Inhaled nintedanib (AP02) for idiopathic pulmonary fibrosis

Abstract

Single and multiple doses of Nintedanib (AP02) are described together with systemic, exposure and in bronchoalveolar lavage fluid (BALF). The present invention establishes that single and repeated and higher inhaled AP02 doses of up to 8 mg BID for 7 days achieve clinically meaningful exposure with a reduced adverse effects profile.

Description

Atorney Docket No: AVY-003WO PATENTINHALED NINTEDANIB (AP02) FOR IDIOPATHIC PULMONARY FIBROSISCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 769,454, filed March 10, 2024; U.S. Provisional Application No. 63 / 804,535, filed May 12, 2025; and U.S. Provisional Application No. 63 / 850,511, filed July 24, 2025, each of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Idiopathic pulmonary fibrosis (IPF) is a severe, chronic, progressive, fibrosing interstitial lung disease with a poor prognosis and a median survival time from diagnosis of 2 to 4 years (Raghu et al. 2022, Am J Respir Crit Care Med. 205: el 8-e47; Raghu et al. 2018, Am J Respir Crit Care Med. 198: e44-e68; Richeldi etal. 2017, TheLancet. 389: 1941-1952; Ley etal. 2011, Am J Respir Crit Care Med. 183: 431-440; Pergolizzi et al. 2023 Am J Respir Crit Care Med. 183: 431-440). The incidence and prevalence of the disease have been increasing, with current estimates of the global prevalence of IPF in the range of 0.33 to 4.51 per 10,000 persons (Pergolizzi et al. 2023 Am J Respir Crit Care Med. 183: 431-440; Maher et al. 2021, Respir Res.22: 197).

[0003] Nintedanib is 1 of 2 oral therapeutics approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of IPF and has been shown to reduce lung function decline in patients with IPF (Richeldi et al. 2014, N Engl J Med. 370: 2071-2082; Surber et al. 2020, Pulm Pharmacol Ther. 63: 101938). Nintedanib acts via inhibition of receptor tyrosine kinases and non-receptor tyrosine kinases, blocking intracellular signaling cascades involved in the pathogenesis of interstitial lung disease (ILD). While oral nintedanib has been demonstrated to be effective in slowing disease progression in individuals with IPF, treatment has been associated with tolerability issues. Gastrointestinal disorders such as diarrhea, nausea, and vomiting have been reported to occur when treatment is given at the approved dosage. Adverse events (AEs) lead to dose reductions or discontinuations in many patients. In a 6-month trial of compliance and persistence of both pirfenidone and nintedanib in 2331 newly prescribed patients, 23.8% patients in the pirfenidone cohort discontinued medication and 33.5% in the nintedanib cohort discontinued medication. Both drugs require1IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTlifetime therapy, and therefore, longer term discontinuation rates are likely higher. Efficacy of both drugs is also not optimal, with each slowing the rate of disease progression as measured by serial forced vital capacity measures by about 50%.

[0004] These adverse events have led to reduced patient compliance and persistence (Podolanczuk and Cotin 2023, Adv Then 40: 2038-2050; Lalla et al. 2017, American Thoracic Society. A5351-A5351; Belhassen et al. 2021, Respir Res. 22: 135). As a result, there is a need for more tolerable and effective IPF therapeutics, either with new mechanisms of action or repurposing proven therapies for direct lung delivery. With direct lung delivery, pulmonary concentrations are maximized while minimizing oral adverse event-associated systemic exposure.

[0005] AP02 is a novel nintedanib solution for inhalation that is delivered by the PARI eFlow Nebulizer System (eFlow). Preclinical data and modeling suggest that, compared to oral nintedanib, small doses reduce toxicity and improve efficacy (Surber et al. 2020, Pulm Pharmacol Then 63: 101938). Because very small inhaled doses achieve this pharmacokinetic parameter while largely avoiding the GI tract, liver and systemic exposure, oral-observed side effects are predicted to be substantially reduced. With reduced side effects, the inhaled dose level may then be increased to test for additional efficacy. Although human studies are required to confirm whether these observations will translate to IPF, the promise for inhalation to reduce nintedanib side effects with possible treatment benefit should motivate such activities.

[0006] As described herein, two phase I studies administered AP02 via oral inhalation. The primary objective of the trials was to assess the safety and tolerability of AP02 when administered in single and multiple ascending doses in healthy volunteers and patients with IPF. Secondary objectives across both studies included assessing nintedanib plasma and bronchoalveolar pharmacokinetics following single or multiple doses of AP02 or a single 150 mg oral nintedanib dose.BRIEF SUMMARY

[0007] The present disclosure relates to methods of treating a pulmonary fibrotic disorder in a human subject in need thereof, where the method comprises administering by inhalation a therapeutically effective amount of nintedanib, or a pharmaceutically acceptable salt thereof, wherein the administering results in a systemic plasma exposure to nintedanib that is lower than2IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTa systemic plasma exposure achieved by oral administration of nintedanib at a therapeutically equivalent dose.

[0008] In some embodiments, the systemic plasma AUC0-24 of nintedanib following administration is at least 10-fold lower than the mean steady-state systemic plasma AUC0-24 of nintedanib following oral administration of nintedanib at 150 mg.

[0009] In some aspects, the systemic plasma AUC0-24 of nintedanib following administration is at least 20-fold lower than the mean steady-state systemic plasma AUC0-24 of nintedanib following oral administration of nintedanib at 150 mg.

[0010] In further aspects, the systemic plasma AUC0-24 of nintedanib following administration is at least 50-fold lower than the mean steady-state systemic plasma AUC0-24 of nintedanib following oral administration of nintedanib at 150 mg.

[0011] In other aspects, the pulmonary fibrotic disorder is idiopathic pulmonary fibrosis (IPF).

[0012] In further embodiments, the therapeutically effective amount is from about 0.5 mg to about 8 mg of nintedanib.

[0013] In other aspects, the therapeutically effective amount is from about 2 mg to about 8 mg of nintedanib.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 demonstrates participant disposition for AP02-001 andAP02-002. InAP02-001, there were 38 randomized participants, receiving doses of 0.5 mg, 1.0 mg, or 2.0 mg AP02. In AP02-002, there were 60 randomized participants, receiving doses of 2.0 mg, 4.0 mg, or 8.0 mg AP02.

[0015] FIG.2 demonstrates the trial design for AP02-001 and AP02-002. Subjects in both studies were dosed once daily or BID.

[0016] FIG.3 depicts the mean (± SD) nintedanib plasma levels following AP02 doses in the single ascending dose portion of the AP02-001 trial, a 2.0 mg dose of AP02 and a 150 mg oral dose of nintedanib in the BAL cohorts, and a 2.0 mg dose of AP02 in patients with IPF. 6 participants were included in the 0.5 mg and 1.0 mg AP02 cohorts for this analysis. 5 participants were included in the 2.0 mg AP02 healthy volunteer and IPF cohorts for this analysis. 4 participants were included in the BAL cohorts for this analysis. Mean ± SD values for each cohort were plotted.3IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0017] FIG.4 depicts the mean (± SD) nintedanib plasma levels following AP02 doses in the single ascending dose portion of the AP02-002 trial and a 4.0 mg dose of AP02 in the BAL cohort. 6 participants were included in each SAD cohort and 12 participants were included in the BAL cohort for this analysis. Mean ± SD values for each cohort were plotted.

[0018] FIG. 5 depicts the mean (± SD) nintedanib plasma levels on Day 1 of treatment in the multiple ascending dose cohorts. The 12 hours post-dose sample was collected after the 12-hour dose was administered for all participants in the AP022.0 mg BID group and therefore was excluded from the pharmacokinetic analysis. 6 participants were included in each MAD cohort for this analysis. Mean ± SD values for each cohort were plotted.

[0019] FIG.6 depicts the mean (± SD) nintedanib plasma levels on Day 7 of treatment following multiple ascending doses for 7 days (13 doses). 6 participants were included in each MAD cohort for this analysis. Mean ± SD values for each cohort were plotted.

[0020] FIG. 7 depicts nintedanib epithelial lining fluid exposure in AP02-002. For the 4 mg AP02 cohort, single BAL samples were collected from n=4 subjects per timepoint at 45 minutes, 4 hours, and 12 hours post-end of inhalation. The slope between 45 minutes and 12 hours was used to conservatively extrapolate to To (dark blue square). For the orally dosed cohort, a single BAL sample was collected per subject in trial AP02-001 at t=9 hours (anticipated ELF Tmax) following a single 150 mg dose (n=4 subjects). ELF values were obtained by using urea to correct for BAL dilution across studies. An ELF: plasma ratio was obtained and applied to the human plasma data from this orally dosed cohort to predict an ELF concentration-time profile.DETAILED DESCRIPTION OF THE INVENTION

[0021] Before the present subject mater is described in detail, it is to be understood that this disclosure is not limited to the particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0022] Unless otherwise defined, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms shall include pluralities and plural terms4IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTshall include the singular. The use of “or” means “and / or” unless stated otherwise. The use of the term “including,” as well as other forms, such as “includes” and “included,” is not limiting.Pulmonary and Regional Diseases

[0023] A number of pulmonary diseases such as interstitial lung disease (ILD; and sub class diseases therein), cancer (lung cancer; and sub-class diseases therein), fibrotic indications of the lungs, kidney, heart and eye, viral infections and diseases of the central nervous system are current areas of unmet clinical need.

[0024] In fibrosis, scarring serves a valuable healing role following injury. However, tissue may become progressively scarred following more chronic, repeated and or idiopathic injuries resulting in abnormal function. In the case of idiopathic pulmonary fibrosis (IPF; and other subclasses of ILD), if a sufficient proportion of the lung becomes scarred respiratory failure can occur. In any case, progressive scarring may result from a recurrent series of insults to different regions of the organ or a failure to halt the repair process after the injury has healed. In such cases the scarring process becomes uncontrolled and deregulated. In some forms of fibrosing disease scarring remains localized to a limited region, but in others it can affect a more diffuse and extensive area resulting in direct or associated organ failure.

[0025] In epithelial injury, epithelial cells are triggered to release several pro-fibrotic mediators, including the potent fibroblast growth factors transforming growth factor-beta (TGF-beta), tumor necrosis factor (TNF), platelet derived growth factor (PDGF), endothelin, other cytokines, metalloproteinases and the coagulation mediator tissue factor. Importantly, the triggered epithelial cell becomes vulnerable to apoptosis, and together with an apparent inability to restore the epithelial cell layer are the most fundamental abnormalities in fibrotic disease.

[0026] In conditions such as diseases, physiological responses characterized by control of pro-fibrotic factors with indolinone derivatives, such as nintedanib is beneficial to attenuate and / or reverse fibrosis, treat cancer, or central nervous system disease. Therapeutic strategies exploiting such indolinone derivative and / or nintedanib effects in these and other indications are contemplated herein.

[0027] Nintedanib and Indolinone Derivative Compounds — Therapeutic Utility5IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0028] The indolinone derivative for use in an indolinone derivative formulation as described herein comprises nintedanib [methyl (3Z)-3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamido)phenyl)amino)(phenyl)methylidene)-2-oxo-2,3-dihydro-lH-indole-6-carboxylate] or a salt thereof.nintedanib

[0029] Other indolinone derivative compounds, or salts thereof, may be used in place of nintedanib. Indolinone derivative compounds include, but are not limited to, those compounds that are structurally similar to nintedanib. Indolinone derivative compounds include, but are not limited to, those compounds that are structurally similar to and have the same type of biological activity as nintedanib. Indolinone derivative compounds include modifications to the nintedanib molecule that are foreseeable based on substitution of chemical moieties that preserve the Structure Activity Relationship (S AR) of nintedanib based on the interaction of nintedanib, or the subject derivative as specific and selective inhibitor of certain tyrosine kinases as described below. Indolinone derivative compounds include, but are not limited to, those compounds described in US Patents 6,762,180 and 7,119,093.

[0030] Nintedanib inhibits a broad range of kinases at pharmacologically relevant concentrations. Examples of targeted kinases include all three VEGFR subtypes (VEGFR-1, IC50 34 nM; VEGFR-2, IC5021 nM; VEGFR-3, IC50 13 nM), FGFR types (FGFR-1, IC5069 nM; FGFR-2, IC5037 nM; FGFR- 3, IC50 108 nM; FGFR-4, IC50610 nM), and PDGFR-a (IC50, 59 nM) and PDGFR-b (IC50, 65 nM). The ability of nintedanib to simultaneously target these three, distinct proangiogenic receptor classes may enhance its antitumor effects and overcome pathways of resistance to VEGF- and VEGFR-2-targeted agents. Nintedanib also inhibited Fit- 36IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTand members of the Src-family (Src, Lyn, and Lek), which may have therapeutic potential for conditions such as hematologic diseases.

[0031] The antifibrotic potential of VEGFR, PDGLR, and LGLR inhibition with orally administered nintedanib has also been evaluated in a series of preclinical studies. Nintedanib was shown to inhibit PDGLR-a and PDGLR-b activation and proliferation of normal human lung fibroblasts in vitro and to inhibit PDGL-BB-, LGL-2-, and VEGL-induced proliferation of human lung fibroblasts from patients with IPF and control donors. Nintedanib atenuated PDGF- or FGF-2-stimulated migration of lung fibroblasts from patients with IPF9 and inhibited transforming growth factor (TGF)-induced fibroblast to myofibroblast transformation of primary human lung fibroblasts from IPF patients. PDGFR activation and downstream signaling was inhibited by nintedanib in a dose-dependent manner in mouse lung tissue when administered orally in vivo. In two different mouse models of IPF, nintedanib exerted anti-inflammatory effects as shown by significant reductions in lymphocyte and neutrophil counts in the bronchoalveolar lavage fluid, reductions in inflammatory cytokines, and reduced inflammation and granuloma formation in histological analysis of lung tissue. IPF mouse models also revealed nintedanib-associated antifibrotic effects as shown by significant reductions in total lung collagen and by reduced fibrosis identified in histological analyses.

[0032] IPF is a chronic and progressive, fibrotic lung disease associated with a short median survival post diagnosis of 2-3 years due to a lack of effective therapies. IPF is characterized by uncontrolled fibroblast / myofibroblast proliferation and differentiation, and excessive collagen deposition within the lung interstitium and alveolar space, leading to symptoms of cough and dyspnea, and ultimately to respiratory failure.

[0033] In some embodiments, administration of nintedanib or salt thereof, by inhalation has reduced gastrointestinal and liver side-effects when compared to oral administration. Reducing these side-effects increases patient safety, maximizes patient compliance, avoids dose reduction and / or stoppage protocols, and enables local lung dose escalation for additional efficacy otherwise not possible with the oral product.Pulmonary Fibrosis7IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0034] A method for treating or preventing progression of pulmonary disease, comprising administering nintedanib or salt thereof or in combination with pirfenidone or pyridone analog to a middle to lower respiratory tract of a patient having or suspected of having pulmonary disease through oral inhalation of an aerosol. A method of treating or preventing progression of interstitial pulmonary fibrosis and includes patients who are being mechanically ventilated.

[0035] A method for treating or preventing progression of idiopathic pulmonary fibrosis (IPF), comprising administering nintedanib or salt thereof or in combination with pirfenidone or pyridone analog to a middle to lower respiratory tract of a subject having or suspected IPF through oral inhalation of an aerosol comprising nintedanib or salt thereof.

[0036] A method for treating or preventing progression of systemic sclerosis associated interstitial lung disease (SSc-ILD), comprising administering nintedanib or salt thereof or in combination with pirfenidone or pyridone analog to a middle to lower respiratory tract of a subject having or suspected of having SSc-ILD through oral inhalation of an aerosol comprising nintedanib or salt thereof.

[0037] IPF as described herein refers to “idiopathic pulmonary fibrosis” and is in some embodiments a chronic disease that manifests over several years and is characterized by scar tissue within the lungs, in the absence of known provocation. Exercise-induced breathlessness and chronic dry cough may be the prominent symptoms. IPF belongs to a family of lung disorders known as the interstitial lung diseases (ILD) or, more accurately, the diffuse parenchymal lung diseases. Within this broad category of diffuse lung diseases, IPF belongs to the subgroup known as idiopathic interstitial pneumonia (IIP). There are seven distinct IIPs, differentiated by specific clinical features and pathological patterns. IPF is the most common form of IIP. It is associated with the pathologic pattern known as usual interstitial pneumonia (UIP); for that reason, IPF is often referred to as IPF / UIP. IPF is usually fatal, with an average survival of approximately three years from the time of diagnosis. There is no single test for diagnosing pulmonary fibrosis; several different tests including chest x-ray, pulmonary function test, exercise testing, bronchoscopy and lung biopsy are used in conjunction with the methods described herein.

[0038] Idiopathic pulmonary fibrosis (also known as cryptogenic fibrosing alveolitis) is the most common form of interstitial lung disease and may be characterized by chronic progressive8IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTpulmonary parenchymal fibrosis. It is a progressive clinical syndrome with unknown etiology; the outcome is frequently fatal as no effective therapy exists. In some embodiments, nintedanib inhibits fibroblast proliferation and differentiation related to collagen synthesis, inhibits the production and activity of TGF-beta, reduces production of fibronectin and connective tissue growth factor, inhibits TNF-alpha and I-CAM, increase production of IL- 10, and / or reduces levels of platelet-derived growth factor (PDGF) A and B in bleomycin-induced lung fibrosis. The methods and compositions described herein may provide tolerability and usefulness in patients with advanced idiopathic pulmonary fibrosis and other lung diseases. In some embodiments, nintedanib methods and compositions described herein may provide tolerability and usefulness in patients with mild to moderate idiopathic pulmonary fibrosis. Increased patient survival, enhanced vital capacity, reduced episodes of acute exacerbation (compared to placebo), and / or slowed disease progression are observed following treatment with the compositions of the invention.

[0039] Because different drug products are known to vary in efficacy depending on the dose, form, concentration and delivery profile, the presently disclosed embodiments provide specific formulation and delivery parameters that produce protection against and treatment for pulmonary fibrosis associated, by non-limiting example with infection, radiation therapy, chemotherapy, inhalation of environmental pollutants (e.g. dust, vapors, fumes, and inorganic and organic fibers), hypersensitivities, silicosis, byssinosis, genetic factors and transplant rejection.

[0040] For the applications described herein, liquid nebulized or dry powder aerosol nintedanib or salt thereof, ) may be co-administered, administered sequentially or prepared in a fixed combination with an antimicrobial (e.g. tobramycin and / or other aminoglycoside such as amikacin, aztreonam and / or other beta or mono-bactam, ciprofloxacin, levofloxacin and / or other, fluoroquinolones, azithromycin and / or other macrolides or ketolides, tetracycline and / or other tetracyclines, quinupristin and / or other streptogramins, linezolid and / or other oxazolidinones, vancomycin and / or other glycopeptides, and chloramphenicol and / or other phenicols, and colistin and / or other polymyxins), bronchodilator (e.g. beta-2 agonists and muscarinic antagonists), corticosteroids (e.g. salmeterol, fluticasone and budesonide), glucocorticoids (e.g. prednisone), Cromolyn, Nedocromil, Leukotriene modifiers (e.g. montelukast, zafirlukast and zileuton) hyperosmolar solution, DNAse or other mucus thinning agent, interferon gamma,9IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTcyclophosphamide, colchicine, N-acetylcysteine, azathioprine, bromhexine, endothelin receptor antagonist (e.g. bosentan and ambrisentan), PDE5 inhibitor (e.g. sildenafil, vardenafil and tadalafil), PDE4 inhibitor (e.g. roflumilast, cilomilast, oglemilast, tetomilast and SB256066), prostinoid (e.g. epoprostenol, iloprost and treprostinin), nitric oxide or nitric oxide-donating compound, IL- 13 blocker, IL- 10 blocker, CTGF-specific antibody, CCN2 inhibitors, angiotensinconverting enzyme inhibitors, angiotensin receptor antagonists, PDGF inhibitors, PPAR antagonist, oral nintedanib, CCL2-specific antibody, CXCR2 antagonist, triple growth factor kinase inhibitor, anticoagulant, TNF blocker, tetracycline or tetracycline derivative, 5 -lipoxygenase inhibitor, pituitary hormone inhibitor, TGF-beta-neutralizing antibody, copper chelator, angiotensin II receptor antagonist, chemokine inhibitor, NF-kappaB inhibitor, NF-kappaB antisense oligonucleotide, IKK-1 and -2 inhibitor (e.g. imidazoquinoxaline or derivative, and quinazoline or derivative), JNK2 and / or p38 MAPK inhibitor (e.g. pyridylimidazolbutyn-I-ol, SB856553, SB681323, diaryl urea or derivative, and indole-5-carboxamide), PI3K inhibitor, LTB4 inhibitor, antioxidant (e.g. Mn-pentaazatetracyclohexacosatriene, M40419, N-acetyl-L-cysteine, Mucomyst, Fluimucil, Nacystelyn, Erdosteine, Ebselen, thioredoxin, glutathione peroxidase memetrics, Curcumin C3 complex, Resveratrol and analogs, Tempol, catalytic antioxidants, and OxSODrol), TNF scavenger (e.g. infliximab, etanercept, adalumimab, PEG-sTNFR 1, afelimomab, and antisense TNF-alpha oligonucleotide), Interferon beta-la (Avonex, Betaseron, or Rebif), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri), Methotrexate, azathioprine (Imuran), intravenous immunoglobulin (IVIg), cyclophosphamide (Cytoxan), lioresal (Baclofen), tizanidine (Zanaflex), benzodiazepine, cholinergic medications, antidepressants and amantadine.

[0041] As shown as a promising approach to treat cancer and pulmonary arterial hypertension, to enable “cocktail therapy” or “cocktail prophylaxis” in fibrotic disease, more specifically idiopathic pulmonary fibrosis and other pulmonary fibrotic disease, methods to administer inhaled nintedanib or salt thereof, are co-administered, administered sequentially, or coprescribed (such that medicines are requested by a prescribing physician to be taken in some sequence as combination therapy to treat the same disease) with agents targeting cancer, fibrotic or inflammatory disease. By non-limiting example, nintedanib or salt thereof, are administered either in fixed combination, co-administered, administered sequentially, or co-prescribed with the monoclonal GS-6624 (formerly known as AB0024), analog or another antibody targeting 10IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTLOXL2 protein associated with connective tissue biogenesis to reduce inflammation, tumor stroma and / or fibrosis. By another non limiting example, nintedanib or salt thereof, are administered either in fixed combination, co-administered, administered sequentially, or coprescribed with IW001 (Type V collagen), analog or other collagen targeting immunogenic tolerance to reduce inflammation, tumor stroma and / or fibrosis. By another non-limiting example, nintedanib or salt thereof, are administered either in fixed combination, coadministered, administered sequentially, or co-prescribed with PRM-151 (recombinant pentraxin-2), CC-930 (Jun kinase inhibitor), analog or other Jun kinase inhibitor to reduce the inflammation, tumor stroma and / or fibrosis, oral imatinib (a.k.a. Gleevec or Glivec (tyrosine kinase inhibitor)), analog or other tyrosine to inhibit lung fibroblast-myofibroblast transformation and proliferation as well as extracellular matrix production and tumor stroma formation / maintenance through inhibition of PDFG and transforming growth factor (TGF)-signaling, STX-100 (monoclonal antibody targeting integrin alpha- v beta-6), analog or other antibody targeting integrin alpha-v beta-6 or other integrin to reduce inflammation, tumor stroma and / or fibrosis, QAX576 (monoclonal antibody targeting interleukin 13 [IL- 13]), analog or other antibody targeting IL- 13 to reduce inflammation, tumor stroma and / or fibrosis, FG-3019 (monoclonal antibody targeting connective tissue growth factor [CTGF]), analog or other antibody targeting CTGF to reduce inflammation, tumor stroma and / or fibrosis, CNTO-888 (a monoclonal antibody targeting chemokine [C-C motif] ligand 2 [CCL2]), analog or other antibody targeting CCL2 to reduce inflammation, tumor stroma and / or fibrosis, Esbriet®, Pirespa® or Pirfenex® (trade names for pirfenidone), or analog targeting inflammation, tumor stroma and / or fibrosis, SM-04646 (inhaled WNT / MET inhibitor), analog or other chemical targeting WNT / MET to reduce inflammation, tumor stroma and / or fibrosis, N- acetylcysteine (NAC; anti-oxidant), analog or other chemical targeting oxidation to reduce inflammation, tumor stroma and / or fibrosis, PRM-151 (intravenous recombinant human pentraxin-3; macrophage signal modulator), analog or other chemical targeting macrophage to reduce inflammation, tumor stroma and / or fibrosis, MK-2 (inhaled MK-2 inhibitor), analog or other chemical targeting MK-2 to reduce inflammation, tumor stroma and / or fibrosis, CC-90001 (oral JNK1 inhibitor), analog or other chemical targeting JNK1 to reduce inflammation, tumor stroma and / or fibrosis, GLPG-1690 (oral autotaxin inhibitor), analog or other chemical targeting autotaxin to reduce inflammation, tumor stroma and / or fibrosis, BI1015550 to reduce inflammation, tumor stroma11IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTand / or fibrosis, Gefapixant (oral cough inhibitor), analog or other chemical targeting cough to reduce inflammation, tumor stroma and / or fibrosis, cromolyn (inhaled cough inhibitor), analog or other chemical targeting cough to reduce inflammation, tumor stroma and / or fibrosis, PBI-4050 (oral endoplasmic reticulum stress (ER stress) inhibitor), analog or other chemical targeting ER stress to reduce inflammation, tumor stroma and / or fibrosis, TD-139 (inhaled galectin-3 inhibitor), analog or other chemical targeting galectin-3 to reduce inflammation, tumor stroma and / or fibrosis, tipelukast (oral leukotriene and PDE inhibitor), analog or other chemical targeting leukotriene and / or PDE to reduce inflammation, tumor stroma and / or fibrosis, or PAT-1251 (oral LoxL2 inhibitor), analog or other chemical targeting LoxL2 to reduce inflammation, tumor stroma and / or fibrosis, and combinations thereof

[0042] As with administration of nintedanib and their salts, oral and parenteral routes of administration (by non-limiting example, intravenous and subcutaneous) of other compounds, molecules and antibodies targeting the reduction of inflammation, tumor stroma and / or fibrosis is often associated with, by non-limiting example, adverse reactions such as gastrointestinal side effects, liver, kidney, skin, cardiovascular or other toxicities. As described herein the benefits of oral or intranasal inhalation directly to the lung or tissues immediately downstream of the nasal and / or pulmonary compartments will also benefit these compounds by avoiding direct delivery to the gastrointestinal tract and / or reducing systemic exposure thereby reducing gastrointestinal symptoms generated in the central nervous system. Therefore, by non-limiting example, the monoclonal GS-6624 (formerly known as AB0024), analog or another antibody targeting LOXL2 protein associated with connective tissue biogenesis to reduce inflammation, tumor stroma and / or fibrosis may be administered by oral or intranasal inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or pulmonary compartments. By another non-limiting example, PRM-151 (recombinant pentraxin-2), analog or other molecule targeting regulation of the injury response to reduce inflammation and / or fibrosis may be administered by oral or intranasal inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or pulmonary compartments, CC-930 (Jun kinase inhibitor), analog or other Jun kinase inhibitor to reduce tumor stroma and / or the inflammatory response may be administered by oral or intranasal inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or pulmonary compartments, oral imatinib (a.k.a. Gleevec or Glivec (tyrosine kinase inhibitor)), transforming growth factor (TGF)- signaling may be administered by oral or12IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTintranasal inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or pulmonary compartments, STX-100 (monoclonal antibody targeting integrin alpha-v beta-6), analog or other antibody targeting integrin alpha-v beta-6 or other integrin to reduce tumor stroma and / or fibrosis, QAX576 (monoclonal antibody targeting interleukin 13 [IL- 13]), analog or other antibody targeting IL- 13 to reduce tumor stroma and / or inflammation, may be administered by oral or intranasal inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or pulmonary compartments, LG-3019 (monoclonal antibody targeting connective tissue growth factor [CTGF]), analog or other antibody targeting CTGF to reduce tumor stroma and / or fibrosis may be administered by oral or intranasal inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or pulmonary compartments, CNTO-888 (a monoclonal antibody targeting chemokine [C-C motif] ligand 2 [CCL2]), analog or other antibody targeting CCL2 to reduce tumor stroma and / or fibrosis, SM-04646 (inhaled WNT / MET inhibitor), analog or other chemical targeting WNT / MET to reduce tumor stroma and / or fibrosis and / or inflammation, N-acetylcysteine (NAC; anti-oxidant), analog or other chemical targeting oxidation to reduce tumor stroma and / or fibrosis and / or inflammation, PRM-151 (intravenous recombinant human pentraxin-3; macrophage signal modulator), analog or other chemical targeting macrophage to reduce tumor stroma and / or fibrosis and / or inflammation, MK-2 (inhaled MK-2 inhibitor), analog or other chemical targeting MK-2 to reduce tumor stroma and / or fibrosis and / or inflammation, CC-90001 (oral JNK1 inhibitor), analog or other chemical targeting JNK1 to reduce tumor stroma and / or fibrosis and / or inflammation, GLPG-1690 (oral autotaxin inhibitor), analog or other chemical targeting autotaxin to reduce tumor stroma and / or fibrosis and / or inflammation, BI1015550 to reduce tumor stroma and / or fibrosis and / or inflammation, Gefapixant (oral cough inhibitor), analog or other chemical targeting cough to reduce tumor stroma and / or fibrosis and / or inflammation, PBI-4050 (oral endoplasmic reticulum stress (ER stress) inhibitor), analog or other chemical targeting ER stress to reduce tumor stroma and / or fibrosis and / or inflammation, TD-139 (inhaled galectin-3 inhibitor), analog or other chemical targeting galectin-3 to reduce tumor stroma and / or fibrosis and / or inflammation, tipelukast (oral leukotriene and PDE inhibitor), analog or other chemical targeting leukotriene and / or PDE to reduce tumor stroma and / or fibrosis and / or inflammation, PAT- 1251 (oral LoxL2 inhibitor), analog or other chemical targeting LoxL2 to reduce tumor stroma and / or fibrosis and / or inflammation, and combinations thereof.13IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0043] A promising approach to treat cancer and pulmonary arterial hypertension is the administration of “cocktail therapy” or “cocktail prophylaxis” where the method is comprised of co administering or sequentially administering inhaled nintedanib or salt thereof with agents targeting cancer, including but not limited to gefitinib (Iressa, also known as ZD1839), Erlotinib (also known as Tarceva), Bortezomib (originally codenamed PS-341; marketed as Velcade ©and Bortecad®), Janus kinase inhibitors, ALK inhibitors, PARP inhibitors (Iniparib; BSI 201); PI3K inhibitors, Apatinib (YN968D1), Selumetinib, Salinomycin, Abitrexate (methotrexate), Abraxane (Paclitaxel Albumin- stabilized Nanoparticle Formulation), Afatinib Dimaleate, Alimta (pemetrexed disodium), Avastin (Bevacizumab), Carboplatin, Cisplatin, Crizotinib, Erlotinib Hydrochloride, Folex (methotrexate), Folex PFS (methotrexate), Gefitinib, Gilotrif (afatinib dimaleate), Gemcitabine Hydrochloride, Gemzar (gemcitabine hydrochloride), Iressa (Gefitinib), Methotrexate, Methotrexate LPF (methotrexate), Mexate (methotrexate), Mexate-AQ (methotrexate), Paclitaxel, Paclitaxel Albumin- stabilized Nanoparticle Formulation, Paraplat (carboplatin), Paraplatin (carboplatin), Pemetrexed Disodium, Platinol (cisplatin), Platinol-AQ (Cisplatin), Tarceva (Erlotinib Hydrochloride), Taxol (Paclitaxel), and Xalkori (Crizotinib).Pharmaceutical Formulation and Packaging

[0044] Selection of a particular nintedanib composition or salt thereof, is accompanied by the selection of a specially designed product packaging and configuration that maximizes the therapeutic utility of the particular composition. Factors to be considered in selecting packaging may include, for example, intrinsic product stability, whether the formulation may be subject to lyophilization, device selection (e.g., liquid nebulizer, dry-powder inhaler, meter-dose inhaler), and / or packaging form (e.g., simple liquid or complex liquid formulation, whether provided in a vial as a liquid or as a lyophilisate to be dissolved prior to or upon insertion into the device; complex suspension formulation whether provided in a vial as a liquid or as a lyophilisate, and with or without a soluble salt / excipient component to be dissolved prior to or upon insertion into the device, or separate packaging of liquid and solid components; dry powder formulations in a vial, capsule or blister pack; and other formulations packaged as readily soluble or low-solubility solid agents in separate containers alone or together with readily soluble or low-solubility solid agents.14IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0045] In one preferred embodiment, the compositions will take the form of a unit dosage form such as vial containing a liquid, solid to be suspended, dry powder, lyophilisate, or other composition and thus the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.

[0046] Liquid pharmaceutical compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like). Solutions to be aerosolized can be prepared in conventional forms, either as liquid solutions or suspensions, or in solid forms suitable for dissolution or suspension in liquid prior to aerosol production and inhalation. The percentage of active compound contained in such aerosol compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. Typically, 0.25%-50.0% of the active agent in an aqueous solution is acceptable for aerosolization.

[0047] Nintedanib or salt thereof compound formulations can be separated into two groups; those of simple formulation or complex formulations providing taste-masking for improved tolerability, pH-optimized for stability and tolerability, immediate or sustained-release, and / or area-under-the-curve (AUC) shape-enhancing properties. Simple formulations can be further separated into three groups. 1. Simple formulations may include water-based liquid formulations for nebulization. Water-based liquid formulations include nintedanib active ingredient with nonencapsulating water soluble excipients; 2) additional organic-based liquid formulations for nebulization or meter-dose inhaler with nintedanib non-encapsulating organic soluble excipients; 3) dry powder formulations for administration with a dry powder inhaler nintedanib alone or with either water soluble or organic soluble non-encapsulating excipients with or without a carrier agent such as lactose.

[0048] Complex formulations containing active ingredient can be further separated into five groups: 1) nintedanib formulations with active ingredient encapsulated or complexed with water-soluble excipients such as lipids, liposomes, cyclodextrins, microencapsulations, and emulsions; 2) organic-based liquid formulations for nebulization or meter-dose inhaler with active ingredient15IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTnintedanib encapsulated or complexed with organic-soluble excipients such as lipids, microencapsulations, and reverse-phase water-based emulsions; 3) formulations including low-solubility, water-based liquid formulations for nebulization comprised of nintedanib , stable nanosuspension alone or in co-crystal / co-precipitate excipient complexes, or mixtures with low solubility lipids, such as lipid nanosuspensions; 4) low- solubility, organic-based liquid formulations for nebulization or meter-dose inhaler nintedanib as a low-organic soluble, stable nanosuspension alone or in co-crystal / co-precipitate excipient complexes, or mixtures with low solubility lipids, such as lipid nanosuspensions; and 5) dry powder formulations for administration using a dry powder inhaler of nintedanib as a co-crystal / co-precipitate / spray dried complex or mixture with low- water soluble excipients / salts in dry powder form with or without a carrier agent such as lactose. Specific methods for simple and complex formulation preparation are described herein.

[0049] The aerosol for delivery to the lungs of a human contains a fine particle fraction between 10 and 100% with increment units of 1%. By example, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%. The fine particle dose is between about 0.0001 mg to about 100 mg nintedanib or salt thereof. By example, about 0.0001 mg, about 0.001 mg, about 0.005 mg, about 0.01 mg, and about 0.05 mg in 0.01 mg increments. By further example, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg in 0.1 mg increments. By example, about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, and about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg in 0.01 mg increments.

[0050] In some embodiments, nintedanib or salt thereof, has an osmolality adjusting agent suitable for pulmonary delivery. The osmolality adjusting agent includes a co solvent selected from propylene glycol, ethanol, polyethylene glycol 400, mannitol and glycerin. The16IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTcompositions further comprise a second anti-fibrotic or anti-cancer or anti-infective or anti-infective agent suitable for pulmonary delivery. The compositions further comprise a second anti-inflammatory agent suitable for pulmonary delivery. The composition may be coadministered with a second anti-fibrotic or anti-cancer or anti-infective agent suitable for pulmonary delivery. The composition co-administered a second anti-inflammatory agent suitable for pulmonary delivery.

[0051] In another embodiment, a pharmaceutical composition is provided that includes a simple or complex liquid nintedanib salt thereof with non-encapsulating water-soluble excipients as described above having an osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg. In other embodiments the osmolality is from about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 mOsmol / kg to about 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000 mOsmol / kg and preferably between about 50 mOsmol / kg and about 600 mOsmol / kg.

[0052] The simple or complex formulation preferably has nintedanib a permeant ion concentration between from about 30 mM to about 150 mM. The permeant ions in the composition are preferably selected from the group consisting of chloride and bromide and combinations thereof.

[0053] Nintedanib nintedanib In another embodiment, a pharmaceutical composition is provided that includes a simple or complex liquid nintedanib or salt thereof compound formulation as a low water-soluble stable nanosuspension alone or in co-crystal / co-precipitate complexes, or mixtures with low solubility lipids, such as lipid nanosuspensions) as described above having a solution osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg. In one embodiment, the osmolality is from about 100 mOsmol / kg to about 500 mOsmol / kg.

[0054] In another embodiment, a pharmaceutical composition is provided that includes a complex suspension of a nintedanib or salt thereof compound formulation having a permeant ion concentration from about 30 mM to about 150 mM. In one such embodiment, one or more permeant ions in the composition are selected from the group consisting of chloride and bromide.

[0055] In another embodiment, a pharmaceutical composition is provided that includes a complex suspension of a nintedanib or salt thereof compound formulation having a permeant ion17IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTconcentration from about 30 mM to about 150 mM. In one such embodiment, one or more permeant ions in the composition are selected from the group consisting of chloride and bromide.

[0056] In other embodiments, nintedanib or includes a taste-masking agent including sugar, saccharin (e.g., sodium saccharin), sweetener or other compound or agent that beneficially affects taste, after-taste, perceived unpleasant saltiness, sourness or bitterness, or that reduces the tendency of an oral or inhaled formulation to irritate a recipient (e.g., by causing coughing or sore throat or other undesired side effect, such as may reduce the delivered dose or adversely influence patient compliance with a prescribed therapeutic regimen). Certain taste-masking agents may form complexes with the nintedanib or salt thereof.

[0057] In another embodiment, a salt form of nintedanib counterion of the salt form of nintedanib is acetate, acetonide, alanine, aluminum, arginine, ascorbate, asparagine, aspartic acid, benzathine, benzoate, besylate, bisulfate, bisulfite, bitartrate, bromide (including bromide and hydrobromide), calcium, carbonate, camphorsulfonate, cetylpridinium, chloride (including chloride and hydrochloride), chlortheophyllinate, cholinate, cysteine, deoxycholate, diethanolamine, diethylamine, diphosphate, diproprionate, disalicylate, edetate, edisylate, estolate, ethylamine, ethylenediamine, ethandisulfonate, esylate, esylate hydroxide, gluceptate, gluconate, glucuronate, glutamic acid, glutamine, glycine, hippurate, histidine, hydrobromide, hydrochloride, hydroxide, iodide, isethionate, isoleucine, lactate, lactobionate, laurylsulfate, leucine, lysine, magnesium, mandelate, meglumine, mesylate, metabisulfate, metabisulfite, methionine, methylbromide, methylsulfate, methyl p-hydroxybenzoate, mucate, naphthoate, napsylate, nitrate, nitrite, octadecanoate, oleate, ornithine, oxalate, pamoate, pentetate, phenylalanine, phosphate, piperazine, polygalacturonate, potassium, procaine, proline, propionate, propyl p-hydroxybenzoate, saccharin, salicylate, selenocysteine, serine, silver, sodium, sorbitan, stearate, succinate, sulfate, sulfite, sulfosalicylate, tartrate, threonine, tosylate, triethylamine, triethiodide, trifluoroacetate, trioleate, tromethamine, tryptophan, tyrosine, valerate, valine, xinafoate, or zinc. Included in the above pharmaceutical composition is the maintenance of the buffers described herein, at a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0, and may include an additional salt form at a level that provides an osmolality of 50 mOsmol / kg and 600 mOsmol / kg. While 300 mOsmol / kg is discussed in the18IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTliterature as important for acute tolerability upon inhalation of this in a nebulized solution, 600 mOsmol / kg has been shown in unpublished studies to be well tolerated with other drug solutions.

[0058] The counterion of the salt form of nintedanib, a indolinone derivative serves as a permeant ion. By non-limiting example, a chloride salt of nintedanib derivative may serve or contribute to the pharmaceutical composition permeant ion. By non-limiting example, a bromide salt of nintedanib derivative may serve or contribute to the pharmaceutical composition permeant ion. While the nintedanib derivative counterion may contribute to permeant ion, additional permeant ion may be added. By non limiting example, nintedanib derivative counterion permeant ion may be supplemented with additional sodium chloride or additional sodium bromide or combinations of chloride and bromide to achieve between about 30 mM to about 150 mM permeant ion. For tolerability, additional solute may be added to the pharmaceutical composition. By non limiting example, osmolality by be adjusted to within about 50 mOsmol / kg to about 2000 mOsmol / kg by addition of sodium chloride, magnesium chloride or calcium chloride. By non limiting example, osmolality by be adjusted to within about 50 mOsmol / kg to about 1000 mOsmol / kg by addition of sodium bromide, magnesium bromide or calcium bromide. By non limiting example, osmolality by be adjusted to within about 50 mOsmol / kg to about 1000 mOsmol / kg by addition of osmolality adjusting agents. By non-limiting example, osmolality adjusting agents include co-solvents selected from ethanol, cetylpridinium chloride, mannitol glycerin, lecithin, propylene glycol, polysorbate (including polysorbate 20, 40, 60, 80 and 85) and sorbitan trioleate.

[0059] The nintedanib salt form salt form is prepared as a chloride or bromide salt form.

[0060] In some embodiments, the therapeutically effective amount is from about 2 mg to about 8 mg of nintedanib. In some embodiments, the therapeutically effective amount is about 0.5 mg of nintedanib. In some embodiments, the therapeutically effective amount is about 1.0 mg of nintedanib. In some embodiments, the therapeutically effective amount is about 2.0 mg of nintedanib. In some embodiments, the therapeutically effective amount is about 4.0 mg of nintedanib. In some embodiments, the therapeutically effective amount is about 6.0 mg of nintedanib. In some embodiments, the therapeutically effective amount is about 8.0 mg of19IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTnintedanib. In some embodiments, the therapeutically effective amount is about 10.0 mg of nintedanib.

[0061] In some embodiments, the therapeutically effective amount is from about 2 mg to about 8 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 0.5 mg to about 10 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 0.5 mg to about 8 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 0.5 mg to about 6 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 0.5 mg to about 4 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 0.5 mg to about 2 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 0.5 mg to about 1 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 1 mg to about 10 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 1 mg to about 8 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 1 mg to about 6 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 1 mg to about 4 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 1 mg to about 2 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 2 mg to about 10 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 2 mg to about 6 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 2 mg to about 4 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 4 mg to about 10 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 4 mg to about 8 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 4 mg to about 6 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 6 mg to about 10 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 6 mg to about 8 mg of nintedanib. In some embodiments, the therapeutically effective amount is from about 8 mg to about 10 mg of nintedanib.

[0062] In some embodiments, the nintedanib is administered once daily. In other embodiments, the nintedanib is administered twice daily (BID).20IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0063] In some embodiments, the nintedanib is administered at about 0.5 mg twice daily. In some embodiments, the nintedanib is administered at about 2.0 mg twice daily. In some embodiments, the nintedanib is administered at about 4.0 mg twice daily. In some embodiments, the nintedanib is administered at about 8.0 mg twice daily.

[0064] In some embodiments, the nintedanib is administered at from about 0.5 mg to about 8.0 mg twice daily. In some embodiments, the nintedanib is administered at from about 0.5 mg to about 4.0 mg twice daily. In some embodiments, the nintedanib is administered at from about 0.5 mg to about 2.0 mg twice daily. In some embodiments, the nintedanib is administered at from about 2.0 mg to about 8.0 mg twice daily. In some embodiments, the nintedanib is administered at from about 2.0 mg to about 4.0 mg twice daily. In some embodiments, the nintedanib is administered at from about 4.0 mg to about 8.0 mg twice daily.

[0065] In some embodiments, the nintedanib is administered for at least 7 days.

[0066] In some embodiments, the nintedanib is administered for at least about 14 days. In some embodiments, the nintedanib is administered for at least about 21 days. In some embodiments, the nintedanib is administered for at least about 28 days. In some embodiments, the nintedanib is administered for at least about 1 month. In some embodiments, the nintedanib is administered for at least about 2 months. In some embodiments, the nintedanib is administered for at least about 3 months. In some embodiments, the nintedanib is administered for at least about 6 months. In some embodiments, the nintedanib is administered for at least about 12 months. In some embodiments, the nintedanib is administered for from about 7 days to about 14 days. In some embodiments, the nintedanib is administered for from about 7 days to about 21 days. In some embodiments, the nintedanib is administered for from about 7 days to about 28 days. In some embodiments, the nintedanib is administered for from about 7 days to about 1 month. In some embodiments, the nintedanib is administered for from about 7 days to about 2 months. In some embodiments, the nintedanib is administered for from about 7 days to about 3 months. In some embodiments, the nintedanib is administered for from about 7 days to about 6 months. In some embodiments, the nintedanib is administered for from about 7 days to about 12 months. In some embodiments, the nintedanib is administered for from about 14 days to about 28 days. In some embodiments, the nintedanib is administered for from about 14 days to about 3 months. In some21IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTembodiments, the nintedanib is administered for from about 14 days to about 6 months. In some embodiments, the nintedanib is administered for from about 14 days to about 12 months. In some embodiments, the nintedanib is administered for from about 1 month to about 3 months. In some embodiments, the nintedanib is administered for from about 1 month to about 6 months. In some embodiments, the nintedanib is administered for from about 1 month to about 12 months. In some embodiments, the nintedanib is administered for from about 3 months to about 6 months. In some embodiments, the nintedanib is administered for from about 3 months to about 12 months. In some embodiments, the nintedanib is administered for from about 6 months to about 12 months.

[0067] In some embodiments, the systemic plasma Cmax of nintedanib following said administration is at least 10-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is at least 15-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg.

[0068] In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 10-fold to about 15-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 10-fold to about 20-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 10-fold to about 25-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 10-fold to about 50-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg.

[0069] In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is less than 20 h*ng / mL. In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is less than 10 h*ng / mL. In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is less than 5.0 h*ng / mL.22IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTIn some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is less than 2.0 h*ng / mL. In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is less than 0.5 h*ng / mL.

[0070] In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is from about 0.1 h*ng / mL to about 20 h*ng / mL. In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is from about 0.1 h*ng / mL to about 10 h*ng / mL. In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is from about 0.1 h*ng / mLto about 5.0 h*ng / mL. In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is from about 0.1 h*ng / mL to about 2.0 h*ng / mL. In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is from about 0.1 h*ng / mLto about 1.0 h*ng / mL. In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is from about 0.1 h*ng / mL to about 0.5 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 0.5 h*ng / mL to about 20 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 0.5 h*ng / mLto about 10 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 0.5 h*ng / mL to about 5.0 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 0.5 h*ng / mL to about 2.0 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 0.5 h*ng / mLto about 1.0 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 1.0 h*ng / mL to about 20 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 1.0 h*ng / mL to about 10 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 1.0 h*ng / mL to about 5.0 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 1.0 h*ng / mL to about 2.0 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 2.0 h*ng / mL to about 20 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from about 2.0 h*ng / mL to about 10 h*ng / mL. In some embodiments, the systemic plasma AUCo-24 of nintedanib following said administration is from 23IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTabout 2.0 h*ng / mLto about 5.0 h*ng / mL. In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is from about 5.0 h*ng / mL to about 20 h*ng / mL. In some embodiments, the systemic plasma AUC0-24 of nintedanib following said administration is from about 5.0 h*ng / mL to about 10 h*ng / mL. In some embodiments, the systemic plasma AUCO-24 of nintedanib following said administration is from about 10 h*ng / mL to about 20 h*ng / mL.

[0071] In some embodiments, the systemic plasma Cmax of nintedanib following said administration is less than 5.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is less than 2.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is less than 1.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is less than 0.5 ng / mL.

[0072] In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.05 ng / mL to about 5.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.05 ng / mL to about 2.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.05 ng / mL to about 1.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.05 ng / mL to about 0.5 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.05 ng / mL to about 0.1 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.1 ng / mL to about 5.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.1 ng / mL to about 2.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.1 ng / mL to about 1.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.1 ng / mL to about 0.5 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.5 ng / mL to about 5.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.5 ng / mL to about 2.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 0.5 ng / mL to about 1.024IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 1.0 ng / mL to about 5.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 1.0 ng / mL to about 2.0 ng / mL. In some embodiments, the systemic plasma Cmax of nintedanib following said administration is from about 2.0 ng / mL to about 5.0 ng / mL.

[0073] In some embodiments, the median time to maximum plasma concentration (Tmax) of nintedanib following inhalation is within about 0.40 hours after the end of inhalation.

[0074] In some embodiments, the median Tmax is within about 0.17 to about 0.40 hours after the end of inhalation.

[0075] In some embodiments, the median Tmax is within from about 0.17 to about 0.25 hours after the end of inhalation. In some embodiments, the median Tmax is within from about 0.17 to about 0.30 hours after the end of inhalation. In some embodiments, the median Tmax is within from about 0.17 to about 0.35 hours after the end of inhalation. In some embodiments, the median Tmax is within from about 0.20 to about 0.40 hours after the end of inhalation. In some embodiments, the median Tmaxis within from about 0.20 to about 0.35 hours after the end of inhalation. In some embodiments, the median Tmaxis within from about 0.20 to about 0.30 hours after the end of inhalation. In some embodiments, the median Tmaxis within from about 0.20 to about 0.25 hours after the end of inhalation. In some embodiments, the median Tmaxis within from about 0.25 to about 0.40 hours after the end of inhalation. In some embodiments, the median Tmaxis within from about 0.25 to about 0.35 hours after the end of inhalation. In some embodiments, the median Tmaxis within from about 0.25 to about 0.30 hours after the end of inhalation. In some embodiments, the median Tmaxis within from about 0.30 to about 0.40 hours after the end of inhalation. In some embodiments, the median Tmaxis within from about 0.30 to about 0.35 hours after the end of inhalation. In some embodiments, the median Tmaxis within from about 0.35 to about 0.40 hours after the end of inhalation. In some embodiments, the median Tmaxis about 0.17 hours after the end of inhalation. In some embodiments, the median Tmaxis about 0.20 hours after the end of inhalation. In some embodiments, the median Tmaxis about 0.25 hours after the end of inhalation. In some embodiments, the median Tmaxis about 0.30 hours after the end of inhalation. In some embodiments, the median Tmaxis about 0.35 hours after25IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTthe end of inhalation. In some embodiments, the median Tmax is about 0.40 hours after the end of inhalation.

[0076] In some embodiments, the nintedanib concentration in epithelial lining fluid (ELF) following said administration exceeds the IC50 of at least one target tyrosine kinase of nintedanib.

[0077] In some embodiments, at least one target tyrosine kinase is selected from the group consisting of VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, PDGFR-a, and PDGFR-0.

[0078] In some embodiments, the nintedanib concentration in ELF is detectable for at least 12 hours following a single inhaled dose. In some embodiments, the ELF Cmax of nintedanib following a single inhaled dose exceeds the ELF Cmax following a single 150 mg oral dose of nintedanib by at least 25-fold. In some embodiments, the ELF AUC0-12 of nintedanib following a single inhaled dose exceeds the ELF AUC0-12 following a single 150 mg oral dose of nintedanib by at least 25-fold.

[0079] In some embodiments, the nintedanib concentration in bronchoalveolar lavage (BAL) fluid following a single inhaled dose exceeds the nintedanib concentration in BAL fluid following a single 150 mg oral dose of nintedanib by at least 9-fold.

[0080] In some embodiments, the geometric mean nintedanib concentration in BAL fluid following a single 2.0 mg inhaled dose is about 3.70 ng / mL.

[0081] In some embodiments, the nintedanib is administered as a solution for inhalation. In some embodiments, the solution is an aqueous solution.

[0082] In some embodiments, the solution is administered using a nebulizer. In some embodiments, the nebulizer is a vibrating mesh nebulizer. In some embodiments, the nebulizer is a PARI eFlow nebulizer.

[0083] In some embodiments, the subject is aged 18 to 80 years.

[0084] In some embodiments, the subject is aged from about 18 to about 70 years. In some embodiments, the subject is aged from about 18 to about 65 years. In some embodiments, the subject is aged from about 18 to about 60 years. In some embodiments, the subject is aged from26IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTabout 18 to about 50 years. In some embodiments, the subject is aged from about 18 to about 40 years. In some embodiments, the subject is aged from about 18 to about 30 years. In some embodiments, the subject is aged from about 25 to about 80 years. In some embodiments, the subject is aged from about 25 to about 70 years. In some embodiments, the subject is aged from about 25 to about 65 years. In some embodiments, the subject is aged from about 25 to about 60 years. In some embodiments, the subject is aged from about 25 to about 50 years. In some embodiments, the subject is aged from about 25 to about 40 years. In some embodiments, the subject is aged from about 30 to about 80 years. In some embodiments, the subject is aged from about 30 to about 70 years. In some embodiments, the subject is aged from about 30 to about 65 years. In some embodiments, the subject is aged from about 30 to about 60 years. In some embodiments, the subject is aged from about 30 to about 50 years. In some embodiments, the subject is aged from about 40 to about 80 years. In some embodiments, the subject is aged from about 40 to about 70 years. In some embodiments, the subject is aged from about 40 to about 65 years. In some embodiments, the subject is aged from about 40 to about 60 years. In some embodiments, the subject is aged from about 50 to about 80 years. In some embodiments, the subject is aged from about 50 to about 70 years. In some embodiments, the subject is aged from about 50 to about 65 years. In some embodiments, the subject is aged from about 60 to about 80 years. In some embodiments, the subject is aged from about 60 to about 70 years. In some embodiments, the subject is aged from about 65 to about 80 years. In some embodiments, the subject is aged from about 70 to about 80 years. In some embodiments, the subject is at least about 18 years of age. In some embodiments, the subject is at least about 25 years of age. In some embodiments, the subject is at least about 30 years of age. In some embodiments, the subject is at least about 40 years of age. In some embodiments, the subject is at least about 50 years of age. In some embodiments, the subject is at least about 60 years of age. In some embodiments, the subject is at least about 65 years of age. In some embodiments, the subject is no more than about 80 years of age. In some embodiments, the subject is no more than about 70 years of age. In some embodiments, the subject is no more than about 65 years of age. In some embodiments, the subject is about 18 years of age. In some embodiments, the subject is about 25 years of age. In some embodiments, the subject is about 30 years of age. In some embodiments, the subject is about 40 years of age. In some embodiments, the subject is about 50 years of age. In some embodiments, the subject is about 60 years of age. In some embodiments, the subject is27IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTabout 65 years of age. In some embodiments, the subject is about 70 years of age. In some embodiments, the subject is about 80 years of age.

[0085] In some embodiments, the subject has an FEVi:FVC ratio of from about 0.70 to about 0.90.

[0086] In some embodiments, the subject has an FEVi:FVC ratio of from about 0.70 to about 0.85. In some embodiments, the subject has an FEVi:FVC ratio of from about 0.70 to about 0.80. In some embodiments, the subject has an FEVi:FVC ratio of from about 0.70 to about 0.75. In some embodiments, the subject has an FEVi:FVC ratio of from about 0.75 to about 0.90. In some embodiments, the subject has an FEVi:FVC ratio of from about 0.75 to about 0.85. In some embodiments, the subject has an FEVi:FVC ratio of from about 0.75 to about 0.80. In some embodiments, the subject has an FEVi:FVC ratio of from about 0.80 to about 0.90. In some embodiments, the subject has an FEVi:FVC ratio of from about 0.80 to about 0.85. In some embodiments, the subject has an FEVi:FVC ratio of from about 0.85 to about 0.90. In some embodiments, the subject has an FEVi:FVC ratio of at least about 0.70. In some embodiments, the subject has an FEVi:FVC ratio of at least about 0.75. In some embodiments, the subject has an FEVi:FVC ratio of at least about 0.80. In some embodiments, the subject has an FEVi:FVC ratio of at least about 0.85. In some embodiments, the subject has an FEVi:FVC ratio of no more than about 0.90. In some embodiments, the subject has an FEVi:FVC ratio of no more than about 0.85. In some embodiments, the subject has an FEVi:FVC ratio of no more than about 0.80. In some embodiments, the subject has an FEVi:FVC ratio of no more than about 0.75. In some embodiments, the subject has an FEVi:FVC ratio of about 0.70. In some embodiments, the subject has an FEVi:FVC ratio of about 0.75. In some embodiments, the subject has an FEVi:FVC ratio of about 0.80. In some embodiments, the subject has an FEVi:FVC ratio of about 0.85. In some embodiments, the subject has an FEVi:FVC ratio of about 0.90.

[0087] In some embodiments, the systemic plasma AUC0-24 of nintedanib following administration of about 2.0 mg of nintedanib is at least about 60-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.028IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTmg of nintedanib is at least about 65-fold lower than the systemic plasma AUC0-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.0 mg of nintedanib is at least about 68-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.0 mg of nintedanib is at least about 70-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.0 mg of nintedanib is at least about 75-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.0 mg of nintedanib is at least about 100-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.0 mg of nintedanib is from about 60-fold to about 100-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.0 mg of nintedanib is from about 60-fold to about 75-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.0 mg of nintedanib is from about 65-fold to about 100-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.0 mg of nintedanib is from about 65-fold to about 75-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.0 mg of nintedanib is from about 68-fold to about 100-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib following administration of about 2.0 mg of nintedanib is from about 68-fold to about 75-fold lower than the systemic plasma AUCo-24 of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma AUCo-24 of nintedanib29IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTfollowing administration of about 2.0 mg of nintedanib is about 68-fold lower than the systemic plasma AUCO-24 of nintedanib following oral administration of nintedanib at 150 mg.

[0088] In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is at least about 10-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is at least about 12-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is at least about 15-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is at least about 18-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is at least about 20-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is at least about 25-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is from about 10-fold to about 25-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is from about 10-fold to about 20-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is from about 10-fold to about 18-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmaxof nintedanib following administration of about 2.0 mg of nintedanib is from about 12-fold to about 25-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is from about 12-fold to about 20-fold lower than 30IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTthe systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is from about 15-fold to about 25-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is from about 15-fold to about 20-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is from about 18-fold to about 25-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg. In some embodiments, the systemic plasma Cmax of nintedanib following administration of about 2.0 mg of nintedanib is about 15-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg.

[0089] In some embodiments, the method further comprises pretreating the subject with a bronchodilator prior to administering the nintedanib by inhalation. In some embodiments, the bronchodilator is salbutamol. In some embodiments, the bronchodilator is administered within 30 minutes prior to the inhalation of nintedanib.

[0090] In some embodiments, nintedanib drug product includes nintedanib at a concentration of about 0.01 mg / mL to about 10 mg / mL in water, optionally a buffer (by non limiting example lysinate, acetylcysteine, glycine, glutamate, borate, succinate, tartrate, phosphate or Tris, optionally an inorganic salts (by non-limiting example sodium chloride, magnesium chloride, calcium chloride, sodium bromide, magnesium bromide, and / or calcium bromide), and optionally a osmolality adjusting agent including co-solvent(s) (by non-limiting example ethanol, propylene glycol, mannitol and glycerin), optionally a surfactant(s) (by non limiting example Tween 80, Tween 60, lecithin, Cetylpyridinium, and Tween 20), at a pH of about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0. The formulation also includes a taste-masking agent (by non-limiting example sodium saccharin). The pharmaceutical composition includes at least about 0.0001 mg to about 100 mg, including all integral values therein such as 0.0001, 0.00025, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 7.0, 8.5, 9.0, 9.5, 10.0, 15, 20, 30, 40, 50, 100 milligrams. The osmolality of the pharmaceutical composition described herein is between about 50 mOsmol / kg to 60031IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTmOsmol / kg. In one aspect, provided herein is a kit comprising: a pharmaceutical composition comprising an nintedanib or salt thereof is formed in a sealed, sterile container, wherein the solution has an nintedanib or salt thereof has a concentration greater than about 0.0001 mg / mL, an osmolality greater than about 100 mOsmol / kg, and a pH greater than about 3.0. The nintedanib or salt thereof salt thereof concentration is greater than about 0.01 mg / mL. The nintedanib or salt thereof, or salt thereof concentration is greater than about 0.025 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.05 mg / mL. The nintedanib or concentration is greater than about 0.1 mg / mL. The nintedanib or concentration is greater than about 0.25 mg / mL. The nintedanib or concentration is greater than about 0.5 mg / mL. The nintedanib or concentration is greater than about 0.75 mg / mL. The nintedanib or concentration is greater than about 1.0 mg / mL. The nintedanib or concentration is greater than about 1.5 mg / mL. The nintedanib or salt thereof is greater than about 2.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 2.5 mg / mL. The nintedanib or salt thereof concentration is greater than about 5.0 mg / mL. The nintedanib or salt thereof salt solution has a permeant ion concentration from about 30 mM to about 150 mM. The permeant ion is chloride or bromide. The nintedanib or salt thereof solution has a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0. The nintedanib or salt thereof solution has an osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg. The nintedanib or salt thereof solution has a taste masking agent selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate and citrate and combinations thereof. In some embodiments, nintedanib or salt thereof, solution has a osmolality adjusting agents suitable for pulmonary delivery. The osmolality adjusting agents include co-solvents selected from propylene glycol, ethanol, polyethylene glycol 400, and glycerin. The kit further comprises a second anti-fibrotic or anti-cancer or anti-infective agent suitable for pulmonary delivery. The kit further comprises a second anti-inflammatory agent suitable for pulmonary delivery. The composition may be coadministered with a second anti-fibrotic or anti-cancer or anti -infective agent suitable for pulmonary delivery. The composition co-administered a second anti-inflammatory agent suitable for pulmonary delivery.

[0091] In one aspect, provided herein is a kit comprising: two containers where upon admixture create a pharmaceutical composition comprising an nintedanib or salt thereof solution in a sterile container, wherein the solution has an nintedanib or salt thereof concentration greater than about 32IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT0.0001 mg / mL, having an osmolality greater than about 50 mOsmol / kg, and having a pH greater than about 3.0. The nintedanib or salt thereof concentration is greater than about 0.01 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.025 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.05 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.1 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.25 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.5 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.75 mg / mL. The nintedanib or salt thereof concentration is greater than about 1.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 1.5 mg / mL. The nintedanib or salt thereof concentration is greater than about 2.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 2.5 mg / mL. The nintedanib or salt thereof concentration is greater than about 5.0 mg / mL.

[0092] In one aspect, provided herein is a kit comprising: a unit dose wherein a pharmaceutical composition comprising an nintedanib or salt thereof and pirfenidone or pyridone analog solution in a sterile container, wherein the solution has an nintedanib or salt thereof concentration greater than about 0.0001 mg / mL and a pirfenidone or pyridone analog concentration greater than about 5 mg / mL, having an osmolality greater than about 50 mOsmol / kg, and having a pH greater than about 3.0. The nintedanib or salt thereof concentration is greater than about 0.01 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.025 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.05 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.1 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.25 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.5 mg / mL. The nintedanib or salt thereof concentration is greater than about 0.75 mg / mL. The nintedanib or salt thereof concentration is greater than about 1.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 1.5 mg / mL. The nintedanib or salt thereof concentration is greater than about 2.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 2.5 mg / mL. The nintedanib or salt thereof concentration is greater than about 5.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 10.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 15.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 20.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 25.0 mg / mL. The nintedanib or salt thereof concentration is 33IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTgreater than about 30.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 35.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 40.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 45.0 mg / mL. The nintedanib or salt thereof concentration is greater than about 50.0 mg / mL.

[0093] The nintedanib or salt thereof solution has a permeant ion concentration from about 30 mM to about 150 mM. The permeant ion is chloride or bromide. The nintedanib or salt thereof solution has a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0. The nintedanib or salt thereof solution has an osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg. The nintedanib or salt thereof solution has a taste masking agent. The taste masking agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, and ascorbate. In some embodiments, nintedanib or salt thereof, solution has a osmolality adjusting agents suitable for pulmonary delivery, including co solvents selected from the group consisting of propylene glycol, ethanol, polyethylene glycol 400, and glycerin and combinations thereof. The solution further comprises a second anti-fibrotic or anti-cancer or anti-infective agent suitable for pulmonary delivery. The kit further comprises a second antiinflammatory agent suitable for pulmonary delivery. The composition may be co-administered with a second anti-fibrotic or anti-cancer or anti-infective agent suitable for pulmonary delivery. The composition co-administered a second anti-inflammatory agent suitable for pulmonary delivery.

[0094] The nintedanib or salt thereof and pirfenidone or pyridone analog solution has a permeant ion concentration from about 30 mM to about 500 mM. The permeant ion is chloride or bromide. The nintedanib or salt thereof solution has a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0. The nintedanib or salt thereof solution has an osmolality from about 50 mOsmol / kg to about 1000 mOsmol / kg. The nintedanib or salt thereof solution has a taste masking agent. The taste masking agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, and ascorbate. In some embodiments, nintedanib or salt thereof, solution has a osmolality adjusting agents suitable for pulmonary delivery, including co-solvents selected from the group consisting of propylene glycol, ethanol, polyethylene glycol 400, and glycerin and combinations thereof. The solution further comprises a second anti-fibrotic or anti-cancer or anti-infective agent suitable for pulmonary delivery. The34IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTcomposition may be co-administered with a second anti-fibrotic or anti-cancer or anti-infective agent suitable for pulmonary delivery. The composition co-administered a second antiinflammatory agent suitable for pulmonary delivery.

[0095] Nebulized aqueous nintedanib formulation requires at least 30 mM permeant ion for good tolerability. However, aqueous nintedanib is unstable at these permeant ion concentrations. To circumvent this issue, aqueous nintedanib may be formulated as a multi -container system for admixture just prior to use. In one configuration a kit is comprised of two-containers for admixture wherein an aqueous solution of nintedanib or salt thereof is dissolved in an aqueous solution in a first container and osmolality adjusting agents, including buffers and permeant and ions are confined to a separate container having no fluid communication between the first and second containers during storage. Just prior to use, the contents of the first and second containers are combined. The first and second containers may be formed as part of the same package specially designed for admixture and for transmiting the contents of the first and second containers once combined into the reservoir of a liquid nebulizer.

[0096] In some embodiments, described herein is a unit dosage adapted for use in a liquid nebulizer comprising from about 0.01 mL to about 10 m of an aqueous solution of nintedanib or salt thereof, wherein the concentration of nintedanib or salt thereof, in the aqueous solution is from about 0.0001 mg / mL to about 10 mg / mL requires admixture prior to administration- For stability purposes the unit dosage form is prepared as a two-container admixture system, wherein container one contains nintedanib or salt thereof is prepared in an aqueous volume from about 0.01 mL to about 10 mL; optionally 0.01 mM to about 1000 mM buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally a osmolality adjusting agent concentration from about 0.1% to about 99%; optionally a taste-masking agent from about 0.01 mM to about 100 mM. Container 2 consists of an aqueous solution from about 0.01 mL to about 10 mL; optionally containing a permeant ion concentration from about 30 mM to about 1500 mM, wherein permeant ions may be selected from chloride ion and bromide ion; optionally 0.01 mM to about 1000 mM buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally a osmolality adjusting agent from about 0.1% to about 99%; optionally a taste-masking agent from about 0.01 mM to about 100 mM. Prior to administration, the two-container admixture system is admixed resulting in a unit dosage35IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTform comprising from about 0.01 mL to about 10 mb of an aqueous solution of nintedanib or salt thereof, wherein the concentration of nintedanib or salt thereof, in the aqueous solution is from about 0.0001 mg / mL to about 10 mg / mL; optionally 0.01 to about 100 mM buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally, a osmolality adjusting agent concentration from about 0.1% to about 20%; optionally a tastemasking agent from about 0.01 mM to about 10 mM; optionally containing a permeant ion concentration from about 30 mM to about 150 mM, wherein permeant ions are selected from chloride ion and bromide ion, with a final admixed solution osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg.

[0097] In some embodiments, described herein is a unit dosage adapted for use in a liquid nebulizer comprising from about 0.01 mL to about 10 mL of an aqueous solution of nintedanib or salt thereof, wherein the concentration of nintedanib or salt thereof, in the aqueous solution is from about 0.0001 mg / mL to about 10 mg / mL requires admixture prior to administration. Lor stability purposes the unit dosage form is prepared as a two-container admixture system, wherein container one contains nintedanib or salt thereof is prepared in an aqueous volume from about 0.01 mL to about 10 mL; optionally 0.01 mM to about 1000 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally a propylene glycol at a concentration from about 0.1% to about 99%; optionally a taste-masking agent from about 0.01 mM to about 100 mM. Container 2 consists of an aqueous solution from about 0.01 mL to about 10 mL; optionally containing a permeant ion concentration from about 30 mM to about 1500 mM, wherein permeant ions may be selected from chloride ion and bromide ion; optionally 0.01 mM to about 1000 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally propylene glycol at a concentration from about 0.1% to about 99%; optionally a taste-masking agent from about 0.01 mM to about 100 mM. Prior to administration, the two-container admixture system is admixed resulting in a unit dosage form comprising from about 0.01 mL to about 10 mL of an aqueous solution of nintedanib or salt thereof, wherein the concentration of nintedanib or salt thereof, in the aqueous solution is from about 0.0001 mg / mL to about 10 mg / mL; optionally 0.01 to about 100 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally, propylene glycol at a concentration from about 0.1% to about 20%; optionally a taste-masking agent from 36IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTabout 0.01 mM to about 10 mM; optionally containing a permeant ion concentration from about 30 mM to about 150 mM, wherein permeant ions may be selected from chloride ion and bromide ion, with a final admixed solution osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg.

[0098] Described herein is a unit dosage adapted for use in a liquid nebulizer comprising from about 0.01 mL to about 10 mL of an aqueous solution of nintedanib or salt thereof, wherein the concentration of nintedanib hydrobromide salt, in the aqueous solution is from about 0.0001 mg / mL to about 5 mg / mL requires admixture prior to administration- For stability purposes the unit dosage form is prepared as a two-container admixture system, wherein container one contains nintedanib hydrobromide salt is prepared in an aqueous volume from about 0.01 mLto about 10 mL; optionally 0.01 mM to about 1000 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally a propylene glycol at a concentration from about 0.1% to about 99%; optionally a taste- masking agent from about 0.01 mM to about 100 mM. Container 2 consists of an aqueous solution from about 0.01 mL to about 10 mL; optionally containing a permeant ion concentration from about 30 mM to about 1500 mM, wherein permeant ions may be selected from chloride ion and bromide ion; optionally 0.01 mM to about 1000 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally propylene glycol at a concentration from about 0.1% to about 99%; optionally a taste-masking agent from about 0.01 mM to about 100 mM. Prior to administration, the two-container admixture system is admixed resulting in a unit dosage form comprising from about 0.01 mL to about 10 mL of an aqueous solution of nintedanib hydrobromide salt, wherein the concentration of nintedanib hydrobromide salt, in the aqueous solution is from about 0.0001 mg / mL to about 5 mg / mL; optionally 0.01 to about 50 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally, propylene glycol at a concentration from about 0.1% to about 20%; optionally a taste-masking agent from about 0.01 mM to about 10 mM; optionally containing a permeant ion concentration from about 30 mM to about 150 mM, wherein permeant ions may be selected from chloride ion and bromide ion with a final admixed solution osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg.37IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0099] In some embodiments, described herein is a unit dosage adapted for use in a liquid nebulizer comprising from about 0.01 mb to about 10 m of an aqueous solution of nintedanib or salt thereof, wherein the concentration of nintedanib hydrochloride salt, in the aqueous solution is from about 0.0001 mg / mL to about 5 mg / mL requires admixture prior to administration- For stability purposes the unit dosage form is prepared as a two-container admixture system, wherein container one contains nintedanib hydrochloride salt is prepared in an aqueous volume from about 0.01 mL to about 10 mL; optionally 0.01 mM to about 1000 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally a propylene glycol at a concentration from about 0.1% to about 99%; optionally a taste-masking agent from about 0.01 mM to about 100 mM. Container 2 consists of an aqueous solution from about 0.01 mL to about 10 mL; optionally containing a permeant ion concentration from about 30 mM to about 1500 mM, wherein permeant ions may be selected from chloride ion and bromide ion; optionally 0.01 mM to about 1000 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally propylene glycol at a concentration from about 0.1% to about 99%; optionally a taste-masking agent from about 0.01 mM to about 100 mM. Prior to administration, the two-container admixture system is admixed resulting in a unit dosage form comprising from about 0.01 mL to about 10 mL of an aqueous solution of nintedanib hydrochloride salt, wherein the concentration of nintedanib hydrochloride salt, in the aqueous solution is from about 0.0001 mg / mL to about 5 mg / mL; optionally 0.01 to about 50 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally, propylene glycol at a concentration from about 0.1% to about 20%; optionally a tastemasking agent from about 0.01 mM to about 10 mM; optionally containing a permeant ion concentration from about 30 mM to about 150 mM, wherein permeant ions may be selected from chloride ion and bromide ion, with a final admixed solution osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg.

[0100] In some embodiments, described herein is a unit dosage adapted for use in a liquid nebulizer comprising from about 0.01 mL to about 10 mL of an aqueous solution of nintedanib or salt thereof, wherein the concentration of nintedanib esylate salt, in the aqueous solution is from about 0.0001 mg / mL to about 5 mg / mL requires admixture prior to administration- For stability purposes the unit dosage form is prepared as a two-container admixture system, wherein 38IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTcontainer one contains nintedanib esylate salt is prepared in an aqueous volume from about 0.01 mL to about 10 mL; optionally 0.01 mM to about 1000 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally a propylene glycol at a concentration from about 0.1% to about 99%; optionally a taste-masking agent from about 0.01 mM to about 100 mM. Container 2 consists of an aqueous solution from about 0.01 mL to about 10 mL; optionally containing a permeant ion concentration from about 30 mM to about 1500 mM, wherein permeant ions may be selected from chloride ion and bromide ion; optionally 0.01 mM to about 1000 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally propylene glycol at a concentration from about 0.1% to about 99%; optionally a taste-masking agent from about 0.01 mM to about 10 mM. Prior to administration, the two-container admixture system is admixed resulting in a unit dosage form comprising from about 0.01 mL to about 10 mL of an aqueous solution of nintedanib esylate salt, wherein the concentration of nintedanib esylate salt, in the aqueous solution is from about 0.0001 mg / mLto about 5 mg / mL; optionally 0.01 to about 50 mM glycine or glutamate buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally, propylene glycol at a concentration from about 0.1% to about 20%; optionally a taste-masking agent from about 0.01 mM to about 10 mM; optionally containing a permeant ion concentration from about 30 mM to about 150 mM, wherein permeant ions may be selected from chloride ion and bromide ion, with a final admixed solution osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg.

[0101] The invention includes a stand-alone, single-container system wherein nintedanib or salt thereof, or an indolinone derivative are stabilized in the presence of pH, and ion concentration, buffer content, osmolality, or other parameters that are otherwise incompatible with nintedanib composition as the active pharmaceutical ingredient. The addition of the active ingredient pirfenidone or pyridone analog further increases nintedanib composition stability, increases aqueous solubility, and reduces viscosity that otherwise exists at high nintedanib composition concentrations greater than about 10 mg / mL to about 50 mg / mL. At these and lower nintedanib or salt thereof, or an indolinone derivative concentrations, the addition of active ingredient pirfenidone or pyridone analog enables formulation of nintedanib or salt thereof, or an indolinone derivative in a stable, single container solution containing ion concentrations, buffer contents, osmolality, pH or other parameters that are otherwise incompatible as a single solution 39IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTproduct. For this, the formulation as administered may be prepared as a unit dosage adapted for use in a liquid nebulizer comprising from about 0.01 mb to about 10 mb of an aqueous solution of nintedanib or salt thereof, or a indolinone derivative or salt thereof at a concentration from about 0.0001 mg / mL to about 50 mg / mL, and pirfenidone or pyridone analog at a concentration from about 5 mg / mL to about 20 mg / mL, optionally one or more osmolality adjusting agents at a concentration of about 0.1% to about 20% to adjust osmolality, inorganic salts at a concentration of about 15 mM to about 500 mM to adjust osmolality and provide a permeant ion at a final concentration from about 30 mM to about 500 mM; and optionally one or more buffers to maintain the pH between about pH 3.0 to about pH 7.0, preferably from about pH 3.0 to about pH 6.0, with a final osmolality between 50 mOsmol / kg and 1000 mOsmol / kg. The aqueous solution may include one or more osmolality adjusting agents, including co-solvents selected from propylene glycol, ethanol, glycerin, and mannitol and combinations thereof at a concentration from about 0.1% to about 20%. The aqueous solution includes one more inorganic salts selected from hydrogen chloride, hydrogen bromide, sodium chloride, magnesium chloride, calcium chloride, potassium chloride, sodium bromide, potassium bromide, magnesium bromide and calcium bromide and combinations thereof. The inorganic salt content of the aqueous solution is from about 15 mM to about 300 mM. The buffer is selected from one or more of lysinate, acetylcysteine, glycine, glutamate, borate, succinate, tartrate, phosphate or Tris and combinations thereof, the pH of the aqueous solution is from about pH 3.0 to about pH 7.0, preferably pH about 3.0 to about pH 6.0. In some embodiments, described herein is an aqueous solution for nebulized inhalation administration comprising: water; nintedanib or salt thereof, at a concentration from about 0.005 mg / mL to about 50 mg / mL; pirfenidone or pyridone analog at a concentration from about 5 mg / mL to about 20 mg / mL; one or more permeant ions; one or more osmolality adjusting agents; and wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 1000 mOsmol / kg.

[0102] The invention includes a population of aqueous droplets of nintedanib or salt thereof wherein the aqueous droplet has a mean diameter less than about 5.0 mhi that may collectively be referred to as an aerosol mist. The population of droplets is produced from a liquid nebulizer having an aqueous solution of nintedanib or salt thereof disposed in the reservoir of the nebulizer. The aqueous solution of nintedanib or salt thereof having a concentration of nintedanib or salt thereof, from about 0.0001 mg / mL to about 10 mg / mL, a permeant ion concentration from 40IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTabout 30 mM to about 150 mM and an osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg.

[0103] The invention includes a population of aqueous droplets of nintedanib or salt thereof and pirfenidone or pyridone analog wherein the aqueous droplet has a mean diameter less than about 5.0 pm that may collectively be referred to as an aerosol mist. The population of droplets is produced from a liquid nebulizer having an aqueous solution of nintedanib or salt thereof and pirfenidone or pyridone analog disposed in the reservoir of the nebulizer. The aqueous solution of nintedanib or salt thereof and pirfenidone or pyridone analog having a concentration of nintedanib or salt thereof, from about 0.0001 mg / mL to about 50 mg / mL and pirfenidone or pyridone analog concentration from about 5 mg / mL to about 20 mg / mL, a permeant ion concentration from about 30 mM to about 500 mM and an osmolality from about 50 mOsmol / kg to about 1000 mOsmol / kg.

[0104] An aqueous aerosol comprising a plurality of aqueous droplets has a volumetric mean diameter (VMD), mass median aerodynamic diameter (MMAD), and / or mass median diameter (MMD) of less than about 5.0 pm. In some embodiments, at least 20% of the aqueous droplets in the aerosol have a diameter less than about 5 pm.

[0105] Although as described below, “high efficiency” liquid nebulizers are preferred for production of the aerosol mist, a number of different nebulizer designs exist including a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an aqueous chamber. A preferred high efficiency nebulizer is comprised of a vibrating mesh or plate with multiple apertures that is in fluid communication with a reservoir for containing the admixture described herein. The liquid nebulizer preferably: (i) achieves lung deposition of at least 7% of the nintedanib or salt thereof to the lung of an adult human; (ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 pm to about 2.5 pm; (iii) provides: a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high efficiency liquid nebulizer of about 1 pm to about 5 pm; b) a volumetric mean diameter (VMD) of about 1 pm to about 5 pm; and / or c) a mass median diameter (MMD) of about 1 pm to about 5 pm; (iv) provides a fine particle41IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTfraction (FPF= % < 5 microns) of droplets emited from the liquid nebulizer of at least about 30%; (v) provides an output rate of at least 0.1 mL / min; and / or (vi) provides at least about 25% of the aqueous solution to the patient.

[0106] The liquid nebulizer preferably possesses at least two, at least three, at least four, at least five, or all six of parameters (i), (ii), (iii), (iv), (v), (vi) listed above and preferably achieves lung deposition of (i) at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% of the nintedanib or salt thereof, or nintedanib or salt thereof and pirfenidone or pyridone analog administered to the patient. The liquid nebulizer: (ii) provides a Geometric Standard Deviation (GSD) of emited droplet size distribution of the aqueous solution of about 1.0 pm to about 2.5 pm, about 1.2 pm to about 2.3 pm, about 1.4 pm to about 2.1 pm, or about 1.5 pm to about 2.0 pm. The liquid nebulizer: (iii) provides a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emited with the high efficiency liquid nebulizer of about less than 5 pm or about 1 pm to about 5 pm; b) a volumetric mean diameter (VMD) of about less than 5 pm or about 1 pm to about 5 pm; and / or c) a mass median diameter (MMD) of about less than 5 pm or about 1 pm to about 5 pm. The liquid nebulizer: (iv) provides a fine particle fraction (FPF= % < 5 microns) of droplets emited from the liquid nebulizer of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%. The liquid nebulizer: (v) provides an output rate of at least 0.1 mL / min, of at least 0.2 mL / min, of at least 0.3 mL / min, of at least 0.4 mL / min, of at least 0.5 mL / min, of at least 0.6 mL / min, of at least 0.7 mL / min, of at least 0.8 mL / min, of at least 0.9 mL / min, of at least 1.0 mL / min, or less than about 1.0 mL / min. The liquid nebulizer: (vi) provides at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 95%, of the aqueous solution to the mammal. The liquid nebulizer provides an respirable delivered dose (RDD) of at least 5%, at least 6%, at least 7%, at least 8%, at least 10%, at least 12%, at least 16%, at least 20%, at least 24%, at least 28%, at least 32%, at least 36%, at least 40%, at least 45%, at least 50%, at least 42IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%.

[0107] The pharmaceutical compositions and methods of the present invention include preparing and administering specific formulations having discrete ranges of concentration, osmolality, and permeant ion concentration in order to generate an aerosol that achieves specific levels of deposition of active ingredient to the lung. The composition comprising nintedanib or salt thereof is prepared in an aqueous solution and administered to the patient with a liquid nebulizer; wherein the aqueous solution comprises water; nintedanib or salt thereof, at a concentration from about 0.001 mg / mL to about 10 mg / mL; wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 600 mOsmol / kg. The liquid (i) achieves lung deposition of at least 7% of the nintedanib or salt thereof administered to the mammal; (ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 pm to about 2.5 pm; (iii) provides: a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high efficiency liquid nebulizer of about 1 pm to about 5 pm; b) a volumetric mean diameter (VMD) of about 1 pm to about 5 pm; and / or c) a mass median diameter (MMD) of about 1 pm to about 5 pm; (iv) provides a fine particle fraction (FPF= % < 5 microns) of droplets emited from the liquid nebulizer of at least about 30%; (v) provides an output rate of at least 0.1 mL / min; and / or (vi) provides at least about 25% of the aqueous solution to the mammal. The liquid nebulizer delivers from about 0.0001 mg to about 100 mg of nintedanib or salt thereof compound to the lungs of the patient in less than about 20 minutes with mass median diameter (MMAD) particles sizes from about 1 to about 5 microns.

[0108] The pharmaceutical compositions and methods of the present invention include preparing and administering specific formulations having discrete ranges of concentration, osmolality, and permeant ion concentration in order to generate an aerosol that achieves specific levels of deposition of active ingredient to the lung. The composition comprising nintedanib or salt thereof and pirfenidone or pyridone analog is prepared in an aqueous solution and administered to the patient with a liquid nebulizer; wherein the aqueous solution comprises water; nintedanib or salt thereof at a concentration from about 0.0001 mg / mL to about 50 mg / mL and pirfenidone or pyridone analog at a concentration from about 5 mg / mL to about 20 mg / mL; wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 1000 mOsmol / kg. The43IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTliquid (i) achieves lung deposition of at least 7% of the nintedanib or salt thereof administered to the mammal; (ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 mpi to about 2.5 mhi; (iii) provides : a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emited with the high efficiency liquid nebulizer of about 1 pm to about 5 pm; b) a volumetric mean diameter (VMD) of about 1 pm to about 5 pm; and / or c) a mass median diameter (MMD) of about 1 pm to about 5 pm; (iv) provides a fine particle fraction (FPF= % < 5 microns) of droplets emited from the liquid nebulizer of at least about 30%; (v) provides an output rate of at least 0.1 mL / min; and / or (vi) provides at least about 25% of the aqueous solution to the mammal. The liquid nebulizer delivers from about 0.0001 mg to about 100 mg of nintedanib or salt thereof and from about 1 mg to about 20 mg pirfenidone or pyridone analog compounds to the lungs of the patient in less than about 20 minutes with mass median diameter (MMAD) particles sizes from about 1 to about 5 microns.

[0109] The methods for the treatment of lung disease in a mammal comprising: administering to mammal in need thereof an aqueous solution comprising nintedanib or salt thereof, with a liquid nebulizer. Described herein is a method for the treatment of lung disease in a mammal comprising: administering to mammal in need thereof an aqueous solution comprising nintedanib or salt thereof with a liquid nebulizer; wherein the aqueous solution comprises water; nintedanib or salt thereof at a concentration from about 0.0001 mg / mL to about 10 mg / mL; optionally one or more inorganic salts, wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 600 mOsmol / kg; optionally a permeant ion from about 30 mM to about 150 mM; optionally one or more buffers maintaining the solution pH between about 3.0 and 7.0; optionally a osmolality adjusting agent from about 0.1 to about 20%; optionally a taste-masker from about 0.01 mM to about 10 mM. The nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an aqueous chamber. In some embodiments, the liquid nebulizer: (i) achieves lung deposition of at least 7% of the nintedanib or salt thereof, administered to the mammal; (ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 pm to about 2.5 pm; (iii) provides: a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emited with the high efficiency liquid nebulizer of about 1 pm to about 5 pm; b) a 44IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTvolumetric mean diameter (VMD) of about 1 pm to about 5 pm; and / or c) a mass median diameter (MMD) of about 1 pm to about 5 pm; (iv) provides a fine particle fraction (FPF= % < 5 microns) of droplets emitted from the liquid nebulizer of at least about 30%; (v) provides an output rate of at least 0.1 mL / min; and / or (vi) provides at least about 25% of the aqueous solution to the mammal.

[0110] The methods for the treatment of lung disease in a mammal comprising: administering to mammal in need thereof an aqueous solution comprising nintedanib or salt thereof and pirfenidone or pyridone analog with a liquid nebulizer. Described herein is a method for the treatment of lung disease in a mammal comprising: administering to mammal in need thereof an aqueous solution comprising nintedanib or salt thereof and pirfenidone or pyridone analog with a liquid nebulizer; wherein the aqueous solution comprises water; nintedanib or salt thereof at a concentration from about 0.0001 mg / mL to about 50 mg / mL and pirfenidone or pyridone analog at a concentration from about 5 mg / mL to about 20 mg / mL; optionally one or more inorganic salts, wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 1000 mOsmol / kg; optionally a permeant ion from about 30 mM to about 500 mM; optionally one or more buffers maintaining the solution pH between about 3.0 and 7.0; optionally a osmolality adjusting agent from about 0.1 to about 10%; optionally a taste-masker from about 0.01 mM to about 10 mM. The nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an aqueous chamber. In some embodiments, the liquid nebulizer: (i) achieves lung deposition of at least 7% of the nintedanib or salt thereof, administered to the mammal; (ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 pm to about 2.5 pm; (iii) provides: a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high efficiency liquid nebulizer of about 1 pm to about 5 pm; b) a volumetric mean diameter (VMD) of about 1 pm to about 5 pm; and / or c) a mass median diameter (MMD) of about 1 pm to about 5 pm; (iv) provides a fine particle fraction (FPF= % < 5 microns) of droplets emited from the liquid nebulizer of at least about 30%; (v) provides an output rate of at least 0.1 mL / min; and / or (vi) provides at least about 25% of the aqueous solution to the mammal.45IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0111] The liquid nebulizer delivers about 0.0001 mg to about 100 mg of nintedanib or salt thereof to the lungs in less than about 20 minutes with mass median diameter (MMAD) particles sizes from about 1 to about 5 microns.

[0112] The liquid nebulizer delivers about 0.0001 mg to about 100 mg of nintedanib or salt thereof and about 1 mg to about 20 mg pirfenidone or pyridone analog to the lungs in less than about 20 minutes with mass median diameter (MMAD) particles sizes from about 1 to about 5 microns.

[0113] The aqueous droplet populations have a median diameter less than about 5.0 pm. The aqueous droplet has a diameter less than about 5.0 pm, less than about 4.5 pm, less than about 3.0 pm, less than about 3.5 pm, less than about 3.0 pm, less than about 2.5 pm, less than about 2.0 pm, less than about 1.5 pm, or less than about 1.0 pm and are further comprised of one or more osmolality adjusting agents including co-solvents selected from ethanol, propylene glycol, mannitol and glycerin and combinations thereof. The aqueous droplet may also be further comprised of a buffer selected from lysinate, acetylcysteine, glycine, glutamate, borate, succinate, tartrate, phosphate or Tris and combinations thereof.

[0114] The aqueous droplet populations may exhibit a varying range in the percent of individual droplets above 5 pm such as, and may vary from at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

[0115] In some embodiments, administration with the liquid nebulizer does not include an initial dose-escalation period.

[0116] In one example, about 0.01 mb to about 10 mb of the aqueous solution is administered to the mammal with a liquid nebulizer, the solution comprising nintedanib or salt thereof, at a concentration from about 0.0001 mg / mL to about 10 mg / mL; optionally one or more inorganic salts, wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 600 mOsmol / kg; optionally a permeant ion from about 30 mM to about 150 mM; optionally one or more buffers maintaining the solution pH between about 3.0 and 7.0; optionally a osmolality adjusting agent from about 0.1 to about 20%; optionally a taste-masker from about 0.01 mM to about 10 mM; and the liquid nebulizer is a nebulizer comprising a vibrating mesh or plate with46IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTmultiple apertures, the liquid nebulizer delivers about 0.0001 mg to about 100 mg of nintedanib or salt thereof to the lungs in less than about 20 minutes with mass median diameter (MMAD) particles sizes from about 1 to about 5 micron.

[0117] In one example, about 0.01 mb to about 10 mb of the aqueous solution is administered to the mammal with a liquid nebulizer, the solution comprising nintedanib or salt thereof, at a concentration from about 0.0001 mg / mL to about 50 mg / mL and pirfenidone or pyridone analog at a concentration from about 5 mg / mL to about 20 mg / mL; optionally one or more inorganic salts, wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 1000 mOsmol / kg; optionally a permeant ion from about 30 mM to about 500 mM; optionally one or more buffers maintaining the solution pH between about 3.0 and 7.0; optionally a osmolality adjusting agent from about 0.1 to about 20%; optionally a taste- masker from about 0.01 mM to about 10 mM; and the liquid nebulizer is a nebulizer comprising a vibrating mesh or plate with multiple apertures, the liquid nebulizer delivers about 0.0001 mg to about 100 mg of nintedanib or salt thereof and from about 1 mg to about 20 mg pirfenidone or pyridone analog to the lungs in less than about 20 minutes with mass median diameter (MMAD) particles sizes from about 1 to about 5 micron.

[0118] In the multi-container approach, a first container contains nintedanib or salt thereof dissolved in an aqueous volume from about 0.01 mL to about 10 mL; optionally 0.01 mM to about 1000 mM buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0, optionally a osmolality adjusting agent concentration from about 0.1% to about 99% and optionally a taste-masking agent from about 0.01 mM to about 100 mM. Because nintedanib lacks long-term stability in the presence of permeant ion, permeant ion is prepared in a separate, second container. The second container contains an aqueous solution from about 0.01 mLto about 10 mL; optionally containing a concentration from about 15 mMto about 1500 mM inorganic salt; optionally 0.01 mM to about 1000 mM buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally a osmolality adjusting agent from about 0.1% to about 99%; optionally a taste-masking agent from about 0.01 mM to about 100 mM. Just prior to administration, the two-container system is admixed resulting in a unit dosage form comprising from about 0.01 mL to about 10 mL of an aqueous solution of nintedanib or salt thereof, wherein the concentration of nintedanib or salt thereof in the aqueous47IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTsolution is from about 0.01 mg / mL to about 10 mg / mL; optionally 0.01 to about 100 mM buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally, a osmolality adjusting agent concentration from about 0.1% to about 20%; optionally a taste-masking agent from about 0.01 mM to about 10 mM; optionally an inorganic salt from about 15 mM to about 300 mM, creating a permeant ion concentration from about 30 mM to about 150 mM, with a final admixed solution osmolality from about 50 mOsmol / kg to about 600 mOsmol / kg.

[0119] In the unit dose approach, the container contains nintedanib or salt thereof and pirfenidone or pyridone analogy dissolved in an aqueous volume from about 0.01 mL to about 10 mL; optionally 0.01 mM to about 100 mM buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0, optionally a osmolality adjusting agent concentration from about 0.1% to about 20%, an inorganic salt from about 15 mM to about 500 mM, providing a permeant ion concentration from about 30 mM to about 500 mM, and optionally a taste-masking agent from about 0.01 mM to about 100 mM. Because pirfenidone stabilizes nintedanib in the presence of permeant ion, this approach permits a stable single container, unit dose configuration. This single container system provides a unit dosage form comprising from about 0.01 mL to about 10 mL of an aqueous solution of nintedanib or salt thereof and pirfenidone or pyridone analog, wherein the concentration of nintedanib or salt thereof in the aqueous solution is from about 0.01 mg / mL to about 50 mg / mL and the concentration of pirfenidone or pyridone analog is from about 5 mg / ml to about 20 mg / mL; optionally 0.01 to about 100 mM buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally, a osmolality adjusting agent concentration from about 0.1% to about 20%; optionally a taste-masking agent from about 0.01 mM to about 10 mM; optionally an inorganic salt from about 15 mM to about 500 mM, creating a permeant ion concentration from about 30 mM to about 500 mM, with a final admixed solution osmolality from about 50 mOsmol / kg to about 1000 mOsmol / kg.

[0120] In the unit dose approach, the container contains nintedanib hydrobromide and pirfenidone dissolved in an aqueous volume from about 0.01 mL to about 10 mL; optionally 0.01 mM to about 100 mM buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0, optionally a osmolality adjusting agent concentration from about48IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT0.1% to about 20%, an inorganic salt from about 15 mM to about 500 mM, providing a permeant ion concentration from about 30 mM to about 500 mM, and optionally a taste-masking agent from about 0.01 mM to about 100 mM. Because pirfenidone stabilizes nintedanib in the presence of permeant ion, this approach permits a stable single container, unit dose configuration. This single container system provides a unit dosage form comprising from about 0.01 mL to about 10 mL of an aqueous solution of nintedanib hydrobromide and pirfenidone, wherein the concentration of nintedanib hydrobromide in the aqueous solution is from about 0.01 mg / mL to about 50 mg / mL and the concentration of pirfenidone is from about 5 mg / ml to about 20 mg / mL; optionally 0.01 to about 100 mM buffer maintaining a pH from about 3.0 to about 7.0, preferably from about pH 3.0 to about pH 6.0; optionally, a osmolality adjusting agent concentration from about 0.1% to about 20%; optionally a taste- masking agent from about 0.01 mM to about 10 mM; optionally an inorganic salt from about 15 mM to about 500 mM, creating a permeant ion concentration from about 30 mM to about 500 mM, with a final admixed solution osmolality from about 50 mOsmol / kg to about 1000 mOsmol / kg.

[0121] Osmolality adjusting agents are comprised of consists of one or more classes of excipients from the following groups: sugars, alcohols, inorganic salts, amino acids, and acids / bases and combinations thereof. Individually, sugars can be selected from, but not limited to: glucose, fructose, lactose, sucrose, maltose, mannose, trehalose and xylose. Alcohols include but not limited to: erythritol, glycerol, inositol, maltitol, mannitol, menthol, propylene glycol, sorbitol, xylitol, threitol, propylene glycol. Inorganic salts may include but not limited to: sodium acetate, sodium bromide, sodium chloride, sodium sulfate, sodium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium iodide, potassium chloride, potassium bromide, magnesium chloride, calcium chloride. Amino acids include, but not limited to: arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, histidine, lysine and proline. Einally, acids and bases may include, but not limited to: boric acid, acetic acid, hydrogen bromide, hydrogen chloride, sulfuric acid, nitric acid, phosphoric acid, sodium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide.

[0122] At the point of use, the contents in the diluent vial is added to the contents in the dry powder vial to make a reconstituted solution for nebulization comprising water; nintedanib or salt thereof, or a indolinone derivative or salt thereof at a concentration from about 0.005 mg / mL49IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTto about 10 mg / mL; optional osmolality adjusting agent at a concentration of about 0.1% to about 20% to adjust osmolality, optional inorganic salts at a concentration of about 15 mM to about 300 mM to adjust osmolality and provide a permeant ion at a final concentration from about 30 mM to about 150 mM; and optional buffers from about 0.01 mM to 100 mM to maintain the pH between about pH 3.0 to about pH 7.0, preferably from about pH 3.0 to about pH 6.0, with a final osmolality between 50 mOsmol / kg and 600 mOsmol / kg. The osmolality adjusting agents used in the diluent solution may include one or more co solvents selected from propylene glycol, ethanol, glycerin and mannitol and combinations thereof to produce a final concentration from about 0.1% to about 20% in the reconstituted solution. The inorganic salts used in either the dry powder vial or the diluent vial are selected from sodium chloride, magnesium chloride, calcium chloride, potassium chloride, sodium bromide, potassium bromide, magnesium bromide and calcium bromide and combinations thereof. The inorganic salt content in the reconstituted aqueous solution is from about 15 mM to about 300 mM. The buffer is selected from one or more of lysinate, acetylcysteine, glycine, glutamate, borate, succinate, tartrate, phosphate or Tris and combinations thereof, the pH of the reconstituted aqueous solution is from about pH 3.0 to about pH 7.0, preferably pH about 3.0 to about pH 6.0. Described herein is a reconstituted aqueous solution for nebulized inhalation administration comprising: water; nintedanib or salt thereof, at a concentration from about 0.005 mg / mL to about 10 mg / mL, preferably not exceeding 5.0 mg / mL; one or more permeant ions at a concentration from about 30 mM to 150 mM; one or more osmolality adjusting agents; and wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 600 mOsmol / kg. The formulation may be administered as an inhaled aerosol created from a dosing volume ranging from about 0.01 mL to about 10 mL. The formulation may be administered as an inhaled aerosol over a few breaths or by tidal breathing up to 20 minutes.Methods to Treat or Prevent Disease

[0123] Lor purposes of the methods described herein, a indolinone, salt or derivative thereof compound, most preferably nintedanib salt is administered using a liquid nebulizer having a vibrating mesh screen that produces an aerosol mist having a particle size distribution optimized for delivery of the aerosol to the pulmonary compartment. In some embodiments, nintedanib or an indolinone derivative compound or salt thereof is formulated as a pharmaceutical composition50IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTsuitable for aerosol formation, dose for indication, deposition location, pulmonary or intra-nasal delivery for pulmonary, intranasal / sinus, or extra-respiratory therapeutic action, good taste, manufacturing and storage stability, and patient safety and tolerability. The methods include steps for performing an admixture of solutions contained in a multi-container system that separates the active pharmaceutical ingredient (API) from other solutions prior to or immediately following placement into a nebulizer for aerosol administration.

[0124] The methods include administering a second anti-fibrotic, anti-cancer, anti-infective antiinflammatory, or anti-pulmonary hypertension agent. The pulmonary diseases subject to treatment under the present invention include interstitial lung disease, such as idiopathic pulmonary fibrosis, and radiation-therapy-induced pulmonary fibrosis, chronic lung allograft dysfunction, bronchiolitis obliterans, restrictive allograft syndrome, and systemic sclerosis associated interstitial lung disease (SSc-ILD).The pulmonary diseases also include chronic obstructive pulmonary disease, chronic bronchitis, and cancer, including small cell lung cancer, large cell carcinoma, mesothelioma, lung carcinoid tumors or bronchial carcinoids, secondary lung cancer resulting from metastatic disease, non-small cell lung cancer, bronchioloalveolar carcinoma, sarcoma, and lymphoma.

[0125] The inhaling step is performed in less than about 10 minutes, less than about 7.5 minutes, less than about 5 minutes, less than about 2.5 minutes, less than about 1.5 minutes, and less than about 30 seconds. The inhaling step may be performed in less than 5 breaths, less than 3 breaths, or less than about 2 breaths.

[0126] The methods include to treat a neurologic disease comprising intranasal inhalation of the aerosol described herein.

[0127] In the methods described herein involving admixture of separate containers, the methods include the affirmative steps of opening and admixing the contents of at least two sterile singleuse containers whose final admixed solution contains between about 0.01 mb to about 10 mb of a solution of nintedanib or salt thereof for introduction into a nebulizer immediately prior to administration to a patient.51IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0128] In the methods described herein, the aerosol comprises particles having a mean aerodynamic diameter from about 1 micron to about 5 microns. The aerosol has a mean particle size from about 1 micron to about 20 pm and preferably from about 1 5 microns volumetric mean diameter and a particle size geometric standard deviation of less than or equal to 3 microns. The inhaling step delivers a dose of a least 0.0001 mg nintedanib or salt thereof, at least 0.001 mg, at least 0.01 mg, at least 0.1 mg, at least 1.0 mg, at least 10 mg, at least 50 mg, at least 100 mg nintedanib or salt thereof.

[0129] In the methods described herein, the aerosol comprises particles having a mean aerodynamic diameter from about 1 micron to about 5 microns. The aerosol has a mean particle size from about 1 micron to about 20 pm and preferably from about 1 5 microns volumetric mean diameter and a particle size geometric standard deviation of less than or equal to 3 microns. The inhaling step delivers a dose of a least 0.0001 mg, at least 0.001 mg, at least 0.01 mg, at least 0.1 mg, at least 1.0 mg, at least 10 mg, at least 50 mg, at least 100 mg nintedanib or salt thereof and at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 10 mg, at least 50 mg, at least 100 mg pirfenidone or pyridone analog.

[0130] In one aspect, described herein is a method for the treatment methods include of administering nintedanib or salt thereof, to treat a patient, wherein the patient avoids abnormal liver function exhibited by a grade 2 or higher abnormality following oral administration in one or more biomarkers of liver function after nintedanib or salt thereof, administration, comprising administering to said patient nintedanib or salt thereof, at doses less than 1056 mg per day."Grade 2 liver function abnormalities" include elevations in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), or gamma-glutamyl transferase (GGT) greater than 2.5-times and less than or equal to 5 -times the upper limit of normal (ULN). Grade 2 liver function abnormalities also include elevations of bilirubin levels greater than 1.5-times and less than or equal to 3 -times the ULN. The nintedanib or salt thereof, is delivered to the patient by oral inhalation or intranasal inhalation. One or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, bilirubin, and alkaline phosphatase. The method further comprises the step of measuring one or more biomarkers of liver function. The blood Cmax following inhaled administration of nintedanib or salt thereof, is less than 100.0 ng / mL. The blood Cmax following administration of nintedanib or52IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTsalt thereof, is less than 10.0 ng / mL, less than 1.0 ng / mL, less than 0.1 ng / mL, less than 0.01 ng / mL.

[0131] The methods of administering nintedanib or salt thereof, include the avoidance of nausea, diarrhea, headaches, leg aches / cramps, fluid retention, visual disturbances, itchy rash, lowered resistance to infection, bruising or bleeding, loss of appetite, weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), headache, edema, congestive cardiac failure observed following oral administration, comprising administering to said patient inhaled nintedanib or salt thereof at doses less than 100 mg per day. The nintedanib or salt thereof is delivered to the patient by oral inhalation or intranasal inhalation-

[0132] The methods of the invention include daily maximum dosages of less than 100 mg per day of nintedanib or salt thereof is delivered to the patient by inhalation. In some embodiments, less than 50 mg, less than 25 mg, less than 10 mg, less than 5 mg, less than 2.5 mg, less than 1 mg, less than 0.1 mg, less than 0.05 mg or less than 0.01, less than 0.005, less than 0.001 mg per day of nintedanib or salt thereof is delivered to the patient by inhalation once per day, twice per day, three times a day, four times a day, five times a day, six times a day or greater than six times per day, and may be administered daily, every other day, every third day, every fourth day, every fifth day, every sixth day or weekly, every other week, every third week or monthly.

[0133] The methods of the invention include daily maximum dosages of less than 100 mg per day of nintedanib or salt thereof and pirfenidone less than 100 mg per day is delivered to the patient by inhalation. In some embodiments, nintedanib or salt thereof is less than 100 mg, less than 50 mg, less than 25 mg, less than 10 mg, less than 5 mg, less than 2.5 mg, less than 1 mg, less than 0.1 mg, less than 0.05 mg or less than 0.01, less than 0.005, less than 0.001 mg per day and pirfenidone is less than 100 mg, less than 50 mg, less than 25 mg, less than 10 mg, less than 5 mg, less than 2.5 mg, less than 1 mg is delivered to the patient by inhalation once per day, twice per day, three times a day, four times a day, five times a day, six times a day or greater than six times per day, and may be administered daily, every other day, every third day, every fourth day, every fifth day, every sixth day or weekly, every other week, every third week or monthly.

[0134] Methods of treatment include as prophylaxis against interstitial lung disease (ILD) by administering nintedanib or salt thereof to a subject having or suspected to have interstitial lung 53IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTdisease. Interstitial lung disease includes those described above and all conditions of idiopathic interstitial pneumonias as defined by American Thoracic Society / European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias, AM. J. Respir. Crit. Care Med. 165, 277-304 (2002) (incorporated herein by reference).

[0135] The therapeutic method may also include a diagnostic step, such as identifying a subject with or suspected of having ILD. The method further sub-classifies into idiopathic pulmonary fibrosis based on extent of disease, progression of disease, rate of advancement, or response to any existing therapy. The delivered amount of aerosol nintedanib or salt thereof compound (or salt thereof) formulation is sufficient to provide acute, sub-acute, or chronic symptomatic relief, slowing of fibrosis progression, halting fibrosis progression, reversing fibrotic damage, and / or subsequent increase in survival and / or improved quality of life.

[0136] The therapeutic method may also include a diagnostic step of identifying a subject with or suspected of having fibrosis in other tissues, by non-limiting example in the heart, liver, kidney or skin and the therapeutic amount of liquid nebulized, dry powder or metered-dose aerosol nintedanib or salt thereof compound is sufficient to provide acute, sub-acute, or chronic symptomatic relief, slowing of fibrosis progression, halting fibrosis progression, reversing fibrotic damage, and / or subsequent increase in survival and / or improved quality of life.

[0137] The therapeutic method may also include a diagnostic step identifying a subject with or suspected of having multiple sclerosis and the therapeutic method comprises administering liquid nebulized, dry powder or metered-dose aerosol nintedanib or salt thereof sufficient to provide acute, sub-acute, or chronic symptomatic relief, slowing of demyelination progression, halting demyelination progression, reversing demyelinated damage, and / or subsequent increase in survival and / or improved quality of life.

[0138] Therapeutic treatment methods include administering a therapeutically effective aerosol doses to a patient wherein the dosage is calculated, titrated, or measured to establish or maintain therapeutically effective threshold drug concentrations in the lung and / or targeted downstream tissue, which may be measured as drug levels in epithelial lining fluid (ELF), sputum, lung tissue, bronchial lavage fluid (B AL), or by deconvolution of blood concentrations through pharmacokinetic analysis. One embodiment includes the use of aerosol administration, delivering 54IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENThigh or titrated concentration drug exposure directly to the affected tissue for treatment of pulmonary fibrosis and inflammation associated with ILD (including idiopathic pulmonary fibrosis) in animals and humans. Peak lung ELF levels achieved following aerosol administration to the lung will be between 0.01 mg / mL and about 100 mg / mL nintedanib or salt thereof or between 0.1 ng / gram lung tissue and about 500 mcg / gram lung tissue nintedanib or salt thereof.

[0139] As a non-limiting example, in a preferred embodiment, a indolinone derivative compound as provided herein (e.g., nintedanib) formulated to permit mist, gas-liquid suspension or liquid nebulized, dry powder and / or metered-dose inhaled aerosol administration to supply effective concentrations or amounts to produce and maintain threshold drug concentrations in the blood and / or lung, which may be measured as drug levels in epithelial lining fluid (ELF), sputum, lung tissue, bronchial lavage fluid (BAL), or by deconvolution of blood concentrations through pharmacokinetic analysis that absorb to the pulmonary vasculature producing drug levels sufficient for extra-pulmonary therapeutics, maintenance or prophylaxis. Therapeutic treatment methods include the use of aerosol administration, delivering high concentration drug exposure in the pulmonary vasculature and subsequent tissues and associated vasculature for treatment, maintenance and / or prophylaxis of, but not limited to cardiac fibrosis, kidney fibrosis, hepatic fibrosis, heart or kidney toxicity, or multiple sclerosis. Peak tissue- specific plasma levels (e.g., heart, kidney and liver) or cerebral spinal fluid levels (e.g. central nervous system) achieved following aerosol administration to the lung following oral inhalation or to the lung or nasal cavity following intra- nasal administration will be between 0.0001 mcg / mL and about 50 mcg / mL nintedanib or salt thereof. Peak lung wet tissue or epithelial lining fluid levels achieved following aerosol administration to the lung are between 0.004 mcg / gram lung tissue or epithelial lining fluid and about 500 mcg / gram lung tissue or epithelial lining fluid nintedanib or salt thereof.

[0140] Therapeutic methods include acute or prophylactic treatment of a patient through nonoral or non-nasal topical administration of nintedanib or salt thereof (or a salt thereof) compound formulation to produce and maintain threshold drug concentrations at a burn site, including the use of aerosol administration, delivering high concentration drug exposure directly to the affected tissue for treatment or prevention of scarring in skin.55IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0141] Therapeutic methods include acute or prophylactic treatment of a patient through nonoral or non-nasal topical administration of nintedanib or salt thereof compound formulation to produce and maintain threshold drug concentrations in the eye. One embodiment includes the use of aerosol administration or formulation drops to deliver high concentration drug exposure directly to the affected tissue for treatment or prevention of scarring following surgical glaucoma surgery (e.g., bleb fibrosis). For example according to these and related embodiments, the term aerosol may include a spray, mist, or other nucleated liquid or dry powder form. A drop may be simple liquid or suspension formulation.

[0142] As a non-limiting example, an indolinone derivative compound remains at the therapeutically effective concentration at the site of pulmonary pathology, suspected pulmonary pathology, and / or site of pulmonary absorption into the pulmonary vasculature for at least about 10 seconds, at least 1 minute, at least about a 5 minute period, at least about a 10 min period, at least about a 20 min period, at least about a 30 min period, at least about a 1 hour period, at least a 2 hour period, at least about a 4 hour period, at least an 8 hour period, at least a 12 hour period, at least a 24 hour period, at least a 48 hour period, at least a 72 hour period, or at least one week. The effective nintedanib or salt thereof concentration is sufficient to cause a therapeutic effect and the effect may be localized or broad-acting to or from the site of pulmonary pathology.

[0143] Delivery sites such as a pulmonary site, nasal cavity or sinus, the an nintedanib or salt thereof compound formulation as provided herein is administered in one or more administrations so as to achieve a respirable delivered dose daily of nintedanib or salt thereof of at least about 0.0001 mg to about 100 mg, including all integral values therein such as 0.0001, 0.001, 0.006, 0.01, 0.02, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 milligrams.

[0144] Delivery sites such as a pulmonary site, nasal cavity or sinus, the an nintedanib or salt thereof compound formulation as provided herein is administered in one or more administrations so as to achieve a respirable delivered dose daily of nintedanib or salt thereof of at least about 0.0001 mg to about 100 mg, including all integral values therein such as 0.0001, 0.001, 0.006, 0.01, 0.02, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 milligrams, and pirfenidone or pyridone analog as provided herein is administered56IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTin one or more administrations so as to achieve a respirable delivered dose daily of pirfenidone or pyridone analog of at least about 0.0001 mg to about 100 mg, including all integral values therein such as 0.0001, 0.001, 0.006, 0.01, 0.02, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200 or 300 milligrams.

[0145] In embodiments where a human is mechanically ventilated, aerosol administration would be performed using an in-line device (by non-limiting example, the Nektar Aeroneb Pro or PARI eFlow in-line system) or similar adaptor with device for liquid nebulization. Aerosol administration could also be performed using an in-line adaptor for dry powder or metered-dose aerosol generation and delivery.

[0146] The methods and the combination of the invention include the administration of a nintedanib salt using a mechanical ventilator wherein an in-line nebulizer is operably connected with the forced air circulation of the ventilator such that an aerosol is generated by the nebulizer and administered to a patient connected to the ventilator such that the breathing support function of the ventilator also administers the formulation of the invention described herein. In in-line nebulizer suitable for use with the invention is compatible with all ventilator models and is capable of matching the performance parameters described herein for generating an aerosol mist having particle size and particle distribution parameters substantially similar to the nebulizers described herein. The in-line nebulizer is typically operated continuously until the equivalent dose as described herein for a portable nebulizer is delivered. Alternatively, the admixture of the first solution and the second solution, or a suitably formulated dry powder is introduced at a point in the ventilator air circuitry wherein inspiration by the patient or movement of air in the ventilator airway advances the admixture into the lungs of the patient. Preferably, the nebulizer is sealed in the airway to prevent additional airflow from being introduced and to permit a combination of the aerosol mist of the admixture with humidified air generated by the ventilator system. In the system described herein, movement of air through the pathway of the ventilator combines humidified air and the aerosol mist containing the admixture and may be triggered by patient inspiration or as part of a continuous or programmed delivery protocol such that the nebulizer is in intermittent or continuous operation during the administration of the admixture. In each case, the formation of the aerosol is maintained for a duration adequate to deliver therapeutically effective amounts of the admixture combination to the lungs of the patient.57IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTAerosol Dosing

[0147] The indolinone derivative compound, most preferably nintedanib as disclosed herein can be administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described. For example, a daily aerosol dose of nintedanib in a nintedanib compound formulation to a 70 kg human.

[0148] The indolinone derivative compound, most preferably nintedanib as disclosed herein can be administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described. In some embodiments, for example, a daily aerosol dose of nintedanib in an nintedanib compound formulation to a 70 kg human may be from about 0.000001 mg to about 4.5 mg nintedanib per kg of body weight per dose. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration, the location of the disease (e.g., whether it is desired to effect intra-nasal or upper airway delivery, pharyngeal or laryngeal delivery, bronchial delivery, pulmonary delivery and / or pulmonary delivery with subsequent systemic or central nervous system absorption), and the judgment of the prescribing physician; for example, a likely dose range for aerosol administration of nintedanib in preferred embodiments, or in other embodiments of indolinone derivative compound would be about 0.0001 mg to 10 mg per dose to about 0.0001 mg to about 100 mg per day. Similarly, if pirfenidone or pyridone analog is included in the formulation, a daily aerosol dose to a 70 kg human may be from about 0.01 mg to about 4.5 mg nintedanib per kg of body weigh per dose. A likely dose range for aerosol administration of pirfenidone in combination with nintedanib in preferred embodiments would be about 2.5 mg to 50 mg per dose to about 2.5 mg to about 300 mg per day.Liquid Nebulizer

[0149] Previously, two types of nebulizers, jet and ultrasonic, have been shown to be able to produce and deliver aerosol particles having sizes between 1 and 5 microns. These particle sizes have been shown as being optimal for middle airway deposition. However, unless a specially formulated solution is used, these nebulizers typically need larger volumes to administer sufficient amount of drug to obtain a therapeutic effect. A jet nebulizer utilizes air pressure 58IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTbreakage of an aqueous solution into aerosol droplets. An ultrasonic nebulizer utilizes shearing of the aqueous solution by a piezoelectric crystal. Typically, however, the jet nebulizers are only about 10% efficient under clinical conditions, while the ultrasonic nebulizer is only about 5% efficient. The amount of pharmaceutical deposited and absorbed in the lungs is thus a fraction of the 10% in spite of the large amounts of the drug placed in the nebulizer. The amount of drug that is placed in the nebulizer prior to administration to the mammal is generally referred to the “nominal dose,” or “loaded dose.” The volume of solution containing the nominal dose is referred to as the “fill volume.” Smaller particle sizes or slow inhalation rates permit deep lung deposition. Both middle-lung and alveolar deposition may be desired for this invention depending on the indication, e.g. , middle and / or alveolar deposition for pulmonary fibrosis and systemic delivery. Exemplary disclosures of compositions and methods for formulation delivery using nebulizers can be found in, e.g., US 2006 / 0276483, including descriptions of techniques, protocols and characterization of aerosolized mist delivery using a vibrating mesh nebulizer.

[0150] Accordingly, a vibrating mesh nebulizer comprising a liquid storage container in fluid contact with a diaphragm and inhalation and exhalation valves is preferably used. In one embodiment, about 0.01 to about 10 mL of the nintedanib compound formulation (or in another related embodiment, of a indolinone derivative is placed in the reservoir and the aerosol generator is engaged producing atomized aerosol of particle sizes selectively between about 1 and about 5 microns. In another embodiment, pirfenidone or pyridone analog is included.

[0151] In some embodiments an nintedanib or salt thereof compound formulation as disclosed herein, is placed in a liquid nebulization inhaler and prepared in dosages to deliver from about 0.0001 mg to 100 mg nintedanib, indolinone derivative compound from a dosing solution of about 0.01 mL to about 10 mL with MMAD particles sizes between about 1 to about 5 micron being produced. In another embodiment, pirfenidone or pyridone analog is included and delivered from about 2.5 mg to about 100 mg pirfenidone or pyridone analog.

[0152] The manner in which the first solution and the second solution are combined to yield an admixture requires only that the solutions are thoroughly mixed. Similarly, where dissolution of a solid in an aqueous solution is provided, the solution is thoroughly combined with the solid and agitated until no solid precipitate remains. Similarly, the combination of any two solutions is59IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTagitated until no solid precipitate remains. The individual concentrations of the nintedanib salt have been specifically formulated as described herein for solubility, even though the discovery has been made that many permeant ion species that are suitable for enabling tolerability of an inhaled aerosol are incompatible with the active ingredient.

[0153] The capability to physically combine the first and the second solution may be provided by providing additional space or volume in either of the container holding the first solution or the container holding the second solution such that the volume of either solution can be accommodated by the available volume or headspace of the other container. An additional container can be used to permit admixture of the first and the second solutions, or the two solutions can simply be added directly into the reservoir of the nebulizer and the admixture created by mixing within the reservoir. Reference to containing the admixture in the reservoir of the nebulizer includes the process of forming admixture of the first and the second solutions in any container, either inside or outside of the reservoir of the nebulizer.

[0154] In one embodiment of a multi-compartment combination, a container having sealed compartments such as a blister pack it is used that have segregated compartments or chambers that contain the first and the second solution in a separate, sterile, sealed configurations for individual placement into the reservoir of a nebulizer or for combination into an admixture immediately before having the combined solutions for containing the admixture within the reservoir of the nebulizer. The individual or multiunit containers may have a pouring fixture, such as a spout or other outflow design that either mates with the input of the nebulizer reservoir or is conveniently sized so that the outflow of the container enables ready insertion of the individual solutions or the admixture into the nebulizer reservoir. Accordingly, in either individual or combined format, the containers are shaped to allow easy dispensing of the individual contents or the admixture. For instance, one side of the container may be tapered or have a tapered portion or region through which the content is dispensable into another vessel upon opening the sealed solution container at a tip or tapered end. Two or more chambers of a container are connected by a channel, the channel being adapted to direct fluid from the one container having the first solution contained therein to the second container, or vice versa, having the other solution and having adequate internal headspace volume to permit thorough mixing of the two solutions. During storage, the individual compartments are sealed and closed, but may60IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTfeature a removable barrier that is literally removed or broken to permit mixture of the liquid solutions. A similar configuration is usable where one component is a solid powder or crystalline form and is segregated from an aqueous solution, particularly including dissolved permeant ions. Typically, a channel is closed with a seal that prevents the two solutions from being combined prior to action by the user. As described herein, this is an ideal arrangement where individual components of the admixture are unstable when combined, but may be combined in the admixture just prior to being contained within the nebulizer.

[0155] In another embodiment for multiple-dose separated-compartment nebulizers, both the solid composition and the liquid solvent are provided as matched unit doses within multiple containers or within multiple chambers of a container. For instance, two-chambered containers can be used to hold one unit of the solid composition in one of the chambers and one unit of liquid in the other. As used herein, one unit is defined by the amount of drug present in the solid composition, which is one unit dose. Such two-chambered containers may, however, also be used advantageously for nebulizers containing only one single drug dose.

[0156] In one embodiment of a separated-compartment nebulizer, a blister pack having two blister-type containers may be used, the blisters representing the containers for separating an aqueous solution containing the active ingredient from other osmolality adjusting agents that cause instability of the chemical structure of nintedanib or salt thereof. The blister pack may be shaped to allow easy dispensing of the admixture into the reservoir of the nebulizer. For instance, one side of the pack may be tapered or have a tapered portion or region through which the content is dispensable into another vessel upon opening the blister pack at the tapered end. The tapered end may represent a tip.

[0157] In one embodiment, a vial or container having two compartments is used, the compartment representing the chambers for containing the solution containing the active ingredient and solution containing osmolality adjusting agents admixed to prepare a unit dosage of the final liquid composition for aerosolization. The first and second liquid compositions respectively are preferably contained in matched quantities for preparing a single unit dosage of the final liquid composition (by non-limiting example in cases where soluble of the nintedanib or salt thereof compound and a osmolality adjusting agent required for formulating the desired61IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTconcentrations of buffer, permeant anion, or other osmolality adjusting agents are unstable for storage, yet all components are desired in the same admixture for administration.

[0158] The two compartments are physically separated but in fluid communication such as when the vial or container are connected by a channel or breakable barrier, the channel or breakable barrier being adapted to direct fluid between the two compartments to enable mixing prior to administration. During storage, the channel is closed with a seal or the breakable barrier intact. In this sense, a seal is any structure that prevents mixing of contents in the two compartments. The seal is preferably breakable or removable; breaking or removing the seal when the nebulizer is to be used will allow the liquid solvent to enter the other chamber and dissolve the solid composition or in the case of two liquids permit mixing of the two solutions. The dissolution or mixing process may be improved by shaking the container.High Efficiency Liquid Nebulizers

[0159] High efficiency liquid nebulizers are inhalation devices that are adapted to deliver a large fraction of a loaded dose to a patient. Some high efficiency liquid nebulizers utilize microperforated membranes. High efficiency liquid nebulizers also utilize one or more actively or passively vibrating microperforated membranes. The high efficiency liquid nebulizer contains one or more oscillating membranes. The high efficiency liquid nebulizer contains a vibrating mesh or plate with multiple apertures and optionally a vibration generator with an aerosol mixing chamber. The mixing chamber functions to collect (or stage) the aerosol from the aerosol generator. An inhalation valve is also used to allow an inflow of ambient air into the mixing chamber during an inhalation phase and is closed to prevent escape of the aerosol from the mixing chamber during an exhalation phase. The exhalation valve is arranged at a mouthpiece which is removably mounted at the mixing chamber and through which the patient inhales the aerosol from the mixing chamber which may operate continuously.

[0160] The high efficiency liquid nebulizer may contain a vibrating microperforated membrane of tapered nozzles against a bulk liquid that generates a plume of droplets without the need for compressed gas. In these designs, a solution in the microperforated membrane nebulizer is in contact with a membrane, the opposite side of which is open to the air. The membrane is perforated by a large number of nozzle orifices of an atomizing head. An aerosol is created when 62IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTalternating acoustic pressure in the solution is built up in the vicinity of the membrane causing the fluid on the liquid side of the membrane to be emited through the nozzles as uniformly sized droplets.

[0161] Some high efficiency liquid nebulizers use passive nozzle membranes and a separate piezoelectric transducer that are in contact with the solution. In contrast, some high efficiency liquid nebulizers employ an active nozzle membrane, which uses the acoustic pressure in the nebulizer to generate very fine droplets of solution via the high frequency vibration of the nozzle membrane.

[0162] Some high efficiency liquid nebulizers contain a resonant system. In some such high efficiency liquid nebulizers, the membrane is driven by a frequency for which the amplitude of the vibrational movement at the center of the membrane is particularly large, resulting in a focused acoustic pressure in the vicinity of the nozzle; the resonant frequency may be about 100 kHz. A flexible mounting is used to keep unwanted loss of vibrational energy to the mechanical surroundings of the atomizing head to a minimum. Additional features of a high efficiency liquid nebulizer with perforated membranes are disclosed in U.S. Pat. Nos. 6,962,151, 5,152,456, 5,261,601, and 5,518,179, US 6,983,747, each of which is hereby incorporated by reference in its entirety. Other embodiments of the high efficiency liquid nebulizers contain oscillatable membranes. Features of these high efficiency liquid nebulizers are disclosed in 7,252,085; 7,059, 320; 6,983,747, each of which is hereby incorporated by reference in its entirety.

[0163] Commercial high efficiency liquid nebulizers are available from: PARI (Germany) under the trade name eFlow®; Nektar Therapeutics (San Carlos, CA) under the trade names AeroNeb® Go and AeroNeb® Pro, and AeroNeb® Solo, Philips (Amsterdam, Netherlands) under the trade names I-Neb®, Omron (Bannockburn, IL) under the trade name Micro-Air®, and Activaero (Germany) under the trade name Akita®. Commercial High Efficiency Nebulizers are also available from Aerogen (Galaway, Ireland) utilizing the OnQ® nebulizer technology, and Pocket Neb from Micro Vapor® devices.Pharmacokinetics63IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0164] Inhalation therapy of aerosolized nintedanib or a indolinone derivative compound enables direct deposition of the sustained-release or active substance in the respiratory tract (be that intranasal or pulmonary) for therapeutic action at that site of deposition or systemic absorption to regions immediately down stream of the vascular absorption site. In the case of central nervous system (CNS) deposition, intra-nasal inhalation aerosol delivery deposits nintedanib or a indolinone derivative compound directly upstream of the CNS compartment.

[0165] Similar to the intra-nasal and pulmonary applications described above, treatment or prevention of organs outside the respiratory tract requires absorption to the systemic vascular department for transport to these extra-respiratory sites. In the case of treating or preventing fibrotic or inflammatory diseases associated with the heart, liver and kidney, deposition of drug in the respiratory tract, more specifically the deep lung will enable direct access to these organs through the left atrium to either the carotid arteries or coronary arteries. Similarly, in the case of treating CNS disorder (e.g., multiple sclerosis), deposition of drug in the respiratory tract (as defined above) or nasal cavity, more specifically the absorption from the nasal cavity to the nasal capillary beds for immediate access to the brain and CNS. This direct delivery will permit direct dosing of high concentration nintedanib or a indolinone derivative compound in the absence of unnecessary systemic exposure. Similarly, this route permits titration of the dose to a level for these indications.

[0166] Pharmacokinetics is concerned with the uptake, distribution, metabolism and excretion of a drug substance. A pharmacokinetic profile comprises one or more biological measurements designed to measure the absorption, distribution, metabolism and excretion of a drug substance. One way of visualizing a pharmacokinetic profile is by means of a blood plasma concentration curve, which is a graph depicting mean active ingredient blood plasma concentration on the Y-axis and time (usually in hours) on the X-axis. Some pharmacokinetic parameters that may be visualized by means of a blood plasma concentration curve include:1) Cmax- The maximum plasma concentration in a patient;2) AUC: area under the curve3) TOE: time of exposure64IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT4) T1 / 2: period of time it takes for the amount in a patient of drug to decrease by half5) TmaX: The time to reach maximum plasma concentration in a patient

[0167] Pharmacokinetics (PK) is concerned with the time course of a therapeutic agent, such as nintedanib or a indolinone derivative compound concentration in the body. Pharmacodynamics (PD) is concerned with the relationship between pharmacokinetics and efficacy in vivo. PK / PD parameters correlate the therapeutic agent, such as exposure with efficacious activity.Accordingly, to predict the therapeutic efficacy of a therapeutic agent, such as with diverse mechanisms of action different PK / PD parameters may be used.

[0168] As used herein, the “peak period” of a pharmaceutical’s in vivo concentration is defined as that time of the pharmaceutical dosing interval when the pharmaceutical concentration is not less than 50% of its maximum plasma or site-of-disease concentration. “Peak period” is used to describe an interval of nintedanib or a indolinone derivative compound dosing. When considering treatment of lung diseases, a method or system described herein provides at least a two-fold enhancement in pharmacokinetic profile for treatment of the lung disease. The methods and systems described herein provide at least a two-fold enhancement in the lung tissue pharmacokinetic profile of nintedanib or salt thereof compound as compared to oral administration.

[0169] The amount of nintedanib or salt thereof compound that is administered to a human by inhalation may be calculated by measuring the amount of nintedanib or salt thereof compound and associated metabolites that are found in the urine. About 80% of administered nintedanib is excreted in the urine. The calculation based on compound and metabolites in urine may be done through a 48 hour urine collection (following a single administration), whereby the total amount of nintedanib or salt thereof compound delivered to the human is the sum of measured nintedanib and its metabolites. By non-limiting example, knowing that 80% of nintedanib is excreted, a 50 mg sum urinary measurement of nintedanib and its metabolites would translate to a delivered dose of about 63 mg (50 mg divided by 80%). If the inhaled aerosol fine-particle fraction (FPF) is 75%, one may assume that about 75% of the drug deposited in the lung (and about 25% was swallowed, and subsequently absorbed from the gut with 80% excreted in the urine). Integrating these two calculations, of a 63 mg delivered dose (as measured by urinary excretion), about 4765IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTmg would be the amount of inhaled aerosol nintedanib delivered to the lung (the actual RDD; calculated as the product of 63 mg and a 75% FPF). This RDD can then be used in a variety of calculations, including lung tissue concentration.

[0170] The lung tissue Cmax and / or AUC of nintedanib or salt thereof, that is obtained after administration of a single inhaled dose to the mammal is about the same or greater than the lung tissue Cmax and / or AUC of nintedanib or salt thereof, that is obtained after a single dose of orally administered dose that is from about 80% to about 120% of the inhaled dose; and / or the plasma Cmax and / or AUC that is obtained after administration of a single inhaled dose to the mammal is less than the plasma Cmax and / or AUC of obtained after a single dose of orally administered nintedanib or salt thereof, at a dose that is from about 80% to about 120% of the inhaled dose. The lung tissue Cmax that is obtained after administration of a single inhaled dose to the mammal is greater than the lung tissue obtained after a single dose of orally administered nintedanib or salt thereof, at a dose that is from about 80% to about 120% of the inhaled dose. The lung tissue AUC of nintedanib or salt thereof, that is obtained after administration of a single inhaled dose to the mammal is greater than the lung tissue AUC obtained after a single dose of orally administered nintedanib or salt thereof, at a dose that is from about 80% to about 120% of the inhaled dose. The plasma Cmax of nintedanib or salt thereof, that is obtained after administration of a single inhaled dose to the mammal is less than the plasma Cmax obtained after a single dose of orally administered nintedanib or salt thereof, at a dose that is from about 80% to about 120% of the inhaled dose. The plasma AUC of nintedanib or salt thereof, that is obtained after administration a single inhaled dose to the mammal is less than the plasma AUC obtained after a single dose of orally administered nintedanib or salt thereof, compound at a dose that is from about 80% to about 120% of the inhaled dose.

[0171] In one aspect, described herein is a method of achieving a lung tissue Cmax of nintedanib or salt thereof compound that is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times a Cmax of up to 200 mg of an orally administered dosage of nintedanib or salt thereof, the method comprising nebulizing an aqueous solution comprising nintedanib or salt thereof, and administering the nebulized aqueous solution to a human. Described herein is a method of achieving a lung tissue66IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTCmax of nintedanib or salt thereof compound that is at least equivalent to or greater than a Cmax of up to 200 mg of an orally administered dosage of nintedanib or salt thereof, the method comprising nebulizing an aqueous solution comprising nintedanib or salt thereof, and administering the nebulized aqueous solution to a human.

[0172] In one aspect, described herein is a method of achieving a lung tissue AUC0-24 of nintedanib or salt thereof, that is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 1.5-30 times, at least 1.5-20 times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times AUC0-24 of up to 200 mg of an orally administered dosage, the method comprising nebulizing an aqueous solution comprising nintedanib or salt thereof compound and administering the nebulized aqueous solution to a human. A method of achieving a lung tissue AUCo-24 of nintedanib or salt thereof compound that is at least equivalent to or greater than AUCo-24 of up to 600 mg of an orally administered dosage of nintedanib or salt thereof, the method comprising nebulizing an aqueous solution comprising nintedanib or salt thereof and administering the nebulized aqueous solution to a human.

[0173] The methods include a method of administering nintedanib or salt thereof, to a human, comprising administering a nebulized aqueous solution containing the nintedanib or salt thereof, wherein the lung tissue Cmax achieved with the nebulized solution is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times the lung tissue Cmax achieved with an orally administered nintedanib or salt thereof, dosage that is from 80% to 120% of the dose amount of nintedanib that is administered by nebulization.

[0174] The methods include a method of administering nintedanib or salt thereof, to a human, comprising administering a nebulized aqueous solution containing the nintedanib or salt thereof, wherein the lung tissue Cmax achieved with the nebulized solution is at least equivalent to or greater than the lung tissue Cmax achieved with an orally administered nintedanib or salt thereof,67IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTdosage that is from 80% to 120% of the dosage of nintedanib or salt thereof, in the nebulized aqueous solution of nintedanib or salt thereof that is administered.

[0175] The methods include a method of administering nintedanib or salt thereof, to a human, comprising administering a nebulized aqueous solution containing the nintedanib or salt thereof, wherein the plasma AUC0-24 achieved with the nebulized solution is less than the plasma AUC0-24 achieved with an orally administered nintedanib or salt thereof, dosage that is from 80% to 120% of the dosage of nintedanib or salt thereof, in the nebulized aqueous solution of nintedanib or salt thereof, that is administered.

[0176] The methods include a method of administering nintedanib or salt thereof comprising administering a nebulized aqueous solution containing the nintedanib or salt thereof, wherein the lung tissue AUCo-24 achieved with the nebulized solution is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 1.5-20 times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times the lung tissue AUCo-24 achieved with an orally administered nintedanib or salt thereof compound dosage that is from 80% to 120% of the dosage of nintedanib or salt thereof, in the nebulized aqueous solution of nintedanib or salt thereof. The methods include a method of administering nintedanib or salt thereof, to a human, comprising administering a nebulized aqueous solution containing the nintedanib or salt thereof, wherein the lung tissue AUCo-24 achieved with the nebulized solution is at least 1.5 times the lung tissue AUCo-24 achieved with an orally administered nintedanib or salt thereof, dosage that is from 80% to 120% of the dosage of nintedanib or salt thereof, in the nebulized aqueous solution of nintedanib or salt thereof compound.

[0177] The methods include a method of improving the pharmacokinetic profile obtained in a human following a single oral dose administration of nintedanib or salt thereof. The single oral dose comprises up to about 200 mg of nintedanib or salt thereof. The method of improving the pharmacokinetic profile further comprises a comparison of the pharmacokinetic parameters following inhalation administration to the same parameters obtained following oral administration and may require multiple measurements of a single patient over time comparing68IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTthe pharmacokinetic parameters in a single patient varying by dosage, route of administration, form of active pharmaceutical ingredient and other parameters as described herein. A prolonged improvement in pharmacokinetic profile is obtained by repeated and frequent administrations of the aqueous solution of nintedanib or salt thereof, as described herein by inhalation. Repeated administration of nintedanib or salt thereof, by inhalation provides more frequent direct lung exposure benefiting the human through repeat high Cmax levels. The inhaled nintedanib or salt thereof, doses are administered once a day, twice a day, three times a day, four time a day, every other day, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, or any combination thereof.

[0178] Small intratracheal aerosol doses deliver a rapidly-eliminated high lung Cmax and low AUC. Human, animal and in vitro studies all indicate that nintedanib efficacy is dose responsive (i.e. larger doses correlate with improved efficacy) and suggest Cmax is a key driver in nintedanib efficacy. While lung Cmax appears important for efficacy, more regular nintedanib exposure is important to enhance this effect. In the context of treating lung diseases in a human, more frequent direct-lung administration of nintedanib or salt thereof compound may provide benefit through both repeat high Cmax dosing and providing more regular exposure of the active therapeutic agent.

[0179] Methods of treatment include a method for the treatment of lung disease in a mammal comprising administering directly to the lungs of the mammal in need thereof nintedanib or salt thereof, or a indolinone derivative compound or salt thereof, on a continuous dosing schedule, wherein the observed lung tissue Cmax of a dose of nintedanib derivative or salt thereof greater than 0.1, 1.0, 10, 100, or 1000, ng / mL lung epithelial lining fluid. . The observed lung tissue Cmax from a dose of nintedanib or salt thereof, or a indolinone derivative compound or salt thereof, is greater than 10, 50, 100, 150, 250, 300, 350, 400, 450, 500, 750, or 1000 mcg / mLlung epithelial lining fluid.Methods of Dosing and Treatment Regimens

[0180] The term “continuous dosing schedule” refers to the administration of a particular therapeutic agent at regular intervals. Continuous dosing schedule refers to the administration of a particular therapeutic agent at regular intervals without any drug holidays from the particular 69IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTtherapeutic agent. Continuous dosing schedule refers to the administration of a particular therapeutic agent in alternating cycles of drug administration followed by a drug holiday (e.g. wash out period) from the particular therapeutic agent. For example, in some embodiments the therapeutic agent is administered once a day, twice a day, three times a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, every other day, every third day, every fourth day, daily for a week followed by a week of no administration of the therapeutic agent, daily for a two weeks followed by one or two weeks of no administration of the therapeutic agent, daily for three weeks followed by one, two or three weeks of no administration of the therapeutic agent, daily for four weeks followed by one, two, three or four weeks of no administration of the therapeutic agent, weekly administration of the therapeutic agent followed by a week of no administration of the therapeutic agent, or biweekly administration of the therapeutic agent followed by two weeks of no administration of the therapeutic agent. The amount of nintedanib or a indolinone derivative compound is administered once-a-day. In some other embodiments, the amount of nintedanib or a indolinone derivative compound is administered twice-a-day. In some other embodiments, the amount of nintedanib or a indolinone derivative compound is administered three times a day.

[0181] Where improvement in the status of the disease or condition in the human is not observed, the daily dose of nintedanib or a indolinone derivative compound is increased for example, a once-a-day dosing schedule is changed to a twice-a-day dosing schedule a three times a day dosing schedule is employed to increase the amount of nintedanib or a indolinone derivative compound that is administered. Frequency of administration by inhalation is increased in order to provide repeat high Cmax levels on a more regular basis. The frequency of administration by inhalation is increased in order to provide maintained or more regular exposure to Nintedanib The frequency of administration by inhalation is increased in order to provide repeat high Cmax levels on a more regular basis and provide maintained or more regular exposure to nintedanib.

[0182] The amount of repeat high Cmax dosing providing more regular exposure of the active therapeutic agent that is given to the human varies depending upon factors such as, but not limited to, condition and severity of the disease or condition, and the identity (e.g., weight) of the human, and the particular additional therapeutic agents that are administered (if applicable).70IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTEXAMPLES

[0183] The current two phase I studies evaluated safety, tolerability, and pharmacokinetics of AP02 when administered via oral inhalation using the PARI eFlow nebulizer. Both trials 1 (AP02-001) and trial 2 (AP02-002) were randomized, double-blind, placebo-controlled studies performed in Australia.Example 1: Single and Multiple Daily Doses of Nintedanib Achieve Clinically Meaningful Exposure with A Reduced Adverse Effects Profile without Adverse Effects in AP02-treated Subjects

[0184] AP02 is a novel nintedanib formulation delivered via a PARI nebulizer and is in development for the treatment of IPF. Nintedanib reduces fibrotic biomarkers in IPF donor precision cut lung slices at concentrations consistent with levels in epithelial lining fluid following AP02 dosing. Nintedanib is FDA-approved as an orally dosed tyrosine kinase inhibitor that slows the progression of pulmonary fibrosis in patients with IPF. Oral nintedanib is associated with reported tolerability challenges that cause discomfort and lack of compliance. Inhaled AP02 is anticipated to provide increased delivery to the lung while reducing systemic exposure. Avalyn Pharma has completed Two Phase 1 studies in healthy subjects (HS) and IPF patients been completed. Data from the second trial evaluated single and repeated and higher AP02 doses of up to 8 mg BID for 7 days in HS.

[0185] Six cohorts (n= 6 active, 2 placebo / cohort) of HS received either single (2, 4, or 8 mg) or multiple inhaled doses (2, 4, or 8 mg BID) of AP02. An additional cohort underwent bronchoalveolar lavage (BAL) following a single 4 mg dose and nintedanib in BAL fluid was evaluated at 45 min, 4 and 12 hours post dose (n=12, 4 subjects / timepoint). BALF exposure was compared between inhaled and oral delivery (at ~Tmax for a 150 mg PO dose) as determined in the prior Phase 1 trial. Trial endpoints for all cohorts included safety, tolerability, and plasma pharmacokinetics.

[0186] No treatment-related withdrawals, SAEs (serious adverse events), or dose-limiting toxicities were observed. Most common treatment- emergent AEs were throat discomfort (n=2) and dizziness (n=2, both in BAL cohort). There were no treatment- related changes in FEVi or incidences of bronchospasm or cough in any subject. Nintedanib plasma exposures increased in a near dose proportional manner between 2 and 8 mg BID. Importantly, at the highest evaluated 71IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTdose, systemic exposures following 8 mg BID dosing remained below systemic exposures following oral dosing.

[0187] Following a 4 mg single dose, nintedanib exposures in BALF and lung ELF (BALF levels corrected via urea normalization) exceeded the half maximal inhibition (IC50) of key tyrosine kinases (TK) and were greater than those estimated following a single 150 mg oral dose throughout the 12-hour dosing interval than those estimated following a 150 mg oral dose.

[0188] AP02 was well-tolerated following single doses and throughout 7 days of twice daily doses of up to the highest dose (8 mg BID). Exposures in BALF exceeded IC50 values of target TKs and were higher than those observed following oral administration at the approved dose, suggesting establishment of clinically meaningful exposure. The safety and PK support further clinical development and suggest AP02 could offer a promising new treatment option for IPF.

[0189] It should be noted that all features, elements, components, functions, and steps described with respect to any invention provided herein are intended to be freely combinable and substitutable with those from any other embodiment. If a certain feature, element, component, function, or step is described with respect to only one embodiment, then it should be understood that that feature, element, component, function, or step can be used with every other invention described herein unless explicitly stated otherwise. This paragraph therefore serves as antecedent basis and writen support for the introduction of claims, at any time, that combine features, elements, components, functions, and steps from different aspects of the present invention, or that substitute features, elements, components, functions, and steps from one aspect with those of another, even if the following description does not explicitly state, in a particular instance, that such combinations or substitutions are possible. It is explicitly acknowledged that express recitation of every possible combination and substitution is overly burdensome, especially given that the permissibility of each and every such combination and substitution will be readily recognized by those of ordinary skill in the art.

[0190] While the individual inventions described herein are susceptible to various modifications and alternative forms, specific examples thereof have been described in detail. It should be understood, however, that these individual inventions are not to be limited to the particular form disclosed, but to the contrary, these concepts cover all modifications, equivalents, and alternatives falling within the spirit of the disclosure. Furthermore, any features, functions, steps, or elements of the several inventions may be recited in or added to the claims, as well as negative72IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTlimitations that define the inventive scope of the claims by features, functions, steps, or elements that are not within that scope.Trial DesignPretreatment with Salbutamol

[0191] Pretreatment with salbutamol was given within 30 minutes prior to AP02 administration to those in the IPF patient cohort in AP02-001 with chronic obstructive pulmonary disease (COPD), current smokers, or those with a significant previous smoking history.Determination of Sample Sizes

[0192] Sample sizes of 38 subjects and up to 68 subjects were planned for AP02-001 and AP02-002, respectively. No formal sample size calculations were performed, as these were not statistically powered efficacy studies. The number of subjects proposed per cohort were considered sufficient to assess the pharmacokinetics and safety of AP02.AP02-001

[0193] AP02-001 was a first-in-human trial that had 6 cohorts in total (n=38). Three SAD (single ascending dose) cohorts were comprised of healthy volunteers who were randomized to receive either AP02 or placebo at a 6:2 ratio (n=8 per cohort). Individuals administered AP02 in these 3 sequential cohorts received either a 0.5 mg, 1.0 mg, or 2.0 mg dose. The dose level was escalated to the next cohort after the Safety Review Committee reviewed blinded safety data from all subjects in that cohort.

[0194] The bronchoalveolar lavage (BAL) cohort was comprised of healthy volunteers who either received 2.0 mg AP02 or oral nintedanib at the approved dosage of 150 mg (n=4 per cohort). These cohorts underwent BAL at either 30 to 45 minutes or 9 hours post-dose, respectively, and the concentration of nintedanib in these samples was determined. Exposure in the epithelial lining fluid (ELF), which lines the luminal surface of respiratory mucous membranes, was determined by using urea to correct for BAL dilution (Rennard et al. 1986, J Appl Physiol 60: 532-538; Kaulbach et al. 1993 , J Allergy Clin Immunol. 92: 457-465).Concentrations in this fluid are used to estimate drug concentrations in the lungs (Rodvoid et al.2011, Clin Pharmacokinet. 50: 637-664).73IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0195] The last cohort in AP02-001 included 6 IPF patients who received 2.0 mg of AP02. The BAL and IPF patient cohorts were run in parallel and were not blinded as no subjects received placebo (Figures 1 and 2).Randomization and Blinding for AP 02-001

[0196] The randomization schedule was generated by Syneos Health using a validated proprietary computer software program (Statistical Analysis System [SAS®] Version 9.4) and was reviewed by a biostatistician.

[0197] For SAD cohorts, healthy volunteers eligible for participation were randomized (on Day -1 or Day 1) to receive either the active AP02 or placebo in a 6:2 ratio, for a total of 6 healthy volunteers receiving AP02 and 2 healthy volunteers receiving the placebo in each cohort. A staggered dosing schedule was used and included 2 sentinel subjects randomized in a 1:1 ratio (1 active and 1 placebo) dosed initially, and the remaining 6 subjects (5 active and 1 placebo) dosed at least 24 hours later. One randomization scheme for dosing was produced for each cohort separately.

[0198] Subjects in the BAL and IPF patient cohorts were not randomized, and all the healthy volunteers in the AP02 BAL cohort and individuals in the patients with IPF cohort received AP02. All healthy volunteers in the oral nintedanib BAL cohort received the therapeutic.

[0199] SAD cohorts of the trial were double-blinded. Trial drug assignment was blinded to trial subjects and trial site personnel except for the unblinded pharmacist and unblinded clinical research associate. The trial site’s unblinded pharmacist not involved with the clinical aspects of the trial had access to the randomization code and the assigned treatments by cohort. The trial personnel responsible for subject dosing were not involved in the collection, monitoring, revision, or evaluation of adverse events. The trial drug and placebo had the same visual appearance in order to avoid compromising the blinding.

[0200] Blinding was maintained at least until the trial had been completed.

[0201] The principal investigator or designee was responsible for making every effort to contact the sponsor prior to unblinding a subject’s treatment assignment and to record in the trial source documents the date and reason for the unblinding.

[0202] In emergent medical situations where treatment assignment was needed for management of the subject (e.g., an on-treatment pregnancy), the principal investigator could unblind the treatment assignment.74IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0203] BAL and IPF patient cohorts were not blinded; no subjects were on placebo.Inclusion Criteria for AP02-001o Male or female, aged 18 to 55 yearso Female subjects had to be:■ Of non-childbearing potential (surgically sterilized or post-menopausal [12 months with no menses without alternative medical cause] OR■ Not pregnant, breastfeeding, or planning to become pregnant and willing to comply with the medically acceptable contraceptive requirements of the trial from screening to at least 30 days after the last trial drug administrationo Able to communicate with site personnel and to understand and voluntarily sign the informed consent formo Have not had any coronavirus disease 2019 vaccines within 7 days of the AP02 dose (Day 1) and, willing to not receive any coronavirus disease 2019 vaccine 7 days after receiving AP02o Have not had any influenza virus vaccines within 7 days of the AP02 dose (Day 1) and willing to not receive any influenza virus vaccine 7 days after receiving AP02 o Additional inclusion criterion for IPF patient cohort:■ Diagnosis of IPF based on 2018 guidelines from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, or Latin American Thoracic Association.ORDiagnosis of progressive fibrosing interstitial lung disease by at least one of the following criteria within 24 months of screening visit:■ Clinically significant decline in FVC % predicted based on a relative decline of >10%■ Marginal decline in FVC % predicted based on a relative decline of >5 to <10% combined with worsening of respiratory symptoms■ Marginal decline in FVC % predicted based on a relative decline of >5 to <10% combined with increasing extent of fibrotic changes on chest imaging75IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT■ Worsening of respiratory symptoms as well as increasing extent of fibrotic changes on chest imaging (Note: changes atributable to comorbidities [e.g., infection, heart failure] were excluded)■ Males or females aged 18 to 80 yearsExclusion Criteria forAP02-001o History of previous allergy or sensitivity to nintedanibo History of reactive airways disease (such as asthma or COPD), cystic fibrosis, or bronchiectasis (AP02-001 healthy volunteer cohorts and AP02-002 only). AP02-001 IPF patient cohort excluded cystic fibrosis and bronchiectasis but allowed a history of COPD or asthma. Subjects with fully resolved childhood asthma with no recurrences or medical needs as an adult were permittedo History of bleeding disorders or currently being treated with anticoagulants o Human immunodeficiency virus positive resulto Active hepatitis B or Co Cigarete / e-Cigarette smoking or use of other nicotine or tobacco containing products within 7 days prior to trial drug administration. Urine cotinine testing is required at screening and Day -1 to confirm non-smoking status prior to drug administration for AP02-002 onlyo Positive for drugs of abuse or alcohol use at screening or admission to phase I facility.A breathalyzer test was used to screen for the presence of alcohol. A urine standard panel was used to test for the following substances (with repeat testing for confirmation, as needed) (AP02-001 healthy volunteer cohorts and AP02-002 only):■ Opiates■ Methadone■ Cocaine■ Tetrahydrocannabinol■ Benzodiazepines■ Amphetamines / methamphetamines■ Barbiturates■ 3,4-methylenedioxy-methamphetamine■ Phencyclidine76IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTo Participation in a clinical trial with administration of an investigational drug product within the previous 30 days, or 5 half-lives of the previously administered investigational producto Donation of blood or significant blood loss within the 8 weeks prior to admission to phase I facilityo Donation of plasma within the week prior to admission to phase I facilityo Any other condition which in the view of the investigator was likely to interfere with the trial or put the subject at risko Use of any medication which in the opinion of the investigator might interact with trial drug or might lead to abnormal chemistry or hematology testso Aspartate aminotransferase or alanine aminotransferase >1.5X upper limit of normal o Clinically significant abnormality which in the opinion of the investigator in baseline hematology or chemistry test resultso Use of anti-platelet drugs with the exception of low-dose aspirin for subjects in APO OO 1 IPF patient cohortSchedule of Activities for AP02-001Table 1: Schedule of Activities for AP02-00177IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTAPTT=activated partial thromboplastin time; BAL=bronchoalveolar lavage; ECG=electrocardiogram; INR=Intemational Normalized Ratio.* Informed consent was obtained prior to any trial procedure being performed.' Vital signs (heart rate, respiratory rate, temperature, blood pressure, and oximetry) were performed predose (within 1 hour) and 15 minutes (±5 min) post-dose. Vital signs on Day 2 were performed at 24 hours (±1 hour) post-dose. Urine samples were collected for pharmacokinetic analysis at the following intervals: spot pre-dose, 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours post-dose." Randomization for eligible subjects were performed up to 1 day in advance of or on Day 1.Screening serum pregnancy screen was performed in female subjects of childbearing potential only. Urine pregnancy test at Day -1.“Spirometry (FVC, FEVi) was performed using American Thoracic Society criteria.**Spirometry (FVC, FEVi) was performed pre-dose (within 1 hour) and 15 minutes (±5 min) post-dose. BAL cohorts did not have spirometry.78IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT' ' Blood collection within 1 hour pre-dose and post-dose: 10 minutes (±5 min), 30 minutes (±5 min), and 1 hour (± 10 min), 2hours (± 10 min), 4 hours (± 10 min), 6 hours (± 10 min), 8 hours (± 10 min), 10 hours (± 10 min), and 24 hours (±1 hour). 2.0 mg AP02 BAL cohort did not have the 1-hour timepoint. 150 mg oral nintedanib BAL cohort did not have the 10-hour timepoint.BBAL between 30 to 45 minutes post-dose for 2.0 mg AP02 BAL cohort and 9 hours (± 10 min) after dosing for 150 mg oral nintedanib BAL cohort.§§Plasma urea levels were measured before dosing (BAL cohorts only).nnDuring bronchoscopy for BAL cohorts only.***BAL and IPF patient cohorts only.Stopping Criteria forAP02-001

[0204] This trial would have been discontinued at any time if, in the opinion of the investigator or sponsor, continuation of the trial represented a significant medical risk to participating subjects.AP02-002

[0205] The AP02-002 trial had 7 cohorts of healthy volunteers and did not involve patients with IPF. In the SAD cohorts, subjects were randomized to receive either single ascending doses of AP02 or placebo at a 6:2 ratio (n=8 per cohort). Individuals who received AP02 in these cohorts received either a 2.0 mg, 4.0 mg, or 8.0 mg once daily dose. These cohorts were run sequentially, with dose escalation occurring after the review of blinded safety data by the Safety Review Committee.

[0206] In another cohort, 12 healthy volunteers received 4.0 mg AP02 and then underwent BAL with collections at 45 minutes, 4 hours, or 12 hours post-treatment (n=4 per timepoint) to determine the ELF exposure. Sequential BALs were not performed on any of the subjects. This cohort was not blinded, as all individuals received active drug.

[0207] In MAD cohorts, healthy volunteers were randomized to receive either multiple ascending doses of AP02 or placebo at a 6:2 ratio (n=8 per cohort). Doses were administered twice daily (BID) on Days 1 to 6 with one final dose administered on Day 7. In individuals who received AP02, doses of either 2.0 mg AP02 BID, 4.0 mg AP02 BID, or 8.0 mg AP02 BID were given to individuals in the 3 MAD cohorts, with different doses given in each cohort (Figures 1 and 2).Randomization and Blinding for AP 02-00279IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0208] The randomization scheme was generated prior to the initiation of the trial by an independent statistician / programmer / designee who was not a member of the trial team. The unblinded pharmacist was provided with the randomization schedule detailing randomization numbers and assigned treatments by cohort. SAD cohorts (Part 1 SAD) and MAD cohorts (Part 2 MAD) were randomized as follows (Table 2). All participants in the BAL cohort received active drug and therefore the cohort was not blinded.Table 2: Randomization Scheme

[0209] No sentinel subjects were required for the BAL cohort, as the dose did not exceed 8 mg.

[0210] Upon admission on Day -1 or prior to planned dosing time on Day 1, healthy volunteers were randomly assigned to receive either active or placebo. The pharmacist or designated pharmacy personnel consulted the randomization schedule for the cohort and selected the next available randomization number. Healthy volunteers who were randomized but who did not receive a dose of blinded trial drug (either active AP02 or placebo) could have been automatically replaced. The randomization schedule included randomization numbers for the replacement volunteers so that the replacement healthy volunteer would receive the same treatment as the healthy volunteer they were replacing. The volume of trial drug was dosed according to cohort.

[0211] Trial drug assignment was blinded to study healthy volunteers and trial site personnel except for the unblinded pharmacist and unblinded clinical research associate.

[0212] Individual treatment disclosure envelopes (code-break envelopes) were provided to the unblinded pharmacist along with the randomization schedule. These code break envelopes were kept in a designated secure location, and the investigator or his / her delegate were able to access these during the trial for safety reasons. The code-break envelopes were used by the investigator if it was necessary to break the blind for an individual healthy volunteer in an emergency. After completion of the trial and finalization of the clinical trial report, all code-break envelopes were destroyed with confirmation to Avalyn.80IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0213] Sponsor safety staff or designee could have unblinded the intervention assignment for any healthy volunteer with a serious adverse event. If the serious adverse event required that an expedited regulatory report be sent to 1 or more regulatory agencies, a copy of the report, identifying the healthy volunteer’s intervention assignment, could have been sent to investigators in accordance with local regulations and / or sponsor policy.Inclusion Criteria forAP02-002o Males or females, aged 18 to 65 years (inclusive) at time of screening and randomizationo Willing and able to provide voluntary writen informed consent to participate in the trialo Female subjects had to be:■ Of non-childbearing potential (surgically sterilized or post-menopausal [12 months with no menses without alternative medical cause] OR■ Not pregnant, breastfeeding, or planning to become pregnant and willing to comply with the medically acceptable contraceptive requirements of the trial from screening to at least 30 days after the last trial drug administrationo Male healthy volunteers had to commit to using condoms during the course of the trialo Healthy volunteer’s body mass index is between 18 and 32 kg / m2(inclusive) o Healthy volunteer has no clinically significant or relevant abnormalities in medical history, physical examination, vital signs, electrocardiogram, or laboratory evaluations (hematology, chemistry, and urinalysis) as assessed by the investigator o At the screening visit, healthy volunteers must have an FEVi:FVC ratio of >0.80■ Alternatively, if the healthy volunteer fails to qualify as per the required FEVi:FVC ratio of >0.80, then eligibility can be assessed using the Global Lung Initiative Lower Limit of Normal calculator (gli- calculator. ersnet. org / index.html)Exclusion Criteria for AP 02-002o Same as for AP02-001 above plus the following:81IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT■ Healthy volunteers with known risk of gastrointestinal perforation or diverticular disease and those who have undergone recent abdominal surgery■ Have had any respiratory syncytial virus vaccines within 7 days of the AP02 dose (Day 1) and / or not willing to refrain from receiving any respiratory syncytial virus vaccine 7 days after receiving AP02■ Active respiratory tract infection within 2 weeks before investigational product administration■ Regular use of aspirin or other non-steroidal anti-inflammatory drugs. As an exception, paracetamol and ibuprofen for occasional pain will be allowed■ Alcohol abuse within 1 month before screening, defined as average consuming 14 units or more of alcohol per week (1 unit = 285 mL of beer, or 25 mL of spirits, or 125 mL of wine) or with a positive result of alcohol breath test at screening■ History of vasovagal collapses in past 3 years■ Unsuitable veins for repeated venipuncture or for cannulation■ Inability to learn correct inhalation techniqueSchedule of Activities forAP02-001Table 3: Schedule of Activities for AP02-002 - Single Doses82IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT83IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTdisease 2019; FEVi=forced expiratory volume in 1 second; FVC=forced vital capacity; FSH=follicle- stimulating hormone; INR=Intemational Normalized Ratio; RSV=respiratory syncytial virus;SAD=single ascending dose.*A 24-hour safety observation period commenced for the sentinel volunteers following dosing to facilitate principal investigator review and decision to continue with a given cohort (SAD cohorts 1, 2, 3).1A final follow-up visit occurred at Days 3 to 5 post-dose to collect clinical laboratory safety assessments. If there was a clinically significant abnormal result in these labs, unscheduled follow-up visits were arranged until resolution.’ Volunteers in BAL cohort were observed for 8 hours post-BAL procedure prior to discharge. Based on the timing of the BAL procedure and the observation period, volunteers in BAL cohort remained inclinic over 2 nights.informed consent was obtained prior to any trial procedure being performed.“Medical history included history of previous allergy or sensitivity to nintedanib, reactive airway diseases, bleeding disorders, etc. (refer to inclusion and exclusion criteria.)**Height and body mass index were calculated at screening only. Weight was tracked as part of physical examination at screening, admission, and discharge.^Prohibited concomitant medications included P-glycoprotein and CYP3A4 inducers and inhibitors and antiplatelet drugs.ital signs (heart rate, respiratory rate, temperature, blood pressure, and oximetry) were performed predose (within 1 hour) and then 15 minutes (±5 min) and 30 minutes (±5 min) post-end-of-nebulization for all cohorts (1-5). Vital signs were performed at 30 hours (±1 hour) post-end-of-nebulization for SAD cohorts. For BAL cohort, vital signs were collected 12 hours (±1 hour) post-end-of-nebulization. Vital signs were also collected prior to and post BAL procedures in BAL cohort at 45 minutes, 4 hours, or 12 hours (as randomized for BAL cohort).§§Coagulation parameters were evaluated at check-in on Day -1, at 30 hours (± 1 hour) post-dose, and also at the follow-up visit as part of clinical laboratory safety assessments (including serum biochemistry and hematology, which was also collected at screening). Note that for BAL cohort, safety laboratory tests were required at discharge, but discharge lab collection time were dependent on the 84IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTrequired observation period following the BAL procedure (8 hours post-BAL procedure).1111At screening and Day -1, only healthy volunteers with negative screen results for (opiates, methadone, cocaine, tetrahydrocannabinol, benzodiazepines, amphetamines / methamphetamines, barbiturates, 3,4- methylenedioxy-methamphetamine, phencyclidine, and alcohol) were included.***Randomization for eligible healthy volunteers was performed up to 1 day in advance (Day -1) of or on Day 1. BAL cohort was not randomized as all volunteers received active AP02.' ' ' Serology included testing for hepatitis B surface antigen, hepatitis C virus, and human immunodeficiency virus.tBAt screening, only healthy volunteers who have not used cigarete / e-Cigarete or used of other nicotine or tobacco containing products within 7 days prior to trial drug administration were included. Urine cotinine testing was performed at screening and Day -1 to confirm smoking status.§§§Serum pregnancy screen was performed in female healthy volunteers of childbearing potential only at screening. Urine pregnancy test at Day -1 and discharge. For postmenopausal women, a follicle- stimulating hormone assessment was performed to confirm postmenopausal status only at Screening (FSH did not need to be repeated at Day -1).niIIISpirometry (FVC, FEVi) was performed at screening and then pre-dose (within 1 hour) and 15 minutes (±5 min) post-end-of-nebulization using American Thoracic Society criteria.****Twelve-lead electrocardiograms was performed at screening and on Day 1 prior to trial drug dosing. If results were abnormal and clinically significant, the electrocardiogram was repeated one time at screening and / or Day 1 to confirm initial reading. If any detected abnormality was deemed clinically significant by the principal investigator, the healthy volunteer was not dosed (and could have been replaced). Electrocardiogram was also performed 45 minutes (± 15 min) post-end-of- nebulization on Day 1.''''Cardiac telemetry monitoring during bronchoscopy was for the BAL cohort only.BBAt screening, only healthy volunteers who had not had any coronavirus disease 2019, respiratory syncytial virus, or influenza vaccines within 7 days of the AP02 dose (Day -1 or Day 1) and who were willing to not receive any coronavirus disease 2019, respiratory syncytial virus, or influenza vaccine 7 days after receiving AP02 were included.§§§§Two sentinel healthy volunteers received trial treatment prior to the remainder of the cohort, pending review of safety data following the 24-hour observation period. (See also Footnote 1.)miiiiiBlood collection in SAD cohorts were performed pre-dose and then post-end-of-nebulization at 10 minutes (±5 min), 30 minutes (±5 min), 1 hour (± 10 min), 2 hours (± 10 min), 4 hours (± 10 min), 8 hours (± 10 min), 12 hours (± 10 min), 24 hours (±1 hour) (Day 2), and 30 hours (±1 hour) (Day 2). Blood collection in BAL cohort occurred pre-dose and then post-end-of-nebulization at 10 minutes (±5 min), 30 minutes (±5 min), 1 hour (± 10 min), 2 hours (± 10 min), 4 hours (± 10 min), 12 hours (± 10 min). The 4-hour and 12-hour plasma samples were collected prior to the respective BAL procedure. A urea blood sample was also collected concomitant with the BAL procedure for the BAL cohort. The window for plasma pharmacokinetic sample collection without a concomitant BAL sample still applied as described. Nintedanib and metabolite of nintedanib was measured in all blood samples processed to plasma.*** ^Bronchoalveolar lavage fluid collection for the BAL cohort occurred at 45 minutes (± 30 min), 4 hours (± 15 min), and 12 hours (± 1 hour) post-end-of-nebulization from 4 healthy volunteers per timepoint. Dose was administered in the morning for both 45 minutes and 4-hour timepoints, while dose was administered in the evening for the 12-hour timepoint (BAL will be collected the following morning). Nintedanib and urea were measured in BAL.85IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENTTable 4: Schedule of Activities for AP02-002 - Multiple Ascending Doses86IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENT87IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENTAPTT=activated partial thromboplastin time; COVID-19=coronavirus disease 2019; FEVi=forced expiratory volume in 1 second; FVC=forced vital capacity; FSH=follicle-stimulating hormone; INR=Intemational Normalized Ratio; RSV=respiratory syncytial virus* A 24-hour safety observation period commenced for the sentinel volunteers following end of the final dose at Day 7 to facilitate principal investigator review and decision to continue with a given cohort (4.0 mg BID AP02 and 8.0 mg BID AP02 cohorts).1A final follow-up visit occurred at Day 5 to 7 post-final dose (Day 12 to 14 post-first dose) to collect clinical laboratory safety assessments. If there was a clinically significant abnormal result in these labs, unscheduled follow-up visits were arranged until resolution.informed consent was obtained prior to any trial procedure being performed.§Medical history included history of previous allergy or sensitivity to nintedanib, reactive airway diseases, bleeding disorders, etc. (Refer to inclusion and exclusion criteria.)“Height and body mass index were calculated at screening only. Weight was captured as part of physical examination at screening, admission, and discharge.88IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENT** Prohibited concomitant medications included P-glycoprotein and CYP3A4 inducers and inhibitors and antiplatelet drugs.Wital signs (heart rate, respiratory rate, temperature, blood pressure, and oximetry) were performed pre-dose (within 1 hour) and then 15 minutes (±5 min) and 30 minutes (±5 min) post-end-of-nebulization for each dose across all cohorts. Vital signs were also required at 24 hours (±1 hour) post-end-of-nebulization for Day 1. Pre-dose vital signs on Days 2 to 7 coincided with 24-hour post-end-of-nebulization collections from the previous day. Of these, only one set of vital signs was required (pre-dose day of or 24-hour post-dose from day before) in addition to the 15-minute and 30-minute post-end-of-nebulization readings.BCoagulation parameters were evaluated at check-in Day -1, on Day 3 post-dose, on Day 5 post-dose, at discharge, and also at the follow-up visit as part of clinical laboratory safety assessments.§§At screening and Day -1, only healthy volunteers with negative screen results for (opiates, methadone, cocaine, tetrahydrocannabinol, benzodiazepines, amphetamines / methamphetamines, barbiturates, 3, 4-methylenedioxy -methamphetamine, phencyclidine, and alcohol) were included.niIRandomization for eligible healthy volunteers was performed up to 1 day in advance (Day -1 or Day 1).***Clinical laboratory safety assessments were conducted at screening, Day -1, Day 1, Day 3, Day 5, Day 8, and at the follow-up visit (see also Footnote 2.)' ' ' Serology included testing for hepatitis B surface antigen, hepatitis C virus, and human immunodeficiency virus.tBAt screening and Day -1, only healthy volunteers who have not used cigarettes / e-Cigarettes or used of other nicotine or tobacco containing products within 7 days prior to trial drug administration were included. Urine cotinine testing was performed at screening and Day -1 to confirm smoking status.§§§Serum pregnancy screen was performed in female healthy volunteers of childbearing potential only at screening. Urine pregnancy test at Day - 1 and discharge. For postmenopausal women, a follicle- stimulating hormone assessment was performed to confirm postmenopausal status only at screening (follicle- stimulating hormone assessment did not need to be repeated at Day -1).niIIISpirometry (FVC, FEVi) was performed using American Thoracic Society criteria at screening, on Day 1 pre-dose (within 1 hour) and 15 minutes (±5 min) post-end-of-nebulization on Days 1 and 7. Spirometry was also collected on Day 3 after the morning dose 15 minutes (±5 min) post-end-of-nebulization.****Twelve-lead electrocardiograms were performed at screening and on Day 1 prior to trial drug dosing. If results were abnormal and clinically significant, the electrocardiogram was repeated one time at screening and / or on Day 1 to confirm initial reading. If any detected abnormality was deemed clinically significant by the principal investigator, the healthy volunteer was not dosed (and could have been replaced).Electrocardiograms were also performed 45 minutes (± 15 min) post-end- of-nebulization on Day 3 and 45 (± 15 minutes) of the last dose the morning of Day 7.BBAt screening, only healthy volunteers who had not had any coronavirus disease 2019, respiratory syncytial virus, or influenza vaccines within 7 days of the AP02 dose (Day -1 or Day 1) and who are willing to not receive any coronavirus disease 2019, respiratory syncytial virus, or influenza vaccines 7 days after receiving AP02 were included.BBOn Day 7, only the morning dose was dispensed and administered to healthy volunteers.§§§§Two sentinel healthy volunteers received treatment for the entire 7-day dosing period with a 24-hour safety observation interval before the remainder of the cohort was initiated; all available safety results were evaluated prior to continuing the cohort. (See also Footnote *.) miiiiiBlood collection on Day 1 and Day 7 occurred within 1 hour pre-dose and then post-end-of-nebulization time at 10 minutes (±5 min), 3089IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENTminutes (±5 min), 1 hour (± 10 min), 2 hours (± 10 min), 4 hours (± 10 min), 8 hours (± 10 min), and 12 hours (±10 min). Also on Day 8, collection occurred at 24 hours (± 1 hour) and 30 hours (± 1 hour;) post-end-of-nebulization.* * * * *Bl00d collection within 1 hour pre-dose (first dose of the day only) occurred on Days 2 and 5.90IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTStopping Criteria for AP02-002

[0214] If any of the below listed events developed at any time during the trial and were considered by the investigator and / or sponsor to be related to the administration of investigational product (either AP02 or placebo), the trial would have been stopped and an ad-hoc Safety Review Committee meeting would have been called immediately to investigate the event and to provide a recommendation for terminating the trial, resuming and continuing the trial as planned, or modifying the protocol before trial continuation.• If 1 or more volunteers administered trial drug in a single cohort of the SAD or MAD experienced a trial drug-related serious adverse event of any of the adverse events that have been reported with the use of oral nintedanib (gastrointestinal issues such as perforation, nausea, vomiting, diarrhea; liver toxicity; high blood pressure; bleeding disorders, or arterial thromboembolic event)• If 2 or more volunteers administered trial drug in a single cohort of the SAD or MAD experienced respiratory findings (such as >20% decrease in FEVi and bronchospasm) • If 1 volunteer in SAD or 2 volunteers in MAD experienced a SAE that was considered related to trial drug treatment, at any point up to the 3- to 5-day SAD follow-up or the 5- to 7-day MAD follow-up, escalation to the next ascending dose would not proceed, and the Safety Review Committee would have been consulted for review• If the observed or projected systemic exposure (Cmax or area under the curve) of nintedanib unexpectedly exceeded the mean steady state exposures of the approved oral 150 mg BID dose in 1 volunteer:O Cmax- 31.95 ng / mLo AUC0-24: 363 ng*h / mL• If TEAEs deemed related to trial drug of > Grade 3 occurred in 50% of volunteers per cohort or TEAEs of > Grade 4 occurred in 25% of volunteers per cohort, escalation to the91IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTnext ascending dose would not have proceeded and the Safety Review Committee would have been consulted for reviewParticipants

[0215] Key inclusion criteria for healthy volunteers in this trial included being aged 18 to 55 years for AP02-001 and aged 18 to 65 years for AP02-002. Healthy volunteers in AP02-002 also needed to have a forced expiratory volume in one second (FEVi) to forced vital capacity (FVC) ratio of >0.80. For patients with IPF in AP02-001, an IPF diagnosis based on 2018 professional society guidelines was required and individuals aged 18 to 80 years were included.

[0216] Key exclusion criteria for healthy volunteers in AP02-001 and AP02-002 included having a history of reactive airway disease (such as asthma or chronic obstructive pulmonary disease [COPD]), cystic fibrosis, or bronchiectasis. Patients with IPF in AP02-001, however, could have a history of COPD or asthma. Full eligibility criteria and additional details are provided in the online data supplement.Trial Endpoints

[0217] The primary endpoint for both studies included measures of safety and tolerability, including assessment of adverse events, laboratory values, vital signs, and pulse oximetry, as well as physical examinations before and after trial drug administration. Spirometry was conducted in the AP02-001 non-BAL cohorts and in all cohorts in AP02-002. Twelve-lead electrocardiograms were assessed in the AP02-001 BAL cohorts and in all cohorts in AP02-002. The main secondary endpoint in both studies was the analysis of nintedanib plasma pharmacokinetics. Plasma pharmacokinetics of the nintedanib metabolite BIBF1202 and bronchoalveolar pharmacokinetics of AP02 following single dosing were also secondary endpoints for the AP02-002 trial. Bronchoalveolar nintedanib exposures were determined via BAL following single AP02 or oral dosing and were analyzed as an exploratory endpoint for AP02-001. Schedules of activities for both studies are provided in the online data supplement.Statistical Analyses

[0218] Descriptive statistics were used to summarize safety and pharmacokinetic parameters.92IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0219] Trial protocols complied with Good Clinical Practice guidelines of the International Council for Harmonization; the recommendations of the Declaration of Helsinki; and any applicable country-specific laws, regulations, and guidelines. Protocols were approved by the local Ethics Committee and all participants provided writen informed consent prior to trial procedures.Method of Analysis

[0220] Nintedanib and BIBF1202 plasma concentrations were quantified by a validated liquid chromatography tandem mass spectrometry (LC-MS / MS) assay with a linear range of 0.05 to 50 ng / mL. A qualified LC-MS / MS method with a linear range of 0.05 to 50 ng / mL was used for nintedanib quantification in BAL fluid. A fit-for purpose colorimetric assay with a linear range of 0.25-5 mg / dL was used for urea quantification in trial AP02-001. A qualified LC-MS / MS method with a linear range of 5-1000 ug / mL for plasma and 0.25-50 ug / mL for BAL was used for urea quantification in trial AP02-002.

[0221] Statistical analyses were generated using SAS® for Windows, Release 9.4 (SAS® Institute Inc., Cary, NC, USA).

[0222] For all pharmacokinetic analyses, Phoenix® WinNonlin® version 8.0 or higher (Certara USA, Inc., Princeton, NJ) were used.

[0223] All features, elements, components, functions, and steps described with respect to any invention provided herein are intended to be freely combinable and substitutable with those from any other embodiment. If a certain feature, element, component, function, or step is described with respect to only one embodiment, then it should be understood that that feature, element, component, function, or step can be used with every other invention described herein unless explicitly stated otherwise. This paragraph therefore serves as antecedent basis and writen support for the introduction of claims, at any time, that combine features, elements, components, functions, and steps from different aspects of the present invention, or that substitute features, elements, components, functions, and steps from one aspect with those of another, even if the following description does not explicitly state, in a particular instance, that such combinations or substitutions are possible. It is explicitly acknowledged that express recitation of every possible combination and substitution is overly burdensome, especially given that the permissibility of each and every such combination and substitution will be readily recognized by those of ordinary skill in the art.93IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0224] While the individual inventions described herein are susceptible to various modifications and alternative forms, specific examples thereof have been described in detail. It should be understood, however, that these individual inventions are not to be limited to the particular form disclosed, but to the contrary, these concepts cover all modifications, equivalents, and alternatives falling within the spirit of the disclosure. Furthermore, any features, functions, steps, or elements of the several inventions may be recited in or added to the claims, as well as negative limitations that define the inventive scope of the claims by features, functions, steps, or elements that are not within that scope.ResultsParticipants and Baseline Characteristics

[0225] A total of 32 healthy volunteers and 6 patients with IPF were included in the AP02-001 trial, and 60 healthy volunteers were included in the AP02-002 trial (Figures 1 and 2).

[0226] Description of demographic and clinical characteristics of trial participants is reported in Tables 5 and 6. In AP02-001, mean (SD) age of participants was 32.8 (17.59) years and approximately half of participants were male (n=18 [47.4%]). Most participants were either White (n=21 [55.3%]) or Asian (n=16 [42.1%]). In the IPF cohort, 4 individuals (66.7%) were pretreated with salbutamol prior to receiving an AP02 dose, and the FEVi / FVC ratio ranged from 0.702 to 0.866. The mean age of participants in the single-dose cohorts of AP02-002 was 33.4 (14.3) years and in the multiple dose cohorts of AP02-002 was 31.5 (11.4) years. Amajority of participants in this trial were male (n=54 [90%]) and White (n=31 [51.7%]) or Asian (n=21[35.0%]).94IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENTTable 5: Demographic Characteristics of Trial Participants in AP02-001All cohorts were comprised of healthy volunteers with the exception of the IPF cohort that was comprised of patients with IPF.BAL=bronchoalveolar lavage; BMI=body mass index; F=females; IPF=idiopathic pulmonary fibrosis; M=males; N=number of subjects dosed; n (%)=number and percent of subjects; SAD=single ascending dose; SD=standard deviation95IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENTTable 6: Demographic Characteristics of Trial Participants in AP02-002All cohorts were comprised of healthy volunteers.BID=twice daily; BMI=body mass index; F=females; M=males; MAD=multiple ascending doses; N / A=not applicable; N=number of subjects dosed; n (%)=number and percent of subjects; SAD=single ascending dose; SD=standard deviation96IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTSafety Evaluation

[0227] In the AP02-001 trial, the maximum AP02 dose evaluated was 2.0 mg, which was deemed tolerable by the Safety Review Committee. Sixteen treatment emergent adverse events (TEAEs) were reported by 11 (28.9%) of the 38 participants. One TEAE was reported by 1 (16.7%) of the 6 participants in the placebo group and 15 TEAEs were reported by 10 (31.3%) of the 32 participants in the AP02 treatment group. No TEAEs were reported in the 0.5 mg AP02 SAD cohort or 150 mg oral nintedanib BAL cohort. The highest frequency of TEAEs overall in AP02-001 was reported in the cohort with IPF, with 83.3% of participants (n=5) in the cohort reporting at least 1 TEAE. Of the 16 TEAEs reported, 10 were considered to be possibly or probably drug-related, with the most common drug-related events being headache (n=2), nausea (n=2), and cough (n=2). The drug-related events were reported by 21.1% of participants (n=8) (Table 7, Table 8). These events were mild except for 1 headache in the IPF cohort that was moderate in severity (Table 9).

[0228] In the AP02-002 trial, 18 TEAEs were reported by 12 (33.3%) of the 36 participants in the SAD and BAL cohorts. A total of 33.3% (n=2) of the participants in the placebo group reported 3 TEAEs and 33.3% (n=10) of participants in the AP02 treatment group reported 15 TEAEs. The 4.0 mg AP02 BAL cohort had the highest frequency of participants that reported TEAEs, with 50% of participants (n=6) reporting 11 of the 18 TEAEs. Four of the 18 TEAEs reported in the SAD and BAL cohorts were considered drug-related, with the most common event being dizziness (Table 10, Table 11). TEAEs reported in the single-dose studies were either mild (n=16) or moderate (n=2) in severity. Eight TEAEs were reported by 6 (25%) of 24 participants in the MAD cohorts, with all 6 of these participants being part of the AP02 treatment group (33.3%). Two of these TEAEs were considered drug-related (Table 4). TEAEs reported in the multiple dose cohorts were all mild (n=7) or moderate (n=l) in severity (Table 12). No TEAEs of cough or diarrhea were reported.

[0229] None of the TEAEs reported led to withdrawal from the studies and no serious adverse events or deaths were reported in either trial. Further, no bronchospasms, decreased oxygen saturation, or TEAEs related to vital signs, electrocardiograms, physical examinations, or spirometry were reported during either trial.97IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTTable 7: Frequency of Subjects Experiencing Treatment-Emergent Adverse Events in AP02-00198IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT*Possibly or probably drug-related adverse events.11 of 2 headache events was considered to be drug-related in the IPF cohort.J2 of 3 headache events were considered to be drug-related in the overall trial population.§2 of 3 cough events were considered to be drug-related in the overall trial population.AE=adverse event; BAL=bronchoalveolar lavage; IPF=idiopathic pulmonary fibrosis;MedDRA®=Medical Dictionary for Regulatory Activities, Version 23.1.; N=number of subjects dosed; n (%)=number and percent of subjects with treatment-emergent adverse events; SAD=single ascending dose; TEAE=treatment-emergent adverse eventThe safety population consisted of all 38 enrolled participants. “All Placebo” reflects placebo subjects pooled from SAD cohorts; “Overall” included results from all treatment groups (including placebo). Table 8: Frequency of Subjects Experiencing Treatment-Emergent Adverse Events in AP02-001 by Relationship (Safety Population)99IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT100IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTEach subject could only contribute once to each of the incidence rates, regardless of the number of occurrences; The highest causality is presented; “All Placebo” reflects placebo subjects pooled from SAD cohorts; “Overall” included results from all treatment groups (including placebo).Table 9: Frequency of Subjects Experiencing Treatment-Emergent Adverse Events in AP02-001 by Severity (Safety Population)101IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT102IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT103IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTRegulatory Activities, Version 23.1.; N=Number of subjects dosed; n (%)=Number and percent of subjects with treatment-emergent adverse events; SAD=single ascending dose; TEAEs=Treatment- emergent Adverse EventsEach subject could only contribute once to each of the incidence rates, regardless of the number of occurrences; The highest severity is presented; The severity grade of adverse events are assessed using the criteria of National Cancer Institute's Common Terminology Criteria for Adverse Events Version (NCI-CTCAE); “All Placebo” reflects placebo subjects pooled from SAD cohorts; “Overall” included results from all treatment groups (including placebo).104IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENTTable 10: Frequency of Subjects Experiencing Treatment-Emergent Adverse Events in AP02-002105IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENT*Possibly or probably drug-related adverse events.f 2 of 3 dizziness events were considered to be drug-related in the BAL cohortALT=alanine aminotransferase; BAL=bronchoalveolar lavage; BID=twice daily; IPF=idiopathic pulmonary fibrosis; MAD=multiple ascending doses; MedDRA®=Medical Dictionary for Regulatory Activities, Version 23.1.; N=number of subjects dosed; n (%)=number and percent of subjects with treatment-emergent adverse events; RTI=respiratory tract infection; SAD=single ascending dose; TEAE=treatment-emergent adverse eventTable 11: Frequency of Subjects Experiencing Treatment-Emergent Adverse Events in AP02-002 by Relationship (Safety Population)106IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENT107IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENTBAL=bronchoalveolar lavage; BID=twice daily; MAD=multiple ascending doses; N=Number of subjects dosed; n (%)=Number and percent of subjects with treatment-emergent adverse events; SAD=single ascending dose; TEAEs=Treatment-emergent Adverse EventsEach subject could only contribute once to each of the incidence rates, regardless of the number of occurrences; The highest causality is presented.Table 12: Frequency of Subjects Experiencing Treatment-Emergent Adverse Events in AP02-002 by Severity (Safety Population)108IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENT109IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENT110IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENT111IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENTBAL=bronchoalveolar lavage; BID=twice daily; MAD=multiple ascending doses; N=Number of subjects dosed; n (%)=Number and percent of subjects with treatment-emergent adverse events; SAD=single ascending dose; TEAEs=Treatment-emergent Adverse EventsEach subject could only contribute once to each of the incidence rates, regardless of the number of occurrences; The highest severity is presented; The severity grade of adverse events are assessed using the criteria of National Cancer Institute's Common Terminology Criteria for Adverse Events Version.112IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTPlasma Pharmacokinetic EvaluationSingle-Dose Cohorts

[0230] In participants administered a single dose of AP02 in the AP02-001 trial (3 SAD cohorts, 2.0 mg AP02 BAL cohort, and IPF patient cohort) and the AP02-002 trial (3 SAD cohorts and 4.0 mg AP02 BAL cohort), median time to maximum nintedanib plasma concentration (Tmax) was observed early, with all AP02 dosed cohorts reporting a median Tmax within 0.40 hours after end of inhalation (Figures 3 and 4; Table 13). Conversely, in participants administered oral nintedanib in the AP02-001 trial, plasma nintedanib levels reached a median Tmax at 6 hours (Figure 3). Mean plasma BIBF1202 concentration over time displayed a similar trend to nintedanib, with participants administered AP02 having a median BIBF1202 Tmaxwithin 0.40 hours after end of inhalation, and participants who received oral nintedanib having a later BIBF1202 Tmaxof 6.00 hours (Tables 14 and 15).

[0231] Nintedanib systemic exposure generally increased with increasing AP02. In AP02-001, geometric mean values for the area under the concentration-time curve from time 0 to 24 hours (AUC0-24) and maximum observed concentration (Cmax) were 0.47 h*ng / mL and 0.33 ng / mL, respectively, for the 0.5 mg AP02 cohort; 1.81 h*ng / mL and 1.02 ng / mL, respectively, for the 1.0 mg AP02 cohort; and 2.17 h*ng / mL and 1.05 ng / mL, respectively, for the 2.0 mg AP02 cohort. In AP02-002, geometric mean values for area under the concentration-time curve from time 0 to the last measurable concentration (AUCo-iast) and Cmaxwere 1.61 h*ng / mL and 0.93 ng / mL, respectively, for the 2.0 mg AP02 cohort; 4.4 h*ng / mL and 1.69 ng / mL, respectively, for the 4.0 mg AP02 cohort; and 13.4 h*ng / mL and 4.75 ng / mL, respectively, for 8.0 mg AP02 cohort. In the AP02-001 trial, the elimination half-life (Ti / 2ei) of nintedanib was fastest following the administration of the 0.5 mg dose and was comparable for the 1.0 and 2.0 mg doses with median half-lives of 0.90, 5.09, and 4.66 hours, respectively. A similar trend was observed in the AP02-002 trial, with a median Ti / 2ei of 8.76, 14.6, and 13.2 hours following a single 2.0 mg, 4.0 mg, and 8.0 mg dose of AP02, respectively (Table 13).

[0232] Plasma nintedanib AUC0-24 and Cmaxfollowing a single 2.0 mg AP02 dose was approximately 68-fold and 15-fold lower, respectively compared to systemic exposure following a single 150 mg oral nintedanib dose in this trial (Table 13).113IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0233] In AP02-001, patients with IPF administered 2.0 mg AP02 (Cohort 6) had a median Tmax (0.40 hours) comparable to Tmax in healthy volunteers administered the same dose of AP02 in the SAD cohort (0.37 hours). Plasma exposure of nintedanib was also similar between these 2 cohorts, with geometric mean values AUC0-24 and Cmax in the IPF cohort being 2.10 h*ng / mL and 0.91 ng / mL, respectively. Median Ti / 2eiof nintedanib in the IPF cohort was 10.74 hours, which was slightly higher than what was observed in the 2.0 mg AP02 SAD cohort (Table 13).114IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENTTable 13: Summary of Nintedanib Plasma Pharmacokinetic Parameters by Treatment in Single-Dose Cohorts (AP02-001 and AP02-002)AUCo-24=area under the concentration-time curve, from time 0 to 24 hours; AUCo-iast=area under the concentration-time curve from 0 to the last measurable concentration; BAL=bronchoalveolar lavage; Cmax=maximum observed concentration; IPF=idiopathic pulmonary fibrosis; N=number of subjects dosed; n=number of observations; SAD=single ascending dose; T,ei=climination half-life; Tmax=time of observed Cmax; %CV=percent 115IPTS / 200337643.1Attorney Docket No: AVY-003WO PATENTcoefficient of variation; ‘-‘=not calculatedIn the AP02-001 trial, 6 participants were included in the 0.5 mg and 1.0 mg AP02 cohorts, 5 participants were included in the 2.0 mg AP02 healthy volunteer and IPF cohorts, and 4 participants were included in the BAL cohorts for this analysis. In the AP02-002 trial, 6 participants were included in each SAD cohort and 12 participants were included in the BAL cohort for this analysis.116IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTTable 14: Summary of BIBF1202 Plasma Pharmacokinetic Parameters by Treatment in AP02-001AUCo-24=area under the concentration-time curve, from time 0 to 24 hours; AUCo-iast=area under the concentration-time curve from 0 to the last measurable concentration; BAL=bronchoalveolar lavage; Cmax=maximum observed concentration; IPF=idiopathic pulmonary fibrosis; N=number of subjects dosed; n=number of observations; SAD=single ascending dose; T / 2ei=elimination half-life; Tmax=time of observed Cmax; %CV=percent coefficient of variation; ‘-‘=not calculatedTable 15: Summary of BIBF1202 Plasma Pharmacokinetic Parameters by Treatment in AP02-002117IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTtau=area under the concentration-time curve from 0 to the end of the dosing interval;BAL=bronchoalveolar lavage; BID=twice daily; Cmax=maximum observed concentration;MAD=multiple ascending doses; N=number of subjects dosed; n=number of observations; SAD=single ascending dose; T / 2ei=elimination half-life; Tmax=time of observed Cmax; %CV=percent coefficient of variationMultiple-Dose Cohorts

[0234] Participants administered BID doses of AP02 for up to 7 days in the AP02-002 trial also had rapid median Tmax plasma nintedanib ranging from 0.17 to 0.18 hours on both days 1 and 7 (Figures 5 and 6; Table 16). BIBF1202 concentration levels in these cohorts followed a similar trend (Table 17).

[0235] Plasma exposures of nintedanib on Day 1 were generally similar in participants administered 2.0 mg and 4.0 mg AP02 BID, with geometric mean values of AUCo-iast of 2.19 and 2.65 h*ng / mL, respectively, and Cmax of 1.59 and 1.31 ng / mL, respectively. Exposures were higher following administration of 8.0 mg AP02 BID, with an AUCo-iast of 7.13 h*ng / mL and Cmax of 3.18 ng / mL. On Day 7, exposures increased with an increase in dosage, with the highest being observed in the 8.0 mg AP02 BID cohort (AUCo-iast=17.9 h*ng / mL and Cmax=3.11 ng / mL). Tv2ei was comparable across cohorts, with shorter elimination half-lives on Day 1 (4.68, 6.63, and 5.79 hours for the 2.0 mg, 4.0 mg, and 8.0 mg AP02 BID cohorts, respectively) compared to Day 7 (16.9, 19.4, and 17.1 hours for the 2.0 mg, 4.0 mg, and 8.0 mg AP02 BID cohorts, respectively) (Table 16)

[0236] The mean steady state exposures of the approved oral 150 mg BID dose are an AUC0-24 of 363 h*ng / mL and Cmax of 31.97 ng / mL. Predicted AUC0-24 values were calculated by multiplying AUCo-tau values by 2. Of note, predicted AUC0-24 and Cmax geometric mean values across all AP02 multiple dose cohorts on Day 7 were 10- to 56-fold lower than these exposure levels.Table 16: Summary of Nintedanib Plasma Pharmacokinetic Parameters by Treatment in Multiple-Dose Cohorts (AP02-002)118IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTAUCo tau=area under the concentration-time curve from 0 to the end of the dosing interval; BID=twice daily; Cmax=maximum observed concentration; N=number of subjects dosed; n=number of observations; T / 2ei=elimination half-life; Tmax=time of observed Cmax; %CV=percent coefficient of variation; ‘-‘=not calculated.Table 17: Summary of BIBF1202 Plasma Pharmacokinetic Parameters by Treatment in AP02-002119IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTAUCo iast=area under the concentration-time curve from 0 to the last measurable concentration; AUCo- tau=area under the concentration-time curve from 0 to the end of the dosing interval;BAL=bronchoalveolar lavage; BID=twice daily; Cmax=maximum observed concentration;MAD=multiple ascending doses; N=number of subjects dosed; n=number of observations; SAD=single ascending dose; T / 2ei=elimination half-life; Tmax=time of observed Cmax; %CV=percent coefficient of variationBronchoalveolar Pharmacokinetic Evaluation

[0237] In AP02-001, concentrations of nintedanib observed in the BAL samples were approximately 9-fold higher following a single dose 2.0 mg AP02 administration when compared to a single 150 mg oral nintedanib dose, with geometric mean values of 3.70 and 0.43 ng / mL, respectively.

[0238] To determine whether nintedanib was still detectable in lung ELF during a 12-hour dosing interval, BAL samples were collected longitudinally at 45 minutes, 4 hours, and 12 hours post-dose in trial AP02-002 following a single 4.0 mg dose. Nintedanib concentrations were detectable in ELF up to 12 hours post-dose and exceeded ELF concentrations following a single 150 mg oral dose in trial AP02-001.

[0239] Nintedanib works by inhibiting multiple receptor tyrosine kinases that have been shown to contribute to ILD pathogenesis, including VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, PDFGR-a, and PDFGR-p. The half maximal inhibitory concentration (IC50) values for these kinases range from 7 to 37 ng / mL. Notably, exposures in ELF following a 4.0 mg dose of AP02 also exceeded IC50 values of these target tyrosine kinases (Figure 7). An additional exploratory analysis was performed to compare nintedanib ELF exposure following a 4.0 mg AP02 dosing versus oral dosing. Nintedanib Cmax (Co; extrapolated to the end of inhalation) and AUC0-12 in ELF following the AP02 dose was estimated to exceed ELF exposure following oral dosing by 27-fold and 26-fold, respectively.Analysis

[0240] The goal of these studies was to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of AP02 in healthy volunteers and patients with IPF. AP02 was well tolerated in single and multiple doses up to 8.0 mg in healthy volunteers and at a single dose of 2.0 mg in patients with IPF. TEAEs were mostly mild in severity; none led to trial withdrawal and no serious adverse events or deaths were reported.120IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT

[0241] Systemic exposure was generally increased with increasing doses of AP02 and was similar between healthy volunteers and patients with IPF who received the same AP02 dose. A single 2.0 mg dose of AP02 resulted in approximately 68-fold lower plasma AUC0-24 and 15-fold lower Cmax compared to exposure observed following oral nintedanib dosing in healthy volunteers in AP02-001. Additionally, in all MAD cohorts, in which 8.0 mg BID was the highest evaluated dose, systemic exposure following AP02 administration remained 10- to 56-fold lower than the mean steady state exposures of the approved oral 150 mg BID dose. Lung exposure, conversely, was higher in individuals who received AP02 compared to oral nintedanib, with nintedanib exposure being ~26-fold higher in ELF following a 4.0 mg AP02 dose compared to oral nintedanib. Together, these findings suggest that direct lung delivery of AP02 by oral inhalation can improve lung exposure of nintedanib while reducing systemic exposure. Further, dosing with AP02 in the AP02-002 trial also resulted in ELF exposure levels that exceeded the published IC50 values of select target tyrosine kinases, suggesting that AP02 may be effective in reducing IPF-associated disease activity.

[0242] The use of inhaled therapeutics to minimize systemic exposure and associated toxicity has been employed in airway diseases. In management of both asthma and COPD, for example, inhaled bronchodilators and corticosteroids have a crucial role in treatment. Several other forms of inhaled therapeutics are also being investigated for use in IPF. A nintedanib dry powder inhalation was shown to be safe and well tolerated in a recent phase I trial and inhalable poly(lactic-co-gly colic acid) nintedanib nanoparticles have also been recently formulated and demonstrated promising results in vitro (Wang et al. 2024, Journal of Drug Delivery Science and Technology. 91 : 105233; Wang et al. 2024, Journal of Drug Delivery Science and Technology.95: 105615). Results from the studies reported here contribute significantly to this growing therapeutic space by demonstrating a favorable safety profile as well as evidence that suggests a delivery of higher lung nintedanib levels using the eFlow nebulizer compared to the oral formulation. Due to the feasibility of collection, human ELF nintedanib concentrations were used as a surrogate for lung tissue exposures; however, it is unknown how ELF concentrations relate to lung tissue concentration following inhaled versus oral dosing. Further investigations are required to determine whether the increased nintedanib levels in the lung and decreased systemic levels translate to increased efficacy in patients. However, inhaled nintedanib was shown to be effective at reducing bleomycin-induced pulmonary fibrosis in a rat model, suggesting that this121IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTavenue may be promising (Surber et al. 2020, Pulm Pharmacol Then 63: 101938). Moreover, a 100 mg BID dose of inhaled pirfenidone solution (AP01) delivered using the same eFlow nebulizer resulted in stable mean FVC % predicted values, further demonstrating improved efficacy using this system (West et al. 2023, Thorax. 78: 882-889).

[0243] Small sample sizes across cohorts are a limitation of these studies, as it reduces the possibility of detecting rare adverse events. However, as the safety profile of oral nintedanib is well characterized and the systemic exposure of nintedanib following AP02 administration was markedly lower than that of the oral formulation, the likelihood of novel systemic adverse events in studies with larger cohort sizes may be low. An additional limitation of this trial is that the average age of most participants in these SAD and MAD cohorts is younger than the mean age of patients with IPF, which is 65 to 70 years (Maher et al. 2021, Respir Res. 22: 197).Nonetheless, the age of the IPF cohort assessed in this trial (mean=69.8 years) reflects what is observed in the real- world. Additionally, a limited number of BAL collections following oral dosing were used to estimate an ELF profile.

[0244] It is notable that no participants in the oral nintedanib cohort reported TEAEs normally associated with oral therapy. The small sample size of this cohort may have contributed to this outcome. The short duration of treatment may have also played a role; it has been reported that the onset of diarrhea occurs around 60 days post-treatment initiation (Podolanczuk and Cottin 2023, Adv Then. 40: 2038-2050; Laskey etal. 2020, Adv Then. 37: 4209-4219). Additionally, only a single dose of oral nintedanib was given to participants, which differs from the approved dosage of oral nintedanib, which is BID.

[0245] In summary, these studies demonstrated that AP02 was well tolerated in a single 2.0 mg dose in IPF patients and in single and multiple doses up to 8.0 mg in healthy volunteers. AP02 also resulted in a lower systemic exposure and a higher ELF exposure relative to oral nintedanib at the approved dosage. These findings support the further clinical advancement of AP02 and suggest that an inhaled delivery of a proven efficacious agent may be a promising new treatment option for IPF.

[0246] The present embodiments are not to be limited in scope by the specific embodiments described herein. Indeed, various modifications in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures.122IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENTSuch modifications are intended to fall within the scope of the embodiments and any appended claims.

[0247] The present specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. Various modifications in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the present disclosure and any appended claims.123IPTS / 200337643.1

Claims

Atorney Docket No: AVY-003WO PATENTCLAIMSWhat is claimed is:

1. A method of treating a pulmonary fibrotic disorder in a human subject in need thereof, the method comprising administering by inhalation a therapeutically effective amount of nintedanib, or a pharmaceutically acceptable salt thereof, wherein the administering results in a systemic plasma exposure to nintedanib that is lower than a systemic plasma exposure achieved by oral administration of nintedanib at a therapeutically equivalent dose.

2. The method of claim 1, wherein the systemic plasma AUC0-24 of nintedanib following said administration is at least 10-fold lower than the mean steady-state systemic plasma AUC0-24 of nintedanib following oral administration of nintedanib at 150 mg.

3. The method of claim 1, wherein the systemic plasma AUC0-24 of nintedanib following said administration is at least 20-fold lower than the mean steady-state systemic plasma AUC0-24 of nintedanib following oral administration of nintedanib at 150 mg.

4. The method of claim 1, wherein the systemic plasma AUC0-24 of nintedanib following said administration is at least 50-fold lower than the mean steady-state systemic plasma AUC0-24 of nintedanib following oral administration of nintedanib at 150 mg.

5. The method of any one of claims 1-4, wherein the pulmonary fibrotic disorder is idiopathic pulmonary fibrosis (IPF).

6. The method of any one of claims 1-5, wherein the therapeutically effective amount is from about 0.5 mg to about 8 mg of nintedanib.

7. The method of any one of claims 1-5, wherein the therapeutically effective amount is from about 2 mg to about 8 mg of nintedanib.124IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT8. The method of any one of claims 1-5, wherein the therapeutically effective amount is about 0.5 mg of nintedanib.

9. The method of any one of claims 1-5, wherein the therapeutically effective amount is about 1.0 mg of nintedanib.

10. The method of any one of claims 1-5, wherein the therapeutically effective amount is about 2.0 mg of nintedanib.

11. The method of any one of claims 1-5, wherein the therapeutically effective amount is about 4.0 mg of nintedanib.

12. The method of any one of claims 1-5, wherein the therapeutically effective amount is about 8.0 mg of nintedanib.

13. The method of any one of claims 1-12, wherein the nintedanib is administered once daily.

14. The method of any one of claims 1-12, wherein the nintedanib is administered twice daily (BID).

15. The method of claim 14, wherein the nintedanib is administered at about 0.5 mg twice daily.

16. The method of claim 14, wherein the nintedanib is administered at about 2.0 mg twice daily.

17. The method of claim 14, wherein the nintedanib is administered at about 4.0 mg twice daily.

18. The method of claim 14, wherein the nintedanib is administered at about 8.0 mg twice daily.125IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT19. The method of any one of claims 1-18, wherein the nintedanib is administered for at least 7 days.

20. The method of any one of claims 1-19, wherein the systemic plasma Cmax of nintedanib following said administration is at least 10-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg.

21. The method of any one of claims 1-19, wherein the systemic plasma Cmax of nintedanib following said administration is at least 15-fold lower than the systemic plasma Cmax of nintedanib following oral administration of nintedanib at 150 mg.

22. The method of any one of claims 1-21, wherein the systemic plasma AUC0-24 of nintedanib following said administration is less than 20 h*ng / mL.

23. The method of any one of claims 6-11, wherein the systemic plasma AUC0-24 of nintedanib following said administration is less than 10 h*ng / mL.

24. The method of claim 8 or 9, wherein the systemic plasma AUC0-24 of nintedanib following said administration is less than 5.0 h*ng / mL.

25. The method of claim 8, wherein the systemic plasma AUC0-24 of nintedanib following said administration is less than 2.0 h*ng / mL.

26. The method of claim 8, wherein the systemic plasma AUC0-24 of nintedanib following said administration is less than 0.5 h*ng / mL.

27. The method of any one of claims 1 -26, wherein the systemic plasma Cmax of nintedanib following said administration is less than 5.0 ng / mL.126IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT28. The method of any one of claims 8-10, wherein the systemic plasma Cmax of nintedanib following said administration is less than 2.0 ng / mL.

29. The method of claim 8 or 9, wherein the systemic plasma Cmax of nintedanib following said administration is less than 1.0 ng / mL.

30. The method of claim 8, wherein the systemic plasma Cmax of nintedanib following said administration is less than 0.5 ng / mL.

31. The method of any one of claims 1 -30, wherein the median time to maximum plasma concentration (Tmax) of nintedanib following inhalation is within about 0.40 hours after the end of inhalation.

32. The method of claim 31, wherein the median Tmax is within about 0.17 to about 0.40 hours after the end of inhalation.

33. The method of any one of claims 1-32, wherein the nintedanib concentration in epithelial lining fluid (ELL) following said administration exceeds the IC50 of at least one target tyrosine kinase of nintedanib.

34. The method of claim 33, wherein the at least one target tyrosine kinase is selected from the group consisting of VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, PDGFR-a, and PDGLR-p.

35. The method of any one of claims 1-34, wherein the nintedanib concentration in ELL is detectable for at least 12 hours following a single inhaled dose.

36. The method of any one of claims 1-35, wherein the ELF Cmax of nintedanib following a single inhaled dose exceeds the ELF Cmax following a single 150 mg oral dose of nintedanib by at least 25 -fold.127IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT37. The method of any one of claims 1-35, wherein the ELF AUC0-12 of nintedanib following a single inhaled dose exceeds the ELF AUC0-12 following a single 150 mg oral dose of nintedanib by at least 25-fold.

38. The method of any one of claims 1-37, wherein the nintedanib concentration in bronchoalveolar lavage (BAL) fluid following a single inhaled dose exceeds the nintedanib concentration in BAL fluid following a single 150 mg oral dose of nintedanib by at least 9-fold.

39. The method of claim 38, wherein the geometric mean nintedanib concentration in BAL fluid following a single 2.0 mg inhaled dose is about 3.70 ng / mL.

40. The method of any one of claims 1-39, wherein the nintedanib is administered as a solution for inhalation.

41. The method of claim 40, wherein the solution is an aqueous solution.

42. The method of claim 40 or 41, wherein the solution is administered using a nebulizer.

43. The method of claim 42, wherein the nebulizer is a vibrating mesh nebulizer.

44. The method of claim 42 or 43, wherein the nebulizer is a PARI eFlow nebulizer.

45. The method of any one of claims 1-44, wherein the subject is aged 18 to 80 years.

46. The method of any one of claims 1-45, wherein the subject has an FEVi:FVC ratio of from about 0.70 to about 0.90.

47. The method of any one of claims 1-46, further comprising pretreating the subject with a bronchodilator prior to administering the nintedanib by inhalation.

48. The method of claim 47, wherein the bronchodilator is salbutamol.128IPTS / 200337643.1Atorney Docket No: AVY-003WO PATENT49. The method of claim 47 or 48, wherein the bronchodilator is administered within 30 minutes prior to the inhalation of nintedanib.129IPTS / 200337643.1

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