Use of alvelestat in specific patients

Abstract

The present invention relates to methods of treatment comprising the use of alvelestat or a salt thereof in treating patients with AATD-mediated respiratory disorders in patients with less severe disease.

Description

USE OF ALVELESTAT IN SPECIFIC PATIENTSGOVERNMENT LICENSE RIGHTS

[0001] This invention was made with government support under TR002450 awarded by The National Institutes of Health. The government has certain rights in the invention.CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority of: U.S. Provisional Patent Application Serial No. 63 / 613247, filed 21 December 2023; U.S. Provisional Patent Application Serial No. 63 / 559771 , filed 29 February 2024; and U.S. Provisional Patent Application Serial No. 63 / 682546, filed 13 August 2024. The contents of these applications are incorporated herein by reference.FIELD OF THE INVENTION

[0003] The present invention discloses a novel method of treatment making use of alvelestat and salts thereof in patients with an AATD-mediated disorder having mild disease.BACKGROUND OF THE INVENTION

[0004] AATD (a-1 antitrypsin deficiency) is the most common genetic cause of COPD (chronic obstructive pulmonary disease) and emphysema, accounting for 1- 4% of cases of COPD in the United States and affecting between 70,000-100,000 individuals. COPD affects nearly 24 million individuals and is the fourth leading cause of death in the United States. COPD is a heterogeneous disease characterized by progressive airflow obstruction, excessive inflammation, and protease / anti-protease imbalance.

[0005] The mechanisms by which AATD leads to COPD and emphysema are based primarily on the paradigm of protease-antiprotease imbalance. AAT (a-1 antitrypsin) is a member of the serine protease inhibitor superfamily of proteins which play a role in inactivating neutrophil elastase (NE) and other proteases. AAT reacts with NE much more readily than other proteases, including proteinase 3 (PR3), cathepsin G (CatG), and trypsin, and in the lung plays a major role inmitigating against NE-mediated elastolysis. In AATD, individuals not only have quantitatively less AAT, but the enzyme is less effective in inhibiting NE. NE is a protease stored in the azurophilic granules of neutrophils and causes more robust proteolysis and connective tissue degradation compared to other proteases, including CatG and PR3, contained in the same azurophilic granules. Under normal circumstances, NE is regulated by AAT, however, in conditions like COPD, and in particular AATD, the extracellular free enzyme NE concentration exceeds the buffering capacity of AAT. Thus, NE causes direct lung tissue destruction and initiates a cascade resulting in pulmonary inflammation, mucus overproduction, and further damage to lung tissue and extracellular matrix.

[0006] Alvelestat is a known inhibitor of neutrophil elastase, suitable for treating diseases mediated by AATD.

[0007] WO 2005 / 026123, which is incorporated herein by reference in its entirety, teaches a class of NE inhibitors that are useful in therapy.WO 2005 / 026123 further discloses 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.

[0008] Similarly, WO 2010 / 094964, which is incorporated herein by reference in its entirety, teaches salt forms of alvelestat, as shown above with respect to WO 2005 / 026123.

[0009] WO 2021 / 209739, which is hereby incorporated by reference in its entirety, discloses dosage regimens for the treatment of patients with a disease mediated by a-1 antitrypsin deficiency with alvelestat.

[0010] Despite previous use of alvelestat in disease mediated by AATD, there is a still a high unmet medical need for some patients, in particular patients with a mild disease state.SUMMARY OF THE INVENTION

[0011] Surprisingly, it has been found that alvelestat is more effective in treating AATD-mediated respiratory disease, as measured by patient-reported quality-of-life measures, in patients with AATD having a milder disease state compared to those having a more severe disease state. In particular, alvelestat has been found to be more effective in patient-reported quality-of-life measures in patients with an FEV1 value that is greater than or equal to about 58%, preferably greater than or equal to about 75%, of their predicted normal FEV1 value, at baseline.

[0012] Specifically, it was observed in analyses of the results of human clinical studies of alvelestat in patients with AATD, such as in planned subgroup analysis of the results of the ATALANTa clinical trial (see Example 2), that alvelestat was more likely to result in an improvement in SGRQ-Activity Score and SGRQ-Total Score, in patients with less severe disease. This demonstrates that milder patients tended to do better with respect to quality-of-life scores as compared to patients in the trials having more severe disease.

[0013] This result was unexpected: no link between the efficacy of alvelestat and the disease state of the patient has before been demonstrated.

[0014] Thus, the invention relates to a method for treating a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, comprising administering an effective amount of alvelestat or a salt thereof to a patient in need thereof, wherein the patient has an FEV1 value that is greater than or equal to about 58%, preferably greater than or equal to about 75%, of their predicted normal FEV1 value. The FEV1 of the patient is typically measured at baseline (i.e. prior to the administration of the alvelestat or a salt thereof).

[0015] Also provided is alvelestat or a salt thereof for use in treating a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency in apatient having an FEV1 values that is greater than or equal to about 58%, preferably greater than or equal to about 75%, of their predicted FEV1 value.

[0016] Also provided is the use of alvelestat or a salt thereof in the manufacture of a medicament treating a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency in a patient having an FEV1 values that is greater than or equal to about 58%, preferably greater than or equal to about 75%, of their predicted FEV1 value.

[0017] In another aspect, the invention provides a method for treating a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency in a patient in need thereof, comprising the steps of: a. taking a baseline measurement of the FEV1 of the patient, b. determining whether the FEV1 of the patient is greater than or equal to about 58%, preferably greater than or equal to about 75%, of the predicted normal value for that patient; and if so c. administering alvelestat or a salt thereof to the patient.

[0018] 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

[0019] Figure 1 is a schematic showing the results of the post hoc analysis of the results of the ASTRAEUS clinical trial described in Example 1 , comparing baseline features and change from baseline at week 12 in (a) SGRQ Total Score and (b) SGRQ Activity Score. Patients with a baseline FEV1 >58.55 predicted, i.e. milder patients) were more likely to have an improvement in SGRQ-Activity Score and SGRQ-Total score.

[0020] Figure 2 is a graph showing the absolute change from baseline in serum neutrophil elastase in the ATALANTa clinical trial described in Example 2, comparing the effect of administration of alvelestat in patients generally having less severe disease (i.e. those having baseline FEV1 of 89.3% of the predicted normal value who are not on AAT augmentation therapy) against those having more severe disease (i.e. those having baseline FEV1 of 69.8% of the predicted normalvalue and on AAT augmentation therapy). In the less severe patient group not on augmentation, significant absolute reduction from baseline and significant reduction from placebo at week 12 (P=0.002) was observed.

[0021] Figure 3 is a graph showing the change from baseline at week 12 in SGRQ Total Score, comparing the effect of administration of alvelestat in patients generally having less severe disease (i.e. those having baseline FEV1 of 89.3% of the predicted normal value who are not on AAT augmentation therapy) against those having more severe disease (i.e. those having baseline FEV1 of 69.8% of the predicted normal value and on AAT augmentation therapy). In the less severe patient group not on augmentation, alvelestat numerically reduced SGRQ Total Score from baseline and as compared to placebo at week 12.

[0022] Figure 4 is a graph showing the change from baseline at week 12 in SGRQ Activity Score, comparing the effect of administration of alvelestat in patients generally having less severe disease (i.e. those having baseline FEV1 of 89.3% of the predicted normal value who are not on AAT augmentation therapy) against those having more severe disease (i.e. those having baseline FEV1 of 69.8% of the predicted normal value and on AAT augmentation therapy). In the less severe patient group not on augmentation, alvelestat reduced SGRQ Activity Score significantly from baseline (P=0.0051 ) and from placebo at week 12 (P=0.0106).

[0023] Figure 5 is a graph showing the change from baseline at week 12 in SGRQ Total and Activity scores for a pool of patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) Grade 1 airflow limitation, having FEV1 >80% predicted, from both the ASTRAEUS and ATALANTa phase II clinical trials described in Examples 1 and 2. Alvelestat reduced both SGRQ Total and Activity scores relative to baseline, and provided a numerical improvement compared to placebo at week 12.DETAILED DESCRIPTION OF THE INVENTION

[0024] The invention relates to the treatment of patients with less severe (i.e. milder) AATD-mediated respiratory disease.

[0025] The severity of respiratory disease can be assessed by determining the FEV1 of the patient and comparing it to the patient’s predicted normal value.

[0026] 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 would be 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 Quanjer et 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.

[0027] Thus, the present invention relates to a method for treating a disease which is mediated by a-1 antitrypsin deficiency comprising administering an effective amount of alvelestat or a salt thereof to a patient in need thereof, wherein the patient has an FEV1 value that is greater than or equal to about 58%, preferably greater than or equal to about 75%, of their predicted normal FEV1 value.

[0028] The patient’s FEV1 value may be greater than or equal to about 60%, or greater than or equal to about 65%, or greater than or equal to about 70%, of their predicted normal FEV1 value. Preferably, the patient’s FEV1 value is greater than or equal to about 75% of their predicted normal FEV1 value, for example greater than or equal to about 80%, or greater than or equal to about 85%, or greater than or equal to about 90%, of their predicted normal FEV1 value. The FEV1 value of the patient may be measured at baseline (i.e. prior to administration of alvelestat or salt thereof).

[0029] It has been found that the treatment effect of alvelestat is greater in patients of the invention as compared to patients with more severe disease outside the present invention, i.e. having an FEV1 value less than about 58%, or more particularly less than about 75%, or even more particularly less than about 90%, of their predicted normal value. In particular, the treatment effect on quality-of-lifemeasures, such as the SGRQ Total Score or SGRQ Activity Score, is greater according to the present invention.

[0030] 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. In long-term follow-up of patients with AATD-LD, the Activity Domain of SGRQ shows the highest rate of annual change, particularly in patients with rapidly progressive AATD-LD defined by decline of percentage of predicted FEV1 and in association with changes in quality of life.

[0031] Thus, in preferred 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.

[0032] In preferred embodiments, the treatment comprises improving (i.e. reducing) the SGRQ Total Score of the patient to achieve a clinically meaningful response. In preferred 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.

[0033] 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 preferred 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.

[0034] 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 preferred 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 .

[0035] Such improvements are typically evaluated by comparing the score at baseline (i.e. prior to administration of alvelestat or salt thereof) to the score determined 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.

[0036] In some embodiments, the treatment comprises decreasing the neutrophil elastase activity in the patient. This may be determined by measuring the serum neutrophil elastase in a patient using any test or assay suitable for determining neutrophil elastase activity. Such improvements are typically evaluated by comparing the neutrophil elastase activity at baseline (i.e. prior to administration of alvelestat or salt thereof) to the score determined 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.

[0037] In preferred embodiments, alvelestat or salt 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, preferably at least 8 hours apart, more preferably at least 10 hours apart, for example about 12 hours apart ± 1 hour. Most preferably, the dose is administered with 12 hours between administrations.

[0038] Preferably, at least about 120 mg of alvelestat or a salt thereof is administered twice daily. Thus, a minimum total daily dose of about 240mg is typically administered. For example, about 120 mg, about 180 mg, or about 240 mg are administered to the patient twice daily.

[0039] Throughout all aspects and embodiments of the invention, doses are referred to as the equivalent amount of alvelestat free base. So, for example, whena 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.

[0040] Thus, in some preferred embodiments, about 120 mg of alvelestat or a salt thereof is administered to the patient twice daily. In other preferred embodiments, about 240 mg of alvelestat or a salt thereof is administered to the patient twice daily.

[0041] For all of the aspects of the invention disclosed herein, preferably a maximum daily dose of alvelestat or salt thereof of about 600 mg is not exceeded, more preferably not more than about 500 mg.

[0042] Alvelestat or a salt thereof may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least one week, at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 12 months, at least about 24 months, or longer. For example, the compound may be administered on a daily or intermittent schedule for the duration of the subject’s life.

[0043] The dose of alvelestat or a salt 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 salt thereof, e.g. of about 120mg twice daily (BID). For example, a dosage escalation regime up to about 120mg twice daily dose of alvelestat or salt thereof according to the invention comprises administration of alvelestat or a salt thereof at a dose of about 60mg of alvelestat or salt 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, preferably each about one week (7 days). In particular, alvelestat or a salt thereof may be administered at 60mg twice daily for one week, followed by about 120mg twice daily thereafter.

[0044] A dose escalation regime may also be used to allow safe titration up to a daily dose of alvelestat or salt thereof, e.g. of about 240mg twice daily (BID). For example, a dosage escalation regime up to about 240mg twice daily dose ofalvelestat according to the invention comprises administration of alvelestat or a salt thereof at a dose of about 60mg of alvelestat or salt 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 a salt 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.

[0045] Preferably, in the invention, alvelestat or a salt thereof is administered orally.

[0046] As used herein, a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency (AATD) may also be referred to as a disease of the respiratory system in a patient with AATD, or an AATD-related respiratory disease. For instance, as used herein, a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency includes a patient with a-1 antitrypsin deficiency who is suffering from a disease of the respiratory system described herein, e.g. chronic obstructive pulmonary disease (COPD) or emphysema.

[0047] A disease of the respiratory system which is mediated by a-1 antitrypsin deficiency includes AATD-related lung disease.

[0048] Alpha-1 antitrypsin deficiency lung disease (AATD-LD) is a rare genetic disease associated with a severe ‘loss of function’ deficiency of the alpha-1 antitrypsin (AAT) protein in serum. Patients with severe AATD are at high risk of early onset emphysema, which occurs in the absence of cigarette smoking. In addition to the young age of onset, this genetic form of emphysema, is different pathologically from the ‘usual COPD’ (which occurs in smokers with sufficient AAT).

[0049] As used herein, a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency includes asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer’s lung and relateddiseases; hypersensitivity pneumonitis; adult respiratory distress syndrome (ARDS); lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, pulmonary hypertension, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus.

[0050] In a preferred embodiment, the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is chronic obstructive pulmonary disease (COPD), emphysema, bronchiectasis, asthma and / or AATD-related lung disease. In a preferred embodiment, the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is chronic obstructive pulmonary disease (COPD). In another preferred embodiment, the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is emphysema. In another preferred embodiment, the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is bronchiectasis. In another preferred embodiment, the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is asthma. In a preferred embodiment, the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is AATD-related lung disease.

[0051] In more preferred embodiments, the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is emphysema.

[0052] Patients according to the invention may have any AATD genotype, i.e. of the SERPPINA1 gene. The SERPPINA1 gene is transmitted via autosomal dominant inheritance and has two alleles. The normal alleles are designated as Pi*M. There are five deficiency genotypes: Pi*MS, Pi*SS, Pi*MZ, Pi*SZ, and Pi*ZZ, expressing ~80%, 60%, 55%, 40%, and 15% of AAT protein, respectively. Apart from the more prevalent Pi*S and Pi*Z alleles, approximately 50 other extremely uncommon, so-called rare, and Pi*null-null deficiency alleles have been characterized. However, in clinical practice, 96% to 98% of individuals withdiseases associated with AATD exhibit Pi*ZZ genotypes, whereas only 2% to 4% present combinations of the “rare” or “null” Pi*Z or Pi*S, alleles.

[0053] In some embodiments, the AATD genotype of the patient is Pi*ZZ, Pi*SZ or Pi*null. In some embodiments, the AATD genotype of the patient is Pi*ZZ. In some embodiments, the AATD genotype of the patient is Pi*SZ. In some embodiments, the AATD genotype of the patient is Pi*null.

[0054] The patient in need of treatment may be being treated concurrently with AAT augmentation therapy. Preferably, however, the patient is not concurrently being treated with AAT augmentation therapy.

[0055] In the invention, alvelestat may be administered as the free base or as any pharmaceutically acceptable salt form of alvelestat. Various salt forms are described in WO 2010 / 094964, for example, which is incorporated by reference in its entirety. Preferably, the free base or the tosylate salt of alvelestat is administered, most preferably the tosylate salt.

[0056] For all of the aspects of the invention disclosed herein, each dosage form is preferably a single solid entity. However, each administration may comprise a plurality of solid dosage forms.

[0057] The solid dosage form or forms as defined herein are preferably in the form of a tablet or capsule, most preferably a tablet.

[0058] Alvelestat or salt 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. Particularly preferred are compositions not containing material capable of causing an adverse reaction, for example, an allergic reaction.

[0059] According to the invention, there is provided a pharmaceutical composition comprising alvelestat or a salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

[0060] For oral administration alvelestat or salts thereof may, for example, 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, com (maize) starch or amylopectin; a cellulose derivative such as microcrystalline cellulose(MCC) or silicified microcrystalline cellulose (SMCC) and the like. In some embodiments mixtures of these may be used.

[0061] 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.

[0062] 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).

[0063] Lubricants include magnesium stearate, calcium stearate, sucrose esters of fatty acids, sodium stearyl fumarate, stearic acid, polyethyleneglycol, wax, paraffin and the like.

[0064] Surfactants include sodium lauryl sulfate, polysorbate 80, hydrogenated oil, polyoxyethylene(160)polyoxypropylene(30)glycol, and the like.

[0065] 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 salt thereof in the manufacture of a medicament for that method.

[0066] In all the methods described herein, the patient is a human patient in need thereof.

[0067] All documents referred to herein are hereby incorporated by reference in their entirety.EXAMPLESEXAMPLE 1

[0068] Alvelestat was studied in the following phase II clinical trial.

[0069] ASTRAEUS (ClinicalTrials.gov Identifier: NCT03636347) was a randomized double-blind placebo-controlled study in patients naive to augmentation or following a 6-month wash-out period to evaluate the mechanisticeffect, 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, Ell and U.K. of which 98 were dosed.

[0070] Patients underwent a twelve-week dosing period followed by a four- week follow-up. The primary endpoints included within individual % change from baseline up to end of treatment within a treatment arm and in comparison to placebo at weeks, four, eight and 12 in blood neutrophil elastase activity, Aa- Val360 levels and desmosine levels. The secondary endpoints were the proportion of patients with NE below the limit of quantitation and PK, safety and tolerability. Exploratory endpoints included rate of acute exacerbations of COPD, pulmonary function tests, St George’s Respiratory Questionnaire, inflammatory and lung damage biomarkers.

[0071] Inclusion Criteria:• Patients with a confirmed diagnosis of alpha-1 -anti-trypsin deficiency and a PiZZ, null or other rare geno / phenotype and serum anti-alpha1 antitrypsin levels of less than 11 uM. FEV1 >20% predicted• Computerised tomography (CT) scan evidence of emphysema• Non-smokers

[0072] Exclusion Criteria:• Primary diagnosis of bronchiectasis• An ongoing acute exacerbation of the underlying lung disease• Underlying liver disease or abnormal liver function tests• Previous augmentation therapy within 6 months of dosingEnrollment Overview

[0073] At the close of the study the number of patients enrolled and completed in the arms were, 41 in the high dose arm, 22 in the low dose arm and 36 in the placebo arm. All patients were of the PiZZ genotype representing the more severe patient population which occurs in Z allele homozygotes and is associated with early-onset emphysema. All patients had low AAT levels and only 11 % of the patients had received prior augmentation therapy. The wash-out period wasgreater than two years for those patients who had received prior augmentation therapy.Post hoc analysis

[0074] A post-hoc analysis of the clinical results (both low and high doses combined), comparing baseline features and change from baseline at week 12 in SGRQ Total and SGRQ Activity indicate that patients with less severe disease enrolled in the study, i.e. those with a baseline FEV1 greater than or equal to about 58% of the predicted normal value, were more likely to have an improvement in SGRQ Activity Score and SGRQ Total Score. This demonstrates that milder patients in ASTRAEUS tended to do better with respect to quality-of-life scores.

[0075] A schematic representation of the post hoc analysis of the SGRQ Total Score and SGRQ Activity Score results are shown in Figure 1(a) and 1 (b) respectively.

[0076] The Figures show the observed difference in effect on SGRQ Activity Score and SGRQ Total Score, depended on the baseline FEV1 as a percent of the predicted value.

[0077] No other subgroup analysis showed such a large deviation in SGRQ results. This indicates that the identification of a patient subgroup with milder disease, in which alvelestat had a greater therapeutic effect on clinical quality of life outcomes (SGRQ Total Score and SGRQ Activity Score), was highly surprising.Example 2

[0078] Alvelestat was studied in the following phase II clinical trial (ATALANTa, NCT03636347).

[0079] The study was a multicenter, double-blind, randomized, placebo- controlled trial. One dose of alvelestat (MPH966), 120 mg BID was tested against placebo. These doses are based on PK and PD modelling of alvelestat (MPH966) inhibition of human neutrophil elastase. It investigated the safety, tolerability and mechanistic effect of alvelestat, an oral neutrophil elastase inhibitor, in a broader range of people with confirmed AATD, including Pi*ZZ, Pi*SZ, Pi*null genotypes or another rare phenotype / genotype associated with either low or functionallyimpaired AAT. Patients receiving augmentation therapy, which represents the only treatment option currently available for AATD, were eligible.

[0080] The participants were those patients with AATD 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) or functionally impairedAAT including “F” or “I” mutations).

[0081] Following a screening period of up to 4 weeks, patients were dosed with 120mg alvelestat or matched placebo, twice daily, for 12 weeks, with a subsequent 4-week follow-up period for safety and determination of the offset of the mechanistic effect of MPH966 on the primary endpoint (desmosine / isodesmosine).Objectives and EndpointsNumber of Participants

[0082] A maximum of 66 participants were randomized so that approximately 60 evaluable participants completed the study.Inclusion Criteria

[0083] Participants were eligible to be included in the study only if ALL of the following criteria apply:Type of Participant and Disease Characteristics1 . Capable of giving signed informed consent2. Age >18 and <80 years3. Patients with a confirmed diagnosis of AATD: 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) or functionally impaired AAT including “F” or “I” mutations.4. FEV1 >25% predicted5. Patients were eligible if they were either a) are not currently receiving augmentation treatment and have not received augmentation in the 12 weeks prior to screening or b) had received weekly infusions of augmentation at 60 mg / kg for at least 12 weeks prior to screening and intended to continue augmentation through the study period.6. Male or female sex a. Male participants must agree to use a highly effective contraception during the treatment period and for at least 4 days after the last dose of study treatment and refrain from donating sperm during this period b. Female participants were eligible to participate if not pregnant; not breastfeeding; and at least one of the following conditions was met: i. Not a woman of childbearing potential OR ii. A woman of childbearing potential who agreed to follow the contraceptive guidance during the treatment phase and for at least 4 days after the last dose of study medication.Exclusion Criteria

[0084] Participants were excluded from the study if any of the following criteria apply:Excluded Medical Conditions1. Subjects with Pi*MZ, Pi*FM, Pi*MS, Pi*SS, or other AATD phenotypes / genotypes not known to be independently associated with emphysema.2. Any clinically diagnosed lung disease other than COPD such as diffuse interstitial lung diseases, cystic fibrosis, or clinically significant bronchiectasis as determined by the Investigator3. Acute exacerbation of underlying lung disease requiring oral steroids and / or antibiotics within 4 weeks of baseline4. Acute or chronic hepatitis, including hepatitis B, hepatitis C (positive serologies, including hepatitis B and C antibody)5. HIV infection or other immunodeficiency or with an absolute neutrophil count <1.0 x 1 O9 / L6. Abnormal liver biochemistry (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase) >1 .5 x upper limit of normal or total bilirubin > upper limit of normal (unless Gilbert’s disease with normal conjugated bilirubin)7. Any of the following laboratory abnormalities are present at baseline: a. Platelet count <150x109 / L b. Serum albumin < 3.5 g / dL c. INR >1.2 d. CPK > ULN.8. History or current evidence of cirrhosis (on biopsy or imaging), esophageal varices, ascites or hepatic encephalopathy.9. Evidence of other forms of chronic liver disease based on diagnostic testing as per the guidelines (i.e. autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson’s disease, Hemochromatosis or iron overload).10. Patients with nonalcoholic fatty liver disease (NAFLD) as diagnosed by any imaging modality (or use of drugs associated with NAFLD for more than 2 weeks in the year prior to screening).11. Subjects with a history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening, defined as average of >20g / day in female subjects and >30g / day in male subjects.12. Fibrosis-4 (FIB-4) score >3.2513. Any of the following cardiovascular conditions within 6 months prior to the screening visit: a. Myocardial infarction or unstable angina b. Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary intervention, or carotid revascularization procedurec. Uncontrolled hypertension d. Stroke or transient ischemic attack14. Congestive heart failure (New York Heart Association lll / IV) with left ventricular ejection fraction < 40%15. Any clinically significant 12-lead electrocardiogram abnormalities at screening or baseline, including corrected QT interval by Fridericia’s correction method >450 ms or history of significant cardiac dysrhythmia, including long QT syndrome16. History of cancer within the last 5 years, except for well-treated basal cell carcinoma and squamous cell carcinoma of the skin17. Other documented comorbidities or laboratory abnormalities that in the opinion of the Investigator could affect the outcome of the study assessments, participant safety, or ability of the participant to comply with the requirements of the protocolExcluded Prior / Concomitant Therapy18. Daily use of prednisone (>10mg daily), or other systemic glucocorticoids at comparable or higher equivalent dose, or use of other immunosuppressant therapies are prohibited19. Immunomodulating monoclonal antibodies within 6 months prior to screening are prohibited20. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs) was prohibited. Daily use of acetaminophen up to 2 g per day and aspirin up to 325 mg per day was permitted.21. Initiation of drugs known for hepatotoxic potential within the 28 days prior to screening including but not limited to: statins, NSAIDS, amoxicillin / clavulanate, PDE inhibitors (theophylline, roflumilast), and anti- epileptics. Subjects on established treatment for more than 28 days prior to screening will not be excluded. Requirement for medications mainly metabolized by CYP2C9 and with narrow therapeutic index (e.g., warfarin, phenytoin) is prohibitedExcluded Prior / Concurrent Clinical Study Experience22. Participation in any clinical investigation using medical devices or non-biologic treatments within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initial dosing (or longer if required by local regulations) was prohibited 23. Participation in any clinical investigation using biologic treatment within 6 months of screening was prohibited.24. Previous participation in a gene therapy study for AATD at any time was prohibited Other Exclusions25. History of hypersensitivity to alvelestat (MPH966) or any of its excipients or the class of neutrophil elastase inhibitors26. Known hypersensitivity to medications used in the study procedures (e.g. midazolam, fentanyl, and lidocaine for bronchoscopy)Treatments AdministeredBaseline characteristicsEnrolment Overview

[0085] The study enrolled 63 patients. The number of patients enrolled were 32 in the 120 mg alvelestat arm (44% of the patients were on concurrent augmentation therapy) and 31 in the placebo arm (48% of the patients were on concurrent augmentation therapy). Most patients were of the Pi*ZZ genotype representing the more severe patient population (75% and 77.42% of patients on treatment arm and placebo arm, respectively). Patients with the Pi*NN genotype (6.5% and 9.68% of patients on treatment arm and placebo arm, respectively) and the PI*SZ genotype (18.75% and 12.9% of patients on treatment arm and placebo arm, respectively) were enrolled as well. All patients had low AAT levels.Results of the planned subgroup analysis

[0086] It was found that patients not on AAT augmentation generally had a less severe (i.e. milder) disease compared to those on AAT augmentation. The average baseline FEV1 as percent predicted for patients not on AAT augmentation was 89.3% whereas average baseline FEV1 as percent predicted for those on AAT augmentation was 69.8%.

[0087] The level of neutrophil elastase is a direct measure of the on-target effect of alvelestat. In patients not on AAT augmentation, a significant absolute reduction from baseline and significant reduction from placebo was observed at week 12 (p = 0.002), as shown in Figure 2. Aa-val360is a biomarker of neutrophil elastase specific fibrinogen degradation. In patients not on AAT augmentation, an absolute reduction from baseline of -1 .2 nM was observed, not reaching statistical significance (p = 0.16) but it is noted that the lack of statistical significance may be because this is a small subgroup analysis.

[0088] In patients not on augmentation, alvelestat reduced SGRQ numerically but did not achieve statistical significance (p = 0.199). The between group change at week 12 was -4.7 (p = 0.10). This is a greater change than the minimal clinical 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, which is 4 for SGRQ Total Score in COPD. No effect was observed in the patients with more severe disease on augmentation. A comparison of these results is shown in Figure 3.

[0089] Surprisingly, alvelestat reduced SGRQ Activity score significantly from baseline (p = 0.0051 ) and from placebo (p = 0.0106), at week 12. The between group change at week 12 was -10 (p = 0.01 ). The MCID for SGRQ Activity Score in COPD is unknown, but estimated to be -7.1 (Jenkins AR et al, Baseline dependent minimally important differences for clinical outcomes of pulmonary rehabilitation in people with COPD, Pulmonology 2023 S2531 ). This is a larger reduction than for 120 mg BID in ASTRAEUS (-1 .7). No effect was observed in the patients with more severe disease on augmentation.Example 3

[0090] A pooled analysis from the phase II clinical trials ASTRAEUS (Example 1) and ATALANTa (Example 2) was performed.

[0091] Alpha-1 antitrypsin disease (AATD) patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) Grade 1 airflow limitation have not been regularly included in AATD studies. Patients with GOLD Grade 1 airflow limitation are defined as those having FEV1 >80% predicted.Objectives

[0092] A pooled analysis of all participants with GOLD Grade 1 airflow limitation from both the ASTRAEUS and ATALANTa phase II studies was carried out, with the objective of determining the effect of 12 weeks alvelestat treatment (120mg BID or 240mg BID) on SGRQ Total and Activity scores within this pool.Methods

[0093] Participants with GOLD 1 airflow limitation (established at baseline) were pooled. Within-group and between-group effects were analysed using a mixed model repeated measures approach.Results

[0094] The pool included 39 participants (22 on alvelestat, 17 on placebo); 17 came from ASTRAEUS and 22 from ATALANTa. Across all participants, the mean(standard deviation) baseline age was 49.1 years (11 .3) and the mean (standard deviation) baseline FEV1 was 95.5% (10.9).

[0095] Further baseline characteristics for the population are provided below, grouped by the treatment received by the patient. Baseline characteristics for population

[0096] After 12 weeks of alvelestat, the mean change from baseline at week 12 for SGRQ Total was -2.6 (95% Cl: -5.76, 0.56, p=0.1 ) and for SGRQ Activity was -6.5 (-10.87, -2.15, p=0.005), as shown in Figure 5.

[0097] Changes for placebo from baseline in either score were not significant(SGRQ Total: -0.29, SGRQ Activity: -1.17, p>0.05). Between group changes for both scores were numerically superior with alvelestat compared to placebo but did not achieve statistical significance. (SGRQ Total -2.31 , SGRQ Activity -5.34). Conclusions

[0098] Alvelestat treatment for 12-weeks was associated with improvement in SGRQ scores in participants with AATD and GOLD Grade 1 airflow limitation in a pooled analysis.Example 4

[0099] A further analysis was carried out on the population of Example 3. The results of a responder analysis of the proportion of patients achieving a clinically meaningful response, using a threshold of 4 for SGRQ Total (validated in COPD) and 7.1 for SGRQ Activity (literature estimate in COPD) to define responders, are presented in the table below.Responder Analysis of SGRQ Total and Activity Scores for Clinically MeaningfulDifferences

[0100] Approximately half of patients achieved a clinically meaningful response. This is further proof that alvelestat treatment for 12 weeks in patients with AATD and GOLD 1 airflow limitation at baseline was associated with improvement in SGRQ scores.DISCUSSION:

[0101] The results of Examples 1 and 2 showed a clear improvement in the effect of alvelestat in patients with less severe disease.

[0102] Moreover, a comparison of the results from Example 1 with those of Example 2 confirms the improved effect of alvelestat in patients with less severe disease.

[0103] The baseline characteristics in the table below show that the patients enrolled in the study of Example 2 that were not on AAT augmentation had milder disease than those enrolled in the study of Example 1 .

[0104] It is believed that this difference in disease severity underlay the difference in effect observed between these examples. In the study of example 1 (ASTRAEUS), the change in SGRQ Total Score in the low dose arm (120mg BID) after 12 weeks compared to placebo was -0.6. For non-augmentation patients in Example 2 (ATALANTa), the change in SGRQ Total Score was greater, reaching -4.7 after 12 weeks.

[0105] Likewise, in the study of example 1 (ASTRAEUS), the change in SGRQ Activity Score in the low dose arm (120mg BID) after 12 weeks compared to placebo was -1.7. For non-augmentation patients in Example 2 (ATALANTa), the change in SGRQ Total Score was greater, reaching -10 after 12 weeks.

[0106] In summary, the analyses of the results of the clinical trials in Examples 1 and 2 demonstrate that alvelestat provides a greater effect on patient-reported clinical outcomes, as shown by SGRQ Activity Score and SGRQ Total Score, in patients with less severe disease.

[0107] The results of Example 3 demonstrate that for patients with GOLD 1 airflow limitation, i.e. , FEV1 > 80% predicted, alvelestat provides an improvement in SGRQ scores relative to baseline, and a numerical improvement compared to placebo.

[0108] The results of Example 4 demonstrate that for patients with GOLD 1 airflow limitation, i.e., FEV1 > 80% predicted, treatment with alvelestat results in ahigher proportion of patients with enough improvement in SGRQ scores relative to baseline to show a clinically meaningful response compared to the proportion of patients on placebo.

Claims

CLAIMS1 . A method for treating a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, comprising administering an effective amount of alvelestat or a salt thereof to a patient in need thereof, wherein the patient has an FEV1 value that is greater than or equal to about 58% of their predicted normal FEV1 value.

2. A method for treating a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency in a patient in need thereof, comprising the steps of:(i) taking a baseline measurement of the FEV1 of the patient,(ii) determining whether the FEV1 of the patient is greater than or equal to about 58% of the predicted normal value for that patient; and if so(iii) administering alvelestat or a salt thereof to the patient.

3. The method of any preceding claim, wherein the patient has an FEV1 value that is greater than or equal to about 60% of their predicted normal FEV1 value.

4. The method of any preceding claim, wherein the patient has an FEV1 value that is greater than or equal to about 65% of their predicted normal FEV1 value.

5. The method of any preceding claim, wherein the patient has an FEV1 value that is greater than or equal to about 70% of their predicted normal FEV1 value.

6. The method of any preceding claim, wherein the patient has an FEV1 value that is greater than or equal to about 75% of their predicted normal FEV1 value.

7. The method of any preceding claim, wherein the patient has an FEV1 value that is greater than or equal to about 80% of their predicted normal FEV1 value.

8. The method of any preceding claim, wherein the patient has an FEV1 value that is greater than or equal to about 85% of their predicted normal FEV1 value.

9. The method of any preceding claim, wherein the patient has an FEV1 value that is greater than or equal to about 90% of their predicted normal FEV1 value.

10. The method of any preceding claim, wherein the treatment comprises improving the quality of life of the patient.11 . The method of claim 10, wherein the treatment comprises improving (i.e. reducing) the St. George's Respiratory Questionnaire (SGRQ) Total Score of the patient.

12. The method of claim 10 or 11 , wherein the treatment comprises improving (i.e. reducing) the St. George's Respiratory Questionnaire (SGRQ) Activity Score of the patient.

13. The method of any one of claims 10 to 12, wherein the treatment comprises improving (i.e. reducing) the St. George's Respiratory Questionnaire (SGRQ) Total Score of the patient to achieve a clinically meaningful response.

14. The method of any one of claims 10 to 13, wherein the treatment comprises improving (i.e. reducing) the St. George's Respiratory Questionnaire (SGRQ) Total Score of the patient by at least 4.

15. The method of any one of claims 10 to 14, wherein the treatment comprises improving (i.e. reducing) the St. George's Respiratory Questionnaire (SGRQ) Activity Score of the patient to achieve a clinically meaningful response.

16. The method of any one of claims 10 to 15, wherein the treatment comprises improving (i.e. reducing) the St. George's Respiratory Questionnaire (SGRQ) Activity Score of the patient by at least 7.1 .

17. The method of any preceding claim, wherein the treatment comprises decreasing neutrophil elastase activity in the patient.

18. The method according to any preceding claim, wherein the method comprises the administration of alvelestat or a salt thereof twice daily.

19. The method according to any preceding claim, wherein the method comprises the administration of at least about 120 mg of alvelestat or a salt thereof twice daily.

20. The method according to claim 19, wherein the method comprises the administration of about 120 mg of alvelestat or a salt thereof twice daily.

21. The method according to claims 19, wherein the method comprises the administration of about 240 mg of alvelestat or a salt thereof twice daily.

22. The method according to any preceding claim, wherein the method comprises the administration of alvelestat or a salt thereof orally.

23. The method according to any preceding claim, wherein the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is AATD-related lung disease.

24. The method according to any preceding claim, wherein the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is selected from the group consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, bronchiectasis, cystic fibrosis, sarcoidosis, farmer's lung, hypersensitivity pneumonitis, adult respiratory distress syndrome (ARDS), lung fibrosis, tuberculosis, aspergillosis, antitussive activity, iatrogenic cough, acute and chronic rhinitis, acute viral infection, pulmonary hypertension, infection due to respiratory syncytial virus, influenza, coronavirus and adenovirus.

25. The method according to claim 24, wherein the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is COPD.

26. The method according to claim 24, wherein the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is emphysema.

27. The method according to claim 24, wherein the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is bronchiectasis.

28. The method according to claim 24, wherein the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is asthma.

29. The method according to any preceding claim, wherein the method comprises the administration of alvelestat or a salt thereof in the form of a tablet or capsule, preferably a tablet.

30. The method according to any preceding claim, wherein the method comprises the administration of alvelestat tosylate.

31. The method according to any preceding claim, wherein the AATD genotype of the patient is Pi*ZZ.

32. The method according to any one of claims 1 to 30, wherein the AATD genotype of the patient is Pi*SZ.

33. The method according to any one of claims 1 to 30, wherein the AATD genotype of the patient is Pi* null.

34. Alvelestat or a salt thereof for use in a method of treatment according to any preceding claim.

35. Use of alvelestat or a salt thereof in the manufacture of a medicament for a treatment according to any preceding claim.

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