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WO2025237912A1 - Inhibiteurs de keap1 destinés à être utilisés dans le traitement de la bronchectasie - Google Patents

Inhibiteurs de keap1 destinés à être utilisés dans le traitement de la bronchectasie

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Publication number
WO2025237912A1
WO2025237912A1 PCT/EP2025/062916 EP2025062916W WO2025237912A1 WO 2025237912 A1 WO2025237912 A1 WO 2025237912A1 EP 2025062916 W EP2025062916 W EP 2025062916W WO 2025237912 A1 WO2025237912 A1 WO 2025237912A1
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WO
WIPO (PCT)
Prior art keywords
bronchiectasis
patient
keapl
inhibitor
exacerbations
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/062916
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English (en)
Inventor
Maria BELVISI
Rodney Jason HUGHES
Marie Helene LARSSON
Gerd Eva Madgalena RHEDIN
Corinne Elizabeth HAMBLET
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AstraZeneca AB
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AstraZeneca AB
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Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of WO2025237912A1 publication Critical patent/WO2025237912A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • 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

Definitions

  • Keapl inhibitors for use in the treatment of bronchiectasis.
  • Nrf2 nuclear factor (erythroid-derived 2)-l ike 2 (Nrf2) is a ubiquitously expressed transcription factor which binds to and activates antioxidant response elements (AREs).
  • AREs antioxidant response elements
  • Nrf2 is tightly regulated in the cytosol by the repressor protein, Keapl (Kelch-like ECH-associated protein 1), which is a component of the Cullin 3 (CUL3)-based E3 ubiquitin ligase complex.
  • Nrf2 This complex is known to control the stability and accumulation of Nrf2 by ubiquinating Nrf2 leading to degradation by the proteasome.
  • Nrf2 dissociates from Keapl, allowing Nrf2 to migrate to the nucleus, where it can bind AREs and increase the transcription of numerous antioxidative and cytoprotective genes such as heme oxygenase-1, NAD(P)H:quinone reductase, glutathione S-transferase, glutamylcysteine synthetase, and UDP-glucuronosyl transferases.
  • Sussan TE et al. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci USA 2009; 106:250-5.
  • Nrf2 signaling pathway plays a critical role in protecting cells from oxidative stress in various pathophysiological conditions, such as chronic obstructive pulmonary disease (COPD). It has been proposed that a Keapl inhibitor may provide a treatment for COPD by targeting the Nrf2 signaling pathway.
  • COPD chronic obstructive pulmonary disease
  • the present application relates to the use of a Keapl inhibitor for the treatment of bronchiectasis.
  • Bronchiectasis is a chronic disease characterized by abnormal and permanent dilation of the bronchi resulting in chronic cough, sputum production, shortness of breath, haemoptysis and recurrent bacterial infections of the airway.
  • Several conditions are known to be caused by or be associated with bronchiectasis and include asthma and COPD.
  • a method of treating bronchiectasis in a patient in need thereof comprising administering to the patient a Keapl inhibitor.
  • a method of improving pre-bronchodilator forced expiratory volume 1 (FEV1) in a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • FEV1 pre-bronchodilator forced expiratory volume 1
  • a method of reducing bronchiectasis exacerbations in a patient in need thereof comprising administering to the patient a Keapl inhibitor.
  • a method of reducing the need for antibiotics in a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • a method of stabilizing lung function in a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • a method of improving the quality of life of a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • Keapl refers to "Kelch-like ECH-associated protein 1".
  • Nrf2 refers to "Nuclear factor (erythroid-derived 2)-like 2".
  • NCFBE non-cystic fibrosis bronchiectasis
  • NQ01 refers to "NAD(P)H quinone dehydrogenase 1".
  • ELISA refers to "enzyme-linked immunosorbent assay”.
  • the present disclosure relates to method of improving e.g. pre-bronchodilator forced expiratory volume 1 (FEV1), cough frequency, cough intensity, and/or the quality of life in a patient with bronchiectasis.
  • FEV1 pre-bronchodilator forced expiratory volume 1
  • the improvement is relative to baseline (i.e. prior to administration with a Keapl inhibitor as disclosed herein).
  • the improvement is 2, 4, 6, 8, 10, 12 or 24 weeks following administration of the Keapl inhibitor.
  • the improvement is 1, 2 or 3 months following administration of the Keapl inhibitor.
  • Quality of life may be assessed using the Quality of life bronchiectasis questionnaire (QOL-B) (Quittner ALet al. Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and determination of minimal important difference scores. Thorax. 2015;70(l):12-20. doi:10.1136/thoraxjnl-2014-205918), the St. George's Respiratory Questionnaire (SGRQ) (Wilson CB, et al., Am J Respir Crit Care Med. 1997;156(2 l):536-541. doi:10.1097/00008483-199803000-00011), and the Bronchiectasis Impact Measure (BIM) questionnaire (Crichton ML, et al., Eur Respir J.
  • QOL-B Quality of Life bronchiectasis questionnaire
  • BIM Bronchiectasis Impact Measure
  • the SGRQ has a 3-month recall period and is therefore performed at baseline and 3 months.
  • the QOL-B and BIM questionnaire have a shorter recall period and are performed monthly.
  • Severity of bronchiectasis may be evaluated using the Bronchiectasis Severity Index and MRC dyspnoea score. Exacerbations may be assessed using the EMBARC definition of exacerbation. (Hill AT, et al.. Eur Respir J. 2017;49(6). doi:10.1183/13993003.00051-2017.)
  • Administration "in combination with” one or more further therapeutic agents includes simultaneous (concurrent) or consecutive administration in any order.
  • airway neutrophilia refers to an accumulation of neutrophils in the airspace of the lungs.
  • sputum neutrophilia refers to the presence of neutrophils in the sputum of a patient.
  • the neutrophils in the sputum of a patient in need of treatment e.g., a patient with bronchiectasis, are increased relative to neutrophils in the sputum of healthy controls.
  • SI Systeme International de Unites
  • Figure 1 illustrates reduction of pulmonary neutrophilic inflammation in a murine model of oxidative stress induced by ozone exposure upon dosing with Compound 1.
  • Figure 2 illustrates intracellular glutathione in human and mouse primary bronchial epithelial cells in vitro upon incubation with Compound 1.
  • Figure 3 illustrates inhibition of menadione induced reactive oxygen species (ROS) production in human primary bronchial epithelial cells in vitro upon incubation with Compound 1.
  • ROS reactive oxygen species
  • tBHP tert-Butyl hydroperoxide
  • Figure 5 illustrates prevention of cigarette smoke extract (CSE) induced cell death in human primary bronchial epithelial cells in vitro upon incubation with Compound 1.
  • CSE cigarette smoke extract
  • Figure 6A illustrates reduction of mucus hypersecretion in air-liquid interface (AU) cultures infected with human rhinovirus) upon incubation with Compound 1 and Bardoxolone methyl (Brdx).
  • Figure 6B illustrates normalization of MUC5AC protein expression, in ALI cultures established from patient cells, upon incubation with Compound 1.
  • Figure 7A illustrates prevention of virus induced reduction in trans-epithelial electrical resistance (TEER ) in ALI cultures infected with HRV upon incubation with Compound 1 and Bardoxolone methyl (Brdx).
  • TEER trans-epithelial electrical resistance
  • Figure 7B illustrates improved recovery of cilia function (Area of active cilia) in ALI cultures infected with HRV upon incubation with Compound 1 and Bardoxolone methyl (Brdx).
  • Figure 8 illustrates reduction of mRNA expression of pro-inflammatory cytokines in LPS treated alveolar macrophages upon incubation with Compound 1.
  • Figure 9 illustrates a dose-dependent increase in the mRNA of Nrf2 target gene NQ01 in response to ex vivo treatment with compound 1 in NCFBE patient blood.
  • Figure 10 illustrates increased oxidative stress, as measured by 8-Hydroxy-2'-deoxyguanosine (8- OHdG), in sputum from NCFBE patients compared to sputum from non-NCFBE smokers.
  • Figure 11 illustrates increased interleukin-1 beta (IL-ip) in sputum from NCFBE patients compared to sputum from non-NCFBE smokers.
  • IL-ip interleukin-1 beta
  • Figure 12 illustrates the direct correlation between 8-OHdG and IL-ip in donor-matched sputum from NCFBE patients.
  • Figure 13 illustrates reduction of pulmonary neutrophilic inflammation in a murine model of lung infection induced by Pseudomonas aeruginosa, upon dosing with Compound 1. * P>0.05, ** P>0.01 ***P>0.001 ****P>0.0001
  • Figure 14 illustrates reduction of plasma SP-D in a murine model of lung infection induced by Pseudomonas aeruginosa, upon dosing with Compound 1. * P>0.05, ** P>0.01, ***P>0.001 & ****P>0.0001
  • Figure 15 illustrates a reduction in BALf IL-ip in a murine model of lung infection induced by Pseudomonas aeruginosa, upon dosing with Compound 1. * P>0.05, ** P>0.01 ***P>0.001
  • a method of treating bronchiectasis in a patient in need thereof comprising administering to the patient a Keapl inhibitor.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor for use in the treatment of bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor in the manufacture of a medicament for the treatment of bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a method of improving pre-bronchodilator forced expiratory volume 1 (FEV1) in a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor for use in improving pre-bronchodilator forced expiratory volume 1 (FEV1) in a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor in the manufacture of a medicament for improving pre-bronchodilator forced expiratory volume 1 (FEV1) in a patient with bronchiectasis.
  • FEV1 pre-bronchodilator forced expiratory volume 1
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a method of reducing bronchiectasis exacerbations in a patient in need thereof comprising administering to the patient a Keapl inhibitor.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • the administration reduces bronchiectasis exacerbations requiring hospitalization and/or reduces bronchiectasis exacerbations requiring antibiotics.
  • a Keapl inhibitor for use in reducing bronchiectasis exacerbations.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • the administration reduces bronchiectasis exacerbations requiring hospitalization and/or reduces bronchiectasis exacerbations requiring antibiotics.
  • a Keapl inhibitor in the manufacture of a medicament for reducing bronchiectasis exacerbations.
  • the bronchiectasis is non- cystic fibrosis bronchiectasis.
  • the administration reduces bronchiectasis exacerbations requiring hospitalization and/or reduces bronchiectasis exacerbations requiring antibiotics.
  • a method of reducing the need for antibiotics in a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • the antibiotics are intravenous or nebulised antibiotics.
  • a Keapl inhibitor for use in reducing the need for antibiotics in a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • the antibiotics are intravenous or nebulised antibiotics.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • the antibiotics are intravenous or nebulised antibiotics.
  • a method of stabilizing lung function in a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor for use in stabilizing lung function in a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor in the manufacture of a medicament for stabilizing lung function in a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a method of improving cough frequency and/or intensity in a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor for use in improving cough frequency and/or intensity in a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor in the manufacture of a medicament for improving cough frequency and/or intensity in a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a method of decreasing bronchiectasis symptoms in a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor for use in decreasing bronchiectasis symptoms in a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor in the manufacture of a medicament for decreasing bronchiectasis symptoms in a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a method of decreasing mucus production in a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor for use in decreasing mucus production in a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a Keapl inhibitor in the manufacture of a medicament for decreasing mucus production in a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • a method of improving the quality of life of a patient with bronchiectasis comprising administering to the patient a Keapl inhibitor.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • quality of life is health-related quality of life.
  • a Keapl inhibitor for use in improving the quality of life of a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • quality of life is health-related quality of life.
  • a Keapl inhibitor in the manufacture of a medicament for improving the quality of life of a patient with bronchiectasis.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • quality of life is health-related quality of life.
  • the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).
  • NCFBE non-cystic fibrosis bronchiectasis
  • CT chest computed tomography
  • the patient has airway neutrophilia and/or sputum neutrophilia.
  • the patient has a history of at least two moderate to severe bronchiectasis exacerbations per year requiring antibiotics.
  • the patient has a history of at least one exacerbation requiring hospital care.
  • the patient in the 12 months prior to administering the Keapl inhibitor the patient has had one or more bronchiectasis exacerbations. In embodiments of the methods and uses provided herein, in the 12 months prior to administering the Keapl inhibitor the patient has had two or more bronchiectasis exacerbations.
  • the patient is on long term antibiotics.
  • the patient has chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the patient has asthma.
  • the bronchiectasis (e.g., non-cystic fibrosis bronchiectasis) was caused by hypogammaglobulinemia.
  • the bronchiectasis (e.g., non-cystic fibrosis bronchiectasis) was caused by immunodeficiency.
  • the bronchiectasis (e.g., non-cystic fibrosis bronchiectasis) was caused by alpha-l-antitrypsin deficiency.
  • the bronchiectasis was caused by cystic fibrosis.
  • the administration of the Keapl inhibitor reduces bacterial load in sputum cultures obtained from the patient.
  • the reduction occurs within 12 weeks of the first administration.
  • the reduction occurs within 8 weeks of the first administration.
  • the reduction occurs within 4 weeks of the first administration.
  • the administration of the Keapl inhibitor decreases antibiotic usage.
  • the patient is a human patient.
  • a pharmaceutical composition comprising a Keapl inhibitor for use in the methods described herein.
  • a pharmaceutical composition comprising a Keapl inhibitor, and one or more pharmaceutically acceptable excipients, for use in the methods described herein.
  • Bronchiectasis The present methods and associated aspects relate to treatment of bronchiectasis in patients in need of such treatment, i.e. patients with bronchiectasis.
  • Bronchiectasis is a chronic, and frequently progressive, lung condition characterized by symptoms including chronic (i.e. persistent) cough, sputum production, shortness of breath, haemoptysis (i.e. coughing up blood), wheezing and chest pain. Bronchiectasis is caused by abnormal and permanent dilation of the bronchi, which can be visualised on a computed tomography (CT) scan. Commonly, this structural damage to the bronchi is caused by an infection, an allergic reaction or an immunodeficiency.
  • CT computed tomography
  • Bronchiectasis can also be caused by cystic fibrosis. Bronchiectasis caused by cystic fibrosis may be referred to as cystic fibrosis (CF) bronchiectasis, whereas bronchiectasis having another cause may be referred to as non-cystic fibrosis bronchiectasis (NCFBE).
  • cystic fibrosis CF
  • NCFBE non-cystic fibrosis bronchiectasis
  • human lungs comprise 5 lobes: the right lung consists of three lobes (upper, middle and lower) and the left lung of two lobes (upper and lower).
  • the right lung consists of three lobes (upper, middle and lower) and the left lung of two lobes (upper and lower).
  • any number of lobes may be affected (with a minimum of one).
  • the more lobes that are affected the more severe is the bronchiectasis.
  • Bronchiectasis is associated with defective immune activity in the airway. Bronchiectasis patients are at heightened risk of lower respiratory tract infections (both viral and bacterial), and bacterial colonisation of the lower airways is often seen. Common colonising bacteria include Haemophilus influenzae and Pseudomonas spp., particularly Pseudomonas aeruginosa. Bacterial colonisation is associated with worsened disease symptoms and increased disease progression, as bacterial colonisation of the airways drives inflammation resulting in progressive lung injury and a gradual worsening of symptoms.
  • bronchiectasis exacerbation is an acute worsening of symptoms, generally sustained for at least several days.
  • a bronchiectasis "exacerbation” is defined herein as a deterioration in three or more of the following symptoms for at least 48 hours: cough; sputum volume and/or consistency; sputum purulence; breathlessness and/or exercise tolerance; fatigue and/or malaise; haemoptysis, which is determined by a clinician to require a change in bronchiectasis treatment.
  • At least 3 exacerbations per year may be prescribed long-term oral or inhaled antibiotic therapy (generally using an antibiotic of the macrolide class) to reduce exacerbation frequency. Though seemingly effective, this does risk driving macrolide resistance in bronchiectasis patients.
  • the severity of bronchiectasis in a patient can be assessed in various ways. Most commonly, the Bronchiectasis Severity Index (BSI) is used.
  • the BSI scores a patient's condition based on factors including age, body mass index (BMI), recent hospital admissions and exacerbation frequency. A score of 0-4 is defined as low severity bronchiectasis, 5-8 is defined as medium severity bronchiectasis and 9+ is defined as high severity bronchiectasis. Patients with high severity bronchiectasis are at increased risk of severe exacerbations, hospitalisation and death from the condition.
  • the BSI is described in Chalmers et al., American Journal of Respiratory and Critical Care Medicine 189(5): 576-585, 2014, which is incorporated herein by reference.
  • the patient treated according to the present methods is a patient who has been diagnosed with, or is suspected of suffering from, bronchiectasis.
  • the patient is a human.
  • the patient may be an adult human or a child.
  • the bronchiectasis may have any cause.
  • the bronchiectasis may have been caused by an immunodeficiency.
  • an immunodeficiency may be a primary immunodeficiency or a secondary immunodeficiency.
  • a primary immunodeficiency is an immunodeficiency with a genetic cause
  • a secondary immunodeficiency is an immunodeficiency with an acquired or environmental cause (e.g. a disease such as HIV, or medical treatment such as chemotherapy).
  • the bronchiectasis may have been caused by an antibody deficiency (i.e.
  • a deficiency resulting in impaired antibody production by B cells also referred to as hypogammaglobulinaemia
  • hypogammaglobulinaemia a deficiency resulting in impaired antibody production by B cells
  • Primary antibody deficiencies which may be associated with bronchiectasis include common variable immunodeficiency (CVID), X-linked agammaglobulinemia, hyper-IgM syndrome and IgG deficiency.
  • Secondary immunodeficiencies which may be associated with bronchiectasis include therapy with immunosuppressants, e.g. post-organ transplant, chemotherapy and infections, e.g. HIV.
  • bronchiectasis may have been caused by alpha-1 antitrypsin (AAT) deficiency.
  • AAT alpha-1 antitrypsin
  • AAT deficiency is an inhibitor of neutrophil serine proteases, and without being bound by theory it is believed that it acts to dampen neutrophil-driven inflammation.
  • AAT deficiency may therefore result in increased neutrophil-driven inflammation, which in the lungs results in tissue damage promoting bronchiectasis development, and a correlation between AAT deficiency and bronchiectasis has been observed (see e.g. Stockley et al., Orphanet Journal of Rare Diseases 18: 243, 2023).
  • the patient may have bronchiectasis caused by defective cilia, resulting in improper mucus clearance from the airways.
  • the bronchiectasis may have been caused by Young's syndrome or primary cilia dyskinesia.
  • the bronchiectasis may have been caused by a severe lung infection, e.g. pneumonia or tuberculosis.
  • the bronchiectasis may have been caused by an allergic reaction or condition within the lungs, which drives inflammation of the airways causing progressive damage to their structure.
  • the bronchiectasis may have been caused by allergic bronchopulmonary aspergillosis (ABPA).
  • ABPA allergic bronchopulmonary aspergillosis
  • the bronchiectasis may have been caused by an inflammatory disease, e.g. rheumatoid arthritis, Sjogren's syndrome, Crohn's disease or ulcerative colitis.
  • an inflammatory disease e.g. rheumatoid arthritis, Sjogren's syndrome, Crohn's disease or ulcerative colitis.
  • the condition is idiopathic, i.e. its cause is unknown.
  • the patient has bronchiectasis affecting at least one lobe of their lungs (i.e. one or more lobes of their lungs). In some embodiments the patient has bronchiectasis affecting at least 2, at least 3 or at least 4 lobes of their lungs. In some embodiments the patient has bronchiectasis affecting no more than 1, no more than 2, no more than 3 or no more than 4 lobes of their lungs. In some embodiments the patient has bronchiectasis affecting 1, 2, 3, 4 or 5 lobes of their lungs.
  • the patient may have been diagnosed with bronchiectasis. Any suitable technique may be used for diagnosis of bronchiectasis. Generally, the patient was diagnosed with bronchiectasis by a CT scan of the chest ("chest CT").
  • the patient may have bronchiectasis which was diagnosed (or confirmed) by chest CT demonstrating (or showing) bronchiectasis affecting one or more lobes of their lungs.
  • the patient has bronchiectasis which was diagnosed (or confirmed) by chest CT demonstrating (or showing) bronchiectasis affecting at least 2, 3 or 4 lobes of their lungs.
  • the patient has bronchiectasis which was diagnosed (or confirmed) by chest CT demonstrating (or showing) bronchiectasis affecting no more than 1, no more than 1, no more than 3 or no more than 4 lobes of their lungs.
  • the patient has bronchiectasis which was diagnosed (or confirmed) by chest CT demonstrating (or showing) bronchiectasis affecting 1, 2, 3, 4 or all 5 lobes of their lungs.
  • the patient may have bronchiectasis of any subtype, i.e. cylindrical (or tubular), varicose or cystic.
  • Cylindrical bronchiectasis is characterised by uniform bronchi, which do not taper and have parallel walls. Varicose bronchiectasis has a beaded appearance with interspersed sites of narrowing. Cystic bronchiectasis is the most severe form, characterised by saccular dilatation of bronchi that extends to the pleural surfaces.
  • Specific bronchiectasis subtypes can be identified by CT scan.
  • the patient has multiple sub-types of bronchiectasis, i.e. different sub-types of bronchiectasis at different locations within their lungs.
  • the patient has airway neutrophilia or sputum neutrophilia.
  • airway neutrophilia refers to an accumulation of neutrophils in the airspace of the lungs.
  • a patient with airway neutrophilia has a greater accumulation of neutrophils in the airspace of the lungs compared to healthy controls.
  • Airway neutrophilia may be identified by an increased neutrophil count in bronchoalveolar lavage fluid or by increased neutrophil biomarkers (e.g. neutrophil elastase or myeloperoxidase) in bronchial fluid compared to healthy controls.
  • sputum neutrophilia refers to the accumulation of neutrophils in the sputum of a patient.
  • a patient with sputum neutrophilia has a greater accumulation of neutrophils in the sputum compared to healthy controls.
  • Sphlegm also known as phlegm, is thick mucus made in the lungs.
  • the sputum becomes purulent.
  • sputum is essentially clear or translucent, purulent sputum is off-white, yellow or green and opaque. This change in colour is indicative of a high concentration of neutrophils.
  • Sputum neutrophilia may be identified by an increased sputum neutrophil count or by increased neutrophil biomarkers (e.g. neutrophil elastase or myeloperoxidase) in sputum compared to healthy controls. Sputum may be obtained from expectoration, or by e.g. hypertonic saline induction.
  • neutrophil biomarkers e.g. neutrophil elastase or myeloperoxidase
  • airway neutrophilia and sputum neutrophilia are associated, so in some embodiments the patient has airway neutrophilia and sputum neutrophilia.
  • Airway and sputum neutrophilia are common in bronchiectasis and have been found to correlate with overall disease severity, in a vicious cycle. Airway damage results in impaired mucus clearance, promoting acute bacterial infection and chronic bacterial colonisation of the airways, driving airway inflammation. Neutrophils are recruited to the site of inflammation, causing airway and sputum neutrophilia. Chronic inflammation and neutrophil presence and activity causes further damage to the airways.
  • the patient may have a history of at least two moderate to severe bronchiectasis exacerbations per year.
  • a bronchiectasis exacerbation of at least moderate severity is defined as an exacerbation requiring antibiotics.
  • the patient may have a history of at least two bronchiectasis exacerbations requiring antibiotic treatment per year.
  • a history of such exacerbations may be meant that the patient has had at least two bronchiectasis exacerbations requiring antibiotic treatment in the previous year (e.g.
  • the patient has a history of at least one exacerbation requiring hospital care. That is to say, the patient may have been hospitalised due to an exacerbation at least once since their bronchiectasis diagnosis.
  • hospitalisation due to an exacerbation is meant that the patient was admitted to hospital (i.e. as an inpatient) due to the severity of the symptoms of a bronchiectasis exacerbation.
  • the hospitalisation may be recent or unrecent, e.g. less than a year previous or less than 2 years previous, or at least 2, 3, 4 or 5 years previous.
  • the patient may have been hospitalised due to an exacerbation only once or more than once, e.g.
  • the hospitalisation may have been for any length of time, e.g. less than a day or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days.
  • the hospitalisation may have been of any severity and any nature and degree of treatment may have been required.
  • the patient may be prescribed an antibiotic for administration in any suitable way.
  • the patient may be prescribed long-term treatment with an oral antibiotic (i.e. an antibiotic taken orally, e.g. an antibiotic tablet or capsule, or an antibiotic liquid).
  • the patient may be prescribed long-term treatment with a nebulised antibiotic, i.e. an inhalable antibiotic.
  • a liquid antibiotic, dissolved in e.g. saline solution, can be nebulised using a nebuliser.
  • the patient may have asthma. That is to say, the patient may have both asthma and bronchiectasis.
  • the patient may have been diagnosed with, or be suspected of suffering from, both asthma and bronchiectasis.
  • Asthma is an inflammatory disease of the airways of the lungs, which may be diagnosed using any suitable method in the art, e.g. spirometry.
  • the patient may be being treated for asthma, e.g. with a bronchodilator and/or a steroid.
  • the patient may have bronchiectasis defined as mild, moderate or severe according to the bronchiectasis severity index (BSI).
  • BSI bronchiectasis severity index
  • the BSI is described in Chalmers et al., American Journal of Respiratory and Critical Care Medicine 189(5): 576-585, incorporated herein by reference in its entirety.
  • the severity of bronchiectasis can be scored using the following system:
  • a patient is defined as having mild bronchiectasis if their score is 0-4, moderate bronchiectasis if their score is 5-8 or severe bronchiectasis if their score is 9 or above.
  • the patient treated according to the methods provided herein may have mild, moderate or severe bronchiectasis.
  • the patient has mild or moderate bronchiectasis according to the BSI, i.e. a BSI score of 0-8 (alternatively described as a BSI score of less than 9).
  • a method of treating bronchiectasis in a patient in need thereof comprising administering to the patient a Keapl inhibitor.
  • Such treatment of bronchiectasis causes an improvement in the patient's condition.
  • Such an improvement may be an absolute improvement, i.e. a reduction or decreased severity of disease symptoms.
  • the improvement may be a relative improvement, i.e. improvement of the patient's condition may mean a reduction in severity compared to how severe the condition would be without the treatment.
  • an improvement may mean stabilisation of the disease (i.e. prevention of disease progression, where otherwise the disease would progress), or a reduced rate of disease progression.
  • disease progression is meant herein a gradual worsening of symptoms over time.
  • administering results in reduced exacerbations, such as reduced exacerbations requiring hospitalization and/or exacerbations requiring antibiotics. That is to say, in one aspect the method of treating bronchiectasis provided herein can be seen as a method of reducing exacerbations in a patient with bronchiectasis.
  • reducing exacerbations is meant that the frequency and/or severity of exacerbations is reduced, compared to their frequency/severity prior to the commencement of treatment with the Keapl inhibitor.
  • the reduction in frequency of exacerbations may last for at least 1, 2, 3, 4 or 5 years, or for the duration of the course of treatment with the Keapl inhibitor.
  • the frequency of exacerbations may be reduced by at least 20 %, 40 %, 60 % or 80 %.
  • the patient may experience an average of no more than 2 exacerbations per year, or an average of no more than 1 exacerbation per year, or an average of no more than 0.5 exacerbations per year (i.e. no more than 1 exacerbation every 2 years).
  • the treatment may prevent bronchiectasis exacerbations.
  • the treatment may reduce exacerbations requiring hospitalization.
  • An exacerbation "requiring hospitalisation” (or requiring hospital care) is defined above. By reducing such exacerbations is meant that the overall number or frequency of exacerbations requiring hospitalisation is reduced. For example, the frequency of exacerbations requiring hospitalisation may be reduced by at least 20 %, 40 %, 60 % or 80 %.
  • the patient may experience an average of no more than 2 exacerbations requiring hospitalisation per year, or an average of no more than 1 exacerbation requiring hospitalisation per year, or an average of no more than 0.5 exacerbations requiring hospitalisation per year (i.e. no more than 1 exacerbation requiring hospitalisation every 2 years).
  • the treatment may prevent bronchiectasis exacerbations requiring hospitalisation. In such embodiments, the treatment may reduce the overall number of exacerbations as well as the number requiring hospitalisation.
  • the overall number may remain essentially unchanged, but their severity reduced so that fewer exacerbations result in hospitalization.
  • the proportion of exacerbations requiring hospitalization may be unchanged, or may decrease or even increase.
  • the treatment may reduce exacerbations requiring antibiotics.
  • the treatment reduces the overall number or frequency of exacerbations of sufficient severity to require antibiotic treatment.
  • an exacerbation requiring antibiotic treatment is defined herein as being of at least moderate severity.
  • the bronchiectasis treatment may reduce the overall number or frequency of exacerbations of at least moderate severity.
  • the frequency of exacerbations requiring antibiotic treatment may be reduced by at least 20 %, 40 %, 60 % or 80 %. In some embodiments, where the frequency of exacerbations requiring antibiotic treatment is reduced following commencement of treatment with the Keapl inhibitor, the patient may experience an average of no more than 2 exacerbations requiring antibiotic treatment per year, or an average of no more than 1 exacerbation requiring antibiotic treatment per year, or an average of no more than 0.5 exacerbations requiring antibiotic treatment per year (i.e. no more than 1 exacerbation requiring antibiotic treatment every 2 years). In some embodiments, the treatment may prevent bronchiectasis exacerbations requiring antibiotic treatment.
  • the treatment may reduce the overall number of exacerbations as well as the number requiring antibiotic treatment.
  • the overall number may remain essentially unchanged, but their severity reduced so that fewer exacerbations require antibiotic treatment.
  • the proportion of exacerbations requiring antibiotic treatment may be unchanged, or may decrease or even increase.
  • treatment with the Keapl inhibitor reduces the patient's need for antibiotics (i.e., compared to the patient's need for antibiotics prior to the commencement of treatment with the Keapl inhibitor).
  • a reduction of a patient's need for antibiotics may be as a result of reducing the number of exacerbations requiring antibiotic treatment, as described above.
  • a reduction in a patient's need for antibiotics may be as a result of a reduction in severity of exacerbations meaning that shorter courses of antibiotics are required to treat them.
  • the patient is on long-term antibiotics
  • the treatment provided herein reduces the patient's need for the antibiotics, such that the dose is reduced (by reducing the frequency of dosing and/or the dose size).
  • the overall dose of antibiotic administered to the patient across a given time period e.g. a week or a month
  • the overall dose of antibiotic administered to the patient across a given time period may be reduced by at least 10 %, 20 %, 30 %, 40 %, 50 %, 60 % or 70 %.
  • treatment of the patient with the Keapl inhibitor means that the patient no longer requires long-term antibiotic therapy. Effective substitution of antibiotic therapy with a Keapl inhibitor may be advantageous due to e.g. reduced side-effects, increased convenience as the Keapl inhibitor would likely be administered less frequently than the antibiotic, and reduced risk of driving development of antibiotic resistance in bacterial populations resulting from their long-term exposure to them.
  • the reduction in the patient's need for antibiotics is a reduction in the patient's need for intravenous antibiotics. This is particularly the case when the treatment reduces exacerbations requiring hospitalisation and antibiotic therapy.
  • a reduction in a patient's need for intravenous antibiotics means that either (1) the frequency with which the patient requires intravenous antibiotic therapy is reduced; and/or (2) the total average time spent annually on intravenous antibiotic therapy is reduced.
  • a reduction in the need for intravenous antibiotics may mean that the patient's need for antibiotic treatment is reduced overall.
  • the average condition of the patient may be improved following the commencement of Keapl inhibitor treatment, such that when the patient needs antibiotic therapy, oral or nebulised antibiotics more frequently suffice and intravenous antibiotics are required less frequently.
  • the reduction in a patient's need for antibiotics is a reduction in the patient's need for nebulised antibiotics. This is particularly the case when the treatment reduces the patient's need for long-term antibiotic therapy.
  • the treatments provided herein stabilise or improve lung function in the patient.
  • the treatments provided herein improve airflow through the lungs of the patient.
  • Airflow through the lungs can be measured as forced expiratory volume in 1 second (FEV1).
  • FEV1 is the maximum volume of air that an individual can forcibly expel during the first second following maximum inhalation.
  • FEV1 is one measure of lung function. Conveniently, FEV1 can be measured by spirometry, as is well known in the art. The higher the FEV1 value, the greater the level of airflow through the patient's lungs; conversely, the lower the FEV1 value, the worse the airflow through the patient's lungs. Accordingly, in some aspects, the treatments provided herein improve (i.e. increase) FEV1 in the patient.
  • the increase in FEV1 is by at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 100 %, relative to the FEV1 observed prior to the commencement of treatment.
  • the patient prior to treatment, has an FEV1 less than 80 % of the predicted normal value (i.e. the value expected for a healthy patient of that age, sex and size).
  • Predicted normal FEV1 values can be obtained from the Global Lung Function Initiative.
  • An FEV1 less than 80 % of the predicted normal value is considered subnormal.
  • the patient prior to treatment, has an FEV1 less than 70, 60, 50, 40 or 30 % of the predicted normal value.
  • the patient may have an improved FEV1 of at least 30, 40, 50, 60, 70 or 80 % of the predicted normal value.
  • the patient may have a subnormal FEV1 prior to commencing treatment with the Keapl inhibitor, which improves to fall within the normal range following commencement of treatment with the Keapl inhibitor.
  • the improvement in FEV1 may be observed at any timepoint following commencement of treatment with the Keapl inhibitor. In some cases the improvement is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the Keapl inhibitor treatment. That is to say, the improvement in FEV1 may occur within 4, 8, 12, 24, 36 or 52 weeks of the first administration of the Keapl inhibitor.
  • FEV1 can be improved by administration of an inhaled bronchodilator (e.g. salbutamol).
  • an inhaled bronchodilator e.g. salbutamol
  • the values described above relate to the patient's baseline FEV1, i.e. without administration of an inhaled bronchodilator.
  • improvement of lung function is achieved by improvement of FEV1.
  • lung function is stabilised by stabilising the patient's FEV1.
  • treatment with the Keapl inhibitor stabilises the patient's FEV1, i.e. it prevents the patient's FEV1 from reducing.
  • FVC forced vital capacity
  • a reduction in lung function can cause a reduction in FVC.
  • stabilisation of lung function causes stabilisation of the patient's FVC, i.e. it prevents the patient's FVC from reducing.
  • treatment with the Keapl inhibitor causes an improvement in lung function, resulting in an increase in FVC.
  • the increase in FVC is by at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 100 %, relative to the FVC observed prior to the commencement of treatment. In some cases the improvement in FVC is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the Keapl inhibitor treatment.
  • FEV1/FVC ratio Another measurement of lung function is the modified Tiffeneau-Pinelli index, also referred to as the FEV1/FVC ratio.
  • An FEV1/FVC ratio of less than 0.7 may be deemed to indicate an obstructive lung disease, with values of less than 0.6 indicating at least a moderate degree of obstruction and values of less than 0.5 indicating severe obstruction. Values of 0.7 and above may be deemed healthy.
  • a reduction in lung function can cause a reduction in FEV1/FVC ratio.
  • the FEV1/FVC ratio is calculated used readings taken post administration of an inhaled bronchodilator.
  • the patient has a post-bronchodilator FEV1/FVC ratio of less than 0.7, 0.6, 0.5, 0.4 or 0.3 prior to commencing Keapl inhibitor treatment.
  • stabilisation of lung function causes stabilisation of the patient's FEV1/FVC ratio, i.e. it prevents the patient's FEV1/FVC ratio from reducing.
  • treatment with the Keapl inhibitor causes an improvement in lung function, resulting in an increase in FEV1/FVC ratio.
  • the increase in FEV1/FVC ratio is of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 100 %, relative to the ratio prior to commencing Keapl inhibitor treatment.
  • the increase in FEV1/FVC is an absolute increase of at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6 or 0.7.
  • the increase in FEV1/FVC ratio is to > 0.5, 0.6 or 0.7.
  • the increase in FEV1/FVC ratio is to > 0.75, > 0.80, > 0.85, > 0.90 or > 0.95. In some cases the improvement in FVC is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the Keapl inhibitor treatment.
  • the treatment provided herein reduce bronchiectasis symptoms in the patient.
  • the treatment may reduce the severity of the patient's cough, sputum production, dyspnoea, haemoptysis, sputum production, wheezing and/or chest pain.
  • the treatment provided herein may prevent, or put an end to, the patient's cough, sputum production, dyspnoea, haemoptysis, sputum production, wheezing and/or chest pain.
  • the Keapl inhibitor treatment may cause one or more of the bronchiectasis patient's symptoms to reduce in severity or disappear.
  • the treatment herein provides a method of treating cough in a patient with bronchiectasis. Also provided is a method of reducing cough in a patient with bronchiectasis. In particular, provided herein is a method of reducing cough severity in a patient with bronchiectasis. Cough severity may be measured in any suitable way.
  • the treatment results in a decrease in objective cough frequency over 24 hours, relative to baseline.
  • Objective cough frequency over 24 hours may be measured using an automated cough monitor (ACM), for example the VitaloJAKTM (Vitalograph, Buckinghamshire, UK), which is fitted and worn by the patient for approximately 24 hours and records cough frequency.
  • ACM automated cough monitor
  • objective cough frequency may be recorded through alternative means, for example recording or direct observation of the patient, followed by construction of a tally or count.
  • the decrease in objective cough frequency is at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 95 % relative to the frequency before commencing Keapl inhibitor treatment.
  • the treatment results in a reduction in severity as measured by the cough visual analogue scale (cough VAS).
  • Cough VAS or cough severity VAS, comprises a 100 mm linear scale marked with a horizontal line by the patient, with 0 mm representing "no cough” and 100 mm representing "worst cough", measuring subjective assessment by the patient of the prior 24 hrs for severity of cough symptoms (Nguyen et al., Therapeutic Advances in Respiratory Disease 15: 17534666211049743, 2021).
  • the reduction in cough severity according to the cough VAS is of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 95 % relative to the severity before commencing Keapl inhibitor treatment.
  • the treatment results in a reduction in severity as measured by the cough severity index (CSI), which is scored from 0-40 based on a 10-question questionnaire (Shembel et al., The Laryngoscope 123(8): 1931-1936, 2013).
  • the reduction in cough severity according to the CSI is of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 95 % relative to the severity before commencing Keapl inhibitor treatment.
  • the reduction in cough is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the Keapl inhibitor treatment.
  • the methods of treatment provided herein reduce sputum production by the patient.
  • Sputum production may be measured based on the total volume of sputum coughed up by the patient during a given length of time, e.g. over the course of a day.
  • the patient may be provided with a collection vessel and instructed to collect the sputum they produce over the specified period of time.
  • the treatment may cause a reduction in sputum production in a given period of time of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 95 % relative to the amount of sputum produced in the same period of time prior to the commencement of the Keapl inhibitor treatment.
  • the reduction in sputum production is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the Keapl inhibitor treatment.
  • the methods of treatment provided herein reduce the viscosity of sputum produced by the patient.
  • Bronchiectasis is commonly characterised by the production of highly viscous sputum, which is believed to be caused by high concentrations of mucins and DNA in the sputum.
  • Sputum hyperviscosity results in impaired sputum transport/clearance from the lungs, contributing to bacterial infection and colonisation.
  • the viscosity of sputum produced by bronchiectasis patients can be analysed by any suitable method. For instance, sputum can either be collected following spontaneous expectoration, or by hypertonic saline induction. Sputum viscosity can be measured by e.g.
  • Mucin concentration in sputum can be measured by e.g. mass spectrometry, and DNA concentration in sputum can be measured using a commercial DNA quantification assay, e.g. the Quant-iTTM PicoGreenTM dsDNA assay (Thermo Fisher, USA).
  • the treatment may cause a reduction in sputum viscosity of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 % or 50 %, relative to the sputum viscosity before commencing Keapl inhibitor treatment.
  • the treatment may cause a reduction in mucin concentration in the sputum of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 % or 50 %, relative to the sputum mucin concentration before commencing Keapl inhibitor treatment.
  • the treatment may cause a reduction in DNA concentration in the sputum of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 95 % relative to the sputum DNA concentration before commencing Keapl inhibitor treatment.
  • the reduction in sputum viscosity, sputum mucin concentration and/or sputum DNA concentration is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the Keapl inhibitor treatment.
  • the treatment causes a reduction in the bacterial load in sputum cultures obtained from the patient.
  • Bacterial infection or colonisation of the patient's lungs results in the presence of bacteria in the patient's sputum.
  • the amount of bacteria in the patient's sputum is referred to herein as the bacterial load.
  • An increased bacterial load is associated with more severe bronchiectasis disease and worse outcomes, primarily due to increased lung inflammation in patients with increased bacterial colonisation.
  • Sputum bacterial load can be routinely measure by sputum culture, methods for which are well known in the art. Sputum is collected as described above, optionally diluted and then plated onto growth medium and incubated, and the resulting number of colonies counted.
  • Bacterial load is measured in colony forming units (cfu) per gram of sputum (cfu/g).
  • a bacterial load of at least 10 7 cfu/g has previously been identified as a bronchiectasis "inflammatory threshold", at which the bacterial load drives worsening inflammation, worse symptoms and more exacerbations (Sibila et al., American Journal of Respiratory and Critical Care Medicine 200(1): 33-41, 2019).
  • the treatment may cause a reduction in bacterial load of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 95 % or 99 %, relative to the bacterial load before commencing Keapl inhibitor treatment.
  • the reduction in bacterial load is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the Keapl inhibitor treatment.
  • the methods of treatment provided herein reduce the severity of bronchiectasis in the patient. That is to say, the methods of treatment provided herein may cause a reduction in severity of bronchiectasis, as measured by the BSI (discussed above). In some embodiments, the methods of treatment provided herein cause a reduction in BSI score of at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points, relative to the BSI score prior to the commencement of treatment. In some embodiments, the methods of treatment provided herein cause a reduction in the grading of the severity of the patient's bronchiectasis, as measured by the BSI.
  • a reduction in the grading of the severity of the patient's bronchiectasis is meant that the BSI score is reduced from a "severe” grade (i.e. a score of at least 9) to a moderate or mild grade (score of 0-8), or from a moderate grade (score of 5-8) to a mild grade (score of 0-4).
  • the reduction in bronchiectasis severity may be observed at week 4, 8, 12, 24, 52 or 104 following commencement of the Keapl inhibitor treatment.
  • the methods of treatment provided herein improve the quality of life of the bronchiectasis patient.
  • the quality of life of a bronchiectasis patient may be quantified by any suitable assessment tool. For example, the Quality of Life-Bronchiectasis (QOL-B) questionnaire (Quittner et al., Thorax 70: 12-20, 2015). This analyses 8 aspects of the impact of bronchiectasis on the patient (respiratory symptoms, physical, role, emotional and social functioning, vitality, health perceptions and treatment burden).
  • QOL-B Quality of Life-Bronchiectasis
  • the St George's Respiratory Questionnaire may be used (Wilson et al., American Journal of Respiratory and Critical Care Medicine 156(2): 536- 541, 1997).
  • the Bronchiectasis Impact Measure BIM
  • the improvement in quality of life is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the Keapl inhibitor treatment.
  • the methods of treatment provided herein relate the administration of a Keapl inhibitor wherein in the 12 months prior to administering the Keapl inhibitor the patient has had one or more bronchiectasis exacerbations, such as two or more bronchiectasis exacerbations.
  • the bronchiectasis exacerbations are NCFBE exacerbations.
  • the number of bronchiectasis exacerbations in the 12 months prior to administering the Keapl inhibitor may be determined by a patient questionnaire or by consulting medical records.
  • the method of selecting a patient having bronchiectasis for treatment comprises a step of selecting a patient if in the 12 months prior to administration of Keapl inhibitor, the patient has had 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more bronchiectasis exacerbations.
  • the Keapl inhibitor is as described below.
  • a Keapl inhibitor is an Nrf2 activator.
  • Keapl inhibitors are disclosed in WQ2020084300, WQ2021214470 and WO2021214472, the contents of which are incorporated by reference.
  • the Keapl inhibitor is a Keapl inhibitor disclosed in WQ2020084300, WQ2021214470 or WO2021214472.
  • the Keapl inhibitor is a compound of Formula (I) wherein
  • R 1 is Ci- 4 al kyl
  • R 2 is Ci- 4 al kyl, optionally substituted with 1 to 3 fluorine atoms, R 3 is H, F or Cl,
  • R 4 is H, F or Cl
  • R 5 is Ci- 4 al kyl, or a pharmaceutically acceptable salt thereof.
  • the Keapl inhibitor is a compound of Formula (I), wherein R 1 is CH3, or a pharmaceutically acceptable salt thereof.
  • the Keapl inhibitor is a compound of Formula (I), wherein R 2 is CH3 or CHF?, or a pharmaceutically acceptable salt thereof.
  • the Keapl inhibitor is a compound of Formula (I), wherein R 3 is H or F, or a pharmaceutically acceptable salt thereof. In embodiments, the Keapl inhibitor is a compound of Formula (I), wherein R 4 is F or Cl, or a pharmaceutically acceptable salt thereof.
  • the Keapl inhibitor is a compound of Formula (I), wherein R 5 is CH3, or a pharmaceutically acceptable salt thereof.
  • the Keapl inhibitor is -chloro-8-((5-(difluoromethyl)-l-methyl-lH-l, 2,3- triazol-4-yl)methoxy)-l-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-l,2,3,4-tetrahydroisoquinoline-2- carbonyl)-l-methylcyclohexane-l-carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • the Keapl inhibitor is -chloro-8-((l,5-dimethyl-lH-l,2,3-triazol-4- yl)methoxy)-7-fluoro-l-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-l,2,3,4-tetrahydroisoquinoline-2- carbonyl)-l-methylcyclohexane-l-carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • the Keapl inhibitor is -chloro-8-((5-(difluoromethyl)-l-methyl-lH-l,2,3- triazol-4-yl)methoxy)-7-fluoro-l-((6-oxo-5-azaspiro[2.4] heptan-5-yl)methyl)-l, 2,3,4- tetrahydroisoquinoline-2-carbonyl)-l-methylcyclohexane-l-carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • the Keapl inhibitor is bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana- l,9(ll)-dien-28-oate) pharmaceutically acceptable salt thereof
  • the Keapl inhibitor is omaveloxolone (N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll- cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydro-4a(2H)-picenyl]-2,2-difluoropropanamide) pharmaceutically acceptable salt thereof.
  • Compound 1 is Keapl inhibitor -chloro-8-((l,5-dimethyl-lH-l,2,3-triazol-4- yl)methoxy)-7-fluoro-l-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-l,2,3,4-tetrahydroisoquinoline-2- carbonyl)-l-methylcyclohexane-l-carboxylic acid.
  • Compound 1 is disclosed in W02020/084300.
  • Example 1 Reduction of pulmonary neutrophilic inflammation in a murine model of oxidative stress induced by ozone exposure
  • Mice were dosed oral ly, once daily, for a total of 4 days with Compound 1 at 10, 30 or lOOmg/kg or vehicle.
  • One hour after the last dose mice were exposed to 3ppm ozone or room air for 3 hours.
  • Eighteen hours after the end of the exposure mice were euthanised and a bronchoalveolar lavage (BAL) performed.
  • Total white blood cell count was determined using a Haematology analyser and differential cell populations determined via standard morphological criteria using stained slide preparations.
  • Example 2 Incubation with Compound 1 increase markers of antioxidant response in human and mouse primary epithelial cells in vitro
  • HBEC Human primary bronchial epithelial cells
  • MBEC mouse primary bronchial epithelial cells
  • PneumaCult-Ex Plus medium Stemcell Technologies
  • Example 3 Incubation with Compound 1 cause a reduction in menadione induced reactive oxygen species (ROS) production in human primary bronchial epithelial cells in vitro
  • ROS reactive oxygen species
  • HBECs human primary bronchial epithelial cells cultivated in BEGM medium were dosed with Compound 1 in dose-response starting at lpM. After 24 hours Menadione (Merck) was added at 25pM final concentration to induce ROS. 4 hours later cells were stained with CellROX (ROS sensitive dye, Invitrogen) and Hoechst (nuclear stain, Invitrogen) and imaged on Yokogawa. Images were analysed in Columbus and GraphPad Prism was used for curve-fitting and pEC 5 o determination
  • HBECs human primary bronchial epithelial cells cultivated in BEGM medium were dosed with Compound 1 in dose-response starting at 30nM. After 24 hours a probe for detection of lipid peroxidation, BDP 581/591 (Dojindo) was added. 30 minutes later t-BHP (tert-butyl hyderogen peroxide) was added at 450pM final concentration. After 3 hours cells were imaged in Yokogawa and images analysed in Columbus. GraphPad Prism was used for curve-fitting and pEC 5 o determination.
  • Example 5 Incubation with Compound 1 prevent CSE (cigarette smoke extract) induced cell death in vitro
  • HBECs human primary bronchial epithelial cells, Lonza
  • BEGM medium cultivated in BEGM medium
  • Compound 1 in dose-response starting at lOOnM.
  • NucLight Rapid Red Sartorius
  • CSE cigarette smoke extract
  • Example 6A Incubation with Compound 1 reduce mucus hypersecretion in air-liquid interface (AU) cultures infected with human rhinovirus
  • HBECs human primary bronchial epithelial cells, Lonza
  • HBECs human primary bronchial epithelial cells, Lonza
  • ALI cultures were treated with compound 1 at several doses for 2 weeks before infection with human rhinovirus.
  • MUC5AC protein in apical washes were measured.
  • Example 6B Incubation with Compound 1 reduce MUC5AC protein expression in air-liquid interface (AU) cultures established from non-cystic fibrosis bronchiectasis (NCFBE) patients
  • Human primary nasal epithelial cells from NCFBE patients (n 7) and 4 healthy controls were cultivated and differentiated into ALI cultures. They were treated with Compound 1 for 2 weeks before collection of apical washes and measurement of MUC5AC protein.
  • Example 7A Incubation with Compound 1 prevent virus induced reduction in trans-epithelial electrical resistance (TEER ) in air-liquid interface (ALI) cultures infected with human rhinovirus (HRV)
  • HBECs human primary bronchial epithelial cells, Lonza
  • TEER was evaluated at 72 h post infection.
  • TEER is a measure of the integrity of the epithelial barrier, which lines the respiratory tract and other organs. A reduction in TEER indicates a compromised barrier, which can lead to increased epithelial permeability. This can lead to the increased entry of additional pathogens and/or inflammatory mediators into the lung tissue, which can then trigger or exacerbate inflammatory responses.
  • Example 7B Incubation with Compound 1 improve recovery of cilia function in air-liquid interface (ALI) cultures infected with human rhinovirus (HRV)
  • HBECs human primary bronchial epithelial cells, Lonza
  • Compound 1 cultivated and differentiated into ALI cultures were treated with Compound 1 at several doses for 2 weeks before infection with human rhinovirus.
  • Cilia function area with active cilia was evaluated 6 days post infection.
  • Example 9 Incubation of bronchiectasis patient blood with Compound 1 increased mRNA expression of NRF2 target gene NQ01
  • NQ01 transcript levels were quantified from synthesized cDNA by TaqMan qPCR assay, then analysed using Delta-Delta-Ct analysis with DMSO as the control condition.
  • NQ01 Ct values were normalized to the average Ct values of housekeeping genes GAPDH, HPRT1, B2M, RPLPO, RPL13, and SDHA.
  • the Baseline condition represents immediate mRNA extraction without 4-hour treatment.
  • Example 10 Bronchiectasis patient sputum displays increased oxidative stress compared to nonbronchiectasis control sputum
  • Example 11 Bronchiectasis patient sputum displays increased IL-1 levels compared to nonbronchiectasis control sputum
  • IL-10 inflammatory cytokine interleukin-1 beta
  • Oxidative stress marker 8-OHdG directly correlates with IL-lbeta levels in bronchiectasis patient sputum
  • Example 13 Reduction of pulmonary neutrophilic inflammation in a murine model of lung infection with Pseudomonas aeruginosa (PsA)
  • mice were dosed orally, once daily, for a total of 4 days with Compound 1 at 10, 30 or lOOmg/kg or vehicle.
  • One hour after the last dose mice were infected, via the lung, with Pseudomonas aeroginosa (PsA).
  • PsA Pseudomonas aeroginosa
  • Eighteen hours after the end of the exposure mice were euthanised and a bronchoalveolar lavage performed.
  • Total white blood cell count was determined using a Haematology analyser and differential cell populations determined via standard morphological criteria using stained slide preparations. The results are shown in Figure 13, which show a statistically significant reduction in infection induced pulmonary neutrophilic inflammation in mice dosed with Compound 1.
  • Example 14 Reduction of plasma surfactant protein D in a murine model of lung infection induced by Pseudomonas aeruginosa
  • mice were dosed orally, once daily, for a total of 4 days with Compound 1 at 10, 30 or lOOmg/kg or vehicle.
  • One hour after the last dose mice were infected, via the lung, with Pseudomonas aeroginosa. Eighteen hours after the end of the exposure mice were euthanised a terminal blood sample was taken. Plasma concentraion of SP-D was determined using a commercially available enzyme linked immunosorbent assay.
  • Example 15 Reduction of BALf IL-ip in a murine model of lung infection induced by Pseudomonas aeruginosa
  • mice were dosed orally, once daily, for a total of 4 days with Compound 1 at 10, 30 or lOOmg/kg or vehicle.
  • One hour after the last dose mice were infected, via the lung, with Pseudomonas aeroginosa. Eighteen hours after the end of the exposure mice were euthanised and a bronchoalveolar lavage performed.
  • Concentraion of IL-ip in BALf was determined using a commercially available enzyme linked immunosorbent assay.
  • Keapl inhibitor for use in the treatment of bronchiectasis.
  • Keapl inhibitor for use according to statement 3A, wherein the Keapl inhibitor reduces bronchiectasis exacerbations requiring hospitalization.
  • Keapl inhibitor for use according to statements 3A or 4A, wherein the Keapl inhibitor reduces bronchiectasis exacerbations requiring antibiotics.
  • Keapl inhibitor for use in reducing the need for antibiotics in a patient with bronchiectasis.
  • a Keapl inhibitor for use in stabilizing lung function in a patient with bronchiectasis A Keapl inhibitor for use in stabilizing lung function in a patient with bronchiectasis.
  • Keapl inhibitor for use in improving the quality of life of a patient with bronchiectasis.
  • Keapl inhibitor for use according to any one of statements 1A to 8A, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis.
  • Keapl inhibitor for use according to statement 9A wherein the non-cystic fibrosis bronchiectasis was confirmed by chest computed tomography (CT) demonstrating bronchiectasis affecting one or more lobes.
  • CT chest computed tomography
  • Keapl inhibitor for use according to any one of statements 1A to 10A, wherein the patient has airway neutrophilia.
  • Keapl inhibitor for use according to any one of statements 1A to 11A, wherein the patient has sputum neutrophilia.
  • Keapl inhibitor for use according to any one of statements 1A to 12A, wherein the patient has a history of at least 2 moderate to severe bronchiectasis exacerbations per year requiring antibiotics.
  • Keapl inhibitor for use according to any one of statements 1A to 13A, wherein the patient has a history of at least 1 exacerbation requiring hospital care.
  • Keapl inhibitor for use according to any one of statements 1A to 14A, wherein in the 12 months prior to administering the Keapl inhibitor the patient has had one or more bronchiectasis exacerbations, optionally two or more bronchiectasis exacerbations.
  • Keapl inhibitor for use according to any one of statements 1A to 15A, wherein the patient is on long term antibiotics.
  • COPD chronic obstructive pulmonary disease
  • 18A The Keapl inhibitor for use according to any one of statements 1A to 17A, wherein the bronchiectasis was caused by hypogammaglobulinemia.
  • Keapl inhibitor for use according to any one of statements 1A to 18A, wherein the bronchiectasis was caused by immunodeficiency.
  • Keapl inhibitor for use according to any one of statements 1A to 19A, wherein the bronchiectasis was caused by alpha-l-antitrypsin deficiency.
  • Keapl inhibitor for use according to any one of statements 1A to 20A, wherein the administration reduces bacterial load in sputum cultures obtained from the patient, optionally wherein the reduction occurs within 12 weeks of the first administration, within 8 weeks of the first administration, or within 4 weeks of the first administration.
  • Keapl inhibitor for use according to any one of statements 1A to 21A, wherein the administration decreases antibiotic usage.
  • Keapl inhibitor for use according to any one of statements 1A to 22A, wherein the Keapl inhibitor is a compound of Formula (I) wherein
  • R 1 is Ci- 4 alkyl
  • R 2 is Ci- 4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
  • R 3 is H, F or Cl
  • R 4 is H, F or Cl
  • R 5 is Ci- 4 alkyl, or a pharmaceutically acceptable salt thereof.
  • Keapl inhibitor is -chloro-8-((5-(difluoromethyl)-l-methyl-lH-l,2,3- triazol-4-yl)methoxy)-l-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-l,2,3,4-tetrahydroisoquinoline-2- carbonyl)-l-methylcyclohexane-l-carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • Keapl inhibitor for use according to any one of statements 1A to 23A, wherein the Keapl inhibitor is -chloro-8-((l,5-dimethyl-lH-l,2,3-triazol-4- yl)methoxy)-7-fluoro-l-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-l,2,3,4-tetrahydroisoquinoline-2- carbonyl)-l-methylcyclohexane-l-carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • Keapl inhibitor for use according to any one of statements 1A to 23A, wherein the Keapl inhibitor is -chloro-8-((5-(difluoromethyl)-l-methyl-lH-l,2,3- triazol-4-yl)methoxy)-7-fluoro-l-((6-oxo-5-azaspiro[2.4] heptan-5-yl)methyl)-l, 2,3,4- tetrahydroisoquinoline-2-carbonyl)-l-methylcyclohexane-l-carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • Keapl inhibitor for use according to any one of statements 1A to 22A, wherein the Keapl inhibitor is bardoxolone methyl, or a pharmaceutically acceptable salt thereof, or omaveloxolone, or a pharmaceutically acceptable salt thereof.
  • Keapl inhibitor in the manufacture of a medicament for improving prebronchodilator forced expiratory volume 1 (FEV1) in a patient with bronchiectasis.
  • Keapl inhibitor in the manufacture of a medicament for reducing the need for antibiotics in a patient with bronchiectasis.
  • Keapl inhibitor in the manufacture of a medicament for stabilizing lung function in a patient with bronchiectasis.
  • Keapl inhibitor in the manufacture of a medicament for improving the quality of life of a patient with bronchiectasis.
  • Keapl inhibitor according to any one of statements IB to 12B, wherein the patient has a history of at least 2 moderate to severe bronchiectasis exacerbations per year requiring antibiotics.
  • Keapl inhibitor according to any one of statements IB to 13B, wherein the patient has a history of at least 1 exacerbation requiring hospital care.
  • Keapl inhibitor according to any one of statements IB to 14B, wherein in the 12 months prior to administering the Keapl inhibitor the patient has had one or more bronchiectasis exacerbations, optionally two or more bronchiectasis exacerbations.
  • Keapl inhibitor according to any one of statements IB to 16B, wherein the patient has chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Keapl inhibitor according to any one of statements IB to 17B, wherein the bronchiectasis was caused by hypogammaglobulinemia.
  • Keapl inhibitor according to any one of statements IB to 19B, wherein the bronchiectasis was caused by alpha-l-antitrypsin deficiency.
  • Keapl inhibitor according to any one of statements IB to 20B, wherein the administration reduces bacterial load in sputum cultures obtained from the patient, optionally wherein the reduction occurs within 12 weeks of the first administration, within 8 weeks of the first administration, or within 4 weeks of the first administration.
  • Keapl inhibitor according to any one of statements IB to 22B, wherein the Keapl inhibitor is a compound of Formula (I) wherein
  • R 1 is Ci- 4 al kyl
  • R 2 is Ci- 4 al kyl, optionally substituted with 1 to 3 fluorine atoms, R 3 is H, F or Cl,
  • R 4 is H, F or Cl
  • R 5 is Ci- 4 al kyl, or a pharmaceutically acceptable salt thereof.
  • Keapl inhibitor according to any one of statements IB to 23B, wherein the Keapl inhibitor is -chloro-8-((5-(difluoromethyl)-l-methyl-lH-l,2,3- triazol-4-yl)methoxy)-l-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-l,2,3,4-tetrahydroisoquinoline-2- carbonyl)-l-methylcyclohexane-l-carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • Keapl inhibitor according to any one of statements IB to 23B, wherein the Keapl inhibitor is -chloro-8-((l,5-dimethyl-lH-l,2,3-triazol-4- yl)methoxy)-7-fluoro-l-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-l,2,3,4-tetrahydroisoquinoline-2- carbonyl)-l-methylcyclohexane-l-carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • Keapl inhibitor according to any one of statements IB to 23B, wherein the Keapl inhibitor is -chloro-8-((5-(difluoromethyl)-l-methyl-lH-l,2,3- triazol-4-yl)methoxy)-7-fluoro-l-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-l,2,3,4- tetrahydroisoquinoline-2-carbonyl)-l-methylcyclohexane-l-carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • 27B The use of a Keapl inhibitor according to any one of statements IB to 22B, wherein the
  • Keapl inhibitor is bardoxolone methyl, or a pharmaceutically acceptable salt thereof, or omaveloxolone, or a pharmaceutically acceptable salt thereof.

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Abstract

La présente invention concerne des inhibiteurs de Keap1 destinés à être utilisés dans le traitement de la bronchectasie.
PCT/EP2025/062916 2024-05-13 2025-05-12 Inhibiteurs de keap1 destinés à être utilisés dans le traitement de la bronchectasie Pending WO2025237912A1 (fr)

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Citations (4)

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WO2021214470A1 (fr) 2020-04-22 2021-10-28 C4X Discovery Limited Composés de tétrahydroisoquinoléine utilisés en tant qu'activateurs de nrf2
WO2021214472A1 (fr) 2020-04-22 2021-10-28 C4X Discovery Limited Composés de tétrahydroisoquinoléine utilisés en tant qu'activateurs de nrf2

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WO2020084300A1 (fr) 2018-10-22 2020-04-30 C4X Discovery Limited Composés thérapeutiques
WO2021214470A1 (fr) 2020-04-22 2021-10-28 C4X Discovery Limited Composés de tétrahydroisoquinoléine utilisés en tant qu'activateurs de nrf2
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