How to treat hidradenitis suppurativa

Abstract

Provided herein are methods of treating a subject suffering from a neutrophilic inflammatory disease of the skin, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, wherein each variable position is defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the neutrophilic inflammatory disease of the skin is hidradenitis suppurativa (HS). TIFF2023548117000018.tif47170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority under U.S. Provisional Patent Application No. 63 / 106,557 and U.S. Provisional Patent Application No. 63 / 106,858, filed on 28 October 2020 under Section 119(e) of the U.S. Patent Act, the contents of which are incorporated herein by reference in whole for all purposes.

[0002] Description of the rights to inventions made under federal government-funded research and development. Not applicable.

[0003] References to “sequence listings,” tables, or appendices to computer program listings submitted on compact discs. Not applicable. [Background technology]

[0004] Hidradenitis suppurativa (HS), also known as reverse acne, is a chronic inflammatory skin disease characterized by inflammatory nodules, abscesses, pocket formation, and fistula formation, as well as skin scarring. It most commonly occurs in areas with a high concentration of apocrine glands, such as the armpits, submammary glands, groin, perineum, and perianal area. In its moderate and severe forms, HS is debilitating and causes significant discomfort, pain, anxiety, depression, and a reduced quality of life.

[0005] The exact cause of HS is unclear, but genetic defects in the gamma-secretase-coding gene have been explained in individuals with HS. Possible target proteins include Notch, E-cadherin, and nicastriin. Notch plays a crucial role in hair follicle development, and defects in Notch can lead to epidermal cyst formation, dysregulation of normal T cell-mediated immune responses, and suppression of Toll-like receptor 4-induced pro-inflammatory macrophage-mediated cytokine responses (Radtke et al, 2010; Wang et al, 2010). Smoking and obesity have been associated with HS (Prens and Deckers, 2015) and potentially with hyperhidrosis, androgenic dysfunction, or genetic causes. Some reports suggest that HS is, at least in part, a neutrophil-mediated disorder.

[0006] Current treatments for patients with HS include topical and systemic antibiotics, analgesics, and anti-TNF-α agents such as adalimumab. Success has been limited with the use of other drugs such as cyclosporine A, dapsone, and isotretinoin (Napolitano et al, 2017). Despite the available treatment options, the majority of patients respond only partially and / or temporarily.

[0007] A recent development in U.S. Patent Application Publication No. 2018 / 0280530 and U.S. Patent Application Publication No. 2018 / 028425 is the use of C5a-targeted antibodies to treat patients suffering from HS. C5a is known to be a potent chemotactic anaphylatoxin, and its binding to C5aR modulates leukocyte transport, migration, and activation. However, direct targeting of C5a with antibodies disrupts not only the C5a / C5aR axis but also the binding of C5a to the C5L2 receptor. The C5a / C5L2 pathway includes beneficial biological functions, including limiting or suppressing pro-inflammatory responses caused by C5a (Gerard et al. J Biol Chem. 2005. 280(48): 39677-80, Wang et al. J Immunol. 2013. 191(8): 4001-9). In fact, disrupting the C5a-C5L2 pathway has been shown to exacerbate inflammation and lead to a more severe response to C5a (Xiao et al. J Am Soc Nephrol. 2014. 25(2):225-31, Karsten et al., Front Immunol. 2018, 15;9:488). Therefore, directly targeting C5a requires blocking signaling pathways associated with mitigating the C5a response. Furthermore, antibody treatment has other disadvantages, such as the need for intravenous delivery, the possibility of patients developing human anti-chimeric antibodies (HACAs), the need for patients to travel to a medical facility to receive treatment, and decreased patient compliance. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] U.S. Patent Application Publication No. 2018 / 0280530 [Patent Document 2] U.S. Patent Application Publication No. 2018 / 028425 [Non-patent literature]

[0009]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Means for Solving the Problems

[0010] Therefore, there is still a need in the art to identify and develop orally administrable compounds useful in the treatment of hidradenitis suppurativa (HS) and related neutrophilic inflammatory skin diseases without blocking the C5a / C5L⁢2 axis, thereby preserving the beneficial functions of the C5L⁢2 pathway. In one aspect, the present disclosure provides a method of treating a neutrophilic inflammatory skin disease in a subject who needs it, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I

Chem.

[0011] In some embodiments, the neutrophilic inflammatory skin disease is hidradenitis suppurativa (HS).

[0012] In some embodiments, the therapeutically effective amount of formula I has a total daily dosage of about 5 - 200 mg. In some embodiments, the therapeutically effective amount of formula I has a total daily dosage of 60 mg or 20 mg.

[0013] Other objects, features, and advantages of the present invention will become apparent to those skilled in the art from the following detailed description and drawings.

Brief Description of the Drawings

[0014] [Figure 1] Shows a schematic diagram of a Phase II trial design.

Modes for Carrying Out the Invention

[0015] I. Overview The present disclosure provides compounds and dosing regimens for the treatment of hidradenitis suppurativa and specific patient populations thereof. The compounds in the methods described herein specifically target C5aR and do not disrupt the C5a-C5L2 interaction. Advantageously, the C5aR inhibitors disclosed herein efficiently regulate neutrophil migration and activation by blocking the C5a-C5aR interaction without blocking the C5a-C5L2 axis. Without being bound by any particular rationale, it is believed that compounds that bind to C5aR avoid the detrimental effect of interrupting the C5a-C5L2 signaling axis. Thereby, subjects undergoing treatment for hidradenitis suppurativa and subsets thereof will benefit from the anti-inflammatory inhibitory activity of the C5a-C5L2 axis.

[0016] II. Definitions As used herein, the terms “to treat” or “treatment” encompass both disease-modifying treatments and symptomatic treatments, either of which may be preventive (i.e., to prevent, delay, or reduce the severity of symptoms before their onset) or therapeutic (i.e., to reduce the severity and / or duration of symptoms after their onset). Treatment methods provided herein generally involve administering to a patient one or more effective amounts of the compounds provided herein. Appropriate patients include those suffering from or susceptible to the disorders or diseases identified herein (i.e., preventive treatment). Typical patients for treatments as described herein include mammals, in particular primates, and especially humans. Other suitable patients include domesticated companion animals such as dogs, cats, and horses, or livestock such as cattle, pigs, and sheep.

[0017] The term “pharmaceutically acceptable salt” includes salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. If the compounds of this disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either without a solvent or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, and zinc salts. Examples of pharmaceutically acceptable salts derived from organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and natural amines. Examples include arginine salt, betaine salt, caffeine salt, choline salt, N,N'-dibenzylethylenediamine salt, diethylamine salt, 2-diethylaminoethanol salt, 2-dimethylaminoethanol salt, ethanolamine salt, ethylenediamine salt, N-ethylmorpholine salt, N-ethylpiperidine salt, glucamine salt, glucosamine salt, histidine salt, hydravamin salt, isopropylamine salt, lysine salt, methylglucamine salt, morpholine salt, piperazine salt, piperadine salt, polyamine resin salt, procaine salt, purine salt, theobromine salt, triethylamine salt, trimethylamine salt, tripropylamine salt, and tromethamine salt. If the compounds of the present disclosure contain relatively basic functionalities, the acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either without a solvent or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochlorides, hydrobroms, nitrates, carbonates, monohydrogen carbonates, phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfates, monohydrogen sulfates, hydroiodides, or phosphates, as well as salts derived from relatively non-toxic organic acids, such as acetates, propions, isobutyrates, malons, benzoates, succinates, suberates, fumarates, mandelates, phthalates, benzenesulfons, p-tolylsulfons, citrates, tartrates, and methanesulfons. Salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid are also included (see, for example, Berge, SM, et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds in this disclosure contain both basic and acidic functional groups that enable the compound to be converted into either a base addition salt or an acid addition salt.

[0018] The neutral form of the compound can be regenerated in the conventional manner by contacting the salt with a base or acid and isolating the parent compound. This parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise, this salt is equivalent to the parent form of the compound for the purposes of this disclosure.

[0019] The present invention provides compounds in both salt and prodrug forms. The prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to become the compounds of the present invention. In addition, the prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment. For example, the prodrug can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with an appropriate enzyme or chemical reagent.

[0020] Certain compounds in this disclosure may exist in solvated forms, including non-solvated and hydrated forms. Generally, the solvated forms are equivalent to the non-solvated forms and are included within the scope of the invention. Certain compounds in this disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses intended by the invention and are included within the scope of the invention.

[0021] Certain compounds of the present invention have an asymmetric carbon atom (optical center) or a double bond, and racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separated enantiomers) are all included within the scope of the present invention. Compounds of the present invention may also contain atomic isotopes in unnatural proportions in one or more of the atoms constituting such compounds. For example, this compound may contain tritium ( 3 H), Iodine-125( 125 I), or carbon-14 ( 14 It can be radiolabeled with radioactive isotopes such as C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0022] When used herein, the wavy line intersecting a single, double, or triple bond in any chemical structure shown herein refers to the wavy line intersecting a single, double, or triple bond. [ka] The symbol represents the attachment point of a single, double, or triple bond to the rest of the molecule.

[0023] III. Detailed Description of Embodiments A. Treatment method In one embodiment, the present disclosure relates to a method for treating a neutrophilic inflammatory disease of the skin in a subject requiring such treatment, wherein the subject is given a therapeutically effective amount of Formula I [ka] [In the formula, Each R 1These are independently selected from the group consisting of CH3, CF3, CH2CH3, Cl, 1-pyrrolidine, -O-CH(CH3)2, and CH2OH. Each R 2 [These are independently selected from the group consisting of CH3 and F.] The present invention provides a method comprising the step of administering a compound or a pharmaceutically acceptable salt thereof.

[0024] Neutrophilic inflammatory diseases of the skin are a class of diseases that are promoted, at least in part, by neutrophil hyperactivity or inappropriate activation. The methods provided herein are particularly useful in the treatment of hidradenitis suppurativa (HS), a disease that is at least in part mediated by neutrophil activity. However, the treatment methods envisioned in this disclosure are not limited to HS, but further include related neutrophilic inflammatory diseases of the skin, such as Sweet's syndrome (SS), pyoderma gangrenosum (PG), PAPA (septic arthritis, PG and acne), PASH (PG, acne and hidradenitis suppurativa), subkeratinous pustular dermatosis (SPD), PAPASH (septic arthritis, acne, PG and hidradenitis suppurativa), erythema elevata (EED), neutrophilic subcutaneous panniculitis, acquired epidermolysis bullosa, syndrome, rheumatic neutrophilic dermatosis, familial Mediterranean fever, erythema, Schnitzler syndrome, gut-associated dermatosis-arthritis syndrome (BADAS), SAPHO (synovitis, acne, pustulosis, osteoporosis, and osteitis), cryopyrin-related disorders, and gout.

[0025] In some embodiments, compounds of formula I are used to treat hidradenitis suppurativa (HS).

[0026] Certain subgroups of subjects may respond remarkably well to treatment with the compound of formula I. For example, in some embodiments, women responded significantly better to treatment than men. In some embodiments, younger subjects (e.g., under 50 years of age) responded significantly better to treatment than older subjects (e.g., 51 years of age or older). In some embodiments, subjects diagnosed with stage III Hurley disease hidradenitis suppurativa responded significantly better than subjects with less severe forms. In some embodiments, subjects who had previously received anti-TNF-α drugs (e.g., adalimumab or infliximab) responded remarkably better than subjects who had not previously received anti-TNF-α drugs. In some embodiments, subjects being treated concomitantly with antibiotic therapy (e.g., doxycycline or minocycline) responded remarkably better than subjects not being treated concomitantly with antibiotic therapy. In each of the above embodiments, further embodiments are embodiments in which avacopan is administered as the compound of formula I in either a dose of 10 mg twice daily or 30 mg twice daily.

[0027] In some embodiments, subjects diagnosed with stage III Hurley disease hidradenitis suppurativa responded significantly better than subjects with less severe forms. In some embodiments, subjects who had previously received anti-TNF-α drugs (e.g., adalimumab or infliximab) responded remarkably better than subjects who had not previously received anti-TNF-α drugs. In each of these embodiments, the treatment is effective when avacopan is administered at a dose of 30 mg twice daily.

[0028] When comparing subgroups of patients, various clinically defined metrics can be used. For example, significant improvement can be measured by the following metrics: count of abscesses and inflammatory nodules (ANs), patient-reported global skin pain score (NRS), percentage of patients experiencing relapse during treatment, percentage of patients receiving oral antibiotic rescue therapy or intra-focal rescue injection of Kenalog®, change in the modified Sartorius score, change in the IHS4 score, change in the Physician Global Assessment (HS-PGA) for hidradenitis suppurativa, change in the Hidradenitis Suppurativa Burden of Disease (HSBOD) score, change in the Cardiff Dermatology LifeQuality Index or DLQI questionnaire, achieving a Hidradenitis Suppurativa Clinical Response (HiSCR), and completing the Work Productivity and Activity Impairment Questionnaire: Specific Health Changes in Problem (WPAI:SHP) (HiSCR is defined as a decrease of at least 50% in the count of abscesses and inflammatory nodules (ANs), with no increase in the abscess count and no increase in the count of purulent fistulas) can be detected by measuring one or more of these.

[0029] When measured by counting abscesses and inflammatory nodules (ANs), populations with a significantly better response to treatment include populations where the proportion of individuals achieving a reduction in AN counts is at least 5, 10, 15, 20, or 25% higher than the proportion of individuals not included in the defined population.

[0030] When measured by the Numerical Rating Scale (NRS), a population of subjects with a significantly better response to treatment includes a population where the proportion of subjects achieving at least a 30% reduction in patient-assigned Numerical Rating Scale (NRS) is at least 5, 10, 15, 20, or 25% higher than the proportion of subjects not included in the defined population size. For NRS30 analysis, the weekly average of the worst-case Numerical Rating Scale (NRS), recorded in a diary every 24 hours for each subject, is calculated at each relevant trial visit.

[0031] When measured by the proportion of subjects who experienced relapse during treatment, a population of subjects with a significantly better response to treatment includes a population where the proportion of individuals who do not experience relapse while receiving treatment is at least 5, 10, 15, 20, or 25% higher than the proportion of subjects who do not fall within the defined population size.

[0032] When measured by the proportion of subjects who received oral antibiotic rescue therapy or intra-focal rescue injection of Kenalog®, a population of subjects with a significantly better response to treatment includes a population where the proportion of individuals receiving treatment but not oral antibiotic rescue therapy is at least 5, 10, 15, 20, or 25% higher than the proportion of subjects that do not fall within the defined population.

[0033] When measured by changes in the modified Sartorius score, populations of subjects that respond significantly better to treatment include those in which the proportion of subjects achieving a reduction of at least 4 or 5 points in the modified Sartorius score is at least 5, 10, 15, 20, or 25% more than the proportion of subjects that do not fall within the defined population size.

[0034] When measured by change in the IHS4 score, a population of subjects with a significantly better response to treatment includes a population in which the proportion of subjects achieving at least a 4 or 5-point reduction in their IHS4 score is at least 5, 10, 15, 20, or 25% greater than the proportion of subjects not included in the defined population. In some embodiments, subjects with Hurley stage III hidradenitis suppurativa respond significantly better to treatment than subjects without Hurley stage III hidradenitis suppurativa. In some embodiments, the proportion of subjects with Hurley stage III hidradenitis suppurativa achieving at least a 4 or 5-point reduction in their IHS4 score after 12 weeks of treatment compared to baseline is at least 10% greater than the proportion of subjects without Hurley stage III hidradenitis suppurativa. In some embodiments, the proportion of subjects with Hurley stage III hidradenitis suppurativa achieving at least a 4 or 5-point reduction in their IHS4 score after 12 weeks of treatment compared to baseline is at least 15% greater than the proportion of subjects without Hurley stage III hidradenitis suppurativa. In some embodiments, the proportion of subjects with Hurley stage III hidradenitis suppurativa achieving a reduction of at least 4 or 5 points in the subject's IHS4 score after 12 weeks of treatment compared to baseline is at least 20% greater than the proportion of subjects without Hurley stage III hidradenitis suppurativa.

[0035] When measured by changes in HS-PGA scores, populations of subjects that respond significantly better to treatment include those in which the proportion of subjects achieving a reduction of at least 2 or 3 points in their HS-PGA score is at least 5, 10, 15, 20, or 25% more than the proportion of subjects that do not fall within the defined population size.

[0036] When measured by changes in the HSBOD score, a population of subjects that respond significantly better to treatment includes a population in which the proportion of subjects achieving a reduction of at least 2 or 3 points in their HSBOD score is at least 5, 10, 15, 20, or 25% more than the proportion of subjects that do not fall within the defined population size.

[0037] When measured by changes in DLQI questionnaire scores, populations of subjects with significantly better response to treatment include those in which the proportion of subjects achieving a reduction of at least 4 or 5 points in their DLQI questionnaire score is at least 5, 10, 15, 20, or 25% more than the proportion of subjects not included in the defined population size.

[0038] When measured by the Work Productivity and Activity Impairment Questionnaire (WPAI:SHP), populations with significantly better response to treatment include those in which the proportion of subjects achieving at least a 15% reduction in WPAI:SHP is at least 5, 10, 15, 20, or 25% greater than the proportion of subjects not included in the defined population.

[0039] When measured by the HiSCR (High-Intensity Surgical Response), a population of subjects with a significantly better response to treatment includes a population where the proportion of individuals achieving HiSCR is at least 5, 10, 15, 20, or 25% higher than the proportion of subjects that do not fall within the defined population. In some embodiments, subjects with Hurley stage III hidradenitis suppurativa respond significantly better to treatment than subjects without Hurley stage III hidradenitis suppurativa. In some embodiments, subjects with Hurley stage III hidradenitis suppurativa respond significantly better to treatment than subjects without Hurley stage III hidradenitis suppurativa. In some embodiments, the proportion of subjects with Hurley stage III hidradenitis suppurativa achieving HiSCR after 12 weeks of treatment compared to baseline is at least 10% greater than the proportion of subjects without Hurley stage III hidradenitis suppurativa. In some embodiments, the proportion of subjects with Hurley stage III hidradenitis suppurativa achieving HiSCR after 12 weeks of treatment compared to baseline is at least 15% greater than the proportion of subjects without Hurley stage III hidradenitis suppurativa. In some embodiments, the proportion of subjects with Hurley stage III hidradenitis suppurativa achieving HiSCR after 12 weeks of treatment compared to baseline is at least 20% greater than the proportion of subjects without Hurley stage III hidradenitis suppurativa.

[0040] The clinical changes observed in a group or subgroup may vary depending on the time frame of comparison. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 2. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 4. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 8. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 12. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 16. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 20. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 24. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 28. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 32. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 36. In some embodiments, the comparisons in each of the above paragraphs are for changes from day 1 to week 44.

[0041] The therapeutically effective dose will depend on various factors, including the activity of the specific compound used, the disease being treated, and, in some embodiments, specific characteristics of the individual being treated. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 5 to 200 mg. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 10 to 150 mg. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 15 to 100 mg. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 20 to 60 mg. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 60 mg. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 50 mg. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 40 mg. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 30 mg. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 20 mg.

[0042] The therapeutically effective amount can also be expressed as the steady-state average plasma concentration. For example, in some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 50 ng / mL to 400 ng / mL. In some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 150 ng / mL to 250 ng / mL. In some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 175 ng / mL to 225 ng / mL. In some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 50 ng / mL to 90 ng / mL. In some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 60 ng / mL to 70 ng / mL. In some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 195 ng / mL. In some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 205 ng / mL. In some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 215 ng / mL. In some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 60 ng / mL. In some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 65 ng / mL. In some embodiments, the compound of Formula I at a therapeutically effective amount achieves and maintains a steady-state average plasma concentration of about 70 ng / mL.

[0043] B. Compound of Formula I The compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure [Chemical Structure] [wherein, each R 1 is independently selected from the group consisting of CH3, CF3, CH2CH3, Cl, 1-pyrrolidine, -O-CH(CH3)2, and CH2OH, each R 2 is independently selected from the group consisting of CH3 and F] and has the following structure.

[0044] In some embodiments, the compound of formula I is formula [ka] [ka] or have pharmaceutically acceptable salts thereof.

[0045] In some embodiments, the compound of formula I is formula [ka] or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the compound of formula I is formula [ka] Abacopan or a pharmaceutically acceptable salt thereof having [a specific compound].

[0047] The compounds of formula (I) described herein can be obtained by following the methods described in International Publication No. 2010 / 075257, International Publication No. 2011 / 163640, and International Publication No. 2016 / 053890, the contents of which are incorporated herein by reference for all purposes. In some embodiments, the compound of formula (I) is a compound described in one of these references.

[0048] C. Administration Method Generally, the treatment methods provided herein include the step of administering an effective amount of a compound to a patient at a specific dose and timing to effectively treat hidradenitis suppurativa (HS) or neutrophilic inflammatory disorders of the skin. In some embodiments, the compound is administered orally to the subject (e.g., a human). The treatment plan may vary depending on the compound used and the route of administration, but a frequency of administration of four times a day or less is preferred. In some embodiments, a twice-daily administration plan is used. In some embodiments, a once-daily administration plan is used.

[0049] The duration of treatment for an individual will depend on the disease being treated, as well as various factors including age, weight, overall health, sex, diet, and the timing and route of compound administration. In some embodiments, subjects receive treatment for 12 weeks. In some embodiments, subjects receive treatment for 26 weeks. In some embodiments, subjects receive treatment for 52 weeks. In some embodiments, subjects receive long-term treatment.

[0050] In some embodiments, the subject is orally administered 10 mg of abacopan twice daily for a total daily dose of 20 mg.

[0051] In some embodiments, the subject is orally administered 15 mg of avacopan twice daily for a total daily dose of 30 mg.

[0052] In some embodiments, the subject is orally administered 20 mg of avacopan twice daily for a total daily dose of 40 mg.

[0053] In some embodiments, the subject is orally administered 25 mg of abacopan twice daily for a total daily dose of 50 mg.

[0054] In some embodiments, the subject is orally administered 30 mg of abacopan twice daily for a total daily dose of 60 mg.

[0055] In some embodiments, therapeutically effective dose

[0056] D. Formula I solid solution capsule formulation In some embodiments, the methods described herein involve abacopan as a free base, either in a neutral form or in the form of a pharmaceutically acceptable salt. [ka] and, At least one nonionic surfactant having a hydrophilic-lipophilic balance (HLB) value of at least 10, and At least one water-soluble solubilizing agent having a melting point of 37°C or higher. Vehicles including A solid solution capsule formulation containing [the specified ingredient] is used.

[0057] Typically, suitable nonionic surfactants having an HLB value of at least 10 include (a) polyoxyethylene castor oil derivatives and (b) polyoxyethylene derivatives of polyol esters, in which case the polyoxyethylene derivative of the polyol ester is derived from a fatty acid containing about 8 to about 22 carbon atoms. The carbon atoms of the fatty acid may contain one or more unsaturated sites or one or more substitution sites (e.g., ricinoleic acid).

[0058] In some embodiments, a suitable nonionic surfactant having an HLB value of at least 10 is a macrogol-glycerol hydroxystearate polymer, for example, polyoxyethylene 40 castor oil, polyoxyethylene 40 hydrogenated castor oil (also known as macrogol-40-glycerol hydroxystearate, formerly known as Cremophor® RH40, and currently known as Kolliphor® RH40), macrogol glycerol ricinoleate (also known as polyethoxyethylene 35 castor oil, formerly known as Cremophor® EL, and currently known as Kolliphor® EL), macrogol-15-hydroxystearate (formerly known as Solutol® HS 15 and currently known as Kolliphor These include polyoxyethylene 60 castor oil (also known as HS15), polyoxyethylene 60 hydrogenated castor oil, polyoxyethylene 100 hydrogenated castor oil, polyoxyethylene 200 castor oil, and polyoxyethylene 200 hydrogenated castor oil.

[0059] A suitable water-soluble solubilizer having a melting point of 37°C or higher can be polyethylene glycol (PEG) having a minimum average molecular weight of 1,000 and a maximum average molecular weight of 20,000. Typical polyethylene glycols used as solubilizers in the present invention are PEG-1000, PEG-1500, PEG-1540, PEG-2000, PEG-3000, PEG-3350, PEG-4000, PEG-6000, PEG-8000, PEG-10000, and PEG-20000. In some embodiments, at least one water-soluble solubilizer is PEG-3000, PEG-3350, PEG-4000, or PEG-6000. In some embodiments, at least one water-soluble solubilizer is PEG-4000.

[0060] Suitable water-soluble solubilizers with a melting point of 37°C or higher include poloxamer polyols having an average molecular weight between 6,000 and 18,000, also known by their trademark name Pluronics®, with the formula HO(C2H4O).a (C3H6O) b (C2H4O) a There are also solid poloxamers that contain H. Suitable examples of poloxamers include poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407.

[0061] In certain embodiments, the single component comprises at least one nonionic surfactant having a hydrophilic-lipophilic balance (HLB) value of at least 10, and at least one water-soluble solubilizer having a melting point of 37°C or higher. Such a component includes a hydrophilic polyethylene glycol (PEG) chain (e.g., macrogol-glycerol hydroxystearate) bonded to a lipophilic fatty acid or aliphatic alcohol component. The longer the PEG chain length, i.e., the higher the HLB value, the more readily dissociates between the PEG chain and the lipophilic component. Such a single-component vehicle provides a nonionic surfactant having at least 10 HLB values ​​and a free PEG polymer chain acting as a water-soluble solubilizer.

[0062] While we do not wish to be bound by any particular theory, a capsule formulation containing a nonionic surfactant with an HLB value of at least 10 and a water-soluble solubilizer with a melting point of 37°C or higher is considered to be a so-called self-emulsifying or self-solubilizing system. Upon oral administration, the capsule shell dissolves in the gastrointestinal tract, and then the solubilizer dissolves in the gastric juice, simultaneously forming micelles containing molecularly dissolved abacopan. In this way, a microemulsion or nanoemulsion is formed that allows abacopan to remain dissolved despite being surrounded by gastric juice with a pH value of 3 or higher (at which abacopan is normally insoluble).

[0063] In some embodiments, the solid solution capsule formulation comprises abacopan as a free base, either in a neutral form or in the form of a pharmaceutically acceptable salt, and a vehicle containing macrogol-40-glycerol hydroxystearate and PEG-4000.

[0064] In some embodiments, the vehicle accounts for approximately 97-99% by weight of the total filling weight of the solid solution capsules. In some embodiments, the vehicle accounts for approximately 98% by weight of the total filling weight of the solid solution capsules.

[0065] In some embodiments, the solid solution capsule contains about 1 to 3% by weight of abacopan based on the total filling weight of the solid solution capsule. In some embodiments, the solid solution capsule contains about 1 to 2.8% by weight of abacopan based on the total filling weight of the solid solution capsule. In some embodiments, the solid solution capsule contains about 2% by weight of abacopan based on the total filling weight of the solid solution capsule.

[0066] In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of 30:70 to 65:35, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 30:70 to 65:35. In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of 35:65 to 65:35, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 35:65 to 65:35. In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of 45:55 to 55:45, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 45:55 to 55:45. In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of about 50:50, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 50:50. In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of about 40:60, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 40:60.In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of about 30:70, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 30:70.

[0067] In some embodiments, the total filling weight of the solid solution capsule is approximately 100 mg to approximately 1,000 mg. In some embodiments, the total filling weight of the solid solution capsule is approximately 130 mg to approximately 900 mg. In some embodiments, the total filling weight of the solid solution capsule is approximately 250 mg to approximately 750 mg. In some embodiments, the total filling weight of the solid solution capsule is approximately 500 mg.

[0068] In some embodiments, the solid solution capsule does not contain ethanol.

[0069] In some embodiments, the solid solution capsule is contained within a capsule of size #00, #0, #1, #2, #3, #4, or #5. In some embodiments, the solid solution capsule is contained within a capsule of size #00. In some embodiments, the solid solution capsule is contained within a capsule of size #0. In some embodiments, the solid solution capsule is contained within a capsule of size #1.

[0070] In some embodiments, the capsule is a hard capsule. In some embodiments, the capsule is a soft capsule.

[0071] The capsules disclosed herein can be sealed using techniques known in the art. For example, the capsules disclosed herein can be sealed using a gelatin sealing band containing a plasticizer such as polysorbate 80.

[0072] E. Method for preparing solid solution capsules of formula I The solid solution capsule formulations described herein are manufactured by filling hard-shell capsules with a heated drug solution. After filling the capsules with the heated drug solution, the solution solidifies to form an amorphous matrix.

[0073] In some embodiments, abacopan as a free base, either in a neutral form or in the form of a pharmaceutically acceptable salt. [ka] and, At least one nonionic surfactant having a hydrophilic-lipophilic balance (HLB) value of at least 10, and At least one water-soluble solubilizing agent having a melting point of 37°C or higher. Vehicles including A method for preparing a solid solution capsule containing, (a) A step of melting the vehicle, (b) A step in which the molten vehicle obtained in step (a) is combined with abacopan to form a drug solution, (c) The step of encapsulating the drug solution in a capsule shell, (d) Cooling the encapsulated drug solution to form a solid solution capsule containing abacopan. Methods including the above are provided herein.

[0074] The melting of the vehicle is achieved using standard techniques in the art. The melting temperature will depend on the characteristics of the vehicle. Typical melting techniques include direct heating ovens and jacketed mixing tanks. In some embodiments, the vehicle in step (a) is heated to about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90°C or higher. In some embodiments, the vehicle in step (a) is heated to about 50°C to 85°C. In some embodiments, the vehicle in step (a) is heated to about 50°C. In some embodiments, the vehicle in step (a) is heated to about 60°C. In some embodiments, the vehicle in step (a) is heated to about 70°C. In some embodiments, the vehicle in step (a) is heated to about 80°C.

[0075] In some embodiments, step (a) is (i) A step of heating at least one nonionic surfactant having an HLB value of at least 10 to form a molten surfactant, (ii) The step of heating at least one water-soluble solubilizer to form a molten solubilizer, and (iii) A step of combining the melted solubilizer with the melted surfactant to form a melted vehicle. Includes.

[0076] As stated above, the melting in step (a) can be carried out using standard heating techniques in the art. This also applies to steps (i) and (ii). In some embodiments, the heating temperatures in steps (i) and (ii) are the same. In some embodiments, the heating temperatures in steps (i) and (ii) are different.

[0077] In some embodiments, the at least one nonionic surfactant having an HLB value of at least 10 in step (i) is heated to about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90°C or higher. In some embodiments, the at least one nonionic surfactant having an HLB value of at least 10 in step (i) is heated to about 50°C to 85°C. In some embodiments, the at least one nonionic surfactant having an HLB value of at least 10 in step (i) is heated to about 50°C to 70°C. In some embodiments, the at least one nonionic surfactant having an HLB value of at least 10 in step (i) is heated to about 50°C. In some embodiments, the at least one nonionic surfactant having an HLB value of at least 10 in step (i) is heated to about 60°C. In some embodiments, the at least one nonionic surfactant having an HLB value of at least 10 in step (i) is heated to about 70°C. In some embodiments, at least one nonionic surfactant having an HLB value of at least 10 in step (i) is heated to about 80°C.

[0078] In some embodiments, at least one water-soluble solubilizer in step (ii) is heated to about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90°C or higher. In some embodiments, at least one water-soluble solubilizer in step (ii) is heated to about 50°C to 90°C. In some embodiments, at least one water-soluble solubilizer in step (ii) is heated to about 80°C to 85°C. In some embodiments, at least one water-soluble solubilizer in step (ii) is heated to about 50°C. In some embodiments, at least one water-soluble solubilizer in step (ii) is heated to about 60°C. In some embodiments, at least one water-soluble solubilizer in step (ii) is heated to about 70°C. In some embodiments, at least one water-soluble solubilizer in step (ii) is heated to about 80°C.

[0079] In some embodiments, the at least one nonionic surfactant having an HLB value of at least 10 in step (i) is heated to about 50-70°C, and the at least one water-soluble solubilizer in step (ii) is heated to about 80-85°C. In some embodiments, the at least one nonionic surfactant having an HLB value of at least 10 in step (i) is heated to about 60°C, and the at least one water-soluble solubilizer in step (ii) is heated to about 80°C.

[0080] After performing steps (i) and (ii), the melted solubilizer may have a temperature adjusted to be within the temperature tolerance range of the capsule shell. For example, the temperature tolerance of a gelatin capsule shell is about 65°C. Different capsule shells may have different temperature tolerances, and those skilled in the art will readily determine the appropriate temperature based on the capsule shell being used.

[0081] When bringing a molten solubilizer into contact with a molten surfactant, stirring is generally applied to ensure mixing of the molten surfactant and molten solubilizer. Typically, stirring is used. The stirring / stirring time will vary depending on the components of the molten surfactant and molten solubilizer, the size of the preparation, and the heating temperature used. In some embodiments, stirring is performed for 0.25, 0.5, 0.75, 1, or 2 hours or more. Stirring can be performed under reduced pressure during this step to prepare the solution.

[0082] Returning to step (b), in step (b), the molten vehicle is brought into contact with abacopan, whereupon the drug dissolves in the heated vehicle. Dissolution of abacopan can be achieved by several techniques, including waiting for a suitable length of time or stirring the solution to increase the dissolution rate. In some embodiments, the heated vehicle and abacopan in step (b) are stirred by agitation. The stirring time can be between 1 and 6 hours or longer. In some embodiments, the stirring time is 1, 2, 3, 4, 5, or 6 hours or longer. In some embodiments, the stirring time is about 3.5 hours.

[0083] The encapsulation of drug solutions is carried out using techniques known in the art. One machine useful for such encapsulation is the Shionogi F40 filling machine. Those skilled in the art are aware of further uniform machines.

[0084] There are several means known in the art for cooling a desired substance. The cooling in step (d) described may include passive activities such as equilibrating the encapsulated drug solution to room temperature, or more active steps such as placing the encapsulated drug solution in a cooled location to increase the cooling rate.

[0085] Those skilled in the art will understand that, in order to prepare solid solution capsules containing abacopan, each of the above steps does not need to be performed in the order described. For example, abacopan can be dissolved in a heated vehicle (step (b)) to form a drug mixture, and then the drug mixture can be cooled to form a solid solution. As described above, cooling may involve passive activities such as equilibrating the encapsulated drug solution to room temperature, or more active steps such as placing the encapsulated drug solution in a cooled location to increase the cooling rate.

[0086] In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of 30:70 to 65:35, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 30:70 to 65:35. In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of 35:65 to 65:35, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 35:65 to 65:35. In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of 45:55 to 55:45, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 45:55 to 55:45. In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of about 50:50, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 50:50. In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of about 40:60, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 40:60.In some embodiments, the total weight of the vehicle includes at least one nonionic surfactant having an HLB value of at least 10 in a ratio of about 30:70, and at least one water-soluble solubilizer having a melting point of 37°C or higher. In preferred embodiments, the ratio of macrogol-40-glycerol hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 30:70. [Examples]

[0087] The following examples are provided to illustrate, but not to limit, the claimed invention.

[0088] Example 1 - Phase 2 Clinical Trial The study is a randomized, double-blind, placebo-controlled, three-group phase 2 trial involving approximately 390 patients with moderate to severe hidradenitis suppurativa (Hurley stage II or III). Patients will be randomized in a 1:1:1 ratio to receive 10 mg of avacopan twice daily, 30 mg of avacopan twice daily, or placebo for 12 weeks. Other systemic treatments for HS, including anti-TNF-α treatment, are prohibited. Stable antibiotic treatment with doxycycline or minocycline is permitted as specified in the protocol. Patients treated with 10 mg or 30 mg twice daily during the blinded, placebo-controlled 12-week treatment period will then have a further 24-week active drug treatment period during which they will continue to receive 10 mg or 30 mg of avacopan twice daily on the same dose regimen. Placebo participants who complete the blinded, placebo-controlled 12-week period will be re-randomized in a 1:1 ratio to receive either 10 mg or 30 mg of avacopan twice daily during a 24-week active drug treatment period. During the 24-week active drug treatment period, the allocation to 10 mg or 30 mg twice daily will not be disclosed to patients, site investigators, or the sponsor. All participants will then be followed for 8 weeks without the study drug, after which the study will be terminated.

[0089] Trial intervention / method Eligible adult subjects (at least 18 years of age) with moderate to severe hidradenitis suppurativa (Hurley stage II or III) as specified by the eligibility criteria will be permitted to enter the study.

[0090] Participants will be randomized in a 1:1:1 ratio to receive either 10 mg of avacopan twice daily, 30 mg of avacopan twice daily, or an equivalent dose of placebo for 12 weeks in a double-blind, placebo-controlled manner.

[0091] To balance treatment groups, a stratified randomization scheme is implemented. The stratification factors and strata within each factor are listed below. Eligible subjects are randomized with equal probability (i.e., 1:1:1) to one of three treatment groups within each strata, based on a non-dynamic, list-based block randomization scheme. 1. Hurley disease stage (stage II vs III): a. Stage II disease: One or more widely separated, recurrent abscesses with sinus formation and scarring, or b. Stage III disease: Multiple interconnected sinuses and abscesses throughout the entire area, diffuse or nearly diffuse lesions. 2. Concomitant antibiotic treatment (applicable vs. not applicable) a. The only permitted antibiotic treatment for HS is concomitant treatment with doxycycline or minocycline, or b. Do not receive concomitant antibiotic treatment. 3. Anti-TNF-α treatment (no treatment vs. previous treatment): a. Not having previously received anti-TNF-α drugs such as adalimumab or infliximab (untreated with anti-TNF-α drugs), or b. Previously received anti-TNF-α medication (but not currently receiving it), and • Although anti-TNF-α treatment has been completed, there is a possibility of relapse, or • Intolerance to anti-TNF-α treatment, or • Previously, the patient did not respond to anti-TNF-α treatment, or the response was inadequate.

[0092] Less than 20% of the target group is included in layer 2a.

[0093] Eligible subjects are randomized with equal probability (i.e., 1:1:1) to one of three treatment groups within each stratum, based on a non-dynamic, list-based block randomization scheme. 1) Placebo twice a day 2) Avacopan 10 mg twice daily 3) Avacopan 30 mg twice daily

[0094] Participants will be screened for eligibility based on disease stage and health status. The screening period will be up to 28 days. The primary efficacy analysis will be performed when the last enrolled participant completes their 12-week visit. After a blinded 12-week treatment period, all participants will continue treatment for another 24 weeks with either 10 mg or 30 mg of avacopan twice daily. The treatment assignment of 10 mg or 30 mg twice daily will not be disclosed to patients, site investigators, or the sponsor. All participants will then be followed up for 8 weeks.

[0095] All subjects will visit the study site during a 28-day screening period, and, if eligible, on day 1 of the study and at weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 44. The study drug will be distributed at the study site, and subjects will take their initial dose of the study drug, i.e., avacopan or an equivalent dose of placebo, while at the study site. Following the initial dose, subjects will take the study drug twice daily for 12 weeks (84 days). After that, all subjects will take the avacopan study drug for 24 weeks (168 days), and then all subjects will be followed up for 8 weeks (56 days) without taking the study drug.

[0096] The trial will be stopped once all procedures for patient visits at week 44 have been completed.

[0097] Subjects experiencing a relapse of HS during the study will be treated by the study physician, and this treatment may include antibiotic rescue treatment with doxycycline or minocycline for up to one week, or intra-focal rescue injection of Kenalog® (triamcinolone acetonide, maximum total dose of 10 mg per subject for up to one week). Such subjects will be asked to remain in the study and complete all study procedures, if possible. During this period, subjects may continue to receive the study drug as directed, if clinically assessed by the study physician as possible.

[0098] Test drug, dosage, and administration method Participants in the study will receive either an active avacopan capsule or a placebo capsule as the study drug. The study drug consists of a hard gelatin capsule containing 10 mg of avacopan or placebo, administered orally. The avacopan and placebo vials and capsules are identical in appearance.

[0099] Participants are required to take three capsules of the test drug orally with water, preferably with food, every morning, and three capsules with water, preferably with food, every evening, approximately 12 hours after the morning dose, as instructed. The test drug will be taken continuously for 36 weeks (252 days).

[0100] The test scheme is shown in Figure 1.

[0101] Main purpose The primary objectives of this clinical trial include: 1. Assessment of the efficacy of avacopan compared to placebo in subjects with Hurley stage II or III hidradenitis suppurativa (HS) who achieved a HiSCR (High-Level Clinical Response) after 12 weeks of treatment. HiSCR is defined as a reduction of at least 50% in the count of abscesses and inflammatory nodules (ANs) at 12 weeks compared to baseline, with no increase in the count of abscesses and no increase in the count of suppurating fistulas. 2. Assessment of the safety of avacopan compared to placebo, based on the incidence of adverse events, laboratory parameters, and changes from baseline in vital signs in these subjects.

[0102] Secondary purpose The secondary objectives of this study include the following: 1. The assessment of the effectiveness of avacopan compared to placebo in these subjects includes the following: a. HiSCR: The percentage of subjects that achieved HiSCR at each time point. b. Numerical Rating Scale (NRS) for the overall assessment of skin pain by the patient. c. Modified Sartorius score, and d. Achieve a count of AN 0, 1, or 2. 2. Evaluation of results reported by subjects, including changes in health-related quality of life with avacopan compared to placebo, based on Short Form-36 version 2 (SF-36 v2), EuroQOL-5D-5L (EQ-5D-5L), Hidradenitis Suppurativa Quality of Life (HiSQOL) Index, Dermatology Life Quality Index (DLQI), and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problems (WPAI:SHP). 3. Assessment of the pharmacokinetic profile of abacopan in subjects with HS. 4. Assessment of the safety and efficacy of avacopan treatment at each time point from day 1 to week 44 in subjects with HS. 5. Assessment of the effectiveness of avacopan compared to placebo in these subjects includes the following: a. Sartorius score, International HS Severity Scoring System (IHS4) score, HS Physician Global Assessment (HS-PGA), b. The proportion of subjects who experienced relapse, subjects who experienced a loss of response during the second phase, subjects who received oral antibiotic rescue treatment or lesion intervention, and subjects who received unapproved opioid pain treatment, and c. Duration of relapse (in days). 6. Assessment of health economic information.

[0103] Test treatment The treatment for each group is shown in Table 1.

[0104] The treatment period is 36 weeks (252 days) followed by an 8-week (56-day) follow-up period without administration of the study drug. Participants are randomized 1:1:1 for the first 12 weeks to receive placebo, 10 mg avacopan, or 30 mg avacopan as a bid for blinded, placebo-controlled treatment. Participants randomized to 10 mg or 30 mg avacopan continue with the same drug dosing regimen for the next 24 weeks of active drug treatment. Participants randomized to placebo during the first 12 weeks are re-randomized to receive either 10 mg or 30 mg avacopan as a bid for the 24 weeks of active drug treatment. A drug kit specific to the treatment group is distributed at the time of the relevant trial visit.

[0105] [Table 1]

[0106] Exam Flow Participants will be screened for eligibility based on disease stage and health status. The screening period will be up to 28 days. The primary efficacy analysis can be performed when the last enrolled participant completes their 12-week visit. After a blinded, placebo-controlled 12-week treatment period, all participants will continue with 24 weeks of active drug treatment: 10 mg of avacopan twice daily or 30 mg of avacopan twice daily. After 36 weeks, all participants will be followed for 8 weeks without receiving the study drug.

[0107] All subjects will visit the study site during the 28-day screening period, and, if eligible, on day 1 of the study and at weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 44. The study drug will be distributed at the study site, and subjects will take their initial dose of the study drug, i.e., avacopan or an equivalent dose of placebo, while at the study site. Preferably, subjects should take their dose while at the site on each visit day. Following the initial dose, subjects will take the study drug twice daily for 12 weeks (84 days). Subsequently, all subjects will take the avacopan study drug for 24 weeks (168 days), and then all subjects will be followed up for 8 weeks (56 days) without taking the study drug.

[0108] The trial will end when all procedures for the 44th week of the trial are completed.

[0109] Subjects experiencing a relapse of HS during the study will be treated by the study physician, and this treatment may include antibiotic rescue treatment with doxycycline or minocycline for up to one week, or intra-lesional rescue injection of Kenalog® (triamcinolone acetonide, up to a total dose of 10 mg per subject for up to one week). Such subjects will be asked to remain in the study and complete all study procedures, if possible. During this period, subjects may continue to receive the study drug if the study physician deems it clinically possible.

[0110] Product Characteristics The test drug consists of a hard gelatin capsule containing 10 mg of avacopan or placebo for oral administration. The vials and capsules of avacopan and placebo are identical in appearance. The capsules are manufactured under current Good Manufacturing Practices.

[0111] Dosage and administration plan Participants are required to take three capsules of the test drug orally with water, preferably with food, every morning, and three capsules with water, preferably with food, every evening, approximately 12 hours after the morning dose, as instructed. The test drug will be taken continuously for 36 weeks (252 days).

[0112] For the purpose of managing the test drug, participants are required to bring all test drug vials, whether empty or not, to the test facility each time they visit the clinic for the trial.

[0113] If you forget to take a dose, you should take the missed dose as soon as possible. If it is close to the next scheduled dose (within 3 hours), you should not take the missed dose, but instead take the next dose at the scheduled time.

[0114] On each trial visit day, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site.

[0115] Test Procedure Day 1 of the exam If eligible for the study, participants will visit the study site on day 1. The following steps will be performed before taking the first dose of the study drug. • Stratification and randomization in IRT systems • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. Blood samples are collected for serum biochemical tests, hematological tests, and serum pregnancy tests (for women of potential pregnancy). A urine sample is collected for a urine test. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS, as well as the Hurley stage of HS, are recorded. • Adherence to daily recording of skin pain in a journal will be checked, and corrective measures will be taken if necessary. • Items related to modified Sartorius scores are collected. • The IHS4 score is calculated. The target group is those who are asked to complete the SF-36 v2, EQ-5D-5L, and HiSQOL Index forms. The physician administering the examination will fill in the HS-PGA form. • Adherence to daily recording of skin pain in a journal, which began one week prior to Day 1, will be checked, and retraining will be provided if necessary. • All pre-treatment adverse events (from the time of the screening visit) are recorded.

[0116] The following steps will then be performed. • The test drug is supplied to the subjects along with instructions for administration. • Participants are required to take the initial dose of the test drug while they are at the testing facility. • The time at which the test drug was administered is recorded. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events after administration are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain and the administration of the test drug in a log. - Coming to the testing facility for the second week of the trial. - During the test period, store the test reagent in a cool, dry place according to the label instructions. - Take the test drug as instructed. On each day of the trial visit, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site, and - Continue taking all other medications you are taking as usual.

[0117] Second week of exams (Day 15) The visit during the second week of the trial must take place within ±2 days of the designated date. During this visit, the following trial procedures will be performed. • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. Blood samples are collected for transmission to a central laboratory for serum biochemical tests, hematological tests, and PK measurements, and the date and time of PK sample collection are recorded. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS are recorded. Adherence to daily recording of skin pain and drug administration in a log will be checked, and retraining will be provided if necessary. • Items related to modified Sartorius scores are collected. • The IHS4 score is calculated. The physician administering the examination will fill in the HS-PGA form. • The date and time of the most recent administration of the test drug prior to the collection of the PK sample are recorded. If the subject has not yet taken the morning dose of the study drug for that day, the subject will be asked to take that dose. • The test drug vial is checked to confirm that the subject is taking the test drug as instructed. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain and the administration of the test drug in a log. - Coming to the trial facility for the fourth week trial visit. - During the test period, store the test reagent in a cool, dry place according to the label instructions. - Take the test drug as instructed. On each day of the trial visit, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site, and - Continue taking all other medications you are taking as usual.

[0118] Week 4 of the exam (Day 29) The visit for the fourth week of the trial must be made within ±2 days of the designated date. During this visit, the following trial procedures will be performed. • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. Blood samples are collected for serum biochemical tests, hematological tests, serum pregnancy tests (for women of potential pregnancy), and PK measurements, and the date and time of PK sample collection are recorded. • The date and time of the most recent administration of the test drug prior to the collection of the PK sample are recorded. If the subject has not yet taken the morning dose of the study drug for that day, the subject will be asked to take that dose. A urine sample is collected for a urine test. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS are recorded. Adherence to daily recording of skin pain and administration of test drugs in a log will be checked, and retraining will be provided if necessary. • Items related to modified Sartorius scores are collected. • The IHS4 score is calculated. The physician administering the examination will fill in the HS-PGA form. The target group is those who are asked to complete the SF-36 v2, EQ-5D-5L, and HiSQOL Index forms. • Drug management will be carried out for returned vials of test drugs. • The test drug is distributed. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain and the administration of the test drug in a log. - Arrive at the trial facility for the 8th week trial visit. - During the test period, store the test reagent in a cool, dry place according to the label instructions. - Take the test drug as instructed. On each day of the trial visit, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site, and - Continue taking all other medications you are taking as usual.

[0119] Week 8 of the exam (Day 57) The visit in week 8 of the trial must take place within ±2 days of the designated date. During this visit, the following trial procedures will be performed. • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. Blood samples are collected for serum biochemical tests, hematological tests, serum pregnancy tests (for women of potential pregnancy), and PK measurements, and the date and time of PK sample collection are recorded. • The date and time of the most recent administration of the test drug prior to the collection of the PK sample are recorded. If the subject has not yet taken the morning dose of the study drug for that day, the subject will be asked to take that dose. A urine sample is collected for a urine test. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS are recorded. • Adherence to daily recording of pain and investigational drug administration in a log will be checked, and retraining will be provided if necessary. • Items related to modified Sartorius scores are collected. • The IHS4 score is calculated. The physician administering the examination will fill in the HS-PGA form. • The test drug vials are checked to ensure that drug management is being performed and that the subjects are taking the test drug as instructed. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain and the administration of the test drug in a log. - Arrive at the trial site for the 12th week trial visit. - During the test period, store the test reagent in a cool, dry place according to the label instructions. - Take the test drug as instructed. On each day of the trial visit, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site, and - Continue taking all other medications you are taking as usual.

[0120] Week 12 of the exam (Day 85) The visit for week 12 of the trial must take place within ±2 days of the designated date. During this visit, the following trial procedures will be performed. • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. Blood samples are collected for serum biochemical tests, hematological tests, serum pregnancy tests (for women of potential pregnancy), and PK measurements, and the date and time of PK sample collection are recorded. • The date and time of the most recent administration of the test drug prior to the collection of the PK sample are recorded. If the subject has not yet taken the morning dose of the study drug for that day, the subject will be asked to take that dose. A urine sample is collected for a urine test. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS are recorded. • Adherence to recording pain in a daily log will be checked, and retraining will be provided if necessary. • Items related to modified Sartorius scores are collected. The physician administering the examination will fill in the HS-PGA form. • The IHS4 score is calculated. The target group is those who are asked to complete the SF-36 v2, EQ-5D-5L, and HiSQOL Index forms. • Drug management will be carried out for returned vials of test drugs. • The investigational drug will be distributed. Note: At this visit, subjects who were assigned to the placebo group will be re-randomized to receive either 10 mg or 30 mg of avacopan twice daily. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain and the administration of the test drug in a log. - Arrive at the trial site for the 16th week trial visit. - During the test period, store the test reagent in a cool, dry place according to the label instructions. - Take the test drug as instructed. On each day of the trial visit, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site, and - Continue taking all other medications you are taking as usual.

[0121] Week 16 of the exam (Day 113) The visit for week 16 of the trial must take place within ±2 days of the designated date. During this visit, the following trial procedures will be performed. • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. Blood samples are collected for serum biochemical tests, hematological tests, serum pregnancy tests (for women of potential pregnancy), and PK measurements, and the date and time of PK sample collection are recorded. • The date and time of the most recent administration of the test drug prior to the collection of the PK sample are recorded. If the subject has not yet taken the morning dose of the study drug for that day, the subject will be asked to take that dose. A urine sample is collected for a urine test. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS are recorded. • Adherence to daily recording of pain and investigational drug administration in a log will be checked, and retraining will be provided if necessary. • Items related to modified Sartorius scores are collected. • The IHS4 score is calculated. The physician administering the examination will fill in the HS-PGA form. The target group is those who are asked to complete the SF-36 v2, EQ-5D-5L, and HiSQOL Index forms. • The test drug vials are checked to ensure that drug management is being performed and that the subjects are taking the test drug as instructed. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain and the administration of the test drug in a log. - Arrive at the trial site for the 20th week trial visit. - During the test period, store the test reagent in a cool, dry place according to the label instructions. - Take the test drug as instructed. On each day of the trial visit, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site, and - Continue taking all other medications you are taking as usual.

[0122] Week 20 of the exam (Day 141) The visit for week 20 of the trial must take place within ±2 days of the designated date. During this visit, the following trial procedures will be performed. • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. Blood samples are collected for serum biochemical tests, hematological tests, serum pregnancy tests (for women of potential pregnancy), and PK measurements, and the date and time of PK sample collection are recorded. • The date and time of the most recent administration of the test drug prior to the collection of the PK sample are recorded. If the subject has not yet taken the morning dose of the study drug for that day, the subject will be asked to take that dose. A urine sample is collected for a urine test. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS are recorded. • Adherence to recording pain in a daily log will be checked, and retraining will be provided if necessary. • Items related to modified Sartorius scores are collected. • The IHS4 score is calculated. The physician administering the examination will fill in the HS-PGA form. • Drug management will be carried out for returned vials of test drugs. • The test drug is distributed. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain and the administration of the test drug in a log. - Arrive at the trial site for your 24th week trial visit. - During the test period, store the test reagent in a cool, dry place according to the label instructions. - Take the test drug as instructed. On each day of the trial visit, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site, and - Continue taking all other medications you are taking as usual.

[0123] Week 24 of the exam (Day 169) The 24th week visit must be made within ±2 days of the designated date. During this visit, the following trial procedures will be performed. Blood samples are collected for serum biochemical tests, hematological tests, serum pregnancy tests (for women of potential pregnancy), and PK measurements, and the date and time of PK sample collection are recorded. • The test drug vials are checked to ensure that drug management is being performed and that the subjects are taking the test drug as instructed. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain and the administration of the test drug in a log. - Arrive at the trial site for the 28th week trial visit. - During the test period, store the test reagent in a cool, dry place according to the label instructions. - Take the test drug as instructed. On each day of the trial visit, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site, and - Continue taking all other medications as usual.

[0124] Week 28 of the exam (Day 197) The visit for week 28 of the trial must take place within ±2 days of the designated date. During this visit, the following trial procedures will be performed. • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. Blood samples are collected for serum biochemical tests, hematological tests, serum pregnancy tests (for women of potential pregnancy), and PK measurements, and the date and time of PK sample collection are recorded. • The date and time of the most recent administration of the test drug prior to the collection of the PK sample are recorded. If the subject has not yet taken the morning dose of the study drug for that day, the subject will be asked to take that dose. A urine sample is collected for a urine test. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS are recorded. • Adherence to daily recording of pain and investigational drug administration in a log will be checked, and retraining will be provided if necessary. • Items related to modified Sartorius scores are collected. • The IHS4 score is calculated. The physician administering the examination will fill in the HS-PGA form. • Drug management will be carried out for returned vials of test drugs. • The test drug is distributed. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain and the administration of the test drug in a log. - Arrive at the trial site for the 32-week trial visit. - During the test period, store the test reagent in a cool, dry place according to the label instructions. - Take the test drug as instructed. On each day of the trial visit, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site, and - Continue taking all other medications you are taking as usual.

[0125] Week 32 of the exam (Day 225) The visit for week 32 of the trial must take place within ±2 days of the designated date. During this visit, the following trial procedures will be performed. Blood samples are collected for serum biochemical tests, hematological tests, serum pregnancy tests (for women of potential pregnancy), and PK measurements, and the date and time of PK sample collection are recorded. • The test drug vials are checked to ensure that drug management is being performed and that the subjects are taking the test drug as instructed. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain and the administration of the test drug in a log. - Arrive at the trial site for your 36-week trial visit. - During the test period, store the test reagent in a cool, dry place according to the label instructions. - Take the test drug as instructed. On each day of the trial visit, if appropriate for that visit, it is preferable for the subject to take the morning dose of the test drug after the PK sample is collected on-site, and - Continue taking all other medications you are taking as usual.

[0126] Week 36 of the exam (Day 253) The visit for week 36 of the trial must take place within ±2 days of the designated date. During this visit, the following trial procedures will be performed. • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. Blood samples are collected for serum biochemical tests, hematological tests, serum pregnancy tests (for women of potential pregnancy), and PK measurements, and the date and time of PK sample collection are recorded. • The date and time of the most recent administration of the test drug prior to the collection of the PK sample are recorded. A urine sample is collected for a urine test. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS are recorded. • Adherence to daily recording of pain and investigational drug administration in a log will be checked, and retraining will be provided if necessary. • Items related to modified Sartorius scores are collected. • The IHS4 score is calculated. The physician administering the examination will fill in the HS-PGA form. The target group is those who are asked to complete the SF-36 v2, EQ-5D-5L, and HiSQOL Index forms. • Drug management will be carried out for returned vials of test drugs. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. After all testing procedures are completed, the subject will be reminded to do the following: - Record the severity of skin pain in a diary. - To come to the trial site for the 44-week trial visit, and - Continue taking all other medications you are taking as usual.

[0127] Week 44 of the exam (Day 309) The follow-up visit at week 44 of the trial must be made within ±4 days of the designated date. During this visit, the following trial procedures will be performed. • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. Blood samples are collected for serum biochemical tests, hematological tests, and PK measurements, and the date and time of PK sample collection are recorded. A urine sample is collected for a urine test. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS are recorded. • Items related to modified Sartorius scores are collected. • The IHS4 score is calculated. The physician administering the examination will fill in the HS-PGA form. The target group is those who are asked to complete the SF-36 v2, EQ-5D-5L, and HiSQOL Index forms. • The completed logbooks are collected. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. All adverse events are recorded. • After all test procedures are completed, the subject will terminate the test.

[0128] Early discontinuation visit If a participant discontinues the trial early, the following discontinuation procedures must be completed as soon as possible. • Physical examination including weight, • Vital signs (body temperature, sitting blood pressure, heart rate) after at least 3 minutes of rest. • Serum biochemical tests, hematological tests, and serum pregnancy tests (for women of potential pregnancy), and blood samples for PK measurement. The date and time of PK sample collection are recorded. A urine sample is collected for a urine test. The anatomical locations and number of inflammatory nodules, abscesses, fistulas, and scars in HS are recorded. • Modified Sartorius score items are collected if the previous visit in which the assessment was performed was more than two weeks ago. If the previous visit in which the SF-36 v2, EQ-5D-5L, and HiSQOL Index forms were evaluated was more than two weeks ago, the patient will be asked to complete these forms. • If the previous visit for the HS-PGA evaluation was more than two weeks ago, the examiner should record this. • Drug management will be carried out for returned vials of test drugs. • The completed logbooks are collected. Changes in concomitant medication use, including alcohol consumption, recreational drug use, non-prescription drugs, herbal preparations, or special diets, will all be recorded. • All adverse events are recorded.

[0129] Test evaluation Evaluation of the site and extent of hidradenitis suppurativa The location and extent of HS are assessed by recording the anatomical site of the disease, as well as the number of inflammatory nodules, abscesses, fistulas, and scars in each site, in the EDC. All study physicians are trained and experienced in studies that assess HS lesions. To ensure consistency, the same study physician should assess the lesions at each visit. If this is not possible, an experienced supporting study physician on site should perform the assessment.

[0130] Information regarding the location and extent of HS lesions is used to determine the Hurley stage and to calculate the HiSCR after baseline visit. The HiSCR is calculated programmatically in the EDC.

[0131] Modified Sartorius score Twelve body regions are assessed to calculate the modified Sartorius score. • Left and right armpits, • Below the left and right breasts, ·Intermammary area, • Left and right buttocks, • Left and right inguinal thigh folds, • Perianal area and perineum, and Other (specify).

[0132] A score of 4 indicates the least severe disease, and as the score increases, the severity of the disease gradually increases. There is no upper limit to this score (Sartorius et al, 2003).

[0133] The presence of nodules, abscesses, fistulas, scars, and other findings are recorded in the EDC. The longest distance between two lesions and whether multiple lesions are separated by normal skin are also recorded.

[0134] International Severity Score System for Hidradenitis Suppurativa The International Severity Score of Hidradenitis Suppurativa (IHS4) is easy to calculate and is determined using results derived by practicing physicians (such as HS-PGA, Hurley classification, MSS, or expert opinion classification) and patient-reported results scales (DLQI). IHS4 score (points) = (number of nodules × 1) + (number of abscesses × 2) + [number of draining perforations (fistulas / pockets) × 4]. A score of 3 or less indicates mild HS, a score of 4-10 indicates moderate HS, and a score of 11 or more indicates severe HS.

[0135] Physician-led hidradenitis suppurativa (HS-PGA) The HS-PGA is an ordinal scale specific to HS that classifies patients into clear, minimal, mild, moderate, severe, or very severe disease, and has been successfully used in a Phase 2 intervention clinical trial. The recently developed six-stage PGA is defined as follows (Kimball et al, 2012): • Clear: No inflammatory or non-inflammatory nodules present. • Minimal: Only the presence of non-inflammatory nodules • Mild: Fewer than 5 inflammatory nodules, or one abscess or draining fistula with no inflammatory nodules. • Moderate: Less than 5 inflammatory nodules, or 1 abscess or draining fistula and 1 or more inflammatory nodules, or 2 to 5 abscesses or draining fistulas and less than 10 inflammatory nodules • Severe: 2-5 abscesses or draining fistulas and 10 or more inflammatory nodules • Extremely severe: More than five abscesses or draining fistulas.

[0136] generalized skin pain The subjects recorded their maximum pain severity on a numerical scale from 0 (no skin pain) to 10 (worst conceivable skin pain) in a diary from one week before day 1 until their visit at week 44.

[0137] The program calculates the weekly average of the maximum pain severity.

[0138] Health-related quality of life assessment The SF-36 v2 and EQ-5D-5L methods are widely accepted, general, disease-nonspecific tools for measuring changes in health-related quality of life in subjects. The forms for these methods are completed by the subjects to measure changes from baseline in health-related quality of life. For non-English speaking subjects, verified translations are used whenever possible.

[0139] The HiSQOL index was developed as a HS-specific method to measure the impact of HS on the quality of life of subjects.

[0140] The examiner will assist the participant in completing the Quality of Life Questionnaire, but will not fill out the form on their behalf. The administrator will establish communication with the participant, emphasize the importance of completing the form, and assist in answering questions and addressing concerns. The questionnaire should be completed by the participant before their consultation with the examiner during their visit.

[0141] Pharmacokinetic evaluation and analysis The concentrations of abacopan (and its metabolites) are determined. The date and time of the most recent administration of the test drug prior to sample collection must be recorded in the EDC system. The date and time of PK sample collection must also be recorded.

[0142] The total plasma concentration of abacopan (and its metabolites) is determined using validated analytical methods.

[0143] Individual plasma concentrations of abacopan and key metabolites are enumerated, plotted, and summarized in descriptions and charts. PK analysis may be performed only on the subpopulation of interest. Where possible, the following parameters are determined: C max maximum plasma concentration T max Time to peak plasma concentration AUC 0-6h Area under the plasma concentration-time curve from 0 to 6 hours on day 1 C min Trough plasma concentration levels upon hospital visits from day 1 onward.

[0144] PK parameters such as HiSCR (for example, C min The relationship between the endpoint and the efficacy endpoint may also be assessed.

[0145] Example 2 - Summary of the most important results of the Phase II trial In the Phase II AURORA clinical trial, 398 patients were randomized to one of three treatment groups. The trial population was evenly stratified across treatment groups, including patients with moderate HS (Hurley stage II) or severe HS (Hurley stage III). The primary endpoint, the proportion of all patients (both moderate Hurley stage II plus severe Hurley stage III) who achieved Hidradenitis Suppurativa Clinical Response (HiSCR), was not statistically significantly achieved at any dose level when the 10 mg twice daily (BID) and 30 mg BID dosing regimens of abacopan were evaluated in the pooled trial population against placebo after 12 weeks of treatment, although a numerical improvement was seen at the 30 mg BID dose. Importantly, in the trial, abacopan 30 mg BID showed a statistically significantly higher response than placebo in a pre-specified population of HS patients with Hurley stage III (severe). The company plans to advance abacopan into Phase III development for the treatment of severe HS.

[0146]

Table 2

[0147] Consistency of the effect of abacopan was seen in patients with Hurley stage III in all secondary endpoints evaluated to date. Compared to placebo, abacopan showed favorable decreases in the International HS Severity Score (IHS4), as well as decreases in the counts of AN (abscesses and inflammatory nodules), draining sinus tracts, and abscesses at week 12 (total % change from baseline to week 12).

[0148] Abacopan demonstrated a favorable safety profile. All types of treatment-emergent adverse events (TEAEs) were found to be less in the abacopan group (48.5%) than in the placebo group (55%). The majority of TEAEs were related to underlying HS and were mild to moderate. Serious TEAEs were seen in 2.3% of placebo patients versus 1.5% of abacopan.

[0149] Hidradenitis Suppurativa and the AURORA Trial Hidradenitis suppurativa (HS), also known as inverse acne, is a chronic, disabling autoimmune skin disease characterized by recurrent, painful nodules, abscesses, and ulcers.

[0150] In the Phase II AURORA clinical trial, 398 patients with moderate to severe HS were randomized to one of three treatment groups. The primary endpoint was the evaluation of abacopan 10 mg BID and 30 mg BID dosing regimens against placebo over 12 weeks of treatment using the HiSCR scale. A HiSCR response was defined as a ≥ 50% reduction in the count of inflammatory lesions (abscesses + inflammatory nodules) compared to baseline and no increase in abscesses or draining fistulas. Secondary endpoints included percent improvement through week 12 between groups, reduction from baseline in IHS4 (International Hidradenitis Suppurativa Severity Scoring System), and other validated secondary measurements.

[0151] After the 12-week double-blind treatment period, the trial remained blinded. Placebo patients were re-randomized to either the abacopan 10 mg BID or 30 mg BID dose groups for an additional 24 weeks. Patients treated with abacopan continued to receive the same dose (either 10 mg BID or 30 mg BID) for an additional 24 weeks. Patients were followed for an additional 44 weeks for safety and efficacy evaluations.

[0152] The selective inhibition of only C5aR by abacopan leaves the beneficial C5a pathway intact due to the normal functioning of the C5L2 receptor.

[0153] Example 3 - Abacopan is surprisingly effective in patients with stage III HS. For the purpose of clarity of understanding, the above invention has been described in some detail by way of illustration and example. However, those skilled in the art will understand that certain changes and modifications can be made within the scope of the appended claims. In addition, each reference described in this specification is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In case of any conflict between this application and the references described in this specification, this application shall prevail. The present invention provides, for example, the following items: (Item 1) A method for treating a neutrophilic inflammatory disease of the skin in a subject requiring such treatment, wherein the subject is given a therapeutically effective amount of formula I

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

1. A formula for treating hidradenitis suppurativa (HS) in a person requiring such treatment. 【Chemistry 11】 A composition comprising abacopan or a pharmaceutically acceptable salt thereof, wherein the subject is diagnosed with HS, has a Hurley score of stage III, and is administered 30 mg of the compound twice daily to the subject. composition.

2. The subject is the composition according to claim 1, which is treated for 12 weeks.

3. The subject is the composition according to claim 1, which is treated for 26 weeks.

4. The subject is the composition according to claim 1, which is treated for 52 weeks.

5. The subject is the composition according to claim 1, which undergoes long-term treatment.

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