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
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to new methods for treating or preventing graft rejection and graft versus host disease comprising administering a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• Transplant of organs, bone marrow and human stem cells has advanced human health. However, transplantation is beset by the immune system's ability to recognise and react to non-self tissue. This is particularly a risk in allogeneic transplants when the tissue is from genetically similar, but not identical donors and there is a human leukocyte antigen (HLA) tissue type mismatch.
• HLA human leukocyte antigen
• Graft rejection following solid organ transplantation can occur when the recipient’s immune system (in particular the recipient’s mature ab T cells) recognises the foreign HLA antigens expressed on the donor organ’s cells. It is dictated by host allo-responsiveness against mismatched donor antigens. Acute rejection typically occurs within the first weeks to several months after transplantation and is a major risk factor for the development of chronic rejection. Other risk factors for chronic rejection include infection. Chronic rejection typically develops within months to years after transplantation and is the major cause of long-term graft loss. Clinically, chronic rejection is characterized as a slow process resulting in the replacement of the allograft parenchyma with fibrous scar tissue.
• Lung transplantation is an important treatment option for patients with advanced lung disease or irreversible pulmonary failure: around 3,500 lung transplantations are performed globally each year.
• acute lung rejection affects about a third of all lung transplant recipients within the first year after transplant, and may develop into chronic lung rejection (or chronic lung allograft dysfunction (CLAD)) which remains a major hurdle to long-term survival post lung transplantation. It is the leading cause of allograft loss and death for recipients of lung transplants surviving beyond 3 months post-transplant.
• chronic lung allograft dysfunction or chronic lung allograft dysfunction
• Lung Transplant associated Bronchiolitis Obliterans Syndrome (LT-BOS) is the most common form of CLAD, and manifests as a decline of lung function, which is often progressive. It is thought to be caused by inflammation, destruction and fibrosis of small airways in the lung allograft that leads to obliterative bronchiolitis (OB). Median survival after diagnosis is between 3-5 years [1]
• LT-BOS chronic graft rejection
• Current options for LT-BOS include immunosuppression therapy (often a triple combination), and neo-macrolides (such as azithromycin), as well as treatment of accompanying gastro-oesophageal reflux and infections.
• immunosuppression therapy greatly impairs immune reconstitution, which increases the risk of infections.
• lung re-transplantation may be considered, but outcomes are poor and donor organs are scarce.
• the ISHLT/ATS/ERS BOS Task Force concluded in 2014 that no currently available therapies have been proven to result in significant benefit in the prevention or treatment of LT-BOS [2]
• GVHD graft versus host disease
• inhibitors of neutrophil elastase such as alvelestat are useful in the treatment and prevention of GVHD and graft rejection, in particular in LT-BOS.
• NE neutrophil elastase
• the main drivers of GVHD and graft rejection are typically considered to be T and B-lymphocytes rather than neutrophils.
• NE inhibitors had not previously been demonstrated to be effective against GVHD or graft rejection. In particular it had not previously been recognised that NE inhibitors could have utility in treating or preventing graft rejection in particular LT-BOS.
• the present invention provides a method for treating or preventing graft rejection, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention further provides a method for treating or preventing lung transplant associated bronchiolitis obliterans syndrome (LT-BOS), comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• LT-BOS lung transplant associated bronchiolitis obliterans syndrome
• the present invention further provides a method for treating or preventing graft versus host disease (GVHD), comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• GVHD graft versus host disease
• the present invention also provides a method for treating or preventing bronchiolitis obliterans syndrome (BOS) associated with GVHD, e.g. BOS associated with haematopoietic stem cell transplant, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• BOS bronchiolitis obliterans syndrome
• FIG. 1 is a series of line graphs showing improved survival with alvelestat.
• FIG. 2 is a series of line graphs showing the effect of different doses of T cells on survival (Fig. 2A), bodyweight (Fig. 2B) and GVHD score (Fig 2C).
• Figure 3 is a series of histological findings of GVHD in mice receiving T- cell depleted bone marrow + 2 x 10 6 T cells. Histological examination of skin from mice receiving TCDBM + T2e6 shows severe skin GVHD (A) with markedly hyalinized/fibrotic dermis, fat atrophy, loss of hair follicles and occasional epithelial apoptosis; likewise, histological examination of small intestinal mucosa from mice receiving TCDBM + T2e6 shows severe gut GVHD (B) with markedly reactive/regenerative epithelium with increased mitotic activity and apoptosis.
• mice receiving TCDBM alone shows no sign of GVHD (C) with loose fibroconnective tissue within the dermis, ample subcutaneous adipose tissue and normal epithelium and hair follicles; likewise, histological examination of intestinal mucosa from mice receiving TCDBM alone shows no sign of GVHD (D) with appropriate cellularity and healthy appearing epithelium.
• C GVHD
• D GVHD
• Figure 4 is a plot showing the histological scoring of Gl GVHD. Mice receiving drug (20 mg/kg) had markedly less GVHD as assessed by an experienced pathologist in a blinded fashion.
• treatment is an approach for obtaining beneficial or desired results.
• beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom associated with a disease or condition.
• Treatment includes one or more of the following: a) inhibiting the disease or condition ⁇ e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition ⁇ e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
• prevention refers to a regimen that protects against the onset of the disease or disorder such that the clinical symptoms of the disease do not develop.
• prevention relates to administration of a therapy ⁇ e.g., administration of a therapeutic substance) to a subject before signs of the disease are detectable in the subject.
• the subject may be an individual at risk of developing the disease or disorder, such as an individual who has one or more risk factors known to be associated with development or onset of the disease or disorder.
• the term “preventing” in the present invention thus includes administering to a subject who will undergo transplantation, or has recently undergone transplantation without yet developing the associated condition.
• the term “therapeutically effective amount” or “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
• the effective amount will vary depending on the particular compound, and characteristics of the subject to be treated, such as age, weight, etc.
• the effective amount can include a range of amounts.
• an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
• An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
• Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g ., additive or synergistic effects) of the compounds.
• solvate is used herein to describe a molecular complex comprising the compound of the invention and a one or more pharmaceutically acceptable solvent molecules, for example, ethanol or water.
• solvent molecules for example, ethanol or water.
• hydrate is employed when the solvent is water and for the avoidance of any doubt, the term “hydrate” is encompassed by the term “solvate”.
• pharmaceutically acceptable salt means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts.
• pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and the like.
• Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
• suitable salts see “Handbook of Pharmaceutical Salts: Properties, Selection and Use” by Stahl and Wermuth (Wiley-VCH, 2011).
• “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms etc. which are suitable for pharmaceutical use.
• subject preferably refers to a human, normally who has received a transplant or is about to receive a transplant.
• the preferred neutrophil elastase inhibitor used in the invention is alvelestat.
• Alvelestat is a potent, orally bioavailable neutrophil elastase inhibitor described in WO 2005/026123 A1 (Example 94, page 85) and [3], which are incorporated herein by reference in their entirety.
• Alvelestat has the chemical name /V- ⁇ [5-(methanesulfonyl)pyridin-2-yl]methyl ⁇ -6-methyl-5-(1 -methyl-1 /-/-pyrazol-5-yl)-2- oxo-1 -[3-(trifluoromethyl)phenyl]-1 ,2-dihydropyridine-3-carboxamide, and the following chemical structure: [0037] Alvelestat has also been referred to as AZD9668 and MPH996.
• Alvelestat may be used in the invention in any pharmaceutically acceptable form, for example any free base form, salt form, and/or solvate form. Alvelestat or a pharmaceutically acceptable salt and/or solvate thereof may be present in any pharmaceutically acceptable physical form, suitably a solid form.
• Certain salts of alvelestat are described in WO 2010/094964 A1 , which is incorporated herein by reference in its entirety. Described salts of alvelestat include the tosylate, p-xylene-2 -sulfonate, chloride, mesylate, esylate, 1 ,5- naphthalenedisulfonate and sulfate.
• alvelestat free base or alvelestat tosylate is used in the methods of the invention, more preferably alvelestat tosylate.
• Alvelestat may also be used in any of the methods of the invention in a pharmaceutically acceptable prodrug form.
• Neutrophil elastase is an enzyme that attacks and progressively damages lung tissue.
• Compounds that inhibit NE are reviewed in [13] and are known from various publications including WO2017207430, WO2017102674,
• W02006098684 W02005026124, W02005026123, W02005021509, W02005021512, W02004043924, W02009060158, W02009037413, W02009013444, W02007129060, W02007107706, W02007107706,
• neutrophil elastase inhibitors that may be used in the present invention include sivelestat, ONO-5046-Na, depelestat, Prolastin, KRP-109, DX-890, pre- elafin, MNEI, BAY 85-8501 , POL6014, a1-AT, sirtinol, ONO-6818 (2-(5-amino-6-oxo- 2-phenyl-1 ,6-dihydro-pyrimidin-1 -yl)-N-[(1 R, 2R)-1 -(5-tert-butyl-1 ,3,4-oxadiazol-2-yl)- 1-hydroxy-3-methylbutan-2-yl]acetamide), elastatinal, SSR 69071 (2-[[6-methoxy-4- (1 -methylethyl)-1 , 1 -dioxo-3-
• neutrophil elastase inhibitor includes all pharmaceutically acceptable forms of the compounds, for example all pharmaceutically acceptable salt, solvate, isomer, and prodrug forms.
• the neutrophil elastase inhibitor is a small molecule compound, i.e. has a molecular weight of less than about 900 daltons.
• the neutrophil elastase inhibitors are inhibitors of human neutrophil elastase.
• the invention generally provides methods for treating or preventing graft rejection, acute graft rejection, chronic graft rejection, CLAD, LT-BOS, GVHD etc., in a subject in need thereof comprising administering to the subject an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• the present invention provides a method for treating or preventing graft rejection in a subject in need thereof comprising administering to the subject an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• Graft rejection may also be referred to as organ transplant rejection.
• the methods described herein are useful for treating or preventing acute graft rejection. In certain embodiments, the method is for treating acute graft rejection. In other embodiments, the method is for preventing acute graft rejection. [0052] The methods described herein are useful for treating or preventing chronic graft rejection. In certain embodiments, the method is for treating chronic graft rejection. In other embodiments, the method is for preventing chronic graft rejection.
• the graft may comprise any solid organ, in particular those solid organs that are frequently transplanted. So, the graft may comprise one or more organs selected from the group consisting of kidney, heart, liver, lung and pancreas.
• CAV cardiac allograft vasculopathy
• the present invention provides a method for treating or preventing CAV in a subject in need thereof comprising administering to the subject an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• Chronic rejection of kidney allografts is manifested by cardiac allograft nephropathy (CAN). CAN is the leading cause of renal function deterioration and accounts for nearly 40% of the graft loss at 10 years.
• the present invention provides a method for treating or preventing CAN in a subject in need thereof comprising administering to the subject an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• the graft comprises a lung.
• the graft may be a single or a double lung transplant.
• the graft may be a heart-lung transplant.
• the present invention provides a method for treating or preventing lung transplant rejection in a subject in need thereof comprising administering to the subject an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof. It may be acute lung transplant rejection or chronic lung transplant rejection.
• Chronic rejection of lung allografts is manifested by chronic lung allograft dysfunction (CLAD).
• the present invention provides a method for treating or preventing CLAD in a subject in need thereof comprising administering to the subject an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• LT-BOS lung transplant associated bronchiolitis obliterans syndrome
• Bronchiolitis obliterans may also be referred to as obliterative bronchiolitis.
• Typical characteristics include an obstructive pulmonary function defect and air trapping/mosaic attenuation on expiratory CT.
• the present invention provides a method for treating or preventing LT- BOS in a subject in need thereof comprising administering to the subject an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• Methods of preventing LT-BOS according to the invention are particularly useful for subjects at risk of LT-BOS.
• Such subjects may possess one or more risk factors selected from the group consisting of primary graft dysfunction, gastro- oesophageal reflux, infection, airway ischemia, acute rejection, lymphocytic bronchiolitis, infection and colonization with micro-organisms (e.g., Pseudomonas aeruginosa and Aspergillus fumigatus), donor and recipient genetics, particulate matter and presence of HLA antibodies, or antibodies to self-antigens (such as K-a1 tubulin and collagen V).
• micro-organisms e.g., Pseudomonas aeruginosa and Aspergillus fumigatus
• donor and recipient genetics e.g., Pseudomonas aeruginosa and Aspergillus fumigatus
• particulate matter and presence of HLA antibodies e.g., Pseudomonas aeruginosa and Aspergillus fumigatus
• the present invention provides a method for treating or preventing GVHD in a subject in need thereof comprising administering to the subject an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• GVHD manifests following tissue transplantation.
• the transplant is selected from the group consisting of skin, hematopoietic stem cells, blood and bone marrow.
• the transplant is hematopoietic stem cells.
• the GVHD may be acute graft versus host disease (aGVHD).
• the disease may be chronic graft versus host disease (cGVHD).
• Acute GVHD is typically characterized by damage to the skin, liver and the gastrointestinal tract, whereas chronic GVHD typically has more diverse manifestations and can resemble autoimmune syndromes with, for example, eosinophilic fasciitis, scleroderma-like skin disease and salivary and lacrimal gland involvement.
• An additional embodiment provides a method for inhibiting the onset of symptoms of GVHD, including aGVHD and cGVHD, the method comprising administering a pharmaceutically effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a recipient of a transplantation of allogenic hematopoietic stem cells.
• the GVHD may be characterised by damage to one or more selected from the group consisting of the eyes, joints, fascia, genital organ, lung, liver, skin, or gastrointestinal tract (e.g. mouth, oesophagus).
• the GVHD may be characterised by damage to one or more selected from the group consisting of the lung, liver, skin, or gastrointestinal tract.
• Chronic GVHD may be classified according to various criteria.
• the 2005 and 2014 National Institutes of Health Consensus Development Projects on Criteria for Clinical Trials in Chronic GVHD standardized the terminology around chronic GVHD classification systems [16]
• One classification system is the NIH severity score, which is divided into mild, moderate or severe based on the number and severity of involved organs.
• the subject may have cGVHD which is mild, moderate or severe according to the NIH severity score.
• the cGVHD may be moderate or severe, typically severe.
• methods for improving the cGVHD severity score in a subject with cGVHD are provided herein, comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• Another classification system based on patient-reported outcomes is the Lee cGVHD Symptom Scale [17] Accordingly, methods for improving the Lee cGVHD Symptom Scale in a patient with cGVHD are provided herein, comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof. In particular, methods for improving the Lee cGVHD Symptom Scale lung score in a subject with cGVHD affecting a lung are provided herein, comprising administering alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• the invention also provides a method for treating or preventing bronchiolitis obliterans syndrome (BOS) associated with GVHD, comprising administering an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to a subject in need thereof.
• the subjects are receiving hematopoietic stem cell transplantation.
• alvelestat or a pharmaceutically acceptable salt thereof for use in treating or preventing bronchiolitis obliterans syndrome (BOS) associated with GVHD.
• BOS bronchiolitis obliterans syndrome
• the use of alvelestat or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing bronchiolitis obliterans syndrome (BOS) associated with GVHD.
• the NE inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, may be administered to the subject prior to transplantation.
• alvelestat administration may start 14 days, 7 days, 3 days, 2 days, or 1 day prior to transplantation.
• the NE inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, may be administered to the subject after transplantation.
• the alvelestat administration may start on the day of transplantation or 1 day, 2 days, 3 days, 7 days, or 14 days after transplantation.
• Methods according to the invention relating to BOS, in particular LT- BOS, may also comprise improving one or more pulmonary function parameters in a subject.
• methods according to the invention may improve the FEV1 of a subject.
• Forced expiratory volume is the expiratory volume of air from a maximally forced effort measured over a set period of time, e.g. 1 second (FEV1).
• FEV1% predicted of a subject is the ratio of FEV1 in a subject to the predicted FEV1 of a normal person of similarly matched race or ethnicity, gender, age, height and weight, expressed as a percentage.
• a method for increasing FEV1% predicted in a subject with LT-BOS by administering an effective amount of a NE inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof.
• treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof increases FEV1% predicted by at least about 1%, 1.5%, 2.0%, 2.5%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10%, 15%, 20%, 30%, 40% or 50% compared to a baseline FVC% predicted measurement.
• treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof prevents FEV1% from worsening.
• Methods according to the invention relating to LT-BOS may also comprise improving the BOS grade of a subject.
• the BOS classification scheme adopted in 1993, provided a staging system based on the severity of lung function decline after transplant and has been used for clinical decision-making and research purposes. This staging system was most recently modified in 2002 [2]
• the BOS classification scheme from 2002 is used according to the invention:
• treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof improves the BOS grading by at least 1 grade.
• treatment with an effective amount of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof prevents the BOS grading from worsening.
• Diagnosis of BOS can be carried out by the skilled clinician. Imaging tests, such as high resolution chest CT scan, and pulmonary function tests can help detect BOS. Chest x- rays may also be used. A surgical lung biopsy can also be carried out to diagnose the BOS. Lung biopsies may show small airway involvement with fibrinous obliteration of the lumen. Bronchoalveolar lavage (BAL) may show neutrophilic and/or lymphocytic inflammation.
• BAL Bronchoalveolar lavage
• Also provided in this invention are methods for treating or preventing BOS associated with connective tissue disease, systemic lupus erythematosus, rheumatoid arthritis, infection, toxic fume exposure, or Stevens-Johnson syndrome, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof.
• a neutrophil elastase inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the patient to be treated in the methods of the present invention may in some embodiments have a baseline FEV1 of 30% of predicted FEV1 or higher, e.g. a baseline FEV1 of 35% or higher, or 40% or higher.
• the patient may have a baseline FEV1 of 20-90% of predicted FEV1 , for example of 30-80%, 35-75%, or 40- 50%.
• the invention also provides methods of inhibiting neutrophil elastase in a subject suffering from, or at risk of, any of the conditions described herein, including graft rejection or GVHD, in particular LT-BOS, comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to the subject.
• each of the above methods for treating or preventing any of the conditions described herein, including graft rejection or GVHD, in particular LT-BOS, by inhibiting neutrophil elastase comprising administering an effective amount of a neutrophil elastase inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to the subject.
• the present invention also relates to methods for improving lung function in a subject referred to in this disclosure, in particular a subject with GVHD affecting the lungs, such as chronic GVHD, said method comprising administering an effective amount of a NE inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to the subject.
• a NE inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also relates to methods for preventing worsening of lung function in a subject referred to in this disclosure, in particular a subject with GVHD affecting the lungs, such as chronic GVHD, said method comprising administering an effective amount of a NE inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to the subject.
• a NE inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also relates to methods for stabilising lung function in a subject referred to in this disclosure, in particular patients with GVHD affecting the lungs, such as chronic GVHD, said method comprising administering an effective amount of a NE inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof to the subject.
• a NE inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof
• the present invention also relates to methods for preventing progression or worsening of disease in a subject referred to in this disclosure, in particular a subject with GVHD, such as cGVHD.
• the present invention also relates to methods for stabilising disease in a subject referred to in this disclosure, in particular a subject with GVHD, such as cGVHD.
• the present invention also relates to methods for preventing progression of disease in a subject referred to in this disclosure, in particular a subject with GVHD, such as cGVHD.
• the present invention also relates to methods for stabilising disease in a subject referred to in this disclosure, in particular a subject with GVHD, such as cGVHD.
• alvelestat or a pharmaceutically acceptable salt and/or solvate thereof for use in treating or preventing graft rejection, for example chronic or acute graft rejection. Also provided is alvelestat or a pharmaceutically acceptable salt thereof for use in treating or preventing lung transplant associated bronchiolitis obliterans syndrome. Also provided is alvelestat or a pharmaceutically acceptable salt thereof for use in treating or preventing GVHD.
• alvelestat or a pharmaceutically acceptable salt and/or solvate thereof for the manufacture of a medicament for treating or preventing graft rejection, for example chronic or acute graft rejection. Also provided is the use of alvelestat or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing lung transplant associated bronchiolitis obliterans syndrome. Also provided is the use of alvelestat or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing GVHD.
• the dose of the neutrophil inhibitor to be administered will depend on the disease being treated, the severity of the disease, the mode of administration, the age, weight and sex of the patient. Such factors may be determined by the attending physician. However, in general, satisfactory results are obtained when the compounds are administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg (measured as the active ingredient).
• the daily dose is from 0.5 to 1000 mg per day, for example from 50 to 800 mg per day, in particular 50 to 600 mg per day, more particularly 120 mg to 550 mg, even more particularly 200 to 500 mg.
• the daily dose is about 240, 270, 300, 330, 360, 390, 420, 450 or 480 mg per day.
• the dose may be administered as a single dose or as a divided dose, for example wherein the total daily dose is divided in to two or more fractions, administered during the day.
• a dose may be administered daily, or multiple times a day (for example twice daily), or multiple times a week, or monthly, or multiple times a month.
• alvelestat or a pharmaceutically acceptable salt and/or solvate thereof is administered twice a day (BID dosing).
• alvelestat or a pharmaceutically acceptable salt and/or solvate thereof is administered twice a day, wherein each dose is equivalent to up to 240 mg of alvelestat free base, for example 60 mg twice a day, 90 mg twice a day, 120 mg twice a day, 150 mg twice a day, 180 mg twice a day, 210 mg twice a day, or 240 mg twice a day.
• 120 mg is administered twice a day or 240 mg is administered twice a day.
• Compounds 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.
• 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.
• the dose of alvelestat or a pharmaceutically acceptable salt and/or solvate thereof may be administered according to a dosage escalation regime in all methods of the invention.
• This allows safe titration up to the standard daily dose of alvelestat, e.g. of 240mg twice daily.
• a dosage escalation regime up to a standard 240mg twice daily dose of alvelestat according to the invention comprises administration of alvelestat or a pharmaceutically acceptable salt and/or solvate 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 10-20 days, e.g. each about two weeks.
• alvelestat or a pharmaceutically acceptable salt and/or solvate thereof is administered at 60mg twice daily for two weeks, followed by 120mg twice daily for two weeks, followed by 180mg twice daily for two weeks, and 240mg twice daily thereafter. Doses are referred to as the equivalent amount of alvelestat free base.
• the neutrophil inhibitor in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, is administered to a subject in the form of a pharmaceutical composition.
• the invention provides a method of treating or preventing any of the conditions described herein comprising administering a pharmaceutical composition comprising an effective amount of a neutrophil inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, and one or more pharmaceutically acceptable excipients, to a subject in need thereof.
• a pharmaceutical composition comprising an effective amount of a neutrophil inhibitor, in particular alvelestat or a pharmaceutically acceptable salt and/or solvate thereof, and one or more pharmaceutically acceptable excipients, to a subject in need thereof.
• compositions may be prepared with one or more pharmaceutically acceptable excipients which may be selected in accord with ordinary practice.
• “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans. All compositions may optionally contain excipients such as those set forth in the Shesky et al, Handbook of Pharmaceutical Excipients, 8 th edition, 2017. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
• compositions include those suitable for various administration routes, including oral administration.
• the compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g ., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients.
• the compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 22 nd Edition, 2012.
• a preferred pharmaceutical composition is a solid dosage form, including a solid oral dosage form, such as a tablet.
• Tablets may contain excipients including glidants, fillers, binders and the like.
• the pharmaceutical compositions can be administered in any form and route which makes the compound bioavailable.
• the pharmaceutical compositions can be administered by a variety of routes, including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, intraadiposally, intrathecally and via local delivery for example by catheter or stent.
• the pharmaceutical compositions are administered orally.
• compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
• the pharmaceutical composition is a tablet.
• Aqueous compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic. [00103] The amount of active ingredient that may be combined with the inactive ingredients to produce a dosage form may vary depending upon the intended treatment subject and the particular mode of administration.
• the methods may further include the step of administering to the subject one or more additional therapeutic agents.
• the administration of the one or more additional therapeutic agents may occur prior to, concurrently with, or after the administration of the neutrophil inhibitor.
• Additional therapeutic agents include immunosuppressive agents, anti- infective agents, anti-inflammatory agents, and pain relievers.
• the one or more additional therapeutic agent are immunosuppressive agents.
• immunosuppressive agents may, for example, be selected from the group consisting of corticosteroids (e.g. methylprednisolone, prednisone, prednisolone, budesonide, dexamethasone), janus kinase inhibitors (e.g. tofacitinib), calcineurin inhibitors (e.g. cyclosporine, tacrolimus), mTOR inhibitors (e.g.
• corticosteroids e.g. methylprednisolone, prednisone, prednisolone, budesonide, dexamethasone
• janus kinase inhibitors e.g. tofacitinib
• calcineurin inhibitors e.g. cyclosporine, tacrolimus
• mTOR inhibitors e.g.
• sirolimus, everolimus, temsirolimus adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab), monoclonal antibodies (e.g. basiliximab, daclizumab), tyrosine kinase inhibitors (e.g. imatinib), thalidomide, pentostatin, azathioprine, mycophenolate and methotrexate.
• biologies e.g. abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab,
• the methods further include the step of administering to the subject a triple combination of immunosuppressive agents, for example tacrolimus, mycophenolate and a corticosteroid.
• immunosuppressive agents for example tacrolimus, mycophenolate and a corticosteroid.
• the one or more additional therapeutic agents may be anti-infective agents.
• Anti-infective agents include antibiotics, antifungals, anthelmintics, antimalarials, antiprotozoals, antituberculosis agents, and antivirals.
• the one or more additional therapeutic agents may be selected from the group of prednisone, methylprednisone, budesonide, beclomethasone dipropionate, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, tilomisole, imuthiol, antithymocyte globulin, azathioprine, azodiacarbonide, bisindolyl maleimide VIII, brequinar, chlorambucil, CTLA4-lg, cyclophosphamide, deoxyspergualin, dexamethasone, leflunomide, mercaptopurine, 6-mercaptopurine, methotrexate, methylprednisolone, mizoribine, mizoribine monophosphate, muromonab CD3, mycophenolate mofetil, OKT3, rho (D) immune globin, vitamin D analogs, MC1288), daclizumab, in
• each of the agents administered individually or combined in a combination therapy or regimen may be administered at an initial dose that may then over time be reduced by a medical professional to reach a lower effective dose.
• systemic glucocorticosteroids corticosteroids
• prednisone and methyl prednisone may be administered to a human patient at a dose of from about 1-2 mg/kg/day.
• Initial daily doses for mTOR agents include sirolimus at 2-40 mg given once daily and everolimus at 0.25-1 mg given twice daily.
• Initial daily doses for calcineurin agents include tacrolimus at from about 0.025-0.2 mg/kg/day and cyclosporine at from about 2.5 - 9 mg/kg/day.
• Mycophenolate mofetil (CellCept®) may be administered at an initial daily dose of about 250-3,000 mg/day.
• Each of these agents may be administered in combination with a pharmaceutically effective amount of a Syk inhibitor as described herein following hematopoietic cell transplant.
• agents useful in treating GVHD may be administered topically to a human in need of such treatment, such as in the form of a topical ointment or cream or in an eye drop formulation.
• the present invention also provides methods for treating GVHD further including the step of administering light therapy (also known as extracorporeal photopheresis).
• Example 1 - Alvelestat is a potent and specific inhibitor of neutrophil elastase (NE)
• the calculated pICso (IC 50 ) and Ki values for alvelestat for human NE are 7.9 (12 nM) and 9.4 nM, respectively.
• Alvelestat is at least 600-fold more selective for human NE compared with another serine protease cathepsin G, and at least 1900-fold more selective for human NE comprised with other serine proteases (proteinase-3, chymotrypsin, pancreatic elastase and trypsin).
• Alvelestat shows good crossover potency for NE from other species, including mice.
• alvelestat is a specific, potent, and rapidly reversible inhibitor of human NE.
• the potent inhibitory activity of alvelestat on NE in biochemical assays was confirmed in whole-blood and cell- based systems.
• Example 2 - Alvelestat shows a protective effect against GVHD
• mice received lethal irradiation (8.5 Gy total body irradiation) followed by transplantation with T-cell depleted bone marrow +/- purified T cells from B10.D2 donors. Negative controls received T-cell depleted bone marrow (TCDBM) only (no T cells, no GVHD), while positive controls received TCDBM + 2 x 10 6 T cells (100% fatal GVHD). In the treatment arms, mice received alvelestat at 20, 50, and 200 mg/kg per day, days -1 to 45 through a pre-mixed custom diet or added as a powder to wet food.
• TDBM T-cell depleted bone marrow
• mice received alvelestat at 20, 50, and 200 mg/kg per day, days -1 to 45 through a pre-mixed custom diet or added as a powder to wet food.
• mice were performed on mice after death or after they were sacrificed at the conclusion of the experiment and support the finding that that mice receiving TCDBM+T2e6 did develop GVHD (Fig. 3A-B) while those that received TCDBM alone did not have signs of GVHD (Fig. 3C-D).
• Tissues were reviewed by a blinded pathologist specializing in GVHD and scored based on architecture (crypt regeneration, surface erosion, ulceration, lamina intestinal inflammation, atrophy, crypt branching, endocrine cell excess, and Paneth cell excess) and epithelial cytology (vacuolization, attenuation, apoptosis, sloughing into lumen, lymphocytic infiltration, neutrophilic infiltration).
• alvelestat and neutrophil elastase inhibitors more generally
• GVHD neutrophil elastase inhibitors
• organ rejection is also principally mediated through the allorecognition of donor MHC-derived peptides by recipient CD4+ and CD8+ T-cells, with the recipient recognising the donor organ tissue antigens.
• the foreign antigens are presented to the recipient’s immune system though donor antigen presenting cells (APCs) released from the organ that migrate to the recipient's draining lymph nodes where recipient dendritic cells process and present the alloantigens and prime T cells for activation and migration back to the organ where damage ensues.
• APCs donor antigen presenting cells
• recipient APCs pick up donor antigens and self-present [11]
• alloreactive T-cells are primed and generated and drive the pathogenic process.
• neutrophil elastase inhibitors such as alvelestat will also be effective in treating or preventing organ rejection.
• alvelestat will be investigated in clinical trials designed to evaluate safety and efficacy in the treatment and prevention of BOS in patients following a lung transplant.
• Alvelestat is administered as part of a multi-centre, randomised, standard-of-care controlled study to demonstrate efficacy and safety of alvelestat in improving survival and preventing BOS when given prophylactically to lung transplant recipients in addition to standard immunosuppressive regimen.
• alvelestat is administered at a dose of up to 240 mg twice daily to patients starting immediately post-lung transplantation. Therapy continues for 2 years and may be extended up to 5 years.
• Alvelestat will show effectiveness in one or more of the above primary endpoints.
• Alvelestat is administered as part of a multi-centre, randomised, standard of care-controlled study to demonstrate efficacy and safety of alvelestat in improving BOS when given to lung transplant recipients in addition to their standard immunosuppressive regimen. [00144] During the study, alvelestat is administered at a dose of up to 240 mg twice daily to patients who have developed BOS following lung transplant.
• Duration of event-free survival corresponding to the length of time between date of randomisation and either death or occurrence of serious bacterial and viral infections that start in the lungs (defined by reporting of an SAE).
• Alvelestat will show effectiveness in one or more of the above primary endpoints.
• Example 5 Phase 1 Study of alvelestat in patients with bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) [00150] A Phase 1 study of alvelestat in patients with BOS after HOT was conducted.
• BOS bronchiolitis obliterans syndrome
• HCT hematopoietic cell transplantation
• This phase 1 study had 2 parts: 8-week intra-patient dose escalation period, followed by a continuation period that allowed for up to 6 months of treatment.
• Alvelestat was given orally starting at 60mg twice daily (the dose previously used in patients with chronic lung disease) and increased every 2 weeks as tolerated to 120mg twice daily, 180mg twice daily, and finally 240mg twice daily. Patients continued this dose until completion of the continuation phase, or occurrence of unacceptable toxicity, dose interruption >28 days, or progression of GVHD or BOS.
• the primary objective was to determine the maximum tolerated dose (MTD) based on dose-limiting toxicities.
• Secondary objectives included determining pharmacokinetics, markers of neutrophil elastase (NE) activity, and markers of inflammation in blood and sputum.
• PFTs and chronic GVHD evaluations were performed at baseline, 4 weeks, 8 weeks during the dose escalation period, and at 3 months and 6 months during the continuation period.
• the median duration of treatment was 6.4 months. Based on NIH chronic GVHD consensus criteria, 6 patients had unchanged disease and 1 patient had progressive disease (decline in FEV1 after pneumonia). Although patients did not achieve the 10% improvement in FEV1 required for an organ response, 2 patients had improvement of 9% in FEV1 and 4 patients had improvement in the Lee chronic GVHD symptom scale lung score.
• Table 1 Patient and disease characteristics.
• Time point C1 is the baseline before treatment.
• Time point C5 is the continuation dosing period up to 6 months.

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