Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

• Cystic fibrosis an autosomal recessive disorder, is a disease of exocrine gland function that involves multiple organ systems, but primarily results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications.
• CFTR CF transmembrane conductance regulator
• Pulmonary outcomes are a key measure of CF health. Pulmonary exacerbations (PEs) that require intravenous antibiotic treatment in the hospital or at home, are associated with morbidity, mortality, and decreased quality of life. Uncontrolled PEs often result in prolong hospitalization and consequently permanent damage to the lung which manifests as lung function decline.
• PEs Pulmonary exacerbations
• CF chronic lung disease
• Currently available pharmacologic treatment for CF PEs includes inhaled antibiotics (tobramycin, aztreonam, and colistin), inhaled corticosteroids, leukotriene modifiers, and inhaled beta agonists.
• a method for treating a CF patient is provided.
• the method comprises, in one embodiment, administering to a patient in need of treatment, for an administration period, a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I): wherein, R 2 is hydrogen, F, Cl, Br, OSO 2 C 1 - 3 alkyl, or C 1 - 3 alkyl; R 3 is hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1-3 alkyl, CONH2 or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; X is O, S or CF 2 ; Y is O or S; Q is CH or N; R 6 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC 1 - 3 alkyl, N(C
• the treating comprises (i) improving the lung function of the patient, as compared to the lung function of the patient prior to the administration period; (ii) improving the patient’s quality of life (QOL) assessed by the cystic fibrosis questionnaire-revised (CFQ-R), as compared to the patient’s QOL prior to the administration period; or (iii) both (i) and (ii).
• the compound of Formula (I) is an S,S diastereomer.
• the compound of Formula (I) has the following stereochemistry: [00012] The other diastereomeric forms are also contemplated by the present invention.
• the compound of Formula (I) is the R,R diastereomer: [00013]
• the compound of Formula (I) is the R,S diastereomer: [00014]
• the compound of Formula (I) is the S,R diastereomer: [00015]
• the pharmaceutical composition comprises an effective amount of (2S)-N- ⁇ (1S)-1- cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane- 2-carboxamide, referred to herein by its international nonproprietary name (INN), brensocatib (and formerly known as INS1007 and AZD7986), or a pharmaceutically acceptable salt thereof.
• INN international nonproprietary name
• brensocatib and formerly known as INS1007 and AZD7986
• the pharmaceutical composition comprises an effective amount of (2S)-N- ⁇ (1R)-l- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane- 2-carboxamide: [00017] or a pharmaceutically acceptable salt thereof.
• the pharmaceutical composition comprises an effective amount of (2R)-N- ⁇ (1S)-l- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane- 2-carboxamide: [00019] or a pharmaceutically acceptable salt thereof.
• the pharmaceutical composition comprises an effective amount of (2R)-N- ⁇ (1R)-l- Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane- 2-carboxamide: [00021] or a pharmaceutically acceptable salt thereof.
• the patient is administered the composition once daily.
• the patient is administered the composition twice daily, or every other day, or once a week.
• Administration in one embodiment, is via the oral route.
• treating comprises improving the lung function of the patient.
• the improvement in the patient’s lung function in one embodiment, comprises increasing the patient’s forced expiratory volume in one second (FEV1), as compared to the patient’s FEV1 prior to the administration period.
• the increase in FEV1 is an increase in pre-bronchodilator FEV1.
• the increase in FEV1 is an increase in post-bronchodilator FEV1.
• the patient’s FEV1 is increased by about 5%, by about 10%, by about 15%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, or by about 50%. In another embodiment, the patient’s FEV 1 is increased by at least about 5%, by at least about 10%, by 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%.
• the patient’s FEV 1 is increased 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%.
• the patient’s FEV 1 is increased about 25 mL to about 500 mL, or about 25 mL to about 250 mL.
• the improvement in the lung function of the patient comprises increasing the patient’s percent predicted forced expiratory volume in one second (ppFEV1) compared to the patient’s ppFEV1 prior to the administration period.
• the increase in ppFEV1 is an increase in pre-bronchodilator ppFEV1.
• the increase in ppFEV 1 is an increase in post-bronchodilator ppFEV 1 .
• the patient’s ppFEV1 is increased by about 1%, 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%, by 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%.
• the patient’s ppFEV 1 is increased by at least about 5%, by at least about 10%, by 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%.
• the patient’s ppFEV 1 is increased 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%.
• the patient’s ppFEV 1 is about 40% or more (e.g., from about 40% to about 90%) prior to the administration period.
• the improvement in the lung function of the patient comprises increasing the patient’s forced vital capacity (FVC), as compared to the patient’s FVC prior to the administration period.
• FVC forced vital capacity
• the increase in FVC is an increase in pre-bronchodilator FVC.
• the increase in FVC is an increase in post- bronchodilator FVC.
• the patient’s FVC is increased by about 1%, 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%, by 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%,.
• the patient’s FVC is increased by at least about 5%, by at least about 10%, by 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%.
• the patient’s FVC is increased 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%.
• improving the lung function of the patient comprises increasing the patient’s forced expiratory flow between 25% and 75% of FVC (FEF (25-75%) ), as compared to the patient’s FEF(25-75%) prior to the administration period.
• FEF(25-75%) is an increase in pre-bronchodilator FEF(25-75%).
• FEF (25-75%) is an increase in post-bronchodilator FEF (25-75%) .
• the patient’s FEF (25-75%) is increased by about 1%, 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%, by 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%.
• the patient’s FEF (25-75%) is increased by at least about 5%, by at least about 10%, by 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%.
• the patient’s FEF (25-75%) is increased 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%.
• improving the lung function of the patient comprises increasing the patient’s peak expiratory flow rate (PEFR), as compared to the patient’s PEFR prior to the administration period.
• PEFR peak expiratory flow rate
• the increase in PEFR is an increase in pre-bronchodilator PEFR.
• the increase in PEFR is an increase in post- bronchodilator PEFR.
• the patient’s PEFR is increased by about 1%, 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%, by 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%.
• the patient’s PEFR is increased by at least about 5%, by at least about 10%, by 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%.
• the patient’s PEFR is increased 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%.
• a patient in need of treatment is administered a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for an administration period.
• the treating comprises improving the patient’s quality of life (QOL) assessed by the cystic fibrosis questionnaire-revised (CFQ-R), as compared to the patient’s QOL assessed by the CFQ-R prior to the administration period.
• the QOL is assessed by a respiratory domain score of the CFQ-R.
• a patient in need of treatment is administered a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for an administration period, and the treating comprises decreasing the sputum and/or blood concentration of an active neutrophil serine protease (NSP) in the patient, as compared to the patient’s active NSP sputum and/or blood concentration prior to the administration period.
• NSP active neutrophil serine protease
• the patient’s active NSP sputum and/or blood concentration is decreased by about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%, 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%, at least about 70%, or at least about 80%.
• the active NSP is active neutrophil elastase (NE).
• the active NSP is active proteinase 3 (PR3).
• the active NSP is active cathepsin G (CatG).
• a patient in need of treatment is administered a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for an administration period, and the treating comprises decreasing a bacterial infection in the lung of the patient, as compared to the bacterial infection in the lung of the patient prior to the administration period.
• the bacterial infection comprises a Pseudomonas infection, e.g., Pseudomonas aeruginosa infection.
• the bacterial infection comprises Staphylococcus aureus infection.
• the Staphylococcus aureus infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection.
• decreasing the bacterial infection in the lung of the patient comprises decreasing a number of colony forming units (CFUs) of the bacteria present in the patient’s sputum, as compared to a number of CFUs of the bacteria present in the patient’s sputum prior to the administration period.
• the number of CFUs of the bacteria present in the treated patient’s sputum is decreased about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.
• the number of CFUs of the bacteria present in the treated patient’s sputum is decreased 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%, at least about 80%, or at least about 90%.
• the number of CFUs of the bacteria present in the treated patient’s sputum is decreased 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%.
• a patient in need of treatment is co-administered an antibiotic together with a compound of Formula (I) or its pharmaceutically acceptable salt.
• the antibiotic is selected from the group consisting of an aminoglycoside, aztreonam, a carbapenem, a cephalosporin, clofazimine, colistimethate, ethambutol, a lincosamide, a macrolide, an oxazolidinone, a penicillin, a quinolone, a rifamycin, a sulfa, a tetracycline, vancomycin, and a combination thereof.
• the antibiotic is selected from the group consisting of amikacin, aztreonam, colistimethate, gentamicin, tobramycin, or a combination thereof.
• the antibiotic is administered to the patient via inhalation.
• a patient in need of treatment is co-administered a cystic fibrosis transmembrane conductance regulator (CFTR) modulator together with a compound of Formula (I) or its pharmaceutically acceptable salt.
• CFTR cystic fibrosis transmembrane conductance regulator
• the patient has not previously been treated with a CFTR modulator.
• the CFTR modulator is one selected from the group consisting of ivacaftor, lumacaftor, tezacaftor, elexacaftor, and a combination thereof.
• a patient in need of treatment has previously been treated with a cystic fibrosis transmembrane conductance regulator (CFTR) modulator.
• the method of treating CF comprises administering the CFTR modulator to the patient, together with an effective amount of a compound of Formula (I).
• the CFTR modulator is one selected from the group consisting of ivacaftor, lumacaftor, tezacaftor, elexacaftor, and a combination thereof.
• a patient in need of treatment has not previously been treated with a CFTR modulator.
• a patient previously untreated with a CFTR modulator is administered a composition comprising an effective amount of a compound of Formula (I) as monotherapy, i.e., the method excludes administering a CFTR modulator to the patient.
• the present disclosure provides the diastereomers of brensocatib disclosed herein, i.e., (2R)-N- ⁇ (1R)-l-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro- 1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane-2-carboxamide (i.e., the R,R isomer), (2S)- N- ⁇ (1R)-l-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4- oxazepane-2-carboxamide (i.e., the S,R isomer), and (2R)-N- ⁇ (1S)-l-Cyano-2-[4-(3-methyl-2- oxo-2
• the mixture comprises brensocatib, or a pharmaceutically acceptable salt thereof, and the R,R isomer, or a pharmaceutically acceptable salt thereof.
• the mixture comprises brensocatib, or a pharmaceutically acceptable salt thereof, and the S,R isomer, or a pharmaceutically acceptable salt thereof.
• the mixture comprises brensocatib, or a pharmaceutically acceptable salt thereof, and the R,S isomer, or a pharmaceutically acceptable salt thereof.
• 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 (PR3), and cathepsin G (CatG).
• NSPs neutrophil serine proteases
• NE neutrophil elastase
• PR3 proteinase 3
• CatG 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. [00039] The three NSPs, abundantly secreted into the extracellular environment upon neutrophil activation at inflammatory sites, are thought to act in combination with reactive oxygen species to assist in degradation of engulfed microorganisms inside phagolysosomes.
• a fraction 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. 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.
• Cystic fibrosis is caused by abnormalities in the CF transmembrane conductance regulator protein, causing chronic lung infections (particularly with Pseudomonas aeruginosa) and excessive inflammation, and leading to bronchiectasis, declining lung function, respiratory insufficiency and quality of life.
• the inflammatory process is dominated by neutrophils that produce NE, as well as other destructive NSPs including CatG and PR3, that directly act upon extracellular matrix proteins and play a role in the host response to inflammation, P aeruginosa infection, and pathogenesis of mucus hypersecretion.
• the compounds of Formula (I), administered via the methods provided herein have beneficial effects via inhibiting the activation of NSPs and decreasing inflammation and mucus hypersecretion, which in turn leads to a decrease in pulmonary exacerbations, a decrease in the rate of pulmonary exacerbations, and/or an improvement in lung function (e.g., cough, sputum production, forced expiratory volume in 1 second [FEV 1 ]) in CF patients.
• lung function e.g., cough, sputum production, forced expiratory volume in 1 second [FEV 1 ]
• “C 1-3 ” means a carbon group having 1, 2 or 3 carbon atoms.
• alkyl 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.
• pharmaceutically acceptable 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.
• a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for an administration period: wherein, R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 alkyl, or C 1-3 alkyl; R 3 is hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1 - 3 alkyl, CONH 2 or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; X is O, S or CF 2 ; Y is O or S; Q is CH or N; R 6 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH,
• the compound of Formula (I) is an S,S diastereomer.
• the compound of Formula (I) has the following stereochemistry: [00048] The other diastereomeric forms are also contemplated by the present invention.
• the compound of Formula (I) is the R,R diastereomer: [00049]
• the compound of Formula (I) is the R,S diastereomer: [00050]
• the compound of Formula (I) is the S,R diastereomer: [00051]
• the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an S,R diastereomer of a compound of Formula (I).
• the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an R,S diastereomer of a compound of Formula (I).
• the composition comprises a mixture of an S,S diastereomer of a compound of Formula (I) and an R,R diastereomer of a compound of Formula (I).
• R 1 is 2 ;
• R is hydrogen, F, Cl, Br, OSO 2 C 1- 3alkyl, or C 1-3 alkyl;
• R 3 is hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1-3 alkyl, CONH2 or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring.
• R 2 is hydrogen, F, Cl or C 1-3 alkyl
• R 3 is hydrogen, F, Cl, CN or SO 2 C 1-3 alkyl.
• R 3 is hydrogen, F or CN.
• R 1 is is O, S or CF2
• Y is O or S
• Q is CH or N
• R 6 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally substituted by OH, OC 1-3 alkyl, N(C 1-3 alkyl)2, cyclopropyl, or tetrahydropyran
• R 7 is hydrogen, F, Cl or CH 3 .
• R 1 is X is O, S or CF 2 ; Y is O or S; R 6 is C 1-3 alkyl, optionally substituted by 1, 2 or 3 F and optionally substituted by OH, OC 1-3 alkyl, N(C 1-3 alkyl)2, cyclopropyl, or tetrahydropyran; and R 7 is hydrogen, F, Cl or CH 3 .
• R 1 is [00057] In another embodiment, R 1 is ; X is O, S or CF2; R 6 is C1- 3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F; and R 7 is hydrogen, F, Cl or CH 3 . [00058] In another embodiment, R 1 is 6 ; X is O; R is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F; and R 7 is hydrogen. In a further embodiment, R 6 is C 1-3 alkyl, i.e., methyl, ethyl, or propyl. In still a further embodiment, R 6 is methyl.
• R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 alkyl or C 1-3 alkyl.
• R 2 is hydrogen, F, Cl or C 1-3 alkyl.
• R 2 is hydrogen, F or C 1-3 alkyl.
• R 3 is hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1-3 alkyl CONH2 or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring.
• R 3 is hydrogen, F, Cl, CN or SO 2 C 1-3 alkyl. [00064] In still a further embodiment, R 3 is hydrogen, F or CN. [00065] In one embodiment, R 6 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC 1-3 alkyl, N(C 1- 3alkyl)2, cyclopropyl, or tetrahydropyran. [00066] In a further embodiment, R 6 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F.
• R 6 is methyl or ethyl. In still a further embodiment, R 6 is methyl.
• R 7 is hydrogen, F, Cl or CH 3 . In a further embodiment R 7 is hydrogen.
• 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 pharmaceutically acceptable salt thereof.
• the compound of Formula (I) is brensocatib.
• the compound of Formula (I) is: [00070] (2S)-N-[(1S)-1-Cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2- carboxamide, [00071] (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, [00072] (2S)-N- ⁇ (1S)-1-Cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol- 5-yl)phenyl]ethyl ⁇ -1,4-oxa
• the compound of Formula (I) is brensocatib.
• brensocatib is in polymorphic Form A as disclosed in U.S. Patent No.9,522,894, the disclosure of which is incorporated herein by reference in its entirety for all purposes.
• brensocatib is characterized by an X-ray powder diffraction pattern having a peak at about 12.2 ⁇ 0.2 (°2-WKHWD ⁇ PHDVXUHG ⁇ XVLQJ ⁇ &X. ⁇ UDGLDWLRQ ⁇ ,Q ⁇ some embodiments, brensocatib is characterized by an X-ray powder diffraction pattern having a peak at about 20.6 ⁇ 0.2 (°2-WKHWD ⁇ PHDVXUHG ⁇ XVLQJ ⁇ &X. ⁇ UDGLDWLRQ ⁇ ⁇ ,Q ⁇ some embodiments, brensocatib is characterized by an X-ray powder diffraction pattern having a peak at about 12.2 ⁇ 0.2 and about 20.6 ⁇ 0.2 (°2-WKHWD ⁇ PHDVXUHG ⁇ XVLQJ ⁇ &X. ⁇ UDGLDWLRQ ⁇ ⁇ ,Q ⁇ some embodiments, brensocatib is characterized by an X-ray powder diffraction pattern having
• 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 H 2 O, 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).
• 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.
• pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.
• 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).
• 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).
• 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, even though the compound of Formula (I), in its preferred form, has S,S stereochemistry.
• the backbone of the compounds of Formula (I) has two chiral centers. Chiral center 1 is the most substituted carbon atom on the 1,4-oxazepane ring.
• Chiral center 2 is the substituted carbon atom to which a cyano group, -NH-, and a benzyl group are attached.
• the present disclosure encompasses the compounds of Formula (I) with the (S)- configuration for the ring substituent at chiral center 1 and the (S)-configuration for the benzyl substituent at chiral center 2 (i.e., the S,S diastereomer disclosed herein); the (S)-configuration for the ring substituent at chiral center 1 and the (R)-configuration for the benzyl substituent at chiral center 2 (i.e., the S,R diastereomer disclosed herein); the (R)-configuration for the ring substituent at chiral center 1 and the (S)-configuration for the benzyl substituent at chiral center 2 (i.e., the R,S diastereomer disclosed herein); and the (R)-configuration for the ring substituent at chiral center 1 and the (R)-configuration for the benzyl substituent at chiral center 2 (i.e., the R,R diastereomer disclosed herein);
• the compound of Formula (I) is (2S)-N- ⁇ (1S)- 1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4- oxazepane-2-carboxamide (i.e., brensocatib, the S,S isomer), shown below. O or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) is (2R)-N- ⁇ (1R)-l-Cyano-2- [4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane-2- carboxamide (i.e., the R,R isomer), shown below. or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) is (2S)-N- ⁇ (1R)-l-Cyano-2- [4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane-2- carboxamide (i.e., the S,R isomer), shown below. or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) is (2R)-N- ⁇ (1S)-l-Cyano-2- [4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane-2- carboxamide (i.e., the R,S isomer), shown below. or a pharmaceutically acceptable salt thereof.
• the composition comprises a mixture of two or more of the aforementioned stereoisomers.
• the mixture in one embodiment, comprises the S,S isomer (brensocatib) and the S,R isomer of a compound of Formula (I).
• composition comprises a mixture of the S,S isomer (brensocatib) and the R,S isomer. In yet another embodiment, the composition comprises a mixture of the S,S isomer (brensocatib) and the R,R isomer.
• Certain 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 present disclosure encompasses all such isomers. Certain compounds of Formula (I) may also contain multiple tautomeric forms.
• the compounds of Formula (I) encompass any isotopically-labeled (or “radio-labelled”) derivatives of a compound of Formula (I).
• 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 include 2 H (also written as “D” for deuterium).
• 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 CF.
• 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).
• prodrugs include in vivo hydrolysable esters of a compound of the Formula (I).
• An in vivo hydrolysable (or cleavable) ester of a compound of 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.
• ester prodrugs derivatives see: Curr. Drug. Metab. 2003, 4, 461, incorporated by reference herein in its entirety for all purposes.
• Various other forms of prodrugs are known in the art, and can be used in the methods provided herein.
• 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.
• the methods provided herein comprise the administration of a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a CF patient in need of treatment.
• the compounds of Formula (I) and their pharmaceutically acceptable salts are reversible inhibitors of dipeptidyl peptidase 1 (DPP1) activity.
• Administration routes include oral administration.
• Administration schedules and administration periods can be determined by the user of the method, e.g., a prescribing physician. In one embodiment, administration is once daily. In another embodiment, administration is twice daily. In another embodiment, administration is every other day, every third day, 3 ⁇ per week or 4 ⁇ per week.
• a method for treating CF comprising administering to a patient in need thereof, a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the compound is administered orally, once daily.
• the method comprises improving the lung function of the patient, as compared to the lung function of the patient prior to the administration period.
• the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
• the improvement in lung function in one embodiment, is measured by spirometry.
• Improving the lung function of the patient comprises increasing the patient’s forced expiratory volume in 1 second (FEV 1 ), increasing the patient’s percentage of the predicted FEV1 (ppFEV1), increasing the patient’s forced vital capacity (FVC), increasing the patient’s peak expiratory flow rate (PEFR), and/or increasing the patient’s forced expiratory flow between 25% and 75% of FVC (FEF (25-75%) ), as compared to the respective value prior to the administration period.
• Increasing, in one embodiment, is by about 5%, by about 10%, by 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 value.
• Increasing, in one embodiment, is by at least about 5%, by at least about 10%, by 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%.
• the increasing 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%.
• increasing is 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%.
• the assessment of lung function comprises comparing the lung function in the patient prior to the administration period, e.g., immediately prior to treatment, to a time point during the administration period, to an average of measurements taken during the administration period, or subsequent to the administration period.
• treatment via a method of the invention 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.
• pulmonary function test by spirometry (e.g., FEV 1 , FVC, PEFR, and FEF(25-75%) 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).
• ATS American Thorasic Society
• ERS European Respiratory Society
• the spirometer is capable of accumulating volume for JUHDWHU ⁇ WKDQ ⁇ RU ⁇ HTXDO ⁇ WR ⁇ ⁇ VHFRQGV ⁇ H ⁇ J ⁇ ⁇ ⁇ VHFRQGV ⁇ VHFRQGV ⁇ VHFRQGV ⁇ 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 .
• the total resistance to airflow of the spirometer at 14 L•s -1 is ⁇ 1.5 cmH2O•L -1 •s -1 (0.15 kPa?
• 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.
• 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.
• BTPS body temperature, ambient pressure, saturated with water vapor
• 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.
• 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).
• FVC forced vital capacity
• BTPS water vapor
• improving the patient’s lung function comprises increasing the patient’s FVC, compared to the patient’s FVC prior to the administration period.
• 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 the patient’
• the FVC of a treated patient is greater by at least about 5%, by at least about 10%, by 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 the patient’s FVC prior to the administration period.
• the FVC of a treated patient is greater 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 the patient’s FVC prior to the administration period.
• the increase in FVC is an increase in pre-bronchodilator FVC. In another embodiment, the increase in FVC is an increase in post-bronchodilator FVC.
• 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.
• TLC total lung capacity
• 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.
• the improvement in lung function in one embodiment, is an improvement compared to lung function immediately prior to the administration period.
• FEV is the volume of gas exhaled in a specified time (typically 1 second, i.e., FEV1) from the start of the forced vital capacity maneuver (Quanjer et al. (1993). Eur. Respir. J. 6, Suppl. 16, pp. 5-40, incorporated by reference herein in its entirety for all purposes).
• FEV 1 may also be expressed as a percentage of the predicted FEV1 (i.e., ppFEV1) obtained from a normal population, based on the patient’s gender, height, and age, and sometimes race and weight.
• the increase in FEV 1 in one embodiment, is an increase of at least about 5%, for example, about 5% to about 50%, about 10% to about 50%, or about 15% to about 50%.
• the FEV1 of the 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%, compared to the patient’s FEV1 prior to the administration period.
• the increase in FEV1 is an increase in pre-bronchodilator FEV1. In another embodiment, the increase in FEV1 is an increase in post-bronchodilator FEV 1 . [000137] In another embodiment, improving the lung function of the patient comprises increasing the patient’s FEV1 about 25 mL to about 500 mL, or about 25 mL to about 250 mL, or about 50 mL to about 200 mL, as compared to the patient’s FEV 1 prior to the administration period. In one embodiment, the increase in FEV 1 is an increase in pre-bronchodilator FEV 1 . In another embodiment, the increase in FEV1 is an increase in post-bronchodilator FEV1.
• improving the lung function of the patient comprises increasing the patient’s ppFEV 1 compared to the patient’s ppFEV 1 prior to the administration period.
• the increase in ppFEV1 in one embodiment, is an increase of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.
• the increase in ppFEV 1 is an increase of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.
• the increase in ppFEV1 is an increase of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%.
• the increase in ppFEV1 is an increase of about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.
• the increase in ppFEV1 is an increase in pre-bronchodilator ppFEV 1 . In another embodiment, the increase in ppFEV 1 is an increase in post-bronchodilator ppFEV 1 .
• the patient’s ppFEV1 is about 40% or greater prior to the administration period. In another embodiment, the patient’s ppFEV 1 is about 50% or greater prior to the administration period. In another embodiment, the patient’s ppFEV 1 is about 60% or greater prior to the administration period. In another embodiment, the patient’s ppFEV1 is about 70% or greater prior to the administration period. In one embodiment, the patient’s ppFEV 1 is from about 40% to about 90% prior to the administration period.
• the patient’s ppFEV1 is from about 40% to about 80% prior to the administration period. In another embodiment, the patient’s ppFEV1 is from about 50% to about 80% prior to the administration period. In another embodiment, the patient’s ppFEV 1 is from about 50% to about 70% prior to the administration period.
• Oxygen saturation is an indication of how much hemoglobin in the blood is bound to oxygen, and is typically provided as a percentage of oxyhemoglobin to the total hemoglobin.
• Saturation of peripheral capillary oxygenation (SpO 2 ) is an indication of oxygen saturation in the peripheral capillaries. Exemplary methods to measure SpO 2 include, but are not limited to, pulse oximetry using a pulse oximeter.
• the patient’s SpO2 on room air is greater than about 90% prior to the administration period. In another embodiment, the patient’s SpO 2 on room air is greater than about 92% prior to the administration period. In another embodiment, the patient’s SpO2 on room air is greater than about 95% prior to the administration period. [000142] In one embodiment, improving the lung function of the patient comprises increasing the mean forced expiratory flow between 25% and 75% of FVC (FEF(25–75%)) (also referred to as the maximum mid-expiratory flow) of the patient, as compared to the patient’s FEF (25–75%) prior to the administration period.
• the increase in FEF is an increase of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.
• the increase in FEF(25–75%) is an increase of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. In another embodiment, the increase in FEF (25– 75%) is an increase of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%.
• the increase in FEF (25–75%) is an increase of about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.
• the increase in FEF (25–75%) is an increase in pre- bronchodilator FEF(25–75%).
• the increase in FEF(25–75%) is an increase in post-bronchodilator FEF(25–75%).
• the measurement is dependent on the validity of the FVC measurement and the level of expiratory effort.
• the FEF (25-75%) index is taken from the blow with the largest sum of FEV1 and FVC.
• improving the lung function of the patient comprises increasing the peak expiratory flow rate (PEFR) of the patient.
• the increasing is an increase compared to the patient’s PEFR immediately prior to the administration period.
• the PEFR measures the fastest rate of air that can be expired by a subject.
• 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%.
• the PEFR of a treated patient is greater by at least about 5%, by at least about 10%, by 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%.
• the PEFR of a treated patient is greater 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%.
• the increase in PEFR is an increase in pre- bronchodilator PEFR.
• the increase in PEFR is an increase in post- bronchodilator PEFR.
• a method for treating CF comprising administering a composition comprising an effective amount of a compound of Formula (I) to a patient in need thereof, wherein treating comprises improving the quality of life (QOL) of the patient assessed by the cystic fibrosis questionnaire-revised (CFQ-R), as compared to the quality of life of the patient prior to the administration period, e.g., a baseline value.
• the QOL is assessed by a respiratory domain score of the CFQ- R.
• the compound is administered orally, once daily.
• the compound of Formula (I) in one embodiment, is brensocatib, or a pharmaceutically acceptable salt thereof.
• the Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a disease-specific validated instrument for assessing health-related quality of life (HRQOL) in children, adolescents and adults with cystic fibrosis (CF). It is a profile measure of HRQOL with 9 QOL domains (Physical Functioning, Vitality, Emotional State, Social Limitations, Role Limitations/School Performance, Embarrassment, Body Image, Eating Disturbances, Treatment Constraints) that assess the impact of CF on overall health, daily life, and perceived well-being. There are 3 symptom scales: weight, respiratory, and digestion.
• a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a patient in need thereof, wherein treating further comprises decreasing a sputum concentration of an active NSP in the patient, as compared to the patient’s active NSP sputum concentration, prior to the administration period.
• the compound of Formula (I) is administered via oral administration.
• administration is 1 ⁇ daily, every other day, 2 ⁇ weekly, 3 ⁇ weekly or 4 ⁇ weekly.
• administration is 1 ⁇ daily.
• the compound of Formula (I) in one embodiment is brensocatib , or a pharmaceutically acceptable salt thereof.
• the active NSP is active NE. In another embodiment, the active NSP is active PR3. In another embodiment, the active NSP is active CatG. [000146] Decreasing the patient’s active NSP sputum concentration, in one embodiment, comprises decreasing by about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%. In another embodiment, decreasing the patient’s active NSP sputum concentration comprises decreasing 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%. In one embodiment, the active NSP is active NE.
• the active NSP is active PR3. In another embodiment, the active NSP is active CatG.
• a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a patient in need thereof, wherein treating further comprises decreasing a concentration of an active NSP in the blood of the patient, as compared to the patient’s active NSP blood concentration, prior to the administration period.
• the compound of Formula (I) is administered via oral administration.
• administration is 1 ⁇ daily, every other day, 2 ⁇ weekly, 3 ⁇ weekly or 4 ⁇ weekly.
• administration is 1 ⁇ daily.
• the compound of Formula (I) in one embodiment, is brensocatib, or a pharmaceutically acceptable salt thereof.
• the active NSP is active NE.
• the active NSP is active PR3.
• the active NSP is active CatG. [000148] Decreasing the patient’s active NSP blood concentration, in one embodiment, comprises decreasing by about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%.
• decreasing the patient’s active NSP blood concentration comprises decreasing 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%.
• the active NSP is active NE.
• the active NSP is active PR3.
• the active NSP is active CatG. [000149] CF patients likely develop bacterial infections in the lungs due to the buildup of thick, sticky mucus in the lungs.
• Bacteria causing the infections include, but are not limited to, Achromobacter xylosoxidans, Burkholderia cepacian, Haemophilus influenzae, nontuberculous mycobacteria (NTM) (e.g., Mycobacterium abscessus, and Mycobacterium avium complex (MAC)), Pseudomonas (e.g., P. aeruginosa), Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), and Stenotrophomonas maltophilia.
• Achromobacter xylosoxidans e.g., Burkholderia cepacian
• Haemophilus influenzae e.g., Haemophilus influenzae
• NTM nontuberculous mycobacteria
• MAC Mycobacterium avium complex
• Pseudomonas e.g., P. aeruginosa
• a method for treating CF comprising administering a composition comprising an effective amount of a compound of Formula (I) to a patient in need thereof, wherein treating further comprises decreasing a bacterial infection in the lung of the patient, as compared to the bacterial infection in the lung of the patient prior to the administration period.
• the compound is administered orally, once daily.
• the compound of Formula (I) in one embodiment, is brensocatib, or a pharmaceutically acceptable salt thereof.
• the bacterial infection comprises a Pseudomonas infection, e.g., Pseudomonas aeruginosa infection.
• the bacterial infection comprises Staphylococcus aureus infection.
• the Staphylococcus aureus infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection.
• MRSA methicillin-resistant Staphylococcus aureus
• the bacterial infection comprises Haemophilus influenzae infection.
• the bacterial infection comprises Stenotrophomonas maltophilia infection.
• the bacterial infection comprises Burkholderia cepacia complex infection.
• the bacterial infection comprises Burkholderia cenocepacia infection.
• decreasing the bacterial infection in the lung of the patient comprises decreasing a number of colony forming units (CFUs) of the bacteria present in the patient’s sputum, as compared to a number of CFUs of the bacteria present in the patient’s sputum prior to the administration period.
• the number of CFUs of the bacteria present in the treated patient’s sputum is decreased about 1%, about 5%, about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.
• the number of CFUs of the bacteria present in the treated patient’s sputum is decreased 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%, at least about 80%, or at least about 90%.
• the number of CFUs of the bacteria present in the treated patient’s sputum is decreased 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%.
• the methods provided herein comprise co-therapy with an antibiotic.
• the patient administered the antibiotic in combination with a compound of Formula (I) or its pharmaceutically acceptable salt has not previously been treated with the antibiotic.
• the patient may have previously been treated with the antibiotic.
• the antibiotic may be adminstered to the patient via oral administration, intravenous administration, intramuscular administration, topical administration, or inhalation.
• the antibiotic is selected from the group consisting of an aminoglycoside, aztreonam, a carbapenem, a cephalosporin, clofazimine, colistimethate, ethambutol, a lincosamide, a macrolide, an oxazolidinone, a penicillin, a quinolone, a rifamycin, a sulfa, a tetracycline, vancomycin, and a combination thereof.
• the antibiotic is selected from the group consisting of amikacin, aztreonam, colistimethate, gentamicin, tobramycin, or a combination thereof.
• amikacin (Arikayce®), aztreonam, colistimethate (Colistin®), gentamicin, tobramycin, or a combination thereof is administered to the patient via inhalation.
• the antibiotic may be administered concurrently, sequentially or in admixture with a compound of Formula (I) or its pharmaceutically acceptable salt.
• the patient has previously been treated with a cystic fibrosis transmembrane conductance regulator (CFTR) modulator.
• the methods provided herein comprise co-therapy with a CFTR modulator.
• the patient administered co-therapy may be CFTR modulator treatment na ⁇ ve, i.e., may never have received the CFTR modulator.
• the patient may have previously been treated with a CFTR modulator.
• CFTR modulators target the defects in CFTR caused by certain mutations in the CFTR gene.
• the CFTR modulator is ivacaftor, lumacaftor, tezacaftor, elexacaftor, or a combination thereof.
• the CFTR modulator may be administered concurrently, sequentially or in admixture with a compound of Formula (I) or its pharmaceutically acceptable salt.
• the patient has not previously been treated with a CFTR modulator.
• the CFTR treatment na ⁇ ve patient is not administered a CFTR modulator.
• the dosage administered will vary with the compound of Formula (I) employed, the mode of administration, and the treatment outcome desired.
• the daily dosage of the compound of Formula (I), if inhaled may be in the range IURP ⁇ PLFURJUDPV ⁇ SHU ⁇ NLORJUDP ⁇ ERG ⁇ ZHLJKW ⁇ J ⁇ NJ ⁇ WR ⁇ PLFURJUDPV ⁇ SHU ⁇ NLORJUDP ⁇ ERG ⁇ ZHLJKW ⁇ ⁇ J ⁇ NJ ⁇ $OWHUQDWLYHO ⁇ in one embodiment, if the compound of Formula (I) is administered orally, then the daily dosage of the compound of the disclosure may be in the UDQJH ⁇ IURP ⁇ PLFURJUDPV ⁇ SHU ⁇ NLORJUDP ⁇ ERG ⁇ ZHLJKW ⁇ J ⁇ NJ ⁇ WR ⁇ PLOOLJUDPV ⁇ SHU ⁇ NLORJUDP ⁇ body weight (mg/kg).
• the daily dosage of the compound of Formula (I) is from about 5 mg to about 70 mg, from about 10 mg to about 40 mg, about 10 mg, about 25 mg, about 40 mg, or about 65 mg.
• the compound of Formula (I) is administered orally.
• the compound of Formula (I) is brensocatib , or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) is administered in an oral dosage form.
• the compound of Formula (I) is administered as a 5 mg to 70 mg, or 10 mg to 40 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, a 40 mg dosage form, or a 65 mg dosage form.
• the dosage form is 10 mg, 25 mg, or 40 mg or 65 mg.
• the dosage form is administered once daily.
• the compound is brensocatib, or a pharmaceutically acceptable salt thereof.
• Treating, in one embodiment, is carried out over an administration period of at least 1 month, from about 1 month to about 12 months, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, from about 6 months to about 24 months, from about 6 months to about 18 months, from about 6 months to about 15 months, about 15 months, about 18 months, about 21 months, about 24 months, from about 2 years to about 20 years, from about 5 years to about 15 years, from about 5 years to about 10 years, about 3 years, about 4 years, about 5 years, about 10 years, about 15 years, or about 20 years.
• 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 pharmaceutical ingredient (API)) is in a composition comprising a pharmaceutically acceptable adjuvant(s), diluents(s) and/or carrier(s).
• 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 Form Designs”, M. E. Aulton, Churchill Livingstone, 2 nd Ed. 2002, incorporated by reference herein in its entirety for all purposes.
• the pharmaceutical composition will comprise from about 0.05 to about 99 wt%, for example, from about 0.05 to about 80 wt%, or from about 0.10 to about 70 wt%, or from about 0.10 to about 50 wt%, of API, all percentages by weight being based on the total weight of the pharmaceutical composition. Unless otherwise provided herein, API weight percentages provided herein are for the respective free base form of the compound of Formula (I).
• the oral dosage form is a film-coated oral tablet.
• the dosage form is an immediate release dosage form with rapid dissolution characteristics under in vitro test conditions.
• the oral dosage form is administered once daily.
• the oral dosage form is administered at approximately the same time every day, e.g., prior to breakfast.
• the composition comprising an effective amount of Formula (I) is administered 2 ⁇ daily.
• the composition comprising an effective amount of Formula (I) is administered 1 ⁇ per week, every other day, every third day, 2 ⁇ per week, 3 ⁇ per week, 4 ⁇ per week, or 5 ⁇ per week.
• 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.
• adjuvant(s) for example, lactose, saccharose, sorbitol, mannitol
• starch for example, potato starch, corn starch or amylopectin
• cellulose derivative for example, gelatine or polyvinylpyrrolidone
• disintegrant for example cellulose derivative
• lubricant for example, magnesium stearate, calcium
• the cores may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s).
• the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
• 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-mentioned excipients for tablets.
• liquid or semisolid formulations of the compound of the disclosure may be filled into hard gelatine capsules.
• 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.
• the composition is an oral thin film or an oral disintegrating film (ODF).
• ODF oral disintegrating film
• 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.
• 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. [000167] In one embodiment of the methods, the pharmaceutical composition is one of the compositions described in International Application Publication No. WO 2019/166626, the disclosure of which is incorporated herein by reference in its entirety for all purposes.
• the pharmaceutical composition administered to the patient is Composition (A) comprising: (a) from about 1 to about 30 wt% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof; (b) from about 45 to about 85 wt% of a pharmaceutical diluent; (c) from about 6 to about 30 wt% of a compression aid; (d) from about 1 to about 15 wt% of a pharmaceutical disintegrant; (e) from about 0.00 to about 2 wt% of a pharmaceutical glidant; and (f) from about 1 to about 10 wt% of a pharmaceutical lubricant; wherein the components add up to 100 wt%.
• Composition (A) comprising: (a) from about 1 to about 30 wt% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof; (b) from about 45 to about 85 wt% of a pharmaceutical diluent; (c) from about 6 to about 30 wt% of a compression aid; (d) from
• the compound of Formula (I) is brensocatib.
• brensocatib is in polymorphic Form A.
• brensocatib is characterized by one of the X-ray powder diffraction patterns described above.
• Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount from about 1 to about 25 wt %; from about 1 to about 20 wt %; from about 1 to about 15 wt %; from about 1 to about 10 wt %; from about 1 to about 5 wt%, or from about 1 to about 3 wt % of the total weight of the composition.
• Formula (I) e.g., brensocatib
• Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount from about 1.5 to about 30 wt%; from about 1.5 to about 25 wt%; from about 1.5 to about 20 wt%; from about 1.5 to about 15 wt%; from about 1.5 to about 10 wt %; or from about 1.5 to about 5 wt% of the total weight of the composition.
• Formula (I) e.g., brensocatib
• Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount from about 3 to about 30 wt%; from about 3 to about 25 wt %; from about 3 to about 20 wt%; from about 3 to about 15 wt %; from about 3 to about 10 wt %; or from about 3 to about 5 wt% of the total weight of the composition.
• the compound of Formula (I) is present at from about 3 to about 10 wt % of the total weight of the composition.
• the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
• Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt% or about 30 wt% of the total
• Composition (A) comprises the compound of Formula (I), e.g., brensocatib, in an amount of about 5 mg to about 70 mg, or about 10 mg to about 40 mg, for example, 5 mg, 10 mg,15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 65 mg.
• Composition (A) comprises the compound of Formula (I) in an amount of 10 mg, 25 mg or 40 mg.
• the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
• Composition (A) comprises one or more pharmaceutical diluents selected from the group consisting of microcrystalline cellulose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose, xylitol, and a combination of the foregoing.
• pharmaceutical diluents selected from the group consisting of microcrystalline cellulose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin
• Composition (A) comprises two or more pharmaceutical diluents. In another embodiment, Composition (A) comprises one pharmaceutical diluent. In a further embodiment, the pharmaceutical diluent is microcrystalline cellulose. Microcrystalline cellulose is a binder/diluent in oral tablet and capsule formulations and can be used in dry-granulation, wet-granulation, and direct- compression processes.
• Composition (A) comprises one or more pharmaceutical diluents in an amount from about 45 to about 80 wt%, from about 45 to about 75 wt%, from about 45 to about 70 wt%, from about 45 to about 65 wt%, from about 45 to about 60 wt%, or from about 45 to about 55 wt% of the total weight of the composition.
• the one or more pharmaceutical diluents comprises microcrystalline cellulose.
• the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
• Composition (A) comprises one or more pharmaceutical diluents in an amount from about 50 to about 85 wt%, from about 50 to about 75 wt%, from about 55 to about 85 wt%, from about 55 to about 70 wt%, from about 60 to about 85 wt%, from about 65 to about 85 wt%, from about 70 to about 85 wt%, or from about 75 to about 85 wt% of the total weight of the composition.
• the one or more pharmaceutical diluents is present at from about 55 to about 70 wt% of the total weight of the composition.
• the one or more pharmaceutical diluents comprises microcrystalline cellulose.
• Composition (A) comprises one or more pharmaceutical diluents in an amount of about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt% or about 85 wt% of the total weight of the composition.
• the one or more pharmaceutical diluents in Composition (A) is microcrystalline cellulose.
• the one or more pharmaceutical diluents comprises calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose and xylitol.
• a disintegrant in the Composition (A) may be, for example: alginic acid, calcium alginate, carboxymethylcellulose calcium, chitosan, croscarmellose sodium, crospovidone, glycine, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose, sodium starch glycolate, starch, or a combination thereof.
• the one or more disintegrants in Composition (A) is sodium starch glycolate.
• the amount of the disintegrants present in Composition (A) is between 2% and 8% of the total weight of the composition. In a further embodiment, the amount of the disintegrants is about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt% or about 4.5 wt% of the total weight of the composition.
• the physical properties of sodium starch glycolate, and hence its effectiveness as a disintegrant, are affected by the degree of crosslinkage, extent of carboxymethylation, and purity.
• the one or more pharmaceutical disintegrants in Composition (A) comprises croscarmellose sodium.
• Composition (A) comprises one or more pharmaceutical disintegrants in an amount from about 2 to about 14 wt%, from about 2 to about 13 wt%, from about 2 to about 12 wt%, from about 2 to about 11 wt%, from about 2 to about 10 wt%, from about 2 to about 9 wt%, from about 2 to about 8 wt%, from about 2 to about 7 wt%, from about 2 to about 6 wt%, from about 2 to about 5 wt%, from about 3.5 to about 4.5 wt% of the total weight of the composition.
• the one or more pharmaceutical disintegrants is present at from about 3.5 to about 4.5 wt% of the total weight of the pharmaceutical composition.
• the one or more pharmaceutical disintegrants is sodium starch glycolate.
• the one or more pharmaceutical diluents comprises microcrystalline cellulose.
• the compound of Formula (I) is brensocatib, or a pharmaceutically acceptable salt thereof.
• a glidant in Composition (A) may be, for example: silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate and talc.
• the one or more pharmaceutical glidants in Composition (A) is selected from silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate, talc, or a combination of the foregoing.
• the glidant is silicon dioxide.
• Typical silicon dioxide concentrations for use herein range from about 0.05 to about 1.0 wt%.
• Porous silica gel particles may also be used as a glidant, which may be an advantage for some formulations, with typical concentrations of 0.25-1%.
• Composition (A) comprises one or more pharmaceutical glidants in an amount from about 0.00 to about 1.75 wt%; from about 0.00 to about 1.50 wt%; from about 0.00 to about 1.25 wt%; from about 0.00 to about 1.00 wt%; from about 0.00 to about 0.75 wt%; from about 0.00 to about 0.50 wt%; from about 0.00 to about 0.25 wt%; from about 0.00 to about 0.20 wt% of the total weight of the composition.
• the one or more pharmaceutical glidants comprises silicon dioxide.
• the one or more pharmaceutical disintegrants is sodium starch glycolate.
• Composition (A) comprises one or more pharmaceutical glidants in an amount from about 0.05 to about 2 wt%; from about 0.05 to about 1.75 wt%; from about 0.05 to about 1.50 wt%; from about 0.05 to about 1.25 wt%; from about 0.05 to about 1.00 wt%; from about 0.05 to about 0.75 wt%; from about 0.05 to about 0.50 wt%; from about 0.05 to about 0.25 wt%; or from about 0.05 to about 0.20 wt% of the total weight of the composition.
• the one or more pharmaceutical glidants is present at from about 0.05 to about 0.25 wt% of the total weight of the composition.
• the one or more pharmaceutical glidants comprises silicon dioxide.
• the one or more pharmaceutical disintegrants is sodium starch glycolate.
• the one or more pharmaceutical diluents comprises microcrystalline cellulose.
• the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof.
• Composition (A) comprises one or more pharmaceutical glidants in an amount from about 0.05 to about 2 wt%; from about 0.10 to about 2 wt%; from about 0.2 to about 2 wt%; from about 0.3 to about 2 wt%; or from about 0.40 to about 2 wt% of the total weight of the composition.
• the one or more pharmaceutical glidants comprises silicon dioxide.
• the one or more pharmaceutical disintegrants is sodium starch glycolate.
• the one or more pharmaceutical diluents comprises microcrystalline cellulose.
• the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof.
• a lubricant may be, for example calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g.
• glyceryl bihenehate, tribehenin and glyceryl behenate leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin and zinc stearate.
• the one or more pharmaceutical lubricants in Composition (A) are selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g., a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin and zinc stearate.
• glyceryl behenate e.g., a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate
• leucine magnesium stearate
• myristic acid palmi
• the one or more pharmaceutical lubricants are selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g., a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, stearic acid, talc, tribehenin and zinc stearate.
• Composition (A) comprises one or more pharmaceutical lubricants and the lubricant is not sodium stearyl fumarate.
• the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof.
• Composition (A) includes glycerol behenate as the lubricant.
• the one or more pharmaceutical lubricants in Composition (A) comprises glyceryl behenate, magnesium stearate, stearic acid, or a combination thereof.
• the lubricant in Composition (A) is glyceryl behenate, magnesium stearate, or a combination thereof.
• the one or more pharmaceutical lubricants in Composition (A) comprises sodium stearyl fumarate and/or one or more behenate esters of glycerine.
• Composition (A) comprises one or more pharmaceutical lubricants in an amount from about 1 wt% to about 9 wt %, from about 1 wt% to about 8 wt %, from about 1 wt% to about 7 wt %, from about 1 wt% to about 6 wt %, from about 1 wt% to about 5 wt %, from about 2 wt% to about 10 wt %, from about 2.5 wt% to about 10 wt %, from about 2 wt% to about 8 wt %, from about 2 wt% to about 7 wt %, from about 2 wt% to about 6 wt %, from about 2 wt% to about 5 wt %, from about 2 wt% to about 4.5 wt %, or from about 2.5 wt% to about 4.5 wt % of the total weight of the composition.
• the one or more pharmaceutical lubricants is present at from about 2.5 to about 4.5 wt% of the total weight of the composition.
• the one or more pharmaceutical lubricants in Composition (A) is glycerol behenate.
• the one or more pharmaceutical glidants in Composition (A) comprises silicon dioxide.
• the one or more pharmaceutical disintegrants in Composition (A) is sodium starch glycolate.
• the one or more pharmaceutical diluents in Composition (A) comprises microcrystalline cellulose.
• the compound of Formula (I) in Composition (A) is brensocatib, or a pharmaceutically acceptable salt thereof.
• the one or more pharmaceutical lubricants in Composition (A) consists of sodium stearyl fumarate and/or one or more behenate esters of glycerine or a mixture thereof.
• the one or more pharmaceutical lubricants in Composition (A) consists of sodium stearyl fumarate, glyceryl dibehenate, glyceryl behenate, tribehenin or any mixture thereof.
• the one or more pharmaceutical lubricants in Composition (A) comprises sodium stearyl fumarate.
• the one or more pharmaceutical lubricants in Composition (A) consists of sodium stearyl fumarate.
• the one or more pharmaceutical lubricants in Composition (A) comprises one or more behenate esters of glycerine. (i.e., one or more of glyceryl dibehenate, tribehenin and glyceryl behenate).
• the compression aid in Composition (A) is dicalcium phosphate dihydrate (also known as dibasic calcium phosphate dihydrate) (DCPD). DCPD is used in tablet formulations both as an excipient and as a source of calcium and phosphorus in nutritional supplements.
• Composition (A) comprises the compression aid, e.g., DCPD, in an amount from about 10 to about 30 wt%, including about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, or about 24 wt% of the total weight of the composition.
• the compression aid is present at about 20 wt % of the total weight of the composition.
• Composition (A) comprises the compression aid, e.g., DCPD, in an amount from about 10 to about 25 wt%, from about 10 to about 20 wt%, from about 10 to about 15 wt%, from about 15 to about 25 wt%, or from about 20 to about 25 wt%, or from about 18 to about 22 wt% of the total weight of the composition.
• the compression aid is present at from about 18 to about 22 wt% of the total weight of the composition.
• the compression aid is DCPD.
• the one or more pharmaceutical lubricants in Composition (A) is glycerol behenate.
• the one or more pharmaceutical glidants in Composition (A) comprises silicon dioxide.
• the one or more pharmaceutical disintegrants in Composition (A) is sodium starch glycolate.
• the one or more pharmaceutical diluents in Composition (A) comprises microcrystalline cellulose.
• the compound of Formula (I) in the exemplary composition is brensocatib, or a pharmaceutically acceptable salt thereof.
• the pharmaceutical composition administered to the patient is Composition (B) comprising: (a) from about 1 to about 30 wt% of the compound of Formula (I), or a pharmaceutically acceptable salt thereof; (b) from about 55 to about 75 wt% of a pharmaceutical diluent; (c) from about 15 to about 25 wt% of a compression aid; (d) from about 3 to about 5 wt% of a pharmaceutical disintegrant; (e) from about 0.00 to about 1 wt% of a pharmaceutical glidant; and (f) from about 2 to about 6 wt% of a pharmaceutical lubricant; wherein the components add up to 100 wt%.
• composition (B) in some embodiments of the methods where Composition (B) is administered to the patient, the identity of the pharmaceutical diluent, compression aid, pharmaceutical disintegrant, pharmaceutical glidant, and pharmaceutical lubricant in the composition may be one of those described above for Composition (A). In other embodiments, the amount of the pharmaceutical diluent, compression aid, pharmaceutical disintegrant, pharmaceutical glidant, and pharmaceutical lubricant in Composition (B) may also be one of those described above for Composition (A), as long as the amount is within the corresponding broader range recited above for Composition (B). [000206]
• the pharmaceutical compositions disclosed herein, including Compositions (A) and (B) may be in a solid dosage form suitable for oral administration to a human being.
• the pharmaceutical composition is a pharmaceutical tablet.
• Pharmaceutical tablets may be prepared using methods known to those skilled in the art including, for example, dry mixing / direct compression process as described in International Application Publication No. WO 2019/166626.
• the pharmaceutical tablet comprises a tablet core wherein the tablet core comprises the pharmaceutical composition as disclosed herein and wherein the tablet core has a coating.
• the coating is a film coating.
• the film coating may be applied using conventional methods known to those skilled in the art.
• a functional coating can be used to provide protection against, for example, moisture ingress or degradation by light. Additionally, a functional coating may be used to modify or control the release of the compound of Formula (I), e.g., brensocatib, from the composition.
• the coating may comprise, for example, about 0.2 to about 10 wt% of the total weight of the pharmaceutical composition, e.g., from about 0.2 to about 4 wt%, from about 0.2 to about 3 wt%, from about 1 to about 6 wt%, or from about 2 to about 5 wt% of the total weight of the pharmaceutical composition
• the compounds of the disclosure may be prepared, in known manner, in a variety of ways.
• compounds of Formula (I) are prepared according to the methods set forth in U.S. Patent No. 9,522,894, incorporated by reference herein in its entirety for all purposes.
• DPP1 inhibitors other than the compounds of Formula (I), or pharmaceutically acceptable salts thereof may also be used in place of, or in combination with, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, according to the disclosed treatment methods.
• DPP1 inhibitors other than the compounds of Formula (I), or pharmaceutically acceptable salts thereof contemplated for use include those disclosed in Chen et al., Journal of Medicinal Chemistry 64(16):11857- 11885 (2021); Banerjee et al., Bioorganic & Medicinal Chemistry Letters 47:128202 (2021); Bondebjerg J et al., Bioorg Med Chem.
• the present disclosure provides the diastereomers of brensocatib disclosed herein, i.e., (2R)-N- ⁇ (1R)-l-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro- 1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane-2-carboxamide (i.e., the R,R isomer), (2S)- N- ⁇ (1R)-l-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4- oxazepane-2-carboxamide (i.e., the S,R isomer), and (2R)-N- ⁇ (1S)-l-Cyano-2-[4-(3-methyl-2- oxo-2
• the mixture comprises brensocatib, or a pharmaceutically acceptable salt thereof, and the R,R isomer, or a pharmaceutically acceptable salt thereof.
• the mixture comprises brensocatib, or a pharmaceutically acceptable salt thereof, and the S,R isomer, or a pharmaceutically acceptable salt thereof.
• the mixture comprises brensocatib, or a pharmaceutically acceptable salt thereof, and the R,S isomer, or a pharmaceutically acceptable salt thereof.
• Example 1 Efficacy, safety and tolerability, and pharmacokinetics of brensocatib administered once daily for 28 days in patients with cystic fibrosis
• Cystic fibrosis is caused by abnormalities in the CF transmembrane conductance regulator protein, causing chronic lung infections (particularly with Pseudomonas aeruginosa) and excessive inflammation, and leading to bronchiectasis, declining lung function, respiratory insufficiency and quality of life.
• This example describes a Phase 2a randomized single-blind placebo-controlled parallel-group study to assess efficacy, safety, tolerability, and pharmacokinetics of brensocatib tablets in adults with cystic fibrosis (CF).
• Brensocatib is the International Nonproprietary Name for (2S)-N- ⁇ (1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3- dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -1,4-oxazepane-2-carboxamide , and will be administered once daily (QD) for 28 days in study participants with CF. Participants are randomized to receive once daily oral dosing of 10 mg brensocatib, 25 mg brensocatib, 40 mg brensocatib, or matching placebo.
• Brensocatib film-coated tablets are round, biconvex, brown, film-coated tablets containing the equivalent of 10 mg, 25 mg, and 40 mg of brensocatib drug substance and to be administered orally once daily (QD).
• Each film-coated tablet contains active ingredient of brensocatib drug substance and compendial ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, sodium starch glycolate, silicon dioxide, and glyceryl behenate.
• Efficacy measures include spirometry, which is a validated method for assessing respiratory function, and the Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain, a validated instrument for assessing quality of life for patients with CF. Additionally, administration of brensocatib for 28 days is expected to produce a decrease in NE, PR3, and CatG concentrations in the blood and sputum of participants with CF Subject Eligibility Criteria [000215] Table 1 below provides certain inclusion criteria for the study.
• Exclusion criteria for the study include severe or unstable CF, as per I nvestigator’s judgement and oxygen saturation (SpO2 ⁇ RQ ⁇ URRP ⁇ DLU ⁇ at the Screening Visit and at Baseline .
• Study Design [000217] Figure 2 provides a schematic diagram of the study design and treatment duration. The study will be conducted in a single-blind fashion, i.e., participants are blinded to their assigned study drug and dose, as are the study center staff and the Investigator; select Sponsor personnel, including the Independent Clinical Pharmacologist and Safety Review Committee (SRC) members, are not blinded.
• SRC Independent Clinical Pharmacologist and Safety Review Committee
• Eligible participants with CF will be randomized to receive 10 mg brensocatib, 25 mg brensocatib, 40 mg brensocatib or its matching placebo orally and once daily (QD) for 28 days.
• QD once daily
• a cohort of participants will receive 65 mg brensocatib QD on the same schedule as the previous cohorts.
• Participants assigned to the 65 mg dose cohort will receive 1 tablet of 25 mg brensocatib and 1 tablet of 40 mg brensocatib.
• the study will enroll 36 to 48 participants to form 3-4 cohorts following randomization by means of an Interactive Web Response System (IWRS).
• IWRS Interactive Web Response System
• Each cohort will enroll 12 participants in a 10:2 ratio (active to placebo). For each cohort, there will be 2 strata: 6 participants (5 active: 1 placebo) who have previously received and will continue to receive cystic fibrosis transmembrane conductance regulator (CFTR) modulators as concomitant medication, and 6 participants (5 active: 1 placebo) who have not and are currently not being treated with CFTR modulators
• the first three dose cohorts (a total of 36 participants) will be 10 mg brensocatib, 25 mg brensocatib, and 40 mg brensocatib cohorts. If there are no safety issues in these cohorts, a 65 mg brensocatib dose cohort will be similarly randomized, raising the total sample size from 36 to 48 participants.
• the Treatment Period is a 28-day period comprising 4 in-clinic visits on Day 1 (baseline, Visit 2), Day 2 (Visit 3), Day 14 (Visit 4), and Day 28 (End of Treatment (EOT), Visit 5).
• Participants must enter the study at the start of either the on-treatment cycle or off- treatment cycle of their inhaled antibiotic regimen.
• the study center staff will administer the study drug to participants for days of in-clinic visits. On Days 1 and 28, the study center staff will administer the study drug to the participant after 8 hours of fasting on Days 1 and 28. Participants will receive a 28-day supply of blinded study drug on Days 1 and 14. On days when there is no in-clinic visit, the participant will self-administer the study drug with or without food at the same time of day each day.
• the Study-Up Period will extend from Day 29 to Day 56 (EOS) and include visits to the study center on Day 29 (Visit 6) and Day 35 (Visit 7) for blood sampling for PK analysis, and for blood and sputum sampling for PD analysis.
• EOS On Day 56 (EOS) a telephone call will be placed from the study center to the participant to check on well-being and to assess the status of any new and/or ongoing AEs.
• the SRC will review safety and PK data of completed cohorts exposed to 10 mg brensocatib, 25 mg brensocatib, and 40 mg brensocatib QD in an unblinded manner to determine whether brensocatib has an acceptable safety and PK profile, and can be escalated to the 65 mg dose.
• the planned cohort receiving 65 mg brensocatib orally and once daily (QD) will have the same dosing schedule (i.e., QD x 28 days) and same allocation rules used in the first 3 cohorts receiving 10 mg brensocatib, 25 mg brensocatib, and 40 mg brensocatib QD, respectively.
• QD dosing schedule
• the objectives and endpoints of the study are shown in Table 2.
• PK Sample Collection Blood samples will be collected on Day 1 (Visit 2), Day 2 (Visit 3), 14 (Visit 4), and Day 28 (Visit 5) during the treatment period, and on Day 29 (Visit 6) and Day 35 (Visit 7) during the follow-up period, for PK analysis as well as for measurement of plasma concentrations of brensocatib.
• Specific timepoints are: Day 1 (predose and at 0.5, 1, 2, 4, 6, 8, and 24 hours postdose (24-hour postdose collection is Day 2 predose collection), Day 14 (predose and at 2 hour postdose), Day 28 (predose and at 0.5, 1, 2, 4, 6, 8, 24 (collected on Day 29), and 168 hours postdose ( ⁇ 24 hours; collected on Day 35).
• the collection windows will be up to 30 minutes prior to dosing for the predose sample, ⁇ 5 minutes for the 0.5, 1, and 2-hour samples, ⁇ 15 minutes for the 4-, 6-, and 8-hour samples, ⁇ 1 hour for the 24-hour sample, and ⁇ 24 hours for the 168-hour sample. Approximately 6 mL of blood is collected at each timepoint. [000227] A maximum of 2 samples may be collected at additional time points during the study if an SAE occurs or at early termination. 2.
• PK Analysis Individual PK parameters of brensocatib will be determined using noncompartmental analysis for the following parameters: C max , t max , C min , AUC 0-24 , AUC last , AUC0– ⁇ , CL/F, Vd/F, t1 ⁇ 2 , Rac(Cmax), and Rac(AUC) on Day 1 and Day 28, as appropriate. Ctrough on Day 2, Day 14, Day 28, and Day 29 will be evaluated by statistical descriptive values. [000229] Among the PK parameters, the primary endpoints for PK evaluation will be Cmax, Tmax, AUC0-24 and t1/2 on Days 1 and 28.
• a secondary analysis of dose-dependency will be performed based on AUC last , AUC 0-24 and C max for Day 1 and Day 28. Additional PK parameters, such as AUC last , AUC inf , CL/F, Vd/F, C min , C trough , R ac(AUC) and R ac(Cmax) , will be determined when data permit. All PK parameters are described in Table 3. [000230] Relationships between PK (brensocatib dose and exposure) and PD effects (e.g., NE concentrations in blood and sputum, ppFEV1) and safety (e.g., AESI, including hyperkeratosis, periodontitis/gingivitis, and infections) will be explored.
• PK e.g., NE concentrations in blood and sputum, ppFEV1
• safety e.g., AESI, including hyperkeratosis, periodontitis/gingivitis, and infections
• Biomarkers [000231] 6 mL of blood and 3 mL of sputum will be collected from each participant at predose during the screening (Visit 1), on Day 1 (Visit 2), Day 2 (Visit 3), Day 14 (Visit 4), and Day 28 (Visit 5) during the treatment period, and on Day 29 (Visit 6) and Day 35 (Visit 7) during the follow-up period, for biomarker research. Sputum samples will be obtained from participants either spontaneously, with chest physiotherapy, or by induction.
• Spirometry assessments will be performed during the screening period (Visit 1), and on Day 1 (Visit 2) and Day 28 (Visit 5) during the treatment period, and include the following: prebronchodilator FEV1, prebronchodilator ppFEV1, FVC, FEF(25-75%), and PEFR.
• Prebronchodilator pulmonary function tests (PFT) by spirometry FEV 1 , ppFEV1, FVC, PEFR, and FEF(25-75%)
• PFT Prebronchodilator pulmonary function tests
• Participants will be provided with detailed instruction on how to conduct the FVC maneuver per ATS/ERS spirometry standardization before performing the test. Time of the last bronchodilator medication use before the procedure will be recorded. [000235] Spirometry will be performed preferably in the morning (AM) at approximately the same time each visit. The same spirometer and standard spirometric techniques, including calibration, will be used to perform spirometry at all visits and, whenever possible, the same person will perform the measurements. Pulmonary function tests will be performed with the participant in a sitting position; however, if necessary to undertake the testing with the participant standing or in another position, this will be noted on the spirometry report. For any participant, the position will be consistent throughout the study.
• the spirometer will be calibrated following the principles of the ATS/ERS guidelines every day that a study participant is assessed and spirometry is carried out.
• the calibration records will be kept in a reviewable log. It is preferred that the calibration equipment (i.e., 3-L syringe) that is used to calibrate the spirometer be subjected to a validated calibration according to the manufacturer’s specifications.
• Participants will be advised to rest at least 30 minutes and not to eat a large meal for at least 2 hours prior to the test. If a participant is scheduled to have pulmonary rehabilitation on the day of their visit, they will be advised to have the PFT done before the rehabilitation on that day. 2.
• Cystic Fibrosis Questionnaire – Revised (CFQ-R) [000238] Efficacy assessment measured by CFQ-R will be performed on Day 1 (Visit 2), Day 14 (Visit 4), Day 28 (Visit 5) during the treatment period, and on Day 35 (Visit 7) during the follow-up period. CFQ-R will be completed as the first procedure of the visit per FDA guidelines. [000239] Plasma concentrations of brensocatib will be listed and summarized by active dose group and by active dose group within strata over each scheduled sampling time, using descriptive statistics (including arithmetic mean, SD, median, minimum and maximum, geometric mean (GM) with 95% CI, and CV(%) of the GM, as appropriate).
• Mean plots versus time will also be presented by treatment group (dose levels of brensocatib and pooled placebo) and by treatment group within each stratum based on CFTR modulator use or not.
• FEV 1 and CFQ-R Respiratory Domain will also be assessed. These variables will be listed and summarized in tables by brensocatib dose levels and placebo.
• Additional PK-PD evaluations will be performed in separate analyses, in which the relationship between brensocatib exposure (dose or AUC) and clinical measurements (PD biomarkers, ppFEV1 and AESI) will be explored.
• PMNs in the CF airway milieu constitute distinct pathological phenotypes, called GRIM (enhanced granule release leading to neutrophil elastase (NE) exocytosis, immunoregulatory function, and metabolic activities).
• GRIM enhanced granule release leading to neutrophil elastase (NE) exocytosis, immunoregulatory function, and metabolic activities.
• NE neutrophil elastase
• An in vitro transmigration model that recapitulates GRIM fate of PMNs has been developed to understand neutrophil plasticity and functional adaptation. See U.S. Patent Application Publication No. US2020/0256866, incorporated herein by reference in its entirety for all purposes.
• the in vitro transmigration model includes a collagen-coated porous 3D scaffold with the H441 club-like small airway cells grown at an air-liquid interface.
• Blood PMNs that are loaded into a porous scaffold transmigrate through the H441 cells into airway milieu, airway supernatant (ASN), collected from CF patients.
• ASN airway supernatant
• Transmigration of PMNs to CF patient ASN showed pathological GRIM phenotypes and functions and expressed similar phenotypes to those found in airway collected from CF patients.
• the ASN and transmigration are both required for inducing pathological conditioning of PMNs.
• the in vitro transmigration model is used to evaluate the effect of brensocatib treatment on neutrophil precursors and/or in a stem cell-derived neutrophil model.
• Brensocatib is a potent inhibitor of dipeptidyl peptidase 1 (DPP1) that activates neutrophil serine proteases (NSPs), such as NE, in the promyelocyte stage of neutrophil development in the bone marrow.
• DPP1 dipeptidyl peptidase 1
• NSPs neutrophil serine proteases
• PMNs are differentiated from neutrophil precursors and/or stem cell-derived neutrophil model in the presence or absence of brensocatib.
• the differentiated PMNs are then tested using the in vitro transmigration model to measure their NSP levels, phenotypes and functions before and after transmigrating into the airway milieu (e.g. ASN) of CF patients.
• the HL-60 cell line is a model of neutrophil precursors. HL-60 cells are at the myeloblast stage of development and are induced to differentiate terminally to a neutrophil- like state with differentiating inducers.
• Primary bone marrow- or umbilical cord blood-derived CD34+ neutrophil progenitor cells are cultured for 7 days in specific stem cell media supplemented with recombinant human Stem Cell Factor and recombinant human IL-3.
• the cells will be differentiated in culture for another 7 days in the stem cell media with recombinant human Granulocyte Colony Stimulating Factor, plus increasing concentrations of brensocatib.
• those cells will be applied to the CF in vitro transmigration model.
• In vitro transmigration model will also be used to test rodent PMNs.
• the rodent PMNs will be obtained from wild type rodents treated with brensocatib, or from a DPP1 deficient (DPP1-/-) rodent model.
• DPP1-/- DPP1 deficient rodent model.
• human PMNs obtained from either CF or non-CF patients, or PMNs obtained from animal models of human genetic disorders treated with brensocatib will also be tested using the CF in vitro transmigration model.
• biomarker and functional analyses will be performed in the above- mentioned in vitro model studies, including (1) granule release to evaluate whether there is increased NE release via primary granule exocytosis (CD63), or a decrease in the surface phagocytic receptor (CD16); (2) immunoregulatory function for modulating T-cell inhibitory molecules, such as increased Arg1 and bimodal PD-L1 expression; (3) metabolic activities such as increased surface Glut1 expression, glycolysis (extracellular acidification rate, ECAR), oxygen consumption (oxygen consumption rate, OCR), ROS production (CellRox), and extracellular lactate levels; and (4) a decrease in bacterial killing.
• CD63 primary granule exocytosis
• CD16 surface phagocytic receptor
• immunoregulatory function for modulating T-cell inhibitory molecules such as increased Arg1 and bimodal PD-L1 expression
• metabolic activities such as increased surface Glut1 expression, glycolysis (extracellular acidification rate, ECAR), oxygen consumption (oxy
• Free DNA in CF airways has been correlated with reduced lung function, as well as increased levels of neutrophil-recruiting chemokines, and risk of infection. See Manzenreiter R et al., “Ultrastructural characterization of cystic fibrosis sputum using atomic force and scanning electron microscopy,” J Cyst Fibros.
• NETs are present at higher levels in the airways of the ⁇ subunit of the epithelial sodium channel (0ENaC)-overexpressing transgenic ( ⁇ ENaC-Tg) mice with CF-like lung disease than in wild type mice.
• 0ENaC epithelial sodium channel
• ⁇ ENaC-Tg transgenic mice with CF-like lung disease
• NETs are present at higher levels in the airways of the ⁇ subunit of the epithelial sodium channel (0ENaC)-overexpressing transgenic ( ⁇ ENaC-Tg) mice with CF-like lung disease than in wild type mice.
• NET formation by the presence of myeloperoxidase (MPO)-DNA complexes in bronchioalveolar lavage fluid (BAL) of adult ⁇ ENaC-Tg and wild type (WT) mice at 6 and 8 weeks of age, and confirmed NET formation by immunofluorescence imaging of BAL cells isolated from both mouse strains.
• MPO myeloperoxidase
• BAL bronchioalveolar lavage fluid
• WT wild type mice
• Flow cytometry was used to quantify the presence of neutrophils undergoing PAD4-mediated NET release.
• CitH3 positive cells/ml There were significantly more CitH3 positive cells/ml in the BAL of ⁇ ENaC-Tg mice at both ages compared to the WT controls.
• Studies of the ⁇ ENaC-Tg mice also demonstrated that increased airway sodium absorption causes airway surface liquid depletion, reduced mucus transport, and spontaneous CF-like lung disease with airway mucus obstruction, impaired mucociliary clearance, emphysema, and chronic inflammation including airway neutrophilia, similar to human CF lung disease.
• Brensocatib is a potent inhibitor of DPP 1 that activates NSPs, which are linked to NET formation.
• ⁇ ENaC-Tg mice with CF-like lung disease are used to evaluate the effect of brensocatib treatment on NET formation in the lungs.
• PENaC-Tg mice are exposed to brensocatib or placebo QD or BID for at least one week prior to the evaluation of NETs using, for example, the methods described in Tucker SL et al., mentioned above.
• WT mice are used as a control for baseline NET formation in the airways. Reduction in the formation of NETs in ⁇ ENaC-Tg mice by brensocatib vs. the placebo may indicate a significant role of brensocatib in attenuating CF.

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