Alvelestat in the treatment of non-cystic fibrosis bronchiectasis

Abstract

The invention relates to medical uses of alvelestat, and pharmaceutically acceptable salts thereof, in the treatment of non-cystic fibrosis bronchiectasis.

Description

NEW TREATMENTSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of UK patent application 2416580.5, filed 11 November 2024, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] The invention relates to novel methods of using alvelestat, or pharmaceutically acceptable salts thereof, in the treatment of non-cystic fibrosis bronchiectasis.BACKGROUND OF THE INVENTION

[0003] Bronchiectasis is a lung disorder which may be characterised by progressive, irreversible damage and widening of the airways ( / .e., bronchi and / or bronchioles). Bronchiectasis encompasses stable state phases interspersed with phases of acute worsening of signs and symptoms. Symptoms of bronchiectasis include persistent cough, shortness of breath, wheezing, coughing up blood or bloodstained phlegm, chest pain, joint pain; and in some cases, clubbing of the fingertips ( / .e., where the tissue beneath the nail thickens and the fingertips become rounded and bulbous). However, at an earlier stage, patients affected by bronchiectasis may be asymptomatic.

[0004] Bronchiectasis is typically idiopathic; however, bronchiectasis may be associated with underlying immunodeficiency, allergic bronchopulmonary aspergillosis, aspiration, severe childhood lung infections (e.g., pneumonia, whooping cough, tuberculosis, or measles), cilia abnormalities (e.g., Young’s syndrome or primary ciliary dyskinesia), or certain inflammatory diseases (i.e., rheumatoid arthritis, Sjogren’s syndrome, Crohn’s disease, and ulcerative colitis).

[0005] The widening of bronchi in the lungs of bronchiectasis patients may allow more mucus than usual to gather in the airways. This, in turn, may lead to an increased risk of infection and pulmonary exacerbation. A pulmonary exacerbation is an acute deterioration in baseline bronchiectasis symptomatology. For example, the EMBARC / BRR working group has defined a pulmonary exacerbation as aperson with bronchiectasis with a deterioration in three or more of the following key symptoms for a period of at least 48 hours: cough; sputum volume and / or consistency; sputum purulence; breathlessness and / or exercise tolerance; fatigue and / or malaise; haemoptysis; and a change in bronchiectasis treatment is required (as determined by a clinician); (Hill AT, Haworth CS, Aliberti S, et al. Pulmonary exacerbation in adults with bronchiectasis: a consensus definition for clinical research. Eur Respir J 2017; 49: 1700051 ). An exacerbation has been defined in the GOLD 2024 report as an event characterized by dyspnea and / or cough and sputum that worsen over <14 days. In some cases, patients experience a severe pulmonary exacerbation which requires hospitalisation.

[0006] Pulmonary exacerbations arising in bronchiectasis patients are frequently alleviated by either antibiotic administration (for pulmonary exacerbations arising from bacterial infection) or oral corticosteroids (for certain other instances); serious risks are associated with the use of both antibiotics (for example, the risk of antibiotic-resistance developing) and oral corticosteroids (for example, increased appetite leading to weight gain, acne, muscle weakness, delayed wound healing, Cushing’s syndrome, osteoporosis, diabetes, glaucoma and cataracts, stomach ulcers, mental health disorders). For patients experiencing frequent pulmonary exacerbations, long-term dosing of antibiotics carries a particular risk of antibiotic resistance developing. Accordingly, there is a need in the art for new means of alleviating pulmonary exacerbations in the treatment of bronchiectasis.

[0007] In addition to presenting acute symptoms, pulmonary exacerbations may lead to further airway damage. This contributes to the progressive worsening of bronchiectasis. Reactive treatments (e.g., antibiotics) prescribed in response to a symptomatic pulmonary exacerbation in bronchiectasis may not be able to prevent such worsening because there may inevitably be some delay in resolving the pulmonary exacerbation. Therefore, it is particularly desirable to prevent or delay pulmonary exacerbations to prevent progressive worsening of lung damage associated with bronchiectasis. Accordingly, there is a need in the art for new longterm treatments which are safe and effective in preventing or delaying pulmonary exacerbations.

[0008] As set out above, there is a need for new means of preventing, delaying and / or alleviating pulmonary exacerbations in the treatment of bronchiectasis. The invention addresses, inter alia, these needs in the art.

[0009] WO 2005 / 026123, which is incorporated herein by reference in its entirety, teaches a class of neutrophil elastase (“NE”) inhibitors that are useful in therapy; including a specific NE inhibitor compound identified therein as 6-methyl- 5-(1 -methyl-1 H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1 -[3- (trifluoromethyl)phenyl]-1 ,2-dihydropyridine-3-carboxamide and salts thereof (Example 94, page 85). This compound is known as alvelestat, AZD9668, or MPH966; and is depicted in formula (I) below. Preventing, delaying and / or alleviating pulmonary exacerbations in the treatment of bronchiectasis is not mentioned.

[0010] Similarly, WO 2010 / 094964, which is incorporated herein by reference in its entirety, teaches salt forms of alvelestat. Preventing, delaying and / or alleviating pulmonary exacerbations in the treatment of bronchiectasis is not mentioned.

[0011] In a short-term phase II signal-searching study evaluating efficacy and safety of alvelestat (60 mg BID) over 4 weeks in patients with bronchiectasis, alvelestat showed some signals indicative of potential clinical efficacy and was well-tolerated but the majority of the primary analyses did not meet statistical significance and there was no adjustment for multiplicity in the testing of these primary analyses (R. Stockley et al., Respiratory Medicine (2013), 107, 524-533). Further, the potential utility of alvelestat in preventing, delaying and / or alleviating pulmonary exacerbations was not examined in this study, nor was it suggested as a potential future outcome.

[0012] The phase 11 study ATALANTa (NCT03679598) was a 12-week, randomised, blinded, controlled clinical trial investigating alvelestat in alpha-1 antitrypsin deficiency associated chronic obstructive pulmonary disease / emphysema.Until now, results from this study regarding the preventing, delaying, and / or alleviating pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis have not been reported.

[0013] WO 2021 / 209739, which is incorporated herein by reference in its entirety, teaches dosage forms comprising alvelestat in methods of treating diseases of the respiratory system mediated by a-1 antitrypsin deficiency. However, preventing, delaying and / or alleviating pulmonary exacerbations in the treatment of bronchiectasis is not mentioned.

[0014] It has furthermore been suggested that specific NE inhibitors such as alvelestat will not be efficacious in bronchiectasis because they cannot achieve the simultaneous reduction in several key inflammatory mediators linked to exacerbation.

[0015] The invention provides, inter alia, a new clinical use of alvelestat by preventing, delaying and / or alleviating pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis.SUMMARY OF THE INVENTION

[0016] Surprisingly, it has been found that alvelestat, or a pharmaceutically acceptable salt or solvate thereof, may be effective in preventing, delaying and / or alleviating pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis. In particular, it has surprisingly now been found in analysis of results from two phase II clinical studies that alvelestat (particularly, at a dose of 120 mg BID or 240 mg BID) may reduce the rate and / or delay the onset of pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis. This is surprising because alvelestat has not previously been shown to prevent, delay and / or alleviate pulmonary exacerbations in patients with non-cystic fibrosis bronchiectasis. These clinical findings are supported by results demonstrating that by administering alvelestat at a dose of 120 mg BID or 240 mg BID, sufficient levels of NE inhibition may be provided to patients with non-cystic fibrosis bronchiectasis.

[0017] Thus, the invention generally relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in preventing, delaying and / or alleviatingpulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0018] The invention also generally relates to a method of treatment comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt or solvate thereof to a patient in need thereof to prevent, delay and / or alleviate pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in the patient.

[0019] The invention also generally relates to the use of alvelestat or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament to prevent, delay and / or alleviate pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0020] In an aspect of the invention, alvelestat, or a pharmaceutically acceptable salt or solvate thereof, is administered to reduce the rate of pulmonary exacerbations.

[0021] In an aspect of the invention, alvelestat, or a pharmaceutically acceptable salt or solvate thereof, is administered to increase the time to a first pulmonary exacerbation.

[0022] In an aspect of the invention, alvelestat, or a pharmaceutically acceptable salt or solvate thereof, is administered to increase the time between pulmonary exacerbations.

[0023] In an aspect of the invention, alvelestat, or a pharmaceutically acceptable salt or solvate thereof, is administered to reduce the duration of a pulmonary exacerbation.

[0024] In an aspect of the invention, alvelestat, or a pharmaceutically acceptable salt or solvate thereof, is administered to reduce healthcare utilisation by the patient.

[0025] In an aspect of the invention, alvelestat, or a pharmaceutically acceptable salt or solvate thereof, is administered to reduce the seventy of pulmonary exacerbations in the patient.

[0026] In an aspect of the invention, alvelestat, or a pharmaceutically acceptable salt or solvate thereof, is administered to reduce concomitant administration of corticosteroids and / or antibiotics to the patient.

[0027] Preferably, alvelestat or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of 120 mg BID or 240 mg BID.

[0028] Preferably, the invention relates to any of the aforementioned aspects wherein the pulmonary exacerbation is a moderate or severe pulmonary exacerbation; more preferably, a severe pulmonary exacerbation. For instance, in particular embodiments the invention comprises reducing in the rate of moderate or severe pulmonary exacerbations, more particularly reducing the rate of severe pulmonary exacerbations. Alternatively, or in addition, the invention may comprise increasing the time to first moderate or severe pulmonary exacerbation; in particular, increasing the time to first severe pulmonary exacerbation.

[0029] Further aspects and embodiments of the invention are described below. Even where not explicitly stated, all embodiments and aspects of the invention may be combined to form further aspects and embodiments.BRIEF DESCRIPTION OF THE FIGURES

[0030] Figure 1 is a plot of plasma concentrations (nM) of alvelestat against the change in sputum NE from baseline (for sputum samples collected 2 hours post-waking): at the pre-dose (Cmin) concentration.

[0031] Figure 2 is a corresponding plot at the post-dose (Cmax) concentration.

[0032] Figures 3 and 4 are corresponding plots for sputum samples collected at waking.

[0033] Figure 5 is a summary of steady state pharmacokinetic (“PK”) data (overall and by treatment) from a simulated population PK model. For the 240 mg dose escalation treatment arm a dose of 240 mg was used to derive the PK metrics.

[0034] Figure 6 is a bar chart showing combined acute exacerbation events across the ATALANTa and ASTRAEUS studies.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0035] As used herein, the term “about” can encompass a deviation around a referenced value of not more than 15%; particularly not more than 10%; particularlynot more than 5%. When the term “about” is used to qualify a particular value, the value itself is also explicitly included.

[0036] As used herein, a “pulmonary exacerbation” may refer to an acute deterioration in bronchiectasis symptoms (particularly, cough; sputum volume and / or consistency; sputum purulence; breathlessness and / or exercise tolerance; fatigue and / or malaise; haemoptysis); optionally caused by a pulmonary infection. More specifically, a “pulmonary exacerbation” may refer to a deterioration in three or more of the following key symptoms for a period of at least 48 hours: cough; sputum volume and / or consistency; sputum purulence; breathlessness and / or exercise tolerance; fatigue and / or malaise; haemoptysis; and a change in bronchiectasis treatment is required (as determined by a clinician).

[0037] As used herein, a “mild” pulmonary exacerbation refers to a pulmonary exacerbation which is treatable by short acting bronchodilators (SABDs) only.

[0038] As used herein, a “moderate” pulmonary exacerbation refers to a pulmonary exacerbation which is treatable by short acting bronchodilators (SABDs) in combination with oral corticosteroids and, optionally, antibiotics.

[0039] As used herein, a “severe” pulmonary exacerbation refers to a pulmonary exacerbation which requires hospitalisation of the patient or a visit to the emergency room for treatment. Alternatively, or in addition, a “severe” pulmonary exacerbation may refer to a pulmonary exacerbation resulting in acute respiratory failure.

[0040] As used herein, the “patient” is a human patient.

[0041] As used herein, the abbreviation “BID” is used to refer to twice-daily administration.

[0042] As used herein, “bronchiectasis" is used to refer to non-cystic fibrosis bronchiectasis.

[0043] Unless stated otherwise, as used herein in the context of bronchiectasis treatment, the term “standard of care” refers to conventional bronchiectasis medications which are known in the art; for example, chronic obstructive pulmonary disease (COPD) medications (typically inhalers, and some tablets and / or injections too), bronchodilators (long-acting beta-agonists and / or anticholinergics), antibiotics (e.g., IV, inhaled or oral), corticosteroids, and airway clearance maintenance treatments. Treatment using alvelestat according to theinvention is not encompassed by the term “standard of care” in the context of this disclosure.Medical Uses of the Invention

[0044] Generally, the invention relates to preventing, delaying and / or alleviating pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0045] Preferred aspects and embodiments of the invention are set out hereinbelow and in the appended claims.Reducing Rate of Pulmonary Exacerbations

[0046] In some aspects, the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the rate of pulmonary exacerbations. Reducing the rate of pulmonary exacerbations is an important clinical endpoint indicating beneficial treatment of the patient. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in reducing the rate of pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0047] The reduction in rate of pulmonary exacerbation may be relative to the rate of pulmonary exacerbations experienced by the patient prior to receiving treatment with alvelestat in accordance with the invention. Alternatively, or in addition, the reduction in rate of pulmonary exacerbation may be relative to a patient treated for non-cystic fibrosis bronchiectasis according to the standard of care or an untreated non-cystic fibrosis bronchiectasis patient.

[0048] In some embodiments, the rate of pulmonary exacerbations is calculated over a period of about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months or about 24 months. For instance, the rate of pulmonary exacerbations may be calculated over a period of about 3 months.

[0049] In some embodiments, the rate of pulmonary exacerbations in the patient is reduced by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 50%, by about 55%, by about 60%, by about 65%, or by about 70%.

[0050] In some embodiments, the rate of pulmonary exacerbations in the patient is reduced by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%. In particular embodiments, the rate of pulmonary exacerbations in the patient is reduced by at least about 50%. In more particular embodiments, the rate of pulmonary exacerbations in the patient is reduced by at least about 65%.

[0051] In particular embodiments, the rate of pulmonary exacerbations can be expressed as an “annualised rate” of pulmonary exacerbations ( / .e., the number of exacerbations experienced by the patient per year). The annualised rate of exacerbations might be measured over a period of at least one year, or the annualised rate might be measured over a period of less than a year and extrapolated therefrom. In some embodiments, the rate of pulmonary exacerbations in the patient is reduced to at most 5 pulmonary exacerbations per year, at most 4 pulmonary exacerbations per year, at most 3 pulmonary exacerbations per year, at most 2 pulmonary exacerbations per year, at most 1 pulmonary exacerbation per year. For instance, the rate of pulmonary exacerbations in the patient may be reduced to at most 5 pulmonary exacerbations per year. In particular embodiments, the rate of pulmonary exacerbations in the patient is reduced to at most 3 pulmonary exacerbations per year. In more particular embodiments, the rate of pulmonary exacerbations in the patient is reduced to at most 2 pulmonary exacerbations per year.

[0052] In the above-defined embodiments, the pulmonary exacerbations may be mild, moderate or severe. It would be particularly beneficial to reduce the rate of moderate and / or severe pulmonary exacerbations.

[0053] In particular aspects, therefore, the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the rate of moderate and / or severe pulmonary exacerbations. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in reducing the rate of moderate and / or severe pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0054] In more particular aspects, the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the rate of severe pulmonaryexacerbations. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in reducing the rate of severe pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient.Increasing Time to a First Pulmonary Exacerbation

[0055] In some aspects, the preventing, delaying and / or alleviating pulmonary exacerbations comprises increasing the time to a first pulmonary exacerbation.Increasing time to a first pulmonary exacerbation is an important measure of delay of exacerbation. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the time to a first pulmonary exacerbation in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0056] The increase in time to a first pulmonary exacerbation may be relative to a patient treated for non-cystic fibrosis bronchiectasis according to the standard of care or an untreated non-cystic fibrosis bronchiectasis patient.

[0057] In some embodiments, the increasing the time to a first pulmonary exacerbation comprises increasing by at least about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 10 weeks, or about 12 weeks. For instance, the increasing the time to a first pulmonary exacerbation comprises increasing by at least about 8 weeks.

[0058] In some embodiments, the increasing the time to a first pulmonary exacerbation comprises an increase by about 20%, about 30% about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%. For instance, increasing the time to a first pulmonary exacerbation may comprise an increase by about 50%.

[0059] In the above-defined embodiments, the pulmonary exacerbations may be mild, moderate or severe. It would be particularly beneficial to increase the time to first moderate and / or severe pulmonary exacerbations.

[0060] In particular aspects, therefore, the preventing, delaying and / or alleviating pulmonary exacerbations comprises increasing the time to a first moderate or severe pulmonary exacerbation. Accordingly, in a particular aspect,the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the time to a first moderate or severe pulmonary exacerbation in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0061] In more particular aspects, the preventing, delaying and / or alleviating pulmonary exacerbations comprises increasing the time to a first severe pulmonary exacerbation. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the time to a first severe pulmonary exacerbation in the treatment of non-cystic fibrosis bronchiectasis in a patient.Increasing the time between Pulmonary Exacerbations

[0062] In some aspects, the preventing, delaying and / or alleviating pulmonary exacerbations comprises increasing the time between pulmonary exacerbations. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the time between pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0063] The increase in time between pulmonary exacerbations may be relative to the time between pulmonary exacerbations experienced by the patient prior to receiving treatment with alvelestat in accordance with the invention. Alternatively, or in addition, the increase in time between pulmonary exacerbations may be relative to a patient treated for non-cystic fibrosis bronchiectasis according to the standard of care or an untreated non-cystic fibrosis bronchiectasis patient.

[0064] In some embodiments, the increasing the time between pulmonary exacerbations comprises increasing by at least about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 10 weeks, or about 12 weeks. For instance, the increasing the time between pulmonary exacerbations comprises increasing by at least about 8 weeks.

[0065] In some embodiments, the increasing the time between pulmonary exacerbations comprises an increase by about 20%, about 30% about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%. For instance,increasing the time between pulmonary exacerbations may comprises an increase by about 50%.

[0066] In the above-defined embodiments, the pulmonary exacerbations may be mild, moderate or severe. It would be particularly beneficial to increase the time between moderate and / or severe pulmonary exacerbations.

[0067] In particular aspects, therefore, preventing, delaying and / or alleviating pulmonary exacerbations comprises increasing the time between moderate and / or severe pulmonary exacerbations. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the time between moderate and / or severe pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0068] In more particular aspects, the preventing, delaying and / or alleviating pulmonary exacerbations comprises increasing the time between severe pulmonary exacerbations. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the time between severe pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient.Reducing the Duration of Pulmonary Exacerbations

[0069] In some aspects, the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the duration of a pulmonary exacerbation. Reducing the duration of an exacerbation is important to minimise the impact on and damage to the patient, and to reduce impact on healthcare utilisation.Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in reducing the duration of a pulmonary exacerbation in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0070] The reduction in duration of pulmonary exacerbation may be relative to the duration of pulmonary exacerbations experienced by the patient prior to receiving treatment with alvelestat in accordance with the invention. Alternatively, or in addition, the reduction in duration of pulmonary exacerbation may be relative to a patient treated for non-cystic fibrosis bronchiectasis according to the standard of care or an untreated non-cystic fibrosis bronchiectasis patient.

[0071] In some embodiments, the duration of a pulmonary exacerbation is reduced to a duration of about 120 hours, about 108 hours, about 96 hours, about 84 hours, about 72 hours, about 60 hours, or about 48 hours. For instance, the duration of a pulmonary exacerbation may be reduced to a duration of about 72 hours.

[0072] In some embodiments, the duration of a pulmonary exacerbation is reduced by at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about 96 hours, or at least about 120 hours. For instance, the duration of a pulmonary exacerbation may be reduced by at least about 48 hours.

[0073] In the above-defined embodiments, the pulmonary exacerbations may be mild, moderate or severe. It would be particularly beneficial to reduce the duration of moderate and / or severe pulmonary exacerbations.

[0074] In particular aspects, therefore, preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the duration of a moderate or severe pulmonary exacerbation. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in reducing the duration of a moderate or severe pulmonary exacerbation in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0075] In more particular aspects, the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the duration of a severe pulmonary exacerbation. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in reducing the duration of a severe pulmonary exacerbation in the treatment of non-cystic fibrosis bronchiectasis in a patient.Reducing Healthcare Utilisation

[0076] In some aspects, the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing healthcare utilisation by the patient.Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in reducing healthcare utilisation by the patient in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0077] The reduction in healthcare utilisations may be relative to the frequency or duration of healthcare utilisations experienced by the patient prior to receiving treatment with alvelestat in accordance with the invention. Alternatively, or in addition, the reduction in frequency or duration of healthcare utilisations may be relative to a patient treated for non-cystic fibrosis bronchiectasis according to the standard of care or an untreated non-cystic fibrosis bronchiectasis patient.

[0078] In some embodiments, reducing healthcare utilisation by the patient comprises reducing the frequency of hospitalisations of the patient; and / or duration of hospitalisation; and / or frequency of GP visits; and / or frequency of primary care interactions; and / or frequency of emergency room attendance; and / or frequency of re-hospitalisations. For example, reducing healthcare utilisation by the patient may comprise reducing the frequency of hospitalisations of the patient; and the duration of hospitalisation; and the frequency of GP visits; and the frequency of primary care interactions; and the frequency of emergency room attendances; and the frequency of re-hospitalisations.

[0079] In some embodiments, reducing healthcare utilisation by the patient comprises reducing the frequency of hospitalisations. Reducing the frequency of hospitalisations of the patient may comprise reducing the frequency of hospitalisations by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 50%, by about 55%, by about 60%, by about 65%, or by about 70%.

[0080] In some embodiments, reducing the frequency of hospitalisations of the patient comprises reducing the frequency of hospitalisations by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%.

[0081] In some embodiments, the frequency of hospitalisations of the patient is reduced to at most 5 hospitalisations per year, at most 4 hospitalisations per year, at most 3 hospitalisations per year, at most 2 hospitalisations per year, at most 1 hospitalisation per year. For instance, the frequency of hospitalisations of the patient may be reduced to at most 5 hospitalisations per year. In particular embodiments, the frequency of hospitalisations of the patient is reduced to at most 3 hospitalisations per year. In more particular embodiments, the frequency of hospitalisations of the patient is reduced to at most 2 hospitalisations per year.

[0082] In some embodiments, reducing healthcare utilisation by the patient comprises reducing the duration of hospitalisation. Reducing the duration of hospitalisation may comprise reducing the duration of hospitalisations by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 50%, by about 55%, by about 60%, by about 65%, or by about 70%.

[0083] In some embodiments, the duration of hospitalisation is reduced to a duration of about 120 hours, about 108 hours, about 96 hours, about 84 hours, about 72 hours, about 60 hours, or about 48 hours, about 36 hours, or about 24 hours. For instance, the duration of hospitalisation may be reduced to a duration of about 48 hours.

[0084] In some embodiments, reducing healthcare utilisation by the patient comprises reducing the frequency of GP (general practitioner, also known as primary care practitioner or family doctor) visits. In some embodiments, reducing the frequency of GP visits by the patient comprises reducing the frequency of GP visits by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 50%, by about 55%, by about 60%, by about 65%, or by about 70%.

[0085] In some embodiments, reducing the frequency of GP visits by the patient comprises reducing the frequency of GP visits by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%. In particular embodiments, the frequency of GP visits by the patient is reduced by at least about 50%.

[0086] In some embodiments, the frequency of GP visits by the patient is reduced to at most 5 visits per year, at most 4 visits per year, at most 3 visits per year, at most 2 visits per year, at most 1 visit per year. For instance, the frequency of GP visits by the patient may be reduced to at most 5 visits per year. In particular embodiments, the frequency of GP visits by the patient is reduced to at most 3 visits per year. In more particular embodiments, the frequency of GP visits by the patient is reduced to at most 2 visits per year.

[0087] In some embodiments, reducing healthcare utilisation by the patient comprises reducing the frequency of primary care interactions. In some embodiments, reducing the frequency of primary care interactions of the patient comprises reducing the frequency of primary care interactions by about 20%, byabout 25%, by about 30%, by about 35%, by about 40%, by about 50%, by about 55%, by about 60%, by about 65%, or by about 70%.

[0088] In some embodiments, reducing the frequency of primary care interactions of the patient comprises reducing the frequency of primary care interactions by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%. In particular embodiments, the frequency of primary care interactions of the patient is reduced by at least about 50%.

[0089] In some embodiments, the frequency of primary care interactions of the patient is reduced to at most 5 interactions per year, at most 4 interactions per year, at most 3 interactions per year, at most 2 interactions per year, or at most 1 interaction per year. For instance, the frequency of primary care interactions of the patient may be reduced to at most 5 interactions per year. In particular embodiments, the frequency of primary care interactions of the patient is reduced to at most 3 interactions per year. In more particular embodiments, the frequency of primary care interactions of the patient is reduced to at most 2 interactions per year.

[0090] In some embodiments, reducing healthcare utilisation by the patient comprises reducing the frequency of emergency room attendances. In some embodiments, reducing the frequency of emergency room attendances by the patient comprises reducing the frequency of emergency room attendances by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 50%, by about 55%, by about 60%, by about 65%, or by about 70%.

[0091] In some embodiments, reducing the frequency of emergency room attendances by the patient comprises reducing the frequency of emergency room attendances by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%. In particular embodiments, the frequency of emergency room attendances by the patient is reduced by at least about 50%.

[0092] In some embodiments, the frequency of emergency room attendances by the patient is reduced to at most 5 attendances per year, at most 4 attendances per year, at most 3 attendances per year, at most 2 attendances per year, or at most 1 attendance per year. For instance, the frequency of emergency roomattendances by the patient may be reduced to at most 5 attendances per year. In particular embodiments, the frequency of emergency room attendances by the patient is reduced to at most 3 attendances per year. In more particular embodiments, the frequency of emergency room attendances by the patient is reduced to at most 2 attendances per year.

[0093] In some embodiments, reducing healthcare utilisation by the patient comprises reducing the frequency of re-hospitalisations. In some embodiments, reducing the frequency of re-hospitalisations of the patient comprises reducing the frequency of re-hospitalisations by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 50%, by about 55%, by about 60%, by about 65%, or by about 70%.

[0094] In some embodiments, reducing the frequency of re-hospitalisations of the patient comprises reducing the frequency of re-hospitalisations by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%. In particular embodiments, the frequency of re-hospitalisations of the patient is reduced by at least about 50%.

[0095] In some embodiments, the frequency of re-hospitalisations of the patient is reduced to at most 5 re-hospitalisations per year, at most 4 rehospitalisations per year, at most 3 re-hospitalisations per year, at most 2 rehospitalisations per year, or at most 1 re-hospitalisation per year. For instance, the frequency of hospitalisations of the patient may be reduced to at most 5 rehospitalisations per year. In particular embodiments, the frequency of rehospitalisations of the patient is reduced to at most 3 re-hospitalisations per year. In more particular embodiments, the frequency of re-hospitalisations of the patient is reduced to at most 2 re-hospitalisations per year.

[0096] In some embodiments, re-hospitalisations are measured as readmission to emergency room or hospital for failure of treatment of the pulmonary exacerbation, within 60 days (optionally, within 30 days) of the initial hospitalisation.Severity of Pulmonary Exacerbations

[0097] In particular embodiments, the pulmonary exacerbation is a moderate or severe pulmonary exacerbation. In more particular embodiments, the pulmonary exacerbation is a severe pulmonary exacerbation.

[0098] In some aspects, preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the seventy of pulmonary exacerbations in the patient. In doing so, even if the rate of frequency of overall pulmonary exacerbations is constant, the patient experiences a reduction in the overall impact of exacerbations. Accordingly, in a particular aspect, the invention relates to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in reducing the seventy of a pulmonary exacerbation in the treatment of non-cystic fibrosis bronchiectasis in a patient.

[0099] In some embodiments, the severity of pulmonary exacerbations in the patient is reduced such that the patient experiences mild or moderate pulmonary exacerbations only during treatment with alvelestat in accordance with the invention. In other words, the severity of pulmonary exacerbations in the patient is reduced such that the patient does not experience a severe pulmonary exacerbation during treatment with alvelestat in accordance with the invention.

[0100] In some embodiments, the severity of pulmonary exacerbations in the patient is reduced such that the patient experiences mild pulmonary exacerbations only during treatment with alvelestat in accordance with the invention. In other words, the severity of pulmonary exacerbations in the patient is reduced such that the patient does not experience a moderate or severe pulmonary exacerbation during treatment with alvelestat in accordance with the invention.Improving Lung Function

[0101] The medical uses of the invention may also further comprise improving the lung function of the patient. Such an improvement may be indicative of an overall improvement in the pathology of the patient. In some embodiments, the improvement in lung function is an increase in forced expiratory volume in one second (FEV1 ); and / or an increase in slow vital capacity (SVC).

[0102] FEV1 is the forced expiratory volume in 1 second, i.e., the volume of air that can be forcibly blown out in the first second after full inspiration, typically measured by spirometry. The predicted normal FEV1 values are those that wouldbe expected for a healthy subject, depending on factors including race, age, sex, and height. Predicted normal values can be easily determined by practitioners, or more usually calculated by spirometry machines. For example, standardized equations for calculating predicted normal FEV1 values are provided in Quanjeret al. (Eur. Respir. J., 1993, 6, Suppl. 16, 5-40). An FEV1 value that is higher as a percentage of the predicted FEV1 value represents milder disease. Pulmonary function testing (FEV1 , FVC, FEV1 / FVC, and maximal mid-expiratory flow) may be performed according to American Thoracic Society (ATS) Standardization of Spirometry 2019. Spirometers are typically used for these assessments.

[0103] In some embodiments, the improvement in lung function is an increase in forced expiratory volume in one second (FEV1 ). In some embodiments, the increase in FEV1 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%.

[0104] In some embodiments, the increase in FEV1 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%.

[0105] In some embodiments, the increase in FEV1 is an increase of about 25 mL to about 300 mL. In particular embodiments, the increase in FEV1 is an increase of about 25 mL to about 150 mL.

[0106] In some embodiments, the improvement in lung function is an increase in slow vital capacity (SVC). In some embodiments, the increase in SVC is an increase of about 25 mL to about 300 mL. In particular embodiments, the increase in SVC is an increase of about 25 mL to about 150 mL.Improving Quality of Life

[0107] In some aspects, the medical uses of the invention further comprise improving the patient's quality of life. In particular embodiments, the quality of life is assessed by the St George's Respiratory Questionnaire (SGRQ).

[0108] The St. George’s Respiratory Questionnaire (SGRQ) is a validated patient reported outcome designed to measure clinical impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. The SGRQ Total Score incorporates scores from each component of the SGRQ.The SGRQ Activity Score is a subset of the results of the SGRQ in the Activity Domain that assesses the effects of breathlessness on mobility and physical activity. Thus, in particular embodiments of the invention, the treatment of the invention comprises improving the patient’s quality of life. More particularly, the treatment comprises improving (i.e. reducing) the SGRQ Total Score of the patient. Even more particularly, the treatment comprises improving (i.e. reducing) the SGRQ Activity Score of the patient.

[0109] In particular embodiments, improving the patient's quality of life comprises improving (i.e. reducing) the SGRQ Total Score of the patient to achieve a clinically meaningful response. In more particular embodiments, the treatment comprises improving (i.e. reducing) the SGRQ Activity Score of the patient to achieve a clinically meaningful response. In this context, achieving a clinically meaningful response can be defined as improving (i.e., reducing) the score beyond a given threshold. Such a threshold may be the minimal clinically important difference (MCID), i.e., the smallest change in a treatment outcome that an individual patient would identify as important, and which would indicate a change in the patient’s management.

[0110] The MCID for SGRQ Total may be about 4, e.g., 4. The threshold for SGRQ Total may be about 4, e.g., 4. In some embodiments, achieving a clinically meaningful response in SGRQ Total Score is improving (i.e. reducing) the score by at least about 4, e.g., improving (i.e. reducing) the score by at least 4. In particular embodiments, the treatment comprises improving (i.e. reducing) the SGRQ Total Score of the patient by at least about 4, e.g., improving (i.e. reducing) the score by at least 4.

[0111] The MCID for SGRQ Activity may be about 7, e.g., 7.1. The threshold for SGRQ Activity may be about 7, e.g., 7.1. In some embodiments, achieving a clinically meaningful response in SGRQ Activity Score is improving (i.e. reducing) the score by at least about 7, e.g., improving (i.e. reducing) the score by at least 7.1. In particular embodiments, the treatment comprises improving (i.e. reducing) the SGRQ Activity Score of the patient by at least about 7, e.g., improving (i.e. reducing) the score by at least 7.1 .

[0112] Such improvements are typically evaluated by comparing the score at baseline (i.e., prior to administration of alvelestat or salt thereof) to the scoredetermined after administration of alvelestat or salt thereof for a period of time. For example, the improvement may be determined after about 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, or 12 weeks of administration.Concomitant Treatments

[0113] In some aspects, the medical uses of the invention further comprise reducing concomitant administration of other treatments for non-cystic fibrosis bronchiectasis, for example reducing the dosage and / or frequency of other treatments for non-cystic fibrosis bronchiectasis. In particular, the concomitant administration of corticosteroids and / or antibiotics to the patient may be reduced.

[0114] In some embodiments, the reducing concomitant administration of corticosteroids to the patient comprises reducing the dosage and / or frequency of concomitant administration of corticosteroids. Corticosteroids include cortisone, prednisolone, prednisone, methylprednisolone, dexamethasone, betamethasone, hydrocortisone, triamcinolone, deflazacort, and budesonide. The concomitant administration of all of these may be reduced in accordance with the invention.

[0115] In some embodiments, the reducing concomitant administration of antibiotics to the patient comprises reducing the frequency of concomitant administration of antibiotics. Antibiotics include: penicillins (such as amoxycillin, piperacillin, co-amoxiclav), tetracyclines (such as doxycycline), macrolides (such as clarithromycin) and fluroquinolones (such as levofloxacin and ciprofloxacin). The concomitant administration of all of these may be reduced in accordance with the invention.

[0116] In particular embodiments, the reducing concomitant administration of corticosteroids and / or antibiotics comprises discontinuing concomitant treatment with corticosteroids and / or antibiotics.

[0117] In some aspects, the medical uses of the invention further comprise administration of a further therapeutic agent in combination with the alvelestat, or pharmaceutically acceptable salt or solvate thereof. In particular embodiments, the further therapeutic agent is a standard of care medication for the treatment of non- cystic fibrosis bronchiectasis.Mode of Administration

[0118] Preferably, the medical uses of the invention involves oral administration of the alvelestat, or pharmaceutically acceptable salt or solvate thereof, to the patient. Accordingly, the corresponding methods of the invention preferably comprise the step of orally administering alvelestat, or pharmaceutically acceptable salt or solvate thereof, to the patient.

[0119] In preferred embodiments, the alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered twice daily to the patient as part of the methods of treatment according to the invention. Twice daily administration means that the administration takes place at regular spaced intervals, particularly at least 8 hours apart, more particularly at least 10 hours apart, for example about 12 hours apart ± 1 hour. For instance, the dose may be administered with 12 hours between administrations.

[0120] In some embodiments at least about 60 mg of alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered twice daily. In particular embodiments, at least about 120 mg of alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered twice daily. Thus, a minimum total daily dose of about 240 mg is typically administered. For example, about 120 mg, about 180 mg, or about 240 mg may be administered to the patient twice daily.

[0121] Throughout all aspects and embodiments of the invention, doses are referred to as the equivalent amount of alvelestat free base. So, for example, when a salt of alvelestat is used, the dose mentioned refers to the amount of alvelestat free base within the salt, meaning that the actual of alvelestat salt will be higher than the quoted value. For example, when a dose of about 120 mg of alvelestat or salt thereof is administered as alvelestat tosylate, the amount of alvelestat tosylate administered will be about 158 mg. Likewise, when a dose of about 240 mg of alvelestat or salt thereof is administered as alvelestat tosylate, the amount of alvelestat tosylate administered will be about 316 mg.

[0122] Thus, in preferred embodiments, about 120 mg of alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered to the patient twice daily. In other preferred embodiments, about 240 mg of alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered to the patient twice daily.

[0123] For all of the aspects of the invention disclosed herein, a maximum total daily dose of alvelestat, or pharmaceutically acceptable salt or solvate thereof, of about 600 mg is not exceeded.

[0124] The alvelestat, or pharmaceutically acceptable salt or solvate thereof, may be administered according to a dosage escalation regime in all methods of the invention. This allows safe titration up to a daily dose of alvelestat, or pharmaceutically acceptable salt or solvate thereof, e.g., of about 120mg twice daily. For example, a dosage escalation regime up to about 120mg twice daily dose of alvelestat, or pharmaceutically acceptable salt or solvate thereof, according to the invention comprises administration of alvelestat, or pharmaceutically acceptable salt or solvate thereof, at a dose of about 60mg of alvelestat, or pharmaceutically acceptable salt or solvate thereof, twice daily for a first period of time, followed by about 120mg twice daily thereafter. The first period may be from 5-20 days, particularly each about one week (7 days). In particular, alvelestat, or pharmaceutically acceptable salt or solvate thereof, may be administered at 60mg twice daily for one week, followed by about 120mg twice daily thereafter.

[0125] A dose escalation regime may also be used to allow safe titration up to a daily dose of alvelestat, or pharmaceutically acceptable salt or solvate thereof, e.g., of about 240mg twice daily. For example, a dosage escalation regime up to about 240mg twice daily dose of alvelestat according to the invention comprises administration of alvelestat, or pharmaceutically acceptable salt or solvate thereof, at a dose of about 60mg of alvelestat, or pharmaceutically acceptable salt or solvate thereof, twice daily for a first period of time, followed by about 120mg twice daily for a second period of time, followed by about 180mg twice daily for a third period of time, and about 240mg twice daily thereafter. The first, second and third periods may each be from 5-20 days, preferably each about one week (7 days). In particular, alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered at about 60mg twice daily for one week, followed by about 120mg twice daily for one week, followed by about 180mg twice daily for one week, and about 240mg twice daily thereafter.Duration of Administration

[0126] In particular embodiments, the alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered for at least 12 weeks; optionally, at least 24 weeks; optionally, at least 36 weeks; optionally, at least 48 weeks.Form of the Medicament

[0127] In particular embodiments, the medical uses and methods of the invention involve administration of alvelestat free base, or a solvate thereof, to the patient. In more particular embodiments, alvelestat free base is administered to the patient.

[0128] In particular aspects, the medical uses and methods of the invention involves administration of alvelestat tosylate, or a solvate thereof, to the patient. In more particular embodiments, alvelestat tosylate is administered to the patient.

[0129] The alvelestat, or pharmaceutically acceptable salt or solvate thereof, may be administered as a solid dosage form (for example, as a tablet or capsule). In particular embodiments, the alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered as a tablet.

[0130] Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, may be used alone when appropriate, or in the form of an appropriate pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particular compositions do not contain material capable of causing an adverse reaction, for example, an allergic reaction.

[0131] In some aspects, the medical uses of the invention involve a pharmaceutical composition comprising alvelestat, or pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0132] For oral administration alvelestat, or pharmaceutically acceptable salts or solvates thereof, may be admixed with an adjuvant, diluent or a filler, for example, lactose, saccharose, sorbitol, mannitol, dibasic calcium phosphate (dicalcium phosphate) including hydrated and anhydrous forms; a starch, for example, potato starch, corn (maize) starch or amylopectin; a cellulose derivativesuch as microcrystalline cellulose (MCC) or silicified microcrystalline cellulose (SMCC) and the like. In some embodiments mixtures of these may be used.

[0133] A binder may be optionally used, for example, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone (PVP) or gelatine. An example of hydroxypropyl cellulose includes HPC LF. Examples of hydroxypropylmethyl cellulose include PVP K30 and PVP K90.

[0134] Disintegrating agents include for example, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone (crosslinked polyvinylpyrrolidone) and the like. Disintegrating agents are exemplified by Kollidon CL (manufactured by BASF).

[0135] Lubricants include magnesium stearate, calcium stearate, sucrose esters of fatty acids, sodium stearyl fumarate, stearic acid, polyethyleneglycol, wax, paraffin and the like.

[0136] Surfactants include sodium lauryl sulfate, polysorbate 80, hydrogenated oil, polyoxyethylene(160)polyoxypropylene(30)glycol, and the like.

[0137] For each and every method of this invention, the invention provides a further embodiment relating to a method of treatment comprising administering alvelestat or a salt thereof to a patient in need in that method. For each and every method of this invention, the invention provides a further embodiment relating to alvelestat or a salt thereof for use in that method. For each and every method of this invention, the invention provides a further embodiment relating to alvelestat, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for that method.Methods of the Invention

[0138] The invention also relates to methods of treatment comprising administering an effective amount of alvelestat, or a pharmaceutically acceptable salt or solvate thereof to a patient in need thereof, for any of the medical uses described herein. The invention also relates to use of alvelestat, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treatment in any of the medical uses described herein.Incorporation by Reference

[0139] All documents referred to herein are hereby incorporated by reference in their entirety. Further embodiments

[0140] The invention also provides the following numbered embodiments:1 . A method of preventing, delaying and / or alleviating pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient in need thereof comprising administering to the patient an effective amount of alvelestat, or a pharmaceutically acceptable salt or solvate thereof.2. The method according to embodiment 1 , wherein the alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered to the patient at a dosage of 120 mg BID or 240 mg BID.3. The method according to any preceding embodiment, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the rate of pulmonary exacerbations.4. The method according to embodiment 3, wherein the rate of pulmonary exacerbations is calculated over a period of about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months or about 24 months.5. The method according to embodiment 3 or 4, wherein the rate of pulmonary exacerbations in the patient is reduced by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 50%, by about 55%, by about 60%, by about 65%, or by about 70%.6. The method according to embodiment 3 or 4, wherein the rate of pulmonary exacerbations in the patient is reduced by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%.The method according to embodiment 3 or 4, wherein the rate of pulmonary exacerbations is reduced to at most 3 pulmonary exacerbations per year; optionally, at most 2 pulmonary exacerbations per year. The method according to embodiment 1 or 2, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises increasing the time to a first pulmonary exacerbation. The method according to embodiment 1 or 2, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises increasing the time between pulmonary exacerbations. The method according to embodiment 8 or 9, wherein the increasing comprises increasing by at least about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 10 weeks, or about 12 weeks. The method according to embodiment 8 or 9, wherein the increasing comprises an increase by about 20%, about 30% about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%. The method according to embodiment 1 or 2, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the duration of a pulmonary exacerbation. The method according to embodiment 12, wherein the duration of a pulmonary exacerbation is reduced to a duration of about 120 hours, about 108 hours, about 96 hours, about 84 hours, about 72 hours, about 60 hours, or about 48 hours. The method according to embodiment 12, wherein the duration of a pulmonary exacerbation is reduced by at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about 96 hours, or at least about 120 hours. The method according to embodiment 1 or 2, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing healthcare utilisation by the patient.The method according to embodiment 15, wherein the reducing healthcare utilisation by the patient comprises reducing the frequency of hospitalisations of the patient; and / or duration of hospitalisations; and / or frequency of GP visits; and / or frequency of primary care interactions; and / or frequency of emergency room attendance; and / or frequency of re-hospitalisations. The method according to any preceding embodiment, wherein the pulmonary exacerbation is a moderate or severe pulmonary exacerbation. The method according to any preceding embodiment, wherein the pulmonary exacerbation is a severe pulmonary exacerbation. The method according to embodiment 1 or 2, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the seventy of pulmonary exacerbations in the patient. The method according to embodiment 19, wherein the seventy of pulmonary exacerbations in the patient is reduced such that the patient experiences mild or moderate pulmonary exacerbations only during treatment with alvelestat. The method according to embodiment 19, wherein the seventy of pulmonary exacerbations in the patient is reduced such that the patient experiences mild pulmonary exacerbations only during treatment with alvelestat. The method according to any preceding embodiment, wherein treatment further comprises improving the lung function of the patient. The method according to embodiment 22, wherein the improvement in lung function is an increase in forced expiratory volume in one second (FEV1 ). The method according to embodiment 23, wherein the increase in FEV1 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 method according to embodiment 23, wherein the increase in FEV1 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 method according to embodiment 23, wherein the increase in FEV1 is an increase of about 25 mL to about 300 mL; optionally, the increase in FEV1 is an increase of about 25 mL to about 150 mL. The method according to any preceding embodiment, wherein the treatment further comprises improving the patient's quality of life; optionally, wherein the quality of life is assessed by the St George's Respiratory Questionnaire (SGRQ). The method according to embodiment 22, wherein the improvement in lung function is an increase in slow vital capacity (SVC). The method according to embodiment 28, wherein the increase in SVC is an increase of about 25 mL to about 300 mL; optionally, the increase in SVC is an increase of about 25 mL to about 150 mL. The method according to any preceding embodiment, wherein the alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered for at least 12 weeks; optionally, at least 24 weeks; optionally, at least 36 weeks; optionally, at least 48 weeks. The method according to any preceding embodiment, wherein the treatment further comprises reducing concomitant administration of corticosteroids and / or antibiotics to the patient. The method according to embodiment 31 , wherein the reducing concomitant administration of corticosteroids to the patient comprises reducing the dosage and / or frequency of concomitant administration of corticosteroids. The method according to embodiment 31 , wherein the reducing concomitant administration of antibiotics to the patient comprises reducing the frequency of concomitant administration of antibiotics. The method according to any preceding embodiment, wherein the treatment further comprises discontinuing concomitant treatment with corticosteroids and / or antibiotics. The method according to any preceding embodiment, in combination with a further therapeutic agent.36. The method according to any preceding embodiment wherein the increasing, reducing or improving is relative to a patient receiving standard of care.37. The method according to any preceding embodiment wherein alvelestat, or a pharmaceutically acceptable salt or solvate thereof, is orally administered to the patient.38. The method according to any preceding embodiment wherein alvelestat is administered as alvelestat free base.39. The method according to any preceding embodiment wherein alvelestat is administered as alvelestat tosylate salt.EXAMPLESThe invention is illustrated by the following non-limiting examples.EXAMPLE 1 - Clinical Evidence for Using Alvelestat to Manage Pulmonary Exacerbations in the Treatment of Bronchiectasis Patients.

[0141] Two 12-week, randomised, blinded, controlled clinical trials investigating alvelestat in alpha-1 antitrypsin deficiency associated chronic obstructive pulmonary disease / emphysema were conducted: ASTRAEUS (NCT03636347) and ATALANTa (NCT03679598).

[0142] ASTRAEUS was a randomized double-blind placebo-controlled study in patients naive to augmentation or following a 6-month wash-out period to evaluate the mechanistic effect, safety, and tolerability of 12 weeks twice daily oral administration in participants with AATD, at two doses: a high dose (240 mg BID) and a low dose (120 mg BID). The study enrolled 99 adults with severe AATD related emphysema across 26 sites in North America, EU and U.K. of which 98 were dosed.

[0143] ATALANTa was a multicenter, double-blind, randomized, placebo- controlled Phase II clinical trial in participants with AATD and at risk for emphysema (Pi*ZZ, Pi*SZ, Pi*null, or another rare phenotype / genotype known to be associated with either low (serum AAT level <11 pM or <57.2 mg / dL) orfunctionally impaired AAT including “F” or “I” mutations). In this study, one dose of alvelestat (MPH966), 120 mg BID was tested against placebo.

[0144] Across both trials 10 / 161 (6.2%) patients had co-existing lung disease of bronchiectasis documented at entry to the study. A total of 9 with bronchiectasis (4 in ASTRAEUS and 5 in ATALANTa) received alvelestat, whilst 85 subjects without bronchiectasis received alvelestat. Randomisation was not stratified for coexisting bronchiectasis and of the 10 subjects, 9 received active treatment and 1 placebo.

[0145] Results

[0146] During the 12-week treatment period across both studies there were 5 acute exacerbations in the AATD patients who did not have bronchiectasis treated with alvelestat, compared with no exacerbations over the same period in those AATD patients with bronchiectasis treated with alvelestat (Table 1 ). The study period included a 4-week follow-up period after the 12-week treatment period. The number of exacerbations by week 16 (i.e. , including the 12-week treatment period and the 4- week follow-up period) is also reported for both groups of patients in Table 1 . Again, there were no acute exacerbations in those AATD patients with bronchiectasis treated with alvelestat, compared with 10 acute exacerbations in 8 patients in the AATD patients who did not have bronchiectasis treated with alvelestat.

[0147] Table 1 : Exacerbations to week 12 and week 16 by Bronchiectasis Status (limited to those treated with alvelestat and excluding placebo)

[0148] During the study, there were overall the number of exacerbations that would be expected to be observed in this population over 12 weeks. However, the observation that patients with bronchiectasis had a markedly lower rate of exacerbations when treated with alvelestat than those similarly treated but with AATD / COPD alone is unexpected, as patients with bronchiectasis and AATD / COPD are expected to have a higher risk of exacerbations that those with AATD / COPDalone (Ni Y et al Clinical characteristics of patients with chronic obstructive pulmonary disease with comorbid bronchiectasis: a systemic review and metaanalysis. International Journal of COPD 2015:10 1465-1475). At 16 weeks, the markedly lower rate of exacerbations in patients with bronchiectasis when treated with alvelestat than those similarly treated but with AATD / COPD alone is observed even more strongly.

[0149] These data support that alvelestat has a particular effect on controlling exacerbations in patients with bronchiectasis. These results are translatable to the wider bronchiectasis population. Bronchiectasis results from damage to respiratory tract from multiple different disorders, including in patients with AATD, all with comparable clinical features and exacerbation characteristics to idiopathic bronchiectasis (Eden et al 2019),

[0150] Exacerbations in patients with bronchiectasis are considered predominantly triggered by infection. Alvelestat is not known to have anti-microbial properties, and in the Phase II study in bronchiectasis (NCT00769119), alvelestat did not affect sputum colour or weight ( / .e., markers of bacterial load). It is therefore unexpected that 12-week alvelestat treatment reduced exacerbation rate in patients that had bronchiectasis.

[0151] Accordingly, based on these data, it has been plausibly demonstrated that alvelestat is effective in preventing, delaying and / or alleviating pulmonary exacerbations in the treatment of bronchiectasis; particularly, when administered at a dose of 120 mg BID or 240 mg BID', more particularly, when a 240 mg BID dosage is administered.EXAMPLE 2 - Pharmacokinetic Support for Exacerbation Management in Bronchiectasis patients.

[0152] The inventors analysed the relationship between alvelestat plasma exposure and changes in sputum NE activity from baseline. This involved analysis of pharmacokinetic (PK) data obtained from the Phase II trial of alvelestat in bronchiectasis ( / .e., NCT00769119; details of which are reported in R. Stockley et al., Respiratory Medicine (2013), 107, 524-533).

[0153] In the Phase II study of alvelestat in non-cystic fibrosis bronchiectasis (NCT00769119), alvelestat reduced NE activity in sputum but not significantly. However, based on the analysis described hereinbelow, alvelestat exposure has been demonstrated to be correlated closely to the reduction of NE activity in sputum in non-cystic fibrosis bronchiectasis patients. This new observation was consistent across two different types of sputum collection (‘2 hours post-waking’ and ‘waking’) and this observation was consistent at different PK measurement timings (‘pre-dose’ and ‘post-dose’). Accordingly, the inventors were able to conclude that plasma pre-dose levels of alvelestat (broadly corresponding to Cmin) correlating to the highest reduction of NE was >750 nM in bronchiectasis patients.

[0154] Plasma PK concentrations (nM) of alvelestat were plotted against the change in sputum NE activity from baseline (for sputum samples collected 2 hours post-waking) at two time points: at the pre-dose (approximately Cmin) concentration (Figure 1); and at the post-dose (approximately Cmax) concentration (Figure 2). Equivalent plots were also prepared for sputum samples collected at waking (Figures 3 and 4).

[0155] Based on these data, the inventors observed that there was a positive correlation between plasma PK concentration of alvelestat and reduction in NE activity in non-cystic fibrosis bronchiectasis patients, and this correlation was particularly strong in the pre-dose (approximately Cmin) samples. In particular, based on these pharmacokinetic analyses, the inventors concluded that a pre-dose alvelestat concentration ( / .e., Cmin) in excess of 750 nM was correlated with the optimal reduction of NE activity in non-cystic fibrosis bronchiectasis patients.

[0156] A population PK model of alvelestat was developed to describe the time course of alvelestat concentrations in healthy subjects, subjects with COPD and subjects with AATD. This utilised 4 studies including Phase 1 studies of healthy volunteers and COPD, and also sparse sampling PK measurements from the ASTRAEUS Phase 2 study in AATD. The model showed that a 2-compartment model that had joint first-order absorption and elimination was found to optimally describe the observed alvelestat concentrations in healthy, COPD and AATD subjects from these 4 studies.

[0157] Based on this population PK model (see Figure 5), the inventors found that the administration of 120 mg BID or 240 mg BID doses of alvelestat ensures that most or all patients have Cmin above this threshold.

[0158] Accordingly, the inventors concluded that these pharmacokinetic data support the utility of 120 mg BID or 240 mg BID as optimal alvelestat doses as part of the invention.EXAMPLE 3 - Combined Exacerbation Events Across ATALANTa and ASTRAEUS AATD Studies.

[0159] A review of the pooled exacerbation data from both the ATALANTa and ASTRAEUS AATD studies was conducted. This analysis was performed on all patients in the safety analysis set (this is, all patients who received at least one dose of investigational product in the study). The pooled exacerbation data are presented in Table 2; n is the number of patients who had an acute exacerbation event by week 16 (i.e., including the 12-week treatment period and the 4-week follow-up period), and [events] is the total number of acute exacerbation events by week 16 (some patients had more than 1 event). A reduction in the proportion of patients experiencing an acute exacerbation was evident for patients taking alvelestat vs placebo. In addition, when patients were split into the groups based upon their GOLD severity at baseline (GOLD stages 1-4), a reduction in the proportion of patients experiencing an acute exacerbation was evident for patients taking alvelestat vs placebo for each of these GOLD stages. These data are represented graphically in Figure 6.

[0160] Table 2: Pooled exacerbation data from the combined ATALANTa and ASTRAEUS studies**G0LD1 defined as FEV1 % predicted > 80***GOLD2 defined as 50 < FEV1 % predicted < 80****GOLD3 defined as 30 < FEV1 % predicted < 50

[0161] An additional analysis of exposure-adjusted exacerbations was performed (Table 3). This analysis was performed to ensure the original analysis (as detailed above) was not biased by the withdrawal of some patients on alvelestat at a stage too early to experience exacerbations. Data is presented as the event rate with the 95% confidence interval in parentheses and calculated both on the number of exacerbation events, or the number of patients with exacerbations (both analyses are shown in Table 3). The data show that even when adjusted by exposure to alvelestat, the reduction of exacerbations observed with alvelestat remains, supporting the outcomes of the analysis of the data of Table 2.

[0162] Table 3: Exposure-adjusted data from the combined ATALANTa and ASTRAEUS studiesinterpret as yearly rate)**patients (number of patients with >0 events in group I sum of days exposure in group x 365.25 to interpret as yearly rate)

Claims

CLAIMS1 . Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use in preventing, delaying and / or alleviating pulmonary exacerbations in the treatment of non-cystic fibrosis bronchiectasis in a patient.

2. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 1 , wherein the alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered to the patient at a dosage of 120 mg BID or 240 mg BID.

3. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to any preceding claim, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the rate of pulmonary exacerbations.

4. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 3, wherein the rate of pulmonary exacerbations is calculated over a period of about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months or about 24 months.

5. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 3 or 4, wherein the rate of pulmonary exacerbations in the patient is reduced by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 50%, by about 55%, by about 60%, by about 65%, or by about 70%.

6. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 3 or 4, wherein the rate of pulmonary exacerbations in the patient is reduced by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%.

7. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 3 or 4, wherein the rate of pulmonary exacerbations is reduced to at most 3 pulmonary exacerbations per year; optionally, at most 2 pulmonary exacerbations per year.

8. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 1 or 2, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises increasing the time to a first pulmonary exacerbation.

9. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 1 or 2, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises increasing the time between pulmonary exacerbations.

10. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 8 or 9, wherein the increasing comprises increasing by at least about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 10 weeks, or about 12 weeks.11 . Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 8 or 9, wherein the increasing comprises an increase by about 20%, about 30% about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%.

12. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 1 or 2, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the duration of a pulmonary exacerbation.

13. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 12, wherein the duration of a pulmonary exacerbation is reduced to a duration of about 120 hours, about 108 hours, about 96 hours, about 84 hours, about 72 hours, about 60 hours, or about 48 hours.

14. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 12, wherein the duration of a pulmonary exacerbation is reduced by at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about 96 hours, or at least about 120 hours.

15. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 1 or 2, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing healthcare utilisation by the patient.

16. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 15, wherein the reducing healthcare utilisation by the patient comprises reducing the frequency of hospitalisations of the patient; and / or duration of hospitalisations; and / or frequency of GP visits; and / or frequency of primary care interactions; and / or frequency of emergency room attendance; and / or frequency of re-hospitalisations.

17. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to any preceding claim, wherein the pulmonary exacerbation is a moderate or severe pulmonary exacerbation.

18. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to any preceding claim, wherein the pulmonary exacerbation is a severe pulmonary exacerbation.

19. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 1 or 2, wherein the preventing, delaying and / or alleviating pulmonary exacerbations comprises reducing the severity of pulmonary exacerbations in the patient.

20. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 19, wherein the severity of pulmonary exacerbations in the patient is reduced such that the patient experiences mild or moderate pulmonary exacerbations only during treatment with alvelestat.21 . Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 19, wherein the severity of pulmonary exacerbations in the patient is reduced such that the patient experiences mild pulmonary exacerbations only during treatment with alvelestat.

22. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to any preceding claim, wherein treatment further comprises improving the lung function of the patient.

23. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 22, wherein the improvement in lung function is an increase in forced expiratory volume in one second (FEV1 ).

24. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 23, wherein the increase in FEV1 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%.

25. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 23, wherein the increase in FEV1 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%.

26. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 23, wherein the increase in FEV1 is an increase of about 25 mL to about 300 mL; optionally, the increase in FEV1 is an increase of about 25 mL to about 150 mL.

27. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to any preceding claim, wherein the treatment further comprises improving the patient's quality of life; optionally, wherein the quality of life is assessed by the St George's Respiratory Questionnaire (SGRQ).

28. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 22, wherein the improvement in lung function is an increase in slow vital capacity (SVC).

29. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 28, wherein the increase in SVC is an increase of about 25 mL to about 300 mL; optionally, the increase in SVC is an increase of about 25 mL to about 150 mL.

30. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to any preceding claim, wherein the alvelestat, or pharmaceutically acceptable salt or solvate thereof, is administered for at least 12 weeks;optionally, at least 24 weeks; optionally, at least 36 weeks; optionally, at least 48 weeks.31 . Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to any preceding claim, wherein the treatment further comprises reducing concomitant administration of corticosteroids and / or antibiotics to the patient.

32. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 31 , wherein the reducing concomitant administration of corticosteroids to the patient comprises reducing the dosage and / or frequency of concomitant administration of corticosteroids.

33. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 31 , wherein the reducing concomitant administration of antibiotics to the patient comprises reducing the frequency of concomitant administration of antibiotics.

34. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to any preceding claim, wherein the treatment further comprises discontinuing concomitant treatment with corticosteroids and / or antibiotics.

35. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to any preceding claim, in combination with a further therapeutic agent.

36. Alvelestat, or a pharmaceutically acceptable salt or solvate thereof, for use according to any preceding claim wherein alvelestat, or a pharmaceutically acceptable salt or solvate thereof, is orally administered to the patient.

37. Alvelestat free base for use according to any preceding claim.

38. Alvelestat tosylate salt for use according to any preceding claim.

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