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WO2024077042A2 - Traitement d'antagoniste du récepteur de l'il-1 pour une maladie pulmonaire neutrophile - Google Patents

Traitement d'antagoniste du récepteur de l'il-1 pour une maladie pulmonaire neutrophile Download PDF

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Publication number
WO2024077042A2
WO2024077042A2 PCT/US2023/075912 US2023075912W WO2024077042A2 WO 2024077042 A2 WO2024077042 A2 WO 2024077042A2 US 2023075912 W US2023075912 W US 2023075912W WO 2024077042 A2 WO2024077042 A2 WO 2024077042A2
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Prior art keywords
ira
alta
lung
neutrophilic
dose
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WO2024077042A3 (fr
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Stephen A. WRING
Michelle PALACIOS
Courtney MCKERNAN
Katelyn R. CRIZER
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Onspira Therapeutics Inc
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Onspira Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2006—IL-1
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose

Definitions

  • the invention relates generally to the field of pharmaceutical science. More particularly, the invention relates to compounds and compositions useful as pharmaceuticals for treating various lower airways disorders.
  • Lung neutrophilia is a common pathological feature of several diseases, including, for example, chronic obstructive pulmonary disease (COPD) (Peter J. Barnes, Immunology of asthma and chronic obstructive pulmonary disease, Nat. Rev. Immunol.
  • COPD chronic obstructive pulmonary disease
  • RA-ILD rheumatoid arthritis-associated interstitial lung disease
  • ARDS acute respiratory distress syndrome
  • Infiltrating neutrophils typically mediate the innate immune response and destroy invading pathogens in the lung through phagocytosis and degranulation.
  • dysregulation of neutrophil activation and recruitment leads to tissue damage and inflammatory diseases (Oliver Soehnlein et al., Neutrophil secretion products pave the way for inflammatory monocytes, Blood 112(4): 1461-71 (2008); E. Abraham et al., Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury, Am. J. Physol. Lung Cell Mol. Physiol.
  • Interleukin 1 alpha (IL- la) and interleukin 1 beta (IL-ip) are cytokines that are part of the interleukin-1 (IL-1) family and bind to the interleukin-1 type 1 receptor (IL-1R1) to activate pro-inflammatory signaling pathways.
  • IL- la and IL-ip can stimulate neutrophil recruitment indirectly by enhancing expression of neutrophil chemo-attractants (T.
  • Intranasal administration of IL-ip to mice increased expression of the neutrophil chemotactic factor CXCL1 as well as the number of neutrophils in the bronchoalveolar lavage fluid (BALF) (Pamela Gasse et al., IL-lRl/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice, J. clin. Invest. 117(12):3786-99 (2007)). These studies show that overexpression of IL-la or IL-ip is sufficient to drive lung neutrophilia.
  • BALF bronchoalveolar lavage fluid
  • IL-1R1 interleukin- 1 receptor antagonist
  • FIGS. 1 A-B show Surface Plasmon Resonance sensorgrams comparing the binding of human IL-ip to IL-1R1 (FIG. 1A) to the binding of the rhIL-IRa protein in the ALTA-2530 formulation to IL-1R1 (FIG. IB).
  • FIGS. 2A-B show Surface Plasmon Resonance sensorgrams comparing the binding of human IL-la to IL-1R1 (FIG. 2A) to the binding of the rhIL-IRa protein in ALTA-2530 formulation to IL-1R1 (FIG. 2B).
  • FIGS. 3A-B show immunohistochemistry of ALTA-2530 in lung samples from cynomolgus monkeys that received once-daily exposure to saline (FIG. 3A) or ALTA-2530 (FIG. 3B) via nebulizer for seven days.
  • FIG. 4 shows immunohistochemistry of ALTA-2530 in lung samples from rats that received once-daily exposure to saline (left), low dose ALTA-2530 (middle), or high dose ALTA-2530 (right) via nebulizer for seven days.
  • FIG. 5 shows results from a human whole blood multiplex assay assessing the efficacy of ALTA-2530 in treating IL-ip stimulated cytokine release.
  • the assays assess the ability of ALTA-2530 to inhibit IL-ip stimulated cytokines CXCL1, CXCL2, IL-6, IL-8, CCL2, and CCL4.
  • FIG. 6 shows results from a study in cynomolgus monkeys to assess rhIL-IRa levels in BALF following exposure of the subject to ALTA-2530.
  • the dotted line represents the amount of ALTA-2530 needed to induce maximal inhibition of IL-ip-stimulated IL-6 release in monkey whole blood.
  • FIGS. 7A-C show histological examination results from a study comparing a healthy rat lung sample (FIG. 7A) to a lung sample from a rat exposed to sulfur mustard and treated with ALTA-2530 (FIG. 7B) and a to lung sample from a rat exposed to sulfur mustard and treated with saline (FIG. 7C).
  • Lung tissues treated with ALTA-2530 show no alveolar edema and few neutrophils, indicating the healing process following sulfur mustard is proceeding at a more rapid pace than that displayed following saline treatment.
  • alveoli depict significant alveolar edema (yellow arrows, wispy eosinophilic strands) and acute neutrophilic inflammation (red arrows).
  • FIG. 8 shows the primary, secondary, and exploratory endpoints from an inhaled lipopolysaccharide challenge in non-human primates.
  • Monkeys were treated with vehicle or low or high dose ALTA-2530.
  • ALTA-2530 treatment led to a significant decrease in the percentage of bronchoalveolar lavage fluid (BALF) neutrophils and a reduction in total neutrophil counts in the BALF.
  • BALF bronchoalveolar lavage fluid
  • ALTA-2530 reduced BALF IL-1 [3 and IL-6 levels. Serum IL-6 and IL-8 levels were significantly decreased in ALTA-2530 treated animals.
  • BALF TNF-a was significantly reduced in ALTA-2530 treated animals.
  • FIGS. 9A-B show results from a study assessing the ability of low dose ALTA- 2530 (top) and high dose ALTA-2530 (bottom) to reduce neutrophil infiltration following exposure to lipopolysaccharide in the 4 hours (FIG. 9A) and 24 hours (FIG. 9B) after lipopolysaccharide administration.
  • n.s. indicates not significant
  • one asterisk (*) indicates p ⁇ 0.05
  • two asterisks (**) indicate p ⁇ 0.01
  • three asterisks (***) indicate p ⁇ 0.001
  • four asterisks (****) indicate p ⁇ 0.0001.
  • FIGS. 10A-B show results from a study assessing the ability of low dose ALTA- 2530 (top) and high dose ALTA-2530 (bottom) to reduce the total cell count in BALF following exposure to lipopolysaccharide in the 4 hours (FIG. 10 A) and 24 hours (FIG. 10B) after lipopolysaccharide administration.
  • n.s. indicates not significant
  • one asterisk (*) indicates p ⁇ 0.05.
  • FIGS. 11A-B show results from a study assessing the ability of low dose ALTA- 2530 (top) and high dose ALTA-2530 (bottom) to reduce absolute neutrophil counts in BALF following exposure to lipopolysaccharide in the 4 hours (FIG. 11 A) and 24 hours (FIG. 1 IB) after lipopolysaccharide administration.
  • n.s. indicates not significant
  • one asterisk (*) indicates p ⁇ 0.05
  • two asterisks (**) indicate p ⁇ 0.01.
  • the results show that treatment with both low-dose and high-dose ALTA-2530 reduced the absolute neutrophil counts in the BALF at 4 hours and at 24 hours after lipopolysaccharide administration.
  • Each line represents an individual animal.
  • FIGS. 12A-B show results from a study assessing the ability of low dose ALTA- 2530 (top) and high dose ALTA-2530 (bottom) to reduce or attenuate IL-ip levels in BALF following exposure to lipopolysaccharide in the 4 hours (FIG. 12 A) and 24 hours (FIG. 12B) after lipopolysaccharide administration.
  • n.s. indicates not significant
  • one asterisk (*) indicates p ⁇ 0.05
  • three asterisks (***) indicate p ⁇ 0.001.
  • FIGS. 13 A-B show results from a study assessing the ability of low dose ALTA- 2530 (top) and high dose ALTA-2530 (bottom) to reduce or attenuate IL-6 levels in BALF following exposure to lipopolysaccharide in the 4 hours (FIG. 13 A) and 24 hours (FIG. 13B) after lipopolysaccharide administration.
  • n.s. indicates not significant
  • two asterisks (**) indicate p ⁇ 0.01
  • three asterisks (***) indicate p ⁇ 0.001.
  • FIGS. 14A-B show results from a study assessing the ability of low dose ALTA- 2530 (top) and high dose ALTA-2530 (bottom) to reduce or attenuate IL-6 levels in serum following exposure to lipopolysaccharide in the 4 hours (FIG. 14 A) and 24 hours (FIG. 14B) after lipopolysaccharide administration.
  • n.s. indicates not significant
  • one asterisk (*) indicates p ⁇ 0.05
  • two asterisks (**) indicate p ⁇ 0.01
  • three asterisks (***) indicate p ⁇ 0.001
  • four asterisks (****) indicate pO.OOOl.
  • IL-1R antagonism by treatment with both low-dose and high-dose ALTA-2530 attenuated the IL-6 levels in the serum at 4 hours and at 24 hours after lipopolysaccharide administration.
  • Each line represents an individual animal.
  • FIG. 15 shows results from a study assessing the ability of low dose ALTA-2530 to reduce or attenuate TNF-a levels in BALF following exposure to lipopolysaccharide in the 4 hours after lipopolysaccharide administration.
  • one asterisk (*) indicates p ⁇ 0.05 and two asterisks (**) indicate p ⁇ 0.01.
  • the results show that IL-1R antagonism by treatment with low-dose ALTA-2530 attenuated TNF-a levels in the BALF at 4 hours after lipopolysaccharide administration.
  • Each line represents an individual animal.
  • FIG. 16 shows results from a study assessing the ability of low dose ALTA-2530 to reduce or attenuate IL-8 levels in serum following exposure to lipopolysaccharide in the 4 hours after lipopolysaccharide administration.
  • n.s. indicates not significant and one asterisk (*) indicates p ⁇ 0.05.
  • the results show that IL-1R antagonism by treatment with low-dose ALTA-2530 attenuated the IL-8 levels in the serum at 4 hours after lipopolysaccharide administration.
  • Each line represents an individual animal.
  • a method for the treatment of neutrophilic lung diseases.
  • the neutrophilic lung disease is characterized by tissue damage and inflammation associated with dysregulation of neutrophil activation and/or recruitment.
  • the treatment includes delivery (e.g., inhaled delivery) of an IL-1R antagonist (“IL-IRa,” e.g., recombinant human IL-IRa), to block the activity of IL- la and IL-ip and to thereby target neutrophil activation and migration.
  • IL-IRa an IL-1R antagonist
  • the invention provides a method for treating a neutrophilic lung disease in a human subject in need thereof, comprising administering a pharmaceutical composition comprising an effective amount of an IL-IRa (e.g., recombinant human IL-IRa) to the human subject, wherein the neutrophilic lung disease is selected from the group consisting of steroid-resistant chronic obstructive pulmonary disease, bronchiectasis, neutrophilic asthma, acute respiratory distress syndrome, chemical lung injury, and rheumatoid arthritis-associated interstitial lung disease.
  • IL-IRa e.g., recombinant human IL-IRa
  • the IL-IRa (e.g., recombinant human IL-IRa) is administered to the airways of the human subject. In some cases, for example, the IL-IRa (e.g., recombinant human IL-IRa) is administered by inhalation. In some cases, the IL-IRa (e.g., recombinant human IL-IRa) is administered intranasally. In certain embodiments, the IL-IRa (e.g., recombinant human IL-IRa) is delivered to the distal regions of the human subject’s lung. In certain embodiments, the IL-IRa (e.g., recombinant human IL-IRa) is administered intratracheally.
  • the IL-IRa e.g., recombinant human IL-IRa
  • the IL-IRa (e.g., recombinant human IL-IRa) is nebulized.
  • the nebulized IL-IRa (e.g., recombinant human IL-IRa) has a mass median aerodynamic diameter (MMAD) of about 1 pm to about 15 pm.
  • MMAD mass median aerodynamic diameter
  • the nebulized IL-IRa (e.g., recombinant human IL-IRa) may have a MMAD of about 3 pm.
  • the pharmaceutical composition comprises ALTA-2530, a formulation of recombinant human IL-IRa.
  • the pharmaceutical composition comprises anakinra.
  • the methods described herein reduce secretion of a chemokine(s) that promotes neutrophil recruitment.
  • the chemokine is selected from the group consisting of CXCL1, CXCL2, CCL2, CCL4, and IL-8.
  • the methods described herein reduce neutrophilic airway inflammation.
  • the methods described herein reduce airway neutrophils.
  • the methods described herein reduce airway neutrophils without eradicating the neutrophils.
  • the methods described herein prevent or reduce alveolar edema and/or neutrophil trafficking.
  • the IL-IRa e.g., recombinant human IL-IRa
  • the pharmaceutical composition binds to an IL-1 receptor with an affinity higher than IL-ip.
  • the IL-IRa e.g., recombinant human IL-IRa
  • the pharmaceutical composition binds to an IL-1 receptor with an affinity higher than IL- la.
  • interleukin 1 receptor antagonist refers to any peptide or protein that inhibits or blocks (either competitively or non-competitively) the activity of an interleukin-1 receptor (e.g., IL-1 type 1 receptor).
  • the IL-IRa is a recombinant human IL-lra (rhIL-IRa).
  • ALTA-2530 when used herein refers to or describes any inhaled (e.g., nebulized) pharmaceutical composition comprising an rhIL-IRa (e.g., anakinra, or a peptide IL-1R antagonist).
  • ALTA-2530 comprises a peptide IL-IRa of about 50 amino acids in length or less.
  • ALTA-2530 comprises anakinra.
  • ALTA-2530 comprises an anakinra-containing pharmaceutical composition.
  • lower airways or “lower respiratory tract” when used herein refers to or describes anatomic regions below the larynx including the trachea and lungs, as well as lower regions of the lung.
  • upper airways or “upper respiratory tract” when used herein refers to or describes the anatomic regions including the passageways from flares or nostrils to the soft palate and includes the sinuses.
  • treating refers to attempted reduction or amelioration of the progression, severity and/or duration of a disorder, or the attempted amelioration of one or more symptoms thereof resulting from the administration of one or more modalities (e.g., one or more therapeutic agents such as a compound or composition of the invention).
  • modalities e.g., one or more therapeutic agents such as a compound or composition of the invention.
  • the terms “prevent,” “preventing” and “prevention” refer to the prevention or inhibiting of the recurrence, onset, or development of a disorder or a symptom thereof in a subject resulting from the administration of a therapy e.g., a prophylactic or therapeutic agent), or the administration of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents).
  • a therapy e.g., a prophylactic or therapeutic agent
  • a combination of therapies e.g., a combination of prophylactic or therapeutic agents
  • therapeutically effective amount refers to any amount that is necessary or sufficient for achieving or promoting a desired outcome.
  • an effective amount is a therapeutically effective amount.
  • a therapeutically effective amount is any amount that is necessary or sufficient for promoting or achieving a desired biological response in a subject.
  • the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation.
  • the terms “subject” and “patient” are used interchangeably herein.
  • the terms “subject” and “subjects” refer to an animal, preferably a mammal including a nonprimate and a primate (e.g., a monkey such as a cynomolgus monkey, a chimpanzee, and a human), and more preferably a human.
  • a primate e.g., a monkey such as a cynomolgus monkey, a chimpanzee, and a human
  • animal also includes, but is not limited to, companion animals such as cats and dogs; zoo animals; wild animals; farm or sport animals such as ruminants, non-ruminants, livestock and fowl (e.g., horses, cattle, sheep, pigs, turkeys, ducks, and chickens); and laboratory animals, such as rodents (e.g., mice, rats), rabbits; and guinea pigs, as well as animals that are cloned or modified, either genetically or otherwise (e.g., transgenic animals).
  • companion animals such as cats and dogs
  • zoo animals such as ruminants, non-ruminants, livestock and fowl (e.g., horses, cattle, sheep, pigs, turkeys, ducks, and chickens)
  • laboratory animals such as rodents (e.g., mice, rats), rabbits; and guinea pigs, as well as animals that are cloned or modified, either genetically or otherwise (e.g., transgenic animals
  • a” or “an” means at least one, unless clearly indicated otherwise.
  • the term “about,” unless otherwise indicated, refers to a value that is no more than 10% above or below the value being modified by the term.
  • the term “about 5% (w/w)” may mean a range of from 4.5% (w/w) to 5.5% (w/w).
  • the term “about” refers to a value that is no more than 5% above or below the value being modified by the term.
  • composition and “composition of the invention”, are used interchangeably. Unless stated otherwise, the terms are meant to encompass, and are not limited to, pharmaceutical compositions and nutraceutical compositions containing drug substance (e.g., rhIL-IRa).
  • the composition may also contain one or more “excipients” that are inactive ingredients or compounds devoid of pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human.
  • vehicle refers to a diluent, adjuvant, excipient, carrier, or filler with which the compound or composition of the invention is stored, transported, and/or administered.
  • the phrase “pharmaceutically acceptable salt” refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention.
  • pharmaceutically acceptable solvate refers to an association of one or more solvent molecules and a compound of the invention. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to water, saline, water-salt mixtures, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, polyethylene glycol and ethanolamine.
  • the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • a method for treating a neutrophilic lung disease includes administering a pharmaceutical composition comprising an effective amount of an interleukin 1 receptor antagonist (IL-IRa) (e.g., rhlL- IRa) to the human subject (e.g., to the airways of the human subject).
  • IL-IRa interleukin 1 receptor antagonist
  • the method may include administering a pharmaceutical composition comprising an effective amount of rhIL-lRa.
  • rhIL-IRa blocks the biologic activity of IL-la and IL-ip by competitively inhibiting IL-la and IL-ip’s binding to IL-1R1.
  • the method may include administering ALTA-2530.
  • RhIL-IRa in ALTA-2530 formulation may have a higher affinity for human IL- 1R1 than either or both IL-la and IL-ip.
  • ALTA-2530 has a KD value of 2.5 x 10' 11 M, while IL-la and IL-ip have KD values of 5.47 x 10' 7 M and 5.75 x 10' 10 M, respectively.
  • IL-IRa e.g., rhIL-IRa
  • IL- la and IL-ip bind to the interleukin- 1 type I receptor which triggers neutrophil recruitment and that IL-IRa (e.g., rhIL-IRa) blocks the activities of these IL-1 cytokines, reducing neutrophilia and thereby treating the neutrophilic lung disease.
  • a method for treating a neutrophilic lung disease in a human subject in need thereof including administering a pharmaceutical composition comprising an effective amount of IL-IRa (e.g., rhIL-IRa) to the human subject.
  • the neutrophilic lung disease may be obstructive pulmonary disease (e.g., COPD), bronchiectasis, neutrophilic asthma, rheumatoid arthritis-associated interstitial lung disease, acute respiratory distress syndrome (ARDS), or chemical lung injury, or combinations of these diseases.
  • the neutrophilic lung disease is obstructive pulmonary disease (e.g., COPD).
  • the neutrophilic lung disease is bronchiectasis. In some embodiments, the neutrophilic lung disease is neutrophilic asthma. In some embodiments, the neutrophilic lung disease is rheumatoid arthritis- associated interstitial lung disease. In some embodiments, the neutrophilic lung disease is acute respiratory distress syndrome (ARDS), e.g., COVID-related ARDS. In some embodiments, the neutrophilic lung disease is chemical lung injury. In some embodiments, the effective amount of IL-IRa (e.g., rhIL-IRa) is from about 0.1 mg to about 200 mg per day.
  • IL-IRa e.g., rhIL-IRa
  • the neutrophilic lung disease is COPD, e.g., steroid- resistant COPD.
  • COPD is a chronic inflammatory lung disease that causes obstructed airflow from the lungs. Symptoms of COPD may include, for example, breathing difficulty, cough, mucus production, and wheezing.
  • COPD is caused by long-term exposure to irritating gases or particulate matter, e.g., cigarette smoke.
  • COPD is associated with an increased risk of developing heart disease and/or lung cancer.
  • Certain steroids can reduce the inflammation in a patient’s lungs and are used in treating COPD.
  • steroid treatment can result in resistance.
  • the neutrophilic lung disease to be treated is steroid-resistant COPD.
  • the effective amount of IL-IRa e.g., rhIL-IRa
  • the effective amount of IL-IRa is from about 0.1 mg to about 200 mg per day.
  • the neutrophilic lung disease is asthma.
  • Asthma is a chronic inflammatory airway disease with several distinct phenotypes (e.g., eosinophilic, neutrophilic, mixed granulocytic and paucigranulocytic asthma).
  • the neutrophilic lung disease is neutrophilic asthma.
  • Neutrophilic asthma is a severe and persistent disease with frequent exacerbations and hospitalizations. Neutrophilic asthma is characterized by the presence of high levels of neutrophils in the lungs and airways and fixed airflow obstruction.
  • the effective amount of IL-IRa (e.g., rhIL-IRa) is from about 0.1 mg to about 200 mg per day.
  • the neutrophilic lung disease is rheumatoid arthritis- associated interstitial lung disease.
  • Rheumatoid arthritis is a systemic inflammatory disorder, with the most common extra-articular manifestation of RA being lung involvement. While any of the lung compartments can be affected and manifest as interstitial lung disease (ILD), pleural effusion, cricoarytenoiditis, constrictive or follicular bronchiolitis, bronchiectasis, pulmonary vasculitis, and pulmonary hypertension, RA-associated ILD is a leading cause of death in patients with RA and is associated with significant morbidity and mortality.
  • the effective amount of IL-IRa e.g., rhIL-IRa
  • the neutrophilic lung disease is ARDS.
  • ARDS is a lifethreatening disease which requires immediate mechanical ventilation to prevent lung failure.
  • the subject having ARDS suffers from neutrophilia mediated by IL-1 and IL-IRa (e.g., rhIL-IRa, such as in ALTA-2530 formulation) blocks the activities of IL- la and/or IL-ip local to the lower airways and thereby effectively treats ARDS.
  • the neutrophilic lung disease is a chemical lung injury.
  • a chemical lung injury includes any injury (e.g., inflammation or damage) to the lung as a result of inhalation of one or more foreign and/or toxic agents.
  • the subject having a chemical lung injury suffers from neutrophilia mediated by IL-la and IL-ip, and IL-IRa (e.g., rhIL-IRa, such as in ALTA-2530 formulation) blocks the activities of these cytokines local to the lower airways and thereby effectively treats neutrophilia and the chemical lung injury.
  • IL-IRa e.g., rhIL-IRa, such as in ALTA-2530 formulation
  • the chemical lung injury is caused by inhalation of one or more chemical warfare agents.
  • the chemical warfare agents include chlorine gas and sulfur mustard. Sulfur mustard exposure, in particular, is associated with neutrophil infiltration into the airways. Persistence of blood neutrophilia was observed in Egyptian sulfur mustard victims years after exposure (Javad Beheshti et al., Mustard lung secrets: long term clinicopathological study following mustard gas exposure, Pathol. Res. Pract. 202(10):739-44 (2006)). Other examples of the chemical warfare agents known in the art are contemplated.
  • the chemical lung injury is chlorine-induced bronchiolitis obliterans syndrome (BOS). In some embodiments, the chemical lung injury is sulfur mustard-induced BOS.
  • the chemical lung injury is caused by inhalation of one or more environmental and/or industrial toxic agents.
  • Various toxic agents exist in the environmental (natural or artificial) and industrial setting.
  • a human subject may come into contact with and inhale these agents (e.g., while working) and suffer from injuries to the lung that lead to inflammation.
  • a human subject may come into contact with and inhale these agents through exposure to toxic vapors and/or gases produced from or associated with burn pits (e.g., as military burn pits).
  • Non-limiting examples of the environmental and industrial toxic agents include isocyanate (e.g., toluene diisocyanate), nitrogen oxide, sulfuric acid, ammonia, phosgene, diacetyl, 2,3-pentanedione, 2,3- hexanedione, fly ash, fiberglass, silica, coal dust, asbestos, hydrogen cyanide, cadmium, acrolein, acetaldehyde, formaldehyde, aluminum, beryllium, iron, cotton, tin oxide, bauxite, mercury, sulfur dioxide, zinc chloride, polymer fumes, and metal fumes (e.g., fumes generated by copper, magnesium, nickel, silver, or zinc).
  • isocyanate e.g., toluene diisocyanate
  • nitrogen oxide e.g., sulfuric acid, ammonia, phosgene, diacetyl, 2,3-pentanedione, 2,3-
  • the chemical lung injury is pneumoconiosis.
  • pneumoconiosis refers to a class of interstitial lung diseases caused by inhalation of various solid particles.
  • the chemical lung injury is bronchiolitis obliterans, commonly referred to as “popcorn lung.”
  • the bronchiolitis obliterans is caused by the inhalation of one or more industrial toxic agents selected from the group consisting of acetaldehyde, formaldehyde, diacetyl, 2,3-pentanedione, and 2,3-hexanedione.
  • the chemical lung injury is a vaping-associated lung injury.
  • Vaping or using electronic cigarettes, may cause the user to inhale harmful chemicals and result in lung injuries.
  • an electronic cigarette user inhales harmful chemicals found in the electronic cigarette liquid, e.g, diacetyl, which causes injuries, e.g, bum, inflammation, to the lung.
  • vaping-associated lung injury is pneumonitis.
  • the vaping-associated lung injury is bronchiolitis obliterans, commonly referred to as “popcorn lung.”
  • IL-IRa (e.g., rhIL-IRa, such as in ALTA-2530 formulation) is administered to the airways, e.g., lower airways, of the human subject.
  • the IL-IRa e.g., rhIL-IRa
  • the airways e.g., the lower airways, of the human subject.
  • Non-limiting examples of administration of IL-IRa (e.g., rhIL-IRa) to the airways of the human subject include administration by inhalation and intranasal administration.
  • Advantages of administration directly to the airways, e.g., local airways include the lack of adverse effects due to systemic exposure of the active ingredient.
  • IL-IRa e.g., rhIL-IRa, such as in ALTA-2530 formulation
  • IL-IRa is delivered to the distal regions of the human subject’s lung(s).
  • IL-IRa e.g., rhIL-IRa, such as in ALTA-2530 formulation
  • IL-IRa is administered via inhalation or via direct instillation into the lower airways.
  • IL-IRa e.g., rhIL-IRa
  • a delivery device is used to administer IL-IRa (e.g., rhIL- IRa, such as in ATLA-2530 formulation) directly to the lower airways.
  • IL-IRa e.g., rhIL- IRa, such as in ATLA-2530 formulation
  • the delivery devices include a nebulizer, an inhaler, and a subminiature aerolizer.
  • the delivery device is a dry powder inhaler.
  • the delivery device is a mesh nebulizer.
  • the delivery devise is a jet nebulizer.
  • the methods described herein beneficially treat the subject’s neutrophilic lung disease.
  • the effectiveness of the treatment may be assessed by various factors, which those skilled in the art will readily understand.
  • the methods described herein reduce the secretion of a chemokine (or chemokines) that promotes neutrophil recruitment.
  • a chemokine or chemokines
  • the administration of IL-IRa e.g., rhIL-IRa, such as in ALTA-2530 formulation
  • the administration of IL-1R1 to reduce the secretion of IL-la and IL-ip.
  • the administration of IL-IRa may reduce the secretion of one or more cytokines or chemokines downstream on IL-1 binding to the IL-1R including but not limited to CXCL1, CXCL2, CCL2, CCL4, and IL-8.
  • the method described herein reduces neutrophilic airway inflammation in the subject. In some embodiments, the method described herein reduces airway neutrophils in the subject. In some cases, the methods may reduce airway neutrophils without eradicating the neutrophils. As noted above, neutrophils play an important role in the innate response, but the dysregulation of neutrophils (e.g., too many or too active neutrophils) lead to tissue damage and disease. Thus, the propensity of the methods described herein to reduce neutrophils (e.g., airway neutrophils) without eradicating the neutrophils advantageously addresses neutrophil dysregulation, and thereby the tissue damage and disease, without negatively impacting the role of neutrophils in the immune system. In some embodiments, the methods described herein prevent or reduce at least one of alveolar edema and neutrophil trafficking.
  • the method for treating a neutrophilic lung disease described herein includes administering IL-IRa (e.g., rhIL-IRa) to a human subject.
  • IL-IRa e.g., rhIL-IRa
  • the method may comprise administering a pharmaceutical composition comprising IL-IRa (e.g., rhIL-IRa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is a spray, aerosol, gel, solution, emulsion, or suspension.
  • the pharmaceutical composition comprises ALTA-2530. In some embodiments, the pharmaceutical composition comprises anakinra. [0069] In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent. The inclusion of a second therapeutic agent may improve the clinical benefit of the disclosed treatment method across indications.
  • the pharmaceutical composition may include, as a second therapeutic agent, cyclosporine, steroids, antibiotics, and combinations thereof.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being comingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
  • the composition may also include additional agents such as an isotonicity agent, a preservative, a surfactant, and, a divalent cation, preferably, zinc.
  • the pharmaceutically acceptable carrier is selected from the group consisting of saline, Ringer's solution, dextrose solution, and a combination thereof.
  • suitable pharmaceutically acceptable carriers known in the art are contemplated. Suitable carriers and their formulations are described in Remington's Pharmaceutical Sciences, 2005, Mack Publishing Co.
  • the pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5.
  • the formulation may also comprise a lyophilized powder.
  • Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles.
  • the pharmaceutical composition may also include an excipient, or an agent for stabilization of IL-IRa (e.g., rhIL-IRa), such as a buffer, a reducing agent, a bulk protein, amino acids (such as e.g., glycine or praline), or a carbohydrate.
  • IL-IRa e.g., rhIL-IRa
  • Bulk proteins useful in formulating IL-IRa e.g., rhIL-IRa
  • Typical carbohydrates useful in formulating IL-IRa include, as non-limiting examples, mannitol, lactose, trehalose, and glucose.
  • the pharmaceutical composition may also include a surfactant.
  • Surfactants may be used to prevent soluble and insoluble aggregation and/or precipitation of proteins (e.g., IL- IRa) included in the composition. Suitable surfactants include but are not limited to sorbitan trioleate, soya lecithin, and oleic acid. In certain cases, solution aerosols are preferred using solvents such as ethanol.
  • the pharmaceutical composition comprising IL-IRa e.g., rhIL-IRa
  • Various conventional surfactants can be employed, such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol fatty acid esters. Amounts will generally range between 0.001% and 4% by weight of the formulation.
  • Especially preferred surfactants include, as non-limiting examples, polyoxyethylene sorbitan mono-oleate, polysorbate 80, and polysorbate 20. Additional agents known in the art can also be included in the pharmaceutical composition.
  • the pharmaceutical compositions further comprise one or more compounds that reduce the rate by which IL-IRa (e.g., rhIL-IRa) will decay or will change in character.
  • stabilizers or “preservatives” may include, but are not limited to, amino acids, antioxidants, pH buffers, or salt buffers.
  • antioxidants include butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, butylated hydroxy anisole and cysteine.
  • preservatives include parabens, such as methyl or propyl p-hydroxybenzoate and benzalkonium chloride.
  • the pharmaceutical composition comprising IL-IRa may be formulated to be compatible with its intended route of administration.
  • routes of administration include, but are not limited to, oral or nasal inhalation (e.g., inhalation of sufficiently small particles to be deposited expressly within the lower airways).
  • the pharmaceutical composition is sterile and in suitable form for administration to a (human) subject.
  • the dosage form of the pharmaceutical composition will typically vary depending on their use.
  • dosage forms include powders; solutions; aerosols (e.g., sprays, metered or nonmetered dose atomizers, oral or nasal inhalers including metered dose inhalers (MDI)); liquid dosage forms suitable for mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and sterile solids (e.g., crystalline or amorphous solids) that can also be reconstituted to provide liquid dosage forms suitable for lower airways administration.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions
  • sterile solids e.g., crystalline or amorphous solids
  • IL-IRa e.g., rhIL-IRa
  • pharmaceutical composition comprising IL-IRa, such at ALTA-2530
  • the frequency and dosage will also vary according to factors specific for each subject, such as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Suitable regimens can be selected by one skilled in the art by considering such factors and by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (71st ed., 2017).
  • the recommended daily dose range of IL-IRa (e.g., rhIL-IRa) for the neutrophilic lung disease described herein lie within the range of from about 0.01 mg to about 200 mg per day, given as a single once-a-day dose preferably or as divided doses throughout a day.
  • the daily dose is administered twice daily in equally divided doses.
  • a daily dose range should be from about 100 micrograms to about 50 milligrams per day, more specifically, between about 500 micrograms and about 5 milligrams per day.
  • the therapy may be initiated at a lower dose, perhaps about 500 micrograms, and increased if necessary up to about 5.0 milligrams per day as either a single dose or divided doses, depending on the patient’s global response. It may be necessary to use dosages of IL-IRa (e.g., rhIL-IRa) outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that in instances where a clinician or treating physician is involved, such a person will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual subject response.
  • IL-IRa e.g., rhIL-IRa
  • the effective amount of IL-IRa is from about 0.1 mg to about 100 mg per day, from about 0.1 mg to about 50 mg per day, or from about 0.1 mg to about 10 mg per day.
  • Effective dosages and schedules for administering IL- IRa may be determined empirically, and making such determinations is within the skill in the art. Those skilled in the art will understand that the dosage of any composition administered will vary depending on, for example, the subject receiving the composition, the route of administration, the particular composition used including the coadministration of other drugs and other drugs being administered to the mammal.
  • a typical daily dosage of IL-IRa (e.g., rhIL-IRa) used alone might range from about e.g., 0.25 mg to up to 20.0 mg per oral or nasal inhalation, or 0.125 mg to 25.0 mg per oral or nasal inhalation, however, depending on symptoms and body weight a higher or lower dosage may be appropriate.
  • the dosage administered can vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, and health of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • treatment can be provided as a one-time or periodic dosage of IL-IRa (e.g., rhIL-IRa) from 0.01 to 200 mg, or 0.01 to 100 mg, such as 0.025, 0.05, 0.075, 0.1, 0.125, 0.25, 0.50, 0.75, 1.0, 1.125, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 mg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively or additionally, at least one of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
  • the effective amount of IL-IRa is from about 0.125 mg to 20.0 mg per day.
  • Different therapeutically effective amounts of IL-IRa e.g., rhIL-IRa
  • different therapeutically effective compounds may be included in a specific composition depending on the subject’s disease.
  • amounts sufficient to prevent, manage, treat or ameliorate such disease, but insufficient to cause, or sufficient to reduce, adverse effects associated with IL-IRa are also encompassed by the above described dosage amounts and dose frequency schedules.
  • IL-IRa e.g., rhIL-IRa
  • the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the compound or it may be decreased to reduce one or more side effects that a particular subject is experiencing.
  • one aspect of the current invention is the local delivery, e.g., directly to the lower airways, of IL-IRa (e.g., rhIL-IRa) to the human subject and the delivery device that accomplishes said dosing.
  • Delivery devices described herein may provide methods for the direct delivery of a pharmaceutical composition whereby IL-IRa (e.g., rhIL-IRa) may have local effects, e.g., directly in the vicinity of the mucosa of the lower airways.
  • the advantages of local therapy for local disease include the lack of adverse effects due to systemic exposure of the active ingredient.
  • IL-IRa e.g., rhIL-IRa
  • IL-IRa e.g., rhIL-IRa
  • delivery by the inhalation device is generally reliable, reproducible, and accurate.
  • the inhalation device can optionally deliver small dry particles, e.g., less than about 10 microns, preferably about 3 to 5 microns, for good respirability, or dry particles with small stokes radius.
  • the inhalation device can optionally deliver a wet mist of particles, e.g., droplets.
  • Suitable liquid nebulizers include, for example, InnoSpire Go mesh nebulizer (Philips), iNeb AAD system (Philips) the iNeb Advance nebulizer (Philips), and PARI nebulizer (PARI).
  • IL-IRa may be nebulized and achieve particles mass median aerodynamic diameter (MMAD) of about between about 1 pm and about 5 pm, between about 5 pm and between about 10 pm, between about 10 pm and 15 pm, or between about 15 pm and 20 pm.
  • MMAD particles mass median aerodynamic diameter
  • the MMAD is about 3 pm, consistent with delivery to lower regions of the lung.
  • An MMAD of about 3 gm permits a high delivered dose to the region of the respiratory tract most associated with neutrophilia. Further, inhaled delivery lowers systemic exposure with the potential benefit of reducing the risk of the adverse events associated with alternative administration routes, e.g., high dose IV infusion therapy.
  • IL-IRa e.g., rhIL-IRa
  • inhalation devices capable of depositing aerosolized formulations in the lower airways of a patient include but are not limited to metered dose inhalers, sprayers, nebulizers, and dry powder generators.
  • Other devices suitable for pulmonary administration of proteins and small molecules, including IL-IRa (e.g., rhIL-IRa), are also known in the art. All such devices can use of formulations suitable for the dispensing of IL-IRa (e.g., rhIL-IRa) in an aerosol.
  • Such aerosols can include nanoparticles, microparticles, solutions (both aqueous and nonaqueous), or solid particles.
  • Nebulizers like AERx Aradigm, the Ultravent nebulizer (Mallinckrodt), and the Acorn II nebulizer (Marquest Medical Products) (U.S. Pat. No. 5,404,871, WO 97/22376, entirely incorporated herein by reference), produce aerosols from solutions.
  • the nebulizer is Monaghan Aeroeclipse II Breath Activated Jet Nebulizer, or the Philips Innospire Go vibrating mesh nebulizer.
  • Metered dose inhalers such as the Ventolin metered dose inhaler, typically use a propellent gas and require actuation during inspiration see, e.g., WO 94/16970, WO 98/35888, entirely incorporated herein by reference).
  • Suitable dry powder inhalers like Turbuhaler (Astra), Rotahaler (Glaxo), Diskus (Glaxo), Spiros inhaler (Dura/Elan) devices, the Spinhaler powder inhaler (Fisons), use breath-actuation of a mixed powder (U.S. Pat. No. 4,668,218, EP 237507, WO 97/25086, WO 94/08552, U.S. Pat. No. 5,458,135, WO 94/06498, all of which are herein entirely incorporated by reference).
  • Metered dose inhalers, dry powder inhalers and the like generate small particle aerosols.
  • a pharmaceutical composition comprising IL-IRa (e.g., rhIL-IRa) is delivered by a dry powder inhaler or a sprayer.
  • a pharmaceutical composition comprising IL- IRa (e.g., rhIL-IRa) is an aerosolized formulation delivered by an aerosolized nebulizer.
  • the pharmaceutical composition comprising IL-IRa can be administered as a topical spray or powder to the lower airways of a human subject by a delivery device (e.g., oral or nasal inhaler, aerosol generator, oral dry powder inhaler, through a fiberoptic scope, or via syringe during surgical intervention).
  • a delivery device e.g., oral or nasal inhaler, aerosol generator, oral dry powder inhaler, through a fiberoptic scope, or via syringe during surgical intervention.
  • a delivery device e.g., oral or nasal inhaler, aerosol generator, oral dry powder inhaler, through a fiberoptic scope, or via syringe during surgical intervention.
  • any of these devices may be selected for use in the current invention, given one or more advantages for a particular indication, technique, and subject.
  • These delivery devices include but are not limited to devices producing aerosols (metered-dose inhalers (MDIs)), nebulizers and other metered and nonmetered inhalers.
  • current container-closure system designs for inhalation spray drug products include both premetered and device-metered presentations using mechanical or power assistance and/or energy from patient inspiration for production of the spray plume.
  • Premetered presentations may contain previously measured doses or a dose fraction in some type of units (e.g., single, multiple blisters, or other cavities) that are subsequently inserted into the device during manufacture or by the patient before use.
  • Typical device-metered units have a reservoir containing formulation sufficient for multiple doses that are delivered as metered sprays by the device itself when activated by the patient.
  • a pharmaceutical composition comprising IL-IRa (e.g., rhIL- IRa) as a spray
  • IL-IRa e.g., rhIL- IRa
  • a suspension or solution of IL-IRa (e.g., rhIL- IRa) inhibitor can be produced by forcing a suspension or solution of IL-IRa (e.g., rhIL- IRa) inhibitor through a nozzle under pressure.
  • the nozzle size and configuration, the applied pressure, and the liquid feed rate can be chosen to achieve the desired output and particle size to optimize deposition expressly in the lower airways.
  • An electrospray can be produced, for example, by an electric field in connection with a capillary or nozzle feed.
  • particles of IL-IRa delivered by a sprayer have a particle size less than about 20 microns, preferably in the range below 10 microns, and most preferably, about 3 to 5 microns, but other particle sizes may be appropriate depending on the device, composition, and subject needs.
  • nebulizers for liquid formulations, including jet nebulizers, mesh nebulizers (e.g., vibrating mesh nebulizers), and ultrasonic nebulizers may also be useful for administration to the lower airways.
  • Liquid formulations may be directly nebulized and lyophilized powder nebulized after reconstitution.
  • the composition may be aerosolized using a metered dose inhaler, or inhaled as a lyophilized and milled powder.
  • the liquid formulation of composition may be instilled through a bronchoscope, placed directly into the affected regions.
  • IL-IRa may be administered by a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • the metered-dose inhaler can contain therapeutically active ingredients dissolved or suspended in a propellant, a mixture of propellants, or a mixture of solvents, propellants, and/or other excipients in compact pressurized aerosol dispensers.
  • the MDI may discharge up to several hundred metered doses of the composition.
  • each actuation may contain from a few micrograms (pg) up to milligrams (mg) of the active ingredients delivered in a volume typically between 25 and 100 micro liters.
  • compositions of IL-IRa for use with a metered- dose inhaler device can include a finely divided powder containing IL-IRa (e.g., rhIL-IRa) as a suspension in a non-aqueous medium, for example, suspended in a propellant with the aid of a surfactant or solubilizing agent.
  • IL-IRa e.g., rhIL-IRa
  • the propellant can be any conventional material including but not limited to chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, di chlorotetrafluoroethanol and 1, 1,1,2-tetrafluoroethane, HFA- 134a (hydrofluroalkane-134a), HFA-227 (hydrofluroalkane-227).
  • Hydrofluorocarbon is a preferred propellant.
  • a surfactant can be chosen to stabilize the IL-IRa (e.g., rhIL-IRa) as a suspension in the propellant, to protect the active agent against chemical degradation.
  • solution aerosols are preferred using solvents such as ethanol for more water- soluble active agents. Additional agents including a protein can also be included in the composition.
  • IL-IRa e.g., rhIL-IRa
  • the current invention also incorporates unitdose metering and nonmetering spray devices that are especially suited for single administration. These devices are typically used for acute short-term treatments (i.e., acute exacerbations) and single-dose delivery (i.e., long acting compositions) and can accommodate a liquid, powder, or mixture of both formulations of the composition. However, in certain circumstances, these unit dose devices may be preferred over multidose devices when used repeatedly in a particular way. Such uses may include but are not limited to repeated procedures where a sterile device is preferred.
  • such an intrapulmonary aerosolizer comprises an aerosolizer attached to a pressure generator for delivery of liquid as an aerosol and which can be positioned in close proximity to the lungs by being inserted into the trachea directly or into an endotracheal tube or bronchoscope positioned within the trachea.
  • a pressure generator for delivery of liquid as an aerosol and which can be positioned in close proximity to the lungs by being inserted into the trachea directly or into an endotracheal tube or bronchoscope positioned within the trachea.
  • Such an aerolizer may operate at pressures of up to about 2000 psi and produces particles with a medium particle size of 12 pm.
  • such an intrapulmonary aerosolizer comprises a substantially elongated sleeve member, a substantially elongated insert, and a substantially elongated body member.
  • the sleeve member includes a threaded inner surface, which is adapted to receive the insert, which is a correspondingly threaded member.
  • the threaded insert provides a substantially helical channel.
  • the body member includes a cavity on its first end, which terminates by an end wall at its second end.
  • the end wall includes an orifice extending therethrough.
  • the body member is connected with the sleeve member to provide the aerosolizer of the present invention.
  • the aerosolizer is sized to accommodate insertion into the trachea of a subject for administration of compositions containing IL-IRa (e.g., rhIL- IRa).
  • the aerosolizer is connected by a suitable tube with a liquid pressure driver apparatus.
  • the liquid pressure driver apparatus is adapted to pass liquid material (e.g., a pharmaceutical composition comprising IL-IRa (e.g., rhIL-IRa)) therefrom which is sprayed from the aerosolizer. Due to the location of the device deep within the trachea, the liquid material is sprayed in close proximity to the lungs, with resulting improved penetration and distribution of the sprayed material in the lungs.
  • such an aerosolizer sized for intratracheal insertion, is adapted for spraying a composition containing IL-IRa (e.g., rhIL-IRa) directly into the lower airways (e.g., in close proximity to the lungs).
  • the aerosolizer is placed into connection with a liquid pressure driver apparatus for delivering of the liquid composition.
  • the aerosolizer comprises a generally elongated sleeve member, which defines a first end and a second end and includes a longitudinally extending opening therethrough. The first end of the sleeve member is placed in connection with the liquid pressure driver apparatus.
  • a generally elongated insert is also provided.
  • the generally elongated insert defines a first end and a second end and is received within at least a portion of the longitudinally extending opening of the sleeve member.
  • the insert includes an outer surface which has at least one substantially helical channel provided surrounding its outer surface which extends from the first end to the second end.
  • the substantially helical channel of the insert is adapted to pass the liquid material, which is received by the sleeve member.
  • a generally elongated body member is also included which is in connection with the sleeve member.
  • the body member includes a cavity provided in its first end, which terminates at an end wall which is adjacent its second end.
  • the end wall is provided having an orifice therein for spraying the liquid material, which is received from the insert.
  • a method of using such an aerosolizer includes the steps of connecting an aerosolizer with a first end of a hollow tube member and connecting the second end of the hollow tube member with the liquid pressure driver apparatus. The method further includes the steps of providing the aerosolizer in the trachea or into a member which is provided in the trachea, and then activating the liquid pressure driver apparatus for spraying a pharmaceutical composition comprising IL-IRa (e.g., rhIL-IRa) therefrom.
  • IL-IRa e.g., rhIL-IRa
  • a powder dose composition containing IL-IRa (e.g., rhIL-IRa) is directly administered to the lower airways via use of a powder dispenser.
  • a powder dispenser e.g., rhIL-IRa
  • Exemplary powder dispensers are disclosed in U.S. Pat. Nos. 5,513,630, 5,570,686 and 5,542,412, all of which are herein incorporated in their entirety.
  • Such a powder dispenser is adapted to be brought into connection with an actuator, which introduces an amount of a gas for dispensing the powder dose.
  • the dispenser includes a chamber for receiving the powder dose and a valve for permitting passage of the powder dose only when the actuator introduces the gas into the dispenser.
  • the powder dose is passed from the dispenser via a tube to the lower airways of the subject.
  • the powder dose may be delivered intratracheally, near the carina, which bypasses the potential for large losses of the powder dose to e.g., the mouth, throat, and trachea.
  • the gas passed from the actuator serves to slightly insufflate the lungs, which provides increased powder penetration.
  • the tube can be effected through an endotracheal tube in anesthetized, ventilated subjects, including animal or human patients, or in conscious subjects, the tube be inserted directly into the trachea preferably using a small dose of local anesthetic to the throat and/or a small amount of anesthetic on the tip of the tube, in order to minimize a “gag” response.
  • a composition containing one or more therapeutic agents described herein is directly administered to the lower airways.
  • Such administration may be carried out via use of an aerolizer, which create an aerosol containing the composition and which may be directly installed into the lower airways.
  • aerolizers are disclosed in U.S. Pat. Nos. 5,579,758; 6,041,775; 6,029,657; 6,016,800; 5,606,789; and 5,594,987 all of which are herein incorporated by reference in their entirety.
  • the invention thus provides for the methods of administering pharmaceutical compositions containing IL-IRa (e.g., rhlL- IRa) directly to the lower airways by an aerolizer.
  • IL-IRa e.g., rhlL- IRa
  • an embodiment of the present invention is a new use for the “intratracheal aerosolizer” device which methodology involves the generation of a fine aerosol at the tip of a long, relatively thin tube that is suitable for insertion into the trachea.
  • the present invention provides a new method of use for this aerosolizer technology in a microcatheter as adapted herein, for use in the lower airways in the prevention, treatment, and care of lower airways disorders.
  • an aerosolizing microcatheter is used to administer a composition containing a pro-inflammatory cytokine inhibitor.
  • intratracheal aerosolization which involves the generation of a fine aerosol at the tip of a long, relatively thin tube that is suitable for insertion into the trachea, are disclosed in U.S. Pat. Nos. 5,579,758; 5,594,987; 5,606,789; 6,016,800; and 6,041,775.
  • a new use for the microcatheter aerosolizer device (U.S. Pat. Nos. 6,016,800 and 6,029,657) is adapted for nasal and paranasal sinus delivery and uses to deliver bioactive agents (e.g., IL-IRa (e.g., rhIL-IRa)) in the treatment, prevention, and diagnosis of lower airways disorders.
  • bioactive agents e.g., IL-IRa (e.g., rhIL-IRa)
  • One advantage of this microcatheter aerosolizer is the potential small size (0.014" in diameter), and thus capable of being easily inserted into the working channel of a human flexible (1 to 2 mm in diameter) or ridged endoscope and thereby directed partially or completely into the ostium of a paranasal sinus.
  • IL-IRa e.g., rhIL-IRa
  • IL-IRa e.g., rhIL-IRa
  • IL-IRa e.g., rhIL-IRa
  • cynomolgus monkeys were administered ALTA-2530 or a saline control once daily for 7 days. Twenty- four hours after the last administration, lung tissue was harvested from the subjects.
  • Immunohistochemistry for rhIL-IRa was performed on lung sections. Positive staining was observed in the epithelium of the bronchioles, the alveolar septae, and the smooth muscle layer of the arteries in subjects that received ALTA-2530. Immunohistochemistry results for the saline-treated and the ALTA-2530-treated subjects are shown in FIG. 3A-B.
  • rats were administered a saline control, a low dose of ALTA- 2530, or a high dose of ALTA-2530 via nebulizer once daily for 7 days. Twenty-four hours after the last administration, lung tissue was harvested from the subjects.
  • Immunohistochemistry for rhIL-IRa was performed on lung sections. Positive staining was observed in the epithelium of the bronchioles, the alveolar septae, and the bronchus- associated lymphoid tissue in subjects that received ALTA-2530. Immunohistochemistry results are shown in FIG. 4.
  • ALTA-2530 inhibits IL-6 (stimulates T- and B-cells and leads to monocyte recruitment; ICso 2.60 ng/mL), IL-8 (promotes neutrophil activation and recruitment; ICso 157.2 ng/mL), CCL2 (promotes leukocyte recruitment to site of inflammation; ICso 66.63 ng/mL), CCL4 (serves as a lymphocyte chemoattractant; ICso 79.21 ng/mL), CXCL1 (promotes neutrophil activation and recruitment; ICso 71.08 ng/mL), and CXCL2 (promotes neutrophil activation and recruitment; ICso 26.94 ng/mL). Results from these assays are shown in FIG. 5.
  • FIGS. 7A-C which compares healthy (FIG. 7A), sulfur mustard exposed, ALTA-2530-treated (FIG. 7B), and sulfur mustard exposed, saline-treated (FIG. 7C) lung samples.
  • LPS Lipopolysaccharide
  • Inhaled LPS serves as a model of acute neutrophilic airway inflammation (Ole Janssen et al., Low-dose endotoxin inhalation in healthy volunteers - a challenge model for early clinical drug development, BMC Pulm. Med. 13: 19 (2013)).
  • the ability of ALTA-2530 to reduce neutrophilic airway inflammation was assessed in a non-human primate inhaled LPS model.
  • the effect of ALTA-2530 treatment on the primary, secondary, and exploratory endpoints is shown in FIG. 8.
  • cynomolgus monkeys were administered vehicle or ALTA-2530 one hour prior to exposure to and inhalation of LPS via mask.
  • Treatment with low-dose ALTA- 2530 reduced the percent neutrophil infiltration in the BALF by 32.7% at 4 hours post-LPS administration.
  • High-dose ALTA-2530 decreased the percent neutrophil infiltration by 36.2% at 24 hours post-LPS administration.
  • Treatment with low-dose ALTA-2350 resulted in a median change in percent neutrophil infiltration in the BALF, as compared to the vehicle control, of -28.01% at 4 hours post-LPS administration and -7.80% at 24 hours post-LPS administration.
  • ALTA-2530 can significantly reduce neutrophilic airway inflammation. Furthermore, ALTA-2530 reduces airway neutrophils without eradicating them, which may protect from overactive neutrophilic lung damage.
  • ALTA-2530 inhibits IL-ip stimulated cytokine and chemokine release and that both low- and high-dose ALTA-2530 reduce neutrophilic airway inflammation (e.g., as quantified by reduction in neutrophil infiltration, IL-ip infiltration, and IL-6 levels) in an LPS model.

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Abstract

L'invention concerne une méthode de traitement d'une maladie pulmonaire neutrophile chez un sujet humain dont l'état le nécessite, comprenant l'administration d'une composition pharmaceutique contenant une quantité efficace d'une IL-IRa (par exemple, rhIL-1Ra) au sujet humain, la maladie pulmonaire neutrophile étant choisie dans le groupe constitué par une maladie pulmonaire obstructive chronique, une maladie pulmonaire obstructive chronique résistante aux stéroïdes, la bronchectasie, l'asthme à neutrophiles, le syndrome de détresse respiratoire aiguë, une lésion pulmonaire chimique et une maladie pulmonaire interstitielle associée à la polyarthrite rhumatoïde, et une autre maladie pulmonaire neutrophile.
PCT/US2023/075912 2022-10-05 2023-10-04 Traitement d'antagoniste du récepteur de l'il-1 pour une maladie pulmonaire neutrophile Ceased WO2024077042A2 (fr)

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