, in fasted conditions are moderate, ranging from 33 to 52%.Pharmacokinetic Results for Part 2 Study:

[0182] For Part 2 ascending repeated dose study, all samples from placebo subjects assayed at around tmax of Day 1 and Day 14 were below the LLOQ and Compound 1 was quantifiable in all subjects having received Compound 1. Pharmacokinetic parameters after single and 14- day repeated doses of Compound 1 administered orally in healthy subjects are summarized in Table 5 and Table 6 respectively. After repeated administration, on Day 1 and Day 14, median tmax ranged from 3 to 4 hours post-dosing with a trend to increase with dose (Figure 3). The mean terminal elimination half-lives were estimated between 6 and 7 hours from 50 mg to 200 mg doses and around 9 hours for 600 mg dose.Table 5 - Descriptive statistics of plasma pharmacokinetic parameters following the first dose of 14-day once daily repeated oral administration of 50 to 600 mg Compound 1 in fasted conditionsMean ± SD (Geometric Mean) Plasma Compound 1[CV%]50 mg 100 mg 200 mg 600 mgDay 1 Day 1 Day 1 Day 1N 8 8 8 8Cmax 1100 ± 151 1950 ± 415 3170 ± 513 5470 ± 1750(ng / mL) (1090) [13.7] (1900) [21.3] (3130) [16.2] (5240) [31.9] tmax0 3.00 3.00 3.00 3.50(h) (2.00 - 4.00) (2.00 - 4.00) (2.00 - 6.00) (2.00 - 6.00)Mean ± SD (Geometric Mean) Plasma Compound 1[CV%]15 100 ± 28 000 ± 64 000 ±AUCo-24h 9070 ± 14302640 4480 19 900(14 800) (27 700) (61 700)(ng»hr / mL) (8970) [15.8][17.5] [16.0] [31.1]Median (Min - Max)Table 6 - Descriptive statistics of plasma pharmacokinetic parameters following the last dose of once daily 14-day repeated oral administration of 50 to 600 mg Compound 1 in fasted conditionsMean ± SD (Geometric Mean) Plasma Compound 1[CV%]50 mg 100 mg 200 mg 600 mgDay 14 Day 14 Day 14 Day 14N 6 8 8 8Cmax 1210 ± 274 1750 ± 358 3250 ± 797 5980 ± 1510(ng / mL) (1180) [22.6] (1720) [20.4] (3160) [24.5] (5810) [25.2] tmax0 3.01 3.00 3.52 4.02(h) (3.00 - 4.00) (2.00 - 3.02) (2.00 - 6.03) (2.00 - 6.02)15 200 ± 67 300 ±AUCo-24h 9240 ± 1590 31 600 ± 80602550 18100(15 000) (30 700) (65 100)(ng»hr / mL) (9110) [17.3][16.8] [25.5] [27.0] ti / 2z 6.32 ± 0.500 6.37 ± 1.11 6.89 ± 2.35 8.99 ± 4.87(h) (6.30) [7.9] (6.29) [17.4] (6.61) [34.1] (8.20) [54.1]CLss / F 5.57 ± 1.08 6.74 ± 1.05 6.70 ± 1.71 9.51 ± 2.55(L / h) (5.49) [19.5] (6.67) [15.6] (6.51) [25.6] (9.21) [26.8]Median (Min - Max)

[0183] On Day 1 and Day 14, Cmax increased less than expected from dose proportionality from 50 to 600 mg and AUCO-24 increased slightly less than expected from dose proportionality from 50 to 600 mg. Overall, using the power model from 50 mg to 600 mg, at Day 1, Cmax and AUC0-24h increased per estimation by 1.54-fold (90% confidence interval [CI]: 1.47 to 1.63) and 1.72-fold (90% CI: 1.65 to 1.80) respectively, for Compound 1 dose increase by 2-fold. At Day 14, Cmax and AUC0-24h increased per estimation by 1.58 (90% CI: 1.49 to 1.67) and 1.75-fold (90% CI: 1.66 to 1.85) respectively, for Compound 1 dose increase by 2-fold (Table 7, Table 8).Table 7 - Dose proportionality assessment for Compound 1 Cmax and AUCo-24h following single oral administration (Day 1)RatioPointParameter Dose ratio estimate 90% CICmax (r) = 2 1.54 (1.47 to 1.63)(r) = 12 4.75 (3.93 to 5.74)Beta Estimate 0.63 (0.55 to 0.70)AUCo-24h (r) = 2 1.72 (1.65 to 1.80)(r) = 12 7.03 (6.00 to 8.23)Beta Estimate 0.78 (0.72 to 0.85)Cmax = 101.55 x dose0 63AUCo-24h = 414.44 x dose0 78Table 8 - Dose proportionality assessment for Compound 1 Cmax and AUCo-24h following 14-day repeated oral administration (Day 14)RatioPointParameter Dose ratio estimate 90% CICmax (r) = 2 1.58 (1.49 to 1.67)(r) = 12 5.13 (4.15 to 6.33)Beta Estimate 0.66 (0.57 to 0.74)AUCo-24h (r) = 2 1.75 (1.66 to 1.85)(r) = 12 7.42 (6.11 to 9.02)Beta Estimate 0.81 (0.73 to 0.89)Cmax = 88.83 X dose0 66AUCo-24h = 387.78 x dose0 81

[0184] Based on descriptive statistics and plots of individual observed profiles of Ctrough by day of drug administration and cohort, the average time to achieve steady state was estimated on Day 2 pre-dose, i.e., steady-state was reached after the first administration of Compound 1.

[0185] For all dose cohorts, the point estimate of the accumulation ratio (Day 14 / Day 1) is close to 1 with 90% CI including 1. The accumulation ratio ranged from 1.01 (90% CI: 0.84 to 1.22) after 200 mg dosing to 1.13 (90% CI: 0.91 to 1.40) after 50 mg dosing on Cmax and 1.01 (90% CI: 0.88 to 1.16) after 100 mg dosing to 1.11 (90% CI: 0.96 to 1.27) after 200 mg dosing on AUCo-24h with no notable dose-related difference (Table 9).

[0186] On Day 1, from 50 mg to 200 mg, the between-subject variability of Compound 1 Cmax and AUCo-24h, in fasted conditions is low (coefficient of variation [CV] <30%). For the 600 mg dose, the between-subject variability of Compound 1 Cmax and AUCo-24h in fasted conditions is moderate (CV 31.9% and 31.1% respectively). On Day 14, for all doses, the between-subject variability of Compound 1 Cmax and AUC0-2411 in fasted conditions is low (CV <30%).

[0187] Accumulation ratio of Day 14 versus Day 1 was assessed for each dose level group separately as well as pooled across dose level groups.Table 9 - Accumulation ratios on Cmax and AUC0-2411 following 14-day repeated oral administration of Compound 1PointParameter Group estimate 90% CIRatio (Cmax) Compound 1 50 mg 1.13 (0.91 to 1.40)Compound 1 100 mg 0.90 (0.75 to 1.08)Compound 1 200 mg 1.01 (0.84 to 1.22)Compound 1 600 mg 1.11 (0.92 to 1.34)Pooled Compound 1 1.03 (0.94 to 1.14) dosesRatio (AUCo-24h) Compound 1 50 mg 1.03 (0.88 to 1.21)Compound 1 100 mg 1.01 (0.88 to 1.16)Compound 1 200 mg 1.11 (0.96 to 1.27)Compound 1 600 mg 1.06 (0.92 to 1.21)Pooled Compound 1 1.05 (0.98 to 1.13) doses

[0188] Descriptive statistics of 4P-hydroxycholesterol Day 14 / Day 1 ratios of all cohorts are presented in Table 10. There was no changes in the plasma levels of 4P-hydroxycholesterol , an endogenous biomarker of CYP3 A4 activity, following eclitasertib treatment suggesting that the potential risk of drug-drug interaction via CYP3 A4 induction is low.Table 10 - Descriptive statistics of 4P-hydroxycholesterol Day 14 / Day 1 ratios4-P hydroxycholesterolGroup Statistics Day 1 Day 14 RatioPlacebo N 8 8 8Mean 27.100 23.025 0.843Geom. Mean 25.860 21.656 0.837SD 8.191 8.063 0.1004-P hydroxycholesterolGroup Statistics Day 1 Day 14 RatioCV 30% 35% 12%Median 28.000 23.400 0.833Minimum 14.60 11.20 0.69Maximum 36.80 33.30 0.97Compound I N 8 6 650 mg Mean 39.988 23.717 0.739Geom. Mean 33.918 22.976 0.637SD 28.168 6.475 0.394CV 70% 27% 53%Median 28.750 23.200 0.749Minimum 15.00 17.20 0.29Maximum 103.00 31.50 1.19Compound I N 8 8 8100 mg Mean 22.413 22.250 1.008Geom. Mean 21.462 21.403 0.997SD 6.162 6.173 0.161CV 27% 28% 16%Median 24.500 24.000 0.985Minimum 11.10 12.60 0.82Maximum 28.00 30.30 1.33Compound200 mg Mean 26.813 29.338 1.106Geom. Mean 24.399 26.742 1.0964-P hydroxycholesterolGroup Statistics Day 1 Day 14 RatioSD 12.901 12.315 0.165CV 48% 42% 15%Median 27.950 31.400 1.121Minimum 12.40 12.90 0.88Maximum 54.20 47.60 1.43Compound I N 8 8 8600 mg Mean 30.588 33.550 1.107Geom. Mean 29.871 32.738 1.096SD 7.640 8.087 0.163CV 25% 24% 15%Median 28.800 33.350 1.144Minimum 21.90 23.30 0.79Maximum 47.60 49.60 1.33Pooled N 32 30 30Compound 1Mean29.950 27.447 1.007 dosesGeom. Mean 26.989 25.802 0.959SD 16.787 9.509 0.258CV 56% 35% 26%Median 27.900 27.100 1.058Minimum 11.10 12.60 0.29Maximum 103.00 49.60 1.43Pharmacodynamics

[0189] Pharmacodynamic or target engagement from Part 1 (single ascending dose study) and Part 2 (multiple ascending dose study) was measured by inhibition of phosphorylation at serine 166 in RIPK1 protein extracted from PBMCs (pS166-RIPKl assay).Part 1

[0190] Inhibition of the phosphorylation of RIPK1 at serinel66 was observed in all the Compound 1 treatment groups reflecting a target engagement of Compound 1 with RIPK1 at all doses. No inhibition was detected in the placebo group (Figure 1). High variability in baseline data for pS166-RIPKl was observed within and between treatment groups. For each subject, inhibition of pS166-RIPKl was evaluated as the percent change compared to baseline at multiple timepoints up to 72 hours after the single dose (SAD study) (Figure 1).Median inhibition larger than 90% were observed in treatment groups 100, 200, and 400 mg. The effect was maintained over 24 hours, 48 hours and 72 hours, respectively (Figure 4A). Surprisingly, the IQR median of the 30mg dose cohort demonstrated less % inhibition (<90%) than even the preceding lOmg dose cohort. However, the 30mg cohort had a larger measured range of pS166-RIPKl amounts between individuals. A similar trend was noted for the placebo treated group. Likewise, the 800 mg treatment group showed lesser overall inhibition than that observed in the 400 mg group (highest median of the percentage of inhibition over time: 73.8% at 48 hours in 800 mg versus 95.4% at 12 hours post dose in 600 mg) and is thought to be a consequence of the sample preparation of the PBMC lysates.Part 2

[0191] Target engagement was measured as inhibition of phosphorylation at serine 166 in RIPK1 protein extracted from PBMCs (pS166-RIPKl assay). Variability in baseline values between individuals was observed across the treatment groups but especially evident in the 600 mg cohort.

[0192] For each subject and dose cohort, the percent change of RIPK1 phosphorylation compared to their baseline value was evaluated between Day 14 pre-dose and multiple hours post dose up to Day 17 (72 hours after Day 14 dose).

[0193] Sustained inhibition of the phosphorylation at Serl66 was observed after last dose administration in all the Compound 1 treatment groups reflecting a target engagement ofCompound 1 with RIPK1. High levels of target engagement (>90%) were maintained over at least 24 hours and 48 hours in the cohorts that received 100 mg and 200 mg repeated doses of Compound 1, respectively (Figure 4B). No consistent inhibition was detected in the placebo group.

[0194] The period of maximal inhibition after administration of the last doses was identified within subjects treated with Compound 1. It corresponds to the period during which the inhibition is not less than the highest inhibition value of the subject minus 10%. In all doses most of the subjects reached the period of maximal inhibition at the first post-dose timepoint (2 hours post dosing)

[0195] The median inhibition achieved during the period of maximal inhibition of the 50 mg group was 88.5% whereas the 100 and 200 mg groups show a median inhibition greater than 90% (93.9% and 91.3%, respectively). Duration of the period of maximal inhibition was longer in 100 and 200 mg groups (median: 58 hours and 65 hours, respectively) than in 50 mg group (median: 22 hours).

[0196] Treatment group 600 mg demonstrated less overall inhibition than the other doses tested; median inhibition during the maximal inhibition period: 37.9%. One potential explanation for the difference in values may be due to overall lower baseline values of the pS166-RIPKl in the 600 mg group (Figure 2). When considering only subjects with a baseline value larger or equal to 900 a.u., the highest median of percentage of inhibition over time increased from 34.1% at 24 hours (n = 8) to 83.1% at 12 hours post dose (n = 2).Population PK

[0197] Based on simulations with Population PK model developed on presented phase 1 data, with a BID dosing (300 mg BID), predose plasma concentrations (Ctrough) (Table 12) are predicted be 3 fold higher compared to a OD regimen (600 mg OD) with similar AUC over the 24h interval (Table 11).Table 11 - Predictive values of OD regimen by popPKTable 12 - Predictive value of BID regimen by popPKSafety

[0198] The safety, tolerability, and PK profile of Compound 1 was assessed in a Phase 1 clinical study in a total of 98 healthy subjects, including 78 who received study drug. In the single ascending dose part of the study (Example 1), healthy participants exposures reached 92 300 ng.h / mL for AUC and 6630 ng / mL for Cmax at the highest dose tested (800 mg), In the multiple ascending dose part, exposures reached 67 300 ng.h / mL for AUCO-24 and 5980 ng / mL for Cmax in the highest dose group (600 mg QD over 14 days).Safety in Healthy Study Participants

[0199] Based on the clinical first-in-human studies Example 1, both in healthy participants, and nonclinical studies of Compound 1, no important risks were identified to date.Part la and Part lb Studies

[0200] In Part la (SAD) of the study, a total of 48 healthy participants were given either 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg of Compound 1 or placebo in this singleascending dose study (Table 13).

[0201] Part lb was an open label, randomized, 3 sequence cross-over study to assess relative bioavailability between two compositions and food effect on Compound 1 absorption.

[0202] In Part lb of the study (food effect and relative bioavailability cohort), an additional 9 subjects received a single dose of 100 mg in each of 3 periods and one subject received only one 100 mg dose in the same cohort before he was withdrawn from the study.In Part la of the study, there were no deaths, serious adverse events (SAEs), severe treatment emergent adverse events (TEAEs), adverse event of special interest (AESI), or TEAEs leading to treatment discontinuation reported. Overall, 20 of 48 subjects experienced at least one TEAE during the study (see Table 13). The percentage of subjects with any TEAEs was balanced between the subjects on placebo and the subjects on active treatment. There was no association with dose. One case of re-activation of oral herpes occurred in the placebo group in Part la. There were no other AEs related to infections in the study.

[0203] In Part lb of the study, there were no deaths, SAEs, severe TEAEs, AESI, or treatment related TEAEs leading to discontinuation of Investigational Medicinal Product (IMP) reported during the study. There was one TEAE considered unrelated that led to treatment discontinuation: The subject had a high rate of premature ventricular contractions warranting evaluation by his primary care physician with a cardiologic evaluation per the Investigator reported on Day 2 and treatment was discontinued for the subsequent periods. The subject was asymptomatic. For the number of subjects with TEAEs see Table 14.

[0204] The most common TEAE in both Part la and Part lb was skin irritation at venous catheter insertion site.

[0205] In both parts, there were no treatment emergent potentially clinically significant abnormalities (PCSAs) for the laboratory values, vital signs, and ECG parameters that wereconsidered clinically relevant. Specifically, there was no significant decrease in hemoglobin (defined as decrease from baseline >20 g / L) and no significant decrease in platelet count (defined as <100 x 109 / L) in any subject in this study. There was one case of transient, mild neutropenia in one subject in the 30 mg treatment group, and one case of transient, mild elevation of eosinophil count in the 10 mg treatment group.Table 13 - Number (%) of subjects with TEAE(s) by primary SOC and PT - Safety population Part laCompound 1Primary System Organ Class Placebo 10 mg 30 mg 100 mg 200 mg 400 mg 800 mgPreferred Term [n (%)] (N=12) (N=6) (N=6) (N=6) (N=6) (N=6) (N=6)6 (50.0) 3 (50.0) 4 1 (16.7) 1 (16.7) 2 (33.3) 3 (50.0) Any class(66.7)Infections and infestations 1 (8.3) 0 0 0 0 0 0Oral herpes 1 (8.3) 0 0 0 0 0 0Immune system disorders 1 (8.3) 0 0 0 0 0 0Allergy to arthropod bite 1 (8.3) 0 0 0 0 0 02 (16.7) 0 2 1 (16.7) 0 1 (16.7) 2 (33.3) Nervous system disorders(33.3)Dysgeusia 0 0 0 0 0 0 1 (16.7)1 (8-3) 0 1 1 (16.7) 0 0 1 (16.7) Headache(16.7)Dizziness 0 0 0 0 0 1 (16.7) 00 0 1 0 0 0 0 Dizziness exertional(16.7)Dizziness postural 1 (8.3) 0 0 0 0 0 0Somnolence 1 (8.3) 0 0 0 0 0 0Compound 1Primary System Organ Class Placebo 10 mg 30 mg 100 mg 200 mg 400 mg 800 mg Preferred Term [n (%)] (N=12) (N=6) (N=6) (N=6) (N=6) (N=6) (N=6)1 (8.3) 1 (16.7) 2 0 1 (16.7) 1 (16.7) 1 (16.7)Gastrointestinal disorders(33.3)Gastrointestinal sounds 0 0 0 0 0 0 1 (16.7) abnormalAbdominal distension 1 (8.3) 1 (16.7) 0 0 0 0 00 0 1 0 0 0 0Abdominal pain(16.7)0 0 1 0 0 0 0Dyspepsia(16.7)Nausea 0 0 0 0 1 (16.7) 1 (16.7) 0Palatal disorder 1 (8.3) 0 0 0 0 0 0Skin and subcutaneous tissue 0 2 (33.3) 0 0 0 0 0 disordersHyperhidrosis 0 1 (16.7) 0 0 0 0 0Skin reaction 0 1 (16.7) 0 0 0 0 0Musculoskeletal and 0 0 0 0 1 (16.7) 0 0 connective tissue disordersBack pain 0 0 0 0 1 (16.7) 0 0Renal and urinary disorders 0 0 0 0 0 0 1 (16.7)Chromaturia 0 0 0 0 0 0 1 (16.7)General disorders and 5 (41.7) 1 (16.7) 3 0 0 0 0 administration site conditions (50.0)Catheter site hematoma 1 (8.3) 0 0 0 0 0 0Fatigue 1 (8.3) 0 0 0 0 0 0Compound 1Primary System Organ Class Placebo 10 mg 30 mg 100 mg 200 mg 400 mg 800 mgPreferred Term [n (%)] (N=12) (N=6) (N=6) (N=6) (N=6) (N=6) (N=6)3 (25.0) 1 (16.7) 3 0 0 0 0Medical device site reaction(50.0)Vessel puncture site reaction 1 (8.3) 0 0 0 0 0 0Table 14 - Overview of adverse event profile: treatment emergent adverse events - safety population Part lbCompound 1 100 mg n (%) SDF fasted SDF fed SF fasted(N=10) (N=9) (N=9)Subjects with any TEAE 4 (40.0) 5 (55.6) 6 (66.7)Subjects with any severe TEAE 0 0 0Subjects with any treatment emergent 0 0 0SAESubjects with any TEAE leading to 0 0 0 deathSubjects with any TEAE leading to 1 (10.0) 0 0 permanent treatment discontinuationSubjects with any TEAE of special 0 0 0 interest (AESI)Safety Results for Part 2 of Study:

[0206] In Part 2 study, a total of 40 healthy participants were given either 50 mg, 100 mg, 200 mg, or 600 mg of Compound 1 or placebo daily for 14 days. Two subjects were withdrawn early in the first cohort, 1 on Day 9 and another on Day 11 (Table 13a). There were no deaths, SAEs, or severe TEAEs reported during the study.

[0207] In the Part 2 study, one participant in the eclitasertib 50 mg group discontinued the study due to an AE on Day 9 (URTI with palpable lymph node). URTI (Grade 2) was reported on Day 2, and palpably lymph node (Grade 1) was reported on Day 8. No corrective treatments were reported for both the events and both the events were considered as not related to study drug by the investigator.

[0208] There were two AESI of elevated alanine aminotransferase (ALT) during the study, one in the 50 mg treatment group and one in the 200 mg treatment group. Both subjects were on active IMP. In both subjects, ALT increased over the first 7-10 days to above 2 x upper limit of normal (ULN), and not 3 x ULN. Both subjects continued with IMP while being monitored. Both subjects experienced rapid recovery of ALT levels upon treatment completion; there were no associated clinical symptoms or other concerning liver enzyme abnormalities associated with these two AESI.

[0209] Overall, 24 of 40 subjects experienced at least one TEAE during the study. The percentage of subjects with any TEAEs was comparable between the subjects on placebo with those on IMP.

[0210] None of the sporadic PCSAs identified in laboratory values and ECG parameters were deemed to be clinically significant.Table 13a - Overview of adverse event profile: Treatment emergent adverse events - Safety populationConclusion:

[0211] Compound 1 was safe and well tolerated without raising safety concerns in healthy subjects at single dose up to 800 mg and at multiple dose administrations up to 600 mg QD. There were no deaths, SAEs, severe TEAEs, AESI, or treatment related TEAEs leading to discontinuation of IMP reported during the study.

[0212] Following single and repeated oral dose administration of 10 to 800 mg Compound 1 in fasted conditions, median tmax was reached between 3.0- and 4.0-hours post dosing with a trend to increase with dose.

[0213] The bioavailability of the SDF and SF compositions are similar in terms of AUCs, and Cmax is slightly increased by 30% for the SDF composition. Concomitant intake of a high fat meal does not modify the bioavailability of the SDF composition. The between subject variability on exposure parameters of the SDF composition (fasted and fed conditions) and SF composition is rather low and similar.

[0214] In single dose from 10 mg to 800 mg, exposure increase was lower than expected from dose proportionality. The between-subjects variability of Compound 1 Cmax and AUC in fasted conditions ranged from low to moderate with the highest variability of 52% observed for Cmax at 400 mg. Mean ti / 2z was estimated around 6 hours from 10 to 200 mg doses and around 9 hours from 400 to 800 mg doses. Mean cumulated amounts of unchanged compound excreted in urine over 24 hours was less than 1% of the administered 800 mg dose.

[0215] Cmax and AUCs showed low-to-moderate interparticipant interindividual variability. In repeated administration of Compound 1, on Day 1 and Day 14, Cmaxand AUC0 24hincreased less than expected from dose proportionality from 50 to 600 mg. Based on descriptive statistics and plots of individual observed profiles, steady state was reached after the first administration which is consistent with the lack of accumulation observed for C max and AUC0 24h. The mean elimination half-live was estimated between 6 and 7 hours from 50 mg to 200 mg doses and around 9 hours for the 600 mg dose. The between-subject variability of Compound 1 Cmaxand AUC0 24hin fasted conditions ranged from low to moderate with the highest variability of 31.9% observed for Cmaxat 600 mg on Day 1. Concomitant food intake did not have a significant impact on eclitasertib bioavailability.

[0216] Autophosphorylation of S166 activates RIPK1 to mediate apoptotic and necrotic cell death and has been used as a marker of RIPK1 activation and of target engagement by RIPK1 inhibitor. Target engagement was observed in each cohort. High levels of target engagement were maintained over at least 24, 48 and 72 hours in the cohorts that received 100 mg, 200 mg and 400 mg single doses of Compound 1, respectively. High levels of target engagement were maintained over at least 24 and 48 hours in the cohorts that received 100 mg and 200 mg repeated doses of Compound 1 respectively. Overall, the maximum target inhibition is maintained for plasma eclitasertib concentration between 50 ng / mL and 100 ng / mL.Relatively low SI 66 phosphorylation at baseline as well as technical anomalies in sample preparation and analysis, leading to higher data variability preclude any meaningful analysis of magnitude of RIPK1 phosphorylation in eclitasertib 600 mg cohort, and hence have not been presented.

[0217] Compound 1 is a highly potent, selective oral RIPK1 kinase inhibitor which is generally well tolerated and did not raise any safety concerns in healthy participants. Compound 1 was well tolerated after single oral doses up to 800 mg and at multiple daily doses up to 600 mg in healthy subjects. Of note, a maximal tolerated dose was not established in either of these clinical studies of healthy participants.

[0218] Recently released clinical data from a RIPK1 competitor in psoriasis patients (Clin Pharmacol Ther. 2020;108(4):808-816), suggest that very high levels of RIPKl kinase activity inhibition are required to have a clinical effect and that the exposure needed to reach high level of inhibition is higher in patients with chronic inflammatory diseases than inhealthy subjects. Based on simulations with Population PK model the predicated plasma concentrations (Ctrough) for a BID dosing (300 mg BID), is 3-fold higher compared to a OD regimen (600 mg OD) with similar AUC over the 24h interval. A BID dosing regimen could increase minimum drug plasma level concentration and reduce PK fluctuation during the entire dosing interval and thus help maintain maximum levels of inhibition.Example 2: Pharmaceutical CompositionTable 15 - Exemplified composition

[0219] The composition was prepared by wet granulation with water. The method of mixing or blending the ingredients in the wet granulation can be carried out using methods known to the skilled artisan.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a receptor-interacting protein kinase 1 -mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazepin-3-yl]-4H-1, 2, 4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof is administered at a dose of about 300 mg per day.

3. The method of claim 1, wherein the 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg per day.

4. The method of claim 1, wherein the 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof is administered at a dose of about 500 mg per a day.

5. The method of claim 1, wherein the 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof is administered at a dose of about 600 mg per a day.

6. The method of claim 1, wherein the 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg twice a day.

7. The method of claim 1, wherein the 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof is administered at a dose of about 150 mg twice a day.

8. The method of claim 1, wherein the 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg twice a day.

9. The method of claim 1, wherein the 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 mg twice a day.

10. The method of claim 1, wherein the 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof is administered at a dose of about 300 mg twice a day.

11. The method of claim 1, wherein the 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3- dihydropyrido[3,2-b] [ 1 ,4]oxazepin-3 -yl]-4H- 1 ,2,4-triazole-3 -carboxamide, or a pharmaceutically acceptable salt thereof is administered at a dose of about 350 mg twice a day.

12. A method of treating an inflammatory disease or disorder, comprising administering to a patient in need thereof an effective amount of a solid dosage form, wherein the solid dosage form comprises: about 10-70 percent (w / w) of Compound 1; about 10-70 percent (w / w) of water- soluble diluent; about 3-30 percent (w / w) of water-insoluble diluent; about 2-10 percent (w / w) of disintegrating agent; about 2-10 percent (w / w) of binder; and about 0.5-5 percent (w / w) of lubricant; wherein the solid dosage form is in a form selected from the group consisting of a tablet, a stock granulation, and a capsule.

13. The method of claim 12, wherein water-soluble diluent is mannitol, water-insoluble diluent is microcrystalline cellulose, disintegrating agent is croscarmellose sodium, binder is polyvinylpyrrolidone and lubricant is magnesium stearate.

14. The compound 5-Benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydropyrido[3,2- b][l,4]oxazepin-3-yl]-4H-l,2,4-triazole-3-carboxamide, or a pharmaceutically acceptable salt thereof for use in a method for treating a receptor-interacting protein kinase 1- mediated disease or disorder in a patient in need thereof.

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