Method of treating fibrotic disease or condition or of interstitial lung disease using src kinase inhibitor

Abstract

To provide more effective therapies that safely and more reliably modify a course of different forms and stages of fibrotic diseases or conditions.SOLUTION: A method of treating a fibrotic disease or condition in a human patient comprises administering a therapeutically effective amount of an Src kinase inhibitor or its pharmaceutically acceptable salt to the human patient, wherein the fibrotic disease or condition is characterized by abnormal collagen deposition, or by persistent, debilitating abnormal formation of lesions or scars determined by high-resolution computed tomography (HRCT) or biopsy.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to certain Src kinase inhibitors or pharma- ceutically acceptable salts thereof and their use in the treatment of fibrosis and fibrotic conditions in warm-blooded animals, such as humans, such as idiopathic pulmonary fibrosis. The present disclosure also relates to the use of said Src kinase inhibitors or pharma- ceutically acceptable salts thereof, alone or in combination with at least one additional therapeutic agent, for the treatment of fibrosis and fibrotic conditions in warm-blooded animals, such as humans, such as interstitial lung diseases, such as idiopathic pulmonary fibrosis. [Background technology]

[0002] Remodeling is a normal response to tissue injury and inflammation and is observed in many tissues throughout the body. After resolution of inflammation and repair of tissue injury, the tissue generally returns to its original state. However, excessive uncontrolled tissue repair or failure to stop remodeling when it is no longer needed leads to conditions characterized by fibrosis. Fibrosis typically involves the accumulation of extracellular matrix components that occurs after trauma, inflammation, tissue repair, immune response, cellular hyperplasia or abnormal proliferation. Examples of tissue fibrosis include, but are not limited to: pulmonary fibrosis, renal fibrosis, myocardial fibrosis, cirrhosis and liver fibrosis, skin scars and keloids, adhesions, fibromatosis, atherosclerosis, and amyloidosis. Fibrosis often significantly impairs the normal function of affected organs, and many fibrotic conditions are actually life-threatening or severely disfiguring. Unfortunately, treatment options for these diseases are limited, and risky and expensive procedures such as organ transplantation are often the only available approach.

[0003] One example of a particularly severe fibrotic condition with high unmet clinical need is idiopathic pulmonary fibrosis (IPF). IPF is a chronic, intractable, and ultimately fatal disorder characterized by scarring (fibrosis) of the lung parenchyma. The disease causes debilitating cough, reduced lung function, fatigue, and dyspnea, and requires high levels of supplemental oxygen, limiting physical activity and dramatically reducing the patient's quality of life and independence over time. The median survival of patients with IPF ranges from 2.5 to 3.5 years, and most patients die from respiratory failure due to worsening disease (Non-Patent Document 1).

[0004] The disease pathology of IPF is poorly understood, and there are few drug treatment options (Non-Patent Document 2). In 2014, the FDA approved two novel antifibrotic agents, pirfenidone (Esbriet®) and nintedanib (OFEV®), for the treatment of IPF. The mechanism of action of pirfenidone has not been fully established. Nintedanib is a tyrosine kinase inhibitor that specifically targets PDGFRα and β receptor kinases, vascular endothelial growth factor receptor (VEGFR1-3) kinases, and fibroblast growth factor receptor (FGFR1-3) kinases. Clinical trials and real-world experience have demonstrated that, on average, both drugs slow the rate of decline in lung function, but responses are variable, compliance is difficult due to unfavorable safety, and neither drug halts the progressive decline in lung function. Furthermore, neither drug treats IPF, improves symptoms, or shows an overall survival benefit. Importantly, clinical experience with these two drugs shows that one year after the initiation of antifibrotic therapy, treatment is discontinued in nearly 40% of patients, with the most common reason for discontinuation being adverse gastrointestinal or skin side effects (Non-Patent Document 3 and Non-Patent Document 4). Furthermore, treatment with pirfenidone, which is indicated for mild to moderate IPF, requires very high and frequent dosing, which presents both safety and patient compliance issues. The recommended daily dose of pirfenidone from day 15 onwards is 2403 mg / day, and patients are required to take 9 Esbriet® capsules per day (three 267 mg capsules three times a day with meals).

[0005] Despite the US approval of Esbriet® and OFEV® in 2014, IPF remains a chronic, fatal disease that impairs patients' quality of life and drives up healthcare utilization and costs. Therefore, there remains an urgent need to develop more effective therapies that safely and more reliably alter the course of the various forms / stages of IPF to maintain / restore quality of life.

[0006] Saracatinib (ADZ0530) is a potent inhibitor of the Src family of tyrosine kinases, with higher selectivity than other protein kinases involved in signal transduction (Non-Patent Document 5 and Non-Patent Document 6). This compound and its preparation are disclosed in Patent Document 1, which relates to the use of quinazoline derivatives for the treatment of tumors. Saracatinib was initially developed for the treatment of cancer, but clinical trials have not shown sufficient efficacy for this indication. Saracatinib is also being investigated in Alzheimer's disease (Non-Patent Document 7).

[0007] Saracatinib has also been tested in the bleomycin mouse lung fibrosis model and found to affect myofibroblast differentiation (Non-Patent Document 8). The bleomycin mouse has the advantage of being very easy to perform and has some similarity to the histological changes seen in IPF. However, a large number of drugs have been tested in this disease model and found to show some activity, but relatively few have progressed to reproduce this activity in humans (Non-Patent Document 9). One reason for this is that this model has an acute inflammatory component that later becomes a fibrotic stage, which does not reproduce IPF and therefore has limited value in providing information on the profile of the activity of compounds in clinical use. Many anti-inflammatory mechanisms have been demonstrated to be effective in the bleomycin challenge model, but have not shown clinical utility (e.g., tralokinumab, lebrikizumab, SNY program of IL-4 / 13). As acknowledged by Hu et al., bleomycin treatment induces pulmonary fibrosis in rodents, and the resulting fibrosis shares many important features of human pulmonary fibrosis, but the bleomycin model does not recapitulate human IPF, and is a model of progressive fibrosis. Fibrosis lasts only 3-4 weeks after bleomycin instillation, after which it tends to spontaneously resolve, with the lungs returning to a near-normal state and minimal fibrosis. In addition to differing from the human disease by showing spontaneous resolution of fibrosis, the bleomycin model also lacks other cell types, processes, and structures that are critically associated with disease progression in humans, such as hyperplastic type II alveolar epithelial cells (AECs), bronchiolization, and honeycomb cysts. The gradual and reversible progression of IPF in patients is not recapitulated in the bleomycin model (Non-Patent Document 10), and thus the bleomycin model has significant limitations in understanding the progressive and irreversible nature of human IPF. This is particularly relevant when the clinical activity of compounds in different stages and / or different forms of progressive IPF is to be evaluated.

[0008] IPF is recognized as a heterogeneous disease that can be characterized by stage and severity. Published studies suggest that the clinical course of IPF varies, but that there are distinct subgroups of patients with, for example, more rapid progression of fibrosis (Non-Patent Document 11 and Non-Patent Document 12). Recently, Herazo-Maya et al. published a retrospective study identifying a peripheral blood transcriptome signature that predicts mortality and transplant-free survival in patients with IPF (Non-Patent Document 13). This signature correlates with FVC and is stable over time in the absence of treatment. Data from a small patient group suggest that high-risk profiles normalize in response to therapeutic intervention. In the local lung environment, Prasse et al. identified a transcriptome signature in bronchial lavage samples from IPF patients that is driven by airway basal cells and predicts high or low risk of mortality or lung transplantation (Non-Patent Document 14). These results provide important insights into biomarkers of disease progression and response to treatment and may suggest novel therapeutic targets. Achieving effective treatment in such diverse patient populations is challenging. Despite this heterogeneity, none of the current drugs halts the progressive loss of lung function, reverses the disease, or cures IPF. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 01 / 94341 Brochure [Non-patent literature]

[0010] [Non-Patent Document 1] Raghu G,et al.,Am J Respir Critical Care Med 2015;Vo.192,No.2:https: / / doi.org / 10.1164 / rccm.201506-1063ST [Non-Patent Document 2] Mason DP et al., Ann Thoracic Surgery 84:1121-8, 2007 [Non-licensed document 3] Corte T,et al.,Respiratory research 2015;16:116

Non-licensed Document 4

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Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

[0011] It is therefore clear that there remains an urgent need to develop more effective treatments that safely and more reliably alter the course of the various forms and stages of fibrotic diseases and conditions.

[0012] Surprisingly, the present disclosure shows that certain Src kinase inhibitors (such as saracatinib) act by different mechanisms of action and provide certain benefits over existing drugs for treating fibrotic conditions.For example, the present disclosure demonstrates that certain Src kinase inhibitors (such as saracatinib) target multiple drivers of fibrotic pathology, are particularly effective in treating and / or preventing fibrosis and fibrotic conditions, such as idiopathic pulmonary fibrosis (including progressive forms and / or various stages of idiopathic pulmonary fibrosis), and / or provide a safe and well-tolerated treatment for such conditions when compared with existing drugs such as pirfenidone and nintedanib.

[0013] Moreover, applicants have also discovered that certain Src kinase inhibitors (e.g., saracatinib) are surprisingly effective when used in combination with at least one additional therapeutic agent (e.g., an anti-fibrotic agent) for the treatment of fibrosis and fibrotic conditions (e.g., idiopathic pulmonary fibrosis) in warm-blooded animals such as humans. [Means for solving the problem]

[0014] The Src kinase inhibitors of the present disclosure are surprisingly effective in treating certain fibrosis and certain fibrotic conditions by a mechanism different from conventional treatment methods. In one embodiment, the fibrosis and fibrotic conditions are characterized by persistent, debilitating, abnormal formation of lesions or scars as determined by high resolution computed tomography (HRCT) or biopsy. In another embodiment, the fibrosis and fibrotic conditions are characterized by abnormal collagen deposition. Thus, the present disclosure relates to a method of treating such fibrosis and fibrotic conditions in a human patient, comprising administering to the human patient a therapeutically effective amount of a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof. In one embodiment, the Src kinase inhibitor is selective for inhibition of Src kinase at a safe and tolerated dose with clinically meaningful efficacy. In one embodiment, the fibrosis and fibrotic conditions are characterized by epithelial-mesenchymal transition (EMT). In one embodiment, the fibrosis and fibrotic conditions are characterized by increased expression of collagen-I, and / or MMP-9, and / or TIMP-1. In one embodiment, the fibrotic disease or condition is characterized by increased expression of sVEGF, and / or sIL-8, and / or sIL-6. In one embodiment, the fibrotic disease or condition is characterized by decreased expression of VCAM-1. In one embodiment, the fibrosis and fibrotic condition is characterized by extracellular matrix (ECM) formation.

[0015] The present disclosure also relates to a method of treating an interstitial lung disease characterized by airway basal cell-mediated lung remodeling in a human patient, comprising administering to the human patient a therapeutically effective amount of a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof. In one embodiment, the interstitial lung disease (ILD) is selected from idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-associated ILD, rheumatoid arthritis-related ILD, fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis, and other ILDs associated with occupational exposure.

[0016] The present disclosure also relates to a method of treating pulmonary fibrosis in a human patient, preferably characterized by airway basal cell-mediated lung remodeling, comprising administering to said human subject a therapeutically effective amount of a Src kinase inhibitor. In one embodiment, the pulmonary fibrosis is characterized by persistent, debilitating, abnormal formation of lesions or scars as determined by high-resolution computed tomography (HRCT) or biopsy. In one embodiment, the pulmonary fibrosis is characterized by epithelial-mesenchymal transition (EMT). In one embodiment, the pulmonary fibrosis is characterized by increased expression of collagen-I, and / or MMP-9, and / or TIMP-1. In one implementation, the pulmonary fibrosis is characterized by extracellular matrix (ECM) formation.

[0017] In another subject, the present disclosure relates to a method for treating fibrosis and fibrotic conditions in a human patient, comprising administering to the human patient a therapeutically effective amount of a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof in combination with at least one additional therapeutic agent. In one embodiment, the fibrosis or fibrotic condition is pulmonary fibrosis. In another embodiment, the fibrosis or fibrotic condition is interstitial lung disease (ILD). In another embodiment, the fibrosis or fibrotic condition is idiopathic pulmonary fibrosis (IPF). In one embodiment, the at least one additional therapeutic agent is an anti-fibrotic agent. In one embodiment, the interstitial lung disease (ILD) is selected from idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, ILD associated with connective tissue disease, ILD associated with rheumatoid arthritis, fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis, and other ILD associated with occupational exposure.

[0018] The present disclosure also relates to a method of treating fibrosis and fibrotic conditions described herein in a human patient by administering to a patient in need thereof a pharmaceutical composition comprising a Src kinase inhibitor together with a pharma- ceutical suitable carrier.

[0019] The present disclosure further relates to pharmaceutical combinations for the treatment of fibrotic diseases and conditions comprising a Src kinase inhibitor in combination with at least one additional therapeutic agent.

[0020] Hereinafter, embodiments of the present disclosure will be further described with reference to the accompanying drawings. [Brief description of the drawings]

[0021] [Figure 1] 1 shows hydroxyproline levels in mice following bleomycin (Bleo)-induced lung injury and fibrosis following treatment with pirfenidone (PIR) at 200 mg / kg BID, nintedanib (NIN) at 30 mg / kg BID, saracatinib at 1 (0530-1), 3 (0530-3), or 10 (0530-10) mg / kg BID. [Diagram 2] % maximum αSMA levels in human lung fibroblasts treated with saracatinib (circles), nintedanib (triangles), or pirfenidone (squares). [Diagram 3] 1 shows the mean IL-6 levels in human lung fibroblasts treated with saracatinib (circles), nintedanib (triangles), or pirfenidone (squares). [Figure 4] Organoid formation of airway basal cells (ABC) treated with saracatinib, pirfenidone, or nintedanib. [Diagram 5] Higher magnification images of organoid formation in ABC treated with saracatinib (SARA), pirfenidone (Prif), or nintedanib (Nin) at the indicated concentrations are shown. [Figure 6] Optical density / well and organoid counts / well for ABC treated with saracatinib, pirfenidone, or nintedanib are shown. [Figure 7] 1 shows DiscoverX assay results showing relative protein expression (log ratio of compound / vehicle control) for saracatinib (3.3 μM). [Figure 8]1 shows DiscoverX assay results showing relative protein expression (log ratio of compound / vehicle control) for nintedanib (1.1 μM). [Figure 9] 4 shows DiscoverX assay results showing relative protein expression (log ratio of compound / vehicle control) for the combination of saracatinib and nintedanib compared to saracatinib alone and nintedanib alone. [Figure 10] Kinase trees for Saracatinib (Sara) and Nintedanib (Ninte) are shown, where each circle represents a kinase inhibited by the respective molecule and the size of the circle represents the potency of this inhibition. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] definition As used herein, the phrase "effective amount" refers to an amount of a Src kinase inhibitor, or an amount of a composition comprising a Src kinase inhibitor, sufficient to significantly and positively alter the symptoms and / or condition being treated (e.g., produce a positive clinical response). The effective amount of the active ingredient used in the pharmaceutical composition will vary within the knowledge and expertise of the attending physician depending on the particular condition being treated, the severity of that condition, the duration of treatment, the nature of any concurrent therapy, the particular active ingredient being employed, the particular pharma- ceutically acceptable excipients / carriers utilized, and similar factors.

[0023] As used herein, the term "pharmacologically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, consistent with a reasonable benefit / risk ratio.

[0024] A reference to a particular value includes at least that particular value, unless the context clearly dictates otherwise. When a range of values ​​is expressed, another embodiment includes from the one particular value and / or to the other particular value. Further, references to values ​​stated in a range include each and every value within that range. All ranges are inclusive and combinable.

[0025] It should be understood that certain features of the disclosed Src kinase inhibitors, compositions, and methods, which are described herein in the context of separate embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed Src kinase inhibitors, compositions, and methods, which are described for brevity in the context of a single embodiment, may also be provided separately or in any subcombination.

[0026] As used herein, the singular forms "a," "an," and "the" include plurals.

[0027] When values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment.

[0028] The term "about" is used when referring to a numerical range, cutoff, or specific value to indicate that the recited value may vary by up to 10% from the recited value. Many of the numerical values ​​used herein are experimentally determined, and therefore, those skilled in the art should understand that such determinations may, and often will, vary between different experiments. The values ​​used herein should not be considered unduly limited by this inherent variation. Thus, the term "about" is used to encompass a variation of ±10% or less, a variation of ±5% or less, a variation of ±1% or less, a variation of ±0.5% or less, or a variation of ±0.1% or less from the specified value.

[0029] As used herein, "treating" and similar terms refer to: reducing the severity and / or frequency of a symptom, eliminating a symptom and / or the underlying cause of said symptom, reducing the frequency or likelihood of a symptom and / or its underlying cause, delaying, preventing, and / or slowing the progression of a fibrotic disease such as IPF, and ameliorating or repairing the damage caused directly or indirectly by a fibrotic disease such as IPF. As used herein, treating is intended to encompass prophylactic and therapeutic treatments.

[0030] Src kinase inhibitors The present disclosure demonstrates that certain Src kinase inhibitors offer particular advantages over existing pharmaceutical agents for the treatment of fibrosis.

[0031] In one embodiment, the Src kinase inhibitor is a selective Src kinase inhibitor, i.e., the Src kinase inhibitor is selective for Src family kinases over other protein kinases involved in signal transduction. Suitably, the Src family includes c-Src, c-Yes, Lck, Lyn, and Fyn, and in one particular embodiment, the Src kinase inhibitor is selective for c-Src kinase, c-Yes kinase, Lck kinase, Lyn kinase, and c-Fyn kinase. In one embodiment, the Src kinase inhibitor has an IC50 or higher for each of c-Src kinase, c-Yes kinase, Lck kinase, Lyn kinase, and c-Fyn kinase. 50 In one embodiment, the Src kinase inhibitor has an IC50 or less for PDGFRα and / or PDGFRβ, such as 100 nM or less, e.g., 75, 50, 40, 30, 20, 15, 12, or 10 nM or less. 50 The assay is greater than 1000 nM.

[0032] In one embodiment, the Src kinase inhibitor is selective for c-Src kinase and has an IC 50In a further embodiment, the Src kinase inhibitor is selective for c-Yes kinase and has an IC50 for c-Yes kinase of less than 100 nM, e.g., less than 75, 50, 40, 30, 20, 15, 12, 10, 8, 6, 4, or about 3 nM. 50 In a further embodiment, the Src kinase inhibitor is selective for Lck kinase and has an IC50 for Lck kinase of 100 nM or less, e.g., 75, 50, 40, 30, 20, 15, 12, 10, 8, 6, or 4 nM or less. 50 In a further embodiment, the Src kinase inhibitor is selective for Lyn kinase and has an IC50 for Lyn kinase of 100 nM or less, e.g., 75, 50, 40, 30, 20, 12, 10, 6, or 4 nM or less. 50 In a further embodiment, the Src kinase inhibitor is selective for c-Fyn kinase and has an IC50 for c-Fyn kinase of 100 nM or less, e.g., 75, 50, 40, 30, 20, 15, 12, 10, 8, 6, or 5 nM or less. 50 In a further embodiment, the Src kinase inhibitor has an IC50 for EGFR of 100 nM or less, e.g., 75, 50, 40, 30, 20, 15, 12, or 10 or less. 50 The assay is at or below 200 nM, for example at or below 150, 100, 70, or about 66 nM.

[0033] In one embodiment, the Src kinase inhibitor is an IC 50 The assay is at 5000 nM or greater, for example 6000, 7000, 10000 nM or greater.

[0034] Tyrosine kinase inhibitors (e.g., VEGFR inhibitors and PDGFR inhibitors) are associated with toxic effects on various organs (e.g., heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract, and nervous system). Thus, the lack of activity against PDGFR may favorably contribute to the good tolerability of Src kinase inhibitors, which may result in an improved safety profile and / or improved patient compliance (Li et al. Eur J Clin Pharmacol. 2017 Oct; 73(10): 1209-1217).

[0035] In one embodiment, the Src kinase inhibitor is saracatinib or a pharma- ceutically acceptable salt thereof. Figure 10 shows a kinase tree for saracatinib and nintedanib, illustrating the superior selectivity of saracatinib. Saracatinib has the chemical name N-(5-chlorobenzo[d][1,3]dioxol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine and is represented by the following: [ka] It has a structure shown below.

[0036] In one embodiment, saracatinib is in the form of a fumarate salt. In another embodiment, saracatinib is in the form of a difumarate salt. Further details of saracatinib and its analogs (e.g., their preparations) are described in International Publication No. WO 01 / 94341, published on December 13, 2001, entitled "Quinazoline Derivatives for the Treatment of Tumors"; and International Publication No. WO 2006 / 064217, published on June 22, 2006, entitled "Chemical Process", the contents of both of which are incorporated herein by reference in their entirety. In another embodiment, the Src kinase inhibitor is selected from dasatinib, bosutinib, or imatinib, or a pharma- ceutically acceptable salt thereof.

[0037] Suitable pharma- ceutically acceptable salts of the present Src kinase inhibitors are, for example, acid addition salts or base salts.Such salts are physiologically non-toxic.

[0038] Examples of pharma- ceutically acceptable acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexylsulfamate, diethylenediamine, ethanesulfonate, formate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-hydroxyethylsulfonate ... Naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate.

[0039] Examples of pharma-ceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as aluminum, calcium, and magnesium salts, salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, etc. Similarly, basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides such as methyl, ethyl, propyl, and butyl halides, dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, diamyl sulfate, long chain halides such as decyl, lauryl, myristyl, and stearyl halides, aryl alkyl halides such as benzyl bromide, and the like.

[0040] Fibrosis "Fibrosis" or "fibrotic disease or condition" as used herein refers to the accumulation of extracellular matrix components following trauma, inflammation, tissue repair, immune response, cellular hyperplasia, and abnormal proliferation. Examples of tissue fibrosis include, but are not limited to, pulmonary fibrosis, renal fibrosis, myocardial fibrosis, cirrhosis and liver fibrosis, skin scars and keloids, adhesions, fibromatosis, atherosclerosis, and amyloidosis.

[0041] In one aspect, a method of treating fibrosis is provided, comprising administering to a human patient a therapeutically effective amount of a Src kinase inhibitor as described herein, or a pharma- ceutically acceptable salt thereof. In another aspect, a Src kinase inhibitor as described herein, or a pharma- ceutically acceptable salt thereof, for use in treating fibrosis in a human patient is provided. In one embodiment, the Src kinase inhibitor exhibits clinically meaningful efficacy at a safe and tolerated dose.

[0042] Suitably, fibrosis and fibrotic conditions are characterized by persistent, debilitating, abnormal formation of lesions or scars as determined by high resolution computed tomography (HRCT) or biopsy, hi another embodiment, fibrosis and fibrotic conditions are characterized by abnormal collagen deposition.

[0043] In one embodiment, the fibrosis and fibrotic condition is characterized by epithelial-mesenchymal transition (EMT). In another embodiment, the fibrosis and fibrotic condition is characterized by increased expression of collagen-I, and / or MMP-9, and / or TIMP-1 in a human patient. In one embodiment, the fibrosis and fibrotic condition is characterized by increased expression of collagen-I, MMP-9, and TIMP-1 in a human patient. In one embodiment, the fibrosis and fibrotic condition is characterized by increased expression of collagen-I and MMP-9 in a human patient. In one embodiment, the fibrosis and fibrotic condition is characterized by increased expression of collagen-I and TIMP-1 in a human patient. In one embodiment, the fibrosis and fibrotic condition is characterized by increased expression of MMP-9 and TIMP-1 in a human patient. In another embodiment, the fibrosis and fibrotic condition is characterized by extracellular matrix (ECM) formation.

[0044] In some embodiments, disclosed herein are methods of reducing fibrosis in a tissue, comprising contacting a fibrotic cell or tissue with a Src kinase inhibitor disclosed herein in an amount sufficient to reduce or inhibit the fibrosis, wherein the fibrosis is characterized by increased expression of collagen-I, and / or MMP-9, and / or TIMP-1. In some embodiments, fibrosis characterized by increased expression of collagen-I, and / or MMP-9, and / or TIMP-1 comprises a fibrotic condition.

[0045] In some embodiments, reducing fibrosis or treating a fibrotic condition includes reducing or inhibiting one or more of the following: formation or deposition of extracellular matrix proteins; the number of pro-fibrotic cell types (e.g., the number of fibroblasts or immune cells); cellular collagen or hydroxyproline content within a fibrotic lesion; the expression or activity of fibrogenic proteins; or reducing fibrosis associated with an inflammatory response.

[0046] In some embodiments, the fibrotic condition is primary fibrosis. In some embodiments, the fibrotic condition is idiopathic. In some embodiments, the fibrotic condition is associated with (e.g., secondary to) a disease (e.g., an infectious disease, an inflammatory disease, an autoimmune disease, a malignant or cancerous disease, and / or a connective disease); a toxin; an insult (e.g., an environmental hazard (e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), smoking, a wound); a medical procedure (e.g., a surgical incision, chemotherapy, or radiation), or a combination thereof.

[0047] In some embodiments, the fibrotic condition is a pulmonary fibrotic condition, a liver fibrotic condition, a cardiac or vascular system fibrotic condition, a renal fibrotic condition, a skin fibrotic condition, a gastrointestinal fibrotic condition, a bone marrow or hematopoietic tissue fibrotic condition, a nervous system fibrotic condition, a joint fibrotic condition, or a combination thereof.

[0048] In one embodiment, a method of treating a fibrotic condition is provided, the treatment comprising administering to a human patient a therapeutically effective amount of a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof, the fibrotic condition being a pulmonary fibrotic condition, a liver fibrotic condition, a cardiac or vascular fibrotic condition, a renal fibrotic condition, a skin fibrotic condition, a gastrointestinal fibrotic condition, a bone marrow or hematopoietic tissue fibrotic condition, a nervous system fibrotic condition, a joint fibrotic condition, or a combination thereof. In another embodiment, a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof for use in treating a fibrotic condition in a human patient is provided, the fibrotic condition being a pulmonary fibrotic condition, a liver fibrotic condition, a cardiac or vascular fibrotic condition, a renal fibrotic condition, a skin fibrotic condition, a gastrointestinal fibrotic condition, a bone marrow or hematopoietic tissue fibrotic condition, a nervous system fibrotic condition, a joint fibrotic condition, or a combination thereof.

[0049] In some embodiments, the fibrotic condition affects a tissue selected from one or more of muscle, tendon, cartilage, skin (e.g., the epidermis or endothelium of the skin), cardiac tissue, vascular tissue (e.g., arteries, veins), pancreatic tissue, lung tissue, liver tissue, kidney tissue, uterine tissue, ovarian tissue, nervous tissue, testicular tissue, peritoneal tissue, colon, small intestine, biliary tract, intestine, bone marrow, or hematopoietic tissue.

[0050] In some embodiments, the fibrotic condition is a pulmonary fibrotic condition. In some embodiments, the pulmonary fibrotic condition is selected from one or more of the following: pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), common interstitial pneumonia (UIP), interstitial lung disease, fibrosing alveolitis of unknown etiology (CFA), bronchiolitis obliterans, or bronchiectasis. In some embodiments, the pulmonary fibrosis is secondary to a disease, a toxin, an insult, a medical procedure, or a combination thereof. In some embodiments, the pulmonary fibrosis is associated with one or more of the following: a disease process, such as asbestosis and silicosis; occupational hazards; environmental pollutants; smoking; an autoimmune connective tissue disorder (e.g., rheumatoid arthritis, scleroderma, and systemic lupus erythematosus (SLE)); a connective tissue disorder, such as sarcoidosis; an infectious disease, such as an infection, particularly a chronic infection; a medical treatment, such as, but not limited to, radiation therapy, and drug therapy, such as chemotherapy (e.g., treatment with bleomycin, methotrexate, amiodarone, busulfan, and / or nitrofurantoin). In some embodiments, the pulmonary fibrotic condition treated by the methods of the present disclosure is associated with (e.g., secondary to) a cancer treatment, such as treatment for cancer (e.g., squamous cell carcinoma with bleomycin, testicular tumors, Hodgkin's disease).

[0051] In some embodiments, the fibrotic condition is a hepatic fibrotic condition. In certain embodiments, the hepatic fibrotic condition is selected from one or more of the following: fatty liver disease, fatty liver (e.g., nonalcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC)), liver cirrhosis, alcohol-induced liver fibrosis, bile duct injury, bile duct fibrosis, cholestasis, or cholangiopathy. In some embodiments, hepatic or liver fibrosis includes, but is not limited to, alcoholism, viral infection, such as hepatitis (e.g., hepatitis C, hepatitis B, or hepatitis D), autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), progressive massive fibrosis, liver fibrosis associated with exposure to toxins or irritants (e.g., alcohol, pharmaceuticals, and environmental toxins).

[0052] In some embodiments, the fibrotic condition is a cardiac fibrotic condition. In certain embodiments, the cardiac fibrotic condition is myocardial fibrosis (e.g., myocardial fibrosis associated with radiation myocarditis, complications of surgery (e.g., postoperative fibrosis of the myocardium), infectious disease (e.g., Chagas disease, bacterial myocarditis, trichinellosis, or fungal myocarditis); granuloma, metabolic storage disorder (e.g., cardiomyopathy, hemochromatosis); developmental disorder (e.g., endocardial fibroelastosis); arteriosclerosis, or exposure to toxins or irritants (e.g., drug-induced cardiomyopathy, drug-induced cardiotoxicity, alcoholic cardiomyopathy, cobalt toxin or exposure). In some embodiments, the myocardial fibrosis is associated with inflammatory disorders of cardiac tissue (e.g., myocardial sarcoidosis).

[0053] In some embodiments, the fibrotic condition is a renal fibrotic condition. In some embodiments, the renal fibrotic condition is selected from one or more of the following: renal fibrosis (e.g., chronic renal fibrosis), nephropathy with injury / fibrosis (e.g., chronic nephropathy with diabetes (e.g., diabetic nephropathy)), lupus, renal scleroderma, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathyrenal fibrosis with human chronic kidney disease (CKD), chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephropathy (PGN), endothelial / thrombotic microangiopathy injury, HIV-associated nephropathy, liver cirrhosis, or fibrosis associated with exposure to toxins, irritants, or chemotherapeutic agents.

[0054] In some embodiments, the fibrotic condition is a fibrotic condition of the skin. In some embodiments, the fibrotic condition of the skin is selected from one or more of the following: dermal fibrosis, scleroderma, nephrogenic systemic fibrosis (e.g., nephrogenic systemic fibrosis occurring after exposure to gadolinium, which is frequently used as a contrast agent for MRI in patients with severe renal failure), scarring, and keloids.

[0055] In some embodiments, the fibrotic condition is a fibrotic condition of the gastrointestinal tract, which is selected from one or more of: fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with anterior gut inflammatory injury, such as Barrett's esophagus and chronic gastritis, and / or fibrosis associated with posterior gut inflammatory injury, such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohn's disease.

[0056] In some embodiments, the fibrotic condition is an adhesion, hi some embodiments, the adhesion is selected from one or more of the following: abdominal adhesion, peritoneal adhesion, pelvic adhesion, pericardial adhesion, epidural adhesion, peritendinous capsulitis, or adhesive capsulitis.

[0057] In some embodiments, the fibrotic condition is an ocular fibrotic condition, in some embodiments, the ocular fibrotic condition includes anterior ocular diseases (e.g., glaucoma and corneal opacities), in some embodiments, the ocular fibrotic condition includes posterior ocular diseases (e.g., age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and neovascular glaucoma), and in some embodiments, the ocular fibrotic condition results from fibrosis following ocular surgery.

[0058] In some embodiments, the fibrotic condition is a fibrotic condition of bone marrow or hematopoietic tissue. In some embodiments, the fibrotic condition of the bone marrow is an essential feature of a chronic myeloproliferative disorder of the bone marrow, such as primary myelofibrosis (also referred to herein as idiopathic myeloid metaplasia or chronic idiopathic myelofibrosis). In some embodiments, the fibrosis of the bone marrow is associated with (e.g., secondary to) a malignant condition or a condition caused by a clonal proliferative disorder. In some embodiments, the myelofibrosis is associated with a hematological disorder (e.g., a hematological disorder selected from one or more of polycythemia vera, essential thrombocythemia, myelodysplasia, hairy cell leukemia, lymphoma (e.g., Hodgkin's lymphoma or non-Hodgkin's lymphoma), multiple myeloma, or chronic myelogenous leukemia (CML)). In some embodiments, the myelofibrosis is associated with (e.g., secondary to) a non-blood disorder (e.g., a non-blood disorder selected from solid tumor metastasis to the bone marrow, an autoimmune disorder (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disorder, or polymyositis), an infection (e.g., tuberculosis), or secondary hyperparathyroidism associated with vitamin D deficiency).

[0059] In some embodiments, the fibrotic condition is a fibrotic condition of the joint. In some embodiments, the fibrotic condition of the joint is arthrofibrosis. In some embodiments, the fibrotic condition of the joint occurs in the knee, hip, ankle, ankle, shoulder, elbow, wrist, hand, spine, or a combination thereof. In some embodiments, arthrofibrosis occurs after total knee replacement or even after partial knee replacement.

[0060] In some embodiments, the fibrosis is associated with graft-versus-host disease (GVHD). In some embodiments, the fibrosis is associated with scleroderma GVHD, chronic lung GVHD, or chronic liver GVHD. In some embodiments, the fibrosis is fibrosis of the liver, lung, pancreas, kidney, bone marrow, heart, skin, intestine, or joints. In some embodiments, the fibrosis is fibrosis of the liver. In some embodiments, the fibrosis is fibrosis of the lung. In some embodiments, the fibrosis is fibrosis of the pancreas. In some embodiments, the patient has cirrhosis of the liver, chronic pancreatitis, cystic fibrosis, or cancer. In some embodiments, the cancer is a solid tumor cancer.

[0061] Suitably, the fibrotic condition characterised by increased expression of ECM, or collagen I, MMP-9 and / or TIMP-1, or EMT in a human patient is liver fibrosis, dilated cardiomyopathy, chronic hypoxia, interstitial lung disease, or idiopathic pulmonary fibrosis.

[0062] Interstitial lung disease and idiopathic pulmonary fibrosis In one embodiment, the fibrotic condition is interstitial lung disease (ILD). In one embodiment, the fibrotic condition is slowly fibrotic interstitial lung disease. In another embodiment, the fibrotic condition is idiopathic pulmonary fibrosis (IPF). In one particular embodiment, the fibrotic condition is progressive IPF. Progressive IPF can be characterized in terms of the rate of disease progression. For example, patients with rapidly progressive IPF and patients with slowly progressive IPF can be differentiated. Slowly progressive IPF can be defined as IPF with a slowly progressive decline in lung function and worsening dyspnea. In many cases, patients with slowly progressive IPF experience a long duration of symptoms before diagnosis and a slowly progressive clinical course (Martinez FX et al., Ann Intern Med 2005;142:963-967). Slowly progressive IPF can lead to death within a few years of diagnosis. Rapidly progressive IPF involves patients who demonstrate a more rapidly progressive clinical course with a shorter duration of symptoms before diagnosis and progression to death.

[0063] In addition to IPF, other progressive fibrosing interstitial lung diseases include, for example, idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, ILD associated with connective tissue disease (e.g., rheumatoid arthritis-associated ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis, and ILDs associated with other occupational exposures. These diseases share certain clinical features with IPF, including: reduced respiratory function; limited treatment options; premature mortality; and severely impaired quality of life. Within this group of ILDs, progressive fibrosis is a key feature strongly associated with morbidity and mortality.

[0064] In one embodiment, a method of treating interstitial lung disease (ILD) is provided, comprising administering to a human patient a therapeutically effective amount of a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof. In another aspect, a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof is provided for use in treating interstitial lung disease in a human patient. In one embodiment, the interstitial lung disease is IPF. In another embodiment, the interstitial lung disease is selected from idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, ILD associated with connective tissue disease (e.g., rheumatoid arthritis-associated ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis, and other ILDs associated with occupational exposure.

[0065] Those skilled in the art will be aware that pulmonary function tests can provide some indications of the degree and severity of IPF. For example, forced vital capacity (FVC), which is a measurement of lung function in liters and represents the amount of air in the lungs that can be exhaled after a full inhalation, can provide an indication of the severity of a patient's IPF. FVC is measured in a test known as spirometry, which is a specific type of pulmonary function test. The pulmonary diffusion capacity for carbon monoxide (DLCO), which represents the degree of oxygen passing from the air sacs of the lungs into the blood, also provides an indication of the degree and severity of a patient's IPF. Both FVC and DLCO can be expressed as a percentage of the expected normal value for a person of the same sex, age, and height. Those skilled in the art will be aware of how to determine and use the FVC and DLCO parameters.

[0066] In one embodiment, progressive IPF is characterized by an FVC threshold of 20%-80% predicted (e.g., 50-75%, 50-65%, 50-60%, or 50-55% predicted). In one embodiment, progressive IPF is characterized by a DLCO of 20-70% predicted (e.g., 35-55%, 35-45%, or 35-40% predicted).

[0067] IPF disease severity can be classified as mild, moderate, or severe. There is no standard definition of mild, moderate, or severe IPF, but clinical trials generally employ a FVC threshold of 50-55% predicted and a DLCO threshold of 35-40% predicted to distinguish patients with mild to moderate disease from those with severe disease (M Kolb et al., Eur. Respir Rev 2014;23:220-224).

[0068] In one embodiment, the fibrotic condition is mild, moderate, or mild-moderate IPF. In one embodiment, mild-moderate IPF is characterized by an FVC threshold of 50% or greater than predicted (e.g., 50 and 75% or 50-55% predicted) and / or a DLCO threshold of 35% or greater than predicted (e.g., 20 and 70% or 35-40% predicted).

[0069] In one embodiment, the fibrotic condition is severe IPF. In one embodiment, severe IPF is characterized by an FVC threshold of less than 50% predicted (e.g., less than 45%, 40%, 35%, 30%, 25%, 20%, 10%, or 5% predicted) and / or a DLCO threshold of less than 35% predicted (e.g., less than 30%, 25%, 20%, 15%, 10%, or 5% predicted).

[0070] In one embodiment, progressive IPF is characterized by an annual rate of decline as measured by FVC of 0.3 L or less (e.g., 0.25 L, 0.15 L, or 0.12 L or less). Preferably, the annual rate of decline as measured by FVC is between 0.1 L and 0.3 L, for example, between 0.13 L and 0.21 L. Preferably, the annual rate of decline as measured by FVC is 0.05 L or more, for example, 0.08 L, 0.10 L, or 0.13 L or more. In one embodiment, progressive IPF is characterized by a rate of decline in FVC of 1% or more (e.g., 2%, 4%, 6%, 8%, 10%, 12%, 14%, 16%, 18%, or 20% or more). Preferably, the rate of decline in FVC is 20% or less, for example, 18%, 16%, 14%, 12%, 10%, 8%, 6%, 4%, 2%, or 1% or less.Preferably, the rate of decline in FVC is about 5%, for example, about 10%, about 15%, or about 20%.

[0071] In one embodiment, progressive IPF is characterized by a decrease in DLCO of 1% or more (e.g., 2%, 4%, 6%, 8%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22%, or 25% or more). Preferably, the decrease in DLCO is 25% or less, e.g., 22%, 20%, 18%, 16%, 15%, 14%, 12%, 10%, 8%, 6%, 4%, 2%, or 1% or less. Preferably, the decrease in DLCO is about 5%, e.g., about 10%, e.g., about 15%, e.g., about 20%, e.g., about 25%.

[0072] In one embodiment, the fibrotic condition is slowly progressive IPF. In one embodiment, slowly progressive IPF is characterized by a rate of decline in FVC of 1% or more (e.g., 2%, 4%, 6%, or 8% or more). In one embodiment, slowly progressive IPF is characterized by a rate of decline in FVC of about 5% (e.g., about 10%). In one embodiment, slowly progressive IPF is characterized by a rate of decline in DLCO of 1% or more (e.g., 2%, 4%, 6%, 8%, 10%, 12%, or 14% or more). In one embodiment, rapidly progressive IPF is characterized by a rate of decline in DLCO of about 5% (e.g., about 10%).

[0073] In one embodiment, the fibrotic condition is rapidly progressive IPF. In one embodiment, rapidly progressive IPF is characterized by a rate of decline in FVC of 10% or more (e.g., 12%, 14%, 16%, 18%, or 20% or more). In one embodiment, rapidly progressive IPF is characterized by a rate of decline in FVC of about 15% (e.g., about 20%). In one embodiment, rapidly progressive IPF is characterized by a rate of decline in DLCO of 15% or more (e.g., 16%, 18%, 20%, 22%, or 25% or more). In one embodiment, rapidly progressive IPF is characterized by a rate of decline in DLCO of about 15% (e.g., about 20% or 25%).

[0074] It is understood that IPF can be mild, moderate, mild-moderate, or severe, and can be rapidly progressive or slowly progressive. Rapidly progressive and slowly progressive relate to the rate of progression of IPF, and mild, moderate, mild-moderate, and severe relate to the level to which IPF has progressed. In one embodiment, the fibrotic condition is rapidly progressive IPF, characterized by mild, moderate, mild-moderate, or severe IPF. In one embodiment, the fibrotic condition is slowly progressive IPF, characterized by mild, moderate, mild-moderate, or severe IPF.

[0075] In one embodiment, a method of treating rapidly progressive and / or slowly progressive IPF is provided, wherein the IPF is characterized as mild, moderate, mild-moderate, or severe, comprising administering to a human patient a therapeutically effective amount of a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof. In another aspect, a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof for use in treating rapidly progressive and / or slowly progressive IPF is provided, wherein the IPF is characterized as mild, moderate, mild-moderate, or severe in a human patient.

[0076] Safety Profile In one embodiment, the Src kinase inhibitor has a well-tolerated safety profile.That is, the Src kinase inhibitor can be used at a dose that elicits efficacy while demonstrating safety and tolerability.In one embodiment, when used to treat IPF, the Src kinase inhibitor (e.g., saracatinib) shows the same or improved efficacy with fewer adverse reactions or discontinuations compared to pirfenidone or nintedanib.

[0077] Adverse reactions are classified into various frequency groups by System Organ Class (SOC): Very common refers to an incidence of ≧1 / 10, common refers to ≧1 / 100 to <1 / 10, uncommon refers to ≧1 / 1000 to <1 / 100, and rare refers to ≧1 / 10000 to <1 / 1000. In one embodiment, the number of adverse reactions associated with Src kinase inhibitors are classified as common, uncommon, and / or rare.

[0078] In one embodiment, the adverse reaction is: infection; invasion; blood disorders; lymphatic system disorders; immune system disorders; metabolic disorders; nutritional disorders; psychiatric disorders; nervous system disorders; vascular disorders; respiratory disorders; thoracic disorders; mediastinal disorders; gastrointestinal disorders; hepatobiliary disorders; skin disorders; subcutaneous tissue disorders; musculoskeletal disorders; connective tissue disorders; systemic disorders; administration site conditions; injury, poisoning; and / or procedural complications.

[0079] In one embodiment, a number of gastrointestinal adverse reactions associated with Src kinase inhibitors are classified as common, uncommon, or rare. Preferably, the gastrointestinal adverse reactions are: diarrhea, nausea, abdominal pain, dyspepsia, gastroesophageal reflux disease, vomiting, abdominal bloating, abdominal discomfort, gastric discomfort, gastritis, constipation, and / or flatulence.

[0080] In one embodiment, a number of hepatobiliary disorders associated with Src kinase inhibitors are classified as common, uncommon, or rare. Preferably, the hepatobiliary disorder results in elevated levels of liver enzymes in a human patient.

[0081] In one embodiment, a number of nutritional disorders associated with Src kinase inhibitors are classified as common, uncommon, or rare. Preferably, the nutritional disorder is anorexia.

[0082] In one embodiment, a number of skin and / or subcutaneous tissue disorders associated with Src kinase inhibitors are classified as common, uncommon, or rare. Preferably, the skin disorder is a photosensitivity reaction and / or a rash.

[0083] In one embodiment, a number of systemic disorders associated with Src kinase inhibitors are classified as common, uncommon, or rare. Preferably, the systemic disorder is fatigue.

[0084] In one embodiment, the Src kinase inhibitor has an improved safety profile relative to nintedanib and / or pirfenidone. In one embodiment, the Src kinase inhibitor has a lower incidence and / or severity of adverse reactions compared to nintedanib and / or pirfenidone. In one embodiment, the Src kinase inhibitor has a lower incidence and / or severity of gastrointestinal adverse reactions compared to nintedanib and / or pirfenidone. In one embodiment, the Src kinase inhibitor has a lower incidence and / or severity of diarrhea, nausea, abdominal pain, dyspepsia, gastroesophageal reflux disease, vomiting, abdominal bloating, abdominal discomfort, stomach discomfort, gastritis, constipation, and / or flatulence compared to nintedanib and / or pirfenidone.

[0085] In one embodiment, administration of a therapeutically effective amount of a Src kinase inhibitor, or a pharma- ceutically acceptable salt thereof, to a human patient increases the overall survival and / or progression-free survival of the human patient.

[0086] In one embodiment, administration of a therapeutically effective amount of a Src kinase inhibitor, or a pharma- ceutically acceptable salt thereof, to a human patient ameliorates, prevents, and / or maintains symptoms of fibrosis, preferably symptoms of IPF, including cough, reduced lung function, fatigue, and shortness of breath.

[0087] Pharmaceutical Compositions According to a further aspect of the present disclosure there is provided a pharmaceutical composition comprising a Src kinase inhibitor as defined herein above, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable diluent, excipient or carrier for use in the treatment of fibrosis as defined herein.

[0088] The compositions of the present disclosure may be in a form suitable for oral use (e.g., tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), in a form suitable for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., finely divided powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., finely divided powders), or in a form suitable for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular administration, or suppositories for rectal administration).

[0089] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings and / or preservatives.

[0090] The amount of active ingredient to be combined with one or more pharma- ceutically acceptable diluents, excipients to produce a single dosage form will necessarily vary depending on the host being treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g (more preferably, 0.5 to 200 mg, e.g., 1 to 150 mg, 75 to 150 mg, 90 to 135 mg, 100 to 125 mg, e.g., 100 mg, e.g., about 125 mg) of active compound and an appropriate and convenient amount of excipient. The size of a therapeutic or prophylactic dose of a Src kinase inhibitor will necessarily vary according to the nature and severity of the condition, the age, sex, and route of administration of the animal or patient, in accordance with known principles of medicine.

[0091] Dosing regimen In the use of Src kinase inhibitors for therapeutic or prophylactic purposes, the Src kinase inhibitor will generally be administered such that a daily dose is administered within the range of, for example, 0.1 mg / kg to 75 mg / kg (body weight), administered in divided doses if necessary. Generally, lower doses will be administered when parenteral routes are used. Thus, for example, when administered intravenously, a dose within the range of, for example, 0.1 mg / kg to 30 mg / kg (body weight) will generally be used. Similarly, when administered by inhalation, a dose within the range of, for example, 0.05 mg / kg to 25 mg / kg (body weight) will be used. In one embodiment, the Src kinase inhibitor, such as saracatinib, is administered by oral administration, for example in the form of a tablet or capsule.

[0092] In one embodiment, the therapeutically effective amount of the Src kinase inhibitor is administered once a day, twice a day, or three times a day.Preferably, the therapeutically effective amount is administered once a day.Advantageously, the therapeutically effective amount is administered once a day for at least two consecutive days, preferably for at least four weeks, preferably for at least fourteen weeks, preferably for at least twenty-six weeks, preferably for at least fifty-two weeks, preferably for at least two years, or longer.

[0093] The appropriate dosage can be determined by referring to the severity of the disease and the size of the subject. Typical dosages are in the range of 0.01 mg to 500 mg (e.g., 0.1 to 175 mg, e.g., 1 to 125 mg) per human dose administered at least once a day (e.g., once or twice a day). For example, the dosage of Src kinase inhibitors such as saracatinib can be 100 mg, 125 mg, or up to 250 mg per day.

[0094] In one embodiment, the therapeutically effective amount of the Src kinase inhibitor is 5-500 mg per day, preferably 10-400 mg per day, preferably 20-300 mg per day, preferably 30-200 mg per day, preferably 75-150 mg per day, preferably 100-150 mg, preferably 110-140 mg, preferably 120-130 mg, or preferably about 125 mg.

[0095] Combination therapy In one embodiment, the method of treating fibrosis further comprises administering to a human patient a therapeutically effective amount of a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of at least one other therapeutic agent. The combined administration may be separate, simultaneous, or sequential. In one embodiment, the fibrosis is characterized by increased expression of collagen-I, and / or MMP-9, and / or TIMP-1.

[0096] A therapeutic agent refers to a chemical or biological molecule (e.g., chemical compounds, peptides, nucleic acids, proteins, and antibodies, or fragments thereof) that can produce a therapeutic effect in a human patient. In one embodiment, a therapeutic agent is a pharma- ceutical active compound. In another embodiment, a therapeutic agent is an anti-fibrotic agent.

[0097] Such pharmacologically active compounds may be, for example, compounds that are also pharmacologically active in the treatment of fibrosis (e.g., pirfenidone or nintedanib). Such pharmacologically active compounds may also be substances with secretolytic, broncholytic and / or anti-inflammatory activity, for example: anticholinergics, beta-2 mimetics, corticosteroids, PDE-IV inhibitors, p38 MAP kinase inhibitors, MK2 inhibitors, galectin inhibitors, NKi antagonists, LTD4 antagonists, EGFR inhibitors, VEGF inhibitors, PDGF inhibitors, FGF inhibitors, TGF beta inhibitors, LPA1 antagonists, LOXL2 inhibitors, CTGF inhibitors, pentoxifylline, N-acetylcysteine, anti-IL13 agents, anti-IL4 agents, alpha V integrin inhibitors (e.g., inhibitors of αVβ1, αVβ2, αVβ3, αVβ4, αVβ5, αVβ6, αVβ7, αVβ8, and any combination thereof), IGF inhibitors, PI3K inhibitors, mTOR inhibitors, JNK inhibitors, pentraxin 2, and / or endothelin antagonists.

[0098] Other pharmacologically active compounds to be used in combination with the Src kinase inhibitor include compounds with antifibrotic activity, such as PDE-III inhibitors, combined anti-IL4 / 13 agents, combined PI3k / mTOR inhibitors, autotaxin inhibitors, P2X2 antagonists, CTGF antagonists, 5-LO antagonists, leukotriene antagonists, ROCK inhibitors, PDGFR inhibitors (alpha and / or beta), FGR inhibitors, and / or VEGFR inhibitors. In one embodiment, the antifibrotic agent is selected from pirfenidone or a pharmaceutically acceptable salt thereof, or nintedanib or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment, the method of treating fibrosis further comprises administering to a human patient a therapeutically effective amount of a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof and a therapeutically effective dose of at least one anti-fibrotic agent, either separately, simultaneously, sequentially, or in the form of a pharmaceutical composition comprising the Src kinase inhibitor or a pharma- ceutically acceptable salt thereof and the at least one anti-fibrotic agent. An anti-fibrotic agent is a drug, as defined herein, that reduces and / or inhibits fibrosis when administered to a human patient.

[0100] In one embodiment, one antifibrotic agent is administered in combination with a Src inhibitor or a pharma- ceutically acceptable salt thereof.In one embodiment, two antifibrotic agents are administered in combination with a Src inhibitor or a pharma- ceutically acceptable salt thereof.

[0101] It is understood that the anti-fibrotic agents may be in the free form (ie, free acid or free base) or in the form of a pharma- ceutically acceptable salt.

[0102] In one particular embodiment, the antifibrotic agent is selected from nintedanib or its pharmaceutically acceptable salt; pirfenidone or its pharmaceutically acceptable salt; and combinations thereof.In one embodiment, the antifibrotic agent is nintedanib or its pharmaceutically acceptable salt.In one embodiment, the antifibrotic agent is pirfenidone or its pharmaceutically acceptable salt.The present disclosure surprisingly shows that Src kinase inhibitors such as saracatinib, when combined with antifibrotic agents such as nintedanib or pirfenidone, produce synergistic effects in treating fibrosis.

[0103] In one embodiment, a pharmaceutical composition is provided that comprises a Src kinase inhibitor or a pharmaceutically acceptable salt thereof and at least a pharmacologically active compound or a pharmaceutically acceptable salt thereof as defined herein.In one embodiment, a pharmaceutical composition is provided that comprises a Src kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one antifibrotic agent or a pharmaceutically acceptable salt thereof.In one embodiment, a pharmaceutical composition is provided that comprises a Src kinase inhibitor or a pharmaceutically acceptable salt thereof, nintedanib or a pharmaceutically acceptable salt thereof, and / or pirfenidone or a pharmaceutically acceptable salt thereof.In one embodiment, a pharmaceutical composition is provided that comprises saracatinib or a pharmaceutically acceptable salt thereof, nintedanib or a pharmaceutically acceptable salt thereof, and / or pirfenidone or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains 0.5 mg to 0.5 g (eg, 0.5 to 200 mg, 1 to 150 mg, 75 to 150 mg, 90 to 135 mg, or 100 to 125 mg) of Src kinase inhibitor.

[0104] kit In a further aspect, there is provided a pharmaceutical combination comprising (a) saracatinib or a pharma- ceutically acceptable salt thereof, and (b) a therapeutically effective amount of at least one additional therapeutic agent, wherein saracatinib is present in an amount of 75-500 mg (e.g., 90-135 mg, e.g., 100-125 mg, e.g., about 100 mg, or e.g., about 125 mg). In one embodiment, saracatinib or a pharma- ceutically acceptable salt thereof is present in an oral dosage form for administration once per day. In one embodiment, the additional therapeutic agent is selected from nintedanib or a pharma- ceutically acceptable salt thereof, pirfenidone or a pharma- ceutically acceptable salt thereof, or a combination thereof.

[0105] In one embodiment, the pharmaceutical combination is a kit of parts comprising instructions for use and a Src kinase inhibitor as defined herein or a pharma- ceutically acceptable salt thereof.

[0106] In a further aspect, there is provided a kit of parts comprising instructions for use, a Src kinase inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, and at least one other pharmacologically active compound, or a pharma- ceutically acceptable salt thereof.

[0107] In one embodiment, a kit of parts is provided comprising instructions for use, a Src kinase inhibitor as defined herein or a pharma- ceutically acceptable salt thereof, and at least one anti-fibrotic agent as defined herein or a pharma- ceutically acceptable salt thereof.

[0108] In a further aspect, there is provided a kit of parts comprising instructions for use and a pharmaceutical composition as defined herein, in one embodiment the pharmaceutical composition comprises a Src kinase inhibitor or a pharma- ceutically acceptable salt thereof and an anti-fibrotic agent or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0109] Example 1 - Kinase Selectivity The IC50 assay values ​​for saracatinib, nintedanib, and 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2) against c-Src kinase, c-Yes kinase, Lck kinase, Lyn kinase, c-Fyn kinase, and EGFR kinase, as well as PGFRTKα and PGFRTKβ, are shown in Table 1 below.

[0110] IC for saracatinib and PP2 50 Assay values ​​are disclosed in Hennequin 2006 DOI:10.1021 / jm060434q. IC for Nintedanib 50The assay values ​​are disclosed in Hilberg et al, "Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy", Cancer Res 2008;68:(12). June 15, 2008. DOI:10.1158 / 0008-5472. CAN-07-6307 published in June 2008.

[0111] [Table 1]

[0112] ICs represented in Table 1 50 Assay values ​​indicate that saracatinib is potent and highly selective for Src family kinases (c-Src, c-Yes, Lck, Lyn, and c-Fyn) when compared to nintedanib or compound PP2.

[0113] Example 2 - Bleomycin Model Bleomycin sulfate was obtained from Sigma-Aldrich. The IU equivalent to enzyme units (U) is approximately 1.5-2 U / mg. A 2 mg / mL solution was prepared in 0.9% NaCl for delivery of 4 U / kg in 50 μL. Bleomycin or vehicle was administered intranasally on day 0. Compounds were administered twice daily by oral gavage starting 7 days after bleomycin induction to coincide with the historical onset of fibrosis (pirfenidone at 200 mg / kg BID, nintedanib at 30 mg / kg BID, saracatinib at 1, 3, or 10 mg / kg BID). Body weights and clinical observations were recorded on days 7, 14, and 21. On day 21, mice were euthanized by cervical dislocation. One lung tissue was dissected and analyzed for hydroxyproline levels as an index of local collagen deposition, and the other lung was fixed in formalin and subjected to histopathological examination (quantitative staining with Sirius red). Half of the animals from each group were dosed 1 h before peripheral bleeding on day 21 (see below) (C max), whereas the other half of the animals were not dosed (C min ) (Table 2).

[0114] [Table 2]

[0115] The results are depicted in Figure 1. The observed effects indicate that saracatinib compares favorably to pirfenidone (at much lower doses) and is potentially superior to nintedanib at clinically relevant doses.

[0116] Example 3 - Effects on TGF-beta-induced changes in primary human lung fibroblasts from healthy donors Normal human lung fibroblasts (passage 5) from a healthy donor were cultured at 1 cm in DMEM culture medium containing 10% FBS and 1% penicillin-streptomycin. 2 50,000 cells per well were seeded on 96-well culture plates. They were cultured at 37°C for 24 hours, then washed twice with DPBS, serum-starved for 24 hours, and then added with treatment in the form of saracatinib, nintedanib, pirfenidone, or positive control SB-525334, Alk-5 inhibitor, or 0.1% DMSO as vehicle control. Cells were incubated for 1 hour, and then 0.123ng / ml TGF-beta1 was added on top of the compound / vehicle treatment, and cells were incubated for 24 hours.

[0117] After 24 hours, media was collected and analyzed for IL-6, and cells were either lysed for RNA isolation, DNA synthesis, and TaqMan quantitative PCR, or fixed and stained for alpha-smooth muscle actin (αSMA) and Hoechst nuclear staining. The percentage of cells staining positive for αSMA, thereby indicating a myofibroblast phenotype, was determined using high content image analysis. Ct values ​​from quantitative PCR were normalized to the geometric mean Ct values ​​of two reference genes and expressed as fold expression relative to these reference genes (2^-delta Ct).

[0118] The dose required to inhibit 50% of the TGF-beta1-induced response (IC50) was determined for various compounds by fitting dose-response curves to the data using a four-parameter nonlinear regression model.

[0119] [Table 3]

[0120] Saracatinib showed good efficacy at therapeutic concentrations (Table 3, Figures 2 and 3). Indeed, saracatinib caused dose-dependent inhibition of αSMA without affecting cell viability. Nintedanib and pirfenidone inhibited αSMA, but at supratherapeutic concentrations and with some evidence of cell death.

[0121] Example 4 - Organoid formation assay Airway basal cells (ABC) from IPF patients have been described as "cancer-like" in their proliferation, migration, and resistance to apoptosis. The ABC are enriched in areas of bronchiole and extend to fibroblastic foci, structures directly related to lung function. Healthy control (HC)-ABC can be stimulated in culture with growth factors and cytokines to produce 3D organoids. However, IPF-ABC spontaneously form 3D organoids in culture. Following the success observed in oncology, IPF-ABC organoid formation is being explored as a tool for screening for therapeutic activity (A Prasse et al., European Respiratory Journal 2017;50; and A Prasse et al., Am J Respir Crit Care Med. 2018 Aug 24. doi:10.1164 / rccm.201712-2551OC).

[0122] ABC is understood to be associated with IPF pathology, and the observed signal correlates with disease severity (reduction in FVC, need for embryo transfer, and risk of death). Indeed, the ABC model recapitulates abnormal wound healing in IPF (e.g., formation of fibroblast tubules, 3D organoid structures, production of ECM components). Mice engrafted with human IPF ABC recapitulate a wide range of IPF pathology, including robust fibrotic responses, migration, invasion of alveolar compartments, and cystic structures.

[0123] Airway basal cells (ABC) derived from either IPF patients or healthy volunteers (HV) were cultured in Matrigel® (Corning in a transwell system with or without lung fibroblasts derived from either IPF patients or normal lungs for up to 35 days in an incubator (5% CO2, 37°C). Medium changes (BEGM (Lonza, Basel, Switzerland, #CC-3170) / DMEM (Dulbecco's Modified Eagle Medium (Gibco, Fisher Scientific / Germany); ratio 1:1) were performed every 7 days. Conditioned medium was used for the Sircol assay (Scientific-Biocolor / UK, #S1000), which was performed as recommended by the manufacturer (https: / / www.biocolor.co.uk / product / sircol-soluble-collagen-assay / ). Organoids were treated with 8, 25, 75, 210, or 600 nM saracatinib, or 1 mM pirfenidone, or 1 μM nintedanib (pirfenidone and nintedanib act as positive controls). Spheroid formation was monitored using Axio Vert.A1 / Zeiss / Germany and Axio Observer. Documented at Z1 / Zeiss / Germany.

[0124] The results are shown in Figures 4, 5, and 6. Figures 4 and 5 show spheroid formation of ABC treated with saracatinib, pirfenidone, or nintedanib at various magnification levels. Saracatinib is non-toxic at the concentrations tested. Nintedanib and pirfenidone at artificially high doses above therapeutic doses have little or no effect on organoid formation. These data in human IPF ABC mouse model suggest that saracatinib has a differentiated and unique effect compared to nintedanib or pirfenidone.

[0125] Example 5 - DiscoverX The BioMAP panel consists of human primary cell-based systems designed to model various aspects of the human body in an in vitro format. The 12 systems available in the Diversity PLUS panel span a broad set of systems that model various human pathologies, allowing characterization of test reagents in an unbiased manner. BioMAP systems are constructed with one or more primary human cell types from healthy human donors and spiked with stimuli (e.g., cytokines or growth factors) to capture relevant signaling networks that naturally occur in human tissues or disease states. The systems recapitulate aspects of the systemic immune response, such as Th1 inflammation driven by monocytes (LPS system) or T cell stimulation (SAg system), chronic Th1 inflammation driven by macrophage activation (1Mphg system), and T cell-dependent activation of B cells occurring in germinal centers (BT system). The BE3C system (Th1) and BF4T system (Th2) represent pulmonary airway inflammation, and the MyoF system models myofibroblast-lung tissue remodeling.

[0126] Each test reagent produces a signature BioMAP profile that is created from changes in protein biomarker readouts within the individual system environment. Biomarker readouts (7-17 per system) are selected for their therapeutic and biological relevance, predict disease outcome or specific drug effect, and are validated using reagents with known mechanisms of action (MoA). Each readout is quantitatively measured by immune-based methods that detect proteins (e.g., ELISA) or functional assays that measure proliferation and survival. BioMAP readouts are diverse and include cell surface receptors, cytokines, chemokines, matrix molecules, and enzymes.

[0127] Using custom-designed software including data mining tools, BioMAP profiles can be compared to a proprietary reference database of over 4,000 BioMAP profiles of bioactive agents (biologics, approved drugs, chemicals, and experimental drugs) and classified to identify the most similar profiles. This robust data platform allows for rapid evaluation and interpretation of BioMAP profiles by performing unbiased mathematical identification of similar activities. Specific BioMAP activities are correlated with in vivo biology, and multi-parameter BioMAP profiles have been used to differentiate compounds based on MoA and target selectivity, and can provide predictive signatures for in vivo toxicological outcomes (e.g., vascular toxicity, developmental toxicity, etc.) across diverse physiological systems.

[0128] Saracatinib and nintedanib were prepared as stock solutions at 10 mM concentration in 100% DMSO. In the Combo ELECT panel, a 4x4 combinatorial array is created to test all mixtures of two serially diluted single test agents / drugs. Test agents / drugs are screened in triplicate at four concentrations each (3-fold dilutions: 3.3, 1.1, 0.367, and 0.123 μM saracatinib; 1, 330, 110, and 37 μM nintedanib) on selected BioMAP systems (50+ human biology and disease model systems available through BioMAP Combo ELECT).

[0129] The results are shown in Figures 7, 8, and 9.

[0130] Figure 7 shows that saracatinib causes a decrease in the expression of N-cadherin and an increase in the expression of α-SMA, both of which are associated with myofibroblast activation. Saracatinib also causes a decrease in the expression of TIMP-1 and MMP-9, both of which are associated with fibrosis-related matrix. Saracatinib causes a decrease in the expression of sVEGF. The expression of sVEGF is associated with tissue remodeling and / or wound healing. In addition, saracatinib causes a decrease in the expression of sIL-8 and sIL-6, and an increase in the expression of VCAM-1 protein, which are associated with inflammation.

[0131] FIG. 8 shows that nintedanib causes a decrease in the expression of TIMP-1 and MMP-9, both of which are associated with fibrosis-associated matrix.

[0132] FIG. 9 shows that the combination of saracatinib and nintedanib causes de novo inhibition of collagen I and greater inhibition of MMP-9 and TIMP-1 compared to saracatinib or nintedanib alone.

[0133] Example 6 - Safety and Tolerability Saracatinib (100 mg or 125 mg per day) is being tested in double-blind, placebo-controlled clinical trials in human patients with Alzheimer's disease (AD). Safety and tolerability results are summarized in Tables 4, 5, and 6 below, in comparison with the safety and tolerability profiles of pirfenidone (Noble et al 2016 doi:10.1183 / 13993003.00026-2015) and nintedanib (Richeldi et al 2016.doi:10.1016 / j.rmed.2016.02.001) for the treatment of idiopathic pulmonary fibrosis (IPF).

[0134] [Table 4]

[0135] As shown in Table 4, saracatinib has a better gastrointestinal tolerability profile than nintedanib.

[0136] [Table 5]

[0137] As shown in Table 5, saracatinib has a similar or better systemic tolerability profile compared to nintedanib and pirfenidone.

[0138] [Table 6]

[0139] As shown in Table 6, saracatinib treatment may be less susceptible to interruptions.

[0140] This written description uses examples to disclose the invention and enables any person skilled in the art to practice the invention (e.g., to make and use any of the disclosed salts, substances, or compositions, and to perform any of the disclosed methods or processes). The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have elements that do not differ from the literal language of the claims, or if they contain equivalent elements that have insubstantial differences from the literal language of the claims. Although preferred embodiments of the invention have been shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in the practice of the invention. The section headings used in this section and the overall disclosure are not intended to be limiting.

[0141] All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of these references is intended only to summarize the assertions made by their authors. No admission is made that any reference (or any part of any reference) is relevant prior art (or any prior art). Applicant reserves the right to challenge the accuracy and pertinence of the cited references.

Claims

1. A method of treating a fibrotic disease or condition in a human patient, comprising administering to the human patient a therapeutically effective amount of a Src kinase inhibitor or a pharma- ceutical acceptable salt thereof, wherein the fibrotic disease or condition is characterized by abnormal collagen deposition or by persistent, debilitating, abnormal formation of lesions or scars as determined by high resolution computed tomography (HRCT) or biopsy.

2. 10. The method of claim 1, wherein the fibrotic disease or condition is further characterized by epithelial-mesenchymal transition (EMT).

3. The method of claim 1 or 2, wherein the fibrotic disease or condition is further characterized by increased expression of collagen I, and / or MMP-9, and / or TIMP-1.

4. The method of any one of claims 1 to 3, wherein the fibrotic disease or condition is further characterized by increased expression of sVEGF, and / or sIL-8, and / or sIL-6.

5. The method of any one of claims 1 to 3, wherein the fibrotic disease or condition is further characterized by reduced expression of VCAM-1.

6. The method of any one of claims 1 to 3, wherein the fibrotic disease or condition is further characterized by extracellular matrix (ECM) formation.

7. 7. The method of any one of claims 1 to 6, wherein the fibrotic disease or condition is a fibrotic disease or condition of the lung, a fibrotic disease or condition of the liver, a fibrotic disease or condition of the heart or vascular system, a fibrotic disease or condition of the kidney, a fibrotic disease or condition of the skin, a fibrotic disease or condition of the gastrointestinal tract, a fibrotic disease or condition of the bone marrow or hematopoietic tissue, a fibrotic disease or condition of the nervous system, a fibrotic disease or condition of a joint, or a combination thereof.

8. 8. The method of claim 7, wherein the fibrotic disease or condition is interstitial lung disease.

9. 1. A method for treating an interstitial lung disease characterized by airway basal cell-mediated pulmonary remodeling in a human patient, comprising administering to the human patient a therapeutically effective amount of a Src kinase inhibitor or a pharmacologic acceptable salt thereof.

10. 10. The method of claim 9, wherein the interstitial lung disease (ILD) is selected from idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, ILD associated with connective tissue disease, ILD associated with rheumatoid arthritis, fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis, and ILD associated with other occupational exposures.

11. A method for treating pulmonary fibrosis characterized by airway basal cell-mediated pulmonary remodeling in a human patient, comprising administering to the human patient a therapeutically effective amount of a Src kinase inhibitor or a pharma- ceutical acceptable salt thereof.

12. The method of any one of claims 9 to 11, wherein the pulmonary fibrosis is further characterized by epithelial-mesenchymal transition (EMT).

13. The method according to any one of claims 9 to 12, wherein the pulmonary fibrosis is further characterized by increased expression of collagen-I, and / or MMP-9, and / or TIMP-1.

14. The method of any one of claims 9 to 13, wherein the pulmonary fibrosis is further characterized by extracellular matrix (ECM) formation.

15. 1. A method of treating pulmonary fibrosis in a human patient, comprising administering to the human patient a therapeutically effective amount of a Src kinase inhibitor, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of at least one additional therapeutic agent.

16. The method of any one of claims 8 to 15, wherein the human patient has idiopathic pulmonary fibrosis (IPF).

17. 17. The method of claim 16, wherein the IPF is characterized by increased expression of collagen-I, and / or MMP-9, and / or TIMP-1.

18. 18. The method of claim 16 or 17, wherein the human patient has mild to moderate or severe, progressive IPF.

19. 19. The method of any one of claims 16 to 18, wherein the human patient has a predicted forced vital capacity threshold of 50-55% and / or a predicted diffusion capacity threshold of the lung for carbon monoxide of 35-40%.

20. 20. The method of any one of claims 16 to 19, wherein the human patient is predicted to have a forced vital capacity threshold of less than 50% and / or a predicted pulmonary diffusion capacity threshold for carbon monoxide of less than 35%.

21. The method of any one of claims 16 to 20, wherein the human patient has rapidly progressive IPF.

22. The method of any one of claims 1 to 21, wherein the Src kinase inhibitor is saracatinib or a pharma- ceutically acceptable salt thereof.

23. 23. The method of claim 22, wherein a therapeutically effective amount of saracatinib or a pharma- ceutically acceptable salt thereof is administered once daily.

24. The method according to claim 22 or 23, wherein the therapeutically effective amount of saracatinib or a pharma- ceutically acceptable salt thereof is 5 to 500 mg per day.

25. The method of any one of claims 15 to 24, wherein the at least one additional therapeutic agent is an anti-fibrotic agent.

26. 26. The method of claim 25, wherein the at least one additional therapeutic agent is selected from nintedanib or a pharma- ceutically acceptable salt thereof, pirfenidone or a pharma- ceutically acceptable salt thereof, or a combination thereof.

27. 27. The method of claim 25 or 26, wherein the Src kinase inhibitor, or a pharma- ceutically acceptable salt thereof, and the at least one additional therapeutic agent are administered separately, simultaneously, or sequentially.

28. a. saracatinib or a pharma- ceutically acceptable salt thereof; b. a therapeutically effective amount of at least one additional therapeutic agent; A pharmaceutical combination comprising: Saracatinib is present in an amount of 75-500 mg, for example 90-135 mg, for example 100-125 mg, for example about 100 mg, or for example about 125 mg; Pharmaceutical combinations.

29. The pharmaceutical combination of claim 28, wherein saracatinib or a pharma- ceutically acceptable salt thereof is in an oral dosage form for once-daily administration.

30. 30. The pharmaceutical combination of claim 28 or 29, wherein the additional therapeutic agent is selected from nintedanib or a pharma- ceutically acceptable salt thereof, pirfenidone or a pharma- ceutically acceptable salt thereof, or a combination thereof.

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