Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses

Definitions

• the present invention discloses a novel dosage form and dosage regimen of 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.
• Elastases are possibly the most destructive enzymes in the body, having the ability to degrade virtually all connective tissue components.
• hNE Human neutrophil elastase
• a member of the chymotrypsin superfamily of serine proteases is a 33-KDa enzyme stored in the azurophilic granules of the neutrophils.
• concentration of NE neutrophil elastase
• NE neutrophil elastase
• NE is rapidly released from the granules into the extracellular space (See Kawabat et al. 2002, Eur. J. Pharmacol. 451 ,1-10).
• the main intracellular physiological function of NE is degradation of foreign organic molecules phagocytosed by neutrophils, whereas the main target for extracellular elastase is elastin (Janoff and Scherer, 1968, J. Exp. Med.
• NE is unique, as compared to other proteases (for example, proteinase 3) in that it has the ability to degrade almost all extracellular matrix and key plasma proteins (See Kawabat et al. , 2002, Eur. J. Pharmacol. 451 ,1-10), including elastin, Type 3 and type 4 collagens, laminin, fibronectin, cytokines, etc. (Ohbayashi, H., 2002, Expert Opin. Investig. Drugs, 11 , 965-980). NE is a major common mediator of many pathological changes seen in chronic lung disease (Stockley, R. A. 1994, Am. J. Resp. Crit. Care Med. 150,109-113).
• Acute lung injury caused by endotoxin in experimental animals is associated with elevated levels of NE (Kawabata, et al., 1999, Am. J. Resp. Crit. Care, 161 , 2013- 2018).
• Acute lung inflammation caused by intratracheal injection of lipopolysaccharide in mice has been shown to elevate the NE activity in bronchoalveolar lavage fluid which is significantly inhibited by a NE inhibitor (Fujie et al. , 1999, Eur. J. Pharmacol.,
• NE also plays an important role in the neutrophil- induced increase of pulmonary microvascular permeability observed in a model of acute lung injury caused by tumour necrosis factor ⁇ x (TNFce) and phorbol myristate acetate (PMA) in isolated perfused rabbit lungs (Miyazaki et al. , 1998, Am. J. Respir. Crit. Care Med., 157, 89-94).
• TNFce tumour necrosis factor ⁇ x
• PMA phorbol myristate acetate
• NE has been implicated in the promotion or exacerbation of a number of diseases such as pulmonary emphysema, pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemia reperfusion injury, rheumatoid arthritis and pulmonary hypertension.
• ARDS adult respiratory distress syndrome
• the present invention discloses dosage forms and dosage regimens of 2- pyridione derivatives that are inhibitors of NE and homologous serine proteases such as proteinase 3 and pancreatic elastase, and are thereby useful in therapy.
• 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 designated herein as compound (I).
• Compound (I) is also known as alvelestat, AZD9668, or MPH966.
• WO 2010/094964 which is incorporated herein by reference in its entirety, teaches salt forms of compound (I), as shown above with respect to WO 2005/026123. This document reports that compound (I) is administered in a maximum daily amount of 200 mg per day.
• Compound (I) may be useful in the treatment of diseases of the respiratory tract/system such as obstructive diseases of the airways including: 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 related diseases; 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
• the present invention aims to provide highly effective NE inhibition, by dose regimens of 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, that achieve and sustain blood levels at or above those needed to inhibit NE throughout the dosing period and in particular prevent the initial activation of NE.
• the present invention provides a solid dosage form comprising 120-300 mg of 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 or a salt thereof.
• the present invention provides a solid dosage form comprising 220-300 mg of 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 or a salt thereof.
• the present invention provides a single or multiple solid dosage form(s) for oral administration of 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 or a salt thereof, for the treatment of a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, said single or multiple solid dosage form(s) comprising a total of 120-300 mg of 6-methyl-5-(l-methyl-1 H-pyrazol-5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo- 1 -[3-(trifluoromethyl)phenyl]-1 ,2-dihydropyridine-3-carboxamide
• the present invention provides a single or multiple solid dosage form(s) for oral administration of 6-methyl-5-(l- methyl-1 H-pyrazol-5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo-1 -[3- (trifluoromethyl)phenyl]-1 ,2-dihydropyridine-3-carboxamide or a salt thereof, for the treatment of a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, said single or multiple solid dosage form(s) comprising a total of 220-300 mg of 6-methyl-5-(l-methyl-1 H-pyrazol-5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo- 1 -[3-(trifluoromethyl)phenyl]-1 ,2-dihydropyridine-3-carboxamide or
• the present invention provides a single or multiple solid dosage form(s) for oral administration of 6-methyl-5-(l-methyl-1 H-pyrazol- 5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo-1 -[3-(trifluoromethyl)phenyl]-1 ,2- dihydropyridine-3-carboxamide or a salt thereof, for the treatment of a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, said single or multiple solid dosage form(s) comprising a total of 120-300 mg of 6-methyl-5-(l-methyl- 1 H-pyrazol-5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo-1 -[3- (trifluoromethyl)phenyl]-1 ,2-dihydropyridine-3-carboxamide or a
• the present invention provides a single or multiple solid dosage form(s) for oral administration of 6-methyl-5-(l-methyl-1 H- pyrazol-5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo-1 -[3- (trifluoromethyl)phenyl]-1 ,2-dihydropyridine-3-carboxamide or a salt thereof, for the treatment of a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, said single or multiple solid dosage form(s) comprising a total of 220-300 mg of 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
• the present invention provides a kit comprising a plurality of solid dosage forms for oral administration of 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 or a salt thereof, said kit containing instructions for sequentially administering a total of 120-300 mg of said 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 or a salt thereof per administration, and wherein the administration of each dose takes place twice daily, with at least 8 hours between
• the present invention provides a kit comprising a plurality of solid dosage forms for oral administration of 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 or a salt thereof, said kit containing instructions for sequentially administering a total of 220-300 mg of said 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 or a salt thereof per administration, and wherein the administration of each dose takes place twice daily, with at least 8 hours between administrations,
• the present invention provides a kit comprising a plurality of solid dosage forms for oral administration, each dosage form comprising 120-300 mg of 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 or a salt thereof, said kit containing instructions for sequential, twice daily administration of each dose, for the treatment of a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency.
• the present invention provides a kit comprising a plurality of solid dosage forms for oral administration, each dosage form comprising 220-300 mg of 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 or a salt thereof, said kit containing instructions for sequential, twice daily administration of each dose, for the treatment of a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency.
• the present invention provides a method for treating a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, comprising the twice daily oral administration of a single or multiple solid dosage form(s), said single or multiple solid dosage form(s) comprising a total of 120- 300 mg of 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 or a salt thereof per administration, to a human patient suffering from a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency.
• the present invention provides a method for treating a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, comprising the twice daily oral administration of a single or multiple solid dosage form(s), said single or multiple solid dosage form(s) comprising a total of 220-300 mg of 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 or a salt thereof per administration, to a human patient suffering from a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency.
• the present invention provides a single or multiple solid dosage form(s) for oral administration of 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 or a salt thereof, for the treatment of COPD (Chronic Obstructive Pulmonary Disease), said single or multiple solid dosage form(s) comprising a total of 120-300 mg of 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 or a salt thereof per administration.
• COPD Chronic Obstructive Pulmonary Disease
• the present invention provides a single or multiple solid dosage form(s) for oral administration of 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 or a salt thereof, for the treatment of COPD (Chronic Obstructive Pulmonary Disease), said single or multiple solid dosage form(s) comprising a total of 220-300 mg of 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 or a salt thereof per administration.
• COPD Chronic Obstructive Pulmonary Disease
• the present invention provides a single or multiple solid dosage form(s) for oral administration of 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 or a salt thereof, for the treatment of COPD (Chronic Obstructive Pulmonary Disease), said single or multiple solid dosage form(s) comprising a total of 120-300 mg of 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 or a salt thereof per administration, and wherein the administration
• the present invention provides a single or multiple solid dosage form(s) for oral administration of 6-methyl-5-(1-methyl-
• said single or multiple solid dosage form(s) comprising a total of 220-300 mg of 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 or a salt thereof per administration, and wherein the administration of each dose takes place twice daily, with at least 8 hours between administrations.
• the present invention provides a kit comprising a plurality of solid dosage forms for oral administration of 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 or a salt thereof, said kit containing instructions for sequentially administering a total of 120-300 mg of said 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 or a salt thereof per administration, and wherein the administration of each dose takes place twice daily, with at least 8 hours between administrations,
• the present invention provides a kit comprising a plurality of solid dosage forms for oral administration of 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 or a salt thereof, said kit containing instructions for sequentially administering a total of 220-300 mg of said 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 or a salt thereof per administration, and wherein the administration of each dose takes place twice daily, with at least 8 hours between administrations,
• the present invention provides a kit comprising a plurality of solid dosage forms for oral administration, each dosage form comprising 120-300 mg of 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 or a salt thereof, said kit containing instructions for sequential, twice daily administration of each dose, for the treatment of COPD (Chronic Obstructive Pulmonary Disease).
• COPD Choronic Obstructive Pulmonary Disease
• the present invention provides a kit comprising a plurality of solid dosage forms for oral administration, each dosage form comprising 220-300 mg of 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 or a salt thereof, said kit containing instructions for sequential, twice daily administration of each dose, for the treatment of COPD (Chronic Obstructive Pulmonary Disease).
• COPD Choronic Obstructive Pulmonary Disease
• the present invention provides a method for treating COPD (Chronic Obstructive Pulmonary Disease), comprising the twice daily oral administration of a single or multiple solid dosage form(s), said single or multiple solid dosage form(s) comprising a total of 120-300 mg of 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 or a salt thereof per administration, to a human patient suffering from COPD.
• COPD Chironic Obstructive Pulmonary Disease
• the present invention provides a method for treating COPD (Chronic Obstructive Pulmonary Disease), comprising the twice daily oral administration of a single or multiple solid dosage form(s), said single or multiple solid dosage form(s) comprising a total of 220-300 mg of 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 or a salt thereof per administration, to a human patient suffering from COPD.
• COPD Chironic Obstructive Pulmonary Disease
• COPD Chronic Obstructive Pulmonary Disease
• AATD a1 -antitrypsin
• the lung is particularly susceptible for two reasons: (1) the day to day inhalation of noxious substances, in particular cigarette smoke, are powerful activators of neutrophils causing release of NE; (2) Elastin - the target of elastase is a major component of lung tissue (more so than other tissues) and without protection of NE inhibitors the elastin that supports delicate structures of the lung is broken down and the lung tissue progressively destroyed.
• the disease of the respiratory system in particular COPD is preferably associated with a1 -antitrypsin deficiency (AATD).
• AATD a1 -antitrypsin deficiency
• the disease of the respiratory system for example COPD is preferably treated via NE inhibition.
• the present invention is not limited to a disease of the respiratory system associated with a1 -antitrypsin deficiency (AATD). Indeed, other diseases, e.g. panniculitis, may be associated with a1 -antitrypsin deficiency (AATD). Therefore, for each aspect of the invention described herein, there is also provided a further additional aspect where the disease can be any disease associated with a1 -antitrypsin deficiency (AATD), for example panniculitis.
• Figure 1 shows a box plot of percentage inhibition of zymosan-stimulated NE activity in plasma by plasma PK concentration (Multiple Ascending Dose study). Note: the dot is the mean value. The line inside the box represents the median (50th percentile). The upper and lower edges of the box represent the 75th and 25th percentiles respectively, i.e. the inter quartile range (IQR). The whiskers represent the extent of the data with 1 5 * IQR beyond the upper and lower percentiles. Outliers from this range are shown.
• IQR inter quartile range
• Figure 2 shows population PK simulated median plasma concentration absolute values for the tosylate salt of doses of up to 240 mg given BID (twice daily) or QD (once daily) 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, showing the 95% confidence intervals (Cl) for trough concentrations (Cmin).
• FIG. 3 shows a visualisation of proteinase/anti-proteinase imbalance model methodology. The following steps are shown. [1] plating of isolated neutrophils at 1 million cells/ml; [2] addition of substrate (fibrinogen) and stimulus (fMLP) beginning a 15 minute incubation period; [3] removal of treated cells from plate and centrifugation; [4-5] transfer of supernatant and disposal of cells. [B] indicates point of alvelestat addition to plated neutrophils alongside the addition of substrate and stimuli, namely “one-step” incubation.
• Figure 4 shows that increasing fibrinogen within a closed model increases elastase signal.
• B Quantity of Aa-Val 360 produced by 1 million neutrophils/ml when exposed to 550 nM uncleaved fibrinogen; n 3; normality determined by Shapiro-Wilk normality test; 0 to 550 significance determined by unpaired t-test; 550 to control significance determined by Mann-Whitney test; error bars mean +/- SEM.
• Figure 9 shows the inhibitory effect of AZD9668 (alvelestat) on proteinase activity. Percentage change in activity produced by increasing concentrations of alvelestat (at 10 nM, 50 nM, 100 nM, 1000 nM) on the activity of neutrophil elastase within a model of proteinase/anti-proteinase imbalance. No inhibitor as 100% activity baseline. Error bars mean +/- SEM.
• 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 related diseases; 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 fun
• COPD chronic ob
• the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is chronic obstructive pulmonary disease (COPD).
• COPD chronic obstructive pulmonary disease
• the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is emphysema.
• the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is bronchiectasis.
• the disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is asthma.
• 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.
• COPD chronic obstructive pulmonary disease
• emphysema emphysema
• a disease which is mediated by a-1 antitrypsin deficiency includes a patient with a-1 antitrypsin deficiency who is suffering from a disease.
• a disease which is mediated by a-1 antitrypsin deficiency includes panniculitis.
• Threshold Cmin values have been shown to be achieved and maintained when a patient suffering from a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency is administered a 120 mg of 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 or a salt thereof, twice daily.
• a minimum of 120 mg, twice per day is administered to the human patient suffering from a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, for example, COPD.
• a minimum total daily dose of 240mg, preferably 440 mg, more preferably 480 mg is administered.
• a minimum of 180 mg of alvelestat or a salt thereof, twice per day is administered to the human patient suffering from a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, for example, COPD.
• a minimum total daily dose of 360 mg, preferably 540 mg is administered.
• threshold Cmin values have been shown to be achieved and maintained when a patient suffering from a respiratory disease mediated by a-1 antitrypsin deficiency, for example COPD, is administered a 240 mg of 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 or a salt thereof, twice daily.
• a-1 antitrypsin deficiency for example COPD
• a minimum of 240 mg, twice per day is administered to the human patient suffering from a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency, for example COPD.
• a minimum total daily dose of 440 mg, preferably 480 mg is administered.
• Cmin is a term used in pharmacokinetics for the minimum blood plasma concentration reached by a drug prior to administration of a second dose. E.g. Cmin can be the trough plasma concentration observed in Figure 2. Cmin is the opposite of Cmax, the maximum concentration that the drug reaches (e.g. peak plasma concentration).
• the administered alvelestat or a salt thereof results in a Cmin plasma concentration of at least 300 nM in the patient.
• the administered alvelestat or a salt thereof results in a Cmax plasma concentration of at least 1000 nM in the patient.
• the administered alvelestat or a salt thereof results in a Cmin plasma concentration of at least 300 nM and a Cmax plasma concentration of at least 1000 nM in the patient.
• each dosage form is preferably a single solid entity.
• each administration may comprise a plurality of solid dosage forms, subject to each administration having no more than 300 mg of 6- methyl-5-(1 -methyl-1 FI-pyrazol-5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo-1 - [3-(trifluoromethyl)phenyl]-1 ,2-dihydropyridine-3-carboxamide or a salt thereof, and preferably 240-480 mg of 6-methyl-5-(1 -methyl-1 FI-pyrazol-5-yl)-N- ⁇ [5- (methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo-1 -[3-(trifluoromethyl)phenyl]-1 ,2- dihydropyridine-3-carboxamide or a salt thereof.
• 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.
• a maximum daily dose of 600 mg is not exceeded, more preferably not more than 500 mg.
• each individual dose contains between 120 and 250 mg of 6-methyl-5-(1 -methyl-1 Fl-pyrazol- 5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo-1 -[3-(trifluoromethyl)phenyl]-1 ,2- dihydropyridine-3-carboxamide or a salt thereof, for example 120 mg, 180 mg or 240 mg.
• each individual dose contains between 160 and 250 mg of 6-methyl-5-(1 -methyl-1 Fl-pyrazol- 5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo-1 -[3-(trifluoromethyl)phenyl]-1 ,2- dihydropyridine-3-carboxamide or a salt thereof, e.g. 180 mg.
• each individual dose contains between 220 and 250 mg of 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 or a salt thereof, e.g. 240 mg.
• the kit comprises a defined supply of dosage forms, such as a weekly, bi-weekly or monthly supply of dosage forms of 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 or a salt thereof.
• dosage forms such as a weekly, bi-weekly or monthly supply of dosage forms of 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 or a salt thereof.
• the salt of 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 is the tosylate salt of 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.
• 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, 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.
• the compound may be administered on a daily or intermittent schedule for the duration of the subject’s life.
• a dosage escalation regime up to a 120mg twice daily dose of alvelestat comprises administration of alvelestat or a salt thereof at a dose of 60mg of alvelestat twice daily for a first period of time, followed by 120mg twice daily thereafter.
• the first period may be from 5-20 days, preferably each about one week (7 days).
• alvelestat or a salt thereof is administered at 60mg twice daily for one week, followed by 120mg twice daily thereafter. Doses are referred to as the equivalent amount of alvelestat free base.
• a dose escalation regime may also be used to allow safe titration up to a daily dose of alvelestat, e.g. of 240mg twice daily (BID).
• a dosage escalation regime up to a 240mg twice daily dose of alvelestat according to the invention comprises administration of alvelestat or a salt thereof at a dose of 60mg of alvelestat twice daily for a first period of time, followed by 120mg twice daily for a second period of time, followed by 180mg twice daily for a third period of time, and 240mg twice daily thereafter.
• the first, second and third periods may each be from 5-20 days, preferably each about one week (7 days).
• alvelestat or a salt thereof is administered at 60mg twice daily for one week, followed by 120mg twice daily for one week, followed by 180mg twice daily for one week, and 240mg twice daily thereafter. Doses are referred to as the equivalent amount of alvelestat free base.
• the amount (e.g. mg) of alvelestat or a salt thereof referred to in the amount administered, the dose or the solid dosage form is the corresponding amount of alvelestat free base in the alvelestat or salt thereof.
• the amount of an alvelestat salt used will be equivalent to 240 mg of alvelestat freebase.
• alvelestat Cmax concentrations achieved by the described dosing regimen suppressed neutrophil elastase (NE) activity by 72.6% (see Figure 9).
• alvelestat may be a more potent inhibitor of NE than AAT augmentation therapy. It is therefore believed that alvelestat may be useful in treating patients who have not responded well to AAT augmentation therapy.
• Such augmentation therapy involves the administration of AAT intravenously in order to slow down progression of diseases of the respiratory system which are mediated by AATD.
• the invention provides a method of treating a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency (e.g. COPD) in a patient in need thereof who has not responded to AAT therapy, comprising administering an effective amount of alvelestat or a salt thereof as disclosed herein (e.g. 120-300 mg BID, in particular 220-300mg BID) to the patient.
• an effective amount of alvelestat or a salt thereof as disclosed herein e.g. 120-300 mg BID, in particular 220-300mg BID
• the administration of alvelestat or a salt thereof is either in place of, or in combination with, AAT augmentation therapy.
• Non-responders may be patients for whom AAT does not treat or delay progression of a disease of the respiratory system which is mediated by AATD, e.g. COPD.
• the patient in need of treatment may have previously been treated for a-1 antitrypsin deficiency, or is currently treated, by the administration of AAT.
• the compound (I) or salt thereof may be used alone when appropriate, or in the form of 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.
• the solid dosage form or forms as defined herein are preferably in the form of a tablet, tablets, capsule or capsules, most preferably a tablet.
• a pharmaceutical composition comprising a compound (I) or salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
• the compound (I) or salt thereof is preferably used in a micronised or a milled form.
• the compound (I) or salt thereof is preferably less than 50% by weight and more preferably less than 30% by weight of the total composition weight in the compositions described herein (including the oral compositions).
• 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.
• the invention provides a further embodiment relating to alvelestat or a salt thereof for use in that method.
• the invention provides a further embodiment relating to alvelestat or a salt thereof in the manufacture of a medicament for that method.
• alvelestat or a salt thereof is administered to a human patient in need thereof.
• the compound (I) 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, corn (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. In one embodiment the compound (I) tosylate is not admixed with mannitol.
• an adjuvant for example, lactose, saccharose, sorbitol, mannitol, dibasic calcium phosphate (dicalcium phosphate) including hydrated and anhydrous forms
• a starch for example, potato starch, corn (ma
• the quantity of hydrophilic celluloses, such as MCC in the complete formulation ranges between 50 % and 98 %.
• These adjuvents, diluents and fillers are used in total in 60 to 98 parts, preferably in 70 to 95 parts, thereof per 100 parts of the solid formulation by weight.
• cellulose derivatives such as microcrystalline cellulose, include Avicel PHIOI, PH 102, PH 102 SCG, PH200, PH301, PH302, and PH-F20, Avicel RC-A591 NF.
• An example of silicified microcrystalline cellulose products is ProSolv 90 HD, a mixture of MCC and colloidal silicon dioxide (manufactured by JRS Pharma).
• Examples of dibasic calcium phosphate dihydrate products are Calipharm D (from ThermoPhos), ICL D (from ICL Performance Products), Calstar (FMC Biopolymer), Di-Cafos (Chemische Fabrik Budenheim), DI-TAB (Innophos) and Emcompress (JRS Pharma LP).
• Examples of dibasic calcium phosphate anhydrate are ICL A (from ICL Performance Products), Fuji Calin (from Fuji Chemicals), A-TAB (Innophos), Di-Cafos AN (Chemische Fabrik Budenheim) and Emcompress Anhydrous (JRS Pharma LP).
• Examples of mannitol products is Pearlitol DC 300 and Pearlitol SD200 (manufactured by Roquette).
• An example of a lactose product is Pharmatose DCL 15 (manufactured by DMV).
• a binder may be optionally used, for example, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone (PVP) or gelatine and 0.5 to 10 parts, preferably 1 to 4 parts, thereof is used per 100 parts of the solid pharmaceutical formulation by weight.
• HPC hydroxypropyl cellulose
• HPMC hydroxypropylmethyl cellulose
• PVP polyvinylpyrrolidone
• gelatine 0.5 to 10 parts, preferably 1 to 4 parts, thereof is used per 100 parts of the solid pharmaceutical formulation by weight.
• An example of hydroxypropyl cellulose includes HPC LF.
• examples of hydroxypropylmethyl cellulose include PVP K30 and PVP K90.
• Disintegrating agents include for example, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone (crosslinked polyvinylpyrrolidone) and the like, and 0.5 to 15 parts, preferably 2 to 10 parts, thereof is used per 100 parts of the solid pharmaceutical formulation by weight. Disintegrating agents are exemplified by Kollidon CL (manufactured by BASF).
• Lubricants include magnesium stearate, calcium stearate, sucrose esters of fatty acids, sodium stearyl fumarate, stearic acid, polyethyleneglycol, wax, paraffin and the like.
• the amount of lubricant is between 0.05 % and 5 % and is preferably between 0.5 % to 3.5 %, wherein the % is by weight of the formulation.
• Surfactants include sodium lauryl sulfate, polysorbate 80, hydrogenated oil, polyoxyethylene(160)polyoxypropylene(30)glycol, and the like.
• the amount of surfactant is less than 2 %, suitably less than 1 .5%, for example less than 1.1 % wherein the % is by weight of the formulation.
• NE activity was evaluated in whole blood.
• NE suppressive effect of alvelestat or placebo was expressed as the percentage inhibition of the pre-treatment (baseline) zymosan stimulated NE.
• Alvelestat concentrations were measured in plasma by protein precipitation followed by liquid chromatography and tandem mass spectrometry, measured at the same timepoints as NE activity. Plasma concentrations were grouped for analysis as ⁇ 3nM; 3-30 nm; 30-300 nM and >300 nM.
• Figure 1 shows the percentage inhibition of zymosan stimulated neutrophil elastase (NE) in plasma at increasing concentrations of alvelestat, and indicates that -100% NE inhibition can be achieved by a plasma concentration of alvelestat of 300 nM or above.
• Figure 2 shows population PK simulated median plasma concentrations (dark line) for the tosylate salt of doses of up to 240 mg given BID (twice daily) or QD (once daily) 6-methyl-5-(1 -methyl-1 FI-pyrazol-5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2- yl]methyl ⁇ -2-oxo-1 -[3-(trifluoromethyl)phenyl]-1 ,2-dihydropyridine-3-carboxamide, showing the 95% Cl.
• the median and 95% Cl bounds show the predicted PK levels of 240 mg BID meet the greater than 300nM threshold (dotted line).
• Figure 2 also shows the predicted PK levels of 120 mg BID meet the 300nM threshold (dotted line).
• Table 1 shows population PK simulated median plasma concentrations for the tosylate salt of doses of up to 240 mg given BID (twice daily) or QD (once daily) 6- methyl-5-(1 -methyl-1 FI-pyrazol-5-yl)-N- ⁇ [5-(methylsulfonyl)pyridin-2-yl]methyl ⁇ -2-oxo-1 - [3-(trifluoromethyl)phenyl]-1 ,2-dihydropyridine-3-carboxamide, showing the median, lower and upper interquartile ranges (IIQ and ulQ), lower and upper 95% Cl (i95%CI) and u95%CI) for QD and BID dosing regimens.
• IIQ and ulQ interquartile ranges
• i95%CI i95%CI
• u95%CI u95%CI
• Example 3 the protection of proteinase associated lung damage by alvelestat (a neutrophil elastase inhibitor) [0096] Summary
• Alpha-1 antitrypsin deficiency is a genetic condition which can result in reduced/no release of the protective anti-proteinase alpha-1 antitrypsin (AAT).
• AAT protective anti-proteinase alpha-1 antitrypsin
• Uninhibited proteinase, in particular elastase, activity causes structural changes to the lung and leads to emphysema and airway obstruction.
• Using an in vitro model of this imbalance allows for physiological assessment of the effect of elastase inhibitors on neutrophil serine proteinases (NSPs) involved in pathophysiology.
• NSPs neutrophil serine proteinases
• This example describes the effect of adding alvelestat into a stimulated neutrophil-fibrinogen buffer model to assess changes in elastase activity by monitoring the release of elastase specific markers of the process.
• a model of the proteinase/anti-proteinase imbalance was developed and validated by describing the effect of the physiological inhibitor AAT on uninhibited NSP activity through elastase footprint activity immunoassays. Alvelestat was then added into the model.
• Results obtained by adding alvelestat indicate that the compound is successfully and rapidly able to inhibit elastase activity in vitro and more effectively than the physiological inhibitor AAT.
• Alpha-1 antitrypsin deficiency is a genetic condition arising from a mutation in the SERPINA1 gene [1] which encodes the glycoprotein alpha-1 antitrypsin (AAT) crucial for inhibition of destructive neutrophil serine proteinases. Mutation of the SERPINA1 gene produces AAT variants that lead to little/no secretion into the blood and tissues, thereby reducing physiological control of potentially damaging proteinases. [00103] In healthy tissues, destructive proteinases are modulated by anti- proteinases (mostly AAT), however in AATD , the lack of AAT means these proteinases retain excessive activity; leading to a major proteinase/anti-proteinase imbalance [2] [3] [4].
• an AAT serum concentration of below 11 mM is regarded as key to a non-physiological interaction resulting in increased emphysematous changes and hence clinical lung disease and is termed the putative “at-risk threshold” [6]
• the primary purpose of this model is to describe changes in elastase activity related to alvelestat NE inhibitor application.
• Enzyme kinetics [00114] The initial steps involved assessment of the biological activity of the enzymes and inhibitors to be used in the more physiological experiments.
• Step 1 involved assessment of the activity of Porcine Pancreatic Elastase using Lineweaver-Burk reciprocal plot analysis [9].
• Step 2 Having confirmed the PPE activity, the inhibitory function of a purified batch of AAT (Athens Research & Technology, US) was determined against this enzyme and used for all subsequent experiments.
• Step 3 involved using the pure AAT to assess inhibition of pure NE preps (Athens Research and Technology, US) to derive their active function. The enzyme activity was then used to assess the activity of alvelestat.
• Activity of alvelestat was calculated by measuring N-succinyl-Ala-Ala-Ala-p- nitroanilide (SlaaapN) cleavage when the compound was titrated against elastase of known concentration and activity [2] Using these methods, alvelestat activity against NE was concluded to be 88%. Results were determined computationally using Prism software.
• N-formyl-L-methionyl-L-leucyl-phenylalanine fMLP; Sigma-Aldrich, St. Louis, MO, US
• concentrations of active AAT between 0-11 mM (Athens Research and Technology, Athens, GA, US) and increasing concentrations of AZD9668 in Roswell Park Memorial Institute media 1640 (RPMI; Sigma-Aldrich; with L-glutamine and sodium bicarbonate) supplemented with Penicillin-streptomycin (1% v/v; Sigma-Aldrich) -
• Flow cytometry confirmed neutrophil degranulation and, also, despite strong stimulation, neutrophil viability remained high. Flow cytometry assessment confirmed that DMSO used to dissolve alvelestat did not stimulate the neutrophils to degranulate. [00136] To assess a more physiological stimulus, neutrophils were then incubated with N-formylmethionine-leucyl-phenylalanine (fMLP).
• fMLP N-formylmethionine-leucyl-phenylalanine
• N-Succinyl-Ala-Ala-Ala- p-nitroanilide can be a chromogenic substrate for chymotrypsin-like serine protease, pancreatic elastase and serine endopeptidase. Procedures for measuring elastase products using SlaaapN as the substrate are known.
• Activity of AAT was assessed kinetically by measuring SlaaapN cleavage by PPE of a known activity, following the incubation of a known active molar concentration of PPE with AAT.
• alvelestat is a highly potent and rapid reversible inhibitor of NE
• the molar ratio of compound required to fully inhibit NE is 0.87:1 , as outlined below.
• AAT was added in increasing functional concentrations to the proteinase/anti proteinase model together with substrate (fibrinogen) and stimulus (fMLP). Pathophysiological concentrations were selected to mimic different disease genotype AAT concentrations as described by the American Thoracic and European Respiratory Societies: 0 mM representing a Pi ’null’ genotype, 2.6-6.5 pM representing a PiZZ genotype, and 10.4-14.3 pM representing a PiSZgenotype [15].
• Literature describes alvelestat as a potent inhibitor of elastase in vitro [14] [16], and this is supported by data in this report using the proteinase/anti-proteinase biomarker model. It was observed that as the concentration of this anti-elastase increased, the quantity of specific elastase cleaved fibrinogen products rapidly decreased.
• the proteinase/anti-proteinase model data supports a role for alvelestat as a potent inhibitor of elastase activity. Moreover the data supports that alvelestat can “normalise” the dysfunction associated with AATD associated disease, being more effective in suppressing elastase that the physiological AAT protein. The data also suggests the mode of action of the inhibitor exceeds that expected suggesting activity against NE is via a different mechanism to physiological inhibitors such as AAT. Alvelestat can, at concentrations achieved by the dosing regimens described in the application, provide NE inhibition greater than AAT at the protein concentration achieved by augmentation treatment in AATD. This supports the use of alvelestat as treatment of AATD, including in patients where augmentation has not worked, either as replacement to augmentation, or in combination with augmentation.
• [00171] 1 Alvelestat or a salt thereof, at doses of 120-300 mg, and alternatively
• BID demonstrates activity in inhibiting neutrophil elastase (NE). This can be seen from Figure 1 where about 100% NE inhibition was observed at a plasma concentration of about 300 nM of alvelestat.
• Simulated PK modelling ( Figure 2) suggests that to achieve a plasma concentration of about 300 nM of alvelestat (or a salt thereof) in a subject, a dose of 120-300 mg BID is required. To have greater confidence in achieving a plasma concentration of about 300 nM of alvelestat (or a salt thereof), a dose of 220- 300 mg BID is required.
• example 3 shows that Alvelestat or a salt thereof, at doses of 120-300 mg, and alternatively 220-300 mg, BID, demonstrates activity in inhibiting neutrophil elastase (NE), e.g. as measured by A-a-Val 360 (Figure 9).
• Figure 9 shows that alvelestat at a concentration of 300 nm achieves NE inhibition via measuring percentage change in A-a-Val 360 .
• Example 3 also shows that A-a-Val 360 is a specific product of neutrophil elastase.
• A-a-Val 360 has been shown to be elevated in patients with AATD.
• a higher concentration of A-a-Val 360 is related to an increased severity of disease, e.g. AATD.
• elevated levels of A-a-Val 360 in a patient may identify them as potential responders to treatment with alvelestat.
• Table 3 shows selected population PK simulated Cmax plasma concentrations for alvelestat tosylate at doses of alvelestat of 120 mg and 240 mg given BID (twice daily), showing the median, lower and upper interquartile ranges (IIQ and ulQ), lower and upper 95% Cl (I95%CI) and u95%CI) for BID dosing regimens.
• the values in Table 3 are 1000 nM or greater, and thus, the dosing regimens of the present invention provide the concentrations of alvelestat in order to achieve improved suppression of NE for therapeutic purposes compared to AAT at concentrations achieved therapeutically in treatment of alpha-1 deficiency, by use of AAT replacement “augmentation”.
• the invention also provides the following numbered embodiments:
• a solid dosage form comprising 120-300 mg of 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.
• a kit comprising a plurality of solid dosage forms for oral administration of 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 or a salt thereof, said kit containing instructions for sequentially administering a total of 120-300 mg of said 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 or a salt thereof per administration, wherein the administration of each dose takes place twice daily, with at least 8 hours between administrations, for the treatment of a disease of the respiratory system which is mediated
• a kit comprising a plurality of solid dosage forms for oral administration, said dosage forms comprising 120-300 mg of 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 or a salt thereof, said kit containing instructions for sequential, twice daily administration of each dose, for the treatment of a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency.
• a method for treating a disease of the respiratory system which is mediated by a- 1 antitrypsin deficiency comprising the twice daily oral administration of a single or multiple solid dosage form(s), said single or multiple solid dosage form(s) comprising a total of 120-300 mg of 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 or a salt thereof per administration, to a human patient suffering from COPD.
• the active ingredient comprises or consists of the tosylate salt of 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.
• solid dosage form as defined in any preceding embodiment, in the form of a tablet, tablets, capsule or capsules, preferably a tablet.
• 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.
• COPD chronic obstructive pulmonary disease
• bronchitis emphysema
• bronchiectasis cystic fibrosis
• sarcoidosis farmer's lung, hypersensitivity pneumonitis, adult respiratory distress syndrome (ARDS), lung fibro
• a solid dosage form comprising 220-300 mg of 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.
• a kit comprising a plurality of solid dosage forms for oral administration of 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 or a salt thereof, said kit containing instructions for sequentially administering a total of 220-300 mg of said 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 or a salt thereof per administration, wherein the administration of each dose takes place twice daily, with at least 8 hours between administrations, for the treatment of a disease of the respiratory system which is mediated
• a kit comprising a plurality of solid dosage forms for oral administration, said dosage forms comprising 220-300 mg of 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 or a salt thereof, said kit containing instructions for sequential, twice daily administration of each dose, for the treatment of a disease of the respiratory system which is mediated by a-1 antitrypsin deficiency .
• a method for treating a disease of the respiratory system which is mediated by a- 1 antitrypsin deficiency comprising the twice daily oral administration of a single or multiple solid dosage form(s), said single or multiple solid dosage form(s) comprising a total of 220-300 mg of 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 or a salt thereof per administration, to a human patient suffering from COPD.
• the active ingredient comprises or consists of the tosylate salt of 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.
• solid dosage form as defined in any preceding embodiment, in the form of a tablet, tablets, capsule or capsules, preferably a tablet.
• 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.
• COPD chronic obstructive pulmonary disease
• bronchitis emphysema
• bronchiectasis cystic fibrosis
• sarcoidosis farmer's lung, hypersensitivity pneumonitis, adult respiratory distress syndrome (ARDS), lung fibro

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