Methods for treating bronchiectasis

Abstract

The present disclosure relates to methods for treating bronchiectasis, for example, non-cystic fibrosis bronchiectasis with compositions comprising from 10 mg to 25 mg of certain (2S)-N- [(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds of Formula (I), including pharmaceutically acceptable salts thereof, (I) that inhibit dipeptidyl peptidase 1 (DPP1) activity. Methods provided herein comprise administering to a patient once daily for an administration period of at least 52 weeks a pharmaceutical composition comprising about 10 mg to about 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof. Treating comprises reducing the annualized rate of pulmonary exacerbations of the patient by at least about 20%, as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. In one embodiment, the compound of Formula (I) is brensocatib, e.g., brensocatib monohydrate.

Description

Attorney Docket No. INMD-215 / 03WO 315953-4453 METHODS FOR TREATING BRONCHIECTASIS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application No.63 / 652,543 filed on May 28, 2024, U.S. Provisional Application No.63 / 667,569 filed on July 3, 2024, and U.S. Provisional Application No. 63 / 712,792 filed on October 28, 2024; the disclosure of each of which are incorporated by reference in their entireties. BACKGROUND OF THE INVENTION

[0002] Bronchiectasis is a disease characterized by localized, irreversible enlargement of bronchi and bronchioles that may lead to obstructed breathing caused by abnormal mucus production. Bronchiectasis symptoms typically include a chronic dry or wet cough. Other symptoms include shortness of breath, coughing up blood, and chest pain. Wheezing and nail clubbing may also occur. People with the disease often get frequent lung infections.

[0003] Bronchiectasis, along with chronic obstructive pulmonary disease (COPD), acute lung injury, acute respiratory distress syndrome, and cystic fibrosis (CF) are all conditions of severe pulmonary dysfunction resulting from a massive inflammatory response. The histological characteristic of these inflammatory lung diseases is the accumulation of neutrophils in the interstitium and alveoli of the lung. Neutrophil activation leads to the release of multiple cytotoxic products including reactive oxygen species and proteases (serine, cysteine, and metalloproteases).

[0004] Subjects having bronchiectasis experience pulmonary exacerbations with an average frequency ranging from 1.5 to 6 per year (Goeminne et al. Respir Med. 2014;108(2):287-96; Kelly et al. Eur J Intern Med 2003; 14(8):488-92; Chalmers et al. Am J Respir Crit Care Med. 2014; 189(5):576-85). Currently, there is no standard-of-care (SOC) pharmacological treatment bronchiectasis. The primary goal of treatment is to treat underlying cause, prevent disease progression, maintain or improve lung function, and improve the symptoms and quality of life.

[0005] The present invention addresses the need for a therapy effective for the treatment of bronchiectasis, e.g., in non-cystic fibrosis patients.Attorney Docket No. INMD-215 / 03WO 315953-4453 SUMMARY OF THE INVENTION

[0006] In one aspect, a method for treating a bronchiectasis patient is provided. The method comprises orally administering to the patient in need of treatment, once daily for an administration period of at least 52 weeks, a pharmaceutical composition comprising about 10 mg to about 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate of Formula (I):R2is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4and R5together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; R6is C1-3alkyl, optionally substituted by 1, 2 or 3 F and / or optionally by OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; R7is hydrogen, F, Cl or CH3; X is O, S or CF2; Y is O or S; Q is CH or N and Z is H or halogen.

[0007] In the methods provided herein, treating comprises reducing the annualized rate of pulmonary exacerbations of the patient by at least about 20%, as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. In theAttorney Docket No. INMD-215 / 03WO 315953-4453 methods provided herein, a pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; and (6) hemoptysis.

[0008] In embodiments of the methods provided herein, treating comprises treating comprises achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1. In embodiments of the methods provided herein, treating comprises achieving median time to first PE of about 40 weeks to about 50 weeks. In embodiments of the methods provided herein, treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in 1 second (FEV1) during or subsequent to the administration period by about 10 mL to about 55 mL. In embodiments of the methods provided herein, treating comprises achieving annualized rate of severe PE of about 0.10 to about 0.17. In embodiments of the methods provided herein, treating comprises achieving annualized rate of severe PE of about 0.10 to about 0.17. In embodiments of the methods provided herein, treating comprises increasing the patient’s odds of remaining free of PEs during the administration period by about 40% to about 50%. In some embodiments, the treating comprises two, three or four of the outcomes selected from (i) achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1, (ii) achieving a median time to first PE of about 40 weeks to about 50 weeks, (iii) reducing the decline in the patient’s post-bronchodilator FEV1during or subsequent to the administration period by about 11 mL to about 50 mL, and (iv) achieving an annualized rate of severe PE of about 0.10 to about 0.17. In some embodiments, the treating comprises two, three, four or five of the outcomes selected from (i) achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1, (ii) achieving a median time to first PE of about 40 weeks to about 50 weeks, (iii) reducing the decline in the patient’s post-bronchodilator FEV1 during or subsequent to the administration period by about 11 mL to about 50 mL, (iv) achieving an annualized rate of severe PE of about 0.10 to about 0.17, and (v) increasing the patient’s odds of remaining free of PEs during the administration period by about 40% to about 50%.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0009] In a preferred embodiment,another embodiment, Z is F. In a further embodiment,.

[0010] In a preferred embodiment of the method for treating bronchiectasis in a patient in need thereof, the pharmaceutical composition comprises about 10 mg to about 25 mg 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, having the structural formula,(brensocatib), or a pharmaceutically acceptable salt or hydrate thereof. In a further preferred embodiment, the pharmaceutical composition comprises about 10 mg to about 25 mg 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 monohydrate, having the structural formula:Attorney Docket No. INMD-215 / 03WO 315953-4453

[0011] In one embodiment, the composition comprises an about 10 mg to about 25 mg of acompound having the following structure:pharmaceutically acceptable salt or hydrate thereof.

[0012] In yet another embodiment, the composition comprises about 10 mg to about 25 mg of (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide, having the structural formula:.

[0013] In yet another embodiment, the composition comprises about 10 mg to about 25 mg of (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide monohydrate, having the structural formula:.

[0014] The bronchiectasis in one embodiment, is present in a cystic fibrosis patient. In another embodiment, the patient treated with one of the methods provided herein does not have cystic fibrosis (referred to herein as “non-CF bronchiectasis” or “NCFBE”).

[0015] According to one embodiment of the method, treating comprises reducing the annualized rate of pulmonary exacerbations of the patient by about 20% to about 40%, by about 20% to about 35%, or by about 20% to about 30%, as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0016] In another embodiment of a method for treating bronchiectasis, the treating comprises reducing the annualized rate of pulmonary exacerbation in the patient over the administration period, as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. In a further embodiment, the rate is calculated over a period of about 12 months, about 15 months, about 18 months, about 21 months, about 24 months or about 36 months. In a further embodiment, treating comprises reducing the annualized rate of pulmonary exacerbations in the patient by about 15%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40% or by about 50%, by about 55%, by about 60%, by about 65%, by about 70%, by at least about 5%, by at least about 10%, by at least about 15%, by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, or at least about 70% as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. In one embodiment, the method for treating bronchiectasis comprises reducing the annualized rate of pulmonary exacerbations of the patient by about 10-40% or about 15-30% and the administration period is about 52 weeks.

[0017] In one embodiment of the method for treating bronchiectasis, the treating comprises increasing the length (also referred to as prolongation) of time to first pulmonary exacerbation of the patient over the administration period by about 15% to about 30%, as compared to an untreated bronchiectasis patient. In a further embodiment, the treating comprises increasing the length of time to first pulmonary exacerbation of the patient over the administration period by about 17.5% to about 30%, for example, by about 17.5% to about 25%, by about 17.5% to about 20%, or about 18% to about 20%, as compared to an untreated bronchiectasis patient. The bronchiectasis, in a preferred embodiment, is non-cystic fibrosis bronchiectasis (NCFBE). In a further embodiment, the increasing comprises increasing the time to first exacerbation 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, or increasing 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, as compared to an untreated bronchiectasis patient. In another embodiment, the increasing comprising increasing of from about 20 days to about 100 days, or from about 30 days to about 100 days, or from about 20 days to about 75 days, or from about 20 days to about 50 days, or from about 20 days to about 40 days. In one embodiment, the length of time to first pulmonary exacerbation over 52 weeks is increased by at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%,Attorney Docket No. INMD-215 / 03WO 315953-4453 at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29% or at least 30%, as compared to an untreated bronchiectasis patient.

[0018] In another embodiment of a method for treating bronchiectasis, a patient in need of treatment is administered a composition comprising from 10 mg to 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In this embodiment, treating comprises reducing the duration of a pulmonary exacerbation in the patient, as compared to the duration of a pulmonary exacerbation experienced by the patient prior to treatment, or compared to an untreated bronchiectasis patient. In a further embodiment, the reduced duration of a pulmonary exacerbation is a reduced duration of about 12 hours, about 24 hours, about 48 hours or about 72 hours, at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about 96 hours, at least about 120 hours, at least about 144 hours or at leat about 168 hours. In another embodiment, the reduced duration of a pulmonary exacerbation is a reduced duration of about 6 hrs to about 96 hrs, about 12 hrs to about 96 hrs, about 24 hrs to about 96 hrs, about 48 hrs to about 96 hrs or about 48 hrs to about 168 hrs. In yet another embodiment, the reduced duration of a pulmonary exacerbation is a reduced duration of about 1 day to about 1 week, about 2 days to about 1 week, about 3 days to about 1 week, about 4 days to about 1 week, about 5 days to about 1 week or about 6 days to about 1 week. In yet another embodiment, the reduced duration of a pulmonary exacerbation is a reduced duration of about 1 day to about 2 weeks, about 2 days to about 2 weeks, about 4 days to about 2 weeks, about 6 days to about 2 weeks, about 8 days to about 2 weeks or about 10 days to about 2 weeks.

[0019] In another embodiment of a method for treating bronchiectasis, a patient in need of treatment is administered a composition comprising from 10 mg to 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one such embodiment, the treating comprises first orally administering to the patient once daily 10 mg of the compound of Formula (I) during the administration period, and then administering orally administering to the patient once daily 25 mg of the compound of Formula (I) during the administration period. In another embodiment, the treating comprises first orally administering to the patient once daily about 25 mg of the compound of Formula (I) of the administration period and continuing administering 25 mg of the compound of Formula (I) until the patient becomes intolerant, and then orally administering once daily 10 mg of the compound of Formula (I). In embodiments, the patient becomes intolerant of about 25 mg of the compound of Formula (I) when the patient experiences headache, hyperkeratosis, rash, infection, pneumonia, dyspnea, hemoptysis,Attorney Docket No. INMD-215 / 03WO 315953-4453 periodontal disease, arthralgia, fatigue, nasopharyngitis, cough, dermatitis contact, pain, and / or dry skin. In embodiments, hyperkeratosis comprises a skin lesion, eczema, hyperkeratosis, keratosis pilaris, exfoliative rash, and / or seborrheic keratosis. In further embodiments, the patient returns to administering 25 mg of the compound of Formula (I) when the headache, hyperkeratosis, rash, and / or dry skin subside.

[0020] In another embodiment of a method for treating bronchiectasis provided herein, the treating comprises increasing the patient’s odds of remaining free of pulmonary exacerbations by about 20% to about 50%, for example, by about 30% to about 50% or by about 40% to about 50%, as compared to an untreated bronchiectasis patient. In a further embodiment, the method comprises increasing the patient’s odds of remaining free of pulmonary exacerbations by about 40% to about 50%, as compared to an untreated bronchiectasis patient. In one embodiment, the method comprises increasing the patient’s odds of remaining free of pulmonary exacerbations by at least 20%, for example, at least about 30%, as compared to an untreated bronchiectasis patient. The bronchiectasis in one embodiment, is NCFBE.

[0021] In yet another embodiment of a method for treating bronchiectasis provided herein, the treating comprises decreasing the annualized rate of severe pulmonary exacerbations by at least about 10%, for example, at least about 20%, as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. A severe pulmonary exacerbation, according to the methods provided herein, requires treatment with intravenous antibiotic drugs, hospitilization or a combination thereof. In a further embodiment, the treating comprises decreasing the rate of severe pulmonary exacerbations by about 10% to about 50%. In a further embodiment, the treating comprises decreasing the rate of severe pulmonary exacerbations by about 25% to about 50%. In even a further embodiment, the treating comprises decreasing the rate of severe pulmonary exacerbations by about 25% to about 40% or by about 20% to about 30%. In even another embodiment, the treating comprises decreasing the rate of severe pulmonary exacerbations by about 25% to about 30%. The bronchiectasis in one embodiment, is NCFBE.

[0022] In yet another embodiment of a method for treating bronchiectasis provided herein, treating comprises (i) reducing the annualized rate of pulmonary exacerbations of the patient by at least about 20%, as compared to the annualized rate of pulmonary exacerbations experienced by a untreated bronchiectasis patient and (ii) reducing lung function decline of the patient, as compared to the lung function decline of an untreated bronchiectasis patient. Reducing lung function decline, in one embodiment, comprises reducing the decline in theAttorney Docket No. INMD-215 / 03WO 315953-4453 patient’s post-bronchodilator forced expiratory volume in one second (FEV1), as compared to an untreated bronchiectasis patient. In a further embodiment, the method comprises reducing post-bronchodilator FEV1 decline of the patient by at least about 10 mL, for example at least about 11 mL, by about 10 mL to about 50 mL, by about 10 mL to about 40 mL, or by about 10 mL to about 30 mL. In another embodiment, treating comprises reducing the decline of the patient’s FEV1by about 30 mL to about 50 mL, about 30 mL to about 40 mL or about 35 mL to about 40 mL. The bronchiectasis in one embodiment, is NCFBE.

[0023] In yet another embodiment, treating comprises reducing the patient’s FEV1 decline by about 35 mL to about 45 mL. In a further embodiment, the patient does not experience a pulmonary exacerbation during the administration period.

[0024] In yet another embodiment, treating comprises reducing the patient’s FEV1 decline by about 25 mL to about 30 mL, as compared to an untreated patient. In a further embodiment, the patient experiences one or more pulmonary exacerbations during the administration period.

[0025] In yet another embodiment, the method for treating bronchiectasis provided herein comprises improving lung function by increasing the patient’s FEV1by about 5%, about 10%, about 15%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45% or by about 50%, as compared to a baseline FEV1of the patient. In yet even another embodiment, treating comprises increasing the patient’s FEV1 by at least about 5%, at least about 10%, at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45% or by at least about 50% as compared to a baseline FEV1of the patient. In yet another embodiment, the increase in FEV1 is an increase by about 5% to about 50%, by about 5% to about 40%, by about 5% to about 30%, by about 5% to about 20%, by about 10% to about 50%, by about 15% to about 50%, by about 20% to about 50% or by about 25% to about 50% as compared to a baseline FEV1of the patient. The bronchiectasis in one embodiment, is NCFBE.

[0026] In another embodiment, the method for treating bronchiectasis provided herein comprises increasing the patient’s forced vital capacity (FVC), as compared to the lung function of the patient prior to treatment (patient baseline). In a further embodiment, the increase in FVC is an increase by about 1%, increase by about 2%, by about 3%, by about 4%, by about 5%, by about 6%, by about 7%, by about 8%, by about 9%, by about 10%, by about 11%, by about 12%, by about 13%, by about 14%, by about 15%, by about 16%, by about 17%, by about 18%, by about 19%, by about 20%, by about 25%, by about 30%, by about 35%, byAttorney Docket No. INMD-215 / 03WO 315953-4453 about 40%, by about 45%, by about 50%, by about 55%, by about 60%, by about 65%, by about 70%, by about 75%, by about 80%, by about 85% or by about 90%, as compared to a FVC of the patient prior to treatment. The bronchiectasis in one embodiment, is NCFBE.

[0027] In another embodiment of a method for treating bronchiectasis, a patient in need of treatment is administered a composition comprising from about 10 mg to about 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof once daily during an administration period of at least 52 weeks. The treating comprises improving the patient’s quality of life (QOL), as compared to the patient’s QOL prior to treatment. The QOL is assessed by the Leicester Cough Questionnaire (LCQ), by the St. George’s Respiratory Questionnaire (SGRQ), or the Quality of Life-Bronchiectasis (QOL-B) questionnaire, or portion thereof. In a preferred embodiment, the quality of life is assessed by the Quality of Life-Bronchiectasis Respiratory Symptoms Domain score (QOL-B RSS). In one embodiment, treating comprises increasing the patient’s QOL-B RSS respiratory score by at least 1 point. In one embodiment, treating comprises increasing the patient’s QOL-B RSS score by 2 points to 10 points or by 3 points to 10 points, by 2 points to 5 points or by 3 points to 5 points. The bronchiectasis in one embodiment, is NCFBE.

[0028] In another embodiment of a method for treating bronchiectasis, a patient in need of treatment is administered a composition comprising from about 10 mg to about 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof once daily during an administration period of at least 52 weeks. In this embodiment, the treating comprises decreasing active neutrophil elastase (NE) sputum concentration in the patient, as compared to the active NE sputum concentration of the patient prior to treatment (patient baseline). In a further embodiment, decreasing the active NE sputum concentration comprises decreasing by about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%. The bronchiectasis in one embodiment, is NCFBE.

[0029] In yet another embodiment of a method for treating bronchiectasis, a patient in need of treatment is administered a composition comprising from about 10 mg to about 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof once daily during an administration period of at least 52 weeks and the treating comprises lightening the patient’s sputum color as compared to the patient’s sputum color prior to treatment, as measured by the sputum color chart of Murray. In a further embodiment, lightening theAttorney Docket No. INMD-215 / 03WO 315953-4453 patient’s sputum color comprises lightening the patient’s sputum color by a single gradation. In a further embodiment, the lightening is from purulent (dark yellow and / or dark green) to mucopurulent (pale yellow and / or pale green). In another embodiment, the lightening is from mucopurulent (pale yellow and / or pale green) to mucoid (clear). In yet another embodiment, the lightening is from purulent (dark yellow and / or dark green) to mucoid (clear). The bronchiectasis in one embodiment, is NCFBE.

[0030] In yet another embodiment of a method for treating bronchiectasis, the patient in need of treatment experienced at least one PE in a 12 month period immediately preceding the administration period. In yet another embodiment of a method for treating bronchiectasis, the patient in need of treatment experienced at least 2 PEs in a 12 month period immediately preceding the administration period. In one embodiment of a method for treating bronchiectasis, the patient in need of treatment received antibiotic treatment for bronchiectasis during the 12 month period immediately preceeding the administration period. In one embodiment of a method for treating bronchiectasis, the patient in need of treatment is an adult patient. In yet another embodiment the adult patient in need of treatment experienced at least 2 PEs in a 12 month period immediately preceding the administration period. In one embodiment of a method for treating bronchiectasis, the patient in need of treatment is a pediatric patient. In yet another embodiment, the pediatric patient in need of treatment experienced at least 1 PE in a 12 month period immediately preceding the administration period. The bronchiectasis in one embodiment, is NCFBE. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG.1 shows that annualized rate of pulmonary exacerbations per year was reduced by 21.1% and 19.4% in patients treated with brensocatib 10 mg and 25 mg, respectively, vs placebo. Exacerbations were adjudicated events in the ITT (intent-to-treat) analysis set analyzed using a negative binomial model.

[0032] FIG.2 shows that the median time to first exacerbation was significantly longer in both groups of patients treated with brensocatib compared with placebo group.

[0033] FIG.3 shows that a significantly larger proportion of patients in both groups of patients treated with brensocatib remaining exacerbation free compared with placebo group.

[0034] FIG.4 shows that patients treated with Brensocatib 25 mg showed a 38 mL less FEV1 decline vs placebo and patients treated with Brensocatib 10 mg showed a 11 mL less FEV1 dcline vs placebo.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0035] FIG. 5 shows that patients treated with placebo showed a larger decrease in post Bronchodilator FVC (forced vital capacity) from baseline to week 52 than patients treated with brensocatib 10 mg or 25 mg.

[0036] FIG.6 shows annualized rate of severe pulmonary exacerbations per year was reduced by 25.8% and 26.0% in patients treated with brensocatib 10 mg and 25 mg, respectively, vs placebo. Severe pulmonary exacerbations were defined as those requiring intravenous antibiotics and / or hospitalization. P value vs. placebo was calculated using a negative binomial model in the ITT analysis sett. ITT, intent to treat.

[0037] FIG. 7 shows nominally significant improvement in QOL-B RSS (Quality of Life- Bronchiectasis questionnaire Respiratory Symptom Domain score) of 3.8 points and 2.0 points in patients treated with brensocatib 10 mg and 25 mg, respectively, vs placebo.

[0038] FIG.8 shows the change from Baseline in Average Daily Bronchiectasis Exacerbation and Symptom Tool (BEST) Score Over Time for adult participants in the ASPEN study.

[0039] FIG.9 shows the patient disposition of the phase 3, randomized, double-blind, placebo- controlled, 52-Week study of brensocatib of Example 1.

[0040] FIG. 10 are graphs of FEV1in patients without (left panel) or with (right panel) pulmonary exacerbations on-study. BD, bronchodilator; FEV1, forced expiratory volume in 1 second; LS, least squares; SE, standard error. DETAILED DESCRIPTION OF THE INVENTION

[0041] Neutrophils contain four main types of granules: (i) azurophilic or primary granules, (ii) specific or secondary granules, (iii) gelatinase or tertiary granules, and (iv) secretory granules. Azurophilic granules are believed to be the first to form during neutrophil maturation in the bone marrow and are characterized by the expression of related neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase 3, and cathepsin G. The lysosomal cysteine dipeptidyl peptidase 1 (DPP1) is the proteinase that activates these 3 NSPs by removal of the N-terminal dipeptide sequences from their precursors during azurophilic granule assembly (Pham et al. (2004). J Immunol.173(12), pp.7277-7281). DPP1 is broadly expressed in tissues, but is highly expressed in cells of hematopoietic lineage such as neutrophils.

[0042] The three NSPs, abundantly secreted into the extracellular environment upon neutrophil activation at inflammatory sights, are thought to act in combination with reactive oxygen species to assist in degradation of engulfed microorganisms inside phagolysosomes. A fractionAttorney Docket No. INMD-215 / 03WO 315953-4453 of the released proteases remains bound in an active form on the external surface of the plasma membrane so that both soluble and membrane-bound NSPs can regulate the activities of a variety of biomolecules such as chemokines, cytokines, growth factors, and cell surface receptors. Without wishing to be bound by theory, regulation is thought to occur by either converting the respective biomolecule to an active form or by degrading the biomolecule by proteolytic cleavage. Secreted proteases can stimulate mucus secretion and inhibit mucociliary clearance, but also activate lymphocytes and cleave apoptotic and adhesion molecules (Bank and Ansorge (2001). J Leukoc Biol.69, pp.197–206; Pham (2006). Nat Rev Immunol.6, pp. 541–550; Meyer-Hoffert (2009). Front Biosci.14, pp.3409–3418; Voynow et al. (2004). Am J Physiol Lung Cell Mol Physiol. 287, pp. L1293-302; the disclosure of each of which is incorporated by reference in its entirety for all purposes).

[0043] The physiological balance between proteases and anti-proteases is required for the maintenance of the lung’s connective tissue. For example, an imbalance in favor of proteases can result in lung injury (Umeki et al. (1988). Am J Med Sci.296, pp.103–106; Tetley (1993). Thorax 48, pp. 560–565; the disclosure of each of which is incorporated by reference in its entirety for all purposes).

[0044] The methods provided herein employ reversible inhibitors of DPP1. Without wishing to be bound by theory, it is thought that the compounds of Formula (I), administered via the methods provided herein have beneficial effects via decreasing inflammation and mucus hypersecretion, which in turn leads to a decrease in pulmonary exacerbations, a decrease in the rate, e.g., annualized rate, of pulmonary exacerbations, the time to first pulmonary exacerbation, quality of life, and / or an improvement in cough, sputum production, and / or lung function (e.g., forced expiratory volume in 1 second (FEV1)) in bronchiectasis patients. Without wishing to be bound by theory, it is thought that the methods provided herein modify bronchiectasis progression by reducing the accelerated rate of lung function decline and / or lung tissue destruction.

[0045] It is to be understood that where in this specification a group is qualified by “defined above” the said group encompasses the first occurring and broadest definition as well as each and all the other definitions for that group.

[0046] As used herein, “C1-3” means a carbon group having 1, 2 or 3 carbon atoms.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0047] The term “alkyl”, unless otherwise noted, includes both straight and branched chain alkyl groups and may be, substituted or non-substituted. “Alkyl” groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl.

[0048] “Halogen”, as used herein, refers to F, Cl, Br, I or their isotopes. “Halogenated” or “halogen substitution” refers to substitution by one or more of the above F, Cl, Br or I or their isotopes, the upper limit of the number of halogen substitution groups is equal to the total number of substitutable hydrogens, and unless specifically defined, the number of halogen substitution groups is any integer between 1 and that upper limit, if the number of halogen substitution groups is greater than 1, substitution by the same or a different halogen is possible. Customarily, 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitution and 1 halogen substitution are involved.

[0049] The the term “pharmaceutically acceptable”, unless otherwised noted, is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0050] All references here to a compound of Formula (I) or any species within Formula (I) includes a pharmaceutically acceptable salt, hydrate, cocrystal and solvates thereof.

[0051] A “pulmonary exacerbation” or “PE” as used herein, is three or more of the following symptoms exhibited for at least 48 hours by a patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; (6) hemoptysis. A “severe pulmonary exacerbation”, as used herein, is a pulmonary exacerbation that requires treatment with intravenous antibiotic drugs and / or hospitilization.

[0052] An “untreated bronchiectasis patient” or “untreated patient”, as used herein, is a patient that has been diagnosed with bronchiectasis, but has not been subjected to once daily administration of a pharmaceutical composition comprising about 10 mg to about 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate of Formula (I), for an administration period of at least 52 weeks. An “untreated bronchiectasis patient”, in some embodiments, is the same patient undergoing treatment via one of the methods provided herein,Attorney Docket No. INMD-215 / 03WO 315953-4453 but refers to the patient, prior to treatment, i.e., prior to the administration period (i.e., prior to treatment commencing).

[0053] In one aspect, a method for treating a bronchiectasis patient is provided. The method comprises orally administering to the patient in need of treatment, once daily for an administration period of at least 52 weeks, a pharmaceutical composition comprising about 10 mg to about 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate of Formula (I):R2is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2or SO2NR4R5, wherein R4and R5together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; R6is C1-3alkyl, optionally substituted by 1, 2 or 3 F and / or optionally by OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; R7is hydrogen, F, Cl or CH3; X is O, S or CF2; Y is O or S; Q is CH or N; and Z is halogen or H.

[0054] In the methods provided herein, treating comprises reducing the annualized rate of pulmonary exacerbations of the patient by at least about 20%, as compared to the annualized rate of pulmonary exacerbations experienced by the patient prior to the administration period,Attorney Docket No. INMD-215 / 03WO 315953-4453 or compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. In the methods provided herein, a pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; and (6) hemoptysis.

[0055] In one embodiment, the annualized rate of pulmonary exacerbations is calculated for apatient undergoing a method of the disclosure as follows:365.25

[0056] wherein the “Number of PEs” are the number of PEs that meet the above criteria, and the “Time at Risk” is calculated as the administration period excluding the time during a pulmonary exacerbation(s).

[0057] For an “untreated patient”, anuualized rate of PEs are calculated over the same time period as the treated patient, excluding the time during which a pulmonary exacerbation(s) is experienced by the untreated patient.

[0058] The bronchiectasis can be present in a cystic fibrosis patient. In one preferred embodiment, the bronchiectasis is not associated with cystic fibrosis (non-CF bronchiectasis or NCFBE).

[0059] In one embodiment R1is; R2is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2or SO2NR4R5, wherein R4and R5together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring.

[0060] In a further embodiment, R1is; R2is hydrogen, F, Cl or C1-3alkyl; and R3is hydrogen, F, Cl, CN or SO2C1-3alkyl.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0061] In still a further embodiment, R1isR2is hydrogen, F or C1-3alkyl; and R3is hydrogen, F or CN.

[0063] X is O, S or CF2; Y is O or S; Q is CH or N; R6is C1-3alkyl, wherein the C1-3alkyl is optionally substituted by 1, 2 or 3 F and / or optionally substituted by OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; and R7is hydrogen, F, Cl or CH3.

[0064] In still a further embodiment,CF2; Y is O or S; R6is C1-3alkyl, optionally substituted by 1, 2 or 3 F and optionally substituted by OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; and R7is hydrogen, F, Cl or CH3.

[0065] In still a further embodiment,3alkyl, wherein the C1-3alkyl is optionally substituted by 1, 2 or 3 F; and R7is hydrogen, F, Cl or CH3.

[0066] In still a further embodiment,3alkyl, wherein the C1-3alkyl is optionally substituted by 1, 2 or 3 F; and R7is hydrogen.

[0067] In one embodiment, R2is hydrogen, F, Cl, Br, OSO2C1-3alkyl or C1-3alkyl.

[0068] In a further embodiment, R2is hydrogen, F, Cl or C1-3alkyl.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0069] In still a further embodiment, R2is hydrogen, F or C1-3alkyl.

[0070] In one embodiment, R3 is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl CONH2 orSO2NR4R5, wherein R4and R5together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring.

[0071] In a further embodiment, R3is selected from hydrogen, F, Cl, CN or SO2C1-3alkyl.

[0072] In still a further embodiment, R3is selected from hydrogen, F or CN.

[0073] In one embodiment, R6is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran.

[0074] In a further embodiment, R6is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F. In still a further embodiment, R6is methyl or ethyl. In still a further embodiment, R6is methyl.

[0075] In one embodiment, R7is hydrogen, F, Cl or CH3. In a further embodiment R7is hydrogen.

[0076] In a preferred 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:pharmaceutically acceptable salt or hydrate thereof. In a further preferred embodiment, the compound of Formula (I) is brensocatib monohydrate (CAS registry no.2923839-30-7).

[0077] In one embodiment, the composition comprises from 10 mg to 25 mg ofAttorney Docket No. INMD-215 / 03WO 315953-4453

[0078] In one embodiment, the composition comprises from 10 mg to 25 mg ofpharmaceutically acceptable salt or hydrate thereof.

[0079] In one embodiment, the compound of Formula (I) is:

[0080] (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide,

[0081] (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,

[0082] (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,

[0083] 4’-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate,

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

[0085] (2S)-N-{(1S)-1-Cyano-2-[4’-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide,

[0086] (2S)-N-[(1S)-1-Cyano-2-(3’,4’-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2- carboxamide,

[0087] (2S)-N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide,

[0088] (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,

[0089] (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,

[0090] (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,Attorney Docket No. INMD-215 / 03WO 315953-4453

[0091] (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,

[0092] (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,

[0093] (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,

[0094] (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,

[0095] (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,

[0096] (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,

[0097] (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,

[0098] (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,

[0099] (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,

[0100] (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,

[0101] (2S)-N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide,

[0102] (2S)-N-[(1S)-2-(4’-Carbamoyl-3’-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane- 2-carboxamide,

[0103] (2S)-N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}- 1,4-oxazepane-2-carboxamide,

[0104] (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,Attorney Docket No. INMD-215 / 03WO 315953-4453

[0105] (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,

[0106] (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,

[0107] (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,

[0108] (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,

[0109] (2S)-N-{(1S)-1-Cyano-2-[4’-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide,

[0110] (2S)-N-{(1S)-2-[4’-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4- oxazepane-2-carboxamide,

[0111] (2S)-N-[(1S)-1-Cyano-2-(4’-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2- carboxamide,

[0112] (2S)-N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide, or

[0113] (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide,

[0114] or a pharmaceutically acceptable salt or hydrate (e.g., monohydrate) of one of the foregoing compounds.

[0115] The methods provided herein comprise the administration of a composition comprising from 10 mg to 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a bronchiectasis patient in need of treatment. The compounds of Formula (I) and their pharmaceutically acceptable salts are inhibitors of dipeptidyl peptidase 1 (DPP1) activity. The bronchiectasis may be in a patient with cystic fibrosis, or a patient that does not have cystic fibrosis (sometimes referred to as “bronchiectasis unrelated to cystic fibrosis” or “non-CF bronchiectasis”). In a preferred embodiment, the bronchiectasis is non-CF bronchiectasis.

[0116] Non-CF bronchiectasis has been reported to be caused by or associated with numerous aetiologies ranging from genetic illness to retained airway foreign body, and has been reported to be present in patients with systemic disease, common respiratory diseases such as chronic obstructive pulmonary disease (COPD) as well as uncommon diseases such as sarcoidosisAttorney Docket No. INMD-215 / 03WO 315953-4453 (Chang and Bilton (2008). Thorax 63, pp. 269-276, incorporated by reference herein in its entirety for all purposes).

[0117] Bronchiectasis is considered a pathological endpoint that results from many disease processes and is a persistent or progressive condition characterized by dilated thick-walled bronchi. The symptoms vary from intermittent episodes of expectoration and infection localized to the region of the lung that is affected to persistent daily expectoration often of large volumes of purulent sputum. Bronchiectasis may be associated with other non-specific respiratory symptoms. The underlying pathological process of bronchiectasis, without wishing to be bound by theory, has been reported as damage to the airways which results from an event or series of events where inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V. 65(Suppl 1), incorporated by reference herein in its entirety for all purposes).

[0118] The term “treating” in one embodiment, includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in the patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (i.e., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); (3) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). In one embodiment, the clinical symptom is a pulmonary exacerbation and / or (4) prophylaxis of the bronchiectasis, e.g., non-CF bronchiectasis.

[0119] Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, bronchiectasis. As such, in one embodiment of the invention, a method for providing prophylaxis of bronchiectasis in a patient in need thereof is provided. The patient in need thereof, in one embodiment, has suffered a previous episode of, or is at increased risk for being diagnosed with bronchiectasis. Without wishing to be bound by theory, it is thought that administration of from 10 mg to 25 mg of a compound of Formula (I), a hydrate thereof, or a pharmaceutically acceptable salt thereof, interrupts the cycle of infection / inflammation / impaired mucociliary clearance and tissue destruction observed in bronchiectasis patients by inhibiting neutrophil elastase activity.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0120] As provided above, in the methods provided herein, treating comprises reducing the annualized rate of pulmonary exacerbations in the patient by at least about 20%, as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. In one embodiment treating comprises reducing the annualized rate of pulmonary exacerbations in the patient by from about 20% to about 40%, or from about 25% to about 40%, or from about 30% to about 40%, as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. As provided above, in the methods provided herein, treating comprises reducing the annualized rate of pulmonary exacerbations in the patient by at least 19%, as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. In one embodiment, treating comprises reducing the annualized rate of pulmonary exacerbations in the patient by about 19% to about 22%, as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. In one embodiment, treating comprises reducing the annualized rate of pulmonary exacerbations in the patient by about 19.4% to about 21.1%, as compared to the annualized rate of pulmonary exacerbations experienced by an untreated bronchiectasis patient. The bronchiectasis in one embodiment, is NCFBE.

[0121] In yet another embodiment, treating comprises reducing the annualized rate of pulmonary exacerbations of the patient, as compared to the annualized rate of pulmonary exacerbation experienced by an untreated bronchiectasis patient by at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29% at least about 30%, at least about 35%, or at least about 40%. In yet another embodiment, the treating comprises reducing the annualized rate of pulmonary exacerbations in the patient by about 20%, by about 25%, by about 30%, by about 35%, or by about 40%, as compared to the rate of pulmonary exacerbation experienced by the patient prior to treatment, or compared to an untreated bronchiectasis patient. In one embodiment, the treating comprises reducing the annualized rate of pulmonary exacerbations in the patient by about 20-40% or about 20-30% over 52 weeks, as compared to an untreated bronchiectasis patient. The bronchiectasis in one embodiment, is NCFBE.

[0122] In a further embodiment, the compound of Formula (I) brensocatib, e.g., brensocatib monohydrate.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0123] In another embodiment of the method disclosed herein, the treating comprises achieving an annualized rate of pulmonary exacerbations of about 1.1 or less, e.g., about 1.1, about 1.0, about 0.9, about 0.8, about 0.7, about 0.6, about 0.5, about 0.4. about 0.3, about 0.2, about 0.1, or about 0.0, including all values and ranges therein. In one embodiment, treating comprises achieving an annualized rate of pulmonary exacerbations in the patient over the administration period of about 1.1 to about 0.5, about 1.1 to about 0.9, or about 1.1 to about 1.0. In a further embodiment, the compound of Formula (I) brensocatib, e.g., brensocatib monohydrate.

[0124] In one embodiment, the treating comprises increasing the length of time to first pulmonary exacerbation, as compared to the length of time to first pulmonary exacerbation in an untreated bronchiectasis patient. The bronchiectasis in one embodiment, is NCFBE.

[0125] In one embodiment of the method for treating bronchiectasis, the treating comprises increasing the length (also referred to as prolongation) of time to first pulmonary exacerbation over the administration period by about 15% to about 30%, as compared to an untreated bronchiectasis patient. In a further embodiment, the treating comprises increasing the length of time to first pulmonary exacerbation over the administration period by about 17.5% to about 30%, for example, by about 17.5% to about 28%, by about 17.5% to about 25%, by about 17.5% to about 20%, or about 18% to about 20%, as compared to an untreated bronchiectasis patient. The bronchiectasis, in a preferred embodiment, is non-cystic fibrosis bronchiectasis (NCFBE).

[0126] In one embodiment, treating bronchiectasis comprises increasing the length of time to first pulmonary exacerbation over the administration period, e.g., 52 weeks, by at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29% or at least 30% for a patient subject to a method of the disclosure, compared to an untreated bronchiectasis patient. The bronchiectasis in one embodiment, is NCFBE.

[0127] In one embodiment, the method provided herein comprises increasing the time to first pulmonary exacerbation of the patient 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, or 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, as compared to an untreated bronchiectasis patient. In yet another embodiment, the increasing comprising increasing by from about 20 days to about 100 days, or from about 30 days to about 100 days,Attorney Docket No. INMD-215 / 03WO 315953-4453 or from about 20 days to about 75 days, or from about 20 days to about 50 days, or from about 20 days to about 40 days. The patient, in one embodiment, is an NCFBE patient.

[0128] In yet even another embodiment, the method provided herein comprises increasing the time to first exacerbation of the patient by about 10 weeks to about 16 weeks, or from about 10 weeks to about 14 weeks, or from about 12 weeks to about 14 weeks, as compared to an untreated bronchiectasis patient. In even a further embodiment, the method provided herein comprises increasing the time to first exacerbation of the patient by about 14 weeks, as compared to an untreated bronchiectasis patient.

[0129] For example, in some embodiments, the length of time to first pulmonary exacerbation in the patient is increased at least about 20 days, as compared to the length of time to first pulmonary exacerbation in an untreated bronchiectasis patient. In other embodiments, the length of time to first pulmonary exacerbation is increased from about 20 to about 100 days in the patient, as compared to the length of time to first pulmonary exacerbation in an untreated bronchiectasis patient. In another embodiment, the length of time to first pulmonary exacerbation is increased from about 25 to about 100 days, from about 30 to about 100 days, from about 35 to about 100 days or from about 40 to about 100 days, or from about 60 days to about 100 days, or from about 70 days to 100 days, or from about 80 days to 100 days, or from about 90 days to 100 days, as compared to the length of time to first pulmonary exacerbation for an untreated bronchiectasis patient. In a further embodiment, the compound of Formula (I) is brensocatib, e.g., brensocatib monohydrate.

[0130] In one embodiment of the method for treating bronchiectasis, the treating comprises achieving a mediam time to the first pulmonary exacerbation of at least 40 weeks. For example, in some embodiments, the mediam time to the first pulmonary exacerbation is at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, at least 48 weeks, at least 49 weeks, at least 50 weeks, at least 51 weeks, or at least 52 weeks. In other embodiments, the mediam time to the first pulmonary ranges from about 40 weeks to about 50 weeks (e.g., about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, or about 52 weeks). In a further embodiment, the compound of Formula (I) is brensocatib, e.g., brensocatib monohydrate. The bronchiectasis in one embodiment, is NCFBE.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0131] In even another embodiment, a method of the disclosure comprises decreasing the duration of a pulmonary exacerbation, as compared to the duration of a pulmonary exacerbation experienced by an untreated bronchiectasis patient. In one embodiment, the method comprises decreasing the duration of a pulmonary exacerbation by about 12 hours, about 24 hours, about 48 hours or about 72 hours, at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about 96 hours, at least about 120 hours, at least about 144 hours or at least about 168 hours, as compared to the duration of a pulmonary exacerbation experienced by an untreated bronchiectasis patient. In another embodiment, the method comprises decreasing the duration of a pulmonary exacerbation by about 6 hrs to about 96 hrs, about 12 hrs to about 96 hrs, about 24 hrs to about 96 hrs, about 48 hrs to about 96 hrs or about 48 hrs to about 168 hrs, as compared to the duration of a pulmonary exacerbation experienced by an untreated bronchiectasis patient. In yet another embodiment, the method comprises decreasing the duration of a pulmonary exacerbation in the patient by about 1 day to about 1 week, about 2 days to about 1 week, about 3 days to about 1 week, about 4 days to about 1 week, about 5 days to about 1 week or about 6 days to about 1 week, as compared to the duration of a pulmonary exacerbation experienced by an untreated bronchiectasis patient. In yet another embodiment, the method comprises decreasing the duration of a pulmonary exacerbation by about 1 day to about 2 weeks, about 2 days to about 2 weeks, about 4 days to about 2 weeks, about 6 days to about 2 weeks, about 8 days to about 2 weeks or about 10 days to about 2 weeks, as compared to the duration of a pulmonary exacerbation experienced by an untreated bronchiectasis patient. The bronchiectasis in one embodiment, is NCFBE.

[0132] The method of the disclosure in one embodiment, comprises decreasing the duration of a pulmonary exacerbation by about 6 hrs to about 96 hrs, about 12 hrs to about 96 hrs, about 24 hrs to about 96 hrs, about 48 hrs to about 96 hrs or about 48 hrs to about 168 hrs, as compared to the duration of a pulmonary exacerbation experienced by an untreated bronchiectasis patient. The bronchiectasis in one embodiment, is NCFBE.

[0133] The reduced duration in one embodiment is the average reduction of exacerbations experienced during treatment. In a further embodiment, the compound of Formula (I) is brensocatib, e.g., brensocatib monohydrate.

[0134] In another embodiment of a method for treating bronchiectasis, the treating comprises increasing the patient’s odds of remaining free of pulmonary exacerbations by at leat about 10%, as compared to an untreated bronchiectasis patient. In one embodiment, the methodAttorney Docket No. INMD-215 / 03WO 315953-4453 comprises increasing the patient’s odds of remaining exacerbation free by at leat about 10%, e.g., at least about 15%, at least about 16%, or at least about 17%, over 52 weeks, as compared to an untreated bronchiectasis patient. In one embodiment, increasing the odds of remaining exacerbation free over the administration period, e.g., 52 weeks, comprises increasing the patient’s odds of remaining exacerbation free by from about 10% to about 40%, from about 10% to about 30%, or from about 10% to about 20%, as compared to an untreated bronchiectasis patient. In another embodiment, increasing the odds of remaining exacerbation free over the administration period, e.g., 52 weeks, comprises increasing the patient’s odds of remaining exacerbation free by from about 10% to about 20%, from about 12% to about 20%, or from about 14% to about 20%, or from about 16% to about 20%, as compared to an untreated bronchiectasis patient.

[0135] In another embodiment provided herein, the treating comprises reducing the annualized rate of severe pulmonary exacerbations in the patient, as compared to an untreated bronchiectasis patient. In one embodiment, the treating comprises reducing the annualized rate of severe pulmonary exacerbations in the patient over the administration period (e.g., 52 weeks) by at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34% at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50%, as compared the annualized rate of severe pulmonary exacerbations in an untreated bronchiectasis patient.

[0136] In one embodiment, the treating comprises reducing the annualized rate of severe pulmonary exacerbations in the patient over the administration period (e.g., 52 weeks) by about 10% to about 50%, by about 15% to about 35% or by about 20% to about 30%. In one embodiment, the treating comprises reducing the annualized rate of severe pulmonary exacerbations in the patient over the administration period by 20% to 30%. In a further embodiment, the treating comprises reducing the annualized rate of severe pulmonary exacerbations in the patient over the administration period (e.g., 52 weeks) by 25% to 28%.

[0137] In one embodiment, the treating comprises achieving an annualized rate of severe pulmonary exacerbations in the patient over the administration period (e.g., 52 weeks) of about 0.17 or less, e.g., about 0.17, about 0.16, about 0.15, about 0.14, about 0.13, about 0.12, about 0.11, about 0.10, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, or less, including all values andAttorney Docket No. INMD-215 / 03WO 315953-4453 ranges therein. In a further embodiment, treating comprises achieving an annualized rate of severe pulmonary exacerbations in the patient over the administration period of about 0.17 to about 0.1, or about 0.15 to 0.10, or about 0.137.

[0138] As provided throughout, aspects of the disclosure relate to the treatment of a bronchiectasis patient, e.g., non-CF bronchiectasis patient, comprising administering to the patient a composition comprising from 10 mg to 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, once daily via oral administration during an administration period. The method, in one embodiment, comprises improving the lung function of the patient, as compared to an untreated bronchiectasis patient, or as compared to the lung function in the patient prior to treatment (the patient’s baseline lung function). The compound of Formula (I) in one embodiment is brensocatib, e.g., brensocatib monohydrate.

[0139] Improving lung function, in one embodiment, comprises reducing lung function decline of the patient, as compared to an untreated bronchiectasis patient.

[0140] Reducing lung function decline, in one embodiment, comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1), as compared to an untreated bronchiectasis patient. In a further embodiment, the method comprises reducing post-bronchodilator FEV1decline of the patient by at least about 10 mL, e.g., at least about 11 mL, at least about 15 mL, at least about 20 mL, at least about 25 mL, at least about 30 mL, at least about 35 mL or at least about 40 mL, as compared to an untreated bronchiectasis patient. In a further embodiment, the method comprises reducing post-bronchodilator FEV1 decline of the patient by at least about 10 mL, e.g., at least about 11 mL, at least about 15 mL, at least about 20 mL, at least about 25 mL, at least about 30 mL, at least about 35 mL, at least about 40 mL, at least about 50 mL, or at least about 55 mL, as compared to an untreated bronchiectasis patient.

[0141] Reducing lung function decline, in one embodiment, comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1), as compared to an untreated bronchiectasis patient by about 10 mL to about 50 mL, by about 10 mL to about 40 mL, or by about 10 mL to about 30 mL. In another embodiment, treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1), as compared to an untreated bronchiectasis patient by about 30 mL to about 50 mL, about 30 mL to about 40 mL or by about 35 mL to about 40 mL. In another embodiment, treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volumeAttorney Docket No. INMD-215 / 03WO 315953-4453 in one second (FEV1), as compared to an untreated bronchiectasis patient by about 10 mL to about 55 mL, about 11 mL to about 55 mL, about 20 mL to about 55 mL, about 30 mL to about 55 m, or about 35 mL to about 55 mL.

[0142] In yet another embodiment, treating comprises reducing the patient’s post- bronchodilator FEV1decline by about 35 mL to about 45 mL. In a further embodiment, the patient does not experience a pulmonary exacerbation during the administration period.

[0143] In yet another embodiment, treating comprises reducing the patient’s post- bronchodilator FEV1decline by about 25 mL to about 30 mL, as compared to an untreated patient. In a further embodiment, the patient experiences one or more pulmonary exacerbations during the administration period.

[0144] In one embodiment, the patient undergoing a method of the disclosure experiences a change compared to baseline in post-bronchodilator FEV1 at week 52 of the administration period of from 5 mL to 40 mL. In one embodiment, the patient undergoing a method of the disclosure experiences a change compared to baseline in post-bronchodilator FEV1 at week 52 of the administration period of from 5 mL to 15 mL. In one embodiment, the patient experiences a change compared to baseline in post-bronchodilator FEV1 at week 52 of from 8 mL to 12 mL. In a further embodiment, the change is about 11 mL. In one embodiment, the patient experiences a change compared to baseline in post-bronchodilator FEV1 at week 52 of from 38 mL to 40 mL. In a further embodiment, the change is about 38 mL.

[0145] The lung function in one embodiment, is measured by spirometry.

[0146] Improving lung function, in one embodiment, comprises increasing the post- bronchodilator forced expiratory volume in 1 second (FEV1), increasing the forced vital capacity (FVC), increasing the peak expiratory flow rate (PEFR), or increasing the forced expiratory flow of the FVC between 25% and 75% (FEF25-75), as compared to the respective value prior to treatment. Increasing, in one embodiment, is by about 5%, about 10%, about 15%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45% or by about 50% of the respective baseline value. Increasing, in one embodiment, is by at least about 5%, at least about 10%, at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45% or by at least about 50%. In yet another embodiment, the increase is by about 5% to about 50%, by about 5% to about 40%, by about 5% to about 30% or by about 5% to about 20%, as compared to the baseline value. In even another embodiment, increasing is by about 10% toAttorney Docket No. INMD-215 / 03WO 315953-4453 about 50%, by about 15% to about 50%, by about 20% to about 50% or by about 25% to about 50%.

[0147] The assessment of lung function, e.g, via FEV1, PEFR or FEF25-75measurement, in one embodiment, comprises comparing the lung function in the patient at baseline. Baseline measurement, in one embodiment, is immediately prior to treatment, a day prior to treatment, from about 1 day to about 14 days prior to treatment, or from about 1 day to about 30 days prior to treatment.

[0148] The method for treating bronchiectasis in one embodiment, comprises improving the lung function in the patient, wherein the lung function is measured by spirometry. Spirometry is a physiological test that measures how an individual inhales or exhales volumes of air. The primary signal measured in spirometry may be volume or flow. For certain methods described herein, pulmonary function test (PFT) by spirometry (e.g., FEV1, FVC, PEFR, and FEF25-75) is performed per the American Thorasic Society (ATS) / European Respiratory Society (ERS) criteria, e.g., as set forth by Miller et al. (Miller et al. (2005). Standardization of Spirometry. Eur. Respir. J.26, pp.319-38, incorporated by reference herein in its entirety for all purposes).

[0149] In one embodiment, the spirometer is capable of accumulating volume for greater than or equal to 15 seconds, e.g., 20 seconds, 25 seconds, 30 seconds, 35 seconds. The spirometer in one embodiment can measure volumes of 8 L (BTPS) with an accuracy of at least ± 3% of reading or ± 0.050 L, whichever is greater, with flows between 0 and 14 L•s-1. In one embodiment, the total resistance to airflow of the spirometer at 14 L•s-1is < 1.5 cmH2O•L-1•s-1(0.15 kPa? L-1•s-1). In one embodiment, the total resistance of the spirometer is measured with any tubing, valves, pre-filter, etc. included that may be inserted between the patient and the spirometer. With respect to devices that exhibit changes in resistance due to water vapor condensation, in one embodiment, spirometer accuracy requirements are met under BTPS (body temperature, ambient pressure, saturated with water vapor) conditions for up to eight successive FVC maneuvers performed in a 10-min period without inspiration from the instrument.

[0150] With respect to the forced expiratory maneuvers described herein, in one embodiment, the range and accuracy recommendations as set forth in Table 6 of Miller et al. are met (Miller et al. (2005). Standardization of Spirometry. Eur. Respir. J. 26, pp. 319-38, incorporated by reference herein in its entirety for all purposes).Attorney Docket No. INMD-215 / 03WO 315953-4453

[0151] In one embodiment, the improvement in lung function is an improvement in the forced vital capacity (FVC), i.e., the maximal volume of air exhaled with maximally forced effort from a maximal inspiration. This measurement is expressed in liters at body temperature and ambient pressure saturated with water vapor (BTPS).

[0152] “Forced vital capacity” (FVC) denotes the volume of gas which is exhaled during a forced expiration starting from a position of full inspiration and ending at complete expiration and is one measure of treatment efficacy. In one embodiment of the methods provided herein, improving the patient’s lung function comprises improving the patient’s FVC, compared to the patient’s FVC prior to treatment, or compared to an untreated bronchiectasis patient. In one embodiment, the FVC of a treated patient is greater by about 1%, greater by about 2%, greater by about 3%, greater by about 4%, greater by about 5%, greater by about 6%, greater by about 7%, greater by about 8%, greater by about 9%, greater by about 10%, greater by about 11%, greater by about 12%, greater by about 13%, greater by about 14%, greater by about 15%, greater by about 16%, greater by about 17%, greater by about 18%, greater by about 19%, greater by about 20%, greater by about 25%, greater by about 30%, greater by about 35%, greater by about 40%, greater by about 45%, greater by about 50%, greater by about 55%, greater by about 60%, greater by about 65%, greater by about 70%, greater by about 75%, greater by about 80%, greater by about 85% or greater by about 90%, as compared to a FVC of the patient prior to treatment (a baseline value).

[0153] FVC maneuvers can be performed according to the procedures known to those of ordinary skill in the art. Briefly, the three distinct phases to the FVC manuever are (1) maximal inspiration; (2) a “blast” of exhalation and (3) continued complete exhalation to the end of test (EOT). The maneuver can be carried out via the closed circuit method or open circuit method. In either instance, the subject inhales rapidly and completely with a pause of less than 1 second at total lung capacity (TLC). The subject then exhales maximally until no more air can be expelled while maintaining an upright posture. The exhalation begins with a “blast” of air from the lungs and then is encouraged to fully exhale. Enthusiastic coaching of the subject continues for a minimum of three manuevers.

[0154] Improving lung function in one embodiment, comprises improving lung function compared to the patient’s lung function prior to treatment. In a further embodiment, improving lung function comprises increasing the forced expiratory volume in one second (FEV1) of the patient compared to the patient’s FEV1prior to treatment. FEV is the volume of gas exhaled in a specified time (typically 1 second, i.e., FEV1) from the start of the forced vital capacityAttorney Docket No. INMD-215 / 03WO 315953-4453 maneuver (Quanjer et al. (1993). Eur. Respir. J. 6, Suppl. 16, pp. 5-40, incorporated by reference herein in its entirety for all purposes).

[0155] Increasing FEV1, in one embodiment, comprises increasing FEV1by at least about 5%, for example, from about 5% to about 50%, or about 10% to about 50%, or about 15% to about 50%. In another embodiment, the method comprises increasing the FEV1of the patient by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, compared to the FEV1 of the patient prior to treatment.

[0156] In one embodiment, improving lung function comprises improving the mean forced expiratory flow between 25% and 75% of the FVC (FEF25–75) (also referred to as the maximum mid-expiratory flow) of the patient, as compared to a FEF25–75of the patient prior to treatment, or as compared to an untreated bronchiectasis patient. The measurement is depedent on the validity of the FVC measurement and the level of expiratory effort. The FEF25-75index is taken from the blow with the largest sum of FEV1 and FVC.

[0157] In one embodiment, improving lung function comprises improving the peak expiratory flow rate (PEFR) of the patient. The improvement is an improvement compared to PEFR immediately prior to treatment, or as compared to an untreated bronchiectasis patient. The PEFR measures the fastest rate of air that can be expired by a subject. In one embodiment, the PEFR of a treated patient is greater by about 1%, greater by about 2%, greater by about 3%, greater by about 4%, greater by about 5%, greater by about 6%, greater by about 7%, greater by about 8%, greater by about 9%, greater by about 10%, greater by about 11%, greater by about 12%, greater by about 13%, greater by about 14%, greater by about 15%, greater by about 16%, greater by about 17%, greater by about 18%, greater by about 19%, greater by about 20%, greater by about 25%, greater by about 30%, greater by about 35%, greater by about 40%, greater by about 45%, greater by about 50%, greater by about 55%, greater by about 60%, greater by about 65%, greater by about 70%, greater by about 75%, greater by about 80%, greater by about 85% or greater by about 90%, as compared to a PEFR of the patient prior to treatment, or as compared to an untreated bronchiectasis patient.

[0158] In yet another embodiment of the disclosure, a method for treating bronchiectasis is provided comprising administering a composition comprising from 10 mg to 25 mg of a compound of Formula (I) to a patient in need thereof, wherein treating comprising increasingAttorney Docket No. INMD-215 / 03WO 315953-4453 the quality of life (QOL) of the patient, as compared to the quality of life of the patient prior to treatment, e.g., a baseline value. The compound of Formula (I) in one embodiment, is brensocatib, e.g., brensocatib monohydrate.

[0159] In one embodiment, the QOL of the patient is assessed via the Quality of Life- Bronchiectasis (QOL-B) questionnaire. The QOL-B questionnaire is a validated, self- administered Patient Reported Outcome (PRO) that assesses symptoms, functioning and health-related QOL for subjects with bronchiectasis (Quittner et al. (2014). Chest 146(2), pp. 437-448; Quittner et al. (2015) Thorax 70(1), pp. 12-20, each of which is incorporated by reference in its entirety for all purposes). The QOL-B contains 37 items on 8 domains (Respiratory Symptoms, Physical Functioning, Role Functioning, Emotional Functioning, Social Functioning, Vitality, Health Perceptions and Treatment Burden).

[0160] In one embodiment, quality of life is assessed by the Quality of Life-Bronchiectasis Respiratory Symptoms Domain score (QOL-B RSS). In one embodiment, treating comprises increasing the patient’s change from baseline in the QoL-B RSS at week 52 of treatment by at least 1.0 points, at least 1.1 points, at least 1.2 points, at least 1.3 points, at least 1.4 points, at least 1.5 points, at least 1.6 points, at least 1.7 points, at least 1.8 points, at least 1.9 points, at least 2.0 points, at least 2.1 points, at least 2.2 points, at least 2.3 points, at least 2.3 points, at least 2.5 points, at least 2.6 points, at least 2.7 points, at least 2.8 points, at least 2.9 points, at least 3.0 points, at least 3.1 points, at least 3.2 points, at least 3.3 points, at least 3.4 points, at least 3.5 points, at least 3.6 points, at least 3.7 points, at least 3.8 points, at least 3.9 points, at least 4.0 points, at least 4.1 points, at least 4.2 points, at least 4.3 points, at least 4.4 points, at least 4.5 points, at least 5.0 points, at least 5.5 points, at least 6.0 points, at least 6.5 points, at leat 7.0 points, at least 7.5 points, at least 8.0 point or at least 8.5 points.

[0161] In one embodiment, the treating comprises increasing the patient’s change from baseline (i.e., prior to treatment) in the QoL-B RSS during or subsequent to the administration period, e.g., at 52 weeks, by from about 2 points to about 9 points, for example, from 3 points to 9 points, 4 points to 9 points, 5 points to 9 points or 6 points to 9 points.

[0162] In yet another embodiment of the method for treating bronchiectasis provided herein, a composition comprising from 10 mg to 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof, is orally administered once daily during an administration period of at least 52 weeks to a patient in need thereof, wherein the method comprises decreasing active neutrophil elastase (NE) sputum concentration of the patient, asAttorney Docket No. INMD-215 / 03WO 315953-4453 compared to the patient’s NE sputum concentration, prior to treatment. The compound of Formula (I), in one embodiment, is brensocatib, e.g., brensocatib monohydrate.

[0163] Decreasing active NE sputum concentration, in one embodiment, comprises decreasing active NE sputum concentration by about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%. In another embodiment, decreasing active NE sputum concentration comprises decreasing active NE sputum concentration by at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% or at least about 80%.

[0164] In yet another embodiment of the method for treating bronchiectasis provided herein, a composition comprising from 10 mg to 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof, is orally administered once daily during an administration period of at least 52 weeks to a patient in need thereof, wherein the method comprises lightening the sputum color of the patient, as measured by the sputum color chart of Murray 2009 (Murray et al. (2009). Eur Respir J.2009; 34:361-364, incorporated by reference herein in its entirety for all purposes), as compared to the patient’s sputum color, prior to treatment. The compound of Formula (I), in one embodiment, is brensocatib, e.g., brensocatib monohydrate.

[0165] The lightening of color, in one embodiment, is a lightening by a single gradation. For example, in one embodiment, the lightening is from purulent (dark yellow and / or dark green) to mucopurulent (pale yellow and / or pale green). In another embodiment, the lightening is from mucopurulent (pale yellow and / or pale green) to mucoid (clear).

[0166] The change in color, in another embodiment, is a lightening of two gradations, i.e., the lightening is from purulent (dark yellow and / or dark green) to mucoid (clear).

[0167] Sputum induction is carried out if the patient cannot produce sputum on his or her own. Sputum induction, in one embodiment, is initiated via patient nebulization of a saline solution. The percentage of saline, e.g., 3% or 7% or 10% or 13%, is decided based on the user of the method’s preference. The selected saline is placed in the nebulizer, and the subject is in a sitting up or in a semi-fowler position. The subject in one embodiment, wears a nose clip during the nebulization. The subject breathes slowly and deeply through the nebulizer mouthpiece inhaling the salt water mist. The subject is reminded to not breathe quickly but to have slow, deep breaths pausing at peak inspiration to allow deposition of particles. The nebulization time in one embodiment, is 10 minutes.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0168] At the end of nebulization, the subject is instructed to take a few deep breaths, swallow the extra saliva in his / her mouth and attempt to cough up a sputum sample. The subject is encouraged to cough forcefully using the deep coughing method and / or “huffing” cough method. All sputum is deposited in the specimen container. The procedure can be repeated if the amount of sputum collected, e.g., less than 1 mL, less than 2 mL, or less than 3 mL, is not sufficient.

[0169] As provided herein, the method of the disclosure comprises in part administering to a patient a composition comprising from 10 mg to 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate of Formula (I) for an administration period of at least 52 weeks. The administration period, in some embodiments, is 52 weeks.

[0170] The length of the administration period in any given case may depend on the nature and severity of the bronchiectasis being treating or prevented and may be determined by the prescribing physician. In some embodiments, the administration period is 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 administration period is about 52 weeks. In yet another embodiment, the administration period is 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.

[0171] In some embodiments, the administration period for the methods provided herein is 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. The administration period, in another embodiment, is from about 12 months to about 36 months, or from about 12 months to about 24 months.

[0172] In yet another embodiment, the administration period is from about 1 year to about 50 years. For example, the administration period, in one embodiment, is from 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, from about 1 year to about 5 years, from about 1 yearAttorney Docket No. INMD-215 / 03WO 315953-4453 to about 3 years, from about 1 year to about 2 years, from about 2 years to about 15 years, from about 2 year to about 10 years, from about 2 years to about 8 years, from about 2 years to about 5 years, from about 2 years to about 4 years, or from about 2 years to about 3 years.

[0173] The methods provided herein can be utilized to treat a bronchiectasis patient (e.g., a non-CF bronchiectasis patient) that presents with a pulmonary infection. In one embodiment, the pulmonary infection is a mycobacterial infection. The mycobacterial infection can be a Mycobacterium tuberculosis infection or a non-tuberculous mycobacterium (NTM). Examples of NTM infections that a patient treatable by the methods provided herein can present with include, but are not limited to, M. avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium, M. avium complex (MAC) (M. avium and M. intracellulare), M. conspicuum, M. kansasii, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense, M. marinum, M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis, M. szulgai, M. terrae, M. terrae complex, M. haemophilum, M. genavense, M. asiaticum, M. shimoidei, M. gordonae, M. nonchromogenicum, M. triplex, M. lentiflavum, M. celatum, M. fortuitum, M. fortuitum complex (M. fortuitum and M. chelonae) or a combination thereof.

[0174] Other pulmonary infections that a bronchiectasis patient can present with include, but are not limited to, Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis. In a further embodiment, the pulmonary bacterial infection is a Pseudomonas aeruginosa infection.

[0175] In one embodiment, the bronchiectasis patient treated by a method of the disclosure also presents with chronic obstructive pulmonary disease (COPD).

[0176] In one embodiment, the compound of Formula (I) is administered in an oral dosage form. In a further embodiment, the compound of Formula (I) is administered as a 10 mg to 50 mg dosage form, for example, 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 or a 50 mg dosage form. In a further embodiment, the dosage form is 10 mg or 25 mg. In a further embodiment, the dosage form is administered once daily. In even a further embodiment, the compound 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, or a pharmaceutically acceptable salt or hydrate thereof.

[0177] In one embodiment, the method comprises administering increasing doses of the compound of Formula (I). In a further embodiment, the method comprises first orallyAttorney Docket No. INMD-215 / 03WO 315953-4453 administering to the patient once daily about 10 mg of the compound of Formula (I) during the administration period, and then orally administering to the patient once daily about 25 mg of the compound of Formula (I) during the administration period. In an even further embodiment, the method comprises orally administering to the patient once daily about 10 mg of the compound of Formula (I) and continuing to administer once daily about 10 mg of the compound of Formula (I) for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days (I). In some embodiments, the method comprises orally administering to the patient once daily, starting on Day 1 of the adminstrartion period, about 10 mg of the compound of Formula (I), and continuing to administer once daily about 10 mg of the compound of Formula (I) for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 5 months. In further embodiments, after administering once daily about 10 mg of the compound of Formula (I), the method comprises orally administering to the patient once daily about 25 mg of the compound of Formula (I).

[0178] In one embodiment, the method comprises administering decreasing doses of the compound of Formula (I). In a further embodiment, the method comprises orally administering to the patient once daily about 25 mg of the compound of Formula (I) starting on Day 1 of the administration period and continuing administering about 25 mg of the compound of Formula (I) until the patient becomes intolerant, and then orally administering once daily about 10 mg of the compound of Formula (I). In an even further embodiment, the patient becomes intolerant when the patient experiences a headache, hyperkeratosis, rash, infection (e.g., respiratory tract infection), pneumonia, dyspnea, hemoptysis, periodontal disease, arthralgia, fatigue, nasopharyngitis, cough, dermatitis contact, pain, and / or dry skin. In embodiments, hyperkeratosis comprises a skin lesion, eczema, hyperkeratosis, keratosis pilaris, exfoliative rash, and / or seborrheic keratosis. In a further embodiment, the patient returns to administering once daily about 25 mg of the compound of Formula (I) when the headache, hyperkeratosis, rash, infection (e.g., respiratory tract infection), pneumonia, dyspnea, hemoptysis, periodontal disease, arthralgia, fatigue, nasopharyngitis, cough, dermatitis contact, pain, and / or dry skin subside.

[0179] In some embodiments, the patient to be treated with Formula (I), or a pharmaceutically acceptable salt or hydrate of Formula (I), is an adult patient aged 18 years or older. In some embodiments, the adult patient to be treated with Formula (I), or a pharmaceutically acceptableAttorney Docket No. INMD-215 / 03WO 315953-4453 salt or hydrate of Formula (I), had at least two pulmonary exacerbations in the past 12 months. The patient, in one embodiment, is an NCFBE patient.

[0180] In some embodiments, the patient to be treated with Formula (I), or a pharmaceutically acceptable salt or hydrate of Formula (I), is a pediatric patient aged 12 years or older. In some aspects, the pediatric patient is between about 12 years to about 17 years of age. In some aspects, pediatric patient to be treated with Formula (I), or a pharmaceutically acceptable salt or hydrate of Formula (I), had at least one pulmonary exacerbation in the past 12 months. The patient, in one embodiment, is an NCFBE patient.

[0181] In some embodiments, the patient to be treated with Formula (I), or a pharmaceutically acceptable salt or hydrate of Formula (I), is a geriatric patient aged 65 years or older. The patient, in one embodiment, is an NCFBE patient.

[0182] In some embodiments, the patient to be treated with Formula (I), or a pharmaceutically acceptable salt or hydrate of Formula (I), has renal impairment. In some embodiments, the patient to be treated with Formula (I), or a pharmaceutically acceptable salt or hydrate of Formula (I), has hepatic impairment.

[0183] The compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the Formula (I) compound / salt (active ingredient) is in a composition comprising a pharmaceutically acceptable adjuvant(s), diluents(s) and / or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage FormDesigns”, M. E. Aulton, Churchill Livingstone, 2ndEd.2002, incorporated by reference hereinin its entirety for all purposes.

[0184] Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99 %w (percent by weight), for example, from 0.05 to 80 %w, or from 0.10 to 70 %w, or from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

[0185] 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.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0186] In one embodiment, the oral dosage form is administered once daily. In a further embodiment, the oral dosage form is administered at approximately the same time every day, e.g., prior to breakfast.

[0187] In one embodiment, the oral dosage is not broken or chewed when admistered. In one embodiment, the oral dosage is administered with water.

[0188] The composition can be administered with or without food.

[0189] In one embodiment, the oral dosage is administered without food. In one embodiment, the oral dosage is administered in the fasted state. In one embodiment, the oral dosage is administered in the fed state. In one embodiment, the oral dosage is administered prior to a meal. In one embodiment, the oral dosage is administered prior to breakfast.

[0190] In one embodiment, the oral dosage form is adminisrtered once daily in the morning. In one embodiment, the oral dosage is administered once daily prior to breakfast. In one embodiment, the oral dosage is administered once daily with water. In one embodimnent, the oral dosage form is administered once daily with water prior to breakfast. In one embodimnent, the oral dosage form is administered once daily in the morning with water prior to breakfast.

[0191] For oral administration the compound of the disclosure may be admixed with adjuvant(s), diluent(s) or carrier(s), for example, lactose, saccharose, sorbitol, mannitol; starch, for example, potato starch, corn starch or amylopectin; cellulose derivative; binder, for example, gelatine or polyvinylpyrrolidone; disintegrant, for example cellulose derivative, and / or lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s). Alternatively, the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.

[0192] The composition for treating bronchiectasis, in one embodiment, is one of the compositions provided in U.S. Patent No. 12,059,424, the contents of which are incorporated by reference herein in their entirety for all purposes.

[0193] For the preparation of soft gelatine capsules, the compound of the disclosure may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using pharmaceutical excipients like the above-mentionedAttorney Docket No. INMD-215 / 03WO 315953-4453 excipients for tablets. Also liquid or semisolid formulations of the compound of the disclosure may be filled into hard gelatine capsules.

[0194] In one embodiment, the composition is an oral disintegrating tablet (ODT). ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole

[0195] In one embodiment, the composition is an oral thin film or an oral disintegrating film (ODF). Such formulations, when placed on the tongue, hydrate via interaction with saliva, and releases the active compound from the dosage form. The ODF, in one embodiment, contains a film-forming polymer such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), pullulan, carboxymethyl cellulose (CMC), pectin, starch, polyvinyl acetate (PVA) or sodium alginate.

[0196] Liquid preparations for oral application may be in the form of syrups, solutions or suspensions. Solutions, for example may contain the compound of the disclosure, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharine and / or carboxymethylcellulose as a thickening agent. Furthermore, other excipients known to those skilled in art may be used when making formulations for oral use.

[0197] The skilled person will recognise that the compounds of the disclosure may be prepared, in known manner, in a variety of ways.

[0198] In one embodiment, a compound of Formula (I) is prepared by a method set forth in U.S. Patent No. 9,522,894, the contents of which are incorporated by reference herein in their entireties for all purposes.

[0199] A person skilled in the art would be capable of preparing the compounds of Formula (I) based on known organic synthesis technology, and the starting materials are commercially available chemicals and (or) compounds mentioned in chemical documents. “Commercially available chemicals” are those that can be obtained from actual commercial sources, such suppliers including: Titan, Energy Chemical, Shanghai Demo, Chengdu Chron Chemicals, Accela ChemBio Co., Ltd., Nanjing PharmaBlock, WuXi AppTec and J&K Scientific etc.

[0200] Reference publications and monographs in this field have described the synthesis of the reagents used in preparation of the compounds described herein, or provide articles that describe such preparation methods for reference. These reference books and monographsAttorney Docket No. INMD-215 / 03WO 315953-4453include: “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York S.R. Sandleret al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H.O. House, “Modern Synthetic Reactions”, 2ndEd., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, “Heterocyclic Chemistry”, 2ndEd., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4thEd., Wiley-Interscience, New York, 1992; Fuhrhop and Penzlin. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R.C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2ndEdition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4thEdition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022- 9; Solomons, T.W.G. “Organic Chemistry” 7thEdition (2000)John Wiley & Sons, ISBN: 0- 471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2ndEdition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopaedia” (1999) John Wiley & Sons, ISBN:3-527-29645- X,in 8 volumes; “Organic Reactions”(1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0201] in addition, the protection and deprotection of functional groups is described in‘Protective Groups in Organic Synthesis’, 4thEd, T.W. Greene and P.G.M. Wuts, Wiley (2006)and ‘Protecting Groups’, 3rdEd P.J. Kocienski, Georg Thieme Verlag (2005), incorporated byreference herein in its entirety for all purposes.

[0202] By accessing the CAS index of known chemical substances prepared by the American Chemical Society, it is possible to selectively identify specific and similar reagents, these indexes are accessible in the majority of public libraries, university libraries and online. Known chemicals in the list that cannot be purchased commercially can alternatively be tailor-made by chemical synthesis laboratories, and many of the standard chemical suppliers (for instance, those listed above) provide a tailor-made synthesis service. The reference publication for preparation and selection of the pharmaceutical salts of the compounds described in this text is P.H. Stahl & C.G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0203] As provided throughout, according to the methods provided herein, a compound of Formula (I) can be administered as a pharmaceutically acceptable salt. A pharmaceutically acceptable salt of a compound of Formula (I) may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in H2O, oil, or other solvent. In some instances, a salt may be used to aid in the isolation or purification of the compound of Formula (I).

[0204] Where the compound of Formula (I) is sufficiently acidic, pharmaceutically acceptable salts include, but are not limited to, an alkali metal salt, e.g., Na or K, an alkali earth metal salt, e.g., Ca or Mg, or an organic amine salt. Where the compound of Formula (I) is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.

[0205] There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions.

[0206] For reviews on suitable salts, and pharmaceutically acceptable salts amenable for use herein, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or “Handbook of Pharmaceutical Salts: Properties, selection and use”, P.H. Stahl, P.G. Vermuth, IUPAC, Wiley-VCH, 2002, incorporated by reference herein in its entirety for all purposes.

[0207] The compounds of Formula (I) may form mixtures of its salt and co-crystal forms. It is also to be understood that the methods provided herein can employ such salt / co-crystal mixtures of the compound of Formula (I).

[0208] Salts and co-crystals may be characterized using well known techniques, for example X-ray powder diffraction, single crystal X-ray diffraction (for example to evaluate proton position, bond lengths or bond angles), solid state NMR, (to evaluate for example, C, N or P chemical shifts) or spectroscopic techniques (to measure for example, O-H, N-H or COOH signals and IR peak shifts resulting from hydrogen bonding).

[0209] It is also to be understood that certain compounds of Formula (I) may exist in solvated form, e.g., hydrates, including solvates of a pharmaceutically acceptable salt of a compound of Formula (I).

[0210] In one embodiment, certain compounds of Formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. It is to be understood that the present disclosure encompasses all such isomeric forms. CertainAttorney Docket No. INMD-215 / 03WO 315953-4453 compounds of Formula (I) may also contain linkages (e.g., carbon-carbon bonds, carbon- nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring bond or double bond. Accordingly, it is to be understood that the methods provided herein can employ such isomers. Certain compound 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, e.g. chromatography or fractional crystallization, or the stereoisomers may be made by stereoselective synthesis.

[0211] In a further embodiment, the compounds of Formula (I) encompass any isotopically-labeled (or “radio-labelled”) derivatives of a compound of Formula (I). Such a derivative is a derivative of a compound of Formula (I) wherein one or more atoms are replaced by an atom 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 include2H (also written as “D” for deuterium). As such, in one embodiment, a compound of Formula (I) is provided where 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 for treating bronchiectasis. In a further embodiment, the bronchiectasis is non-CF bronchiectasis.

[0212] In a further embodiment, the compounds of Formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the Formula (I). Examples of prodrugs include in vivo hydrolysable esters of a compound of the Formula (I).

[0213] An in vivo hydrolysable (or cleavable) ester of a compound of the Formula (I) that contains a carboxy or a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol. For examples of ester prodrugs derivatives, see: Curr. Drug. Metab.2003, 4, 461, incorporated by reference herein in its entirety for all purposes.

[0214] 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: Nature Reviews Drug Discovery 2008, 7, 255, the disclosure of which is incorporated by reference herein in its entirety for all purposes.Attorney Docket No. INMD-215 / 03WO 315953-4453 EMBODIMENTS

[0215] Embodiment 1. A method for treating bronchiectasis in a patient in need of treatment, comprising, administering to the patient once daily for an administration period of at least 52 weeks, a pharmaceutical composition comprising from 10 mg to 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof, ,R2is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2 or SO2NR4R5, wherein R4and R5together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; R6is C1-3alkyl, optionally substituted by 1, 2 or 3 F and / or optionally by OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; R7is hydrogen, F, Cl or CH3; X is O, S or CF2; Y is O or S; and Q is CH or N and Z is or H or halogen, wherein, treating comprises reducing the annualized rate of pulmonary exacerbations of the patient by at least about 20%, as compared to an untreated bronchiectasis patient; and wherein, a pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; and (6) hemoptysis.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0216] Embodiment 2. The method of embodiment 1, wherein Z is H.

[0217] Embodiment 3. The method of embodiment 1, wherein Z is halogen.

[0218] Embodiment 4. The method of embodiment 1, wherein the compound of Formula

[0220] Embodiment 6. The method of embodiment 3, wherein Z is F.

[0221] Embodiment 7. The method of any one of embodiments 1-6, wherein,X is O, S or CF2; Y is O or S; R6is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; and R7is H, F, Cl or CH3. The method of any one of embodiments 1-4, wherein R1is

[0223] Embodiment 9. The method of embodiment any one of embodiments 1-8, wherein, X is O; R6is C1-3alkyl; and R7is H.

[0224] Embodiment 10. The method of any one of embodiments 1-6, wherein,Attorney Docket No. INMD-215 / 03WO 315953-44533alkyl, wherein the C1-3alkyl is optionally substituted by 1, 2 or 3 F; and R7is hydrogen.

[0225] Embodiment 11. The method of any one of embodiments 1-, wherein, R1is

[0227] Embodiment 13. The method of embodiment 1, wherein the compound of Formula (I) is selected from the group consisting of (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (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; (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; 4’-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate; (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4’-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(3’,4’-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (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;Attorney Docket No. INMD-215 / 03WO 315953-4453 (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (2S)-N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-2-(4’-Carbamoyl-3’-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4- oxazepane-2-carboxamide; (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; (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;Attorney Docket No. INMD-215 / 03WO 315953-4453 (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; (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; (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; (2S)-N-{(1S)-1-Cyano-2-[4’-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-2-[4’-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(4’-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; or (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; and pharmaceutically acceptable salts or hydrates thereof.

[0228] Embodiment 14. The method of embodiment 1, wherein 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:; or a pharmaceutically acceptable salt or hydrate thereof.

[0229] Embodiment 15. The method of embodiment 1, wherein 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, or a hydrate thereof.

[0230] Embodiment 16. The method of embodiment 1, wherein the compound of Formula (I) is brensocatib monohydrate.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0231] Embodiment 17. The method of embodiment 1, wherein the compound of Formula (I) is depicted by the following structure:.

[0232] Embodiment 18. The method of embodiment 1, wherein the compound of Formula (I) is depicted by the following structure:.

[0233] Embodiment 19. The method of any one of embodiments 1-18, wherein the composition comprises a pharmaceutically acceptable adjuvant, diluent or carrier.

[0234] Embodiment 20. The method of any one of embodiments 1-19, wherein the annualized rate of pulmonary exacerbations of the patient is reduced by about 20%.

[0235] Embodiment 21. The method of any one of embodiments 1-19, wherein the annualized rate of pulmonary exacerbations of the patient is reduced by about 20% to about 40%.

[0236] Embodiment 22. The method of any one of embodiments 1-19, wherein the annualized rate of pulmonary exacerbations of the patient is reduced by about 20% to about 30%.

[0237] Embodiment 23. The method of any one of embodiments 1-19, wherein the annualized rate of pulmonary exacerbations of the patient is reduced by about 20% to about 25%.

[0238] Embodiment 24. The method of any one of embodiments 1-23, wherein the treating comprises increasing the length of time to first pulmonary exacerbation in the patient by at least about 17.5%, as compared to an untreated bronchiectasis patient.

[0239] Embodiment 25. The method of embodiment 24, wherein treating comprises increasing the length of time to first pulmonary exacerbation in the patient by about 17.5% to about 30%, as compared to an untreated bronchiectasis patient.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0240] Embodiment 26. The method of any one of embodiments 1-25, wherein the treating comprises increasing the patient’s odds of remaining free of pulmonary exacerbations during the administration period by at least about 40%.

[0241] Embodiment 27. The method of embodiment 26, wherein the treating comprises increasing the patient’s odds of remaining free of pulmonary exacerbations during the administration period by about 40% to about 50%.

[0242] Embodiment 28. The method of any one of embodiments 1-27, wherein the treating comprises decreasing the annualized rate of severe pulmonary exacerbations of the patient by at least about 25%, as compared to the annualized rate of severe pulmonary exacerbations experienced by an untreated bronchiectasis patient; and wherein, a severe pulmonary exacerbation requires treatment with intravenous antibiotic drugs, hospitilization or a combination thereof and wherein the annualized rate of severe pulmonary exacerbations is calculated over the length of the administration period.

[0243] Embodiment 29. The method of embodiment 28, wherein the treating comprises decreasing the annualized rate of severe pulmonary exacerbations of the patient by from about 25% to about 50%.

[0244] Embodiment 30. The method of embodiment 29, wherein the treating comprises decreasing the annualized rate of severe pulmonary exacerbations of the patient by from about 25% to about 40%.

[0245] Embodiment 31. The method of any one of embodiments 1-30, wherein treating comprising reducing the decline in lung function of the patient during or subsequent to the administration period, as compared to the lung function decline of an untreated patient.

[0246] Embodiment 32. The method of embodiment 31, wherein reducing the decline in lung function of the patient comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period.

[0247] Embodiment 33. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by at least about 10 mL.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0248] Embodiment 34. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by at least about 11 mL.

[0249] Embodiment 35. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 10 mL to about 50 mL.

[0250] Embodiment 36. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 10 mL to about 40 mL.

[0251] Embodiment 37. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 10 mL to about 30 mL.

[0252] Embodiment 38. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 30 mL to about 50 mL.

[0253] Embodiment 39. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 30 mL to about 40 mL.

[0254] Embodiment 40. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 35 mL to about 40 mL.

[0255] Embodiment 41. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 40 mL.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0256] Embodiment 42. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 25 mL to about 30 mL.

[0257] Embodiment 43. The method of embodiment 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 29 mL.

[0258] Embodiment 44. The method of embodiment 40 or 41, wherein the patient experiences zero pulmonary exacerbations during the administration period.

[0259] Embodiment 45. The method of embodiment 42 or 43, wherein the patient experiences one or more pulmonary exacerbations during the administration period.

[0260] Embodiment 46. The method of embodiment 42 or 43, wherein the patient experiences one pulmonary exacerbation during the administration period.

[0261] Embodiment 47. The method of embodiment 42 or 43, wherein the patient experiences two exacerbation during the administration period.

[0262] Embodiment 48. The method of any one of embodiments 1-45, wherein treating comprises improving the patient’s quality of life (QOL), as compared to the patient’s QOL prior to treatment, as mesaured by a change from baseline in the Quality of Life-Bronchiectasis (QOL-B) Respiratory Score of at least 2.0 points.

[0263] Embodiment 49. The method of embodiment 48, wherein treating comprises improving the patient’s quality of life (QOL), as compared to the patient’s QOL prior to treatment, as mesaured by a change from baseline in the Quality of Life-Bronchiectasis (QOL- B) Respiratory Score of by about 2.0 points to about 10 points.

[0264] Embodiment 50. The method of embodiment 48, wherein treating comprises improving the patient’s quality of life (QOL), as compared to the patient’s QOL prior to treatment, as mesaured by a change from baseline in the Quality of Life-Bronchiectasis (QOL- B) Respiratory Score of by about 2 points to about 9 points.

[0265] Embodiment 51. The method of embodiment 48, wherein treating comprises improving the patient’s quality of life (QOL), as compared to the patient’s QOL prior to treatment, as mesaured by a change from baseline in the Quality of Life-Bronchiectasis (QOL- B) Respiratory Score of by about 3 points to about 9 points.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0266] Embodiment 52. The method of any one of embodiments 48-51, wherein the baseline QOL-B Respiratory Score is measured about 1 hour to about 7 days prior to the administration period.

[0267] Embodiment 53. The method of any one of embodiments 48-51, wherein the baseline QOL-B Respiratory Score is measured immediately prior to the administration period.

[0268] Embodiment 54. The method of any one of embodiments 1-53, wherein the bronchiectasis is non-cystic fibrosis (CF) bronchietasis.

[0269] Embodiment 55. The method of any one of embodiments 1-42, wherein the patient has cystic fibrosis.

[0270] Embodiment 56. The method of any one of embodiments 1-55, wherein the pharmaceutical composition comprises about 10 mg of the compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof.

[0271] Embodiment 57. The method of any one of embodiments 1-55, wherein the pharmaceutical composition comprises about 25 mg of the compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof.

[0272] Embodiment 58. The method of any one of embodiments 1-55, wherein the pharmaceutical composition comprises about 20 mg of the compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof.

[0273] Embodiment 59. The method of any one of embodiments 1-58, wherein the pharmaceutical composition is administered in the morning.

[0274] Embodiment 60. The method of any one of embodiments 1-58, wherein the pharmaceutical composition is administered prior to breakfast.

[0275] Embodiment 61. The method of any one of embodiments 1-60, wherein the pharmaceutical composition is administered with water.

[0276] Embodiment 62. The method of any one of embodiments 1-61, wherien treating comprises lightening the patient’s sputum color as compared to the patient’s sputum color prior to treatment, as measured by the sputum color chart of Murray.

[0277] Embodiment 63. The method of embodiment 62, wherein lightening the patient’s sputum color comprises lightening the patient’s sputum color by a single gradation.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0278] Embodiment 64. The method of embodiment 62 or 63, wherein the lightening the patient’s sputum color comprises lightening from purulent (dark yellow and / or dark green) to mucopurulent (pale yellow and / or pale green).

[0279] Embodiment 65. The method of embodiment 59 or 60, wherein the lightening the patient’s sputum color comprises lightening from mucopurulent (pale yellow and / or pale green) to mucoid (clear).

[0280] Embodiment 66. The method of embodiment 62, wherein the lightening the patient’s sputum color comprises lightening from purulent (dark yellow and / or dark green) to mucoid (clear).

[0281] Embodiment 67. The methof of any one of embodiments 1-66, wherein the patient presents with a pulmonary infection.

[0282] Embodiment 68. The method of embodiment 67, wherein the pulmonary infection is a mycobacterial infection.

[0283] Embodiment 69. The method of embodiment 68, wherein the mycobacterial infection is a Mycobacterium tuberculosis infection.

[0284] Embodiment 70. The method of embodiment 68, wherein the mycobacterial infection is a non-tuberculous mycobacterium (NTM) infection.

[0285] Embodiment 71. The method of embodiment 70, wherein the NTM infection is M. avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium, M. avium complex (MAC) (M. avium and M. intracellulare), M. conspicuum, M. kansasii, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense, M. marinum, M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis, M. szulgai, M. terrae, M. terrae complex, M. haemophilum, M. genavense, M. asiaticum, M. shimoidei, M. gordonae, M. nonchromogenicum, M. triplex, M. lentiflavum, M. celatum, M. fortuitum, M. fortuitum complex (M. fortuitum and M. chelonae) or a combination thereof.

[0286] Embodiment 72. The method of embodiment 67, wherein the pulmonary infection is a M. avium complex (MAC) (M. avium and M. intracellulare) infection.

[0287] Embodiment 73. The method of embodiment 67, wherein the pulmonary infection is a Haemophilus influenzae infection.

[0288] Embodiment 74. The method of embodiment 67, wherein the pulmonary infection is a Pseudomonas aeruginosa infection.

[0289] Embodiment 75. The method of embodiment 67, wherein the pulmonary infection is a Streptococcus pneumoniae infection.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0290] Embodiment 76. The method of embodiment 67, wherein the pulmonary infection is a Staphylococcus aureus infection.

[0291] Embodiment 77. The method of embodiment 67, wherein the pulmonary infection is a Moraxella catarrhalis infection.

[0292] Embodiment 78. The method of any one of embodiments 1-77, wherein the administration period is 52 weeks.

[0293] Embodiment 79. The method of any one of embodiments 1-78, wherein the administration period is about 12 months, about 18 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.

[0294] Embodiment 80. The method of any one of embodiments 1-78, wherein the administration period is at least about 12 months, at least about 18 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.

[0295] Embodiment 81. The method of any one of embodiments 1-78, wherein the administration period is about 12 months.

[0296] Embodiment 82. The method of any one of embodiments 1-78, wherein the administration period is from about 12 months to about 36 months.

[0297] Embodiment 83. The method of any one of claims 1-59, wherein the administration period is from about 18 months to about 36 months.

[0298] Embodiment 84. The method of any one of claims 1-59, wherein the administration period is from about 1 year to about 50 years.

[0299] Embodiment 85. The method of embodiment 84, wherein the administration period is from about 1 year to about 40 years.

[0300] Embodiment 86. The method of embodiment 84, wherein the administration period is from about 1 year to about 30 years.

[0301] Embodiment 87. The method of embodiment 84, wherein the administration period is from about 1 year to about 25 years.

[0302] Embodiment 88. The method of embodiment 84, wherein the administration period is from about 1 year to about 20 years.

[0303] Embodiment 89. The method of embodiment 84, wherein the administration period is from about 1 year to about 15 years.

[0304] Embodiment 90. The method of embodiment 84, wherein the administration period is from about 1 year to about 10 years.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0305] Embodiment 91. The method of embodiment 84, wherein the administration period is from about 1 year to about 5 years.

[0306] Embodiment 92. The method of embodiment 84, wherein the administration period is from about 1 year to about 3 years.

[0307] Embodiment 93. The method of embodiment 84, wherein the administration period is from about 1 year to about 2 years.

[0308] Embodiment 94. The method of embodiment 84, wherein the administration period is from about 2 years to about 15 years.

[0309] Embodiment 95. The method of embodiment 84, wherein the administration period is from about 2 years to about 10 years.

[0310] Embodiment 96. The method of embodiment 84, wherein the administration period is from about 2 years to about 8 years.

[0311] Embodiment 97. The method of embodiment 84, wherein the administration period is from about 2 years to about 5 years.

[0312] Embodiment 98. The method of embodiment 84, wherein the administration period is from about 2 years to about 4 years.

[0313] Embodiment 99. The method of any one of embodiments 1-98, the method comprising first orally administering to the patient once daily about 10 mg of the compound of Formula (I) during the administration period, and then administering orally administering to the patient once daily about 25 mg of the compound of Formula (I) during the administration period.

[0314] Embodiment 100. The method of any one of embodiments 1-98, comprising first orally administering to the patient once daily about 25 mg of the compound of Formula (I) of the administration period and continuing administering about 25 mg of the compound of Formula (I) until the patient becomes intolerant, and then orally administering once daily 10 mg of the compound of Formula (I).

[0315] Embodiment 101. The method of embodiment 100, wherein the patient becomes intolerant of about 25 mg of the compound of Formula (I) when the patient experiences headache, hyperkeratosis, rash, infection, pneumonia, dyspnea, hemoptysis, periodontal disease, arthralgia, fatigue, nasopharyngitis, cough, dermatitis contact, pain, and / or dry skin.

[0316] Embodiment 102. The method of embodiment 101, wherein hyperkeratosis comprises a skin lesion, eczema, hyperkeratosis, keratosis pilaris, exfoliative rash, and / or seborrheic keratosis.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0317] Embodiment 103. The method of any one of embodiments 100-102, wherein the patient returns to administering 25 mg of the compound of Formula (I) when the headache, hyperkeratosis, rash, and / or dry skin subside.

[0318] Embodiment 104. A method for treating bronchiectasis in a patient in need of treatment, comprising, orally administering to the patient once daily for an administration period of at least about 52 weeks, a pharmaceutical composition comprising about 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof,R2is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2or SO2NR4R5, wherein R4and R5together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; R6is C1-3alkyl, optionally substituted by 1, 2 or 3 F and / or optionally by OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; R7is hydrogen, F, Cl or CH3; X is O, S or CF2; Y is O or S; Q is CH or N; and Z is H or halogen,Attorney Docket No. INMD-215 / 03WO 315953-4453 wherein, treating comprises (i) achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1, (ii) achieving median time to first PE of about 40 weeks to about 50 weeks, (iii) reducing the decline in the patient’s post-bronchodilator forced expiratory volume in 1 second (FEV1) during or subsequent to the administration period by about 10 mL to about 55 mL, and / or (iv) achieving annualized rate of severe PE of about 0.10 to about 0.17, wherein a pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; and (6) hemoptysis.

[0319] Embodiment 105. The method of embodiment 104, wherein Z is H.

[0320] Embodiment 106. The method of embodiment 104, wherein Z is halogen.

[0321] Embodiment 107. The method of embodiment 104, wherein the compound of Formula

[0322] Embodiment 108. The method of embodiment 104, wherein the compound of Formula

[0323] Embodiment 109. The method of embodiment 106, wherein Z is F.

[0324] Embodiment 110. The method of any one of embodiments 104-107, wherein,X is O, S or CF2; Y is O or S; R6is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; andAttorney Docket No. INMD-215 / 03WO 315953-4453 R7is H, F, Cl or CH3.

[0325] Embodiment 111. The method of any one of embodiments 104-107, wherein R1is.

[0326] Embodiment 112. The method of any one of embodiments 104-109, wherein, X is O; R6is C1-3alkyl; and R7is H.

[0327] Embodiment 113. The method of any one of embodiments 104-107, wherein,3alkyl, wherein the C1-3alkyl is optionally substituted by 1, 2 or 3 F; and R7is hydrogen.

[0328] Embodiment 114. The method of any one of embodiments 104-107, wherein,

[0330] Embodiment 116. The method of embodiment 104, wherein the compound of Formula (I) is selected from the group consisting of (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (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; (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; 4’-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate;Attorney Docket No. INMD-215 / 03WO 315953-4453 (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4’-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(3’,4’-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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;Attorney Docket No. INMD-215 / 03WO 315953-4453 (2S)-N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-2-(4’-Carbamoyl-3’-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4- oxazepane-2-carboxamide; (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; (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; (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; (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; (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; (2S)-N-{(1S)-1-Cyano-2-[4’-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-2-[4’-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(4’-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; or (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; and pharmaceutically acceptable salts or hydrates thereof.

[0331] Embodiment 117. The method of embodiment 104, wherein 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:pharmaceutically acceptable salt or hydrate thereof.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0332] Embodiment 118. The method of embodiment 104, wherein 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), or a hydrate thereof.

[0333] Embodiment 119. The method of embodiment 104, wherein the compound of Formula (I) is brensocatib monohydrate.

[0334] Embodiment 120. The method of embodiment 104, wherein the compound of Formula (I) is (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol- 5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide, having the structural formula:pharmaceutically acceptable salt or hydrate thereof.

[0335] Embodiment 121. The method of embodiment 104, wherein the compound of Formula (I) is (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol- 5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide monohydrate, having the structural formula:.

[0336] Embodiment 122. The method of any one of embodiments 104-121, comprising orally administering to the patient once daily about 25 mg of the compound of Formula (I) starting on Day 1 of the administration period and continuing administering once daily 25 mg of the compound of Formula (I) until the patient becomes intolerant, and then orally administering once daily 10 mg of the compound of Formula (I).

[0337] Embodiment 123. The method of embodiment 122, wherein the patient becomes intolerant when the patient experiences headache, hyperkeratosis, rash, infection, pneumonia,Attorney Docket No. INMD-215 / 03WO 315953-4453 dyspnea, hemoptysis, periodontal disease, arthralgia, fatigue, nasopharyngitis, cough, dermatitis contact, pain, and / or dry skin.

[0338] Embodiment 124. The method of embodiment 123, wherein hyperkeratosis comprises a skin lesion, eczema, hyperkeratosis, keratosis pilaris, exfoliative rash, and / or seborrheic keratosis.

[0339] Embodiment 125. The method of any one of embodiments 122-124, wherein the patient returns to administering once daily 25 mg of the compound of Formula (I) when the headache, hyperkeratosis, rash, and / or dry skin subside.

[0340] Embodiment 126. The method of any one of embodiments 104-125, wherein the treating comprises achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1.

[0341] Embodiment 127. The method of any one of embodiments 104-126, wherein the treating comprises achieving a median time to first PE of about 40 weeks to about 50 weeks.

[0342] Embodiment 128. The method of any one of embodiments 104-127, wherein the treating comprises reducing the decline in the patient’s post-bronchodilator FEV1 during or subsequent to the administration period by about 11 mL to about 50 mL.

[0343] Embodiment 129. The method of any one of embodiments 104-128, wherein the treating comprises achieving an annualized rate of severe PE of about 0.10 to about 0.17.

[0344] Embodiment 130. The method of any one of embodiments 104-129, wherein the treating comprises two or more of (i) achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1, (ii) achieving a median time to first PE of about 40 weeks to about 50 weeks, (iii) reducing the decline in the patient’s post-bronchodilator FEV1during or subsequent to the administration period by about 11 mL to about 50 mL, and (iv) achieving an annualized rate of severe PE of about 0.10 to about 0.17.

[0345] Embodiment 131. The method of any one of embodiments 104-130, wherein the treating comprises three or more of (i) achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1, (ii) achieving a median time to first PE of about 40 weeks to about 50 weeks, (iii) reducing the decline in the patient’s post-bronchodilator FEV1during or subsequent to the administration period by about 10 mL to about 50 mL, and (iv) achieving an annualized rate of severe PE of about 0.10 to about 0.17.

[0346] Embodiment 132. The method of any one of embodiments 104-131, wherein the treating comprises (i) achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1, (ii) achieving a median time to first PE of about 40 weeks to about 50 weeks, (iii) reducing the decline in the patient’s post-bronchodilator FEV1during orAttorney Docket No. INMD-215 / 03WO 315953-4453 subsequent to the administration period by about 10 mL to about 50 mL, and (iv) achieving an annualized rate of severe PE of about 0.10 to about 0.17.

[0347] Embodiment 133. The method of any one of embodiments 104-132, wherein the treating comprises reducing the decline in the patient’s post-bronchodilator FEV1during or subsequent to the administration period by at least about 11 mL to about 50 mL.

[0348] Embodiment 134. The method of embodiment 133, wherein the treating comprises reducing the decline in the patient’s post-bronchodilator FEV1 during or subsequent to the administration period by about 11 mL to about 40 mL.

[0349] Embodiment 135. The method of any one of embodiments 104-134, wherein the treating comprises increasing the time to the first PE after starting the administration period by at least 15%, as compared to the the time to the first PE experienced by an untreated bronchiectasis patient.

[0350] Embodiment 136. The method of any one of embodiments 104-135, wherein the treating comprises increasing the time to the first PE after starting the administration period by 15% to 30%.

[0351] Embodiment 137. The method of any one of embodiments 104-136, wherein the treating comprises increasing the patient’s odds of remaining free of PEs during the administration period by at least about 40%.

[0352] Embodiment 138. The method of any one of claims 100-137, wherein the treating comprises increasing the patient’s odds of remaining free of PEs during the administration period by about 40% to about 50%.

[0353] Embodiment 139. The method of any one of embodiments 1-138, wherein the patient experienced at least one PE in a 12 month period immediately preceding the administration period.

[0354] Embodiment 140. The method of any one of embodiments 1-138, wherein the patient experienced at least 2 PEs in a 12 month period immediately preceding the administration period.

[0355] Embodiment 141. The method of embodiment 140, wherein the patient received antibiotic treatment during the 12 month period immediately preceeding the administration period.

[0356] Embodiment 142. The method of any one of embodiments 1-141, wherein the patient is an adult patient.

[0357] Embodiment 143. The method of any one of embodiments 1-142, wherein the patient is a pediatric patient.Attorney Docket No. INMD-215 / 03WO 315953-4453 EXAMPLES

[0358] The present invention is further illustrated by reference to the following Examples. However, it should be noted that this Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the invention in any way. Example 1. Phase 3, Randomized, Double-Blind, Placebo-Controlled, 52-Week Study of Brensocatib

[0359] A phase 3, randomized, double-blind, placebo-controlled, 52-Week study of brensocatib was conducted. (Clinical Trials dot Gov ID: NCT04594369). Patient disposition for this trial is provided at FIG.9.

[0360] Brensocatib 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, shown by the structure. Brensocatib, in monohydrate form (CAS registry number 2923839-30-7), was administered once daily (QD) for 52 weeks in subjects with non-cystic fibrosis (CF) bronchiectasis (NCFBE).

[0361] 1680 adult subjects and 41 adolescents (12 to <18 yrs) were recruited for this study. The subjects are randomly assigned into three gourps A, B and C for treatment (1:1:1 for adults and 2:2:1 for adolescents). Group A: Brensocatib 10 mg once daily. Group B: Brensocatib 25 mg once daily. Group C: placebo once daily.

[0362] Study Duration

[0363] The maximum study duration was 52 weeks total for an individual participant, including a Screening Period of up to 6 weeks, a Treatment Period of 52 weeks, and an End- of-Study Visit 4 weeks following the end of treatment.

[0364] The primary endpointAttorney Docket No. INMD-215 / 03WO 315953-4453

[0365] The primary endpoint was the annualized rate of adjudicated pulmonary exacerbations (PEs) over 52 weeks. Only exacerbation events that met the protocol definition of PE diagnosis were included into the analysis.

[0366] PE diagnosis

[0367] A minimum of 14 days must have occurred between the end date of one pulmonary exacerbation and the start date of the next pulmonary exacerbation. Any exacerbations that occur less than 14 days from the prior exacerbation were not considered a new exacerbation. Any PE that meets the protocol criteria after randomization through the end of study were included in the primary endpoint calculation.

[0368] Subject’s time at risk was the time on study excluding the time during exacerbations.

[0369] Main analysis for primary endpoint

[0370] A pulmonary exacerbation (PE) is defined as the presence of 3 of the following symptoms for at least 48 hours, resulting in a physician’s decision to prescribe systemic antibiotics: 1. Increased cough; 2. Increased sputum production or change in sputum consistency; 3. Increased sputum purulence; 4. Increased breathlessness and / or decreased exercise tolerance; 5. Fatigue and / or malaise; or 6. Hemoptysis. All PEs were adjudicated by an independent adjudication committee.

[0371] The primary estimand was the On-Study estimand in which all observed data up to Week 52 was included in the analysis. The ITT Analysis Set was used for this estimand. The ITT Analysis Set comprises all subjects who were randomized subjects. This set was analyzed using the treatment to which the subject was randomized, regardless of the treatment actually received.

[0372] The annualized rate of PE was analyzed using the negative binomial model at the study- wise 2-sided significance level of 0.01, or 2-sided significance level of 0.005 for each of 2 null hypotheses, at finalanalysis. This analysis was be based on the Intent to Treat (ITT) population. The model includes treatment group and randomization stratification factors (geographic region [North America, Europe, Japan, and the rest of the world], Screening sputum sample positive or negative for Pseudomonas aeruginosa, and the number of prior pulmonary exacerbations [2, or 3] in the previous 12 months) as fixed effects, and the time in study (log scale) as an offset variable. The PE rate per treatment group, the ratios of PE rates between each brensocatib dose and placebo, and the associated 95% confidential interval (CI) was estimated from the negative binomial model.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0373] Annualized Rate of PEs

[0374] The annualized rate of PEs for each treatment group, the ratios of PE rates between each brensocatib dose and placebo, and the associated 95% CIs were estimated from the negative binomial model.

[0375] For the primary analysis, the response variable is the number of PEs the participant experiences up to Week 52, with the time at risk of experiencing a PE included as offset in the model.

[0376] PEs with a start date that occurs after a participant’s discontinuation from IP (investigational product) while remaining in the study for follow-up was managed according to the Estimand. The time at risk was adjusted too (see Table 1).

[0377] For descriptive summaries, the crude Annualized Rate of PEs is calculated as:365.25wherein number of PEs and Time at Risk is following the definitions described in Table 1.

[0378] Sensitivity analyses for primary endpointAttorney Docket No. INMD-215 / 03WO 315953-4453

[0379] Sensitivity analyses were conducted to assess the robustness of the primary results in the presence of missing data.

[0380] In the event that there were study participants who discontinue randomized IP (investigational product) early and also declined to remain in the study, ascertainment of data was incomplete, and a true treatment policy / ITT analysis could not be achieved. A MAR (missing at random) assumption for the missing data was made implicitly for the On-Study estimand using the observed data alone, and a hypothetical strategy was inherently implemented for the ICEs (intercurrent events) of early study withdrawn.

[0381] The main analysis using the negative binomial model was unbiased under the MAR assumption for the missing data. However, in some instances, the fact that data were missing may be directly related to the unobserved values (ie, MNAR: missing not-at-random). Therefore, robustness of the main analysis to departures from the MAR assumption was assessed using tipping-point analyses. Due to the inherent difficulties in identifying the missing data mechanism in practice, all missing data was assumed MNAR, and the tipping-point penalties was applied accordingly.

[0382] Supportive analysis for primary endpoint

[0383] The supportive estimand for the primary endpoint is the On-Treatment estimand and utilized the ITT Analysis Set. The same negative binomial regression model was implemented for this estimand; however, only data up until the occurrence of a relevant ICE (ie, early discontinuation of randomized study treatment, early discontinuation of standard of care, or addition of chronic antibiotics) was included in the analysis. Time at risk was defined as the time of exposure until the occurrence of an ICE or until the last dosing date of IP if no ICE occurred. Time during an exacerbation was excluded from the time at risk.

[0384] The secondary endpoints

[0385] The secondary endpoins include Time-to-first PE (pulmonary exacerbation), Percentage PE free, Change in FEV1 (Forced expiratory volume in 1 second), Rate of severe PEs, and Change in Quality of Life-Bronchiectasis Questionnaire (QoL-B) respiratory score.

[0386] Secondary endpoints were analyzed as follows: • For time to first pulmonary exacerbation, the survival curves were compared between the brensocatib dose and placebo using the stratified log rank test based on ITTAttorney Docket No. INMD-215 / 03WO 315953-4453 population. The stratum for the stratified log rank test included the stratification factors used for the randomization. • For proportion of subjects who are exacerbation-free, the comparison between the brensocatib dose and placebo was analyzed using logistic regression with treatment group and randomization stratification factors as fixed effects and treatment duration (log scale) as an offset variable. • Absolute change in postbronchodilator FEV1was analyzed using repeated measures analyses with fixed effects of treatment, stratification factors, visit, as well as the continuous, fixed covariate of baseline value. • The annualized rate of severe PEs was analyzed using the same method as the primary endpoint. • The change in QOL-B Respiratory Symptoms Domain scores was analyzed using the same method as for absolute change from Baseline in postbronchodilator FEV1. • Safety endpoints including incidence and severity of treatment-emergent adverse events, clinical laboratory test results, vital signs, and electrocardiogram (ECG) was descriptively summarized by treatment.

[0387] Inclusion Criteria 1. Clinical history consistent with non-cystic fibrosis bronchiectasis (NCFBE) (cough, chronic sputum production and / or recurrent respiratory infections) that was confirmed by chest computerized tomography (CT) scan. 2. For adult patients, at least 2 PEs defined by need for antibiotic prescription by a physician for the signs and symptoms of respiratory infections in the past 12 months before the Screening Visit. (Adolescent participants were required to have at least 1 pulmonary exacerbation in the prior 12 months.) 3. Women were postmenopausal (defined as no menses for 12 months without an alternative medical cause), surgically sterile, or using highly effective contraception (ie, methods that can achieve a failure rate <1% per year when used consistently and correctly) from Day 1 to at least 90 days after the last dose. 4. Male participants with female partners of childbearing potential were using effective contraception from Day 1 to at least 90 days after the last dose. 5. Male participants with pregnant or non-pregnant women of child-bearing potential partners used condoms to avoid potential exposure to the embryo / fetus.

[0388] Exclusion Criteria:Attorney Docket No. INMD-215 / 03WO 315953-4453 1. A primary diagnosis of chronic obstructive pulmonary disease (COPD) or asthma judged by the Investigator. 2. Bronchiectasis due to cystic fibrosis. 3. Current smokers as defined per Centers for Disease Control (CDC). 4. Known or suspected immunodeficiency disorder, including history of invasive opportunistic infections. 5. Known history of human immunodeficiency virus (HIV) infection. 6. Currently treated for nontuberculous mycobacteria (NTM) lung infection, allergic bronchopulmonary aspergillosis, or tuberculosis (TB). 7. Active and current symptomatic infection by 2019 corona virus disease (COVID-19). 8. Inability to follow the procedures of the study (eg, due to language problems or psychological disorders). 9. Received medications or therapy that are prohibited as concomitant medications. 10. Previously participated in a clinical trial for brensocatib. 11. Received any live attenuated vaccine within 4 weeks prior to the first administration of brensocatib. 12. Suffered an exacerbation 4 weeks before Screening or during the Screening period. 13. Adult participants only: Have compliance issues with completion of electronic diary entries during the Screening Period and in the opinion of the Investigator, compliance is unlikely to improve during the study. 14. Participated in any other interventional clinical studies within 3 months before Screening Visit. 15. History of alcohol or drug abuse within 6 months prior to the Screening Visit. 16. Is the Investigator or any Sub-Investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study. 17. Known history of hypersensitivity to brensocatib or any of its excipients.

[0389] Statistical Analysis • The trial was designed to provide 90% power to detect a 30% reduction in the exacerbation rate ratio between either brensocatib treatment group and placebo after 52 weeks of treatment with an overall 2-sided alpha level of 0.01. • Efficacy analyses were based on the intent-to-treat (ITT) population, which comprised all patients who underwent randomization, and using the treatment to which the patients were randomized.Attorney Docket No. INMD-215 / 03WO 315953-4453 • The primary endpoint was analyzed using a negative binomial model. • All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC, US).

[0390] Study Treatment

[0391] Study subjects were assigned to 1 of 3 treatment arms. Based on treatment assignment, subjects were supplied either brensocatib 10 mg oral tablets, brensocatib 25 mg oral tablets, or matching placebo oral tablets. Study treatment was taken by subjects QD by mouth with water in the morning before breakfast.

[0392] Pulmonary function test (PFT)

[0393] Pulmonary function test (PFT) by spirometry (FEV1) was performed per the American Thoracic Society (ATS / European Respiratory Society [ERS]) criteria at Visit 1 (Screening), Visit 6, and Visit 9. Spirometry criteria were described in Miller et al. (2005). Standardization of Spirometry. Eur. Respir. J. 26, pp. 319-38, incorporated by reference herein in its entirety for all purposes.

[0394] Subjects were advised to withhold short-acting inhaled drugs (e.g., the -agonist albuterol / salbutamol or the anticholinergic agent ipratropium bromide) within 6 hr. prior to the test. Long-acting -agonist bronchodilators (e.g., salmeterol or formoterol) or long-acting muscarinic bronchodilators (e.g., tiotropium) or oral therapy with aminophylline or slow release -agonists were withheld for 12-24 hours depending on the medication used for the minimum time intervals for a list of restricted medications) prior to the testing.

[0395] Subjects were advised to withhold the use of their inhaled corticosteroids at least 24 hours prior to the test. In the event a subject had taken a restricted medication during the specified time interval before the test, the test was rescheduled for another visit within the protocol-specified visit window. If rescheduling the visit was not feasible for the subject, the test was conducted as usual with appropriate notation in the source documents.

[0396] The chacterization of the subjects studied are included in Table 2, which shows that the baseline characteristics were well-balanced across treatment arms.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0397] Study results are included in Table 3. The result shows that primary endpoint achieved statistical significance on both doses of brensocatib in the study.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0398] As shown in Table 3 and FIG. 1, the annualized rate of PEs per year was reduced by 21.1% and 19.4% in patients treated with brensocatib 10 and 25 mg, respectively, vs placebo. The annualized rate of severe PEs was 1.015 in the 10-mg brensocatib group (n=583), 1.036 in the 25-mg brensocatib group (n=575), and 1.286 in the placebo group (n=563). FIG.1. These rates, when compared with placebo, were significantly lower in the 10-mg and 25-mg brensocatib groups, with rate ratios of 0.789 (95% CI, 0.68-0.916; P=0.0019) and 0.806 (95% CI, 0.694-0.936; P=0.0046), respectively. These P values are statistically significant when adjusted from multiplicity control.

[0399] The proportion of patients with no pulmonary exacerbations is provided at FIG.2. Over the 52 weeks, 283 (48.5%) patients remained exacerbation-free in the 10-mg brensocatib group,Attorney Docket No. INMD-215 / 03WO 315953-4453 279 (48.5%) in the 25-mg brensocatib group, and 227 (40.3%) in the placebo group. FIG. 3. Differences between both brensocatib groups with placebo were statistically significant, with odds ratios of 1.412 (95% CI, 1.105-1.806; P=0.0059) for the 10 mg brensocatib group and 1.400 (95% CI, 1.095-1.792; P=0.0074) for the 25 mg brensocatib group. P values were calculated from logistic regression Wald test in the ITT (intent-to-treat) analysis set and were statistically significant when adjusted for multiplicity control.

[0400] FEV1in the placebo group declined at week 52 by 62 mL vs. baseline. FIG. 4. Brensocatib 25-mg significantly reduced FEV1 decline vs. placebo by 38 mL (95% CI, 11-65; P=0.0054; FIG. 4). Brensocatib 10-mg nonsignificantly reduced FEV1decline vs. placebo (least squares [LS] mean difference 11 mL [95% CI, 14 to 37); P=0.3841]).

[0401] Analysis of change from baseline in FVC showed a decrease of 87 mL with placebo at week 52 that was reduced by 36 mL (95% CI, 3-69; nominal P=0.0331) and 75 mL (95% CI, 40-110; nominal P<0.0001) with 10-mg and 25-mg brensocatib treatment, respectively (FIG. 5, Table 4).

[0402] The annualized rate of severe exacerbations was 0.137 in the 10-mg and 25-mg brensocatib groups, and 0.185 in the placebo group. FIG. 6. Brensocatib groups had numerically lower rates vs. placebo: rate ratios 0.742 (95% CI, 0.51-1.09; P=0.1277) and 0.740 (95% CI, 0.52-1.06; P=0.1025) for the 10-mg and 25-mg brensocatib groups, respectively.Attorney Docket No. INMD-215 / 03WO 315953-4453 Stated another way, patients in the 10 mg and 25 mg brensocatib groups had a 25.8% and 26.0% exacerbation risk reduction, respectively.

[0403] Treatment with 10-mg brensocatib resulted in numerically improved change from baseline in the Quality of Life-Bronchiectasis questioinairre Respiratory Symptom Domain Score (QOL-B RSS) at week 52 (least squares (LS) mean difference, 2.03 points; P=0.0594). Treatment with 25-mg brensocatib resulted in a nominally significant improvement in the QOL-B RSS score at week 52 (LS mean difference, 3.77 points; nominal P=0.0004). FIG. 7. See Quittner et al.2014. Chest 146(2), pp.437-448.

[0404] Change in average daily BEST score (see, Artaraz et al. Development and initial validation of the bronchiectasis exacerbation and symptom tool (BEST). Respir Res 2020;21:18) at week 52 aligned with QOL-B RSS indicating a nominally significant improvement vs. placebo with 25-mg brensocatib (LS mean difference, 0.572; SE, 0.1303; nominal P<0.0001) but not 10-mg brensocatib (LS mean difference, 0.168; SE, 0.1221; P=0.1696) (FIG.8).

[0405] Rates of treatment-emergent adverse events (TEAEs) and treatment discontinuations are included in Table 5. The rates of treatment-emergent AEs, treatment discontinuations, and AEs of special interest were similar in the brensocatib and placebo arms (Table 5). Among the patients with hyperkeratosis, only 1 patient in the brensocatib 25 mg treatment arm discontinued treatment due to the AE.Attorney Docket No. INMD-215 / 03WO 315953-4453Attorney Docket No. INMD-215 / 03WO 315953-4453 Conclusion of the Study

[0406] The study shows that Brensocatib at both doses, 10 and 25 mg once daily, significantly reduced the annualized rate of pulmonary exacerbations, significantly prolonged the time to first pulmonary exacerbation and ignificantly increased the odds of remaining exacerbation- free over the treatment period.

[0407] Brensocatib 25 mg significantly reduced the rate of loss of lung function, as measured by the change from baseline in post-bronchodilator FEV1 (forced expiratory volume in 1 second) at week 52 vs placebo.

[0408] Both doses demonstrated numerical reductions in the rate of severe pulmonary exacerbations that were not statistically significant.

[0409] Brensocatib 25 mg showed a nominally significant improvement in quality of life.

[0410] Brensocatib at both doses was generally well tolerated and demonstrated a favorable safety profile. Example 2 – Efficacy of Brensocatib in Patients with Eosinophilic Bronchiectasis: An Analysis of the ASPEN Trial

[0411] ASPEN enrolled patients with bronchiectasis and a history of pulmonary exacerbations in the 12 months prior to screening (adults [18-85 years], 2; adolescents [12-<18 years], 1). Patients were randomized to receive once-daily brensocatib (10- or 25-mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1), as described in Example 1. Subgroupanalyses were explored in patients with high ( 300 / mm3) or low (<300 / mm3) baseline bloodeosinophil counts at screening. Endpoints were annualized exacerbation rate, time to first exacerbation, rate of severe exacerbation, change in post-bronchodilator forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and change in Quality of Life- Bronchiectasis Respiratory Symptoms Domain score (QOL-B RSS).

[0412] Results

[0413] Demographics and baseline characteristics were balanced between subgroups, with the exception of lower lung function and higher inhaled corticosteroid use in the high eosinophil subgroup (Table 5). Consistent with overall ASPEN results, brensocatib 10- and 25-mg reduced the annualized rate of exacerbations, prolonged the time to first exacerbation, and increased the odds of remaining exacerbation-free in both subgroups (Table 5). Brensocatib 25-mg reduced both FEV1 and FVC decline, and improved QOL-B RSS at week 52 vs placeboAttorney Docket No. INMD-215 / 03WO 315953-4453 regardless of baseline blood eosinophil count (Table 6). Adverse events were similar across treatment groups, and consistent with the overall ASPEN results. Conclusions

[0414] Consistent with the overall study population, brensocatib reduced the annualized rate of exacerbations, reduced lung function decline, and improved patient-reported symptoms regardless of high or low eosinophil counts at baseline.Attorney Docket No. INMD-215 / 03WO 315953-4453Example 3 – Efficacy of Brensocatib in Patients With Non-Cystic Fibrosis Bronchiectasis With vs Without Maintenance Use of Macrolides: An Analysis of the ASPEN Trial

[0415] ASPEN enrolled patients with bronchiectasis and a history of pulmonary exacerbations in the 12 months prior to screening (adults [18-85 years], 2; adolescents [12-<18 years], 1). Patients were randomized to receive once-daily brensocatib (10- or 25-mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1). Subgroup analyses were explored in patients with or without maintenance use of macrolides at baseline. Endpoints were annualized exacerbation rate, time to first exacerbation, rate of severe exacerbation, change in post- bronchodilator forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), as well as change in Quality of Life-Bronchiectasis Respiratory Symptoms Domain score (QOL-B RSS). Results

[0416] Demographics were balanced, with some differences in baseline characteristics indicating greater disease severity among patients with maintenance macrolide use, including increased exacerbation rate and more exacerbations requiring hospitalization, prior to enrollment. Patients with maintenance macrolide use experienced higher rates of exacerbations and severe exacerbations over the study period vs those without, regardless of treatment group (Table 7). Consistent with overall ASPEN results, brensocatib 10- and 25-mg reduced theAttorney Docket No. INMD-215 / 03WO 315953-4453 annualized rate of exacerbations, prolonged the time to first exacerbation, and increased the odds of remaining exacerbation-free in both subgroups (Table 7). Brensocatib 25-mg reduced both FEV1 and FVC decline, and improved QOL-B RSS at week 52 vs placebo for patients regardless of baseline maintenance macrolide use (Table 7). Adverse events were similar across treatment groups, and consistent with the overall ASPEN results. Conclusions

[0417] Consistent with the overall study population, brensocatib reduced the annualized rate of exacerbations, reduced lung function decline, and improved patient-reported symptoms regardless of maintenance use of macrolides at baseline.Attorney Docket No. INMD-215 / 03WO 315953-4453Example 4 – Health Care Resource Utilization in Patients with Non-Cystic Fibrosis Bronchiectasis treated with Brensocatib vs Placebo: An analysis of the ASPEN trial

[0418] ASPEN enrolled patients with BE and a history of pulmonary exacerbations (PEs) in the 12 months prior to screening (adults [18-85 years], 2; adolescents [12-<18 years], 1). Patients were randomized to receive once daily brensocatib (10 or 25 mg) or matched placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1), as described in detail in Example 1.

[0419] Endpoints were annualized PE rate, time to first PE, rate of severe PE, change in post- bronchodilator forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and change in Quality of Life-BE (QOL-B) Respiratory Symptoms Domain score.

[0420] Results

[0421] In total, 583, 575, and 563 patients received brensocatib 10 mg, 25 mg, and placebo, respectively. The annualized rate of PEs over 52 weeks vs placebo was significantly reduced by brensocatib 10 mg (RR 0.79 [95% CI, 0.68-0.92, P=0.0019]) and 25 mg (0.81 [0.69-0.94; P=0.0046]). Time to first PE was significantly prolonged (HR 0.81 [95% CI, 0.70-0.95; P=0.0100]; 0.83 [0.70-0.97; P=0.0182]) and odds of remaining PE-free were significantly increased (OR 1.41 [95% CI, 1.11-1.81; P=0.0059]; 1.40 [1.10-1.79; P=0.0074]) with brensocatib 10 and 25 mg vs placebo. The 25 mg dose also significantly reduced FEV1 decline vs placebo (difference: 38mL, P=0.0054). Other efficacy endpoints were not significant.

[0422] Overall rates of adverse events were similar across groups.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0423] Fewer patients with brensocatib 10 and 25 mg had 1 BE-related hospitalization vs placebo (38 [6.5%], 42 [7.3%], 55 [9.8%], respectively) and the number of BE-related hospitalizations was lower in brensocatib arms (57, 57, and 88, respectively). Conclusions

[0424] Brensocatib-treated patients had significant reductions in annualized rates of PEs vs placebo. Brensocatib was associated with numerically fewer BE-related hospitalizations vs placebo, providing further evidence of a substantial clinical and economic impact for patients living with BE. Example 5 – Exacerbation Rate and Lung Function in Adolescent Patients With Non- Cystic Fibrosis Bronchiectasis: An Analysis of the ASPEN Trial

[0425] In the phase 3, randomized, double-blind ASPEN trial (NCT04594369), which enrolled patients aged 12-85 years, treatment with once-daily brensocatib 10- or 25-mg significantly reduced the annualized rate of adjudicated pulmonary exacerbations over 52 weeks vs placebo; brensocatib 25-mg also significantly reduced lung function decline and improved patient- reported symptoms. Despite increasing recognition among pediatric populations (<18 years), bronchiectasis remains a highly neglected pulmonary disease in children and adolescents. Here, efficacy and safety in adolescent patients from the ASPEN trial is reported. Methods

[0426] As described in Example 1, ASPEN enrolled patients with bronchiectasis and a history of pulmonary exacerbations in the 12 months prior to screening (adults [18-85 years], 2; adolescents [12-<18 years], 1). Patients were randomized to receive once-daily brensocatib (10- or 25-mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1). Adolescents were not stratified. Primary efficacy and safety analyses for the adolescent population are reported, including for adolescents who had not yet completed 52 weeks of treatment by the data cutoff (28 March 2024). Results

[0427] In total, 41 adolescents were treated with brensocatib 10-mg (n=17), 25-mg (n=16), or placebo (n=8). Demographic and baseline characteristics were comparable across groups, with a mean age of 14.7 years and 10 (24.4%) having 3 exacerbations in the prior 12 months.

[0428] For adolescent patients in ASPEN, there was a numerical reduction of 59% and 27% in the annualized rate of adjudicated pulmonary exacerbations for 10- and 25-mg brensocatibAttorney Docket No. INMD-215 / 03WO 315953-4453 groups vs placebo (annualized rate [95% CI], 10-mg: 0.35 [0.15-0.86], 25-mg: 0.64 [0.28- 1.46], placebo: 0.87 [0.32-2.35]). A greater proportion of patients treated with brensocatib remained exacerbation-free, and improvements in FEV1 were observed in both brensocatib groups compared with a loss in the placebo group (Table 8). Adverse events were similar across treatment groups and consistent with overall ASPEN results. Conclusions

[0429] Consistent with the overall study population, brensocatib was associated with numerical improvements in the annualized rate of adjudicated pulmonary exacerbations and reduced lung function decline in adolescent patients enrolled in the ASPEN trial.Attorney Docket No. INMD-215 / 03WO 315953-4453Example 6 – Lung Function in Patients With Non-Cystic Fibrosis Bronchiectasis, With vs Without Pulmonary Exacerbations: An Analysis of the ASPEN Trial

[0430] In the phase 3, randomized, double-blind ASPEN trial (NCT04594369), treatment with once-daily brensocatib 10- or 25-mg significantly reduced the annualized rate of adjudicated pulmonary exacerbations over 52 weeks vs placebo; brensocatib 25-mg also significantly reduced lung function decline and improved patient-reported symptoms.

[0431] Here, the impact of brensocatib on lung function in patients with bronchiectasis is further evaluated. Methods

[0432] ASPEN enrolled patients with bronchiectasis and a history of pulmonary exacerbations in the 12 months prior to screening (adults [18-85 years], 2; adolescents [12-<18 years], 1). Patients were randomized to receive once-daily brensocatib (10- or 25-mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1), as described in greater detail in Example 1. Post-hoc analyses were conducted to evaluate the extent of lung function response to treatment, as measured by change from baseline in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) over the 52-week treatment period in patients who did have (FIG. 10, right panel) vs did not have (FIG. 10, left panel), 1 on-study pulmonary exacerbation, and the level of change in post-BD FEV1 and forced vital capacity (FVC) at weekAttorney Docket No. INMD-215 / 03WO 315953-4453 Results

[0433] A total of 583 patients received brensocatib 10-mg, 575 received brensocatib 25-mg, and 563 received placebo.

[0434] Overall, a greater decline in FEV1 was observed among patients with 1 on-study pulmonary exacerbation vs those without. Treatment with brensocatib 10-mg or 25-mg led to less FEV1 decline at week 52 vs placebo for patients regardless of on-study exacerbation (No exacerbation: -42mL (10 mg), -8mL (25 mg), vs -48mL (placebo), respectively; 1 exacerbation: -59mL (10 mg), -41mL (25 mg), vs -70mL (placebo), respectively (FIG.10)).

[0435] In the overall population, no change or an improvement ( 0 mL difference vs baseline)in post-BD FEV1at week 52 was observed in 39.0%, 45.9%, and 31.5% of patients in the brensocatib 10-mg, 25-mg, and placebo groups, respectively. Similar benefits of brensocatib were observed in FVC (no change or improvement, 10-mg: 41.5%; 25-mg: 49.3%; placebo: 31.9%). Conclusions

[0436] Overall, greater lung function decline was observed in patients who had on-study pulmonary exacerbations vs those who did not. Brensocatib 25-mg reduced lung function decline vs placebo regardless of whether patients had on-study exacerbations, consistent with overall ASPEN results. Example 7 – Summary of Phase 3 ASPEN Clinical Trial

[0437] Provided herein is a summary of the phase 3, randomized, double-blind ASPEN trial (NCT04594369) assessing treatment with once-daily brensocatib 10- or 25-mg. This was a placebo-controlled, parallel-group, multicenter, multinational study with a total of 1721 patients 12 years of age or older with NCFBE (1680 adults and 41 adolescents).

[0438] All subjects were randomized to one of two doses of brensocatib (25 mg: n =575) or placebo (n=563), administered once daily for 52 weeks.

[0439] All adult patients enrolled had a history of confirmed NCFBE by chest computed tomography with at least 2 documents pulmonary exacerbations prior to screening in the past 12 months. Adolescent patients had at least one pulmonary exacerbation in the prior 12 months.

[0440] The primary endpoint was the annulized rate of pulmonary exacerbations (PE) over the 52-week treatment period.Attorney Docket No. INMD-215 / 03WO 315953-4453

[0441] Pulmonary exacerbations were defined as worsening of 3 or more major symptoms over 48 hours with increase in cough, sputum volume, sputum purulence or increased breathlessness or decreased exercise tolerance and fatigue and / or malaise and, hemoptysis. Exacerbations were considered as severe if requiring treatment with IV antibacterial drugs and / or resulted in hospitalization.

[0442] In the trial, treatment with 10 mg or 25 mg of brensocatib in patients with NCFBE demonstrated significant reductions in the annualized rate of pulmonary exacerbations compared with placebo (Table 9). The time to first pulmonary exacerbation was significantly longer for patients receiving 10 mg or 25 mg of brensocatib compared to placebo. Treatment with 10 mg or 25 mg of brensocatib significantly increased the proportion of patients remaining exacerbation free throughout the 52-week treatment period. There were fewer severe exacerbations with 10 mg or 25 mg of brensocatib compared with placebo.

[0443] Change in baseline in post-bronchodilator FEV1was assessed as a secondary endpoint. Brensocatib 25 mg significantly reduced FEV1 decline in comparison to placebo at week 52 (Table 10).Attorney Docket No. INMD-215 / 03WO 315953-4453* * * * * * *

[0444] All, documents, patents, patent applications, publications, product descriptions, and protocols which are cited throughout this application are incorporated herein by reference in their entireties for all purposes.

[0445] The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention. Modifications and variation of the above-described embodiments of the invention are possible without departing from the invention, as appreciated by those skilled 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

Attorney Docket No. INMD-215 / 03WO 315953-4453 CLAIMS 1. A method for treating bronchiectasis in a patient in need of treatment, comprising, orally administering to the patient once daily for an administration period of at least about 52 weeks, a pharmaceutical composition comprising about 10 mg to about 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof,R2is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2or SO2NR4R5, wherein R4and R5together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; R6is C1-3alkyl, optionally substituted by 1, 2 or 3 F and / or optionally by OH, OC1-3alkyl, N(C1- 3alkyl)2, cyclopropyl, or tetrahydropyran; R7is hydrogen, F, Cl or CH3; X is O, S or CF2; Y is O or S; Q is CH or N; and Z is H or halogen, wherein, treating comprises reducing the annualized rate of pulmonary exacerbations of the patient by at least about 20%, as compared to the annualized rate of pulmonary exacerbations experienced by the patient prior to the administration period, or compared to the annualized rate of pulmonary exacerbations experienced by a untreated bronchiectasis patient; and wherein, a pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increasedAttorney Docket No. INMD-215 / 03WO 315953-4453 breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; and (6) hemoptysis.

2. The method of claim 1, wherein Z is H.

3. The method of claim 1, wherein Z is halogen.

4. The method of claim 1, wherein the compound of Formula (I) is . claim 1, wherein the compound of Formula (I) isThe method of claim 3, wherein Z is F. The method of any one of claims 1-4, wherein,X is O, S or CF2; Y is O or S; R6is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; and R7is H, F, Cl or CH3. The method of any one of claims 1-4, wherein.Attorney Docket No. INMD-215 / 03WO 315953-4453 9. The method of claim any one of claims 1-6, wherein, X is O; R6is C1-3alkyl; and R7is H.

10. The method of any one of claims 1-4, wherein,; X is O; R6is C1-3alkyl, wherein the C1-3alkyl is optionally substituted by 1, 2 or 3 F; and R7is hydrogen.

11. The method of any one of claims 1-4, wherein,3alkyl; and R7is hydrogen.

12. The method of any one of claims 1-4, wherein R1 is.

13. The method of claim 1, wherein the compound of Formula (I) is selected from the group consisting of (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (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; (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; 4’-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate; (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4’-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(3’,4’-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide;Attorney Docket No. INMD-215 / 03WO 315953-4453 (2S)-N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (2S)-N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-2-(4’-Carbamoyl-3’-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4- oxazepane-2-carboxamide;Attorney Docket No. INMD-215 / 03WO 315953-4453 (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; (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; (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; (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; (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; (2S)-N-{(1S)-1-Cyano-2-[4’-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-2-[4’-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(4’-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; or (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; and pharmaceutically acceptable salts or hydrates thereof.

14. The method of claim 1, wherein 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:; or a pharmaceutically acceptable salt or hydrate thereof.

15. The method of claim 1, wherein 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), or a hydrate thereof.Attorney Docket No. INMD-215 / 03WO 315953-4453 16. The method of claim 1, wherein the compound of Formula (I) is brensocatib17. The method of claim 1, wherein the compound of Formula (I) is (S)-N-((S)-1-cyano-2- (2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide, having the structural formula:, or a pharmaceutically acceptable salt or hydrate thereof.

18. The method of claim 1, wherein the compound of Formula (I) is (S)-N-((S)-1-cyano-2- (2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2- carboxamide monohydrate, having the structural formula:.

19. The method of any one of claims 1-18, wherein the composition comprises a pharmaceutically acceptable adjuvant, diluent or carrier.

20. The method of any one of claims 1-19, wherein the administration period is about 52 weeks.

21. The method of any one of claims 1-20, wherein the annualized rate of pulmonary exacerbations is calculated over the length of the administration period.

22. The method of any one of claims 1-21, wherein the annualized rate of pulmonary exacerbations of the patient is reduced by about 20% to about 40%.Attorney Docket No. INMD-215 / 03WO 315953-4453 23. The method of any one of claims 1-21, wherein the annualized rate of pulmonary exacerbations of the patient is reduced by about 20% to about 30%.

24. The method of any one of claims 1-23, wherein the treating comprises increasing the length of time to first pulmonary exacerbation in the patient by at least about 17.5%, as compared to an untreated bronchiectasis patient.

25. The method of claim 24, wherein treating comprises increasing the length of time to first pulmonary exacerbation in the patient by about 17.5% to about 30%, as compared to an untreated bronchiectasis patient.

26. The method of any one of claims 1-25, wherein the treating comprises increasing the patient’s odds of remaining free of pulmonary exacerbations during the administration period by at least about 40%.

27. The method of claim 26, wherein the treating comprises increasing the patient’s odds of remaining free of pulmonary exacerbations during the administration period by about 40% to about 50%.

28. The method of any one of claims 1-27, wherein the treating comprises decreasing the annualized rate of severe pulmonary exacerbations of the patient by at least about 25%, as compared to the annualized rate of severe pulmonary exacerbations experienced by an untreated bronchiectasis patient; and wherein, a severe pulmonary exacerbation requires treatment with intravenous antibiotic drugs, hospitilization or a combination thereof.

29. The method of claim 28, wherein the treating comprises decreasing the annualized rate of severe pulmonary exacerbations of the patient by from about 25% to about 50%.

30. The method of claim 28, wherein the treating comprises decreasing the annualized rate of severe pulmonary exacerbations of the patient by from about 25% to about 40%.

31. The method of any one of claims 1-30, wherein treating comprising reducing the decline in lung function of the patient during or subsequent to the administration period, as compared to the lung function decline of an untreated patient.

32. The method of claim 31, wherein reducing the decline in lung function of the patient comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period.Attorney Docket No. INMD-215 / 03WO 315953-4453 33. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by at least about 10 mL.

34. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by at least about 11 mL.

35. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 10 mL to about 50 mL.

36. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 10 mL to about 40 mL.

37. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 10 mL to about 30 mL.

38. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 30 mL to about 50 mL.

39. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 30 mL to about 40 mL.

40. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 35 mL to about 40 mL.

41. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 40 mL.

42. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 25 mL to about 30 mL.Attorney Docket No. INMD-215 / 03WO 315953-4453 43. The method of claim 32, wherein treating comprises reducing the decline in the patient’s post-bronchodilator forced expiratory volume in one second (FEV1) during or subsequent to the administration period by about 29 mL.

44. The method of claim 40 or 41, wherein the patient experiences zero exacerbations during the administration period.

45. The method of claim 42 or 43, wherein the patient experiences one or more exacerbations during the administration period.

46. The method of any one of claims 32-45, wherein the post-bronchodilator forced expiratory volume in one second (FEV1) is measured about 1 hour to about 7 days subsequent to the administration period.

47. The method of any one of claims 32-45, wherein the post-bronchodilator forced expiratory volume in one second (FEV1) prior to treatment, is measured about 1 hour to about 7 days prior to the administration period.

48. The method of any one of claims 1-47, wherein treating comprises improving the patient’s quality of life (QOL), as compared to the patient’s QOL prior to treatment, as mesaured by the change from baseiline in the Quality of Life-Bronchiectasis (QOL-B) Respiratory Score of at least 2.0 points.

49. The method of claim 47 or 48, wherein treating comprises improving the patient’s quality of life (QOL), as compared to the patient’s QOL prior to treatment, as mesaured by the change from baseiline in the Quality of Life-Bronchiectasis (QOL-B) Respiratory Score of by about 2 points to about 10 points.

50. The method of claim 47 or 48, wherein treating comprises improving the patient’s quality of life (QOL), as compared to the patient’s QOL prior to treatment, as mesaured by the change from baseiline in the Quality of Life-Bronchiectasis (QOL-B) Respiratory Score of by about 2 points to about 9 points.

51. The method of claim 47 or 48, wwherein treating comprises improving the patient’s quality of life (QOL), as compared to the patient’s QOL prior to treatment, as mesaured by the change from baseiline in the Quality of Life-Bronchiectasis (QOL-B) Respiratory Score of by about 3 points to about 9 points.

52. The method of any one of claims 1-51, wherein the bronchiectasis is non-cystic fibrosis (CF) bronchietasis.Attorney Docket No. INMD-215 / 03WO 315953-4453 53. The method of any one of claims 1-52, wherein the pharmaceutical composition comprises about 10 mg of the compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof.

54. The method of any one of claims 1-53, wherein the pharmaceutical composition comprises about 25 mg of the compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof.

55. The method of any one of claims 1-53, wherein the pharmaceutical composition comprises about 20 mg of the compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof.

56. The method of any one of claims 1-55, wherein the pharmaceutical composition is administered in the morning.

57. The method of any one of claims 1-55, wherein the pharmaceutical composition is administered prior to breakfast.

58. The method of any one of claims 1-55, wherein the pharmaceutical composition is administered with water.

59. The method of any one of claims 1-58, wherein the administration period is 52 weeks.

60. The method of any one of claims 1-59, wherein the administration period is, about 12 months, about 18 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.

61. The method of any one of claims 1-59, wherein the administration period is at least about 30 days, 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 18 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.

62. The method of any one of claims 1-59, wherein the administration period is about 12 months.

63. The method of any one of claims 1-59, wherein the administration period is from about 12 months to about 36 months.Attorney Docket No. INMD-215 / 03WO 315953-4453 64. The method of any one of claims 1-59, wherein the administration period is from about 18 months to about 36 months.

65. The method of any one of claims 1-59, wherein the administration period is from about 1 year to about 50 years.

66. The method of claim 65, wherein the administration period is from about 1 year to about 40 years.

67. The method of claim 65, wherein the administration period is from about 1 year to about 30 years.

68. The method of claim 65, wherein the administration period is from about 1 year to about 25 years.

69. The method of claim 65, wherein the administration period is from about 1 year to about 20 years.

70. The method of claim 65, wherein the administration period is from about 1 year to about 15 years.

71. The method of claim 65, wherein the administration period is from about 1 year to about 10 years.

72. The method of claim 65, wherein the administration period is from about 1 year to about 5 years.

73. The method of claim 65, wherein the administration period is from about 1 year to about 3 years.

74. The method of claim 65, wherein the administration period is from about 1 year to about 2 years.

75. The method of claim 65, wherein the administration period is from about 2 years to about 15 years.

76. The method of claim 65, wherein the administration period is from about 2 years to about 10 years.

77. The method of claim 65, wherein the administration period is from about 2 years to about 8 years.Attorney Docket No. INMD-215 / 03WO 315953-4453 78. The method of claim 65, wherein the administration period is from about 2 years to about 5 years.

79. The method of claim 65, wherein the administration period is from about 2 years to about 4 years.

80. The method of any one of claims 1-79, the method comprising first orally administering to the patient once daily about 10 mg of the compound of Formula (I) during the administration period, and then administering orally administering to the patient once daily about 25 mg of the compound of Formula (I) during the administration period.

81. The method of any one of claims 1-79, comprising first orally administering to the patient once daily about 25 mg of the compound of Formula (I) of the administration period and continuing administering about 25 mg of the compound of Formula (I) until the patient becomes intolerant, and then orally administering once daily 10 mg of the compound of Formula (I).

82. The method of claim 81, wherein the patient becomes intolerant of about 25 mg of the compound of Formula (I) when the patient experiences headache, hyperkeratosis, rash, infection, pneumonia, dyspnea, hemoptysis, periodontal disease, arthralgia, fatigue, nasopharyngitis, cough, dermatitis contact, pain, and / or dry skin.

83. The method of claim 82, wherein hyperkeratosis comprises a skin lesion, eczema, hyperkeratosis, keratosis pilaris, exfoliative rash, and / or seborrheic keratosis.

84. The method of any one of claims 81-83, wherein the patient returns to administering 25 mg of the compound of Formula (I) when the headache, hyperkeratosis, rash, and / or dry skin subside.

85. A method for treating bronchiectasis in a patient in need of treatment, comprising, orally administering to the patient once daily for an administration period of at least about 52 weeks, a pharmaceutical composition comprising about 25 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof,Attorney Docket No. INMD-215 / 03WO 315953-4453R2is hydrogen, F, Cl, Br, OSO2C1-3alkyl, or C1-3alkyl; R3is hydrogen, F, Cl, Br, CN, CF3, SO2C1-3alkyl, CONH2or SO2NR4R5, wherein R4and R5together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; R6is C1-3alkyl, optionally substituted by 1, 2 or 3 F and / or optionally by OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; R7is hydrogen, F, Cl or CH3; X is O, S or CF2; Y is O or S; Q is CH or N; and Z is H or halogen, wherein, treating comprises (i) achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1, (ii) achieving median time to first PE of about 40 weeks to about 50 weeks, (iii) reducing the decline in the patient’s post-bronchodilator forced expiratory volume in 1 second (FEV1) during or subsequent to the administration period by about 10 mL to about 55 mL, and / or (iv) achieving annualized rate of severe PE of about 0.10 to about 0.17, wherein a pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; and (6) hemoptysis.

86. The method of claim 85, wherein Z is H.

87. The method of claim 85, wherein Z is halogen.Attorney Docket No. INMD-215 / 03WO 315953-4453 88. The method of claim 85, wherein the compound of Formula (I) is . claim 85, wherein the compound of Formula (I) is.

90. The method of claim 87, wherein Z is F.

91. The method of any one of claims 85-88, wherein,X is O, S or CF2; Y is O or S; R6is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC1-3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; and R7is H, F, Cl or CH3.

92. The method of any one of claims 85-88, wherein.

93. The method of any one of claims 85-90, wherein, X is O; R6is C1-3alkyl; and R7is H.

94. The method of any one of claims 85-88, wherein,Attorney Docket No. INMD-215 / 03WO 315953-4453The method of any one of claims 85-88, wherein,3alkyl; and R7is hydrogen.

96. The method of any one of claims 85-88, wherein R1is.

97. The method of claim 85, wherein the compound of Formula (I) is selected from the group consisting of (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (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; (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; 4’-[(2S)-2-Cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate; (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4’-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(3’,4’-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (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;Attorney Docket No. INMD-215 / 03WO 315953-4453 (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (2S)-N-{(1S)-1-Cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-2-(4’-Carbamoyl-3’-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-1-Cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4- oxazepane-2-carboxamide; (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; (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;Attorney Docket No. INMD-215 / 03WO 315953-4453 (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; (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; (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; (2S)-N-{(1S)-1-Cyano-2-[4’-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-{(1S)-2-[4’-(Azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; (2S)-N-[(1S)-1-Cyano-2-(4’-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; (2S)-N-{(1S)-2-[4-(1,3-Benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2- carboxamide; or (2S)-N-[(1S)-1-Cyano-2-(4’-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide; and pharmaceutically acceptable salts or hydrates thereof.

98. The method of claim 85, wherein 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:; or a pharmaceutically acceptable salt or hydrate thereof.

99. The method of claim 85, wherein 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), or a hydrate thereof.

100. The method of claim 85, wherein the compound of Formula (I) is brensocatib monohydrate.Attorney Docket No. INMD-215 / 03WO 315953-4453 101. The method of claim 85, wherein the compound of Formula (I) is (S)-N-((S)-1-cyano- 2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane- 2-carboxamide, having the structural formula:pharmaceutically acceptable salt or hydrate thereof.

102. The method of claim 85, wherein the compound of Formula (I) is (S)-N-((S)-1-cyano- 2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane- 2-carboxamide monohydrate, having the structural formula:.

103. The method of any one of claims 85-102, comprising orally administering to the patient once daily about 25 mg of the compound of Formula (I) starting on Day 1 of the administration period and continuing administering once daily 25 mg of the compound of Formula (I) until the patient becomes intolerant, and then orally administering once daily 10 mg of the compound of Formula (I).

104. The method of claim 103, wherein the patient becomes intolerant when the patient experiences headache, hyperkeratosis, rash, infection, pneumonia, dyspnea, hemoptysis, periodontal disease, arthralgia, fatigue, nasopharyngitis, cough, dermatitis contact, pain, and / or dry skin.

105. The method of claim 104, wherein hyperkeratosis comprises a skin lesion, eczema, hyperkeratosis, keratosis pilaris, exfoliative rash, and / or seborrheic keratosis.

106. The method of any one of claims 103-105, wherein the patient returns to administering once daily 25 mg of the compound of Formula (I) when the headache, hyperkeratosis, rash, and / or dry skin subside.

107. The method of any one of claims 85-106, wherein the treating comprises achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1.Attorney Docket No. INMD-215 / 03WO 315953-4453 108. The method of any one of claims 85-107, wherein the treating comprises achieving a median time to first PE of about 40 weeks to about 50 weeks.

109. The method of any one of claims 85-108, wherein the treating comprises reducing the decline in the patient’s post-bronchodilator FEV1 during or subsequent to the administration period by about 11 mL to about 50 mL.

110. The method of any one of claims 85-109, wherein the treating comprises achieving an annualized rate of severe PE of about 0.10 to about 0.

17.

111. The method of any one of claims 85-110, wherein the treating comprises two or more of (i) achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1, (ii) achieving a median time to first PE of about 40 weeks to about 50 weeks, (iii) reducing the decline in the patient’s post-bronchodilator FEV1 during or subsequent to the administration period by about 11 mL to about 50 mL, and (iv) achieving an annualized rate of severe PE of about 0.10 to about 0.

17.

112. The method of any one of claims 85-111, wherein the treating comprises three or more of (i) achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1, (ii) achieving a median time to first PE of about 40 weeks to about 50 weeks, (iii) reducing the decline in the patient’s post-bronchodilator FEV1 during or subsequent to the administration period by about 10 mL to about 50 mL, and (iv) achieving an annualized rate of severe PE of about 0.10 to about 0.

17.

113. The method of any one of claims 85-112, wherein the treating comprises (i) achieving an annualized rate of pulmonary exacerbations (PE) of about 1.0 to about 1.1, (ii) achieving a median time to first PE of about 40 weeks to about 50 weeks, (iii) reducing the decline in the patient’s post-bronchodilator FEV1during or subsequent to the administration period by about 10 mL to about 50 mL, and (iv) achieving an annualized rate of severe PE of about 0.10 to about 0.

17.

114. The method of any one of claims 85-113, wherein the treating comprises reducing the decline in the patient’s post-bronchodilator FEV1 during or subsequent to the administration period by at least about 11 mL to about 50 mL.

115. The method of claim 114, wherein the treating comprises reducing the decline in the patient’s post-bronchodilator FEV1during or subsequent to the administration period by about 11 mL to about 40 mL.Attorney Docket No. INMD-215 / 03WO 315953-4453 116. The method of any one of claims 85-115, wherein the treating comprises increasing the time to the first PE after starting the administration period by at least 15%, as compared to the the time to the first PE experienced by an untreated bronchiectasis patient.

117. The method of any one of claims 85-116, wherein the treating comprises increasing the time to the first PE after starting the administration period by 15% to 30%.

118. The method of any one of claims 85-117, wherein the treating comprises increasing the patient’s odds of remaining free of PEs during the administration period by at least about 40%.

119. The method of any one of claims 81-118, wherein the treating comprises increasing the patient’s odds of remaining free of PEs during the administration period by about 40% to about 50%.

120. The method of any one of claims 1-119, wherein the patient experienced at least one PE in a 12 month period immediately preceding the administration period.

121. The method of any one of claims 1-119, wherein the patient experienced at least 2 PEs in a 12 month period immediately preceding the administration period.

122. The method of claim 120, wherein the patient received antibiotic treatment during the 12 month period immediately preceeding the administration period.

123. The method of any one of claims 1-122, wherein the patient is an adult patient.

124. The method of any one of claims 1-123, wherein the patient is a pediatric patient.

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