Avacopan and related compounds of formula (I) for use in the treatment of hidradenitis suppurativa in patients in Hurley stage III

Abstract

This document describes methods for treating a subject suffering from a neutrophilic cutaneous inflammatory disease, comprising administering to a subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, where each variable position is defined herein. In some forms, the neutrophilic cutaneous inflammatory disease is hidradenitis suppurativa (HS).

Description

Avacopan and related compounds of formula (I) for use in the treatment of hidradenitis suppurativa in patients in Hurley stage III Background of the invention Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory skin disease characterized by the formation of inflammatory nodules, abscesses, internal and external fistulas, and scarring, most commonly in areas rich in apocrine glands such as the armpits, inframammary area, groin, perineum, and perianal area. In its moderate and severe forms, HS is debilitating and causes significant discomfort, pain, anxiety, and depression, as well as a decline in quality of life. The exact cause of HS has not been identified, although genetic defects in the gene encoding β-secretase have been described in individuals with HS. Potential target proteins include Notch, E-cadherin, and nicastin. Notch plays an important role in hair follicle development, and a defect in Notch can lead to epidermal cyst formation, dysregulation of normal T-cell-mediated immune responses, and suppression of proinflammatory macrophage-mediated cytokine responses and Toll-like receptor 4-induced responses (Radtke et al., 2010; Wang et al., 2010). Smoking and obesity have been associated with HS (Prens and Deckers, 2015), as well as excessive sweating, androgen dysfunction, and possible genetic causes. Some reports suggest that HS is, at least in part, a neutrophil-mediated disease. Current treatment for individuals with HS includes local and systemic antibiotics, analgesic medications, and anti-TNF agents such as adalimumab. Other drugs such as cyclosporine A, dapsone, and isotretinoin have been used with limited results (Napolitano et al., 2017). Despite the available treatment options, most patients only experience a partial and / or temporary response. A recent treatment option advanced in US patents 2018 / 0280530 and 2018 / 028425 is the use of an antibody targeting C5a to treat patients with HS. C5a is known to be a potent chemotactic anaphylatoxin, and the binding of C5a to C5aR modulates leukocyte trafficking, migration, and activation. However, specifically targeting C5a with an antibody not only disrupts the C5a / C5aR axis but also alters the binding of C5a to the C5L2 receptor. The C5a / C5L2 pathway includes beneficial biological functions such as limiting or suppressing the pro-inflammatory response triggered 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, disruption of the C5a-C5L2 pathway has been shown to exacerbate inflammation, resulting in a more intense reaction to C5a (Xiao et al., J. Am. Soc. Nephrol. 2014, 25(2): 225-31; Karsten et al., Front. Immunol. 2018, 15;9: 488).Therefore, the specific selection of C5a as a target involves blocking signaling pathways associated with attenuation of the response to C5a. In addition, antibody treatments have other disadvantages, such as the need for intravenous administration, the possibility that patients may develop human antichimeric antibodies (HACA), the need for patients to travel to a medical center for treatment, and poor patient compliance. Therefore, there remains a need in this field to identify and develop orally available compounds useful in the treatment of hidradenitis suppurativa (HS) and related neutrophilic cutaneous inflammatory diseases that do not block the C5a / C5L2 axis, thereby preserving the beneficial functions of the C5L2 pathway. US patents 2018 / 282425 and 280530 relate to inhibitors of C5a activity and their use in the treatment of neutrophilic inflammatory skin diseases in a subject. WO patent 2020 / 112961 relates to solid-dissolving capsule formulations and methods of treatment of individuals suffering from or prone to suffering from a disease or disorder involving pathological activation of C5a receptors. Brief summary of the invention The present description provides a compound that is formula I, or is a pharmaceutically acceptable salt thereof for use in a method of treating hidradenitis suppurativa (HS) in a subject in need thereof, wherein said subject has been diagnosed with Hurley stage III HS and receives 30 mg of the compound twice daily, wherein each R1 is independently selected from the group consisting of CH3, CF3, CH2CH3, Cl, 1-pyrrolidine, -O-CH(CH3)2 and CH2OH; and each R2 is independently selected from the group consisting of CH3 and F. Other objects, features, and advantages of the present invention will become evident to a person skilled in the art from the following detailed description and figures. Brief description of the drawings Figure 1 shows a schematic of the phase II study design. Detailed description of the invention I. General This description provides compounds and dosage regimens for the treatment of hidradenitis suppurativa and specific patient populations. The compounds in the methods described herein specifically target C5aR and do not disrupt the C5a-C5L2 interaction. Advantageously, the C5aR inhibitors described in this application effectively modulate neutrophil migration and activation by blocking the C5a-C5aR interaction, while not blocking the C5a-C5L2 axis. Without being limited to any particular theory, it is believed that compounds that bind to C5aR prevent the detrimental effects of disruption of the C5a-C5L2 signaling axis. This allows subjects treated for hidradenitis suppurativa and subpopulations thereof to benefit from the pro-inflammatory suppressive activity of the C5a-C5L2 axis. II. Definitions As used herein, the term "treat" or "treatment" encompasses both disease-modifying and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, for the purpose of preventing, delaying, or reducing the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, for the purpose of reducing the severity and / or duration of symptoms). The treatment methods provided herein generally include administering to a patient an effective amount of one or more of the compounds provided herein. Suitable patients include those who have or are likely to develop (i.e., prophylactic treatment) a disorder or disease identified herein.Typical patients for the treatment described herein include mammals, particularly primates, especially humans. Other suitable patients include domesticated companion animals such as dogs, cats, horses, and similar animals, or livestock such as cows, pigs, sheep, and similar animals. The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents present in the compounds described herein. When the compounds described herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of these compounds with a sufficient quantity of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable salts derived from inorganic bases include those of aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and similar bases.Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, natural amines, and the like, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds described herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of said compounds with a sufficient quantity of the desired acid, either pure or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic or phosphoric acids and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic and the like. Also included are amino acid salts, such as arginate and the like, and salts of organic acids such as glucuronic or galactunoric acids and the like (see, for example, Berge, SM, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).Certain specific compounds in this description contain both basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts. The neutral forms of the compounds can be regenerated by contacting the salt with a base or an acid and isolating the original compound in the conventional manner. The original form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the original form of the compound for the purposes of this description. Certain compounds of the present invention may exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are intended to be included within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; it is intended that racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., separate enantiomers) are included within the scope of the present invention. The compounds of the present invention may also contain non-natural proportions of atomic isotopes in one or more of the atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I), or carbon-14 (14C). It is intended that all isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. As used herein, a wavy line, " ", intersecting with a single, double, or triple bond in any chemical structure illustrated herein, represents the point of attachment of the single, double, or triple bond to the rest of the molecule. III. Detailed description of the invention A. Treatment methods References in this document to therapeutic treatment methods shall be understood to refer to the compounds of the invention for use in such treatments. The present description provides methods for hidradenitis suppurativa (HS) in a subject in need thereof, wherein said subject has been diagnosed with Hurley stage III HS and receives 30 mg of the compound twice daily, wherein said method comprises administering to said subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from the group consisting of CH3, CF3, CH2CH3, Cl, 1-pyrrolidine, -O-CH(CH3)2 and CH2OH; and Each R2 is selected independently of the group consisting of CH3 and F. Neutrophilic inflammatory skin diseases are a class of diseases caused, at least in part, by neutrophil hyperactivity or inappropriate activation. The methods provided herein treat hidradenitis suppurativa (HS), a disease mediated, at least in part, by neutrophil activity. Certain subpopulations of subjects may respond surprisingly well to treatment with compounds from Formulation I. For example, in some implementations, women responded significantly better to treatment compared to men. In some implementations, younger subjects (e.g., 50 years of age or younger) responded significantly better to treatment compared to older subjects (e.g., 51 years of age or older). Subjects diagnosed with Hurley stage III hidradenitis suppurativa responded significantly better than subjects with less severe forms. In some implementations, subjects who had previously received an anti-TNF drug (e.g., adalimumab or infliximab) responded surprisingly better compared to those who had not previously received any anti-TNF drug.In some embodiments, subjects receiving concomitant antibiotic treatment (e.g., doxycycline or minocycline) responded significantly better compared to subjects not receiving concomitant antibiotic treatment. In each of the above embodiments, still other embodiments are those in which avacopan is administered as compound I. Subjects diagnosed with Hurley stage III hidradenitis suppurativa responded significantly better than subjects with less severe forms. In some implementations, subjects who had previously received an anti-TNF drug (e.g., adalimumab or infliximab) responded strikingly better compared to those who had not previously received any anti-TNF drug. In each of these implementations, treatment is effective when avacopan is administered at a dose of 30 mg twice daily. When comparing patient subpopulations, various clinically defined parameters can be used. For example, significant improvements can be observed by measuring one or more of the following parameters: the abscess and inflammatory nodule (AN) count, a subject's skin pain global assessment (NRS), the proportion of subjects who worsened during treatment, the proportion of subjects who received oral rescue antibiotic treatment or an intralesional rescue injection of Kenalog, a change in the modified Sartorius score, a change in the IHS4 score, a change in the physician's global assessment of hidradenitis suppurativa (HS-PGA), a change in the hidradenitis suppurativa burden of disease (HSBOD) score, a change in the Cardiff dermatological quality of life index or DLQI questionnaire.a change in the Work Productivity and Activity Impairment for a Specific Health Problem (WPAI:SHP) questionnaire, the extent of a hidradenitis suppurativa clinical response (HiSCR) (HiSCR is defined as a reduction of at least 50% in the abscess and inflammatory nodule (AN) count, no increase in abscess count and no increase in suppurative fistula count), etc., As measured by the count of abscesses and inflammatory nodules (AN), populations of subjects who respond significantly better to treatment include those where the proportion of the population that achieves a reduction in AN count is at least 5, 10, 15, 20, or 25% or more than the proportion of subjects who are not in the defined population. As measured by the National Skin Pain Rating (NSR), subject populations that respond significantly better to treatment include those where the proportion of subjects achieving at least a 30% reduction in their NSR is at least 5, 10, 15, 20, or 25% higher than the proportion of subjects not in the defined population. For the NRS30 analysis, weekly averages of the worst skin pain reported by subjects for each 24-hour period in daily diaries will be calculated for each relevant study visit. As measured by the proportion of subjects with a worsening during treatment, populations of subjects who respond significantly better to treatment include those where the proportion of the population who do not experience a worsening while receiving treatment is at least 5, 10, 15, 20, or 25% or more than the proportion of subjects who are not in the defined population. As measured by the proportion of subjects who received oral rescue antibiotic treatment or intralesional rescue injection of Kenalog, treatment-responsive subject populations include those where the proportion of the population not receiving any oral rescue antibiotic treatment during treatment is at least 5, 10, 15, 20, or 25% or more than the proportion of subjects not in the defined population. As measured by a change in the modified Sartorius score, populations of subjects who respond significantly better to treatment include those where the proportion of subjects who achieve at least a 4 or 5 point reduction in the subject's modified Sartorius score is at least 5, 10, 15, 20, or 25% or more than the proportion of subjects who are not in the defined population. As measured by a change in the IHS4 score, subject populations that respond significantly better to treatment include those in which the proportion of subjects achieving at least a 4- or 5-point reduction in the subject's IHS4 score is at least 5, 10, 15, 20, or 25% or more than the proportion of subjects not in the defined population. In some embodiments, subjects in the method of the present invention (who have Hurley stage III hidradenitis suppurativa) respond significantly better to treatment compared to subjects who do not have Hurley stage III hidradenitis suppurativa.In some embodiments, the proportion of subjects in the method of the present invention (who have Hurley stage III hidradenitis suppurativa) who achieve at least a 4 or 5 point reduction in the subject's IHS4 score is at least 10% higher than the proportion of subjects who do not have Hurley stage III hidradenitis suppurativa after 12 weeks of treatment compared to baseline. In some embodiments, the proportion of subjects in the method of the present invention (who have Hurley stage III hidradenitis suppurativa) who achieve at least a 4 or 5 point reduction in the subject's IHS4 score is at least 15% higher than the proportion of subjects who do not have Hurley stage III hidradenitis suppurativa after 12 weeks of treatment compared to baseline.In some embodiments, the proportion of subjects in the method of the present invention (who have Hurley stage III hidradenitis suppurativa) who achieve at least a 4 or 5 point reduction in the subject's IHS4 score is at least 20% higher than the proportion of subjects who do not have Hurley stage III hidradenitis suppurativa after 12 weeks of treatment compared to baseline. As measured by the change in the HS-PGA score, subject populations that respond significantly better to treatment include those where the proportion of subjects who achieve at least a 2 or 3 point reduction in the subject's HS-PGA score is at least 5, 10, 15, 20, or 25% or more than the proportion of subjects who are not in the defined population. As measured by the change in HSBOD score, subject populations that respond significantly better to treatment include those where the proportion of subjects who achieve at least a 2 or 3 point reduction in the subject's HSBOD score is at least 5, 10, 15, 20, or 25% or more than the proportion of subjects who are not in the defined population. As measured by the change in DLQI questionnaire score, populations of subjects who respond significantly better to treatment include those where the proportion of subjects who achieve at least a 4 or 5 point reduction in the subject's DLQI questionnaire score is at least 5, 10, 15, 20, or 25% or more than the proportion of subjects who are not in the defined population. As measured by the Work Productivity and Activity Impairment for a Specific Health Problem (WPAI:SHP) questionnaire, populations of subjects who respond significantly better to treatment include those where the proportion of subjects who achieve at least a 15% reduction in the WPAI:SHP is at least 5, 10, 15, 20, or 25% or more than the proportion of subjects who are not in the defined population. As measured by the Hidradenitis Suppurativa Clinical Response (HiSCR), populations of subjects who respond significantly better to treatment include those in which the proportion of the population achieving a HiSCR assessment is at least 5, 10, 15, 20, or 25% or more higher than the population of subjects not in the defined population. In some embodiments, subjects in the method of the present invention (who have Hurley stage III hidradenitis suppurativa) respond significantly better to treatment compared to subjects who do not have Hurley stage III hidradenitis suppurativa.In some embodiments, the proportion of subjects in the method of the present invention (who have Hurley stage III hidradenitis suppurativa) who achieve a HiSCR assessment is at least 10% higher than the proportion of subjects who do not have Hurley stage III hidradenitis suppurativa after 12 weeks of treatment compared to baseline. In some embodiments, the proportion of subjects in the method of the present invention (who have Hurley stage III hidradenitis suppurativa) who achieve a HiSCR assessment is at least 15% higher than the proportion of subjects who do not have Hurley stage III hidradenitis suppurativa after 12 weeks of treatment compared to baseline.In some embodiments, the proportion of subjects in the method of the present invention (who have Hurley stage III hidradenitis suppurativa) who achieve a HiSCR assessment is at least 20% higher than the proportion of subjects who do not have Hurley stage III hidradenitis suppurativa after 12 weeks of treatment compared to baseline. The clinical changes observed in populations or subpopulations may vary depending on the time interval of the comparison. In some implementations, the comparison in the preceding paragraphs is the change from day 1 to week 2. In some implementations, the comparison in the preceding paragraphs is the change from day 1 to week 4. In some implementations, the comparison in the preceding paragraphs is the change from day 1 to week 8. In some implementations, the comparison in the preceding paragraphs is the change from day 1 to week 12. In some implementations, the comparison in the preceding paragraphs is the change from day 1 to week 16. In some implementations, the comparison in the preceding paragraphs is the change from day 1 to week 20. In some implementations, the comparison in the preceding paragraphs is the change from day 1 to week 24.In some realizations, the comparison in the preceding paragraphs is the change from day 1 to week 28. In some realizations, the comparison in the preceding paragraphs is the change from day 1 to week 32. In some realizations, the comparison in the preceding paragraphs is the change from day 1 to week 36. In some realizations, the comparison in the preceding paragraphs is the change from day 1 to week 44. The subjects in the method of the present invention receive a therapeutically effective amount of 30 mg of the compound twice a day. In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 50 ng / mL to 400 ng / mL. In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 150 ng / mL to 250 ng / mL. In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 175 ng / mL to 225 ng / mL. In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 50 ng / mL to 90 ng / mL.In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 60 to 70 ng / mL. In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 195 ng / mL. In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 205 ng / mL. In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 215 ng / mL.In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 60 ng / mL. In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 65 ng / mL. In some embodiments, a therapeutically effective amount of the compound in Formula I, 30 mg twice daily, achieves and maintains a mean steady-state plasma concentration of approximately 70 ng / mL. B. Compounds of formula I The compounds of formula (I), or a pharmaceutically acceptable salt thereof, have the structure where each R1 is independently selected from the group consisting of CH3, CF3, CH2CH3, Cl, 1-pyrrolidine, -O-CH(CH3)2 and CH2OH; and Each R2 is selected independently of the group consisting of CH3 and F. In some embodiments, the compound of formula I has the formula either or is a pharmaceutically acceptable salt of the same. In some embodiments, the compound of formula I has the formula or is a pharmaceutically acceptable salt of the same. In some embodiments, the compound of formula I is avacopan, which has the formula , or a pharmaceutically acceptable salt thereof. The compounds of formula (I) described herein can be obtained according to methods described in WO 2010 / 075257, WO 2011 / 163640 and WO 2016 / 053890. In some embodiments, the compound of formula (I) is a compound described in one of these references. C. Administration methods In general, the treatment methods provided herein comprise administering an effective dose of 30 mg of the compound to a patient twice daily to effectively treat hidradenitis suppurativa (HS). In some embodiments, the compound is administered to a subject (e.g., a human) orally. The duration of treatment depends on several factors, including the disease being treated, as well as age, body weight, general health, sex, diet, timing, and route of administration of the compound. In some embodiments, the subject receives treatment for 12 weeks. In some embodiments, the subject receives treatment for 26 weeks. In some embodiments, the subject receives treatment for 52 weeks. In some embodiments, the subject receives chronic treatment. In some embodiments, the subject is administered 30 mg of avacopan orally twice a day, for a total daily dose of 60 mg. D. Formula I Solid Dissolving Capsule Formulations In some embodiments, the methods described herein use solid dissolvable capsule formulations comprising avacopan as a free base, in its neutral form or in the form of a pharmaceutically acceptable salt, and a vehicle comprising (avacopan) at least one non-ionic surfactant with a hydrophilic-lipophilic equilibrium (HLB) value of at least 10, and at least one water-soluble solubilizer with a melting point of 37 °C or higher. Typically, suitable nonionic surfactants with an HLB value of at least 10 include (a) polyoxyethylenated castor oil derivatives and (b) polyoxyethylenated polyol ester derivatives, wherein the polyoxyethylenated polyol ester derivative is derived from a fatty acid containing from approximately 8 to approximately 22 carbon atoms. The carbon atoms of the fatty acid may include one or more points of unsaturation or one or more points of substitution (e.g., ricinoleic acid). In some embodiments, suitable nonionic surfactants with an HLB value of at least 10 are glycerol macrogol-hydroxystearate polymers such as polyoxyethylene 40-castor oil, hydrogenated polyoxyethylene 40-castor oil (also known as glycerol macrogol 40-hydroxystearate, its former trade name Cremophor® RH40 and its current trade name Kolliphor® RH40), glycerol macrogol ricinoleate (also known as polyethoxyethylene 35-castor oil, its former trade name Cremophor® EL and its current trade name Kolliphor® EL), macrogol-15-hydroxystearate (also known by its former trade name Solutol® HS 15 and its current trade name Kolliphor HS15), polyoxyethylene 60-castor oil, hydrogenated polyoxyethylene 60-castor oil, polyoxyethylene 100-hydrogenated castor oil, polyoxyethylene 200-castor oil, polyoxyethylene 200-hydrogenated castor oil. Water-soluble solubilizers with a melting point of 37°C or higher may be polyethylene glycols (PEGs) with a minimum average molecular weight of 1000 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-10,000, and PEG-20,000. 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. Solid poloxamers, also known as poloxameric polyols with average molecular weights between 6000 and 18000, or by their trade name Pluronics®, of the formula HO(C2H4O)a(C3H6O)6(C2H4O)aH, are also suitable as water-soluble solubilizers with a melting point of 37 °C or higher. Examples of suitable poloxamers include poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407. In certain embodiments, the at least one nonionic surfactant with a hydrophilic-lipophilic equilibrium (HLB) value of at least 10 and the at least one water-soluble solubilizer with a melting point of 37 °C or higher are a single component. Such a component includes a hydrophilic polyethylene glycol (PEG) chain attached to a lipophilic fatty acid or fatty alcohol component (e.g., a glycerol macrogol-hydroxystearate).The longer the PEG chain length, i.e., the higher the HLB value, the more likely dissociation between the PEG chain and the lipophilic component is to occur. Such single-component vehicles provide a nonionic surfactant with an HLB value of at least 10 and free PEG polymer chains that act as water-soluble solubilizers. Without wishing to be limited to any particular theory, it is thought that a capsule formulation comprising 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 provides a system termed self-emulsifying or self-solubilizing. Following oral administration, the capsule shell dissolves in the gastrointestinal tract, followed by the dissolution of the solubilizer in gastric juice with the simultaneous formation of micelles comprising molecularly dissolved avacopan. A microemulsion or nanoemulsion is thus formed, allowing the avacopan to remain in solution despite being surrounded by gastric juice with a pH value of 3 or higher, a pH at which avacopan is not normally soluble. In some embodiments, the solid dissolving capsule formulations comprise avacopan as a free base, in its neutral form or in the form of a pharmaceutically acceptable salt, and a vehicle, wherein said vehicle comprises glycerol macrogol 40-hydroxystearate and PEG-4000. In some embodiments, the vehicle comprises approximately 97 to 99% by weight of the total fill weight of said solid dissolving capsule. In some embodiments, the vehicle comprises approximately 98% by weight of the total fill weight of said solid dissolving capsule. In some embodiments, the solid dissolving capsule comprises approximately 1 to 3% by weight of avacopan with respect to the total fill weight of said solid dissolving capsule. In some embodiments, the solid dissolving capsule comprises approximately 1 to 2.8% by weight of avacopan with respect to the total fill weight of said solid dissolving capsule. In some embodiments, the solid dissolving capsule comprises approximately 2% by weight of avacopan with respect to the total fill weight of said solid dissolving capsule. In some embodiments, the total weight of the vehicle comprises a ratio of 30:70 to 65:35 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 30:70 to 65:35. In some embodiments, the total weight of the vehicle comprises a ratio of 35:65 to 65:35 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 35:65 to 65:35.In some embodiments, the total weight of the vehicle comprises a ratio of 45:55 to 55:45 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 45:55 to 55:45. In some embodiments, the total weight of the vehicle comprises a ratio of approximately 50:50 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 50:50.In some embodiments, the total weight of the vehicle comprises a ratio of approximately 40:60 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 40:60. In some embodiments, the total weight of the vehicle comprises a ratio of approximately 30:70 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 30:70. In some embodiments, the total filling weight of said solid dissolving capsule is approximately 100 mg to approximately 1000 mg. In some embodiments, the total filling weight of said solid dissolving capsule is approximately 130 mg to approximately 900 mg. In some embodiments, the total filling weight of said solid dissolving capsule is approximately 250 mg to approximately 750 mg. In some embodiments, the total filling weight of said solid dissolving capsule is approximately 500 mg. In some embodiments, the solid dissolution capsule does not include ethanol. In some embodiments, the solid dissolution capsule is a capsule of size no. 00, no. 0, no. 1, no. 2, no. 3, no. 4, or no. 5. In some embodiments, the solid dissolution capsule is a capsule of size no. 00. In some embodiments, the solid dissolution capsule is a capsule of size no. 0. In some embodiments, the solid dissolution capsule is a capsule of size no. 1. In some embodiments, the capsule is a hard capsule. In some embodiments, the capsule is a soft capsule. The capsules described herein may be sealed using techniques known in the field. For example, a gelatin sealing strip comprising a plasticizer such as polysorbate 80 may be used to seal the capsules described herein. E. Method of producing a solid dissolution capsule of formula I The solid-dissolving 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 and forms an amorphous matrix. In some respects, this document provides methods for preparing a solid dissolvable capsule comprising avacopan as a free base, in its neutral form or in the form of a pharmaceutically acceptable salt. (avacopan) and a vehicle comprising at least one non-ionic surfactant with a hydrophilic-lipophilic equilibrium (HLB) value of at least 10, and at least one water-soluble solubilizer with a melting point of 37 °C or higher; where said method comprises (a) melt the vehicle; (b) combining the molten vehicle obtained in step (a) with avacopan to form a drug solution; (c) encapsulating the drug solution in a capsule shell; and (d) cooling the encapsulated drug solution to form a solid dissolution capsule comprising avacopan. The vehicle is melted using conventional techniques in the field. The melting temperature depends on the vehicle's characteristics. Typical melting techniques include a direct-heated furnace and jacketed mixing tanks. In some embodiments, the vehicle in stage (a) is heated to approximately 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 °C or higher. In some embodiments, the vehicle in stage (a) is heated to approximately 50 °C to 85 °C. In some embodiments, the vehicle in stage (a) is heated to approximately 50 °C. In some embodiments, the vehicle in stage (a) is heated to approximately 60 °C. In some embodiments, the vehicle in stage (a) is heated to approximately 70 °C. In some embodiments, the vehicle in stage (a) is heated to approximately 80 °C. In some implementations, stage (a) comprises (i) heating at least one non-ionic surfactant with an HLB value of at least 10 to form a molten surfactant; (ii) heating at least one water-soluble solubilizer to form a molten solubilizer; and (iii) combine the molten solubilizer with the molten surfactant to form a molten vehicle. As described above, the melting of step (a) can be carried out using conventional heating techniques. This also applies to steps (i) and (ii). In some embodiments, the heating temperatures of steps (i) and (ii) are the same. In other embodiments, the heating temperatures of steps (i) and (ii) are different. In some embodiments, at least one nonionic surfactant with an HLB value of at least 10 in step (i) is heated to approximately 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 °C or higher. In some embodiments, at least one nonionic surfactant with an HLB value of at least 10 in step (i) is heated to approximately 50 °C to 85 °C. In some embodiments, at least one nonionic surfactant with an HLB value of at least 10 in step (i) is heated to approximately 50 °C to 70 °C. In some embodiments, at least one nonionic surfactant with an HLB value of at least 10 in step (i) is heated to approximately 50 °C. In some embodiments, at least one nonionic surfactant with an HLB value of at least 10 in step (i) is heated to approximately 60 °C. In some embodiments, at least one nonionic surfactant with an HLB value of at least 10 in step (i) is heated to approximately 70 °C.In some embodiments, the at least one nonionic surfactant with an HLB value of at least 10 in step (i) is heated to approximately 80 °C. In some embodiments, the at least one water-soluble solubilizer in step (ii) is heated to approximately 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 °C or higher. In some embodiments, the at least one water-soluble solubilizer in step (ii) is heated to approximately 50 °C to 90 °C. In some embodiments, the at least one water-soluble solubilizer in step (ii) is heated to approximately 80 °C to 85 °C. In some embodiments, the at least one water-soluble solubilizer in step (ii) is heated to approximately 50 °C. In some embodiments, the at least one water-soluble solubilizer in step (ii) is heated to approximately 60 °C. In some embodiments, the at least one water-soluble solubilizer in step (ii) is heated to approximately 70 °C.In some embodiments, the at least one water-soluble solubilizer in step (ii) is heated to approximately 80 °C. In some embodiments, the at least one nonionic surfactant with an HLB value of at least 10 in step (i) is heated to approximately 50 to 70 °C and the at least one water-soluble solubilizer in step (ii) is heated to approximately 80 to 85 °C. In some embodiments, the at least one nonionic surfactant with an HLB value of at least 10 in step (i) is heated to approximately 60 °C and the at least one water-soluble solubilizer in step (ii) is heated to approximately 80 °C. After performing steps (i) and (ii), the temperature of the molten solubilizer can be adjusted to a temperature within the tolerance of the capsule shell. For example, the temperature tolerance of a gelatin capsule shell is approximately 65 °C. Different capsule shells may tolerate different temperatures; an expert in the field will easily identify the appropriate temperatures based on the capsule shell being used. When the molten solubilizer is brought into contact with the molten surfactant, stirring is generally applied to ensure thorough mixing. Stirring is typically employed. The stirring / stirring time will vary depending on the components of the molten surfactant and solubilizer, the batch size, and the heating temperatures used. In some embodiments, stirring is carried out for 0.25, 0.5, 0.75, 1, 2, or more hours. During this stage, vacuum stirring may be performed to deaerate the solution. Returning to step (b), when the molten vehicle is contacted with avacopan in step (b), the drug dissolves in the heated vehicle. Dissolution of avacopan can be achieved by various techniques, such as waiting an appropriate amount of time or stirring the solution to increase the dissolution rate. In some embodiments, the heated vehicle containing avacopan in step (b) is stirred. Stirring times can range from one to six or more hours. In some embodiments, the stirring time is 1, 2, 3, 4, 5, 6, or more hours. In some embodiments, the stirring time is approximately 3.5 hours. Encapsulation of the drug solution is performed using techniques known in the art. One such machine useful for encapsulation is a Shionogi F40 filling device. A person skilled in the art will be familiar with additional equivalent machines. There are several known methods for cooling a desired substance. Cooling in step (d) mentioned above may include passive activities such as allowing the encapsulated drug solution to reach room temperature or more active steps such as placing the encapsulated drug solution in a refrigerated area to increase the cooling rate. A person skilled in the art will recognize that it is not necessary to perform each of the preceding steps in the order listed to prepare a solid dissolution capsule comprising avacopan. For example, after dissolving avacopan in the heated vehicle (step (b)) to form a drug mixture, the drug mixture can be cooled to form a solid solution. As discussed above, cooling can include passive activities such as allowing the encapsulated drug solution to reach room temperature or more active steps such as placing the encapsulated drug solution in a refrigerated area to increase the cooling rate. In some embodiments, the total weight of the vehicle comprises a ratio of 30:70 to 65:35 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 30:70 to 65:35. In some embodiments, the total weight of the vehicle comprises a ratio of 35:65 to 65:35 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 35:65 to 65:35.In some embodiments, the total weight of the vehicle comprises a ratio of 45:55 to 55:45 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 45:55 to 55:45. In some embodiments, the total weight of the vehicle comprises a ratio of approximately 50:50 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 50:50.In some embodiments, the total weight of the vehicle comprises a ratio of approximately 40:60 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 40:60. In some embodiments, the total weight of the vehicle comprises a ratio of approximately 30:70 between at least one nonionic surfactant with an HLB value of at least 10 and at least one water-soluble solubilizer with a melting point of 37 °C or higher. In a preferred embodiment, the ratio of glycerol macrogol 40-hydroxystearate to polyethylene glycol 4000 (PEG-4000) is 40:70. IV. Examples The following examples are offered to illustrate, but not to limit, the claimed invention. Example 1 - Phase II Clinical Trial The study is a randomized, double-blind, placebo-controlled, three-arm phase II trial in approximately 390 subjects with moderate to severe hidradenitis suppurativa (Hurley stage II or III). Subjects will be randomized 1:1:1 to treatment with either 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 therapies, are prohibited. Stable antibiotic therapy with doxycycline or minocycline is permitted as specified in the protocol. Subjects treated with 10 mg or 30 mg twice daily during the 12-week, placebo-controlled, blinded treatment period will be followed by an additional 24-week active treatment period, during which they will continue to receive the same dosing regimen of 10 mg or 30 mg of avacopan twice daily.Subjects who receive placebo and complete the 12-week, placebo-controlled, blinded period will be re-randomized 1:1 to receive either 10 mg or 30 mg of avacopan twice daily for the 24-week active treatment period. During the 24-week active treatment period, the patient, study staff at the site, and the sponsor will not be informed of the assignment to either 10 mg or 30 mg twice daily. All subjects will then be followed off the study drug for 8 weeks before leaving the study. Interventions / study methodology Eligible adult subjects (at least 18 years of age) with moderate to severe hidradenitis suppurativa (Hurley stage II or III) are eligible to participate in the study, as specified in the eligibility criteria. Subjects will be randomized 1:1:1 to receive either 10 mg of avacopan twice daily, 30 mg of avacopan twice daily, or equivalent placebo for 12 weeks, in a double-blind, placebo-controlled manner. To achieve a balance among all treatment groups, a stratified randomization scheme will be implemented. The stratification factors and strata within each factor are listed below. Eligible subjects will be randomly assigned with equal probability (i.e., 1:1:1) to one of the three treatment groups within each stratum using a non-dynamic block randomization scheme, as listed. 1. Hurley Stadium (Stadium II or III): a. Stage II disease: one or more widely separated recurrent abscesses with fistula formation and scarring, or b. Stage III disease: multiple interconnected fistulas and abscesses throughout an area, with diffuse or almost diffuse involvement. 2. Concomitant antibiotic treatment (yes or no) a. concomitant treatment with doxycycline or minocycline as the only permitted antibiotic treatment for HS, or b. without concomitant antibiotic treatment. 3. Anti-TNF treatment (with or without prior treatment): a. did not previously receive any anti-TNF-drug such as adalimumab or infliximab (no prior exposure to any anti-TNF-drug), or b. previously received (but no longer received) an anti-TNF-and drug • completed anti-TNF treatment, but may have relapsed, or • did not tolerate anti-TNF-treatment, or • failed to respond previously or had an inadequate response to anti-TNF-treatment. No more than 20% of the subjects will be in stratum 2a. Eligible subjects will be randomly assigned with equal probability (i.e., 1:1:1) to one of the three treatment groups within each stratum from a non-dynamic block randomization scheme, as per list. 1) Placebo twice a day 2) Avacopan 10 mg twice a day 3) Avacopan 30 mg twice a day Subjects will be screened for eligibility based on disease stage and health status. The screening period will last up to 28 days. The primary efficacy analysis will take place when the last enrolled subject has completed their 12-week visit. Following the 12-week blinded treatment period, all subjects will continue with an additional 24 weeks of treatment with either 10 mg or 30 mg of avacopan twice daily. The patient, study staff at the site, and sponsor will not be informed of the assignment to the 10 mg or 30 mg twice-daily regimen. All subjects will then be followed for 8 weeks. All subjects will visit the study site during the 28-day screening period and, if eligible, on day 1 and weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 44 of the study. The study drug will be dispensed at the study site, and subjects will receive their first dose of the study drug—either avacopan or equivalent placebo—while at the study site. After the first dose, subjects will take the study drug twice daily for 12 weeks (84 days). Following this, all subjects will take the study drug avacopan for 24 weeks (168 days), after which all subjects will be followed for 8 weeks (56 days) without taking the study drug. Subjects will be withdrawn from the study when all procedures of the week 44 study visit have been completed. Subjects who experience worsening of HS during the study will be treated by the investigator. This may include a maximum 1-week course of rescue antibiotic therapy with doxycycline or minocycline, or intralesional rescue injections of Kenalog (triamcinolone acetonide, a maximum of 10 mg total per subject within a period of no more than 1 week). These subjects will be asked to remain in the study and complete all study procedures, if possible. During this time, subjects may continue to receive the study drug as prescribed, if the investigator determines that it is clinically feasible. Study drug, dosage, and route of administration Study participants will receive either active avacopan or placebo capsules as the study drug. The study drug consists of hard gelatin capsules containing 10 mg of avacopan or placebo, administered orally. The bottles and capsules of avacopan and placebo will look identical. Subjects will be instructed to take 3 capsules of the study drug orally with water, preferably with food, each morning, and 3 capsules with water, preferably with food, at night approximately 12 hours after the morning dose, as directed. The study drug will be taken continuously for 36 weeks (252 days). Figure 1 shows a diagram of the study. Main objectives The main objectives of this clinical trial include: 1. To evaluate the efficacy of avacopan compared with placebo in subjects with Hurley stage II or III hidradenitis suppurativa (HS), starting from the date on which subjects achieve a hidradenitis suppurativa clinical response (HiSCR) after 12 weeks of treatment. HiSCR is defined as a reduction of at least 50% in abscess and inflammatory nodule (AN) counts without an increase in abscess count and without an increase in suppurative fistula count at week 12 compared with baseline. 2. The evaluation of the safety of avacopan compared to placebo in these subjects based on the incidence of adverse events, changes in laboratory parameters with respect to the initial level and vital signs. Secondary objectives The secondary objectives of this study include: 1. The evaluation of the efficacy of avacopan compared to placebo in these subjects includes: a. HiSCR: the proportion of subjects who achieve HiSCR at each time point, b. the subject's skin pain global assessment numerical rating scale (NRS), c. the modified Sartorius score, and d. the scope of an AN count of 0, 1 or 2 2. The assessment of subject-reported outcomes, including changes in health-related quality of life from the Short Form 36, Version 2 (SF-36 v2), the EuroQOL-5D-5L (EQ-5D-5L) questionnaire, the Hidradenitis Suppurativa Related Quality of Life Index (HiSQOL), the Dermatologic Quality of Life Index (DLQI), and the Work Productivity and Activities Impairment for a Specific Health Problem (WPAI:SHP) questionnaire with avacopan compared with placebo. 3. Evaluation of the pharmacokinetic profile of avacopan in subjects with HS. 4. Evaluation of the safety and efficacy of avacopan treatment from day 1 at each time point up to week 44 in subjects with HS. 5. The evaluation of the efficacy of avacopan compared to placebo in these subjects includes: a. the Sartorius score, the International HS4 Severity Scoring System score, the Physician-Assessment Global Assessment (HS-PGA), b. the proportion of subjects who experience worsening, who experience loss of response during period 2, who receive rescue oral antibiotic treatment or injury intervention, and who receive non-permitted opioid pain treatment, and c. the duration of worsening in days. 6. The evaluation of health economics information. Study treatments The treatments for each group are shown in Table 1. The treatment period is 36 weeks (252 days), followed by an 8-week (56-day) follow-up period without the study drug. Subjects will be randomized 1:1:1 to receive placebo, 10 mg of avacopan, or 30 mg of avacopan twice daily for blinded, placebo-controlled treatment during the first 12 weeks. Subjects randomized to 10 mg and 30 mg of avacopan will continue on the same drug regimen during the subsequent 24-week active drug treatment period. Subjects randomized to placebo during the first 12-week period will be re-randomized to receive either 10 mg or 30 mg of avacopan twice daily during the 24-week active drug treatment period. Study-group-specific drug kits will be dispensed at relevant study visits. Table 1: Avacopan / placebo treatment for the two study groups Study flow Subjects will be screened for eligibility based on disease stage and health status. The screening period will last up to 28 days. The primary efficacy analysis may occur once the last enrolled subject has completed their week 12 visit. Following the 12-week, placebo-controlled, blinded treatment period, all subjects will continue with 24 weeks of active treatment with either 10 mg of avacopan twice daily or 30 mg of avacopan twice daily. After week 36, all subjects will be followed for 8 weeks without receiving the study drug. All subjects will visit the study site during the 28-day screening period and, if eligible, on day 1 and weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 44 of the study. The study drug will be dispensed at the study site, and subjects will receive their first dose of the study drug—either avacopan or equivalent placebo—while at the study site. Preferably, on visit days, subjects should take their dose while at the site. After the first dose, subjects will take the study drug twice daily for 12 weeks (84 days). Following this, all subjects will take the study drug avacopan for 24 weeks (168 days), after which they will be followed for 8 weeks (56 days) without taking the study drug. Subjects will leave the study when all procedures of the week 44 study visit have been completed. Subjects who experience worsening of HS during the study will be treated by the investigator. This may include a maximum 1-week course of rescue antibiotic therapy with doxycycline or minocycline, or intralesional rescue injections of Kenalog® (triamcinolone acetonide, a maximum of 10 mg total per subject within a period of no more than 1 week). These subjects will be asked to remain in the study and complete all study procedures, if possible. During this time, subjects may continue to receive the study drug if the investigator deems it clinically feasible. Product features The study drug consists of hard gelatin capsules containing 10 mg of avacopan or placebo, administered orally. The bottles and capsules of avacopan and placebo will look identical. The capsules are manufactured according to current Good Manufacturing Practices. Dosage and regimens Subjects will be instructed to take 3 capsules of the study drug orally with water, preferably with food, each morning, and 3 capsules with water, preferably with food, at night approximately 12 hours after the morning dose, as directed. The study drug will be taken continuously for 36 weeks (252 days). Subjects will be asked to bring all study drug bottles to the study site at each study visit, whether empty or not, for study drug counting. If a person misses a dose, they should take the missed dose as soon as possible. If it is almost time for their next dose (within 3 hours), they should skip the missed dose and take their next dose at the usual time. On study visit days, it is preferable for subjects to take their morning dose of the study drug at the center after the collection of samples for PK, if applicable to that visit. Study procedures Day 1 of the study If eligible for the study, the subject will go to the study center on day 1. The following procedures will be performed before taking the first dose of the study drug: • Stratification and randomization in the IRT system; • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be taken to determine serum biochemistry, hematology and a serum pregnancy test (in women of childbearing potential); • A urine sample will be collected for urine analysis; • The anatomical location and number of inflammatory nodules, abscesses, fistulas and HS scars and the Hurley stage of HS will be recorded; • Compliance with the daily recording of skin pain in diaries will be checked and corrective actions will be taken, if necessary; • Data will be collected for the modified Sartorius score; • the IHS4 score will be calculated; • Subjects will be asked to complete the SF-36 v2, EQ-5D-5L and HiSQOL index forms; • The researcher will administer the HS-PGA; • Compliance with the daily recording of skin pain in the daily diary will be checked from 1 week before day 1 and the introduction will be repeated, if necessary; • Any adverse events prior to treatment will be recorded (from the time of the screening visit). The following procedures will then be carried out: • The study drug will be provided to the subject with dosage instructions; • The subject will be asked to take the first dose of the study drug at the study center; • The time of the study drug dosage will be recorded; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events following dosing will be recorded; • After all study procedures have been completed, the subject will be reminded that: - Record the intensity of skin pain and the dosage of the study drug in your daily diary; - Attend the study center for your week 2 study visit; - Store the study drug in a cool, dry place according to the label instructions for the duration of the study; - Take the study drug as directed; on study visit days, it is preferable for the subject to take the morning dose of the study drug at the center after the PK sample collection, if applicable to that visit, and - Continue taking all other accompanying medications as usual. Week 2 of the study (day 15) The week 2 study visit should take place within ± 2 days of the scheduled date. During this visit, the following study procedures will be performed: • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be drawn for shipment to the central laboratory to determine serum biochemistry, hematology and PK measurements; the date and time of sample collection for PK will be recorded; • The anatomical location and number of inflammatory nodules, abscesses, fistulas and HS scars will be recorded; • Compliance with the daily recording of skin pain and drug dosage in diaries will be checked and the introduction will be repeated if necessary; • Data will be collected for the modified Sartorius score; • the IHS4 score will be calculated; • the researcher will perform the HS-PGA; • The date and time of the last dose of the study drug will be recorded before the sample is taken for PK; • If the subject has not yet taken the morning dose of the study drug for this day, the subject will be asked to take the dose; • The study drug bottle will be checked to ensure that the subject is taking the study drug as directed; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will be reminded that: - Record the intensity of skin pain and the dosage of the study drug in your daily diary; - Attend the study center for the week 4 study visit; - Store the study drug in a cool, dry place according to the label instructions for the duration of the study; - Take the study drug as directed; on study visit days, it is preferable for the subject to take the morning dose of the study drug at the center after the PK sample collection, if applicable to that visit, and - Continue taking all other accompanying medications as usual. Week 4 of the study (day 29) The week 4 study visit should take place within ± 2 days of the scheduled date. During this visit, the following study procedures will be performed: • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be taken to determine serum biochemistry, hematology, a serum pregnancy test (in women of childbearing potential) and PK measurements; the date and time of the PK sample collection will be recorded; • The date and time of the last dose of the study drug will be recorded before the sample is taken for PK; • If the subject has not yet taken the morning dose of the study drug for this day, the subject will be asked to take the dose; • A urine sample will be collected for urine analysis; • The anatomical location and number of inflammatory nodules, abscesses, fistulas, and HS scars will be recorded; • Compliance with the daily recording of skin pain and the dosage of the study drug in diaries will be checked and the introduction will be repeated, if necessary; • Data will be collected for the modified Sartorius score; • the IHS4 score will be calculated; • the researcher will perform the HS-PGA; • Subjects will be asked to complete the SF-36 v2, EQ-5D-5L and HiSQOL index forms; • The drug count will be performed using the returned study drug bottle; • the study drug will be dispensed; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will be reminded that: - Record the intensity of skin pain and the dosage of the study drug in your daily diary; - Attend the study center for your week 8 study visit; - Store the study drug in a cool, dry place according to the label instructions for the duration of the study; - Take the study drug as directed; on study visit days, it is preferable for the subject to take the morning dose of the study drug at the center after the PK sample collection, if applicable to that visit, and - Continue taking all other accompanying medications as usual. Week 8 of the study (day 57) The week 8 study visit should take place within ± 2 days of the scheduled date. During this visit, the following study procedures will be performed: • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be taken to determine serum biochemistry, hematology, a serum pregnancy test (in women of childbearing potential) and PK measurements; the date and time of the PK sample collection will be recorded; • The date and time of the last dose of the study drug will be recorded before the sample is taken for PK; • If the subject has not yet taken the morning dose of the study drug for this day, the subject will be asked to take the dose; • A urine sample will be collected for urine analysis; • The anatomical location and number of inflammatory nodules, abscesses, fistulas, and HS scars will be recorded; • Compliance with the daily recording of pain and the dosage of the study drug in diaries will be checked and the introduction will be repeated, if necessary; • Data will be collected for the modified Sartorius score; • the IHS4 score will be calculated; • the researcher will perform the HS-PGA; • The drug count will be performed, and the study drug bottle will be checked to ensure that the subject is taking the study drug as directed; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will be reminded to: - record the intensity of skin pain and the dosage of the study drug in the daily diary; - attend the study center for the week 12 study visit; - Store the study drug in a cool, dry place according to the label instructions for the duration of the study; - Take the study drug as directed; on study visit days, it is preferable for the subject to take the morning dose of the study drug at the center after the PK sample collection, if applicable to that visit, and - Continue taking all other accompanying medications as usual. Week 12 of the study (day 85) The week 12 study visit should take place within ± 2 days of the scheduled date. During this visit, the following study procedures will be performed: • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be taken to determine serum biochemistry, hematology, a serum pregnancy test (in women of childbearing potential) and PK measurements; the date and time of the PK sample collection will be recorded; • The date and time of the last dose of the study drug will be recorded before the sample is taken for PK; • If the subject has not yet taken the morning dose of the study drug for this day, the subject will be asked to take the dose; • A urine sample will be collected for urine analysis; • The anatomical location and number of inflammatory nodules, abscesses, fistulas, and HS scars will be recorded; • Compliance with the daily recording of pain in diaries will be checked and the introduction will be repeated, if necessary; • Data will be collected for the modified Sartorius score; • the researcher will perform the HS-PGA; • the IHS4 score will be calculated; • Subjects will be asked to complete the SF-36 v2, EQ-5D-5L and HiSQOL index forms; • The drug count will be performed using the returned study drug bottle; • Study drug will be dispensed; note: at this visit, subjects who were assigned to the placebo arm will be re-randomized to receive either 10 mg or 30 mg of avacopan twice daily; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will be reminded that: - Record the intensity of skin pain and the dosage of the study drug in your daily diary; - Attend the study center for the week 16 study visit; - Store the study drug in a cool, dry place according to the label instructions for the duration of the study; - Take the study drug as directed; on study visit days, it is preferable for the subject to take the morning dose of the study drug at the center after the PK sample collection, if applicable to that visit, and - Continue taking all other accompanying medications as usual. Week 16 of the study (day 113) The week 16 visit should take place within ± 2 days of the scheduled date. During this visit, the following study procedures will be performed: • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be taken to determine serum biochemistry, hematology, a serum pregnancy test (in women of childbearing potential) and PK measurements; the date and time of the PK sample collection will be recorded; • The date and time of the last dose of the study drug will be recorded before the sample is taken for PK; • If the subject has not yet taken the morning dose of the study drug for this day, the subject will be asked to take the dose; • A urine sample will be collected for urine analysis; • The anatomical location and number of inflammatory nodules, abscesses, fistulas, and HS scars will be recorded; • Compliance with the daily recording of pain and the dosage of the study drug in diaries will be checked and the introduction will be repeated, if necessary; • Data will be collected for the modified Sartorius score; • the IHS4 score will be calculated; • the researcher will perform the HS-PGA; • Subjects will be asked to complete the SF-36 v2, EQ-5D-5L and HiSQOL index forms; • Drug counts will be performed, and the study drug bottle will be checked to ensure that the subject is taking the study drug as directed; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will be reminded that: - Record the intensity of skin pain and the dosage of the study drug in your daily diary; - Attend the study center for the week 20 study visit; - Store the study drug in a cool, dry place according to the label instructions for the duration of the study; - Take the study drug as directed; on study visit days, it is preferable for the subject to take the morning dose of the study drug at the center after the PK sample collection, if applicable to that visit, and - Continue taking all other accompanying medications as usual. Week 20 of the study (day 144) The week 20 study visit should take place within ± 2 days of the scheduled date. During this visit, the following study procedures will be performed: • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be taken to determine serum biochemistry, hematology, a serum pregnancy test (in women of childbearing potential) and PK measurements; the date and time of the PK sample collection will be recorded; • The date and time of the last dose of the study drug will be recorded before the sample is taken for PK; • If the subject has not yet taken the morning dose of the study drug for this day, the subject will be asked to take the dose; • A urine sample will be collected for urine analysis; • The anatomical location and number of inflammatory nodules, abscesses, fistulas, and HS scars will be recorded; • Compliance with the daily recording of pain and the dosage of the study drug in diaries will be checked and the introduction will be repeated, if necessary; • Data will be collected for the modified Sartorius score; • the IHS4 score will be calculated; • the researcher will perform the HS-PGA; • The drug count will be performed using the returned study drug vial; • The study drug will be dispensed • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will be reminded that: - Record the intensity of skin pain and the dosage of the study drug in your daily diary; - Attend the study center for the week 24 study visit; - Store the study drug in a cool, dry place according to the label instructions for the duration of the study; - Take the study drug as directed; on study visit days, it is preferable for the subject to take the morning dose of the study drug at the center after the PK sample collection, if applicable to that visit, and - Continue taking all other accompanying medications as usual. Week 24 of the study (day 169) The week 24 visit should take place within ± 2 days of the scheduled date. During this visit, the following study procedures will be performed: • Blood samples will be taken to determine serum biochemistry, hematology, a serum pregnancy test (in women of childbearing potential) and PK measurements; the date and time of the PK sample collection will be recorded; • The drug count will be performed, and the study drug bottle will be checked to ensure that the subject is taking the study drug as directed; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will be reminded to: - record the intensity of skin pain and the dosage of the study drug in the daily diary; - attend the study center for the week 28 study visit; - Store the study drug in a cool, dry place according to the label instructions for the duration of the study; - Take the study drug as directed; on study visit days, it is preferable for the subject to take the morning dose of the study drug at the center after the PK sample collection, if applicable to that visit, and - Continue taking all other accompanying medications as usual. Week 28 of the study (day 197) The week 28 study visit should take place within ± 2 days of the scheduled date. During this visit, the following study procedures will be performed: • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be taken to determine serum biochemistry, hematology, a serum pregnancy test (in women of childbearing potential) and PK measurements; the date and time of the PK sample collection will be recorded; • The date and time of the last dose of the study drug will be recorded before the PK sample is taken; • If the subject has not yet taken the morning dose of the study drug for this day, the subject will be asked to take the dose; • A urine sample will be collected for urine analysis; • The anatomical location and number of inflammatory nodules, abscesses, fistulas, and HS scars will be recorded; • Compliance with the daily recording of pain and the dosage of the study drug in diaries will be checked and the introduction will be repeated, if necessary; • Data will be collected for the modified Sartorius score; • the IHS4 score will be calculated; • the researcher will perform the HS-PGA; • The drug count will be performed using the returned study drug vial; • The study drug will be dispensed; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will be reminded that: - Record the intensity of skin pain and the dosage of the study drug in your daily diary; - Attend the study center for your week 32 study visit; - Store the study drug in a cool, dry place according to the label instructions for the duration of the study; - Take the study drug as directed; on study visit days, it is preferable for the subject to take the morning dose of the study drug at the center after the PK sample collection, if applicable to that visit, and - Continue taking all other accompanying medications as usual. Week 32 of the study (day 225) The week 32 visit should take place within ± 2 days of the scheduled date. During this visit, the following study procedures will be performed: • Blood samples will be taken to determine serum biochemistry, hematology, a serum pregnancy test (in women of childbearing potential) and PK measurements; the date and time of the PK sample collection will be recorded; • The drug count will be performed, and the study drug bottle will be checked to ensure that the subject is taking the study drug as directed; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will be reminded that: - Record the intensity of skin pain and the dosage of the study drug in your daily diary; - Attend the study center for your week 36 study visit; - Store the study drug in a cool, dry place according to the label instructions for the duration of the study; - Take the study drug as directed; on study visit days, it is preferable for the subject to take the morning dose of the study drug at the center after the PK sample collection, if applicable to that visit, and - Continue taking all other accompanying medications as usual. Week 36 of the study (day 253) The week 36 study visit should take place within ± 2 days of the scheduled date. During this visit, the following study procedures will be performed: • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be taken to determine serum biochemistry, hematology, a serum pregnancy test (in women of childbearing potential) and PK measurements; the date and time of the PK sample collection will be recorded; • The date and time of the last dose of the study drug will be recorded before the sample is taken for PK; • A urine sample will be collected for urine analysis; • The anatomical location and number of inflammatory nodules, abscesses, fistulas, and HS scars will be recorded; • Compliance with the daily recording of pain and the dosage of the study drug in diaries will be checked and the instruction will be repeated if necessary; • Data will be collected for the modified Sartorius score; • the IHS4 score will be calculated; • the researcher will perform the HS-PGA; • Subjects will be asked to complete the SF-36 v2, EQ-5D-5L and HiSQOL index forms; • The drug count will be performed using the returned study drug bottle(s); • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will be reminded that: - record the intensity of the pain on the skin in your daily diary; - Come to the study center for your week 44 study visit, and - Continue taking all other accompanying medications as usual. Week 44 of the study (day 309) The week 44 follow-up visit should take place within ± 4 days of the scheduled date. During this visit, the following study procedures will be performed: • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be drawn to determine serum biochemistry, hematology and PK measurements; the date and time of the PK sample collection will be recorded; • A urine sample will be collected for urine analysis; • The anatomical location and number of inflammatory nodules, abscesses, fistulas, and HS scars will be recorded; • Data will be collected for the modified Sartorius score; • the IHS4 score will be calculated; • the researcher will perform the HS-PGA; • Subjects will be asked to complete the SF-36 v2, EQ-5D-5L and HiSQOL index forms; • The completed daily diary will be collected; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded; • After all study procedures have been completed, the subject will leave the study. Early termination visit If a subject withdraws from the study early, the following termination procedures should be completed where possible: • a physical examination that includes body weight; • vital signs (temperature, blood pressure while seated, heart rate) after at least 3 minutes of rest; • Blood samples will be taken to determine serum biochemistry, hematology and a serum pregnancy test (in women of childbearing potential) and PK measurements; the date and time of the PK sample collection will be recorded; • A urine sample will be collected for urine analysis; • The anatomical location and number of inflammatory nodules, abscesses, fistulas, and HS scars will be recorded; • Data will be collected for the modified Sartorius score if the previous visit at which this assessment was performed was more than 2 weeks prior; • Subjects will be asked to complete the SF-36 v2, EQ-5D-5L and HiSQOL index forms if the previous visit in which these assessments were performed was more than 2 weeks prior; • The investigator will perform the HS-PGA if the previous visit in which this assessment was performed was more than 2 weeks prior; • The drug count will be performed using the returned study drug vials; • The completed daily log will be collected; • Any changes in the use of concomitant medications will be recorded, including alcohol intake, drug use, non-prescription medications, herbal preparations, or special diets; • Any adverse events will be recorded. Study evaluations Assessment of the location and extent of hidradenitis suppurativa The location and extent of HS will be assessed by recording the anatomical location(s) of the disease, as well as the number of inflammatory nodules, abscesses, fistulas, and HS scars at each location, in the EDC system. All study investigators will receive and have completed specific training in assessing HS lesions. The same investigator should assess the lesions at each visit to ensure consistency. If this is not possible, a trained support investigator at the site should perform the assessment. Information regarding the location and extent of HS involvement will be used to determine the Hurley stage and also to calculate the HiSCR at subsequent visits beyond the initial level. The HiSCR will be calculated using a program in the EDC system. Modified Sartorius score Twelve body zones will be assessed to calculate the modified Sartorius score: • left and right armpits, • left and right inframammary zones, • intermammary area, • left and right buttocks, • left and right inguinal folds, • perianal area and perineal area, and • other (specify) . A score of 4 indicates the least severe disease, and higher scores indicate increasingly severe disease. There is no upper limit for the score (Sartorius et al., 2003). The presence of nodules, abscesses, fistulas, scars, and other findings will be recorded in the EDC system. The greatest distance between any two lesions and whether the lesions are separated by normal skin will also be recorded. International scoring system for the severity of hidradenitis suppurativa The International Hidradenitis Suppurativa Severity Score (IHS4) is easy to calculate and validate using existing clinician-provided outcomes (such as HS-PGA, Hurley classification, MSS, or expert opinion classification) and the Patient-Reported Outcome Measure (DLQI). IHS4 score (points) = (number of nodules multiplied by 1) + (number of abscesses multiplied by 2) + [number of draining tunnels (internal fistulas / external fistulas) multiplied by 4]. A score of 3 or less indicates mild HS, a score of 4–10 indicates moderate HS, and a score of 11 or higher indicates severe HS. Physician-Assessed Global Evaluation of Hidradenitis Suppurativa (HS-PGA) The HS-PGA is a HS-specific ordinal scale that classifies patients as having no disease, minimal, mild, moderate, severe, or very severe disease, and has been used successfully in a phase II intervention clinical trial. A recently developed six-stage PGA has been defined as follows (Kimball et al., 2012): • No disease: no inflammatory or non-inflammatory nodules • Minimal: only the presence of non-inflammatory nodules • Mild: less than 5 inflammatory nodules, or 1 abscess or suppurative fistula and no inflammatory nodules • Moderate: fewer than 5 inflammatory nodules, or one abscess or suppurative fistula and one or more inflammatory nodules, or 2-5 abscesses or suppurative fistulas and fewer than ten inflammatory nodules • Severe: 2-5 suppurative abscesses or fistulas and ten or more inflammatory nodules • Very serious: more than 5 abscesses or suppurating fistulas Global skin pain Subjects will record peak pain intensity on a numerical rating scale from 0 (no skin pain) to 10 (the worst skin pain imaginable) in a daily diary from one week prior to day 1 until the week 44 visit. The weekly average of maximum pain intensity will be calculated using a program. Health-related quality of life assessments The SF-36 v2 and EQ-5D-5L instruments are comprehensive, disease-free tools widely accepted for measuring changes in health-related quality of life. Study participants will complete the forms for these instruments to measure changes in health-related quality of life from baseline. Approved translations will be used for non-English-speaking participants whenever possible. The HiSQOL index has been developed as a specific instrument for HS to measure the impact of HS on the quality of life of the subjects. Study staff will assist participants in completing the quality of life questionnaires, but will not complete the forms for them. The administrator will establish rapport with the participant, emphasize the importance of completing the form, and be available to answer any questions and address any concerns. Participants must complete the questionnaires before their scheduled visit with the researcher. Pharmacokinetic evaluations and analyses Avacopan (and metabolite) concentrations will be determined. The date and time of the last study drug dose before sample collection must be recorded in the EDC system. The date and time of sample collection for PK must also be recorded. Total plasma concentrations of avacopan (and metabolites) will be determined using validated analytical methods. Individual plasma concentrations of avacopan and significant metabolites will be recorded, plotted, and summarized descriptively and graphically. PK analysis will be performed only in a subset of subjects. Whenever possible, the following parameters will be determined: Cmax Maximum plasma concentration Tmax Time to maximum plasma concentration ABC0-6h Area under the plasma concentration-time curve from time 0 to hour 6 of day 1 Cmin Trough plasma concentrations on visits after day 1 The relationship between PK parameters (e.g., Cmin) and efficacy assessment criteria such as HiSCR can also be evaluated. Example 2 - Summary of preliminary results from the phase II trial The phase II AURORA clinical trial randomly assigned 398 patients to one of three treatment arms. The study population included patients with moderate (Hurley stage II) or severe (Hurley stage III) HS, who were evenly stratified across all treatment groups. The primary endpoint of the proportion of all patients (both moderate Hurley stage II and severe Hurley stage III) achieving a clinical response from hidradenitis suppurativa (HiSCR), as assessed with avacopan dosing regimens of 10 mg twice daily (BID) and 30 mg BID versus placebo after 12 weeks of treatment in the pooled study population, was not reached to statistical significance at any dose level, although a numerical improvement was observed with the 30 mg BID dose.Importantly, avacopan 30 mg twice daily demonstrated a statistically significant superior response to placebo in the previously specified population of patients with Hurley stage III (severe) HS in the study. The company plans to advance avacopan to Phase III development for the treatment of severe HS. Table 2: Results of the clinical response of hidradenitis suppurativa (HiSCR) *p = 0.0349 A consistent effect was observed with avacopan in Hurley stage III patients for all secondary endpoints assessed to date. Favorable reductions for avacopan were observed in the International Health Severity Score (IHS4), as well as a reduction in the number of inflammatory nodules and abscesses (ANs), draining fistulas, and abscesses at week 12 (all changes in % from baseline to week 12), compared to placebo. Avacopan demonstrated a favorable safety profile. Treatment-related adverse events (TREEs) were less frequent in the avacopan group (48.5%) than in the placebo group (55%). Most TREEs were related to underlying HS and were mild to moderate. Severe TREEs occurred in 2.3% of patients in the placebo group compared to 1.5% in the avacopan group. About hidradenitis suppurativa and the AURORA trial Hidradenitis suppurativa (HS), also known as inverse acne, is a chronic, debilitating autoimmune skin disease characterized by recurrent and painful nodules, boils, and abscesses. The phase II AURORA clinical trial randomly assigned 398 patients with moderate to severe HS to one of three treatment arms. The primary endpoint assessed avacopan dosing regimens of 10 mg twice daily (BID) and 30 mg BID versus placebo at 12 weeks of treatment, using the HiSCR scale. A HiSCR response was defined as a 50% reduction in the inflammatory lesion count (abscesses + inflammatory nodules) and no increase in abscesses or draining fistulas compared to baseline. Secondary endpoints included percentage improvement between groups through week 12, reduction in IHS4 (International Hidradenitis Suppurativa Severity Scoring System) from baseline, and other validated secondary measures. After the 12-week double-blind treatment period, the study will remain blinded. Patients receiving placebo will be re-randomized to the 10 mg twice-daily (BID) or 30 mg BID avacopan dose group for an additional 24 weeks; patients receiving avacopan will continue to receive the same dose (10 mg BID or 30 mg BID) for an additional 24 weeks. Patients will be followed for an additional 44 weeks for safety and efficacy assessment. Selective inhibition by avacopan of only C5aR allows the beneficial C5a pathway through the C5L2 receptor to continue functioning normally. Example 3 - Avacopan is surprisingly effective in patients with stage III HS Although the prior invention has been described in some detail by way of illustration and example for the sake of clarity, a person skilled in the art will appreciate that certain changes and modifications may be implemented within the scope of the appended claims. In the event of a conflict between this application and a reference provided herein, this application shall prevail.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in a method of treating hidradenitis suppurativa (HS) in a subject in need thereof, wherein said subject has been diagnosed with Hurley stage III HS and receives 30 mg of the compound twice daily, wherein each R1 is independently selected from the group consisting of CH3, CF3, CH2CH3, Cl, 1-pyrrolidine, -O-CH(CH3)2, and CH2OH; and each R2 is independently selected from the group consisting of CH3 and F.

2. The compound for the use of claim 1, wherein the compound is selected from the group consisting of, or is a pharmaceutically acceptable salt thereof.

3. The compound for the use of claim 1, wherein the compound is, or is a pharmaceutically acceptable salt thereof.

4. The compound for the use of claim 1, wherein the compound is avacopan, having the formula [formula missing], or a pharmaceutically acceptable salt thereof. 5.The compound for use according to any one of claims 1 to 4, wherein the subject receives treatment for 12 weeks.

6. The compound for use according to any one of claims 1 to 4, wherein the subject receives treatment for 26 weeks.

7. The compound for use according to any one of claims 1 to 4, wherein the subject receives treatment for 52 weeks.

8. The compound for use according to any one of claims 1 to 4, wherein the subject receives chronic treatment.

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