Decrease in urinary sCD163 by C5aR inhibitor

Abstract

Methods for treating ANCA-associated vasculitis (AAV) are provided, comprising administering a complement component 5a receptor (C5aR) antagonist to an individual in need thereof. Also provided are methods for treating ANCA-associated vasculitis (AAV) with renal impairment in an individual in need thereof, comprising administering a complement component 5a receptor (C5aR) antagonist to the individual when the individual exhibits an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV. In some embodiments, the complement component 5a receptor (C5aR) antagonist is avacopan. [Selected figure] Figure 3

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 579,716, filed October 31, 2017, the entire contents of which are incorporated herein by reference.

[0002] STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT Not applicable

[0003] [reference to a "sequence listing," table, or computer program listing submitted on a compact disc] Not applicable [Background technology]

[0004] BACKGROUND OF THE INVENTION Antineutrophil cytoplasmic antibodies (ANCA) are a group of IgG autoantibodies that react with the cytoplasmic components of neutrophils and monocytes. The presence of ANCA is associated with a variety of idiopathic systemic vasculitic disorders (i.e., inflammation and weakening of the blood vessel wall) and other inflammatory disorders.

[0005] ANCA-associated vasculitis (AAV) is a condition in which ANCA is detectable in serum and is highly likely to be associated with rapidly progressive disease, including renal involvement.

[0006] Despite improved methods for identifying ANCA and diagnosing associated diseases and disorders, there remains a need in the art to identify and develop compounds useful for the treatment of ANCA-associated vasculitis (AAV), as well as to identify biomarkers that accurately report on AAV disease state. Summary of the Invention

[0007] The present disclosure is particularly directed to a method of treating ANCA-associated vasculitis (AAV) with nephropathy in an individual in need thereof, comprising administering a complement component 5a receptor (C5aR) antagonist to the individual when the individual exhibits an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV.

[0008] In another aspect, the present disclosure provides a method of treating ANCA-associated vasculitis (AVV), comprising administering to an individual in need thereof an effective amount of a complement component 5a receptor (C5aR) antagonist.

[0009] In some embodiments, the C5aR antagonist is a compound having formula (I), or a pharmaceutically acceptable salt thereof: [ka] where C 1 is 1 to 3 R 1 phenyl optionally substituted with substituents; C 2 is 1 to 3 R 2 phenyl optionally substituted with substituents; C 3 is C 3-8 cycloalkyl and phenyl, and each C 3 is 1 to 3 R 3 optionally substituted with substituents; Each R 1 are independently halogen, -CN, -R c , -CO2R a , -CONR a R b , -C(O)R a , -OC(O)NR a R b , -NR b C(O)R a , -NR b C(O)2R c , -NR a C(O)NR a R b, -NR a R b , -OR a and -S(O)NR a R b wherein each R a and R b are independently hydrogen, C 1-8 Alkyl and C 1-8 haloalkyl, or, when connected to the same nitrogen atom, can combine with the nitrogen atom to form a 5- or 6-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O, or S; each R c is independently C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R a , R b and R c The aliphatic and cyclic portions of may be optionally further substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, and dialkylamino groups; and two R 1 When the substituents are on adjacent atoms, they combine to form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently halogen, -CN, -R f , -CO2R d , -CONR d R e , -C(O)R d , -OC(O)NR d R e , -NR e C(O)R d , -NR e C(O)2R f , -NR d C(O)NR d R e , -NR d C(O)NR d R e , -NR d R e , -OR d and -S(O)NR d Re wherein each R d and R e are independently hydrogen, C 1-8 Alkyl and C 1-8 haloalkyl, or, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a 5- or 6-membered ring having 0-2 additional heteroatoms as ring members selected from N, O, or S; each R f is independently C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R d , R e and R f the aliphatic and cyclic portions of may be optionally further substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, and dialkylamino groups; Each R 3 are independently halogen, -CN, -R i , -CO2R g , -CONR g R h , -C(O)R g , -OC(O)NR g R h , -NR h C(O)R g , -NR h C(O)2R i , -NR g C(O)NR g R h , -NR g R h , -OR g , -S(O)NR g R h , -X 4 -R j , -X 4 -NR g R h , -X 4 -CONR g R h , -X 4 -NR h C(O)R g, -NHR j and -NHCH2R j where X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and R h are independently halogens, C 1-8 Alkyl, C 3-6 Cycloalkyl and C 1-8 haloalkyl, or, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a 5- or 6-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O, or S, and optionally substituted with 1 or 2 oxo; each R i is independently C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and each R j is C 3-6 is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g , R h , R i and R j the aliphatic and cyclic portions of may be optionally further substituted with 1 to 3 halogen, methyl, CF, hydroxy, amino, alkylamino, and dialkylamino groups; and X is hydrogen or CH3.

[0010] In some embodiments, the C5aR antagonist has the formula: [ka] Avacopan has the following properties: [Brief explanation of the drawings]

[0011] [Figure 1A-B]Figures 1A-E show the rapid decline in disease activity and significant improvement in health-related quality of life (QOL) in patients treated with avacopan. Panel A is a plot of the Birmingham Vasculitis Activity Score; Panel B is a plot of the urinary albumin:creatinine ratio; [Figure 1C-D] Panel C is a plot of the EQ-5D-5L visual analog scale, a measure of health-related quality of life, expressed as mean ± SEM over the treatment period; Panels D and E are plots of the Medical Outcomes Study SF-36 version 2 Physical Functioning and Role Emotional components, a measure of health-related quality of life, expressed as mean ± SEM over the treatment period. [Figure 1E] Panels D and E are plots of the Medical Outcomes Study SF-36 version 2 Physical Functioning and Role Emotional components, a measure of health-related quality of life, expressed as mean ± SEM over the treatment period. [Figure 2] Figures 2A-B show the urinary sCD163 / creatinine ratio at baseline. Figure 2A shows the urinary sCD163 / creatinine ratio levels in patients with anti-MPO and anti-PR3 autoantibodies. Figure 2B shows the urinary sCD163 / creatinine ratio levels in patients randomized to three different treatment groups. [Figure 3] Figure 3 shows the rapid decrease in urinary sCD163 / creatinine ratio in patients treated with avacopan. As shown in the graph, *p<0.05; **p<0.01; ***p<0.001; #p=0.076 compared to baseline in each group. [Figure 4]Figure 4 shows a strong positive correlation between urinary sCD163 / Cr and UACR. P<0.0001 for correlation; data from all patients and time points were included in the analysis. [Figure 5] Figure 5 shows a strong positive correlation between urinary sCD163 / Cr and MCP-1 / Cr. P<0.0001 for correlation; data from all patients and time points were included in the analysis. [Figure 6] Figure 6 shows that there is no correlation between urinary sCD163 / Cr and eGFR. P for correlation = 0.655; data from all patients and time points were included in the analysis. [Figure 7A] Figures 7A-C show the time course of changes from baseline urinary sCD163 / Cr, eGFR, UACR, and MCP-1 / Cr in all subjects. Figure 7A is a plot of eGFR and sCD163 / Cr over time. [Figure 7B] Figure 7B is a time course plot of sCD163 / Cr and UACR. [Figure 7C] FIG. 7C is a time course plot of sCD163 / Cr and MCP-1 / Cr. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description of the Invention Overview The present disclosure provides methods for treating ANCA-associated vasculitis (AAV). In particular, the present disclosure demonstrates that avacopan is effective in treating AAV in human patients.

[0013] This disclosure demonstrates that urinary sCD163 levels decreased within one week in patients with ANCA-associated vasculitis (AAV) receiving avacopan, whereas urinary sCD163 levels decreased more slowly (up to 8 weeks) in AAV patients treated with prednisone alone. Thus, avacopan treatment is associated with a surprisingly rapid improvement in renal inflammation. Unexpectedly, patients demonstrated a strong positive temporal correlation between the urinary monocyte chemoattractant protein-1 (MCP-1) / creatinine (Ctr) ratio and the sCD163 / Cr ratio, whereas other renal function parameters, such as eGFR and urinary albumin-to-creatinine ratio (UACR), did not. Collectively, the data presented demonstrate that the urinary sCD163 / Cr ratio is positively correlated with nephritis in AAV patients, and further demonstrate that resolution of nephritis precedes improvement in renal function.

[0014] Abbreviations and Definitions The term "alkyl," by itself or as part of another substituent, unless otherwise stated, means an alkyl group having the specified number of carbon atoms (i.e., C 1-8 means 1 to 8 carbons) straight or branched chain hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. The term "alkenyl" refers to unsaturated alkyl groups having one or more double bonds. Similarly, the term "alkynyl" refers to unsaturated alkyl groups having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, and 3-butynyl, as well as higher homologs and isomers. The term "cycloalkyl" refers to any group having the specified number of ring atoms (e.g., C 3-6"Cycloalkyl" refers to a hydrocarbon ring that is either fully saturated or has at most one double bond between the ring vertices. "Cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane. The term "heterocycloalkyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S, in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. Heterocycloalkyls may be monocyclic, bicyclic, or polycyclic. Non-limiting examples of heterocycloalkyl groups include, but are not limited to, pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. Heterocycloalkyl groups may be attached to the remainder of the molecule via a ring carbon or heteroatom.

[0015] The term "alkylene" by itself or as part of another substituent means a divalent group derived from an alkane, an example of which is -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, although groups having 10 or fewer carbon atoms are preferred in the present invention. A "lower alkyl" or "lower alkylene" is an alkyl or alkylene group with a shorter chain, generally having four or fewer carbon atoms. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having a double or triple bond, respectively.

[0016] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear, branched, or cyclic hydrocarbon radical, or combination thereof, consisting of the specified number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, and S may be located at any interior position of the heteroalkyl group. The heteroatom Si may be located at any position of the heteroalkyl group (e.g., the position at which the alkyl group is attached to the remainder of the molecule). Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two consecutive heteroatoms may be present, for example, -CH2-NH-OCH3 or -CH2-O-Si(CH3)3. Similarly, the terms "heteroalkenyl" and "heteroalkynyl," by themselves or in combination with other terms, mean, unless otherwise stated, an alkenyl or alkynyl group, respectively, containing the specified number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The one or more heteroatoms O, N, and S may be present at any intramolecular position of the heteroalkyl group.

[0017] The term "heteroalkylene" by itself or as part of another substituent means a saturated or unsaturated or polyunsaturated divalent radical derived from heteroalkyl, and includes, by way of example, -CH-CH-S-CHCH- and -CH-S-CH-CH-NH-CH-, -O-CH-CH=CH-, -CH-CH=C(H)CH-O-CH-, and -S-CH-C≡C-. For heteroalkylene groups, heteroatoms can also occupy either or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).

[0018] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to alkyl groups connected to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. In addition, in the case of a dialkylamino group, the two alkyl moieties may be the same or different and may form a 3- to 7-membered ring together with the nitrogen atom to which each is attached. Thus, -NR a R b The group represented by the formula (I) includes piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

[0019] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0020] The term "aryl," unless otherwise specified, refers to a polyunsaturated, typically aromatic hydrocarbon group that can be monocyclic or polycyclic (up to three rings) fused or covalently linked together. The term "heteroaryl" refers to an aryl group (or ring) containing from 1 to 5 heteroatoms selected from N, O, and S, the nitrogen and sulfur atoms of which may be optionally oxidized, and one or more nitrogen atoms may be optionally quaternized. A heteroaryl group can be linked to the remainder of the molecule via a heteroatom. Non-limiting examples of aryl groups are phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indoline, and cyclohexane. Examples include lysinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0021] For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" includes those groups in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.).

[0022] In some embodiments, the above terms (e.g., "alkyl," "aryl," and "heteroaryl") will include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. For brevity, the terms aryl and heteroaryl refer to either substituted or unsubstituted forms as provided below, while the term "alkyl" and related aliphatic groups are meant to refer to the unsubstituted form unless otherwise indicated as "substituted."

[0023] A variety of groups are possible as substituents on the alkyl group (including groups often referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) and are selected from the following: -halogen, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR R', R'', and R''' are each independently selected from hydrogen, unsubstituted C(O)R ... 1-8 Alkyl groups, unsubstituted heteroalkyl groups, unsubstituted aryl groups, aryl groups substituted with 1 to 3 halogen atoms, unsubstituted C 1-8 Alkyl groups, unsubstituted C 1-8 Alkoxy group or unsubstituted C 1-8 Thioalkoxy group or unsubstituted aryl-C 1-4means an alkyl group. When R' and R" are attached to the same nitrogen atom, these groups can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl. The term "acyl" by itself or as part of another substituent means an alkyl group in which both substituents on the carbon nearest to the point of attachment of the group are replaced with the substituent =0 (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0024] Similarly, substituents on the aryl and heteroaryl groups are varied and generally include the following: -halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -CO2R', -CONR'R'', -C(O)R', -OC(O)NR' R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R'", -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -N3, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, the number of which ranges from zero (0) to the total number of open valences on the aromatic ring system; wherein R', R'', and R'" are independently selected from hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, unsubstituted aryl, unsubstituted heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene chain of 1 to 4 carbon atoms.

[0025] Two of the substituents on adjacent atoms of the aryl and heteroaryl rings may optionally be of the general formula -TC(O)-(CH) qIt may be substituted with a substituent of -U- (wherein T and U are independently -NH-, -O-, -CH2-, or a single bond, and q is an integer of 0 to 2).

[0026] Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -A-(CH) r A and B may be independently replaced with a substituent of the formula -B- (where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 3). One of the single bonds in the new ring thus formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a group of the formula -(CH2) s -X-(CH2) t (wherein s and t are independently an integer of 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-). The substituent R' in -NR'- and -S(O)2NR' is hydrogen or an unsubstituted C 1-6 alkyl.

[0027] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[0028] As used herein, the terms "treat" or "treatment" encompass both disease-modifying or palliative therapy, either of which may be prophylactic (i.e., to prevent, delay or reduce the severity of symptoms before the onset of symptoms) or therapeutic (i.e., to reduce the severity and / or duration of symptoms after the onset of symptoms).

[0029] The term "pharmaceutically acceptable salts" includes salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. In cases where a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines (including substituted amines, cyclic amines, naturally occurring amines, etc.), such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, Vol. 66, pp. 1-19). Certain specific compounds of the present invention contain both acidic and basic functional groups.

[0030] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid, followed by isolation of the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms with respect to certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for purposes of this invention.

[0031] The compounds described in the following embodiments can be obtained according to the methods described in WO2010 / 075257, WO2011 / 163640 and WO2016 / 053890.

[0032] [Embodiment] The present disclosure is directed to a method of treating ANCA-associated vasculitis (AAV) with nephropathy in an individual in need thereof, comprising administering a complement component 5a receptor (C5aR) antagonist to the individual when the individual exhibits an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV.

[0033] In another aspect, the disclosure provides a method for assessing the effectiveness of treatment with a complement component 5a receptor (C5aR) antagonist in an individual diagnosed with or suspected of having ANCA-associated vasculitis, comprising measuring the soluble CD163 (sCD163) to creatinine ratio in a urine sample from the individual before and after administration of the C5aR antagonist, wherein treatment is efficacious if the urinary sCD163 concentration decreases after administration.

[0034] In some embodiments, an effective treatment reduces the sCD163 to creatinine ratio of a urine sample from an individual after administration of a C5aR antagonist by at least 20, 30, 40, 50, 60, 70, 80% or more compared to the sCD163 to creatinine ratio of a urine sample from the individual before administration of the C5aR antagonist. In some embodiments, an effective treatment reduces the sCD163 to creatinine ratio of a urine sample from an individual after administration of a C5aR antagonist by at least 40% compared to the sCD163 to creatinine ratio of a urine sample from the same individual before administration of the C5aR antagonist. In some embodiments, an effective treatment reduces the sCD163 to creatinine ratio of a urine sample from an individual after administration of a C5aR antagonist by at least 50% compared to the sCD163 to creatinine ratio of a urine sample from the same individual before administration of the C5aR antagonist. In some embodiments, the ratio of sCD163 to creatinine in a urine sample from the individual after administration of the C5aR antagonist is reduced by at least 60% compared to the ratio of sCD163 to creatinine in a urine sample from the individual before administration of the C5aR antagonist.

[0035] In some embodiments, the urinary sCD163 to creatinine ratio is measured relative to the albumin to creatinine ratio of a urine sample from the individual.

[0036] In some embodiments, the urinary sCD163 to creatinine ratio is measured relative to the ratio of monocyte chemoattractant protein-1 (MCP-1) in a urine sample from the individual.

[0037] Methods for treating ANCA-associated vasculitis (AAV) provide for a reduction in the concentration of soluble CD163 (sCD163) in urine, the amount of which will vary depending on the starting amount of sCD163 and the individual's disease state. In some embodiments, the concentration of sCD163 in a urine sample obtained from an individual 8 days after administration of a C5aR antagonist is reduced by at least 10, 15, 20, 25, 30, 35, 40, 45, 50%, or more. In some embodiments, the concentration of sCD163 in a urine sample obtained from an individual 8 days after administration of a C5aR antagonist is reduced by at least 20%. In some embodiments, the concentration of sCD163 in a urine sample obtained from an individual 8 days after administration of a C5aR antagonist is reduced by at least 25%. In some embodiments, the concentration of sCD163 in a urine sample obtained from an individual 8 days after administration of a C5aR antagonist is reduced by at least 30%.

[0038] In some aspects, methods are provided for reducing the concentration of urinary soluble CD163 (sCD163) in an individual diagnosed with or suspected of having ANCA-associated vasculitis (AAV), comprising administering a complement component 5a receptor (C5aR) antagonist to the individual, wherein administration of the C5aR antagonist reduces the concentration of urinary sCD163 in a urine sample provided by the individual.

[0039] The relative decrease in urinary soluble CD163 (sCD163) concentration will vary depending on the starting dose and the individual's condition. In some embodiments, the concentration of sCD163 in a urine sample obtained from an individual 8 days after administration of a C5aR antagonist is reduced by at least 10, 15, 20, 25, 30, 35, 40, 45, 50%, or more. The concentration of sCD163 in a urine sample obtained from an individual 8 days after administration of a C5aR antagonist is reduced by at least 20%. In some embodiments, the concentration of sCD163 in a urine sample obtained from an individual 8 days after administration of a C5aR antagonist is reduced by at least 25%. The concentration of sCD163 in a urine sample obtained from an individual 8 days after administration of a C5aR antagonist is reduced by at least 30%.

[0040] In some aspects, methods of treating ANCA-associated vasculitis (AAV) are provided, comprising administering to a patient in need thereof an effective amount of a complement component 5a receptor (C5aR) antagonist, thereby treating the ANCA-associated vasculitis. Indeed, patients administered the complement component 5a receptor (C5aR) antagonist (avacopan) have demonstrated a surprisingly rapid response to treatment. In some embodiments, the individual has ANCA-associated vasculitis accompanied by renal impairment.

[0041] In some embodiments, treatment with the complement component 5a receptor (C5aR) antagonist avacopan reduces the urinary albumin to creatinine ratio by at least 30% four weeks after treatment compared to the individual's urinary albumin to creatinine ratio before treatment. In some embodiments, treatment with the complement component 5a receptor (C5aR) antagonist avacopan reduces the urinary albumin to creatinine ratio by at least 35% four weeks after treatment compared to the individual's urinary albumin to creatinine ratio before treatment. In some embodiments, treatment with the complement component 5a receptor (C5aR) antagonist avacopan reduces the urinary albumin to creatinine ratio by at least 40% four weeks after treatment compared to the individual's urinary albumin to creatinine ratio before treatment. In some embodiments, treatment with the complement component 5a receptor (C5aR) antagonist avacopan reduces the urinary albumin to creatinine ratio by at least 45% four weeks after treatment compared to the individual's urinary albumin to creatinine ratio before treatment.

[0042] In some embodiments, treatment with the complement component 5a receptor (C5aR) antagonist avacopan reduces the Birmingham Vasculitis Activity Score by at least 50% four weeks after treatment compared to the individual's score before treatment. In some embodiments, treatment with the complement component 5a receptor (C5aR) antagonist avacopan reduces the Birmingham Vasculitis Activity Score by at least 60% four weeks after treatment compared to the individual's score before treatment.

[0043] In some embodiments, the C5aR antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] where C 1 is 1 to 3 R 1 phenyl optionally substituted with substituents; C 2 is 1 to 3 R 2 phenyl optionally substituted with substituents; C 3 is C 3-8 cycloalkyl and phenyl, and each C 3 is optionally substituted with 1 to 3 substituents; Each R 1 are independently halogen, -CN, -R c , -CO2R a , -CONR a R b , -C(O)R a , -OC(O)NR a R b , -NR b C(O)R a , -NR b C(O)2R c , -NR a C(O)NR a R b , -NR a R b , -OR a and -S(O)NR a R b wherein each R a and R b are independently hydrogen, C 1-8 Alkyl and C 1-8 haloalkyl, or, when connected to the same nitrogen atom, can be combined with the nitrogen atom to form a 5- or 6-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O, or S; each R c is independently C 1-8 Alkyl, C 1-8 Haloalkyl, C3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R a , R b and R c The aliphatic and cyclic portions of may be optionally further substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, and dialkylamino groups; and two R 1 When the substituents are on adjacent atoms, they together form a fused 5- or 6-membered carbocyclic ring; Each R 2 are independently halogen, -CN, -R f , -CO2R d , -CONR d R e , -C(O)R d , -OC(O)NR d R e , -NR e C(O)R d , -NR e C(O)2R f , -NR d C(O)NR d R e , -NR d C(O)NR d R e , -NR d R e , -OR d and -S(O)NR d R e wherein each R d and R e are independently halogens, C 1-8 Alkyl and C 1-8 haloalkyl, or, when connected to the same nitrogen atom, can combine with the nitrogen atom to form a 5- or 6-membered ring having 0-2 additional heteroatoms as ring members selected from N, O, or S; each R f is independently C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and R d, R e and R f the aliphatic and cyclic portions of may be optionally further substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, and dialkylamino groups; Each R 3 are independently halogen, -CN, -R i , -CO2R g , -CONR g R h , -C(O)R g , -OC(O)NR g R h , -NR h C(O)R g , -NR h C(O)2R i , -NR g C(O)NR g R h , -NR g R h , -OR g , -S(O)NR g R h , -X 4 -R j , -X 4 -NR g R h , -X 4 -CONR g R h , -X 4 -NR h C(O)R g , -NHR j and -NHCH2R j where X is selected from the group consisting of 4 is C 1-4 alkylene; each R g and R h are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl and C 1-8 haloalkyl, or, when attached to the same nitrogen atom, can be combined with the nitrogen atom to form a 5- or 6-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O, or S, and optionally substituted with 1 or 2 oxo; each R i is independently C1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and each R j is C 3-6 is selected from the group consisting of cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and R g , R h , R i and R j the aliphatic and cyclic portions of may be optionally further substituted with 1 to 3 halogen, methyl, CF, hydroxy, amino, alkylamino, and dialkylamino groups; and X is hydrogen or CH3.

[0044] In some embodiments, the C5aR antagonist has the formula (Ia): [ka]

[0045] In some embodiments, the C5aR antagonist has the formula (Ib): [ka] where X 1 CH and CR 1 selected from the group consisting of: The subscript n is an integer between 0 and 2; X 2 CH and CR 2 selected from the group consisting of: The subscript m is an integer between 0 and 2.

[0046] In some embodiments, the C5aR antagonist has the formula (Ic): [ka] where X 1 CH and CR1 selected from the group consisting of: The subscript n is an integer between 0 and 2; X 2 CH and CR 2 selected from the group consisting of: The subscript m is an integer between 0 and 2.

[0047] In some embodiments, the C5aR antagonist has the formula (Id): [ka] where the subscript p is an integer between 0 and 3; X 1 CH and CR 1 selected from the group consisting of: The subscript n is an integer between 0 and 2; X 2 CH and CR 2 selected from the group consisting of: The subscript m is an integer between 0 and 2.

[0048] In some embodiments, the compound has the formula (Ie): [ka] where p is 0, 1, or 2.

[0049] In some embodiments, the C5aR antagonist is avacopan, which has the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0050] Some compounds of the present invention can exist in unsolvated and solvated forms (including hydrated forms). In general, solvated forms are equivalent to unsolvated forms and are intended to be within the scope of the present invention. Some compounds of the present invention can exist in polycrystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by this disclosure and are intended to be within the scope of the present invention.

[0051] Some compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds. All racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., individual enantiomers) are intended to be within the scope of the present invention. The compounds of the present disclosure may contain unnatural proportions of elemental isotopes at one or more of the atoms that constitute such compounds. For example, compounds may be radioisotopes, such as tritium ( 3 H), iodine-125( 125 I), carbon-14( 14 C)). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0052] The compounds disclosed herein are intended to encompass all pharmaceutically acceptable salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and avacopan, which are isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or atomic number. Examples of isotopes that can be incorporated into the disclosed compounds include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl,123 I and 125 Isotopically labeled compounds of certain formulas (I), (Ia), (Ib), (Ic), (Id), (Ie) and avacopan, e.g., those containing a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e., 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0053] Heavy isotopes, such as deuterium, i.e. 2 Substitution with H can confer therapeutic efficacy due to greater metabolic stability; for example, the in vivo half-life may be increased or the required dose may be reduced. Thus, heavier isotopes may be preferable in some circumstances.

[0054] Positron-emitting isotopes, e.g. 11 C. 18 F, 15 O and 13 Substitution at N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) and avacopan can generally be prepared by conventional techniques well known to those skilled in the art, or by methods similar to those described in the Examples set forth below, substituting the appropriate isotopically labeled reagent for the non-labeled reagent conventionally used.

[0055] The methods, compositions, kits, and articles of manufacture provided herein utilize or include compounds (e.g., (I), (Ia), (Ib), (Ic), (Id), (Ie), and avacopan) or pharmaceutically acceptable salts, prodrugs, or solvates thereof, in which 1 to n hydrogen atoms (where n is the number of hydrogen atoms in the molecule) bonded to a single carbon atom have been replaced by deuterium atoms, i.e., D. As is well known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may be useful for increasing the half-life of the compounds or their pharmaceutically acceptable salts, prodrugs, or solvates when administered to mammals due to their increased resistance to metabolism. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0056] The therapeutic methods provided herein generally involve administering an effective amount of a compound provided herein to a patient, including those suffering from or suspected of suffering from antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AVV).

[0057] In general, the therapeutic methods provided herein comprise administering to a patient an effective amount of a compound described herein. In a preferred embodiment, the compound(s) of the present invention are preferably administered to a patient (e.g., a human), typically orally. In another embodiment, the compound(s) of the present invention are administered to a patient (e.g., a human) systemically (intravenously or subcutaneously). An effective amount is an amount sufficient to modulate C5a receptor activity and / or to reduce or alleviate symptoms exhibited by the patient. Preferably, the administered amount is an amount sufficient to produce a plasma concentration of the compound (or of its active metabolite, if the compound is a prodrug) high enough to detectably inhibit chemotaxis of leukocytes (e.g., neutrophils) in vitro. Treatment regimens may vary depending on the compound used and the particular disease to be treated. A dosing frequency of four times per day or less is preferred for the treatment of most diseases. Generally, a twice-daily dosing regimen is more preferred, with once-daily administration being particularly preferred. It will be understood, however, that the specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, such as the activity of the particular compound used, the patient's age, body weight, general health, sex, diet, timing of administration, route of administration, rate of excretion, concurrent use of drugs (i.e., other drugs are administered to the patient), the severity of the particular condition being treated, and the judgment of the prescribing medical professional. In general, it is preferable to use the lowest dosage sufficient to provide effective treatment. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria appropriate to the condition being treated or prevented.

[0058] Dosage levels on the order of about 0.1 mg to about 140 mg per kg of body weight per day are useful in treating or preventing diseases involving pathogenic C5a activity (about 0.5 mg to about 7 g per human patient per day). The amount of a compound of the invention which can be combined with a pharmaceutical carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain from about 1 mg to about 500 mg of active ingredient. In some embodiments, dosage unit forms are 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of pharmaceutical agent. For compounds administered orally, transdermally, intravenously, intramuscularly, or subcutaneously, it is preferred to administer an amount of compound sufficient to achieve a serum concentration of 5 ng (nanogram) / mL to 10 μg (microgram) / mL serum. More preferred is administering sufficient compound to achieve a serum concentration of 20 ng to 1 μg / mL serum, and most preferred is administering sufficient compound to achieve a serum concentration of 50 ng / mL to 200 ng / mL serum. For direct injection into the synovium (for the treatment of arthritis), an amount of compound sufficient to achieve a local concentration of approximately 1 micromolar should be administered.

[0059] In some embodiments, the amount of C5aR antagonist administered is 30 mg. In some embodiments, the total daily dose of C5aR antagonist is 60 mg. In some embodiments, the C5aR antagonist is administered orally. In some embodiments, 30 mg of C5aR antagonist is administered orally twice daily.

[0060] Dosage frequency can vary depending on the compound used and the specific disease to be treated.However, in the treatment of most diseases, the administration frequency of 4 times a day or less is preferred, 3 times a day or less is preferred, and the administration regimen of 1 or 2 times a day is particularly preferred.However, it should be understood that the specific dosage level of a specific patient will depend on various factors, such as the activity of the specific compound used, age, body weight, general health condition, sex, diet, timing of administration, route of administration, excretion rate, concurrent use of drugs (i.e., other drugs are administered to the patient), the severity of the disease being treated, and other factors, such as the judgment of the prescribing medical professional.

[0061] Pharmaceutical Composition The compounds described herein can be administered as a composition which will typically include a pharmaceutical carrier or diluent.

[0062] As used herein, the term "composition" is intended to include a product containing specified ingredients in specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0063] In some embodiments, the pharmaceutical composition further comprises one or more additional pharmaceutical agents.

[0064] Pharmaceutical compositions for administering the compounds of the present invention may conveniently be provided in unit dosage form and may be prepared by any method well known in the art of pharmacy and drug delivery. All methods include the step of combining the active ingredient with a pharmaceutical carrier which constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the desired active compound is present in an amount sufficient to produce the desired effect upon the process or condition of a disease.

[0065] Pharmaceutical compositions containing the active ingredient can be in a form suitable for oral administration. Examples of such forms include tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders, dispersible granules, emulsions and self-emulsifying formulations such as those described in U.S. Patent Application Publication No. 2002-0012680, hard or soft capsules, syrups, elixirs, liquids, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, effervescent tablets, and the like. Oral compositions can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide a pharmaceutically elegant and palatable formulation. Tablets contain the active ingredient in admixture with pharmaceutically acceptable, non-toxic excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, sodium phosphate, etc.; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or can be enteric or otherwise coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged action. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used. These can be coated by the techniques described in U.S. Patent Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for sustained release.

[0066] Oral formulations can be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin, polyethylene glycols (PEG) of various average particle sizes (e.g., PEG400, PEG4000) and certain surfactants (e.g., Cremophor or Solutol), or as soft capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. In addition, emulsions can be prepared using water-immiscible ingredients such as fats and oils, and can be stabilized with surfactants such as mono- or diglycerides.

[0067] Aqueous suspensions contain the active compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum arabic; dispersing agents or wetting agents can be natural phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols (e.g., polyoxyethylene sorbitol monooleate), condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example, ethyl benzoate, n-propyl benzoate, p-hydroxybenzoic acid, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0068] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, coconut oil, or mineral oil, such as liquid paraffin. Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those listed above) and flavoring agents can be added to make the oral preparation palatable. These compositions can be preserved by adding antioxidants, such as ascorbic acid.

[0069] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Examples of suitable dispersing agents, wetting agents, and suspending agents have already been mentioned above. Additional excipients, for example sweetening, flavoring, and coloring agents, may also be present.

[0070] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural gums, such as gum arabic or gum tragacanth, natural phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylenesorbitan monooleate. Such emulsions can also contain sweeteners and flavoring agents.

[0071] Syrups and elixirs can be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain demulcents, preservatives, flavorings, and coloring agents. Oral liquids can be prepared in combination with, for example, cyclodextrin, PEG, and surfactants.

[0072] The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. Such suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable composition can also be a sterile injectable solution or suspension in a non-toxic parenterally administrable diluent or solvent (e.g., a solution in 1,3-butanediol). Acceptable excipients and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution, among others. In addition, sterile fixed oils are conveniently used as solvents or suspending agents. For this purpose, bland, odorless fixed oils can be used, such as synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used to prepare injectable solutions.

[0073] The compounds of the present disclosure can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting and releasing the drug in the rectum. Such materials include cocoa butter, polyethylene glycol, and the like. Additionally, the compounds of the present disclosure can be administered via ocular delivery in the form of liquids or ointments. Furthermore, transdermal delivery of the target compounds of the present disclosure can be achieved using iontophoretic patches and the like. For topical administration, creams, ointments, jellies, solutions, suspensions, and the like containing the compounds of the present disclosure can be used. As used herein, topical administration also includes the use of mouthwashes and gargles.

[0074] The compounds of the present disclosure can be used in combination with suitable polymeric carriers as targetable drug carriers. Examples of such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, and palmitoyl-substituted polyethyleneoxide-polylysine. Furthermore, the compounds of the present invention can be coupled to carriers that represent a class of biodegradable polymers useful for achieving controlled drug release. Examples of such biodegradable polymers include polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, crosslinked hydrogels, or amphiphilic block copolymers. Polymers and semipermeable polymer matrices can be formed into shaped articles such as valves, stents, tubes, prostheses, and the like. In one aspect of the present invention, the compounds of the present invention are coupled to a polymeric or semipermeable polymeric matrix, which is then formed into a stent or stent-graft device.

[0075] Kits and Packaging The terms "kit" and "pharmaceutical kit" refer to a commercial kit or package containing, in one or more suitable containers, one or more pharmaceutical compositions and instructions for their use. In one embodiment, a kit is provided that includes a compound of the invention or a pharmaceutically acceptable salt thereof and instructions for its administration. In one embodiment, a kit is provided that includes a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) or avacopan, or a pharmaceutically acceptable salt thereof, and instructions for its administration. In one embodiment, a kit is provided that includes a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) or avacopan, or a pharmaceutically acceptable salt thereof, and one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents and instructions for their administration.

[0076] In one embodiment, the disclosed compound is formulated into a dosage unit and packaged in an individual package. Individual packages include, but are not limited to, bottles, child-resistant containers, ampoules, tubes, etc. In one embodiment, the disclosed compound and optional additional therapeutic agents are formulated into dosage units and packaged individually in individual packages, each containing one dosage unit. Such individually packaged units can contain the pharmaceutical composition in any dosage form, including, but not limited to, liquid, solid, powder, granules, effervescent powder, tablets, hard or soft capsules, emulsions, suspensions, syrups, suppositories, tablets, troches, lozenges, liquids, buccal patches, thin layers, oral gels, chewable tablets, chewing gums, disposable syringes, etc. Such individually packaged units can be combined in a package made of one or more paper, cardboard, paperboard, metal foil, or plastic foil, such as a blister pack. One or more dosage units can be administered once or several times a day. One or more dosage units may be administered three times a day. One or more dosage units may be administered twice daily, one or more dosage units may be administered on the first day and one or more dosage units on subsequent days.

[0077] Avacopan has the formula: [ka] [Example]

[0078] [Example] The following examples are given by way of illustration and not by way of limitation. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to yield essentially the same results.

[0079] Example 1: Rapid decrease in urinary sCD163 correlates with clinical benefit of the C5aR inhibitor avacopan in ANCA-associated vasculitis The clinical trial results presented below included three patient groups: (1) full-dose prednisone (60 mg), standard of care; (2) avacopan 30 mg bid (twice daily) plus low-dose prednisone (20 mg); and (3) avacopan 30 mg bid plus no prednisone. All patients received either intravenous (IV) cyclophosphamide or intravenous (IV) rituximab. sCD163 (ELISA) and creatinine were measured before and at days 8, 15, 29, 57, and 85 after treatment. The classification method is further described in Table 1. [Table 1]

[0080] The goals of this study were to evaluate the efficacy of avacopan in human patients with AAV, to assess the effects of three different treatment regimens on urinary sCD163, and to examine the correlation between urinary sCD163 levels and the following renal function parameters: eGFR, UACR, and the urinary MCPP-1 / creatinine ratio as a marker of inflammation. CD163 is a glycosylated membrane protein expressed exclusively on monocytes and macrophages. Membrane-bound CD163 can undergo enzymatic cleavage to form soluble CD163 (sCD163) via shedding of the extracellular domain in response to inflammatory stimuli. Urinary sCD163 levels have been reported to be elevated in patients with active renal vasculitis compared with levels in patients in remission and healthy controls. Increased urinary sCD163 levels in active AAV are associated with a higher number of CD163-positive cells in the kidney.

[0081] Materials and Methods Serum samples were collected using serum separator tubes (SSTs), shipped refrigerated to a central laboratory the same day, and measured for creatinine and eGFR (calculated using the MDRD serum creatinine formula).

[0082] Midstream urine samples were collected by clean catch method and shipped refrigerated to a central laboratory the same day for analysis of creatinine, albumin, and UACR.

[0083] Another fraction of urine was centrifuged at 1200 g for 10 minutes at 2-8° C. The supernatant was aliquoted into cryovials and stored at −70° C. until analysis.

[0084] Urinary sCD163 and MCP-1 were analyzed by ELISA in the entire subject set using ELISA kits from R&D Systems.

[0085] Urinary sCD163 / creatinine ratio, UACR and urinary MCP-1 / creatinine ratio were log-transformed for normal distribution.

[0086] Changes from baseline in urinary sCD163 / creatinine ratio at each time point within each group were analyzed by mixed effects of repeated measures. P<0.05 was considered statistically significant.

[0087] The correlations between the urinary sCD163 / creatinine ratio and eGFR, UACR, and the urinary MCP-1 / creatinine ratio were analyzed using a repeated measures regression model.

[0088] As shown in Table 2, avacopan treatment significantly reduced the sCD163 / creatinine ratio by day 8 and further reduced it over the 12-week follow-up period. [Table 2] Paired t-test against baseline in each group: * p<0.05; ** p<0.01; *** p<0.001; # p=0.076;FD=adequate dose;LD=low dose

[0089] In contrast, the standard-of-care control group receiving adequate prednisone treatment showed no improvement in urinary sCD163 by day 57. Urinary sCD163 / creatinine levels were highly correlated with previously reported improvements in urinary albumin / creatinine and MCP-1 / creatinine ratios (p<0.0001).

[0090] 1A-1E show the rapid reduction in disease activity and significant improvement in health-related quality of life in patients treated with avacopan. Panel A is a plot of the Birmingham Vasculitis Activity Score; Panel B is a plot of the urinary albumin:creatinine ratio; Panel C is a plot of the EQ-5D-5L visual analog scale, a measure of health-related quality of life, expressed as mean ± SEM over the treatment period; and Panels D and E are plots of the Medical Outcomes Study SF-36 version 2 Physical Functioning and Role Emotional components, a measure of health-related quality of life, expressed as mean ± SEM over the treatment period.

[0091] Figures 2A-B show the urinary sCD163 / creatinine ratio at baseline. Figure 2A shows the urinary sCD163 / creatinine ratio levels in patients with anti-MPO and anti-PPR3 autoantibodies. Figure 2B shows the urinary sCD163 / creatinine ratio levels in patients randomized to three different treatment groups. The urinary sCD163 / creatinine ratio at baseline was comparable in patients with anti-MPO and anti-PPR3 autoantibodies and among the three different treatment groups.

[0092] Figure 3 shows the rapid decrease in urinary sCD163 / creatinine ratio in patients treated with avacopan. As shown in the graph, * p<0.05; ** p<0.01; *** p<0.001; #p=0.076 compared to baseline in each group.

[0093] Figure 4 shows a strong positive correlation between urinary sCD163 / Cr and UACR. P<0.0001 for correlation; data from all subjects and time points were included in the analysis.

[0094] Figure 5 shows a strong positive correlation between urinary sCD163 / Cr and MCP-1 / Cr. P<0.0001 for correlation; data from all subjects and time points were included in the analysis.

[0095] Figure 6 shows that there is no correlation between urinary sCD163 / Cr and eGFR. P for correlation = 0.655; data from all subjects and time points were included in the analysis.

[0096] Figures 7A-C show the time course of changes from baseline urinary sCD163 / Cr, eGFR, UACR, and MCP-1 / Cr in all subjects. Figure 7A shows plots of eGFR and sCD163 / Cr over time. Figure 7B shows plots of sCD163 / Cr and UACR over time. Figure 7C shows plots of sCD163 / Cr and MCP-1 / Cr over time. As can be seen from the figures, the decrease in sCD163 / Cr preceded the improvement in eGFR, the decrease in sCD163 / Cr preceded the decrease in UACR, and there was a good temporal correlation between the decreases in sCD163 / Cr and MCP-1 / Cr.

[0097] Avacopan treatment resulted in a rapid decrease in sCD163, which correlated with a rapid improvement in nephritic markers and rapid improvement in signs and symptoms of AAV in this study. The significant positive and temporal correlation between urinary sCD163 / Cr and MCP-1 / Cr supports urinary sCD163 as a marker of renal inflammation in patients with AAV.

Claims

1. 1. A composition comprising Avacopan for treating ANCA-associated vasculitis (AAV) in an individual in need thereof, wherein the composition is administered to the individual when the individual exhibits an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV; wherein administration of avacopan (1) rapidly improves renal inflammation within about one week, and (2) rapidly reduces the urinary sCD163 to creatinine ratio within about one week.

2. 2. The composition of claim 1, wherein there is a temporal correlation between the urinary sCD163 to creatinine ratio and the urinary monocyte chemoattractant protein-1 (MCP-1) to creatinine ratio.

3. 2. The composition of claim 1, wherein the urinary sCD163 to creatinine ratio is measured relative to the albumin to creatinine ratio in a urine sample from the individual.

4. 2. The composition of claim 1, wherein the urinary sCD163 to creatinine ratio is measured relative to the monocyte chemoattractant protein-1 (MCP-1) to creatinine ratio in a urine sample from the individual.

5. 2. The composition of claim 1, wherein the concentration of sCD163 in a urine sample obtained from the individual 8 days after administration of avacopan is reduced by at least 25%.

6. The composition of claim 1, wherein effective treatment reduces the sCD163 to creatinine ratio of a urine sample from an individual after administration of avacopan by at least 50% compared to the sCD163 to creatinine ratio of a urine sample from the individual before administration of avacopan.

7. The composition of any one of claims 1 to 6, wherein avacopan is administered twice daily.

8. The composition of any one of claims 1 to 6, wherein avacopan is administered once daily.

9. The composition of any one of claims 1 to 8, wherein avacopan is administered orally.

10. The composition of any one of claims 1 to 7, wherein 30 mg of avacopan is administered twice daily.

11. The composition of any one of claims 1 to 7, wherein 30 mg of avacopan is administered by oral administration twice daily.

12. The composition of any one of claims 1 to 11, wherein the individual is a human.

13. The composition of any one of claims 1 to 12, wherein the individual is treated for 12 weeks.

14. The composition of any one of claims 1 to 12, wherein the individual is treated for 26 weeks.

15. The composition of any one of claims 1 to 12, wherein the individual is treated for 52 weeks.

16. The composition of any one of claims 1 to 12, wherein the individual is undergoing chronic treatment.

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