Certain N-(1-cyano-2-phenylethyl)-1,4-oxazepane-2-carboxamides for treating chronic sinusitis

Abstract

The present disclosure relates to a method for treating chronic sinusitis with a composition comprising an effective amount of a N-(1-cyano-2-phenylethyl)-1,4-oxazepane-2-carboxamide DPP1 inhibitor compound of formula (I), or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (brensocatib). [Formula 1] JPEG2024540142000058.jpg3565

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 273,540, filed October 29, 2021, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Chronic rhinosinusitis (CRS) is a common upper respiratory tract condition that affects the physical and mental health of more than 50 million people worldwide. CRS patients have symptoms such as stuffy nose, facial pain or pressure, nasal obstruction, runny nose, and loss of smell, which can last for more than 12 weeks. CRS therefore leads to a reduced quality of life due to its adverse effects on health, vitality, and social functioning, and is associated with increased rates of depression and antidepressant use.

[0003] Current treatments include intranasal or oral steroids, antihistamines, oral antibiotics, and endoscopic sinus surgery (ESS). While a small percentage of CRS patients (approximately 20%) develop nasal polyps (a condition called chronic rhinosinusitis with nasal polyps or CRSwNP), most CRS patients do not develop nasal polyps and have chronic rhinosinusitis without nasal polyps (CRSsNP). Chronic sinusitis, especially CRSsNP, is associated with a skewed type 1 immune response with a predominance of neutrophilic inflammation, which may affect treatment outcomes in CRS patients. Neutrophilia is associated with a poor response to corticosteroid therapy.

[0004] CRSsNP is the most common type of rhinosinusitis and is characterized by chronic inflammation of the sinus mucosa and paranasal sinuses. The most common symptoms include nasal congestion, mucus discharge from the nose or dripping down the back of the throat, nasal or mucus coughing, facial pain, and decreased sense of smell. Currently, there is no approved treatment for CRSsNP, leaving a significant unmet medical need.

[0005] Therefore, there is an urgent need to develop effective interventions for patients with chronic sinusitis, especially refractory chronic sinusitis as well as CRSsNP. Summary of the Invention

[0006] The disclosure, in one aspect, provides a method of treating chronic rhinosinusitis (CRS), comprising administering to a subject, for an administration period, a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharma- ceutical acceptable salt thereof; [ka] During the ceremony, R 1 teeth, [ka] and R 2 is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R 3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3 alkyl, CONH2, or SO2NR 4 R 5 and R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, or piperidine ring, X is O, S, or CF2; Y is O or S; Q is CH or N; R 6 is C 1-3 is an alkyl group, 1-3 The alkyl is optionally substituted by one, two or three F, and is selected from the group consisting of OH, OC1-3 alkyl, N(C 1-3 Optionally substituted by one substituent selected from the group consisting of alkyl, cyclopropyl, and tetrahydropyran; R 7is hydrogen, F, Cl, or CH3.

[0007] In one embodiment of the method provided herein, the CRS is CRS without nasal polyps (CRSsNP).In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period.In another embodiment, the CRS treated is steroid-refractory CRS, for example steroid-refractory CRSsNP.

[0008] In one embodiment, a method for treating CRS comprises decreasing the subject's Lund-Mackay score during or after the administration period compared to the subject's Lund-Mackay score before the administration period.

[0009] In another embodiment, the method comprises decreasing the subject's rhinoscopy total score during or after the administration period compared to the subject's rhinoscopy total score before the administration period.

[0010] In another embodiment, the method comprises decreasing the subject's Sinus Outcome Test-22 (SNOT-22) score during or after the administration period compared to the subject's SNOT-22 score before the administration period.

[0011] In yet another embodiment, the method includes increasing the subject's University of Pennsylvania Smell Identification Test (UPSIT) score during or after the administration period compared to the subject's UPSIT score before the administration period.

[0012] In yet another embodiment, the method includes decreasing the subject's modified Lund-Kennedy (MLK) score during or after the administration period compared to the subject's MLK score before the administration period.

[0013] In one embodiment, the method comprises decreasing the subject's composite severity score of two or more CRS symptoms during or after the administration period compared to the subject's composite severity score before the administration period.

[0014] In one embodiment, the method comprises decreasing the subject's Total Sinus Symptom Score (sTSS) during or after the administration period compared to the subject's sTSS prior to the administration period.

[0015] In one embodiment, the method comprises decreasing the subject's nasal congestion score (NCS) during or after the administration period compared to the subject's NCS before the administration period.

[0016] In one embodiment, the method comprises reducing the subject's anterior / posterior nasal drip severity score during or after the administration period compared to the subject's anterior / posterior nasal drip severity score before the administration period.

[0017] In one embodiment, the method comprises reducing the subject's facial pain / pressure severity score during or after the administration period compared to the subject's facial pain / pressure severity score before the administration period.

[0018] In one embodiment, the method comprises decreasing the subject's visual analog scale (VAS) score during or after the administration period compared to the subject's VAS score before the administration period.

[0019] In one embodiment, the method involves increasing the subject's peak nasal inspiratory flow (PNIF) during or after the administration period compared to the subject's PNIF prior to the administration period.

[0020] In one embodiment, the method includes reducing the subject's percentage of sinus opacification, as measured by CT scan volumetry, during or after the administration period compared to the subject's percentage of sinus opacification before the administration period.

[0021] In one embodiment, the method includes improving the subject's Patient Global Impression of Severity (PGI-S) score or Patient Global Impression of Change (PGI-C) score during or after the administration period, compared to the subject's PGI-S score or PGI-C score before the administration period.

[0022] In one embodiment of the methods provided herein, the compound of formula (I) is an S,S diastereomer, i.e., the compound of formula (I) has the following stereochemistry: [ka]

[0023] In some embodiments, R 1 teeth, [ka] In a further embodiment, X is O and R 6 is C 1-3 is alkyl, R 7 is hydrogen.

[0024] In some embodiments, the compound of formula (I) is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, referred to herein as its International Nonproprietary Name (INN), brensocatib (formerly known as INS1007 and AZD7986): [ka] or a pharma- ceutically acceptable salt thereof.

[0025] In one embodiment, the pharmaceutical composition is administered once daily during the administration period.

[0026] In one embodiment, the pharmaceutical composition is administered orally during the administration period.

[0027] In one embodiment, the compound of formula (I) is present in the pharmaceutical composition in an amount of about 1 mg to about 100 mg, such as about 10 mg, about 25 mg, or about 40 mg.In a further embodiment, the compound of formula (I) is brensocatib.

[0028] In one embodiment, the administration period is the overall survival of the subject after initial diagnosis of CRS, hi another embodiment, the administration period is from about 1 year to about 50 years, from about 1 year to about 30 years, or from about 1 year to about 10 years. [Brief description of the drawings]

[0029] [Figure 1] FIG. 1 is a schematic diagram of the study design described in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] The present disclosure provides a method of using a reversible inhibitor of dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, to treat chronic rhinosinusitis, such as chronic rhinosinusitis without nasal polyps (CRSsNP). DPP1 catalyzes the removal of dipeptides from the N-terminus of protein and peptide substrates. Through this enzymatic function, DPP1 activates many serine proteases in immune / inflammatory cells, such as neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), and neutrophil serine protease 4 (NSP4). Neutrophil serine proteases can mediate neutrophilic inflammation, which is often seen in patients with chronic rhinosinusitis, such as CRSsNP. Thus, in some embodiments, the method of use is a method of treating chronic rhinosinusitis (CRS), such as CRSsNP. In a further embodiment, the CRS being treated is steroid-refractory CRS, such as steroid-refractory CRSsNP.

[0031] Without wishing to be bound by theory, it is believed that inhibition of DPP1 function by the disclosed DPP1 inhibitors leads to inhibition of NSPs and / or reduces neutrophilic inflammation and thus can treat chronic sinusitis. In poorly controlled CRS, such as CRSsNP, neutrophils are the main drivers of remodeling and inflammatory processes. Targeting neutrophil activation and infiltration may provide a potential therapeutic approach to improve clinical outcomes in patients with steroid-refractory CRS characterized by neutrophilic inflammation or mixed eosinophilic-neutrophilic inflammation (Ahern and Cervin (2019). Medicina (Kaunas) 55(4), 95; Cho et al. (2016). J Allergy Clin Immunol Pract. 4(4), 575-582; De Greve et al. (2017). Clin Transl Allergy. 7, 22; and Delemarre et al. (2020). J Allergy Clin Immunol. 146(2), 337-43.e6, each of which is incorporated herein by reference in its entirety), inhibition of DPP1 by administering the disclosed DPP1 inhibitors can reduce NSP activity, resulting in a reduction in neutrophil-mediated inflammation, tissue damage, and mucus production in CRSsNP patients, leading to an improvement in symptoms (e.g., nasal congestion, facial pain, runny nose) and a significant reduction in the inflammatory cascade.

[0032] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this application, representative methods and materials are described herein.

[0033] In accordance with the rules of long-term patent law, the terms "a," "an," and "the" refer to "one or more" when used in this application, including the claims. Thus, for example, reference to a "carrier" includes one or more carriers, mixtures of two or more carriers, and the like, and reference to a "process" includes references to equivalent steps and / or methods known to those skilled in the art.

[0034] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and the like used in the present specification and claims should be understood as being modified in all cases by the term "about". Thus, unless otherwise indicated, the numerical parameters described in the present specification and the appended claims are approximate and may vary depending on the desired properties sought to be obtained by the present application. In general, as used herein, the term "about" refers to measurable values ​​such as weight, time, dosage, and the like, and is meant to encompass values ​​within the degree of variation acceptable in the art. In some embodiments, the degree of variation is based on FDA guidelines.

[0035] Also, as used herein, "and / or" refers to any and all possible combinations of one or more of the associated listed items, as well as including the absence of a combination when interpreted in the alternative ("or").

[0036] As used herein, "C 1-3 " means a carbon group having 1, 2, or 3 carbon atoms.

[0037] The term "alkyl", unless otherwise specified, includes both straight and branched chain alkyl groups, and may be substituted or unsubstituted. "Alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, and pentyl.

[0038] The term "pharmaceutical acceptable," unless otherwise specified, is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as appropriate for use in accordance with sound medical judgment. Generally, a pharmaceutical acceptable moiety has one or more benefits that outweigh any adverse effects that the moiety may have. Adverse effects may include, for example, excessive toxicity, irritation, allergic responses, and other problems and complications.

[0039] As used herein, "treatment" or "treat" or "ameliorate" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to any therapeutically relevant improvement or effect on one or more diseases, conditions, or symptoms being treated. In one embodiment, the term "treating" includes: (1) preventing or delaying the appearance of clinical symptoms of a condition, disorder, or condition that occurs in a patient who may be afflicted or affected by the condition, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition (e.g., halting, reducing, or delaying the onset of the disease with respect to at least one clinical or subclinical symptom thereof, or, in the case of maintenance treatment, halting, reducing, or delaying its recurrence); and (3) alleviating the condition (e.g., by causing regression or a reduction in severity of the condition, disorder, or condition, or at least one of its clinical or subclinical symptoms).

[0040] The term "effective amount" or "therapeutically effective amount" refers, for example, to an amount of an agent sufficient to bring about a beneficial or desired result. The therapeutically effective amount can vary depending on one or more of the subject and disease state being treated, the weight and age of the subject, the severity of the disease state, the method of administration, and the like.

[0041] As used herein, the terms "subject," "individual," and "patient" are used interchangeably to refer to a vertebrate, such as a mammal. A mammal may be, for example, a mouse, a rat, a rabbit, a cat, a dog, a pig, a sheep, a horse, a non-human primate (e.g., a cynomolgus monkey, a chimpanzee), or a human. Also included are subject tissues, cells, or derivatives thereof obtained in vivo or cultured in vitro. A human subject may be an adult, a teenager, a child (2-14 years), an infant (1-24 months), or a newborn (up to 1 month). In some embodiments, an adult is about 65 years of age or older, or an elderly person about 60 years of age or older. In some embodiments, the subject is a pregnant woman or a woman who is intending to become pregnant. In one embodiment, the subject is 18 years of age or older to 85 years of age or younger.

[0042] In one aspect, a method is provided for inhibiting dipeptidyl peptidase (DPP1) in a subject having or at risk of developing chronic rhinosinusitis (CRS), the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I) during an administration period. In some embodiments, DPP1 is expressed by neutrophils. In some embodiments, the administration results in a delay in the onset of CRS in the subject.

[0043] In another aspect, a method is provided for treating chronic sinusitis in a subject in need thereof. The method, in one embodiment, comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I) during an administration period. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0044] In some embodiments, the CRS is CRS without nasal polyps (CRSsNP). In some embodiments, the CRS is CRS with nasal polyps (CRSwNP). In some embodiments, the CRS is refractory CRS. In some embodiments, the refractory CRS is refractory CRS without nasal polyps (CRSsNP). In some embodiments, the refractory CRS is refractory CRS with nasal polyps (CRSwNP).

[0045] In one aspect, a method of treating CRS in a subject in need thereof is provided, the method comprising administering to the subject, during an administration period, an effective amount of a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof; [ka] During the ceremony, R 1 teeth, [ka] and R 2 is hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C 1-3 is alkyl, R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2, or SO2NR 4 R 5 and R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, or piperidine ring, or R 6 is C 1-3 alkyl, optionally substituted by 1, 2 or 3 F, and / or OH, OC 1-3 Alkyl, N(C 1-3 Optionally substituted by alkyl, cyclopropyl, or tetrahydropyran; R 7 is hydrogen, F, Cl, or CH3, X is O, S, or CF2; Y is O or S; Q is CH or N.

[0046] In one embodiment of the methods provided herein, the compound of formula (I) is an S,S diastereomer. In other words, the compound of formula (I) has the following stereochemistry: [ka]

[0047] Other diastereomeric forms are also contemplated by the present invention. For example, in one embodiment, the compound of formula (I) is an R,R diastereomer. [ka]

[0048] In another embodiment, the compound of formula (I) is the R,S diastereomer. [ka]

[0049] In yet another embodiment, the compound of formula (I) is the S,R diastereomer. [ka]

[0050] In one embodiment of the methods provided herein, R 1 teeth, [ka] X is O, S, or CF2, Y is O or S, Q is CH or N, and R 6 is C 1-3 is an alkyl group, 1-3 Alkyl is optionally substituted by one, two or three F, and is substituted with OH, OC1-3 alkyl, N(C 1-3 alkyl), cyclopropyl, and tetrahydropyran; 7 is hydrogen, F, Cl, or CH3.

[0051] In one embodiment, R 1 teeth, [ka] and R 2 is hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C 1-3 is alkyl, R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2, or SO2NR 4 R 5 and R 4 and R 5 taken together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, or piperidine ring.

[0052] In a further embodiment, R 1 teeth, [ka] and R 2 is hydrogen, F, Cl, or C 1-3 is alkyl, R 3 is hydrogen, F, Cl, CN, or SO2C 1-3 It is an alkyl.

[0053] In a further embodiment, R 1 teeth, [ka] and R 2 is hydrogen, F, or C 1-3 is alkyl, R 3 is hydrogen, F, or CN.

[0054] In another embodiment, R 1 teeth [ka] and

[0055] X is O, S, or CF2, Y is O or S, Q is CH or N, and R 6 is C 1-3 Alkyl, C 1-3 The alkyl is optionally substituted by one, two or three F and / or OH, OC 1-3 Alkyl, N(C 1-3 alkyl), cyclopropyl, or tetrahydropyran; 7 is hydrogen, F, Cl, or CH3.

[0056] In one embodiment, R 1 teeth, [ka] It is.

[0057] In another embodiment, R 1 teeth [ka] where X is O and R 6 is C 1-3 is alkyl, R 7 is hydrogen. In a further embodiment, R 6 is methyl.

[0058] In one embodiment, R 1 teeth [ka] X is O, S, or CF2, Y is O or S, and R 6 is optionally substituted by one, two or three F and is selected from the group consisting of OH, OC 1-3 Alkyl, N(C 1-3C optionally substituted by alkyl, cyclopropyl, or tetrahydropyran 1-3 is alkyl, R 7 is hydrogen, F, Cl, or CH3.

[0059] In another embodiment, R 1 teeth [ka] X is O, S, or CF2; R 6 is C 1-3 Alkyl, C 1-3 Alkyl is optionally substituted with 1, 2, or 3 F; R 7 is hydrogen, F, Cl, or CH3.

[0060] In one embodiment, X is O and R 6 is C 1-3 is alkyl, R 7 is hydrogen.

[0061] In one embodiment, R 1 teeth, [ka] In a further embodiment, X is O and R 6 is C 1-3 is alkyl, R 7 is hydrogen.

[0062] In one embodiment, R 1 teeth [ka] where X is O and R 6 is C 1-3 is alkyl, R 7 is hydrogen.

[0063] In another embodiment, R 1 teeth, [ka] X is O and R 6 is C 1-3 Alkyl, C 1-3 The alkyl is optionally substituted by one, two, or three F; R 7 is hydrogen.

[0064] In one embodiment, R 2 is hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C 1-3 It is an alkyl.

[0065] In a further embodiment, R 2 is hydrogen, F, Cl, or C 1-3 It is an alkyl.

[0066] In yet a further embodiment, R 2 is hydrogen, F, or C 1-3 It is an alkyl.

[0067] In one embodiment, R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2, or SO2NR 4 R 5 and R 4 and R 5 taken together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, or piperidine ring.

[0068] In a further embodiment, R 3 is hydrogen, F, Cl, CN, or SO2C 1-3 It is an alkyl.

[0069] In yet a further embodiment, R 3 is hydrogen, F, or CN.

[0070] In one embodiment, R 6 is C 1-3 is an alkyl group,1-3 Alkyl is optionally substituted by 1, 2 or 3 F and OH, OC 1-3 Alkyl, N(C 1-3 Optionally substituted by one substituent selected from the group consisting of alkyl, cyclopropyl, and tetrahydropyran;

[0071] In a further embodiment, R 6 is C 1-3 is an alkyl group, 1-3 The alkyl is optionally substituted with one, two, or three F. In yet a further embodiment, R 6 is methyl or ethyl. In yet a further embodiment, R 6 is methyl.

[0072] In one embodiment, R 7 is hydrogen, F, Cl, or CH. In a further embodiment, R 7 is hydrogen.

[0073] In one embodiment of the methods provided herein, the composition administered to the patient comprises an effective amount of (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (referred to herein by its International Nonproprietary Name (INN) brensocatib), [ka] or a pharma- ceutically acceptable salt thereof.

[0074] In one embodiment, the compound of formula (I) is

[0075] (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide,

[0076] (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0077] (2S)-N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0078] 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate,

[0079] (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0080] (2S)-N-{(1S)-1-cyano-2-[4'-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide,

[0081] (2S)-N-[(1S)-1-cyano-2-(3',4'-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide,

[0082] (2S)-N-{(1S)-1-cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0083] (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0084] (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0085] (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,

[0086] (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,

[0087] (2S)-N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide,

[0088] (2S)-N-{(1S)-1-cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0089] (2S)-N-{(1S)-1-cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0090] (2S)-N-{(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0091] (2S)-N-[(1S)-1-cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,

[0092] (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,

[0093] (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,

[0094] (2S)-N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0095] (2S)-N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,

[0096] (2S)-N-{(1S)-1-cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0097] (2S)-N-[(1S)-2-(4'-carbamoyl-3'-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide,

[0098] (2S)-N-{(1S)-1-cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0099] (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,

[0100] (2S)-N-{(1S)-2-[4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide,

[0101] (2S)-N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,

[0102] (2S)-N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide,

[0103] (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide,

[0104] (2S)-N-{(1S)-1-cyano-2-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide,

[0105] (2S)-N-{(1S)-2-[4'-(azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide,

[0106] (2S)-N-[(1S)-1-cyano-2-(4'-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide,

[0107] (2S)-N-{(1S)-2-[4-(1,3-benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, or

[0108] (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, or a pharma- ceutically acceptable salt of one of the foregoing compounds.

[0109] It will also be understood that certain compounds of formula (I) may exist in solvated forms such as hydrates, including solvates of pharma- ceutically acceptable salts of compounds of formula (I).

[0110] In one embodiment, the compound of Formula (I) provided in the methods described herein is a hydrate. In a further embodiment, the compound is a hydrate of brensocatib.

[0111] In one embodiment, the compound of formula (I) is a racemate, a racemic mixture, a single enantiomer, an individual diastereomer, or a diastereomeric mixture. It should be understood that the present disclosure encompasses all such isomeric forms, such as the S,S diastereomer, the S,R diastereomer, the R,S diastereomer, and the R,R diastereomer disclosed herein, as well as mixtures of any two or more of the foregoing diastereomers.

[0112] Thus, in one embodiment, the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (i.e., brensocatib), as shown below: [ka] or a pharma- ceutically acceptable salt thereof. In one embodiment, brensocatib is a hydrate.

[0113] In one embodiment, the compound of formula (I) is (2R)-N-{(1R)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (i.e., the R,R isomer), as shown below: [ka] or a pharma- ceutically acceptable salt thereof.

[0114] In one embodiment, the compound of formula (I) is (2S)-N-{(1R)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (i.e., the S,R isomer), as shown below: [ka] or a pharma- ceutically acceptable salt thereof.

[0115] In one embodiment, the compound of formula (I) is (2R)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (i.e., the R,S isomer), as shown below: [ka] or a pharma- ceutically acceptable salt thereof.

[0116] In one embodiment, the composition comprises a mixture of one or more of the foregoing stereoisomers. In one embodiment, the mixture comprises a mixture of the S,S isomer (brensocatib) and the S,R isomer of the compound of formula (I). In another embodiment, the composition comprises a mixture of the S,S isomer (brensocatib) and the R,S isomer. In yet another embodiment, the composition comprises a mixture of the S,S isomer (brensocatib) and the R,R isomer.

[0117] Certain compounds of formula (I) may also contain linkages (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) where bond rotation is restricted about that particular linkage (e.g., restrictions resulting from the presence of ring bonds or double bonds). It is therefore to be understood that the present disclosure encompasses all such isomers. Certain compounds of formula (I) may also contain multiple tautomeric forms. It is to be understood that the present disclosure encompasses all such tautomeric forms. Stereoisomers may be separated using conventional techniques, such as chromatography or fractional crystallization, or stereoisomers may be made by stereoselective synthesis.

[0118] In a further embodiment, the compounds of formula (I) include any isotopically labeled (or radiolabeled) derivatives of the compounds of formula (I). Such derivatives are derivatives of the compounds of formula (I) in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include: 2 H (also represented as "D" for deuterium). Thus, in one embodiment, there is provided a compound of formula (I) in which one or more hydrogen atoms are replaced by one or more deuterium atoms, and the deuterated compound is used in one of the methods provided herein.

[0119] In a further embodiment, the compound of formula (I) is administered in the form of a pro-drug, which is broken down in the human or animal body to ultimately provide a compound of formula (I). Examples of pro-drugs include in vivo hydrolysable esters of a compound of formula (I).

[0120] In vivo hydrolyzable (or cleavable) esters of compounds of formula (I) containing a carboxy or hydroxy group are, for example, pharma- ceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent acid or alcohol. For examples of ester prodrug derivatives, see, for example, Beaumont et al. (2003). Curr. Drug. Metab. 4, 461-485 (incorporated herein by reference in its entirety for all purposes).

[0121] Various other forms of prodrugs are known in the art and can be used in the methods provided herein. For examples of prodrug derivatives, see, for example, Rautio et al. (2008). Nature Reviews Drug Discovery, 7, 255-270 (incorporated herein by reference in its entirety for all purposes).

[0122] The dosage of the compound of formula (I) varies depending on the compound used, the mode of administration, the desired treatment, and the type, symptoms, or severity of CRS being treated. In some embodiments, the subject is administered a compound of formula (I) at a daily dose of about 10 mg to about 100 mg, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg (including all values ​​and subranges therebetween) during the administration period. In some embodiments, the subject is administered a compound of formula (I) at a daily dose of about 10 mg to about 65 mg. In one embodiment, the subject is administered a compound of formula (I) at a daily dose of about 10 mg. In another embodiment, the subject is administered a daily dose of about 40 mg of the compound of formula (I).In a further embodiment, the compound of formula (I) is brensocatib.

[0123] In some embodiments, the daily dose of the compound of Formula (I) during the administration period is within the range of 0.01 micrograms per kilogram of body weight (μg / kg) to 100 milligrams per kilogram of body weight (mg / kg), e.g., about 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 5 μg / kg, 10 μg / kg, 20 μg / kg, 30 μg / kg, 40 μg / kg, 50 μg / kg, 60 μg / kg, 70 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 120 μg / kg, 140 μg / kg, 160 μg / kg, 180 μg / kg, 190 μg / kg, 200 μg / kg, 250 μg / kg, 260 μg / kg, 270 μg / kg, 280 μg / kg, 290 μg / kg, 300 μg / kg, 310 μg / kg, 320 μg / kg, 330 μg / kg, 340 μg / kg, 350 μg / kg, 360 μg / kg, 370 μg / kg, 380 μg / kg, 390 μg / kg, 40 ... g / kg, 90 μg / kg, 100 μg / kg, 200 μg / kg, 300 μg / kg, 400 μg / kg, 500 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 900 μg / kg, 1 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, or 100 mg / kg (including all values ​​and subranges therebetween).

[0124] In one embodiment, the composition comprising an effective amount of a compound of formula (I) is in an oral dosage form. In a further embodiment, the compound of formula (I) is administered in a dosage form of 10 mg to 50 mg, for example, a 5 mg dosage form, a 10 mg dosage form, a 15 mg dosage form, a 20 mg dosage form, a 25 mg dosage form, a 30 mg dosage form, a 35 mg dosage form, a 40 mg dosage form, a 45 mg dosage form, or a 50 mg dosage form. In a further embodiment, the dosage form is a 10 mg, 25 mg, or 40 mg dosage form. In a further embodiment, the dosage form is administered once a day. In a further embodiment, the compound is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0125] In some embodiments, the compound of formula (I) is brensocatib and is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 100 mg, e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg, including all values ​​and subranges therebetween. In some embodiments, the amount of brensocatib in the pharmaceutical composition is in the range of about 10 mg to about 40 mg. In some embodiments, the amount of brensocatib in the pharmaceutical composition is in the range of about 25 mg to about 40 mg. In some embodiments, the amount of brensocatib in the pharmaceutical composition is in the range of about 10 mg to about 25 mg.

[0126] In a preferred embodiment, the compound of formula (I) is brensocatib and is present in the pharmaceutical composition at about 10 mg. In a further embodiment, the pharmaceutical composition is administered to the subject once daily for the administration period.

[0127] In another preferred embodiment, the compound of formula (I) is brensocatib and is present in the pharmaceutical composition at about 25 mg. In a further embodiment, the pharmaceutical composition is administered to the subject once daily during the administration period.

[0128] In another preferred embodiment, the compound of formula (I) is brensocatib and is present in the pharmaceutical composition at about 40 mg. In a further embodiment, the pharmaceutical composition is administered to the subject once daily during the administration period.

[0129] The methods provided herein include administering to a patient in need of treatment or prevention of CRS a composition comprising an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, during the administration period. The compound of formula (I) is an inhibitor of dipeptidyl peptidase 1 (DPP1) activity. In one embodiment, the compound is brensocatib, or a pharma- ceutically acceptable salt thereof. In a further embodiment, the compound is brensocatib.

[0130] In some embodiments, a subject undergoing one of the methods of treatment provided herein exhibits one or more symptoms of CRS. In further embodiments, the one or more symptoms of CRS are (a) stuffy nose, (b) nasal obstruction, (c) runny nose, (d) postnasal drip, (e) facial pressure, (f) facial pain, (g) facial fullness, (h) reduced sense of smell, (i) depression, (j) mucosal edema, (k) mucopurulent secretions, (l) middle meatus obstruction, (m) mucosal changes in the middle meatus ostium and paranasal sinuses, (n) rhinorrhea, or (o) any combination thereof. In some embodiments, the obstruction of the middle meatus is mucosal obstruction, edematous obstruction, or a combination thereof.

[0131] In some embodiments, administration of the pharmaceutical composition relieves, reduces the severity, delays the onset, or eliminates one or more symptoms of CRS. In further embodiments, the one or more symptoms of CRS are (a) stuffy nose, (b) nasal obstruction, (c) runny nose, (d) postnasal drip, (e) facial pressure, (f) facial pain, (g) facial fullness, (h) reduced sense of smell, (i) depression, (j) mucosal edema, (k) mucopurulent secretions, (l) middle meatus obstruction, (m) mucosal changes in the middle meatus orifice and sinuses, (n) rhinorrhea, (o), or any combination thereof. In some embodiments, administration of the pharmaceutical composition enhances sinus drainage. In some embodiments, the one or more symptoms of CRS exhibited by the subject may be any symptom described herein or known in the art to be associated with CRS. In some embodiments, the one or more symptoms of CRS are stuffy nose, reduced sense of smell, rhinorrhea, or any combination thereof. In some embodiments, the rhinorrhea is anterior rhinorrhea. In some embodiments, the rhinorrhea is post-nasal drip.

[0132] In some embodiments of the methods for treating CRS provided herein, the subject's symptoms, quality of life, or other characteristics are assessed (i) before the period of administration of the pharmaceutical composition, (ii) during the period of administration of the pharmaceutical composition, (iii) after the period of administration of the pharmaceutical composition, or a combination thereof. For example, in one embodiment, the subject's symptoms, quality of life, or other characteristics are assessed (i) before the period of administration of the pharmaceutical composition, and (ii) during the period of administration of the pharmaceutical composition. In another embodiment, the subject's symptoms, quality of life, or other characteristics are assessed (i) before the period of administration of the pharmaceutical composition, and (ii) after the period of administration of the pharmaceutical composition.

[0133] When assessing a subject's symptoms, quality of life, or other characteristics prior to an administration period, the assessment can be performed immediately prior to the administration period. As used herein, "immediately prior to an administration period" refers to 0 to 24 hours prior to the first administration of a pharmaceutical composition comprising a compound of Formula (I) to the subject. In one embodiment, when assessing a subject's symptoms, quality of life, or other characteristics prior to an administration period, the assessment is performed 1 to 14 days prior to the administration period, 1 to 13 days prior to the administration period, 1 to 12 days prior to the administration period, 1 to 11 days prior to the administration period, 1 to 10 days prior to the administration period, 1 to 9 days prior to the administration period, 1 to 8 days prior to the administration period, 1 to 7 days prior to the administration period, 1 to 6 days prior to the administration period, 1 to 5 days prior to the administration period, 1 to 4 days prior to the administration period, 1 to 3 days prior to the administration period, or 1 to 2 days prior to the administration period. In yet another embodiment, where a subject's symptoms, quality of life, or other characteristic is assessed prior to the administration period, the assessment is performed 1, 2, 3, 4, 5, 6, or 7 days prior to the administration period.

[0134] In one embodiment, the evaluation of the subject's symptoms, quality of life, or other characteristics is performed more than once, for example, (i) more than once before the administration period, (ii) more than once during the administration period, and / or (iii) more than once after the administration period. In these embodiments, the average power of the two or more evaluations is used to determine the subject's symptoms, quality of life, or other characteristics. For example, the evaluation can be performed on two or more consecutive days, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days. In another embodiment, the evaluation is performed more than once, every other day, or every third day.

[0135] In some embodiments, the methods for treating CRS provided herein include reducing a composite severity score of two or more symptoms of CRS. As used herein, a "composite severity score" is a quantitative scale of symptoms of CRS exhibited by a subject. In one embodiment, the composite severity score is the sum of all daily symptoms exhibited by the subject. In one embodiment, the composite severity score is a 0-9 point score based on the symptoms of nasal congestion, anterior and / or posterior nasal drip, and loss of smell. See, e.g., Bachert et al. (2019). Lancet 394, 1638-1650, especially p. 1641 right column and Table 2. In some embodiments, the composite severity score is reduced during or after the administration period compared to the composite severity score measured before the administration period.

[0136] In some embodiments, the subject's composite severity score during or after the administration period of the pharmaceutical composition is lower than the subject's composite severity score before the administration period (e.g., immediately before the administration period). In some embodiments, the subject's composite severity score during or after the administration period is at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) lower than the subject's composite severity score before the administration period, e.g., 1 day, 2 days, 3 days, 4 days, 5 days, or the average of multiple days before the administration period. In some embodiments, the subject's composite severity score during or after the administration period of the pharmaceutical composition is about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, or about 9 points lower than the subject's composite severity score before the administration period. In further embodiments, the subject is a CRSsNP patient. In further embodiments, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In another embodiment, the subject is a refractory CRS patient, for example a refractory CRSsNP patient.

[0137] In one embodiment, the subject's composite severity score before or during / after the administration period is the subject's average composite severity score, taken for two or more consecutive days, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, and the composite severity score is calculated as the average of these measurements, i.e., the average daily composite severity score. In one embodiment, to assess the composite severity score before or during / after the administration period, the composite severity score is assessed daily for two or more days, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, and the composite severity score is calculated as the average of these measurements for the corresponding time periods, i.e., the average daily composite severity score before or during / after the administration period.

[0138] In one embodiment of the method for treating CRS, the treatment comprises reducing a composite severity score of two or more symptoms of CRS, the composite severity score being the Total Sinus Symptom Score (sTSS). In one embodiment, the sTSS reflects the signs and symptoms of patients with CRS sNP and is considered a well-defined and reliable patient-reported nasal symptom score. In one embodiment, the sTSS is derived from the following items over the past 24 hours: nasal congestion, anterior and / or posterior nasal drip, and facial pain / pressure. In one embodiment, the severity of each symptom included in the sTSS is scored daily by the subject, for example, on an electronic device. In one embodiment, the assessment is performed in the morning (AM). In one embodiment, before treatment (i.e., before the administration period), the subject has an sTSS of 5 or more.

[0139] In one embodiment, to assess sTSS, subjects rate the following symptoms over the past 24 hours using a categorical scale of 0-3 (0=no symptoms, 1=mild symptoms, 2=moderate symptoms, and 3=severe symptoms): (i) blockage and / or obstruction; (ii) anterior / posterior nasal drip (runny nose); (iii) facial pain / pressure. See Fokkens et al., (2020). Rhinology 58(2), 82-111, which is incorporated herein by reference in its entirety.

[0140] In one embodiment, when assessing sTSS, prior to the administration period, the subject self-assess sTSS daily for two or more consecutive days immediately prior to the administration period, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days immediately prior to the administration period, and sTSS is calculated as the average of these measurements. In a further embodiment, when assessing sTSS, prior to the administration period, the subject self-assess sTSS daily for two or more consecutive days immediately prior to the administration period, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days immediately prior to the administration period, and sTSS is calculated as the average of these measurements. In another embodiment, a once-daily sTSS assessment is performed, e.g., 1, 2, or 3 days immediately prior to the administration period, and the single score is used as the daily sTSS immediately prior to the administration period. In one embodiment, to assess sTSS during or after administration, the subject self-assess sTSS daily for two or more days, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, and sTSS is calculated as the average of these measurements, i.e., the average daily sTSS during or after administration. In a further embodiment, to assess sTSS during or after administration, the subject self-assess sTSS daily for two or more consecutive days, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, and sTSS is calculated as the average of these measurements. In another embodiment, a single sTSS assessment is performed daily, and the single score is used as the daily sTSS score during or after the administration period.

[0141] In one embodiment, the method for treating CRS disclosed herein comprises reducing the daily or average daily sTSS of a CRSsNP subject during or after the administration period, compared to the subject's sTSS before the administration period. In one embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In another embodiment, the subject is a CRSsNP patient who has previously undergone nasal surgery. In another embodiment, the subject is a CRSsNP patient who has not previously undergone nasal surgery. In another embodiment, the subject is a CRSsNP patient who has an sTSS of 5 or more (including nasal congestion, anterior / posterior nasal drip, facial pain / pressure) before the administration period.

[0142] In some embodiments, methods for treating CRS disclosed herein include reducing a subject's sTSS by at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) during or after the administration period compared to the subject's sTSS before the administration period. In some embodiments, the subject's sTSS during or after the administration period is about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, or about 9 points lower than the subject's sTSS before administration of the pharmaceutical composition (i.e., before the administration period). In further embodiments, the subject is a CRSsNP patient. In further embodiments, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In another embodiment, the subject is a refractory CRS patient, for example a refractory CRSsNP patient.

[0143] In some embodiments, the methods for treating CRS provided herein include reducing the subject's nasal congestion score (NCS) during or after the administration period compared to the subject's NCS before the administration period. In one embodiment, when assessing NCS before the administration period, the subject self-assess NCS daily for two or more consecutive days, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, and NCS is calculated as the average of these measurements. In a further embodiment, when assessing NCS before the administration period, the subject self-assess NCS daily for two or more consecutive days, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, and NCS is calculated as the average of these measurements. In another embodiment, NCS assessment is performed once a day, and the single score is used as the daily NCS score before the administration period. In one embodiment, to assess NCS during or after the administration period, the subject self-assess NCS daily for two or more days, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 days, and NCS is calculated as the average of these measurements. In a further embodiment, the subject self-assess NCS daily for two or more consecutive days, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive days, and NCS is calculated as the average of these measurements. In another embodiment, a once-daily NCS assessment is performed during or after the administration period, and the single score is used as the daily NCS score during or after the administration period.

[0144] In one embodiment, the NCS is a congestion / obstruction severity score over a 24-hour period (i.e., daily NCS). In a further embodiment, the NCS is a portion of the daily total sinus symptom score (sTSS) assessed by the subject. The NCS score, in one embodiment, is assessed on the following scale: 0 (= no symptoms), 1 (=Mild symptoms (symptoms are clearly present, but barely noticeable and easily tolerated)); 2 (= moderate symptoms (disturbing but tolerable symptoms)), and 3 (= severe symptoms (symptoms that are intolerable and interfere with activities or daily life)).

[0145] In one embodiment, NCS is assessed as daily NCS, hi another embodiment, NCS is assessed as average daily NCS, e.g., over a period of two or more days, e.g., two or more consecutive days.

[0146] In one embodiment, the subject is a CRSsNP patient with a baseline NCS of 2 or greater (i.e., the subject's NCS prior to the administration period is 2 or greater). In some embodiments, the methods provided herein include reducing the subject's NCS during or after the administration period by at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) compared to the subject's NCS prior to the administration period. In some embodiments, the subject's NCS during or after the administration period of the pharmaceutical composition is about 0.5, about 1, about 1.5, about 2, about 2.5, or about 3 points lower than the subject's NCS before the administration period. In further embodiments, the subject is a CRSsNP patient. In further embodiments, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In another embodiment, the subject is a refractory CRS patient, for example a refractory CRSsNP patient.

[0147] In some embodiments, the method of treating CRS provided herein comprises reducing the subject's prenasal drip / postnasal drip severity score during or after the administration period, compared to the subject's prenasal drip / postnasal drip severity score before the administration period. In one embodiment, when assessing the prenasal drip / postnasal drip severity score before the administration period, the subject self-assess the prenasal drip / postnasal drip severity score daily for two or more days, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, and the prenasal drip / postnasal drip severity score is calculated as the average of these measurements, i.e., the average daily prenasal drip / postnasal drip severity score before the administration period. In a further embodiment, the average daily prenasal drip / postnasal drip severity score is the average of the scores obtained on two or more consecutive days. In another embodiment, the prenasal drip / postnasal drip severity score assessment is performed once a day, and the one score is used as the prenasal drip / postnasal drip severity score for the day before the administration period. In one embodiment, to assess the prenasal drip / postnasal drip severity score during or after the administration period, the subject self-assess the prenasal drip / postnasal drip severity score daily for 2 or more days, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, and the prenasal drip / postnasal drip severity score is calculated as the average of these measurements, i.e., the average daily prenasal drip / postnasal drip severity score during or after the administration period. In a further embodiment, the average daily prenasal drip / postnasal drip severity score is the average of the scores obtained on 2 or more consecutive days. In another embodiment, the prenasal drip / postnasal drip severity score assessment is performed once a day, and the single score is used as the daily prenasal drip / postnasal drip severity score during or after the administration period.

[0148] In one embodiment, the prenasal drip / postnasal drip severity score evaluated is the daily prenasal drip / postnasal drip severity score. In another embodiment, the prenasal drip / postnasal drip severity score evaluated is the average daily prenasal drip / postnasal drip severity score. In one embodiment, the subject is a CRSsNP patient.

[0149] In one embodiment, the anterior / posterior drip severity score is a component of the sTSS score. In one embodiment, whether the anterior / posterior drip severity score is a component of the sTSS score, the former is assessed as follows: 0 (= no symptoms), 1 (=Mild symptoms (symptoms are clearly present, but barely noticeable and easily tolerated)); 2 (= moderate symptoms (disturbing but tolerable symptoms)), and 3 (= severe symptoms (symptoms that are intolerable and interfere with activities or daily life)).

[0150] In some embodiments, the methods provided herein include reducing the subject's prenasal drip / postnasal drip severity score during or after the administration period by at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween). In some embodiments, the subject's prenasal drip / postnasal drip severity score during or after the administration period is about 0.5, about 1, about 1.5, about 2, about 2.5, or about 3 points lower than the subject's prenasal drip / postnasal drip severity score before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In another embodiment, the subject is a refractory CRS patient, for example a refractory CRSsNP patient.

[0151] In some embodiments, the method of treating CRS provided herein comprises reducing the subject's facial pain / pressure severity score during or after the administration period, compared to the subject's facial pain / pressure severity score before the administration period. In one embodiment, when assessing the facial pain / pressure severity score before the administration period, the subject self-assess the facial pain / pressure severity score daily for two or more days, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, and the facial pain / pressure severity score is calculated as the average of these measurements, i.e., the average daily facial pain / pressure severity score before the administration period. In a further embodiment, the average daily facial pain / pressure severity score is the average of the scores obtained on two or more consecutive days. In another embodiment, the facial pain / pressure severity score assessment is performed once a day, and the one score is used as the daily facial pain / pressure severity score before the administration period. In one embodiment, to assess the facial pain / pressure severity score during or after the administration period, the subject self-assess the facial pain / pressure severity score every day for two or more days, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, and the facial pain / pressure severity score is calculated as the average of these measurements, i.e., the average daily facial pain / pressure severity score during or after the administration period. In a further embodiment, the average daily facial pain / pressure severity score is the average of the scores obtained on two or more consecutive days. In another embodiment, the facial pain / pressure severity score assessment is performed once a day, and the single score is used as the daily facial pain / pressure severity score during or after the administration period. In one embodiment, the facial pain / pressure severity score assessed is the daily facial pain / pressure severity score, i.e., a score assessed based on the facial pain / pressure severity over the past 24 hours. In another embodiment, the facial pain / pressure severity score that is assessed is the average daily facial pain / pressure severity score.In one embodiment, the subject is a CRSsNP patient.

[0152] In one embodiment, the Facial Pain / Pressure Severity Score is a portion of the sTSS score. In one embodiment, the Facial Pain / Pressure Severity Score is assessed as follows: 0 (= no symptoms), 1 (=Mild symptoms (symptoms are clearly present, but barely noticeable and easily tolerated)); 2 (= moderate symptoms (disturbing but tolerable symptoms)), and 3 (= severe symptoms (symptoms that are intolerable and interfere with activities or daily life)).

[0153] In some embodiments, the methods provided herein include reducing the subject's facial pain / pressure severity score by at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) during or after the administration period compared to the subject's facial pain / pressure severity score before the administration period. In some embodiments, the subject's facial pain / pressure severity score during or after the administration period is about 0.5, about 1, about 1.5, about 2, about 2.5, or about 3 points lower than the subject's facial pain / pressure severity score before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In another embodiment, the subject is a refractory CRS patient, for example a refractory CRSsNP patient.

[0154] In some embodiments, the methods of treating CRS provided herein include reducing the subject's Lund-Mackay (LMK) score during or after the administration period, compared to the subject's Lund-Mackay (LMK) score before the administration period. In further embodiments, the subject is a CRSsNP patient. In further embodiments, the subject is a refractory CRSsNP patient.

[0155] The LMK total score is based on the evaluation of computed tomography (CT) scan findings for each sinus region of the subject. The degree of opacification is rated between 0 (normal), 1 (partial opacification) and 2 (complete opacification). These points may then be applied to the maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinuses on each side. The middle meatus ostium route may also be rated as 0 (not obstructed) or 2 (obstructed) in the LMK score. Thus, a maximum score of 12 per side is then derived for a total score of 24 (see Lund and Mackay (1993). Rhinology 31, 183-184, which is incorporated herein by reference in its entirety).

[0156] In some embodiments, the CT scan is of one or both of the subject's paranasal sinuses, the subject's middle meatal ostium, or a combination thereof. In some embodiments, the CT scan is of the subject's right middle meatal ostium, the subject's left middle meatal ostium, or a combination thereof. In some embodiments, the CT scan is of one or more of: (a) right frontal sinus, (b) left frontal sinus, (c) right anterior ethmoid sinus, (d) left anterior ethmoid sinus, (e) right posterior ethmoid sinus, (f) left posterior ethmoid sinus, (g) right maxillary sinus, (h) left maxillary sinus, (i) the subject's right sphenoid sinus, (j) the subject's left sphenoid sinus, or (k) a combination thereof.

[0157] In some embodiments, the subject's LMK score before the administration period is greater than the LMK score of a subject without CRS. In some embodiments, the subject's Lund-Mackay score before the administration period of the pharmaceutical composition is 4 or greater. For example, in some embodiments, the subject in need of treatment has a Lund-Mackay score of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 before the administration period of the pharmaceutical composition. In further embodiments, the subject is a CRSsNP patient.

[0158] In some embodiments, the methods for treating CRS provided herein comprise reducing the subject's Lund-Mackay (LMK) score during or after the administration period compared to the subject's LMK score before the administration period. In further embodiments, treating comprises reducing the LMK score to less than 4. In some embodiments, treating comprises reducing the subject's LMK score during or after the administration period to 0, 1, 2, or 3. In some embodiments, the methods provided herein include reducing the subject's LMK score by at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) during or after the administration period compared to the subject's LMK score before the administration period, e.g., 1, 2, 3, 4, 5, 6, or 7 days before the administration period. In some embodiments, the methods provided herein comprise decreasing the subject's LMK score by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 during or after the administration period. In further embodiments, the subject is a CRSsNP patient. In further embodiments, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In one embodiment, the subject is a refractory CRSsNP patient.

[0159] CT scans are useful for assessing changes in the sinonasal mucosa. Mucosal thickening on CT is currently considered an objective diagnostic criterion for CRS. Three-dimensional assessments that determine the percentage of disease volume from CT images are the most comprehensive and accurate information that can be obtained about the severity of disease on CT images. In some embodiments, the methods of treating CRS provided herein include reducing the percentage of sinus opacification in a subject measured by CT scan volume measurement during or after a dosing period, compared to the percentage of sinus opacification in the subject before the dosing period. In further embodiments, the subject is a CRSsNP patient. In further embodiments, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the dosing period, e.g., 1, 2, 3, 4, 5, 6, or 7 days before the dosing period. In one embodiment, the subject is a refractory CRSsNP patient.

[0160] In some embodiments, one or more symptoms of CRS are assessed in a subject by rhinoscopy. In one embodiment, rhinoscopy of a subject can reveal one or more of: (i) nasal dryness, (ii) dry nasal mucus, (iii) fibrin deposits, (iv) nasal obstruction, or (v) any combination thereof. In some embodiments, the method of treating CRS provided herein comprises decreasing the subject's rhinoscopy total score during or after a dosing period, compared to the subject's rhinoscopy total score before the dosing period, e.g., 1, 2, 3, 4, 5, 6, or 7 days before the dosing period. As used herein, "rhinoscopy total score" refers to a total score achieved from objectively recorded clinical endoscopic findings based on: (i) nasal dryness, (ii) dry nasal mucus, (iii) fibrin deposits, and (iv) nasal obstruction. All variables related to rhinoscopy mucosal findings are assessed using a 4-point scale as follows: none=0, mild=1, moderate=2, and severe=3. Further details of the rhinoscopy total score are provided in Gouteva et al. (2014). J Allergy (Cairo). 2014, 635490, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the methods provided herein include performing a rhinoscopy on the subject, the rhinoscopy being performed both (I) before the administration period, and (ii) during or after the administration period.

[0161] In some embodiments, the subject's total rhinoscopy score before the administration period is greater than that of a control subject without CRS.In some embodiments, the subject's total rhinoscopy score before the administration period, for example, 1, 2, 3, 4, 5, 6, or 7 days before the administration period, is greater than 1.For example, in some embodiments, the subject's total rhinoscopy score before the administration period, for example, 1, 2, 3, 4, 5, 6, or 7 days before the administration period, is 2 or 3.

[0162] In some embodiments, the subject's rhinoscopy total score during or after the administration period is 1 or more. In further embodiments, the subject's rhinoscopy total score during or after the administration period is 0 or 1. In further embodiments, the subject is a CRSsNP patient. In further embodiments, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In one embodiment, the subject is a refractory CRSsNP patient.

[0163] In some embodiments, the method of treating CRS provided herein includes decreasing the subject's Sinus Outcome Test-22 (SNOT-22) score during or after the administration period, compared to the subject's SNOT-22 score before the administration period, e.g., 1, 2, 3, 4, 5, 6, or 7 days before the administration period. "Snot-22" is a patient-reported outcome measure developed for use in CRS with or without nasal polyps, and includes 22 individual questions on a 5-category scale. The questions cover a wide range of issues related to health and health-related quality of life, including physical problems, functional limitations, and emotional impact. SNOT-22 scores range from 0 to 110, with a minimal clinically important difference (MCID) of 8.9 points or greater. Lower scores indicate less impact and better quality of life. The recall period for subjects reporting SNOT-22 scores is the past 2 weeks. The 22 individual questions of the SNOT-22 are grouped into five (5) domains, including nose, ear, sleep, general / practical, and emotional domains. Further details of the SNOT-22 are provided in Hopkins, et al. (2009). Clin. Otolaryngol. 34, 447-454, and Kennedy et al. (2013). Ann Allergy Asthma Immunol. 111(4), 246-251, the contents of each of which are incorporated herein by reference in their entirety.

[0164] In some embodiments, the method for treating CRS comprises reducing the subject's SNOT-22 score by 8 or more, 9 or more, or 10 or more points during or after the administration period, compared to the subject's SNOT-22 score before the administration period. In one embodiment, the SNOT-22 score is measured immediately before receiving the treatment method. In another embodiment, the SNOT-22 score is measured 1, 2, 3, 4, 5, 6, or 7 days before the administration period.

[0165] In some embodiments, the method for treating CRS comprises reducing the subject's SNOT-22 score by about 8 to about 40 points, about 8 to about 30 points, about 8 to about 20 points, about 8 to about 18 points, about 8 to about 16 points, or about 8 to about 14 points during or after the administration period compared to the subject's SNOT-22 score before the administration period. In some embodiments, the method for treating CRS comprises reducing the subject's SNOT-22 score by about 9 to about 40 points, about 9 to about 30 points, about 9 to about 20 points, about 9 to about 18 points, about 9 to about 16 points, or about 9 to about 14 points during or after the administration period compared to the subject's SNOT-22 score before the administration period.

[0166] In some embodiments, the subject's SNOT-22 score before the administration period is greater than that of a control subject without CRS. In some embodiments, the subject's SNOT-22 score before the administration period is 30 or greater. For example, in some embodiments, the subject's SNOT-22 score before the administration period is about 30 to about 110, about 30 to about 100, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, or about 30 to about 50. In another embodiment, the subject's SNOT-22 score is about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, or about 40 to about 60. In yet another embodiment, the subject's SNOT-22 score prior to the administration period is about 50 to about 110, about 60 to about 110, about 70 to about 110, about 80 to about 110, or about 90 to about 110.

[0167] In some embodiments, the SNOT-22 score of the subject before the administration period is greater than that of the control subject without CRS.In some embodiments, the SNOT-22 score of the subject before the administration period is 30 or more.For example, in some embodiments, the SNOT-22 score of the subject before the administration period is 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, or 110. In some embodiments, the subject's SNOT-22 score prior to the administration period is 20 or greater.

[0168] In some embodiments, the method for treating CRS provided herein comprises reducing the subject's SNOT-22 score by at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) during or after the administration period, compared to the subject's SNOT-22 score before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In one embodiment, the subject is a refractory CRSsNP patient.

[0169] In some embodiments, the methods for treating CRS provided herein comprise reducing the subject's SNOT-22 score during or after the administration period by at least about 10%. In some embodiments, the subject's SNOT-22 score during or after the administration period is less than 30. For example, in some embodiments, the subject's SNOT-22 score during or after the administration period is 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0. In some embodiments, the subject's SNOT-22 score during or after the administration period is less than 20. In one embodiment, where treating CRS comprises reducing the subject's SNOT-22 score, the subject is a CRSsNP patient. In further embodiments, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In one embodiment, the subject is a patient with refractory CRSsNP.

[0170] In some embodiments, the method of treating CRS provided herein comprises reducing the subject's visual analog scale (VAS) score during or after the administration period, compared to the subject's VAS score before the administration period. In one embodiment, the subject has a VAS score of 5 or more before the administration period, for example, immediately before the treatment method or 1, 2, 3, 4, 5, 6, or 7 days before the administration period. In another embodiment, the subject is a CRSsNP patient. In one embodiment, the subject is a refractory CRSsNP patient.

[0171] The VAS has been validated for use in adults with CRS to assess the overall severity of the disease. As described in Fokkens et al.,(2012).Rhinol Suppl.;50(23),1-298, which is incorporated herein by reference in its entirety. Participants are asked to answer the question, "How bothersome are your rhinosinusitis symptoms?" The VAS is ranked from 0 (not bothersome) to 10 (the most bothersome you can think of). The VAS scale can be used to determine the severity of the disease (mild, moderate, or severe). A VAS score of less than 5 is considered to affect quality of life (i.e., uncontrolled symptoms), a VAS score of greater than 2 to less than or equal to 5 is considered to have partially controlled symptoms, and less than 2 is considered to have well-controlled symptoms. As described in Mullol et al.(2022).J Allergy Clin Immunol Pract.10(6),1434-1453, which is incorporated herein by reference in its entirety. Based on the total severity, the VAS scores are as follows:

[0172] Mild = VAS 0-3

[0173] Moderate = VAS >3~7

[0174] Severe = VAS over 7~10

[0175] In one embodiment, the VAS score is used to assess the subject's symptoms over the past 24 hours. In a further embodiment, the VAS is self-administered by the subject. In a further embodiment, the VAS is self-administered electronically.

[0176] In some embodiments, the method for treating CRS provided herein comprises reducing the subject's VAS score by at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) during or after the administration period, compared to the subject's VAS score before the administration period, e.g., immediately before the treatment method, or 1, 2, 3, 4, 5, 6, or 7 days before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In one embodiment, the subject is a patient with refractory CRSsNP.

[0177] In one embodiment, the method for treating CRS comprises reducing a subject's VAS score from a severe score to a moderate score. In another embodiment, the method for treating CRS comprises reducing a subject's VAS score from a severe score to a mild score. In yet another embodiment, the method for treating CRS comprises reducing a subject's VAS score from a moderate score to a mild score.

[0178] In one embodiment, prior to the administration period, the subject has a VAS score of 5 or greater.

[0179] In some embodiments, the methods provided herein include increasing the subject's peak nasal inspiratory flow (PNIF) during or after the administration period compared to the subject's PNIF before the administration period. PNIF is an assessment of nasal obstruction by measuring airflow through both nasal passages during forced inspiration expressed in liters per minute. PNIF is a well-validated technique for assessing nasal flow through the nose (Scadding et al. (2011). Clin Transl Allergy 1:2, incorporated herein by reference in its entirety). In one embodiment, PNIF is measured using an InCheck portable nasal inspiratory flowmeter. In a further embodiment, the subject is a CRSsNP patient. In one embodiment, the subject is a refractory CRSsNP patient.

[0180] In one embodiment, three PNIF readings are obtained within a day, and the highest reading is used for evaluation. In some embodiments, the methods provided herein include increasing the subject's PNIF by at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) during or after the administration period compared to the subject's PNIF before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In one embodiment, the subject is a refractory CRSsNP patient.

[0181] In some embodiments, the methods provided herein include improving the subject's Patient Global Impression of Severity (PGI-S) score or Patient Global Impression of Change (PGI-C) score during or after the administration period, compared to the subject's respective score before the administration period. In further embodiments, the subject is a CRSsNP patient. In further embodiments, the subject is a refractory CRSsNP patient. Both PGI-S and PGI-C are one-item questionnaires using a balanced Likert scale that ask participants to evaluate the severity of CRS. Specifically, PGI-S uses a single-state 5-point categorical scale, with higher scores indicating more severe CRS. PGI-C is used to assess the perceived change in CRS status in response to treatment at a particular time point via a transitional 7-point categorical scale. For PGI-C, a decrease in score indicates improvement in CRS, and an increase in score indicates worsening of CRS.

[0182] In some embodiments, the methods provided herein include improving the subject's PGI-S score or PGI-C score by at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) during or after the administration period, compared to the subject's PGI-S score or PGI-C score before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In one embodiment, the subject is a refractory CRSsNP patient.

[0183] In some embodiments, the methods provided herein include improving a subject's PGI-S score by about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, or about 4.5 points during or after the administration period compared to the subject's PGI-S score before the administration period. In one embodiment, the method provided herein includes improving the subject's PGI-S score by about 0.5 to about 4.5 points, about 1 to about 4.5 points, about 1.5 to about 4.5 points, about 2 to about 4.5 points, about 2.5 to about 4.5 points, about 3 to about 4.5 points, about 0.5 to about 4 points, about 0.5 to about 3.5 points, about 0.5 to about 3 points, about 0.5 to about 2.5 points, about 0.5 to about 2 points, about 1 to about 4 points, about 1 to about 3.5 points, about 1.5 to about 3 points, about 1.5 to about 2.5 points, or about 1.5 to about 2 points during or after the administration period, compared to the subject's PGI-S score before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In one embodiment, the subject is a patient with refractory CRSsNP.

[0184] In some embodiments, the methods provided herein include improving the subject's PGI-C score by about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, or about 6.5 points during or after the administration period compared to the subject's PGI-C score before the administration period. In one embodiment, the method provided herein includes improving the subject's PGI-C score by about 0.5 to about 6.5 points, about 1 to about 6.5 points, about 1.5 to about 6.5 points, about 2 to about 6.5 points, about 2.5 to about 6.5 points, about 3 to about 6.5 points, about 3.5 to about 6.5 points, about 4 to about 6.5 points, about 4.5 to about 6.5 points, about 5 to about 6.5 points, about 0.5 to about 6 points, about 0.5 to about 5.5 points, about 0.5 to about 5 points, about 0.5 to about 4.5 points, about 0.5 to about 4 points, about 1 to about 6.5, about 1.5 to about 6, about 2 to about 5.5, about 2.5 to about 5, or about 3 to about 4.5 points during or after the administration period, compared to the subject's PGI-C score before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL prior to the administration period. In one embodiment, the subject is a refractory CRSsNP patient.

[0185] In some embodiments, the methods provided herein include increasing the time to first use of systemic corticosteroids, antibiotics, or nasal surgery rescue in a subject compared to a control subject, where the control subject has CRS and is not administered the pharmaceutical composition. In further embodiments, the subject and the control subject are each a CRSsNP patient, such as a refractory CRSsNP patient. In one embodiment, the time to first use of rescue is increased by about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks. In another embodiment, the time to first use of rescue is increased by at least about 1 day, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, or at least about 6 weeks. In another embodiment, the time to first use of rescue is increased by about 20 days to about 100 days, about 30 days to about 100 days, about 20 days to about 75 days, about 20 days to about 50 days, or about 20 days to about 40 days. In another embodiment, the time to first use of rescue is increased by at least 1 month, for example, from about 1 month to about 6 months, from about 1 month to about 4 months, or from about 1 month to about 3 months.

[0186] In some embodiments, the method of treating CRS provided herein comprises reducing the frequency of rescue by systemic corticosteroids, antibiotics, or nasal surgery in a subject due to worsening of CRS symptoms compared to a control subject, the control subject having CRS and not receiving the pharmaceutical composition. In further embodiments, the subject and the control subject are each a CRSsNP patient, such as a refractory CRSsNP patient. In one embodiment, the frequency of rescue is calculated over a period of about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months, or about 24 months. In one embodiment, the frequency of rescue in the subject is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 50%. In another embodiment, the frequency of rescue in a subject is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 50%.

[0187] In some embodiments, the method includes increasing the subject's University of Pennsylvania Smell Discrimination Test (UPSIT) score during or after the administration period compared to the subject's UPSIT score before the administration period, e.g., immediately before the treatment method, or 1, 2, 3, 4, 5, 6, or 7 days before the administration period. The "UPSIT" is a commercially available test for assessing the olfactory discrimination function of an individual's olfactory system. The theoretical range of UPSIT scores falls within the range of 0 to 40. Further details are provided in Doty et al. (1989). Perception & Psychophysics 45, 381-384 and Saltagi et al. (2021). Allergy & Rhinology, 12, 1-17, the contents of each of which are incorporated herein by reference in their entirety.

[0188] In some embodiments, the method of treating CRS comprises increasing the UPSIT score of the subject during or after the administration period, compared to the UPSIT score of the subject before the administration period. In some embodiments, the UPSIT score of the subject before the administration period is less than 33. In one embodiment, the UPSIT score of the subject before the administration period is less than 18. In some embodiments, the UPSIT score of the subject before the administration period is 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.

[0189] In some embodiments, the UPSIT score of the subject during or after the administration period is greater than the UPSIT score of the subject before the administration period. In some embodiments, the UPSIT score of the subject during or after the administration period is greater than 33. In some embodiments, the UPSIT score of the subject during or after the administration period is greater than 18. In some embodiments, the UPSIT score of the subject during or after the administration period is 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. In some embodiments, the methods provided herein include increasing the subject's UPSIT score by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 during or after the administration period. In another embodiment, the methods provided herein include increasing the subject's UPSIT score by about 1 to about 40, about 1 to about 30, about 1 to about 20, about 2 to about 30, about 2 to about 20, about 5 to about 40, about 5 to about 30, about 5 to about 20, or about 5 to about 10 during or after the administration period.

[0190] In some embodiments, the method comprises reducing the subject's UPSIT score by at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) during or after the administration period, compared to the subject's UPSIT score before the administration period, e.g., immediately before the treatment method, or 1, 2, 3, 4, 5, 6, or 7 days before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In another embodiment, the subject is a patient with refractory CRSsNP.

[0191] In some embodiments, the method comprises increasing the UPSIT score of the subject by at least about 2-fold, for example, about 3-fold, about 4-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, or about 40-fold (including all values ​​and subranges therebetween) during or after the administration period, compared to the UPSIT score of the subject before the administration period, for example, immediately before the treatment method, or 1, 2, 3, 4, 5, 6, or 7 days before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In another embodiment, the subject is a refractory CRSsNP patient.

[0192] In some embodiments, the methods for treating CRS provided herein include determining a subject's sinus endoscopic score, for example, via the modified Lund-Kennedy (MLK) endoscopic scoring system. As used herein, the "MLK" endoscopic scoring system is described in Psaltis et al. (2014) The Laryngoscope 124, 2216-2223, the entirety of which is incorporated herein by reference. The theoretical range of the MLK endoscopic scoring system is 0-12.

[0193] One embodiment of the method of treating CRS in a subject in need thereof comprises reducing the subject's MLK endoscopic score during or after the administration period compared to the subject's MLK endoscopic score before the administration period, e.g., immediately before the treatment method or 1, 2, 3, 4, 5, 6, or 7 days before the administration period. In some embodiments, the subject's MLK score before the administration period is 4 or greater. For example, in some embodiments, the subject's MLK score before the administration period is 5, 6, 7, 8, 9, 10, 11, or 12. In another embodiment, the subject's MLK score before the administration period is about 5 to about 12, about 6 to about 12, about 7 to about 12, about 8 to about 12, or about 10 to about 12. In some embodiments, the subject's MLK score before the administration period is higher than that of a control subject not having CRS.

[0194] In some embodiments, the MLK score of the subject on sinus endoscopy during or after the administration period is less than 4. For example, in some embodiments, the MLK score of the subject on sinus endoscopy during or after the administration period is 3, 2, 1, or 0. In some embodiments, the MLK score of the subject on or after the administration period is reduced by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In another embodiment, the MLK score of the subject on or after the administration period is reduced by about 1 to about 12, about 2 to about 12, about 3 to about 12, about 4 to about 12, about 5 to about 12, about 6 to about 12, about 7 to about 12, about 8 to about 12, or about 9 to about 12. In yet another embodiment, the MLK score of the subject on or after the administration period is reduced by 1 to about 12, about 2 to about 11, about 3 to about 10, or about 4 to about 9.

[0195] In some embodiments, the method for treating CRS in a subject in need thereof comprises reducing the subject's MLK score by at least about 2%, e.g., about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% (including all values ​​and subranges therebetween) during or after the administration period, compared to the subject's MLK score before the administration period. In a further embodiment, the subject is a CRSsNP patient. In a further embodiment, the subject is a CRSsNP patient with an eosinophil count of less than 300 cells / μL before the administration period. In one embodiment, the subject is a refractory CRSsNP patient.

[0196] In some embodiments, the number of neutrophils in the biological sample obtained from the subject prior to the administration period is greater than the number of neutrophils in the biological sample obtained from the control subject without CRS. In some embodiments, the number of neutrophils in the biological sample obtained from the subject prior to the administration period is at least about 1.2 times, e.g., about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 7.5 times, about 8 times, about 8.5 times, about 9 times, about 9.5 times, about 10 times, about 15 times, about 20 times, about 25 times, or about 30 times (including all values ​​and subranges therebetween) greater than the number of neutrophils in the biological sample obtained from the control subject without CRS. In some embodiments, the neutrophil count in a biological sample obtained from the subject prior to the administration period is at least about 2%, e.g., about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% (including all values ​​and subranges therebetween) greater than the neutrophil count in a biological sample obtained from a control subject without CRS.

[0197] In some embodiments, the level of intercellular adhesion molecule 1 (ICAM1) in a biological sample obtained from the subject prior to the administration period is greater than the level of ICAM1 in a biological sample obtained from the subject prior to the administration period, as compared to a control subject not having CRS. In some embodiments, the level of ICAM1 in a biological sample obtained from the subject prior to the administration period is at least about 1.2-fold, e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween) greater than the level of ICAM1 in a biological sample obtained from a control subject not having CRS. In some embodiments, the level of ICAM1 in a biological sample obtained from the subject prior to the administration period is at least about 2%, e.g., about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% (including all values ​​and subranges therebetween) greater than the level of ICAM1 in a biological sample obtained from a control subject without CRS.

[0198] In some embodiments, the expression of the one or more genes is altered in the tissue of the subject prior to the administration period, compared to the expression of the one or more genes in tissue obtained from a control subject without CRS. In some embodiments, the expression of the one or more genes is increased in the tissue of the subject prior to the administration period, compared to the expression of the one or more genes in tissue obtained from a control subject without CRS. In some embodiments, the expression of the one or more genes in tissue obtained from the subject prior to the administration period is at least about 1.2-fold, e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween) higher than the expression of the one or more genes in tissue obtained from a control subject without CRS.

[0199] In some embodiments, expression of the one or more genes in tissue obtained from the subject prior to the administration period is at least about 2%, e.g., about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% (including all values ​​and subranges therebetween) higher compared to expression of the one or more genes in tissue obtained from a control subject without CRS.

[0200] In some embodiments, expression of the one or more genes is decreased in tissue of the subject prior to the administration period compared to a control subject without CRS. In some embodiments, expression of the one or more genes in tissue obtained from the subject prior to the administration period is at least about 2%, e.g., about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% (including all values ​​and subranges therebetween) less than expression of the one or more genes in tissue obtained from a control subject without CRS.

[0201] In some embodiments, the tissue is sinonasal tissue. In some embodiments, the one or more genes encode a protein selected from the group consisting of T-bet, GATA binding protein 3 (GATA-3), RAR-related orphan receptor C, IFN-γ, interleukin (IL)-5, IL-17A, IL-22, IL-23, IL-8, TLR-2, and IL-10.

[0202] In some embodiments, the subject in need of treatment is at risk of developing CRS. Thus, if the subject in need of treatment is at risk of developing CRS, the methods provided herein may be considered prophylactic. In some embodiments, the subject at risk of developing CRS has or has had one or more of the following conditions: acute rhinosinusitis, viral airway infection, allergic rhinitis, nonallergic rhinitis, asthma, bronchitis, pneumonia, gastroesophageal reflux disease, adenotonsillitis, sleep apnea, otitis media, allergic or nonallergic upper airway disease, allergic or nonallergic lower airway disease, epithelial cell disorder, common variable immunodeficiency, HIV infection, cystic fibrosis (CF), ciliary dyskinesia, granulomatosis with polyangiitis, sarcoidosis, and chronic obstructive pulmonary disease.

[0203] In some embodiments, the subject in need of treatment is or has been repeatedly exposed to tobacco smoke. As used herein, "repeated exposure" to tobacco smoke refers to exposure that is frequent enough to be associated with, result in, or increase the risk of developing one or more adverse effects from inhaling tobacco smoke. Non-limiting adverse effects of inhaling tobacco smoke are cancer (e.g., lung cancer), coronary heart disease, respiratory infections, stroke, lung disease, diabetes, chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, tuberculosis, eye disease, immune dysfunction, and rheumatoid arthritis. In some embodiments, the subject is exposed to tobacco smoke at least once a month, for example, at least once every two weeks, at least once a week, at least every other day, at least daily, or several times a day. In some embodiments, the subject is an active smoker of tobacco-containing products, such as cigarettes. In some embodiments, the subject is passively exposed to tobacco smoke.

[0204] In some embodiments, the subject in need of treatment has one or more mutations in a gene encoding a protein selected from the group consisting of Ring1A and YY1 binding protein (RYBP), acyloxyacyl hydrolase (AOAH), IL-1 receptor associated kinase 4, IL-1 receptor-like 1, Toll-like receptor (TLR)-2, TLR-1, TLR-5, cystic fibrosis transmembrane conductance regulator (CFTR), and transforming growth factor beta-1. In some embodiments, the one or more mutations are single nucleotide polymorphisms. In some embodiments, the single nucleotide polymorphism is rs4504543 in the gene encoding AOAH, or rs4532099 in the gene encoding RYBP. Further details regarding mutations and risk factors associated with CRS are provided in Cho et al., J Allergy Clin Immunol Pract. 2016, the contents of which are incorporated herein by reference in their entirety.

[0205] In some embodiments of the methods of treating CRS provided herein, the CRS is associated with the presence or onset of one or more conditions selected from the group consisting of allergic conjunctivitis, atopic dermatitis, asthma, urinary tract infections, and skin / soft tissue infections.

[0206] In one embodiment, the subject in need of treatment is an adult with CRS having two or more symptoms for 12 weeks or more, including any one of the following: nasal congestion, nasal obstruction, stuffy nose, or runny nose (anterior / posterior nasal drip); (i) facial pain and / or pressure; and (ii) reduced or lost sense of smell.

[0207] In one embodiment, the subject in need of treatment is a child with CRS who has had two or more of the following symptoms for 12 weeks or more: nasal congestion, nasal obstruction, stuffy nose, or runny nose (anterior / posterior nasal drip), (i) with or without facial pain and / or pressure, and (ii) with or without cough.

[0208] In one embodiment, the subject in need of treatment has difficult-to-treat CRS, i.e., has persistent symptoms of CRS despite being treated with recommended medications (e.g., intranasal corticosteroid therapy and up to two short courses of antibiotics or systemic corticosteroids in the past year) and surgery. Difficult-to-treat CRS is also referred to herein as "refractory CRS."

[0209] In one embodiment, the subject in need of treatment has primary CRS, which may be localized primary CRS or diffuse primary CRS. In another embodiment, the subject in need of treatment has secondary CRS, which may be localized secondary CRS or diffuse secondary CRS (described in Fokkens et al. (2020). Rhinology. 58(2), 82-111, the entire contents of which are incorporated herein by reference).

[0210] In some embodiments, the level of DPP1 in a biological sample obtained from a subject is in the range of about 1 ng / mL to about 1000 ng / mL before the administration period. The present disclosure further provides a method of treating CRS in a subject in need thereof, the method comprising: (a) determining the level of DPP1 in a biological sample obtained from the subject; and (b) administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein. In some embodiments, the level of DPP1 determined in step (a) or the level of DPP1 in a biological sample obtained from a subject before the administration period is in the range of about 1 ng / mL to about 1000 ng / mL, e.g., about 3 ng / mL, about 5 ng / mL, about 7 ng / mL, about 10 ng / mL, about 13 ng / mL, about 15 ng / mL, about 17 ng / mL, about 20 ng / mL, about 30 ng / mL, about 40 ng / mL, about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, about 100 ng / mL, about 15 ... g / mL, about 100 ng / mL, about 150 ng / mL, about 200 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, about 500 ng / mL, about 550 ng / mL, about 600 ng / mL, about 650 ng / mL, about 700 ng / mL, about 750 ng / mL, about 800 ng / mL, about 850 ng / mL, about 900 ng / mL, about 950 ng / mL, or about 1000 ng / mL (including all values ​​and subranges therebetween). In some embodiments, the level of DPP1 determined in step (a), or the level of DPP1 in a biological sample obtained from the subject prior to administration of the composition, is in the range of about 5 ng / mL to about 20 ng / mL. In some embodiments, the level of DPP1 determined in step (a), or in a biological sample obtained from the subject prior to administration of the composition, is in the range of about 1 ng / mL to about 100 ng / mL.

[0211] In some embodiments, the level or activity of DPP1 determined in step (a), or the level or activity of DPP1 in a biological sample obtained from the subject prior to the administration period, is at least about 1.2-fold, e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween) higher than the level or activity of DPP1 in a control subject not having CRS.

[0212] In some embodiments, the level or activity of DPP1 determined in step (a), or in a biological sample obtained from the subject prior to administration of the composition, is at least about 2%, e.g., about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% (including all values ​​and subranges therebetween) higher than the level or activity of DPP1 in a control subject not having CRS.

[0213] In some embodiments, the activity of DPP1 in a biological sample obtained from the subject during or after the administration period is less than (a) the activity of DPP1 in a biological sample obtained from the subject before administration of the composition, and / or (b) the activity of DPP1 in a biological sample obtained from a control subject, where the control subject has CRS and does not receive the composition. In some embodiments, the activity of DPP1 in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% (including all values ​​and subranges therebetween) lower than (a) the activity of DPP1 in a biological sample obtained from the subject before the administration period, and / or (b) the activity of DPP1 in a biological sample obtained from a control subject, wherein the control subject has CRS and is not administered the pharmaceutical composition.

[0214] In some embodiments, the level of DPP1 in a biological sample obtained from the subject during or after the administration period is lower than (a) the level of DPP1 in a biological sample obtained from the subject before administration of the composition, and / or (b) the level of DPP1 in a biological sample obtained from a control subject, where the control subject has CRS and is not administered the composition. In some embodiments, the level of DPP1 in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% (including all values ​​and subranges therebetween) lower than (a) the level of DPP1 in a biological sample obtained from the subject before the administration period, and / or (b) the level of DPP1 in a biological sample obtained from a control subject, wherein the control subject has CRS and is not administered the pharmaceutical composition.

[0215] In some embodiments, DPP1 and its levels can be detected and / or quantified using methods such as, for example, Western blotting and enzyme activity assays. Further details are provided in Pham et al. (1999). Proc Natl Acad Sci 96(15), 8627-32; Chen et al. (2021). J. Med. Chem. 64, 11857-11885; Hamon et al. (2016). J Biol Chem. 291(16), 8486-99, and International Patent Application Publication No. 2021 / 154812, the contents of each of which are incorporated herein by reference in their entirety.

[0216] In some embodiments, the level of neutrophil extracellular traps (NETs) in a biological sample obtained from the subject is in the range of about 1 ng / mL to about 1000 ng / mL prior to the administration period. The present disclosure further provides a method of treating CRS in a subject in need thereof, the method comprising: (a) determining the level of NETs in a biological sample obtained from the subject; and (b) administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein for the administration period. In some embodiments, the level of NETs determined in step (a), or the level of neutrophil extracellular traps (NETs) in a biological sample obtained from the subject prior to the administration period, is in the range of about 1 ng / mL to about 1000 ng / mL, e.g., about 3 ng / mL, about 5 ng / mL, about 7 ng / mL, about 10 ng / mL, about 13 ng / mL, about 15 ng / mL, about 17 ng / mL, about 20 ng / mL, about 30 ng / mL, about 40 ng / mL, about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL , about 90 ng / mL, about 100 ng / mL, about 150 ng / mL, about 200 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, about 500 ng / mL, about 550 ng / mL, about 600 ng / mL, about 650 ng / mL, about 700 ng / mL, about 750 ng / mL, about 800 ng / mL, about 850 ng / mL, about 900 ng / mL, about 950 ng / mL, or about 1000 ng / mL (including all values ​​and subranges therebetween).

[0217] In some embodiments, the level of NETs determined in step (a), or the level of NETs in a biological sample obtained from the subject prior to the administration period, is at least about 1.2 times, e.g., about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 7.5 times, about 8 times, about 8.5 times, about 9 times, about 9.5 times, about 10 times, about 15 times, about 20 times, about 25 times, or about 30 times (including all values ​​and subranges therebetween) higher than the level of NETs in a healthy subject without CRS.

[0218] In some embodiments, the level of NETs determined in step (a), or in a biological sample obtained from the subject prior to the administration period, is at least about 2%, e.g., about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% (including all values ​​and subranges therebetween) higher than the level of NETs in a control subject without CRS.

[0219] In some embodiments, the level of neutrophil extracellular traps (NETs) in a biological sample obtained from the subject during or after the administration period is lower than (a) the level of NETs in a biological sample obtained from the subject before the administration period, and / or (b) the level of NETs in a biological sample obtained from a control subject, where the control subject has CRS and is not administered the pharmaceutical composition. In some embodiments, the level of NETs in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% (including all values ​​and subranges therebetween) lower than (a) the level of NETs in a biological sample obtained from the subject prior to the administration period, and / or (b) the level of NETs in a biological sample obtained from a control subject, wherein the control subject has CRS and is not administered the pharmaceutical composition.

[0220] In some embodiments, the level of NETs is the level of circulating plasma NETs. In some embodiments, the level of NETs is determined by measuring DNA complexed with NET molecules such as myeloperoxidase (MPO-DNA) or neutrophil elastase (NE-DNA) using enzyme-linked immunosorbent assay (ELISA), by measuring the presence of citrullinated histones by fluorescence microscopy, detecting NET components by flow cytometry, detecting the localization of NET-associated molecules (NE, MPO, CitH3) to extracellular DNA by immunofluorescence, or using flow cytometry or confocal microscopy-based methods. Further details regarding determining the levels of NETs are provided in Arends et al. (2019). J. Vis. Exp. 143, e59150; Gal et al. (2020). Sci Rep 10, 4320; and Thalin, et al. (2019). Arteriosclerosis, Thrombosis, and Vascular Biology 39, 1724-1738, each of which is incorporated by reference in its entirety for all purposes.

[0221] In some embodiments, the level of neutrophil serine protease (NSP) in a biological sample obtained from the subject is in the range of about 1 ng / mL to about 1000 ng / mL prior to the administration period. The present disclosure further provides a method of treating CRS in a subject in need thereof, the method comprising: (a) determining the level of NSP in a biological sample obtained from the subject; and (b) administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein for the administration period. In some embodiments, the level of NSP determined in step (a), or the level of NSP in a biological sample obtained from the subject prior to the administration period, is in the range of about 1 ng / mL to about 1000 ng / mL, e.g., about 3 ng / mL, about 5 ng / mL, about 7 ng / mL, about 10 ng / mL, about 13 ng / mL, about 15 ng / mL, about 17 ng / mL, about 20 ng / mL, about 30 ng / mL, about 40 ng / mL, about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, or about 100 ng / mL. / mL, about 100ng / mL, about 150ng / mL, about 200ng / mL, about 250ng / mL, about 300ng / mL, about 350ng / mL, about 400ng / mL, about 450ng / mL, about 500ng / mL, about 550ng / mL, about 600ng / mL, about 650ng / mL, about 700ng / mL, about 750ng / mL, about 800ng / mL, about 850ng / mL, about 900ng / mL, about 950ng / mL, or about 1000ng / mL (including all values ​​and subranges therebetween).

[0222] In some embodiments, the level or activity of the NSP determined in step (a), or the level or activity of the NSP in a biological sample obtained from the subject prior to the administration period, is at least about 1.2-fold, e.g., about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, or about 30-fold (including all values ​​and subranges therebetween) greater than the level or activity of the NSP in a control subject not having CRS.

[0223] In some embodiments, the level or activity of the NSP determined in step (a), or in a biological sample obtained from the subject prior to the administration period, is at least about 2%, e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, less than the level or activity of the NSP in a control subject not having CRS, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, or at least about 1000% higher (including all values ​​and subranges therebetween).

[0224] In some embodiments, the activity of a neutrophil serine protease (NSP) in a biological sample obtained from the subject during or after the administration period is less than (a) the activity of the NSP in a biological sample obtained from the subject before the administration period, and / or (b) the activity of the NSP in a biological sample obtained from a control subject, where the control subject has CRS and is not administered the pharmaceutical composition. In some embodiments, the activity of the NSP in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) less than (a) the activity of the NSP in a biological sample obtained from the subject before the administration period, and / or (b) the activity of the NSP in a biological sample obtained from a control subject, wherein the control subject has CRS and is not administered the pharmaceutical composition.

[0225] In some embodiments, the level of neutrophil serine protease (NSP) in a biological sample obtained from the subject during or after the administration period is lower than (a) the level of NSP in a biological sample obtained from the subject before the administration period, and / or (b) the level of NSP in a biological sample obtained from a control subject, where the control subject has CRS and is not administered the pharmaceutical composition. In some embodiments, the level of the NSP in a biological sample obtained from the subject during or after the administration period is at least about 2% (e.g., at least about 3%, about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% (including all values ​​and subranges therebetween) lower than (a) the level of the NSP in a biological sample obtained from the subject before the administration period, and / or (b) the level of the NSP in a biological sample obtained from a control subject, wherein the control subject has CRS and is not administered the pharmaceutical composition.

[0226] In some embodiments, the NSP is a secreted NSP or an NSP in a cytoplasmic granule. In some embodiments, the NSP is a proform of the NSP. In some embodiments, the NSP is an active form of the NSP. In some embodiments, the NSP is a secreted proform of the NSP. In some embodiments, the NSP is neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), neutrophil serine protease 4 (NSP4), or any combination thereof. In some embodiments, the NSP is a cell surface localized NSP, an intracellular NSP, or a combination thereof. In some embodiments, the level of cell surface localized NSP or intracellular NSP is measured using flow cytometry.

[0227] In some embodiments, neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), or levels thereof may be detected and / or quantified using methods such as, for example, western blotting, ELISA assays, enzyme activity assays, or any combination thereof. Non-limiting examples of ELISA assays include ProteaseTag® Active NE Immunoassay, ProteaseTag® Active PR3 Immunoassay, and ProteaseTag® Active CatG Immunoassay from ProAxsis (Belfast, Northern Ireland). Non-limiting examples of activity assays include NE enzyme kinetic assay, PR3 enzyme kinetic assay, and CatG enzyme kinetic assay. In some embodiments, NSP4 and levels thereof may be detected and / or quantified using methods such as, for example, western blotting and enzyme activity assays. Further details are provided in Perera et al. (2012). PNAS 109, 6229-6234; Perera et al. (2013). J Immunol 191, 2700-2707; Kasperkiewicz et al. (2015). PLoS One 10(7):e0132818, each of which is incorporated by reference in its entirety.

[0228] In some embodiments, the biological sample comprises sinus tissue, blood, serum, white blood cells (WBCs), neutrophils, or any combination thereof.

[0229] In the methods of treating CRS provided herein, the pharmaceutical composition is administered by a suitable route of administration, including oral, enteral, mucosal, rectal, nasal, inhalation (e.g., via aerosol), buccal (e.g., sublingual), intravaginal, intrathecal, intraocular, transdermal, intrauterine (or intrauterine), parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular (including administration to skeletal muscle, diaphragm muscle, and / or cardiac muscle), intradermal, intrapleural, intracerebral, intraarticular, intravascular, or via injection), topical (e.g., to both cutaneous and mucosal surfaces, including airway surfaces, and transdermal administration), intralymphatic, etc., as well as direct injection into a tissue or organ (e.g., into the liver, skeletal muscle, cardiac muscle, diaphragm muscle, or brain). In some embodiments, administration is by injection into the central nervous system. In one embodiment, administration is via the enteral route, via the nasogastric (NG) tube.

[0230] In a preferred embodiment, the route of administration is oral. In a further embodiment, the administration is oral, once a day. In an even further embodiment, the pharmaceutical composition comprises 10 mg, 25 mg, or 40 mg of the compound of formula (I). In an even even further embodiment, the compound of formula (I) is brensocatib.

[0231] The length of the administration period in any given case may depend on the nature and severity of the CRS to be treated or prevented and may be determined by the prescribing physician. In some embodiments, the administration period is about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 30 months, about 36 months, about 4 years, about 5 years, about 10 years, about 15 years, or about 20 years. In some embodiments, the compounds or compositions disclosed herein may be administered for about 24 weeks. In some embodiments, the compounds or compositions disclosed herein may be administered for about 52 weeks. In yet another embodiment, the administration period is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years, or at least about 20 years.

[0232] In some embodiments, the administration period for the methods provided herein is at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years. In another embodiment, the administration period for the methods provided herein is from about 30 days to about 180 days. In another embodiment, the administration period is from about 30 days to about 36 months, from about 30 days to about 30 months, or from about 30 days to about 24 months, or from about 30 days to about 18 months, or from about 30 days to about 12 months, or from about 30 days to about 6 months, or from about 6 months to about 30 months, or from about 6 months to about 24 months, or from about 6 months to about 18 months, or from about 12 months to about 36 months, or from about 12 months to about 24 months.

[0233] In one embodiment, the administration period is about 1 year to about 50 years. For example, in one embodiment, the administration period is about 1 year to about 40 years, about 1 year to about 25 years, 1 year to about 20 years, about 1 year to about 15 years, about 1 year to about 10 years, about 1 year to about 5 years, about 1 year to about 3 years, about 1 year to about 2 years, about 2 years to about 15 years, about 2 years to about 10 years, about 2 years to about 8 years, about 2 years to about 5 years, about 2 years to about 4 years, or about 2 years to about 3 years.

[0234] In one embodiment, the subject is administered the pharmaceutical composition chronically, i.e., the subject is administered the composition for their entire life once treatment for CRS is initiated.

[0235] In some embodiments, the pharmaceutical composition may be administered to the subject once a day or more than once a day during the administration period. In some embodiments, the composition may be administered to the subject twice a day during the administration period. In some embodiments, the composition may be administered to the subject every day, every other day, every third day, every fourth day, every fifth day, or every sixth day during the administration period. In some embodiments, the pharmaceutical composition may be administered to the subject every week, every other week, or every three weeks during the administration period. In some embodiments, the pharmaceutical composition is administered at about the same time every day during the administration period.

[0236] In a preferred embodiment, administration of the pharmaceutical composition is once a day. In another embodiment, administration of the pharmaceutical composition is twice a day. In another embodiment, administration is once a week, twice a week, three times a week, four times a week, five times a week, or six times a week.

[0237] The compound of formula (I) or its pharmaceutically acceptable salt can be used by itself or in conjunction with standard treatment administered by the treating physician. Any standard treatment agent can be used in combination with the compounds disclosed herein. In some embodiments, the subject has already undergone or will undergo surgery to treat CRS.

[0238] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered to the subject in combination with a second therapy. In some embodiments, the second therapy includes one or more of a steroid, an antihistamine, an antibiotic, an antidepressant, a biologic, an anti-leukotriene, nasal saline irrigation, and a surgical intervention. In some embodiments, the steroid is fluticasone propionate or mometasone furoate. In further embodiments, the steroid is mometasone furoate. In some embodiments, the steroid is administered topically, intranasally, systemically, or orally. Non-limiting examples of antihistamines include pseudoephedrine, loratadine, cetirizine, and diphenhydramine. In some embodiments, the antibiotic is a macrolide antibiotic. In some embodiments, the macrolide antibiotic is erythromycin, roxithromycin, azithromycin, or clarithromycin. In some embodiments, the antidepressant is desipramine or fluoxetine. In some embodiments, the biologic is dupilumab, omalizumab, benralizumab, reslizumab, or mepolizumab. Non-limiting examples of anti-leukotrienes include montelukast, zafirlukast, and pranlukast, and 5-lipoxygenase inhibitors (e.g., zileuton). In some embodiments, the surgical intervention is functional endoscopic sinus surgery (FESS).

[0239] As used herein, the term administered "in combination" is understood to mean that two (or more) different therapies are delivered to a subject while the subject is suffering from a disorder (such as CRS) such that the effects of the therapies on the patient overlap at some point. In certain embodiments, there is an overlap in terms of administration because the delivery of one treatment is still occurring when the delivery of the second begins. This may be referred to herein as "simultaneous" or "concurrent" delivery. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins, which may be referred to as "sequential" or "serial" delivery.

[0240] In some embodiments, the combined administration makes the treatment more effective. For example, the second treatment is more effective. For example, the second treatment requires less of the same effect than when the second treatment is administered without the first treatment, or the second treatment reduces symptoms to a greater extent, or a similar situation is observed with the first treatment. The effect of the two treatments may be partially additive, totally additive, or greater than additive (synergistic).

[0241] As used herein, the compositions contain an effective amount of any one or more of the compounds disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0242] The compounds of formula (I), or pharma- ceutically acceptable salts thereof, may be used on their own, but are generally administered in the form of a pharmaceutical composition in which the compound / salt of formula (I) (active pharmaceutical ingredient (API)) is in a pharmaceutical composition comprising a pharma- ceutically acceptable adjuvant, diluent, and / or carrier. In one embodiment, the pharmaceutical composition is one of the pharmaceutical compositions described in WO 2019 / 166626, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0243] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 2nd Ed. 2002 (incorporated herein by reference in its entirety for all purposes). Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical textbooks. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.

[0244] Depending on the method of administration, the pharmaceutical composition may contain about 0.05 to about 99% by weight of API, e.g., about 0.05 to about 80% by weight, or about 0.10 to about 70% by weight, or about 0.10 to about 50% by weight, all weight percentages being based on the total weight of the pharmaceutical composition. Unless otherwise stated herein, the API weight percentages provided herein are relative to the respective free base form of the compound of Formula (I).

[0245] In one embodiment, the pharmaceutical composition is an oral dosage form of a film-coated oral tablet. In another embodiment, the oral dosage form is an immediate release dosage form with rapid dissolution characteristics under in vitro test conditions. In one embodiment, the oral dosage form is administered once a day to reach the daily dose disclosed herein. In a further embodiment, the oral dosage form is administered at about the same time every day, for example, before breakfast. In another embodiment, the oral dosage form is administered twice a day to reach the daily dose disclosed herein.

[0246] In some embodiments, the compositions of the present disclosure are formulated using pharma- ceutically acceptable salts of the compounds of formula (I). Pharmaceutically acceptable salts include, for example, acid addition salts derived from inorganic acids, such as hydrochloric acid or phosphoric acid, or organic acids, such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc. In some embodiments, the salts can be derived from inorganic bases (e.g., sodium, potassium, ammonium, calcium, or ferric hydroxide), or organic bases (e.g., isopropylamine, trimethylamine, histidine, procaine), etc.

[0247] The present disclosure provides compositions comprising an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in the methods provided herein. Any of the compounds provided herein may be used in the compositions for delivery via one of the methods provided herein.

[0248] In some embodiments, the composition is in a solid form such as a lyophilized powder, liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder suitable for reconstitution. In some embodiments, delivery vehicles such as liposomes, nanocapsules, microparticles, microspheres, lipid particles, vesicles, etc. may be used.

[0249] In some embodiments, the compositions disclosed herein further comprise at least one pharma- ceutically acceptable carrier, excipient, and / or vehicle, such as a solvent, buffer, solution, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents. In some embodiments, the pharma- ceutically acceptable carrier, excipient, and / or vehicle may comprise saline, buffered saline, dextrose, water, glycerol, sterile isotonic aqueous buffer, and combinations thereof. In some embodiments, the pharma- ceutically acceptable carrier, excipient, and / or vehicle comprises phosphate buffered saline, sterile saline, lactose, sucrose, calcium phosphate, dextran, agar, pectin, peanut oil, sesame oil, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), or suitable mixtures thereof. In some embodiments, the compositions disclosed herein further contain minor amounts of emulsifying or wetting agents, or pH buffering agents.

[0250] In some embodiments, the compositions disclosed herein further comprise other conventional pharmaceutical ingredients such as preservatives or chemical stabilizers such as chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, parabens, ethyl vanillin, glycerin, phenol, parachlorophenol, or albumin. In some embodiments, the compositions disclosed herein may further comprise antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, or thimerosal, isotonic agents such as sugars or sodium chloride, and / or absorption delaying agents such as aluminum monostearate and gelatin.

[0251] In some embodiments, the amount of the compound of formula (I) present in the pharmaceutical composition depends on the mode of administration. In some embodiments, the pharmaceutical composition comprises about 0.05% by weight to about 99% by weight (percent by weight), for example, about 0.5% by weight, about 1% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, about 90% by weight, about 95% by weight, about 98% by weight, or about 99% by weight (including all values ​​and subranges therebetween). In some embodiments, the pharmaceutical compositions contain from about 0.05% to about 80% by weight, or from about 0.10% to about 70% by weight, or from about 0.10% to about 50% by weight of the active ingredient (a compound of formula (I)), all weight percentages being based on the total composition.

[0252] In some embodiments, the adjuvant, diluent or carrier present in the pharmaceutical composition is selected based on the mode of administration.For example, for oral administration, the compound of the present disclosure may be mixed with an adjuvant, diluent or carrier, such as lactose, saccharose, sorbitol, mannitol; starch, such as potato starch, corn starch or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; disintegrants, such as cellulose derivatives, and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets.When coated tablets are required, the cores prepared as described above may be coated with a suitable polymer that is dissolved or dispersed in water or easily volatile organic solvents.Alternatively, the tablets may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talcum, and titanium dioxide.

[0253] For the preparation of soft gelatin capsules, the compound of the present disclosure may be mixed with, for example, vegetable oil or polyethylene glycol.Hard gelatin capsules may contain granules of the compound using pharmaceutical excipients such as the excipients mentioned above for tablets.Also, liquid or semi-solid formulations of the compound of the present disclosure may be filled into hard gelatin capsules.

[0254] In some embodiments, the form of the pharmaceutical composition depends on the mode of administration. For example, in one oral administration embodiment, the oral dosage form is a film-coated oral tablet. In a further embodiment, the dosage form is an immediate release dosage form with rapid dissolution characteristics under in vitro test conditions.

[0255] In one embodiment, the composition is an orally disintegrating tablet (ODT). ODTs differ from traditional tablets in that they are designed to dissolve on the tongue rather than being swallowed whole.

[0256] In one embodiment, the composition is an oral thin film or oral disintegrating film (ODF). When placed on the tongue, such a formulation hydrates through interaction with sputum and releases the active compound from the dosage form. In one embodiment, the ODF contains a film-forming polymer such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), pullulan, carboxymethylcellulose (CMC), pectin, starch, polyvinyl acetate (PVA), or sodium alginate.

[0257] Liquid preparations for oral administration may be in the form of syrups, solutions or suspensions. Solutions may contain, for example, the compound of the present disclosure, the balance being a mixture of sugar, ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, saccharin, and / or carboxymethylcellulose as a thickening agent. In addition, other excipients known to those skilled in the art may be used when preparing preparations for oral use.

[0258] The compounds of the present disclosure can be prepared in a variety of ways in known manner.For example, in one embodiment, the compound of formula (I) is prepared according to the method described in U.S. Patent No. 9,522,894 (incorporated herein by reference in its entirety for all purposes).

[0259] As provided throughout, according to the methods provided herein, the compound of formula (I) may be administered as a pharma- ceutically acceptable salt. The pharma- ceutically acceptable salt of the compound of formula (I) may be advantageous due to one or more of its chemical or physical properties, such as stability at different temperatures and humidities, or desirable solubility in H2O, oil, or other solvents. In some cases, the salt may be used to aid in the isolation or purification of the compound of formula (I).

[0260] When the compound of formula (I) is sufficiently acidic, pharma- ceutically acceptable salts include, but are not limited to, alkali metal salts, such as Na or K, alkaline earth metal salts, such as Ca or Mg, or organic amine salts.When the compound of formula (I) is sufficiently basic, pharma-ceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.

[0261] Depending on the number of charged functional groups and the valency of the cation or anion, there may be more than one cation or anion. For a review of suitable salts and pharma- ceutically acceptable salts suitable for use herein, see Berge et al. (1977). J.Pharm.Sci., 66, 1-19, or "Handbook of Pharmaceutical Salts: Properties, selection and use", PH Stahl, PG Vermuth, IUPAC, Wiley-VCH, 2002 (incorporated herein by reference in its entirety for all purposes). Compounds of formula (I) may form mixtures of their salts and co-crystal forms. It is also understood that the methods provided herein may use such salt / co-crystal mixtures of compounds of formula (I).

[0262] The salts and co-crystals may be characterized using well-known techniques, such as X-ray powder diffraction, single crystal X-ray diffraction (e.g., to assess proton positions, bond lengths, or bond angles), solid state NMR (e.g., to assess C, N, or P chemical shifts), or spectroscopic techniques (e.g., to measure OH, NH, or COOH signals, and IR peak shifts resulting from hydrogen bonding).

[0263] In another embodiment of the method, the pharmaceutical composition administered to the patient comprises: (a) about 1 to about 30% by weight of a compound of formula (I) or a pharma- ceutically acceptable salt thereof; (b) about 45 to about 85 weight percent of a pharmaceutical diluent; and (c) about 6 to about 30 weight percent of a compression aid; and (d) about 1 to about 15% by weight of a pharmaceutical disintegrant; (e) about 0.00 to about 2% by weight of a pharmaceutical flow enhancer; and (f) about 1 to about 10% by weight of a pharmaceutical lubricant, The components add up to 100% by weight.

[0264] In a further embodiment, the compound of formula (I) is brensocatib. In one embodiment, brensocatib is polymorphic Form A as disclosed in U.S. Pat. No. 9,522,894. In another embodiment, brensocatib is characterized by one of the X-ray powder diffraction patterns described in WO 2019 / 166626.

[0265] In some embodiments of the method, composition (A) comprises a compound of formula (I), e.g., brensocatib, in an amount of about 1 to about 25 weight percent, about 1 to about 20 weight percent, about 1 to about 15 weight percent, about 1 to about 10 weight percent, about 1 to about 5 weight percent, or about 1 to about 3 weight percent of the total weight of the composition.

[0266] In some embodiments of the method, composition (A) comprises a compound of formula (I), e.g., brensocatib, in an amount of about 1.5 to about 30 weight percent, about 1.5 to about 25 weight percent, about 1.5 to about 20 weight percent, about 1.5 to about 15 weight percent, about 1.5 to about 10 weight percent, or about 1.5 to about 5 weight percent of the total weight of the composition.

[0267] In some embodiments of the method, composition (A) comprises a compound of formula (I), e.g., brensocatib, in an amount of about 3 to about 30%, about 3 to about 25%, about 3 to about 20%, about 3 to about 15%, about 3 to about 10%, or about 3 to about 5% by weight of the total weight of the composition. In further embodiments, the compound of formula (I) is present in an amount of about 3 to about 10% by weight of the total weight of the composition. In further embodiments, the compound of formula (I) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0268] In some embodiments of the method, composition (A) comprises a compound of formula (I), e.g., brensocatib, in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt% of the total weight of the composition.

[0269] In some embodiments of the method, composition (A) comprises one or more pharmaceutical diluents selected from the group consisting of microcrystalline cellulose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose, xylitol, and combinations of the foregoing. In one embodiment, composition (A) comprises two or more pharmaceutical diluents. In another embodiment, composition (A) comprises one pharmaceutical diluent. In a further embodiment, the pharmaceutical diluent is microcrystalline cellulose. Microcrystalline cellulose is a binder / diluent in oral tablet and capsule formulations and can be used in dry granulation, wet granulation, and direct compression processes.

[0270] In some embodiments of the method, composition (A) comprises one or more pharmaceutical diluents in an amount of about 45 to about 80%, about 45 to about 75%, about 45 to about 70%, about 45 to about 65%, about 45 to about 60%, or about 45 to about 55% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still further embodiments, the compound of formula (I) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0271] In some embodiments of the method, composition (A) comprises one or more pharmaceutical diluents in an amount of about 50 to about 85 weight percent, about 50 to about 75 weight percent, about 55 to about 85 weight percent, about 55 to about 70 weight percent, about 60 to about 85 weight percent, about 65 to about 85 weight percent, about 70 to about 85 weight percent, or about 75 to about 85 weight percent of the total weight of the composition. In further embodiments, the one or more pharmaceutical diluents are present in an amount of about 55 to about 70 weight percent of the total weight of the composition. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still further embodiments, the compound of formula (I) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0272] In some embodiments of the method, composition (A) comprises one or more pharmaceutical diluents in an amount of about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85% by weight of the total weight of the composition.

[0273] In some embodiments of the method, the one or more pharmaceutical diluents in composition (A) are microcrystalline cellulose. In other embodiments, the one or more pharmaceutical diluents include calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose, and xylitol.

[0274] In the present disclosure, the terms "disintegrant" and "disintegrants" are intended to be interpreted in the context of pharmaceutical formulation science. Thus, the disintegrant in composition (A) may be, for example, alginic acid, calcium alginate, calcium carboxymethylcellulose, chitosan, croscarmellose sodium, crospovidone, glycine, guar gum, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose, sodium starch glycolate, starch, or a combination thereof.

[0275] In some embodiments of the method, the one or more disintegrants in composition (A) is sodium starch glycolate. In one embodiment, the amount of disintegrant present in composition (A) is 2% to 8% of the total weight of the composition. In further embodiments, the amount of disintegrant is about 2%, about 2.5%, about 3%, about 3.5%, about 4%, or about 4.5% by weight of the total weight of the composition. The physical properties of sodium starch glycolate, and therefore its effectiveness as a disintegrant, are affected by the degree of crosslinking, the degree of carboxymethylation, and the purity.

[0276] In some embodiments of the method, the one or more pharmaceutical disintegrants in composition (A) comprise croscarmellose sodium.

[0277] In some embodiments of the method, composition (A) comprises one or more pharmaceutical disintegrants in an amount of about 2 to about 14%, about 2 to about 13%, about 2 to about 12%, about 2 to about 11%, about 2 to about 10%, about 2 to about 9%, about 2 to about 8%, about 2 to about 7%, about 2 to about 6%, about 2 to about 5%, about 3.5 to about 4.5% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical disintegrants are present in an amount of about 3.5 to about 4.5% by weight of the total weight of the pharmaceutical composition. In further embodiments, the one or more pharmaceutical disintegrants are sodium starch glycolate. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still further embodiments, the compound of formula (I) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0278] In this disclosure, the terms "glidant" and "gliding agent" are intended to be interpreted in the context of pharmaceutical formulation science. Thus, the glidant in composition (A) may be, for example, silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate, and talc.

[0279] Thus, in some embodiments of the method, the one or more pharmaceutical glidants in composition (A) are selected from silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate, talc, or combinations of the foregoing. In one embodiment, the glidant is silicon dioxide. Its small particle size and large specific surface area provide desirable flow characteristics that are utilized to improve the flow properties of dry powders in many processes, such as tableting and capsule filling. Typical silicon dioxide concentrations for use herein range from about 0.05 to about 1.0% by weight. Porous silica gel particles may also be used as glidants, which may be advantageous for some formulations, with typical concentrations of 0.25 to 1%.

[0280] In some embodiments of the method, composition (A) comprises one or more pharmaceutical glidants in an amount of about 0.00 to about 1.75 wt%, about 0.00 to about 1.50 wt%, about 0.00 to about 1.25 wt%, about 0.00 to about 1.00 wt%, about 0.00 to about 0.75 wt%, about 0.00 to about 0.50 wt%, about 0.00 to about 0.25 wt%, or about 0.00 to about 0.20 wt% of the total weight of the composition. In further embodiments, the one or more pharmaceutical glidants comprise silicon dioxide. In further embodiments, the one or more pharmaceutical disintegrants are sodium starch glycolate. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still further embodiments, the compound of formula (I) in composition (A) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0281] In some embodiments of the method, composition (A) comprises one or more pharmaceutical glidants in an amount of about 0.05 to about 2%, about 0.05 to about 1.75%, about 0.05 to about 1.50%, about 0.05 to about 1.25%, about 0.05 to about 1.00%, about 0.05 to about 0.75%, about 0.05 to about 0.50%, about 0.05 to about 0.25%, or about 0.05 to about 0.20% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical glidants are present in an amount of about 0.05 to about 0.25% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical glidants comprise silicon dioxide. In further embodiments, the one or more pharmaceutical disintegrants are sodium starch glycolate. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still a further embodiment, the compound of formula (I) in composition (A) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0282] In some embodiments of the method, composition (A) comprises one or more pharmaceutical glidants in an amount of about 0.05 to about 2%, about 0.10 to about 2%, about 0.2 to about 2%, about 0.3 to about 2%, or about 0.40 to about 2% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical glidants comprise silicon dioxide. In further embodiments, the one or more pharmaceutical disintegrants are sodium starch glycolate. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In still further embodiments, the compound of formula (I) in composition (A) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0283] In the present disclosure, the terms "lubricant" and "lubricants" as used herein are intended to be interpreted in the context of pharmaceutical formulation science. Thus, the lubricant may be, for example, calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenic acid esters of glycerin (e.g., a mixture of glyceryl bihenehate, tribehenin, and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin, and zinc stearate.

[0284] Thus, in some embodiments of the method, the one or more pharmaceutical lubricants in composition (A) are selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenic acid esters of glycerin (e.g., a mixture of glyceryl bihenehate, tribehenin, and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin, and zinc stearate. In other embodiments, the one or more pharmaceutical lubricants are selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenic acid esters of glycerin (e.g., a mixture of glyceryl bihenehate, tribehenin, and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, stearic acid, talc, tribehenin, and zinc stearate.

[0285] In some embodiments of the method, composition (A) comprises one or more pharmaceutical lubricants, and the lubricant is not sodium stearyl fumarate. In further embodiments, the compound of formula (I) in composition (A) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0286] In one embodiment of the method, composition (A) includes glycerol behenate as a lubricant.

[0287] In some embodiments of the method, the one or more pharmaceutical lubricants in composition (A) comprise glyceryl behenate, magnesium stearate, stearic acid, or a combination thereof.

[0288] In one embodiment of the method, the lubricant in composition (A) is glyceryl behenate, magnesium stearate, or a combination thereof.

[0289] In one embodiment of the method, the one or more pharmaceutical lubricants in composition (A) comprise sodium stearyl fumarate and / or one or more behenic acid esters of glycerin.

[0290] In some embodiments of the method, composition (A) comprises one or more pharmaceutical lubricants in an amount of about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 2% to about 10%, about 2.5% to about 10%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4.5%, or about 2.5% to about 4.5% by weight of the total weight of the composition. In further embodiments, the one or more pharmaceutical lubricants in composition (A) are glycerol behenate. In further embodiments, the one or more pharmaceutical glidants in composition (A) comprise silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants in composition (A) are sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents in composition (A) comprise microcrystalline cellulose. In yet a further embodiment, the compound of formula (I) in composition (A) is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0291] In one embodiment of the method, the one or more pharmaceutical lubricants in composition (A) consist of sodium stearyl fumarate and / or one or more behenic acid esters of glycerin, or mixtures thereof.

[0292] In another embodiment of the method, the one or more pharmaceutical lubricants in composition (A) consist of sodium stearyl fumarate, glyceryl dibehenate, glyceryl behenate, tribehenin, or any mixture thereof.

[0293] In one embodiment of the method, the one or more pharmaceutical lubricants in composition (A) comprise sodium stearyl fumarate. In another embodiment, the one or more pharmaceutical lubricants in composition (A) consist of sodium stearyl fumarate.

[0294] In one embodiment of the method, the one or more pharmaceutical lubricants in composition (A) comprise one or more behenic acid esters of glycerin (i.e., one or more of glyceryl dibehenate, tribehenin, and glyceryl behenate).

[0295] In one embodiment of the method, the compression aid in composition (A) is dicalcium phosphate dihydrate (also known as dibasic calcium phosphate dihydrate) (DCPD). DCPD is used in tablet formulations as an excipient and as a source of calcium and phosphorus in dietary supplements.

[0296] In one embodiment of the method, composition (A) comprises a compression aid, such as DCPD, in an amount of about 10 to about 30%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, or about 24% by weight of the total weight of the composition, hi a further embodiment, the compression aid is present at about 20% by weight of the total weight of the composition.

[0297] In one embodiment of the method, composition (A) comprises a compression aid, such as DCPD, in an amount of about 10 to about 25%, about 10 to about 20%, about 10 to about 15%, about 15 to about 25%, or about 20 to about 25%, or about 18 to about 22% by weight of the total weight of the composition. In a further embodiment, the compression aid is present in about 18 to about 22% by weight of the total weight of the composition. In a further embodiment, the compression aid is DCPD. In a further embodiment, the one or more pharmaceutical lubricants in composition (A) are glycerol behenate. In a further embodiment, the one or more pharmaceutical glidants in composition (A) comprise silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants in composition (A) are sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents in composition (A) comprise microcrystalline cellulose. In still further embodiments, the compound of Formula (I) in the exemplary composition is brensocatib, or a pharma- ceutically acceptable salt thereof.

[0298] In one embodiment of the method, the pharmaceutical composition administered to the patient comprises: (a) about 1 to about 30% by weight of a compound of formula (I) or a pharma- ceutically acceptable salt thereof; (b) about 55 to about 75 weight percent of a pharmaceutical diluent; (c) about 15 to about 25 weight percent of a compression aid; and (d) about 3 to about 5% by weight of a pharmaceutical disintegrant; (e) about 0.00 to about 1% by weight of a pharmaceutical flow enhancer; and (f) about 2 to about 6% by weight of a pharmaceutical lubricant, The components add up to 100% by weight.

[0299] In some embodiments of the method in which composition (B) is administered to a patient, the identities of the pharmaceutical diluents, compression aids, pharmaceutical disintegrants, pharmaceutical flow enhancers, and pharmaceutical lubricants in the composition may be one of those described above for composition (A). In other embodiments, the amounts of the pharmaceutical diluents, compression aids, pharmaceutical disintegrants, pharmaceutical flow enhancers, and pharmaceutical lubricants in composition (B) may also be one of those described above for composition (A), so long as the amounts are within the corresponding broader ranges recited above for composition (B).

[0300] The pharmaceutical compositions disclosed herein, including compositions (A) and (B), may be in a solid dosage form suitable for oral administration to humans. For example, the pharmaceutical composition is a pharmaceutical tablet. The pharmaceutical tablet may be prepared using methods known to those skilled in the art, including, for example, the dry blend / direct compression process described in WO 2019 / 166626. In some embodiments, the pharmaceutical tablet comprises a tablet core, the tablet core comprises a pharmaceutical composition disclosed herein, and the tablet core has a coating. In some embodiments, the coating is a film coating. The film coating may be applied using conventional methods known to those skilled in the art. A functional coating may be used to provide protection against, for example, moisture ingress or degradation by light. Additionally, a functional coating may be used to modify or control the release of a compound of formula (I), such as brensocatib, from the composition. The coating may comprise, for example, about 0.2 to about 10% by weight of the total weight of the pharmaceutical composition, for example, about 0.2 to about 4% by weight, about 0.2 to about 3% by weight, about 1 to about 6% by weight, or about 2 to about 5% by weight of the total weight of the pharmaceutical composition. EXAMPLES

[0301] The present disclosure will be further illustrated by reference to the following examples, however, it should be noted that the examples, like the above-mentioned embodiments, are illustrative and should not be construed as limiting the scope of the present invention in any way.

[0302] Example 1 - A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of the Efficacy and Safety of Brensocatib in Participants With Moderate-to-Severe Chronic Rhinosinusitis Without Nasal Polyps (CRSsNP) Brensocatib, a compound of formula (I), is an oral reversible DPP1 inhibitor. DPP1 catalyzes the activation of neutrophil serine proteases (NSPs) in neutrophils during neutrophil maturation in the bone marrow. NSPs are the main agents of neutrophil-mediated inflammation, tissue damage, and excessive mucus production. By inhibiting DPP1, Brensocatib prevents the activation of NSPs, allowing neutrophils to mature and be released without active NSPs. Thus, Brensocatib may inhibit the neutrophilic inflammatory components associated with CRSsNP by blocking DPP1.

[0303] This example describes a Phase 2b, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of brensocatib in participants with moderate to severe chronic rhinosinusitis without nasal polyps (CRSsNP). Brensocatib is the International Nonproprietary Name for (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide. [ka] Approximately 360 adult male and female participants (aged ≥18-≤85 years) with moderate to severe CRSsNP will be administered once daily (QD) for 24 weeks, followed by a 4-week follow-up period. Eligible participants will be randomized in a 1:1:1 ratio into three treatment arms, with approximately 120 participants per treatment arm receiving 10 mg brensocatib, 40 mg brensocatib, and matching placebo once daily orally for 24 weeks. Approximately 180 participants will have a blood eosinophil count of less than 300 cells / μL (primary population), resulting in approximately 60 participants per treatment arm in the primary population, and approximately 180 participants will have a blood eosinophil count of ≥300 but ≤750 cells / μL. Participants may be screened for study enrollment regardless of current or lack of use of nasal mometasone furoate. At the screening visit, all participants, regardless of use history, will begin treatment with nasal mometasone furoate 200 μg twice daily (BID) or once daily (QD) if BID is not tolerated, throughout the study, including the treatment period.

[0304] Brensocatib oral tablets will be used in the study. The tablets are round, biconvex, brown, film-coated, and considered an immediate release dosage form. The tablets contain the equivalent of 10 mg or 40 mg of brensocatib drug substance and are identical in size and appearance. Each film-coated tablet contains the active ingredient of the brensocatib drug substance and the official ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, sodium starch glycolate, silicon dioxide, and glyceryl behenate. The corresponding placebo without active ingredient is a film-coated tablet identical in shape, size, and color to the brensocatib film-coated tablet.

[0305] Efficacy parameters include the sinus total symptom score (sTSS) to assess nasal symptoms, Lund-MacKay (LMK) computed tomography (CT) scan score and CT scan volumetry to assess CT sinus opacification, the Sinus Outcome Study (Snot-22) to assess quality of life, the Nasal Congestion Score (NCS) to assess nasal congestion, (eDiary) visual analog scale (VAS) scores to assess nasal symptoms, peak nasal inspiratory flow (PNIF) to assess peak nasal inspiratory flow, and the use of rescue therapy with systemic corticosteroids, antibiotics, or nasal surgery to assess clinical exacerbation / acute rhinosinusitis. Without wishing to be bound by theory, administration of brensocatib may have beneficial effects on patients suffering from CRSsNP through a reduction in inflammation and mucus hypersecretion, resulting in improved symptoms (e.g., nasal congestion, facial pain, nasal discharge) and quality of life. Without intending to be bound by theory, because brensocatib inhibits the maturation of NSPs, brensocatib may result in a significant reduction in the inflammatory cascade.

[0306] Eligibility Criteria Table 1 below provides certain inclusion criteria for the studies. [Table 1]

[0307] Study design Figure 1 provides a schematic of the study design and treatment period. In this randomized, double-blind, parallel-group, placebo-controlled study, approximately 360 adult male and female participants (ages ≥18-≥85 years) with moderate to severe CRSsNP will receive brensocatib once daily for 24 weeks, followed by a 4-week follow-up period. Investigators (including clinicians providing care to participants), sponsors, and participants / healthcare providers will be blinded to the study drug. Approximately 180 participants will have a blood eosinophil count below 300 cells / μL, and approximately 180 participants will have a blood eosinophil count ≥300 but ≤750 cells / μL.

[0308] Randomization will be stratified by history of surgery for CRSsNP before screening (yes / no), region (North America, Europe, and other regions), and current diagnosis of asthma as a comorbid condition. An additional stratification factor for the population with eosinophil counts ≥ 300 cells / μL will then be based on their cell counts (300-500 cells / μL vs. 501-750 cells / μL). Eosinophil count stratification will be based on blood eosinophil counts obtained at screening.

[0309] The study included three study periods:

[0310] Screening Period - Participant eligibility will be determined during a screening period of at least 2 weeks and up to 4 weeks.

[0311] Treatment Period - Eligible participants will be randomized in a double-blind fashion to receive brensocatib 10 mg, brensocatib 40 mg, or placebo film-coated tablets orally once daily for 24 weeks.

[0312] Follow-up Period - Participants will be followed for 4 weeks after the last dose of study medication.

[0313] Participants may be screened for study enrollment regardless of current use of intranasal mometasone furoate or lack of history of use of intranasal mometasone furoate. At the screening visit, all participants, regardless of history of use, will begin treatment with intranasal mometasone furoate 200 μg BID, or QD if BID is not tolerated, as background therapy throughout the study, including the treatment period.

[0314] The PD substudy will be conducted in a subset of participants. Nasal fluid samples will be collected from approximately 60 participants, including 30 participants from the population with blood eosinophil counts <300 cells / μL at screening and 30 participants from the population with blood eosinophil counts ≥300 cells / μL. Samples will be collected at clinic visits on Day 1, Week 4, and Week 24.

[0315] The maximum study duration is approximately 32 weeks for each individual participant, including a maximum 4-week screening period, a 24-week double-blind treatment period, and a 4-week follow-up period.

[0316] Result evaluation Study objectives and endpoints are shown in Table 2. Unless otherwise stated, the population attribute for the primary efficacy estimate is participants with CRSsNP with baseline eosinophil counts <300 cells / μL. The entire population of participants with CRSsNP is secondary for efficacy estimates and primary for safety, pharmacokinetic, and pharmacodynamic estimates. For all estimates, the treatment regimen is the randomized study treatment (i.e., brensocatib 10 mg QD, brensocatib 40 mg QD, or placebo QD). The PK objective is to assess the systemic exposure of brensocatib in participants with CRSsNP. [Table 2-1] [Table 2-2] [Table 2-3]

[0317] Efficacy evaluation 1.sTSS Participants will self-manage the sTSS via eDiary every morning throughout the study until week 28 (end of study (EOS)).

[0318] Participants will have a sTSS (nasal congestion, anterior / posterior nasal drip, facial pain / pressure) score ≥ 5 at screening and in the weekly average score for the week prior to randomization, which will be used by the investigator to determine eligibility. For end of treatment (EOT) analysis, the 4-week average of symptom scores will be used.

[0319] Each day, participants used the eDiary to answer individual morning rhinosinusitis symptom questions using a 0–3 categorical scale (0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms) to rate symptoms over the past 24 hours.

[0320] Clogging and / or blockage

[0321] Anterior / posterior nasal drip (runny nose)

[0322] Facial pain / pressure

[0323] 2. Lund-MacKay (LMK) CT scan score The LMK total score is based on the assessment of CT scan findings for each sinus region. The degree of opacification is scored between 0 (normal), 1 (partial opacification) and 2 (complete opacification). These points are then applied to the maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinuses on each side. The middle meatus ostium is scored as 0 (not obstructed) or 2 (obstructed). A maximum score of 12 per side is then derived.

[0324] CT scans will be performed any time during the screening period prior to randomization and again at week (EOT) 24. Participants must have bilateral ethmoid sinus opacification prior to randomization.

[0325] 3.CT Scan Volumetric Assessment CT scans performed during screening and at week 24 will be used for CT scan volumetric assessment.

[0326] 4.SNOT-22 The SNOT-22 is a validated patient-reported outcomes (PRO) questionnaire. The questionnaire includes 22 assessment items on a 5-category scale. Scores range from 0 to 110, with higher scores indicating a greater health burden associated with rhinosinusitis.

[0327] The SNOT-22 has 22 items with a 5-category scale applicable to sinus conditions and surgical treatments. Global scores range from 0 to 110, and the minimal clinically important difference (MCID), i.e., the smallest difference in mean change (point estimate) between clinical trial arms from baseline that is interpreted as important, is 8.9 points or greater. Lower scores indicate less impact and the recall period is the past 2 weeks. There are five domains that can be accounted for within the SNOT-22, including nose, ear, sleep, general / practical, and affective.

[0328] The SNOT-22 PRO will be completed in the eDiary throughout the study until week 28 (EOS) to assess symptoms over the past 2 weeks. Participants must have a SNOT-22 score of ≥20 at screening and baseline visits.

[0329] 5. Nasal congestion score (NCS) The nasal congestion symptom severity score is assessed by the participant daily. The severity of nasal congestion / obstruction symptoms over each 24-hour period is scored by the participant as follows:

[0330] 0 = no symptoms

[0331] 1 = Mild symptoms (symptoms are clearly present but barely noticeable and easily tolerated)

[0332] 2 = Moderate symptoms (disturbing but tolerable symptoms)

[0333] 3 = Severe symptoms (symptoms that are intolerable and interfere with activities or daily life)

[0334] NC symptom severity scores will be recorded as part of the sTSS every morning in the eDiary until week 28 (EOS). Participants must have had ongoing NC / obstruction symptoms for at least 12 consecutive weeks prior to screening and an NCS ≥2 at screening and the week prior to randomization, with a weekly average score of ≥2.

[0335] 6. VAS score Participants will electronically self-administer a VAS to assess symptoms over the past 24 hours. Participants must have a VAS score of ≥5 at screening and baseline visits. 7. Peak Nasal Inspiratory Flow (PNIF)

[0336] PNIF will be measured using the InCheck portable nasal inspiratory flow meter. At screening, participants will be provided with a PNIF meter to record their morning inspiratory flow measurements. Participants will be instructed on the use of the device and the investigator will instruct participants on how to record the following variables in their daily eDiary:

[0337] Morning PNIF is performed within 15 minutes of waking (before noon) before taking mometasone furoate nasal spray.

[0338] Three PNIF readings will be taken by the participant and all three values ​​will be recorded by the participant in their eDiary. The highest of the three recorded values ​​will be used for the evaluation.

[0339] Baseline morning PNIF is the average morning measurement recorded during the 7 days prior to the first dose of investigational medication (IMP). PNIF will be performed daily until week 28 (EOS).

[0340] 8. PGI-S and PGI-C The PGI-S and PGI-C scales will be used to assess participants' global perception of the severity and change in their CRSsNP status. These scales aim to identify meaningful change thresholds for sTSS and other relevant outcomes.

[0341] Participants will complete the PGI-S and PGI-C to assess symptoms over the past two weeks.

[0342] 9. Percentage of participants receiving rescue treatment Participants requiring rescue treatment due to worsening CRS symptoms will be recorded. Rescue treatment may include antibiotics, steroids, and / or nasal surgery.

[0343] 10. Anterior / posterior nasal drip severity score Anterior / posterior nasal drip severity scores are recorded daily as part of the sTSS.

[0344] 11. Daily Facial Pain / Pressure Severity Score Daily facial pain / pressure severity scores are recorded daily as part of the sTSS.

[0345] 12. University of Pennsylvania Smell Identification Test (UPSIT) score The UPSIT test is a quick and easy-to-perform test that assesses olfactory function with 40 items. The UPSIT shows high test-retest reliability (r: 0.981) and the scores of this test correlate strongly with the detection threshold of phenylethyl alcohol in the same individual. When the UPSIT is administered in a standardized manner, clinical participants show high uniformity in their performance on the UPSIT when tested in different laboratories. A particular strength of this test is that it provides an olfactory diagnosis based on a comparison of the patient's test score with normative data, providing the individual's percentile score relative to a normal group of the same age. The UPSIT test score makes it possible to distinguish between patients with normal smell ("normal smell"), those with reduced smell ("mild, moderate or severe anosmia"), or those who have a complete loss of smell ("anosmia").

[0346] The test consists of four booklets, each containing 10 odorants. The stimuli are embedded in plastic microcapsules measuring 10-50 (mu) in diameter on a brown strip at the bottom of each page. Participants release the odorants by rubbing the embedded odorant. Above each odorant is a multiple-choice question with four words to describe that odor. The UPSIT test odorants utilized in this study take cultural differences into account. Participants receive a score out of 40 possible correct answers.

[0347] 13. Modified Lund-Kennedy endoscopic score The Lund-Kennedy endoscopic scoring system visually assesses pathological conditions within the nose and sinuses, including polyps, discharge, edema, scarring, and crusting. A modified LK system that removes the scarring and crusting subscores improves reliability with patient-reported results. See Psaltis et al., Laryngoscope 124(10):2216-23 (2014), which is incorporated herein by reference in its entirety.

[0348] The modified Lund-Kennedy rating system is as follows: [Table 3]

[0349] For outcome analyses, endoscopic readings at screening will be compared with readings at week 24. 14. Percentage of participants who require nasal surgery

[0350] Participants who require nasal surgery due to worsening CRS symptoms will be recorded, including the type of surgery, reason for surgery, date of surgery, and outcome of surgery.

[0351] Pharmacokinetic evaluation Approximately 6 mL blood samples will be collected for measurement of brensocatib plasma concentrations and PK analysis. Time points for PK sample collection include pre-dose, 1 hour (± 5 minutes), 2 hours (± 10 minutes), and 6 hours (± 2 hours) on Day 1; post-dose at Week 4; pre-dose at Week 8; post-dose at Week 12; pre-dose at Week 16; post-dose at Week 20; and pre-dose at Week 24.

[0352] Pharmacological evaluation 1.PD biomarkers Blood samples and nasal secretions are collected to evaluate the effect of brensocatib on NSP and NET activity compared to placebo. Biomarkers include NE, CatG, PR3, and other relevant biomarkers. Samples are taken at the following time points: Day 1, and Weeks 4, 8, 12, 16, 20, 24, and 28.

[0353] Changes from baseline will be examined for the inhibitory effect of brensocatib on biomarkers.

[0354] 2.PD substudy The PD substudy will be conducted in a subset of participants. Nasal fluid samples will be collected from approximately 60 participants: 30 participants from the population with blood eosinophil counts <300 cells / μL at screening, and 30 participants from the population with blood eosinophil counts ≥300 cells / μL. Samples will be collected at clinic visits on Day 1, Week 4, and Week 24.

[0355] The sinus packs are inserted into both nasal cavities for 5 min. The two packs are transferred to a tube and the adsorbed analytes are eluted from the packs by adding 3 mL of saline (0.9% NaCl) followed by centrifugation. Supernatant aliquots are stored at -70 °C.

[0356] Population PK and PK / PD assessment Plasma concentration data from this study will be used as an exploratory scale in population PK analyses. max , T max , AUC 0~24 , vanishing t 1 / 2 , CL / F, and V d Individual PK parameters, such as / F, are determined using population PK models.

[0357] Based on the predicted systemic exposure from the population PK model, PK efficacy and PK safety relationships are evaluated, including efficacy (e.g., sTSS), safety (AESI), and blood NSP activity (NE, CatG, PR3) response measures. The identified PK-PD relationships are used to predict clinical outcomes by Monte Carlo simulation to support dose and dosing regimen selection for future clinical trials.

[0358] The population attribute for the primary efficacy estimate is participants with CRSsNP with baseline eosinophil counts <300 cells / μL. The entire population of participants with CRSsNP is secondary for efficacy estimates and primary for safety, pharmacokinetic, and pharmacodynamic estimates. For all estimates, the treatment regimen is the randomized study treatment (i.e., brensocatib 10 mg QD, brensocatib 40 mg QD, or placebo QD).

[0359] Safety parameters Safety parameters included AEs, clinical laboratory results, vital sign measurements, ECG measurements, and physical examination results. Adverse events of special interest (AESIs) included hyperkeratosis, periodontitis / gingivitis, and severe infections. 4. Data Analysis

[0360] Analysis Set Screened analysis set - included all participants who provided written informed consent.

[0361] Full analysis set - includes all randomized participants. Participants are analyzed according to treatment assigned.

[0362] Safety Analysis Set - includes all randomized participants who receive at least one dose of study treatment. Participants will be analyzed according to the treatment they received.

[0363] PK Concentration Analysis Set - Includes all participants who received at least one dose of brensocatib and have at least one post-dose concentration value.

[0364] PD analysis set - includes all participants who received at least one dose of assigned study treatment and had at least one pre-dose and one post-dose biomarker measurement.

[0365] Efficacy Analysis Efficacy estimates utilize a combined strategy for handling intervening events (ICE) associated with rescue (i.e., systemic corticosteroids, antibiotics, or nasal surgery). Data following ICE of nasal surgery are imputed using the worst possible score, and data following ICE of rescue medications (systemic corticosteroids or antibiotics) are imputed using the worst observed future (WOCF). Early discontinuation of treatment without rescue-associated ICE is addressed using a treatment policy strategy.

[0366] The primary efficacy outcome measure was the change from baseline to the 28-day mean of daily sTSS at week 24 in participants with CRSsNP with baseline eosinophil counts <300 cells / μL, analyzed using an analysis of covariance (ANCOVA) model with a main effect of treatment, a continuous covariate of baseline daily mean, and randomization stratification factors for history of surgery for CRSsNP (yes / no), geography, and current asthma diagnosis (yes / no).Least squares mean differences, two-sided 95% confidence intervals (CIs), and corresponding p-values ​​for brensocatib 10 mg vs. placebo and brensocatib 40 mg vs. placebo are summarized.

[0367] Secondary analyses of the primary outcome will be performed in the overall population of participants with CRSsNP using a similar ANCOVA model, but with the addition of the continuous covariate of baseline blood eosinophil count. Additionally, we will check for confounding between asthma diagnosis and blood eosinophil count.

[0368] For secondary variables assessed at week 24 (i.e., change from baseline in LMK CT score, change from baseline in percentage of sinus opacification measured volumetrically, and change from baseline in SNOT-22, change from baseline to 28-day mean in daily NCS, change from baseline to 28-day mean in daily VAS score, and change from baseline to 28-day mean in daily PNIF), separate ANCOVA models are fitted to the data for each variable. Models for the primary population include main effects for treatment, continuous covariates for the corresponding baseline values, and randomization stratification factors for history of surgery for CRSsNP (yes / no), geography, and current asthma diagnosis. Analytical models for the entire population also include a continuous covariate for baseline blood eosinophil count. Least squares mean differences, 95% CIs, and corresponding p-values ​​are summarized for brensocatib 10 mg vs. placebo and brensocatib 40 mg vs. placebo.

[0369] Time to first use of rescue (systemic corticosteroids, antibiotics, or nasal surgery) is compared between treatments using Cox proportional hazards regression. Estimated hazard ratios with corresponding 95% confidence limits and two-sided Wald p-values ​​from the Cox models are reported for each comparison. Kaplan-Meier plots summarize the probability of each rescue event (systemic corticosteroids, antibiotics, or nasal surgery) by treatment over time.

[0370] The proportion of participants needing rescue (systemic corticosteroids, antibiotics, or nasal surgery) will be compared between treatments using logistic regression. Estimated odds ratios with corresponding 95% confidence limits and two-sided Wald p-values ​​from the logistic regression models are reported for the comparisons of brensocatib 10 mg vs. placebo and brensocatib 40 mg vs. placebo.

[0371] Pharmacokinetic analysis Plasma concentrations of brensocatib will be listed and summarized by dose level at each scheduled sampling time point using descriptive statistics. Individual plasma concentration data versus time will be listed, along with graphical plots of individual and mean plasma concentration-time plots presented on linear and semi-log scales.

[0372] Pharmacodynamic analysis NSP activity in blood and nasal secretions (NE, CatG, and PR3) will be assessed as percent inhibition from baseline. Data will be listed and summarized by treatment group at each scheduled sampling time point using descriptive statistics. Model-based analyses can be performed if sample size permits. Other biomarkers may also be assessed.

[0373] Safety analysis Safety analyses will evaluate the frequency and severity of treatment-emergent adverse events, including SAEs and AESIs, changes from baseline in clinical laboratory results, and vital signs and ECGs. All safety analyses will be performed by treatment received in the safety analysis set. * * * * * * *

[0374] All articles, publications, and patents cited herein are incorporated by reference as if each individual article, publication, or patent was specifically and individually indicated to be incorporated by reference, and are incorporated by reference herein to disclose and describe the methods and / or materials in connection with which the cited publications are incorporated. However, mention of any references, articles, publications, patents, patent publications, and patent applications cited herein is not, and should not be taken as, an admission or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country throughout the world.

[0375] The embodiments described and discussed herein are intended only to teach those of ordinary skill in the art the best way known to the inventor to make and use the invention. The embodiments of the invention described above can be modified and varied without departing from the invention, as will be understood by those of ordinary skill in the art in light of the above teachings. It is therefore understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

Claims

1. A pharmaceutical composition for treating chronic rhinosinusitis (CRS) in a subject in need thereof, comprising: The compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, R １ teeth, 【Chemistry 2】 and R ２ is hydrogen, F, Cl, Br, OSO ２ C １ - ３ Alkyl, or C １ - ３ is alkyl, R ３ is hydrogen, F, Cl, Br, CN, CF ３ , S.O. ２ C １ - ３ Alkyl, CONH ２ , or SO ２ NR ４ R ５ and R ４ and R ５ together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, or piperidine ring, or X is O, S, or CF ２ and Y is O or S; Q is CH or N; R ６ is C １－３ alkyl, １－３ The alkyl may be substituted by one, two or three F groups and may be substituted by OH, OC １ - ３ Alkyl, N(C １－３ alkyl) ２ , cyclopropyl, and tetrahydropyran; R ７ is hydrogen, F, Cl, or CH ３ A pharmaceutical composition comprising:

2. The pharmaceutical composition of claim 1, wherein the CRS is CRS without nasal polyps (CRSsNP).

3. The pharmaceutical composition of claim 1, wherein the CRS is CRS with nasal polyps (CRSwNP).

4. The pharmaceutical composition of claim 1, which is administered to the subject during an administration period and reduces the subject's Total Paranasal Sinus Symptom Score (sTSS) during or after the administration period compared to the subject's sTSS before the administration period, wherein the sTSS is a composite score of symptoms of nasal congestion, anterior and / or posterior nasal drip, and facial pain / pressure over the past 24 hours, and optionally wherein the subject has an sTSS of 5 or greater before the administration period.

5. The pharmaceutical composition described in claim 1, which is administered to the subject during an administration period and reduces the subject's Lund-Mackay score during or after the administration period compared to the subject's Lund-Mackay score before the administration period.

6. 6. The pharmaceutical composition of claim 5, wherein the Lund-Mackay score before the administration period and the Lund-Mackay score during or after the administration period are calculated based on a computed tomography (CT) scan of the subject, and optionally the CT scan is performed on one or more of the right frontal sinus, left frontal sinus, right anterior ethmoid sinus, left anterior ethmoid sinus, right posterior ethmoid sinus, left posterior ethmoid sinus, right maxillary sinus, left maxillary sinus, right sphenoid sinus of the subject, left sphenoid sinus of the subject, or a combination thereof.

7. The pharmaceutical composition of claim 1, administered to the subject during a dosing period, and wherein the subject exhibits one or more of the following therapeutic outcomes: (i) reducing the subject's Sinus Outcome Test-22 (SNOT-22) score during or after the administration period, compared to the subject's SNOT-22 score before the administration period; (ii) reducing the subject's nasal congestion score (NCS) during or after the administration period compared to the subject's NCS before the administration period; (iii) increasing the subject's peak nasal inspiratory flow (PNIF) during or after the administration period compared to the subject's PNIF before the administration period; (iv) reducing the subject's percentage of sinus opacification as measured by CT scan volumetry during or after the administration period compared to the subject's percentage of sinus opacification before the administration period; (v) reducing the frequency of rescue with systemic corticosteroids, antibiotics, or nasal surgery in the subject due to worsening CRS symptoms, compared to control subjects, wherein the control subjects have CRS and are not administered the pharmaceutical composition.

8. 10. The pharmaceutical composition of claim 1, wherein the second therapy comprises a steroid, and optionally the steroid is fluticasone propionate or mometasone furoate.

9. The compound of formula (I), or a pharmaceutically acceptable salt thereof, may be an S,S diastereomer: 【Transformation 3】 The pharmaceutical composition according to any one of claims 1 to 8, wherein

10. During the ceremony, R １ teeth, 【Chemistry 4】 and X is O, S, or CF ２ and Y is O or S; Q is CH or N; R ６ is C １－３ alkyl, １－３ The alkyl may be substituted by one, two or three F groups and may be substituted by OH, OC １ - ３ Alkyl, N(C １－３ alkyl) ２ , cyclopropyl, and tetrahydropyran; R ７ is hydrogen, F, Cl, or CH ３ The pharmaceutical composition of claim 9, wherein

11. During the ceremony, R １ teeth, 【Transformation 5】 and X is O, S, or CF ２ and Y is O or S; R ６ is C １－３ alkyl, １－３ The alkyl may be substituted by one, two or three F groups and may be substituted by OH, OC １ - ３ Alkyl, N(C １－３ alkyl) ２ , cyclopropyl, and tetrahydropyran; R ７ is hydrogen, F, Cl, or CH ３ The pharmaceutical composition of claim 9, wherein

12. R １ but, 【Transformation 6】 The pharmaceutical composition of claim 9, wherein

13. X is O and R ６ is C １－３ alkyl, and R ７ The pharmaceutical composition of claim 12, wherein is hydrogen.

14. During the ceremony, R １ teeth, 【Transformation 7】 and X is O, R ６ is C １－３ alkyl, １－３ The alkyl may be substituted by one, two, or three F groups; R ７ The pharmaceutical composition of claim 9, wherein is hydrogen.

15. The compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 15, administered to the subject once daily.

17. 17. The pharmaceutical composition of claim 16, wherein the compound of formula (I) is present in the pharmaceutical composition in an amount of from about 5 mg to about 50 mg.

Images