Methods of treating fibrotic diseases or conditions or interstitial lung disease using SRC kinase inhibitors

Abstract

The present disclosure relates to certain Src kinase inhibitors or pharmaceutically acceptable salts thereof, and their use in treating fibrosis in warm-blooded animals such as humans and fibrotic conditions such as idiopathic pulmonary fibrosis. The present disclosure also relates to the use of the Src kinase inhibitors or pharmaceutically acceptable salts thereof in combination with at least one additional therapeutic agent for treating fibrosis in warm-blooded animals such as humans and fibrotic conditions such as idiopathic pulmonary fibrosis.

Description

Technical Field

[0001] The present disclosure relates to certain Src kinase inhibitors or pharmaceutically acceptable salts thereof, and their use in treating fibrosis in warm-blooded animals such as humans and fibrotic conditions such as idiopathic pulmonary fibrosis. The present disclosure also relates to the use of the Src kinase inhibitors or pharmaceutically acceptable salts thereof, alone or in combination with at least one additional therapeutic agent, for treating fibrosis and fibrotic conditions such as interstitial lung disease (e.g., idiopathic pulmonary fibrosis) in warm-blooded animals such as humans. Background Art

[0002] Remodeling is a normal response to tissue damage and inflammation, and is observed in many tissues throughout the body. After inflammation subsides and tissue damage is repaired, tissues will usually return to their original state. However, excessive uncontrolled tissue repair or failure to stop remodeling when no longer needed can lead to a situation characterized by fibrosis. Fibrosis is generally related to the accumulation of extracellular matrix components that occur after trauma, inflammation, tissue repair, immune response, cell proliferation or tumor formation. Examples of tissue fibrosis include but are not limited to pulmonary fibrosis, renal fibrosis, cardiac fibrosis, cirrhosis and liver fibrosis, skin scars and keloids, adhesions, fibromatosis, atherosclerosis and amyloidosis. Fibrosis usually seriously damages one or more normal functions of the affected organs, and in fact, many fibrotic conditions are life-threatening or cause serious disfigurement. Unfortunately, the treatment options for these diseases are limited; risky and expensive surgery (such as organ transplantation) is usually the only feasible method.

[0003] An example of a particularly severe fibrotic disorder with a high unmet clinical need is idiopathic pulmonary fibrosis (IPF). IPF is a chronic, relentless, ultimately fatal disorder characterized by scarring (fibrosis) of the lung parenchyma. The disease can cause debilitating cough, decreased lung function, fatigue, and dyspnea, and its need for high levels of supplemental oxygen limits physical activity and significantly reduces the patient's quality of life and independence over time. The median survival of IPF patients is in the range of 2.5 to 3.5 years, and most patients die of respiratory failure caused by disease progression (Raghu G et al., Am J Respir Critical Care Med [USA Respiratory and Critical Care Medicine] 2015; Vol. 192, No. 2: https: / / doi.org / 10.1164 / rccm.201506-1063ST).

[0004] The disease pathology of IPF is poorly understood and few drug treatment options exist (Mason DP et al., Ann Thoracic Surgery 84:1121-8, 2007). In 2014, the FDA approved two new antifibrotic drugs for the treatment of IPF: pirfenidone ( ) and nintedanib ( ). The mechanism of action of pirfenidone has not been fully established. Nintedanib is a tyrosine kinase inhibitor that specifically targets PDGFRα and β receptors, vascular endothelial growth factor receptor (VEGFR 1-3), and fibroblast growth factor receptor (FGFR 1-3) kinases. Clinical trials and real-world experience have demonstrated that, although both drugs generally slow the rate of decline in lung function, responses are variable, compliance is challenging due to a poor safety profile, and neither drug prevents progressive loss of lung function. In addition, neither drug cures IPF, relieves symptoms, or demonstrates an overall survival benefit. Importantly, clinical experience with both agents has shown that one year after initiating antifibrotic therapy, almost 40% of patients have discontinued treatment, with adverse gastrointestinal or skin side effects being the most common reasons for discontinuation of treatment (Corte T et al., Respiratory research [Respiratory Research] 2015;16:116 and Xaubet A et al., Am J Respir Critical Care Med [American Respiratory and Critical Care Medicine] 2003;168(4):431-5). Furthermore, treatment with pirfenidone (indicated for mild to moderate IPF) requires titration to very high and frequent doses, which raises safety and patient compliance issues. From day 15 onwards, the recommended daily dose of pirfenidone is 2403 mg / day, which requires patients to take 9 pills per day. Capsules (three 267 mg capsules three times daily with food).

[0005] Although the United States approved and But IPF is still a chronic, fatal disease that impairs the patient's quality of life and increases health care utilization and costs. Therefore, there is still an urgent need to develop more effective treatments that safely and more reliably change the course of different forms / stages of IPF to maintain / restore quality of life.

[0006] Saracatinib (ADZ0530) is a potent inhibitor of the Src tyrosine kinase family with high selectivity compared to other protein kinases involved in signal transduction (Chang YM et al., Oncogene 2008: 27(49): 6365-75 and Greet TO et al., Mol Oncol. 2009; 3(3): 248-61). The compound, along with its manufacture, is disclosed in PCT patent application WO 01 / 94341, which relates to quinazoline derivatives for the treatment of tumors. Saracatinib was originally developed for the treatment of cancer, but clinical trials failed to show sufficient efficacy in this indication. Saracatinib has also been studied in Alzheimer's disease (Nygaard et al., Alzheimer's Res Therapeutic 2015; 7(1): 35).

[0007] Saracatinib has also been tested in the bleomycin mouse model of pulmonary fibrosis and was found to affect myofibroblast differentiation (Hu M et al., Journal of Pharmacology and Experimental Therapeutics; 2014, 351: 87-95). The bleomycin mouse model has the advantages that it is fairly easy to perform and that some similarities in histological changes can be seen in IPF. However, while many agents have been tested in this disease model and found to exhibit some activity, relatively few have progressed to reproduce this activity in humans (Moeller A et al., Int J Biochem Cell Biol. 2008; 40(3): 362-282). In part, this is because the model has an acute inflammatory component that does not replicate the later fibrotic stages of IPF and is therefore of limited value in providing information about the activity profile of compounds in clinical applications. Many anti-inflammatory mechanisms have been shown to be effective in the bleomycin challenge model, but have failed to show clinical utility (e.g., tralokinumab, lebrikizumab, SNY program of IL-4 / 13). As Hu et al. acknowledge, although bleomycin treatment induces pulmonary fibrosis in rodents, and the resulting fibrosis has many key features of human pulmonary fibrosis, the bleomycin model does not replicate human IPF and is not a model of progressive fibrosis. Fibrosis tends to exist only 3-4 weeks before spontaneous regression after bleomycin instillation, restoring the lungs to a near-normal state. In addition to showing spontaneous regression of fibrosis, which is different from human disease, the bleomycin model also lacks other cell types, processes, and structures that are closely related to human disease progression, such as hyperplastic type II alveolar epithelial cells (AEC), bronchiolization, and honeycomb cysts. The slow and reversible progression of IPF in patients is not reproduced in the bleomycin model (Chua F et al., Am J Respir Cell Molecular Biology 2005; 33(1): 9-13), and as such the bleomycin model has significant limitations in understanding the progressive and irreversible nature of human IPF. This is particularly relevant when evaluating the clinical activity of a compound in different disease stages and / or different forms of progressive IPF.

[0008] IPF is considered a heterogeneous disease characterized by stage and severity. Published studies have shown that the clinical course of IPF is variable, but distinct subgroups of patients do exist, such as those with more rapid progression of fibrosis (Ley B et al. Ann Intern Med 2012;156(10):684-91 and Martinez FJ et al. 2005;142(12):963-7). Recently, Herazo Maya et al. published a retrospective study identifying a peripheral blood transcriptomic signature that predicts mortality and transplant-free survival in IPF patients (Herazo-Maya et al. Lancet Respir Med 2017;5:857-68). The signature correlated with FVC and was stable over time in the absence of treatment. Data from a small cohort of patients suggested that the high-risk profile normalized with response to therapeutic intervention. In the local lung environment, Prasse et al. have identified a transcriptomic signature from bronchial lavage samples from IPF patients that is driven by airway basal cells and predicts high versus low risk of mortality or lung transplantation (Prasse et al. 2018 https: / / doi.org / 10.1164 / rccm.201712-2551OC, PMID: 30141961). These results provide important insights into biomarkers of disease progression and treatment response and may implicate new therapeutic targets. Achieving effective treatment in such diverse patient groups is challenging. Regardless of the heterogeneity, current drugs are unable to halt the progressive loss of lung function, reverse the disease, or cure IPF.

[0009] It is evident, therefore, that there remains an urgent need to develop more effective therapeutic approaches to safely and more reliably alter the course of different forms and stages of fibrotic diseases and conditions.

[0010] Surprisingly, the present disclosure has shown that certain Src kinase inhibitors, such as saracutinib, act through different mechanisms of action and provide specific benefits compared to existing drugs for treating fibrotic conditions. For example, the present disclosure has demonstrated that certain Src kinase inhibitors, such as saracutinib, target multiple drivers of fibrotic pathology and are particularly effective in treating and / or preventing fibrosis and fibrotic conditions (e.g., idiopathic pulmonary fibrosis (including progressive forms and / or different stages of idiopathic pulmonary fibrosis)) and / or provide safer and better tolerated treatments for such conditions when compared to existing drugs such as pirfenidone and nintedanib.

[0011] Furthermore, Applicants have discovered that certain Src kinase inhibitors, such as saracatinib, are unexpectedly 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 disorders (e.g., idiopathic pulmonary fibrosis) in warm-blooded animals (e.g., humans). Summary of the invention

[0012] The Src kinase inhibitors disclosed herein are unexpectedly effective in treating certain fibrosis and specific fibrotic disorders by mechanisms different from conventional treatment methods. In one embodiment, fibrosis and fibrotic disorders are characterized by abnormal formation of lesions or scars that are persistent, debilitating, and determined by high-resolution computed tomography (HRCT) or biopsy. In another embodiment, fibrosis and fibrotic disorders are characterized by abnormal collagen deposition. Therefore, the present disclosure relates to methods for treating such fibrosis and fibrotic disorders in human patients. Such methods include administering a therapeutically effective amount of a Src kinase inhibitor or a pharmaceutically acceptable salt thereof to a human patient. In one embodiment, a Src kinase inhibitor selectively inhibits Src kinases at its safe and tolerable dose, with clinically relevant efficacy. In one embodiment, fibrosis and fibrotic disorders are characterized by epithelial-mesenchymal transition (EMT). In one embodiment, fibrosis and fibrotic disorders are characterized by increased expression of collagen I and / or MMP-9 and / or TIMP-1. In one embodiment, a fibrotic disease or disorder is characterized by increased expression of sVEGF and / or sIL-8 and / or sIL-6. In one embodiment, the fibrotic disease or disorder is characterized by decreased expression of VCAM-1. In one embodiment, fibrosis and fibrotic disorders are characterized by the formation of extracellular matrix (ECM).

[0013] The disclosure also relates to a method for treating interstitial lung disease in human patients, which is characterized by airway basal cell-mediated lung remodeling. The method includes applying a Src kinase inhibitor or a pharmaceutically acceptable salt thereof to human patients for treatment of an effective amount. In one embodiment, interstitial lung disease (ILD) is selected from idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, idiopathic interstitial pneumonia that can not be classified, ILD associated with connective tissue disease, ILD associated with rheumatoid arthritis, fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and the ILD associated with other occupational exposures.

[0014] The present disclosure also relates to a method for treating pulmonary fibrosis in a human patient, which is suitably characterized by airway basal cell-mediated lung remodeling, the method comprising administering a therapeutically effective amount of a Src kinase inhibitor to the human patient. In one embodiment, pulmonary fibrosis is characterized by abnormal formation of persistent, debilitating lesions or scars determined by high-resolution computed tomography (HRCT) or biopsy. In one embodiment, pulmonary fibrosis is characterized by epithelial-mesenchymal transition (EMT). In one embodiment, pulmonary fibrosis is characterized by increased expression of collagen I and / or MMP-9 and / or TIMP-1. In one embodiment, pulmonary fibrosis is characterized by the formation of an extracellular matrix (ECM).

[0015] On the other hand, the disclosure relates to a method for treating fibrosis and fibrotic disorders in human patients, the method comprising administering a therapeutically effective amount of a Src kinase inhibitor or a pharmaceutically acceptable salt thereof and a combination of at least one other therapeutic agent to human patients. In one embodiment, fibrosis or fibrotic disorders are pulmonary fibrosis. In another embodiment, fibrosis or fibrotic disorders are interstitial lung disease (ILD). In another embodiment, fibrosis or fibrotic disorders are idiopathic pulmonary fibrosis (IPF). In one embodiment, at least one other therapeutic agent is an antifibrotic drug. In one embodiment, interstitial lung disease (ILD) is selected from idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, idiopathic interstitial pneumonia that cannot be classified, connective tissue disease-related ILD, rheumatoid arthritis-related ILD, fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and the ILD related to other occupational exposures.

[0016] The present disclosure also relates to methods of treating fibrosis and fibrotic disorders as described herein in human patients by administering to a patient in need thereof a pharmaceutical composition comprising a Src kinase inhibitor and a pharmaceutically suitable carrier.

[0017] The present disclosure also relates to pharmaceutical combinations for treating fibrotic diseases and disorders comprising a Src kinase inhibitor in combination with at least one additional therapeutic agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Embodiments of the present disclosure are further described below with reference to the accompanying drawings, in which:

[0019] Figure 1 Shown are hydroxyproline levels in mice following bleomycin (Bleo)-induced lung injury and fibrosis, treated with 200 mg / kg BID of pirfenidone (PIR), 30 mg / kg BID of nintedanib (NIN), and 1 (0530-1) mg / kg BID, 3 (0530-3) mg / kg BID, or 10 (0530-10) mg / kg BID of salactinib.

[0020] Figure 2 Shown are the % maximum αSMA levels in human lung fibroblasts treated with salactinib (circles), nintedanib (triangles), or pirfenidone (squares).

[0021] Figure 3 Shown are mean IL-6 levels in human lung fibroblasts treated with salactinib (circles), nintedanib (triangles), or pirfenidone (squares).

[0022] Figure 4 Shown is organoid formation of airway basal cells (ABC) treated with salactinib, pirfenidone, or nintedanib.

[0023] Figure 5 Shown are higher magnification images of organoid formation of ABCs treated with salactinib (SARA), pirfenidone (Pirf), or nintedanib (Nin) at the indicated concentrations.

[0024] Figure 6 Optical density / well and organoid counts / well of ABC treated with salactinib, pirfenidone, or nintedanib are shown.

[0025] Figure 7 Shown are the results of the DiscoverX assay indicating the relative protein expression (log ratio of compound / vehicle control) of Saracatinib (3.3 μM).

[0026] Figure 8 Shown are the results of the DiscoverX assay indicating the relative protein expression (log ratio of compound / vehicle control) of nintedanib (1.1 μM).

[0027] Fig. 9 Shown are the results of the DiscoverX assay indicating the relative protein expression (log ratio of compound / vehicle control) of the combination of saracutinib and nintedanib compared to saracutinib and nintedanib alone.

[0028] Fig.10 A kinase tree for Sara and Nintedanib is shown, where each circle marks a kinase inhibited by the respective molecule, and the size of the circle indicates the potency of this inhibition. DETAILED DESCRIPTION

[0029] definition

[0030] As used herein, the phrase "effective amount" refers to the amount of a Src kinase inhibitor or a composition comprising a Src kinase inhibitor that is sufficient to significantly and positively alter the symptoms and / or condition to be treated (e.g., provide a positive clinical response). The effective amount of the active ingredient(s) used in the pharmaceutical composition will vary with the specific condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific active ingredient(s) utilized, the specific pharmaceutically acceptable excipient / carrier(s) utilized, and similar factors that are within the knowledge and expertise of the attending physician.

[0031] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and with a reasonable benefit / risk ratio commensurate.

[0032] Unless the context clearly states otherwise, a reference to a specific value includes at least that specific value. When a range of values ​​is expressed, another embodiment includes starting from that specific value and / or ending at another specific value. In addition, reference to the values ​​described in a range includes each and all values ​​within that range. All ranges are inclusive and combinable.

[0033] It should be understood that, for the sake of clarity, certain features of the Src kinase inhibitors, compositions and methods of the present disclosure described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, various features of the Src kinase inhibitors, compositions and methods of the present disclosure described in the context of a single embodiment may also be provided individually or in any subcombination.

[0034] As used herein, the singular form "a", "an" and "the" include plural forms.

[0035] When values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment.

[0036] When used with respect to a numerical range, a cutoff value, or a specific value, the term "about" is used to indicate that the listed value may differ from the listed value by up to 10%. Since many of the numerical values ​​used herein are determined experimentally, it will be appreciated by those skilled in the art that such determinations can and often will vary in different experiments. The values ​​used herein should not be considered to be unduly restrictive due to this inherent variation. Therefore, the term "approximately" is used to cover a variation of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from the specified value.

[0037] As used herein, "treatment" and similar terms refer to reducing the severity and / or incidence of symptoms, eliminating symptoms and / or the potential causes of the symptoms, reducing the incidence or possibility of symptoms and / or their potential causes, delaying, preventing and / or slowing down the progress of fibrosis (such as IPF), and alleviating or repairing the damage caused directly or indirectly by fibrosis (such as IPF). As used herein, treatment is intended to include preventive and therapeutic treatments.

[0038] Src kinase inhibitors

[0039] The present disclosure has demonstrated that certain Src kinase inhibitors offer specific benefits compared to existing drugs used to treat fibrosis.

[0040] In one embodiment, the Src kinase inhibitor is a selective Src kinase inhibitor, i.e., the Src kinase inhibitor is more selective for Src family kinases than for other protein kinases involved in signal transduction. Suitably, the Src family includes c-Src, c-Yes, Lck, Lyn, and Fyn, and in a specific 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 IC of less than or equal to 100 nM (such as less than or equal to 75 nM, 50 nM, 40 nM, 30 nM, 20 nM, 15 nM, 12 nM, or 10 nM) 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 IC greater than 1000 nM for PDGFRα and / or PDGFRβ. 50 Determination.

[0041] In one embodiment, the Src kinase inhibitor is selective for c-Src kinase and has an IC less than or equal to 100 nM (such as less than or equal to 75 nM, 50 nM, 40 nM, 30 nM, 20 nM, 15 nM, 12 nM, 10 nM, 8 nM, 6 nM, 4 nM or about 3 nM) for c-Src kinase. 50 In another embodiment, the Src kinase inhibitor is selective for c-Yes kinase and has an IC less than or equal to 100 nM (such as less than or equal to 75 nM, 50 nM, 40 nM, 30 nM, 20 nM, 15 nM, 12 nM, 10 nM, 8 nM, 6 nM or 4 nM) for c-Yes kinase. 50In yet further embodiments, the Src kinase inhibitor is selective for Lck kinase and has an IC less than or equal to 100 nM (such as less than or equal to 75 nM, 50 nM, 40 nM, 30 nM, 20 nM, 12 nM, 10 nM, 6 nM or 4 nM) for Lck kinase. 50 In yet further embodiments, the Src kinase inhibitor is selective for Lyn kinase and has an IC less than or equal to 100 nM (such as less than or equal to 75 nM, 50 nM, 40 nM, 30 nM, 20 nM, 15 nM, 12 nM, 10 nM, 8 nM, 6 nM or 5 nM) for Lyn kinase. 50 In yet further embodiments, the Src kinase inhibitor is selective for c-Fyn kinase and has an IC less than or equal to 100 nM (such as less than or equal to 75 nM, 50 nM, 40 nM, 30 nM, 20 nM, 15 nM, 12 nM or 10 nM) for c-Fyn kinase. 50 In yet further embodiments, the Src kinase inhibitor has an IC less than or equal to 200 nM (such as less than or equal to 150 nM, 100 nM, 70 nM, or about 66 nM) for EGFR. 50 Determination.

[0042] In one embodiment, the Src kinase inhibitor has an IC greater than or equal to 5000 nM (eg, greater than or equal to 6000 nm, 7000 nm, 10000 nm) for PDGFRα and / or PDGFRβ. 50 Determination.

[0043] Tyrosine kinase inhibitors (such as VEGFR inhibitors and PDGFR inhibitors) are associated with toxic effects in various organs (such as the heart, lungs, liver, kidneys, thyroid, skin, coagulation system, gastrointestinal system, and nervous system). Therefore, the lack of activity against PDGFR advantageously contributes to better tolerance of Src kinase inhibitors, which in turn can lead to an improvement in the safety profile and / or an improvement in patient compliance (Li et al. Eur J Clin Pharmacol. [European Journal of Clinical Pharmacology] October 2017; 73(10): 1209-1217).

[0044] In one embodiment, the Src kinase inhibitor is saracatinib or a pharmaceutically acceptable salt thereof. Fig.10A kinase tree of saracatinib and nintedanib is shown, which illustrates the excellent selectivity of saracatinib. The chemical name of saracatinib is 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 its structure is shown below:

[0045]

[0046] 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, including formulations thereof, are described in WO 01 / 94341, published on December 13, 2001, entitled "Quinazoline Derivatives for the Treatment of Tumors"; and in 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 pharmaceutically acceptable salt thereof.

[0047] Suitable pharmaceutically acceptable salts of the Src kinase inhibitors are, for example, acid addition salts or base salts. Such salts are physiologically non-toxic.

[0048] Examples of pharmaceutically acceptable acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclamate, diethylenediamine, ethanesulfonate, formate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, hydrogenphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, aminobenzenesulfonate, sulfate, tartrate, toluenesulfonate (p-toluenesulfonate), trifluoroacetate, and undecanoate.

[0049] Examples of pharmaceutically 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 salts and N-methyl D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, etc. In addition, basic nitrogen-containing groups can be quaternized with lower alkyl halides such as methyl, ethyl, propyl and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl sulfates; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; aralkyl halides such as benzyl bromide and others.

[0050] Fibrosis

[0051] As used herein, "fibrosis" or "fibrotic diseases or conditions" refers to the accumulation of extracellular matrix components that occurs following trauma, inflammation, tissue repair, immune response, cell proliferation, and tumor formation. Examples of tissue fibrosis include, but are not limited to, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, cirrhosis and liver fibrosis, skin scars and keloids, adhesions, fibromatosis, atherosclerosis, and amyloidosis.

[0052] In one aspect, a method for treating fibrosis is provided, comprising administering to a human patient a therapeutically effective amount of a Src kinase inhibitor as described herein or a pharmaceutically acceptable salt thereof. In another aspect, a Src kinase inhibitor as described herein or a pharmaceutically acceptable salt thereof is provided for treating fibrosis in a human patient. In one embodiment, the Src kinase inhibitor demonstrates clinically relevant efficacy at its safe and tolerable dose.

[0053] Suitably, fibrosis and fibrotic disorders are characterised by abnormal formation of persistent, debilitating lesions or scars as determined by high resolution computed tomography (HRCT) or biopsy. In another embodiment, fibrosis and fibrotic disorders are characterised by abnormal collagen deposition.

[0054] In one embodiment, fibrosis and fibrotic disorders are characterized by epithelial-mesenchymal transition (EMT). In another embodiment, fibrosis and fibrotic disorders are characterized by increased expression of collagen I and / or MMP-9 and / or TIMP-1 in human patients. In one embodiment, fibrosis and fibrotic disorders are characterized by increased expression of collagen I, MMP-9 and TIMP-1 in human patients. In one embodiment, fibrosis and fibrotic disorders are characterized by increased expression of collagen I and MMP-9 in human patients. In one embodiment, fibrosis and fibrotic disorders are characterized by increased expression of collagen I and TIMP-1 in human patients. In one embodiment, fibrosis and fibrotic disorders are characterized by increased expression of MMP-9 and TIMP-1 in human patients. In another embodiment, fibrosis and fibrotic disorders are characterized by the formation of extracellular matrix (ECM).

[0055] In some embodiments, disclosed herein is a method of reducing fibrosis in a tissue, the method comprising contacting fibrotic cells or tissues with a Src kinase inhibitor disclosed herein in an amount sufficient to reduce or inhibit 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 includes fibrotic disorders.

[0056] In some embodiments, reducing fibrosis or treating a fibrotic disorder comprises reducing or inhibiting one or more of: the formation or deposition of extracellular matrix proteins; the number of profibrotic cell types (e.g., fibroblasts or immune cells); the cellular collagen or hydroxyproline content in fibrotic lesions; the expression or activity of fibrinogens; or reducing fibrosis associated with an inflammatory response.

[0057] In some embodiments, the fibrotic disorder is primary fibrosis. In some embodiments, the fibrotic disorder is idiopathic. In some embodiments, the fibrotic disorder 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 tissue disease), a toxin, an insult (e.g., an environmental hazard (e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), smoking, a wound), a medical treatment (e.g., surgical resection, chemotherapy, or radiation therapy), or a combination thereof.

[0058] In some embodiments, the fibrotic disorder is a fibrotic disorder of the lung, a fibrotic disorder of the liver, a fibrotic disorder of the heart or vasculature, a fibrotic disorder of the kidney, a fibrotic disorder of the skin, a fibrotic disorder of the gastrointestinal tract, a fibrotic disorder of the bone marrow or hematopoietic tissue, a fibrotic disorder of the nervous system, a fibrotic disorder of the joints, or a combination thereof.

[0059] In one embodiment, a method of treating a fibrotic disorder is provided, the treatment comprising administering to a human patient a therapeutically effective amount of a Src kinase inhibitor or a pharmaceutically acceptable salt thereof, wherein the fibrotic disorder is a fibrotic disorder of the lung, a fibrotic disorder of the liver, a fibrotic disorder of the heart or vasculature, a fibrotic disorder of the kidney, a fibrotic disorder of the skin, a fibrotic disorder of the gastrointestinal tract, a fibrotic disorder of the bone marrow or hematopoietic tissue, a fibrotic disorder of the nervous system, a fibrotic disorder of the joints, or a combination thereof. In another aspect, a Src kinase inhibitor or a pharmaceutically acceptable salt thereof is provided for use in treating a fibrotic disorder in a human patient, wherein the fibrotic disorder is a fibrotic disorder of the lung, a fibrotic disorder of the liver, a fibrotic disorder of the heart or vasculature, a fibrotic disorder of the kidney, a fibrotic disorder of the skin, a fibrotic disorder of the gastrointestinal tract, a fibrotic disorder of the bone marrow or hematopoietic tissue, a fibrotic disorder of the nervous system, a fibrotic disorder of the joints, or a combination thereof.

[0060] In some embodiments, the fibrotic disorder affects one or more tissues selected from muscle, tendon, cartilage, skin (e.g., skin epidermis or endoderm), cardiac tissue, vascular tissue (e.g., artery, vein), pancreatic tissue, lung tissue, liver tissue, kidney tissue, uterine tissue, ovarian tissue, neural tissue, testicular tissue, peritoneal tissue, colon, small intestine, bile duct, intestine, bone marrow, or hematopoietic tissue.

[0061] In some embodiments, fibrotic disorder is fibrotic disorder of lung.In some embodiments, fibrotic disorder of lung is selected from following one or more: pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), bronchiolitis obliterans or bronchiectasis.In some embodiments, fibrosis of lung is secondary to disease, toxin, damage, medical treatment or its combination.In some embodiments, fibrosis of lung is associated with following one or more: disease process, such as asbestosis and silicosis; occupational hazard; environmental pollutant; smoking; autoimmune connective tissue disorder (such as rheumatoid arthritis, scleroderma and systemic lupus erythematosus (SLE)); connective tissue disorder, such as sarcoidosis; infectious disease, such as infection, particularly chronic infection; medical treatment, including but not limited to radiotherapy and drug therapy (such as chemotherapy (for example, with bleomycin, methotrexate, amiodarone, busulfan and / or nitrofurantoin treatment)). In some embodiments, the fibrotic disorder of the lung treated with the methods of the disclosure is associated with (e.g., secondary to) cancer therapy, e.g., treatment of cancer (e.g., treatment of squamous cell carcinoma, testicular cancer, Hodgkin's disease with bleomycin).

[0062] In some embodiments, the fibrotic disorder is a fibrotic disorder of the liver. In certain embodiments, the fibrotic disorder of the liver is selected from one or more of fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis (NASH), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC), cirrhosis, alcoholic liver fibrosis, bile duct injury, bile duct fibrosis, cholestasis, or biliary disease. In some embodiments, the liver or liver fibrosis includes, but is not limited to, liver fibrosis associated with alcoholism, viral infection (e.g., hepatitis (e.g., hepatitis C, hepatitis B, or hepatitis D)), autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins).

[0063] In some embodiments, the fibrotic disorder is a fibrotic disorder of the heart. In certain embodiments, the fibrotic disorder of the heart is myocardial fibrosis (e.g., myocardial fibrosis associated with radiation myocarditis, surgical complications (e.g., myocardial postoperative fibrosis), infectious diseases (e.g., Chagas disease, bacterial myocarditis, myocarditis caused by trichinosis, or fungal myocarditis); granulomas, metabolic storage disorders (e.g., cardiomyopathy, hemochromatosis); developmental disorders (e.g., endocardial fibroelastosis); atherosclerosis, or exposure to toxins or irritants (e.g., drug-induced cardiomyopathy, drug-induced cardiotoxicity, alcoholic cardiomyopathy, cobalt poisoning or exposure). In some embodiments, myocardial fibrosis is associated with an inflammatory disorder of cardiac tissue (e.g., myocardial sarcoidosis).

[0064] In some embodiments, the fibrotic disorder is a fibrotic disorder of the kidney. In some embodiments, the fibrotic disorder of the kidney is selected from one or more of the following: renal fibrosis (e.g., chronic renal fibrosis), renal disease associated with injury / fibrosis (e.g., chronic kidney disease associated with diabetes (e.g., diabetic nephropathy)), lupus, renal scleroderma, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy renal fibrosis associated 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 damage, HIV-related nephropathy, cirrhosis, or fibrosis associated with exposure to toxins, irritants, or chemotherapeutic agents.

[0065] In some embodiments, the fibrotic disorder is a fibrotic disorder of the skin. In some embodiments, the fibrotic disorder of the skin is selected from one or more of: cutaneous fibrosis, scleroderma, nephrogenic systemic fibrosis (e.g., in patients with severe renal failure, following exposure to gadolinium, which is commonly used as an MRI contrast agent), scars, and keloids.

[0066] In some embodiments, the fibrotic disorder is a fibrotic disorder of the gastrointestinal tract. In some embodiments, the fibrotic disorder is selected from one or more fibrosis associated with scleroderma; radiation intestinal fibrosis; fibrosis associated with foregut inflammatory disorders (e.g., Barrett's esophagus and chronic gastritis), and / or fibrosis associated with hindgut inflammatory disorders (e.g., inflammatory bowel disease (IBD), ulcerative colitis, and Crohn's disease).

[0067] In some embodiments, the fibrotic disorder is adhesions. In some embodiments, the adhesions are selected from one or more of: intra-abdominal adhesions, peritoneal adhesions, pelvic adhesions, pericardial adhesions, epidural adhesions, perimembranous or adhesive cystitis.

[0068] In some embodiments, the fibrotic disorder is a fibrotic disorder of the eye. In some embodiments, the fibrotic disorder of the eye involves diseases of the anterior segment of the eye, such as glaucoma and corneal opacities; in some embodiments, the fibrotic disorder of the eye involves diseases of the posterior segment of the eye, such as age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and neovascular glaucoma; in some embodiments, the fibrotic disorder of the eye is caused by fibrosis following ophthalmic surgery.

[0069] In some embodiments, the fibrotic disorder is a fibrotic disorder of the bone marrow or hematopoietic tissue. In some embodiments, the fibrotic disorder of the bone marrow is an intrinsic feature of a chronic myeloproliferative tumor of the bone marrow, such as primary myelofibrosis (also referred to herein as idiopathic myeloid metaplasia or chronic idiopathic myelofibrosis). In some embodiments, myelofibrosis is associated with a malignant disorder or a disorder caused by a clonal proliferative disease (e.g., secondary to it). In some embodiments, myelofibrosis is associated with a hematological disorder (e.g., selected from polycythemia vera, essential thrombocythemia, myelodysplasia, hairy cell leukemia, lymphoma (e.g., Hodgkin's lymphoma or non-Hodgkin's lymphoma), multiple myeloma, or chronic myeloid leukemia (CML) One or more hematological disorders) is associated. In some embodiments, myelofibrosis is associated with (e.g., is secondary to) a non-hematological disorder (e.g., selected from a non-hematological disorder that metastasizes to the bone marrow from a solid tumor), 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.

[0070] In some embodiments, the fibrotic condition is a fibrotic condition of a joint. In some embodiments, the fibrotic condition of a joint is arthrofibrosis. In one embodiment, the fibrotic condition of a joint occurs in the knee, hip, ankle, foot joint, shoulder, elbow, wrist, hand joint, spine, or a combination thereof. In some embodiments, arthrofibrosis occurs after a total knee replacement or even a partial knee replacement.

[0071] In some embodiments, fibrosis is associated with graft-versus-host disease (GVHD). In some embodiments, fibrosis is associated with scleroderma GVHD, chronic GVHD of the lungs, or chronic GVHD of the liver. In some embodiments, fibrosis is fibrosis of the liver, lungs, pancreas, kidneys, bone marrow, heart, skin, intestines, or joints. In some embodiments, fibrosis is fibrosis of the liver. In some embodiments, fibrosis is fibrosis of the lungs. In some embodiments, 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, cancer is a solid tumor cancer.

[0072] Suitably, the fibrotic disorder in the human patient (characterised by increased expression of ECM, or collagen I, MMP-9 and / or TIMP-1, or EMT) is liver fibrosis, dilated cardiomyopathy, chronic hypoxia, interstitial lung disease or idiopathic pulmonary fibrosis.

[0073] Interstitial lung disease and idiopathic pulmonary fibrosis

[0074] In one embodiment, the fibrotic condition is interstitial lung disease (ILD). In one embodiment, the fibrotic condition is progressive fibrosing interstitial lung disease. In another embodiment, the fibrotic condition is idiopathic pulmonary fibrosis (IPF). In a specific embodiment, the fibrotic condition is progressive IPF. The characteristics of progressive IPF can be related to the rate of disease progression. For example, rapidly progressive IPF patients and slowly progressive IPF patients can be distinguished. Slowly progressive IPF can be defined as IPF in which lung function slowly and progressively decreases and dyspnea worsens. Typically, slowly progressive IPF patients experience long duration symptoms before diagnosis and experience a slowly progressive clinical course (Martinez FX et al., Ann InternMed [Annals of Internal Medicine] 2005; 142: 963-967). Slowly progressive IPF can lead to death within a few years of diagnosis. Rapidly progressive IPF involves patients who show a more rapid progressive clinical course and a shorter duration of symptoms before diagnosis and progression to death.

[0075] In addition to IPF, other progressive fibrosing interstitial lung diseases include, for example, idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-related ILD (e.g., rheumatoid arthritis-related ILD), fibrosing chronic hypersensitivity pneumonitis, fibrosing chronic sarcoidosis, and ILD associated with other occupational exposures. These diseases share certain clinical features with IPF, including: decreased respiratory function; limited treatment options; premature death; and significantly impaired quality of life. In this group of ILDs, progressive fibrosis is an important feature that is closely associated with morbidity and mortality.

[0076] In one embodiment, a method for treating interstitial lung disease (ILD) is provided, the method comprising applying a therapeutically effective amount of a Src kinase inhibitor or a pharmaceutically acceptable salt thereof to a human patient. On the other hand, a Src kinase inhibitor or a pharmaceutically acceptable salt thereof is provided for treating the 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, idiopathic interstitial pneumonia that cannot be classified, ILD associated with connective tissue disease (such as rheumatoid arthritis associated ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and the ILD associated with other occupational exposures.

[0077] The technician will know that pulmonary function tests can provide certain indications of IPF degree or severity. For example, forced vital capacity (FVC) is a lung function measurement in liters, representing the volume of air in the lungs that can be exhaled after complete inhalation, which can provide an indication of IPF severity in a patient. FVC is measured in a test called spirometry, which is a specific type of pulmonary function test. The diffusion capacity of the lungs for carbon monoxide (DLCO) represents the degree to which oxygen penetrates the blood from the air sacs of the lungs, and can also provide an indication of IPF degree and severity in a patient. Both FVC and DLCO can be expressed as a normal percentage for people of the same sex, age and height prediction. The technician will know the method for determining and using FVC and DLCO parameters.

[0078] In one embodiment, progressive IPF is characterized by a predicted FVC threshold between 20% and 80%, such as between 50% and 75%, between 50% and 65%, between 50% and 60%, or between 50% and 55%. In one embodiment, progressive IPF is characterized by a predicted DLCO between 20% and 70%, such as between 35% and 55%, between 35% and 45%, or between 35% and 40%.

[0079] The disease severity of IPF can be classified as mild, moderate or severe. Although there is no standardized definition of mild, moderate or severe IPF, clinical trials often use a predicted FVC threshold of 50%-55% and a predicted DLCO threshold of 35%-40% to separate mild to moderate patients from those with severe disease (M Kolb et al., Eur. Respir Rev [European Respiratory Review] 2014; 23: 220-224).

[0080] In one embodiment, the fibrotic condition is mild, moderate, or mild to moderate IPF. In one embodiment, mild to moderate IPF is characterized by a FVC threshold of greater than or equal to 50%, such as 50% and 75% or 50% to 55% of the prediction and / or a DLCO threshold of greater than or equal to 35%, such as 20% and 70% or 35% to 40% of the prediction.

[0081] In one embodiment, the fibrotic disorder is severe IPF. In one embodiment, severe IPF is characterized by a FVC threshold of less than 50%, such as less than 45%, 40%, 35%, 30%, 25%, 20%, 10%, or 5% of the prediction, and / or a DLCO threshold of less than 35%, such as less than 30%, 25%, 20%, 15%, 10%, or 5% of the prediction.

[0082] In one embodiment, progressive IPF is characterized by an annual rate of decline (as measured by FVC) of less than or equal to 0.3L, such as less than or equal to 0.25L, 0.15L or 0.12L. Suitably, the annual rate of decline (as measured by FVC) is between 0.1L and 0.3L, such as between 0.13L and 0.21L. Suitably, the annual rate of decline (as measured by FVC) is greater than or equal to 0.05L, such as greater than or equal to 0.08L, 0.10L or 0.13L. In one embodiment, progressive IPF is characterized by a rate of decline of FVC greater than or equal to 1%, such as greater than or equal to 2%, 4%, 6%, 8%, 10%, 12%, 14%, 16%, 18% or 20%. Suitably, the rate of decline of FVC is less than or equal to 20%, such as less than or equal to 18%, 16%, 14%, 12%, 10%, 8%, 6%, 4%, 2% or 1%. Suitably, the rate of decline of FVC is about 5%, such as about 10%, about 15% or about 20%.

[0083] In one embodiment, progressive IPF is characterized by a rate of decrease of DLCO of greater than or equal to 1%, such as greater than or equal to 2%, 4%, 6%, 8%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22% or 25%. Suitably, the rate of decrease of DLCO is less than or equal to 25%, such as less than or equal to 22%, 20%, 18%, 16%, 15%, 14%, 12%, 10%, 8%, 6%, 4%, 2% or 1%. Suitably, the rate of decrease of DLCO is about 5%, such as about 10%, such as about 15%, such as about 20%, such as about 25%.

[0084] In one embodiment, the fibrotic disorder is slowly progressive IPF. In one embodiment, slowly progressive IPF is characterized by a rate of decline of FVC greater than or equal to 1%, such as greater than or equal to 2%, 4%, 6% or 8%. In one embodiment, slowly progressive IPF is characterized by a rate of decline of FVC of about 5%, such as about 10%. In one embodiment, slowly progressive IPF is characterized by a rate of decline of DLCO of greater than or equal to 1%, such as greater than or equal to 2%, 4%, 6%, 8%, 10%, 12%, or 14%. In one embodiment, rapidly progressive IPF is characterized by a rate of decline of DLCO of about 5%, such as about 10%.

[0085] In one embodiment, the fibrotic disorder is a rapidly progressive IPF. In one embodiment, the rapidly progressive IPF is characterized by a rate of decline of FVC of greater than or equal to 10%, such as greater than or equal to 12%, 14%, 16%, 18% or 20%. In one embodiment, the rapidly progressive IPF is characterized by a rate of decline of FVC of about 15%, such as about 20%. In one embodiment, the rapidly progressive IPF is characterized by a rate of decline of DLCO of greater than or equal to 15%, such as greater than or equal to 16%, 18%, 20%, 22% or 25%. In one embodiment, the rapidly progressive IPF is characterized by a rate of decline of DLCO of about 15%, such as about 20% or 25%.

[0086] It should be understood that IPF can be slight, moderate, slight to moderate or severe, and can be fast or slowly progressive.Fast and slowly progressive are relevant with the rate of progression of IPF, and slight, moderate, slight to moderate and severe are relevant with the development level of IPF.In one embodiment, fibrotic condition is fast progressive IPF, and wherein IPF is characterized by slight, moderate, slight to moderate or severe IPF.In one embodiment, fibrotic condition is slowly progressive IPF, and wherein IPF is characterized by slight, moderate, slight to moderate or severe IPF.

[0087] In one embodiment, a method for treating rapidly and / or slowly progressive IPF is provided, wherein IPF is characterized by mild, moderate, mild to moderate or severe, the method comprising administering to a human patient a therapeutically effective amount of a Src kinase inhibitor or a pharmaceutically acceptable salt thereof. On the other hand, a Src kinase inhibitor or a pharmaceutically acceptable salt thereof is provided for treating rapidly and / or slowly progressive IPF, wherein in a human patient, IPF is characterized by mild, moderate, mild to moderate or severe.

[0088] Safety features

[0089] 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 induces efficacy while demonstrating safety and tolerability. In one embodiment, when used to treat IPF, the Src kinase inhibitor (e.g., salactinib) shows the same or improved efficacy with reduced adverse reactions or discontinuation compared to pirfenidone or nintedanib.

[0090] Adverse reactions are divided into different frequency groups according to system organ class (SOC). Very common means an incidence of ≥1 / 10, common means ≥1 / 100 to <1 / 10, uncommon means ≥1 / 1000 to <1 / 100, and rare means ≥1 / 10000 to <1 / 1000. In one embodiment, the number of adverse reactions associated with Src kinase inhibitors is classified as common, uncommon and / or rare.

[0091] In one embodiment, the adverse reaction is infection; infestation; blood disorder; lymphatic system disorder; immune system disorder; metabolic disorder; nutritional disorder; psychiatric disorder; nervous system disorder; vascular disorder; respiratory disorder; thoracic disorder; mediastinal disorder; gastrointestinal disorder; hepatobiliary disorder; skin disorder; subcutaneous tissue disorder; musculoskeletal disorder; connective tissue disorder; general disorder; administration site condition; injury, poisoning and / or surgical complication.

[0092] In one embodiment, the number of gastrointestinal adverse reactions associated with a Src kinase inhibitor is categorized as common, uncommon or rare. Suitably, the gastrointestinal adverse reaction is diarrhea, nausea, abdominal pain, dyspepsia, gastroesophageal reflux disease, vomiting, bloating, abdominal discomfort, stomach discomfort, gastritis, constipation and / or flatulence.

[0093] In one embodiment, the number of hepatobiliary disorders associated with a Src kinase inhibitor is categorized as common, uncommon or rare. Suitably, the hepatobiliary disorder results in increased levels of liver enzymes in a human patient.

[0094] In one embodiment, the number of nutritional disorders associated with a Src kinase inhibitor is categorized as common, uncommon or rare. Suitably, the nutritional disorder is loss of appetite.

[0095] In one embodiment, the number of skin and / or subcutaneous tissue disorders associated with a Src kinase inhibitor is categorized as common, uncommon or rare. Suitably, the skin disorder is a photosensitivity reaction and / or a rash.

[0096] In one embodiment, the number of common disorders associated with Src kinase inhibitors is categorized as common, uncommon or rare. Suitably, the common disorder is fatigue.

[0097] In one embodiment, the Src kinase inhibitor has an improved safety profile for nintedanib and / or pirfenidone. In one embodiment, the Src kinase inhibitor has a lower incidence and / or severity of adverse reactions relative to nintedanib and / or pirfenidone. In one embodiment, the Src kinase inhibitor has a lower incidence and / or severity of gastrointestinal adverse reactions relative 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 distension, abdominal discomfort, stomach discomfort, gastritis, constipation and / or flatulence relative to nintedanib and / or pirfenidone.

[0098] In one embodiment, administering a therapeutically effective amount of a Src kinase inhibitor or a pharmaceutically acceptable salt thereof to a human patient increases the overall survival rate and / or progression-free survival rate of the human patient.

[0099] In one embodiment, administration of a therapeutically effective amount of a Src kinase inhibitor or a pharmaceutically acceptable salt thereof to a human patient reduces, prevents and / or maintains symptoms of fibrosis (suitably, symptoms of IPF), including cough, decreased lung function, fatigue and dyspnea.

[0100] Pharmaceutical composition

[0101] According to another aspect of the present disclosure, there is provided a pharmaceutical composition for treating fibrosis as defined herein, the pharmaceutical composition comprising a Src kinase inhibitor as defined above, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent, excipient or carrier.

[0102] The compositions of the present disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, 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., as creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as finely divided powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as finely divided powders), or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular administration; or as suppositories for rectal administration).

[0103] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0104] The amount of active ingredient combined with one or more pharmaceutically acceptable diluents, excipients or carriers to produce a single dosage form will necessarily vary according to the treated host and the specific route of administration. For example, a formulation intended for oral administration to humans typically contains, for example, 0.5 mg to 0.5 g (more suitably from 0.5 mg to 200 mg, for example from 1 mg to 150 mg, 75 mg to 150 mg, 90 mg to 135 mg, 100 mg to 125 mg, such as 100 mg, such as about 125 mg) and an active compounded with an appropriate and suitable amount of excipients. The dosage size of the Src kinase inhibitor for the purpose of treatment or prevention will naturally vary according to the nature and severity of the disease, the age, sex and administration route of the animal or patient, according to well-known medical principles.

[0105] Dosage regimen

[0106] When using a Src kinase inhibitor for therapeutic or preventive purposes, it will generally be administered so as to receive a daily dose in the range of, for example, 0.1 mg per kilogram of body weight to 75 mg per kilogram of body weight, if necessary in divided doses. Generally speaking, when a parenteral route is employed, lower doses will be administered. Thus, for example, for intravenous administration, a dose in the range of, for example, 0.1 mg per kilogram of body weight to 30 mg per kilogram of body weight will generally be used. Similarly, for administration by inhalation, a dose in the range of, for example, 0.05 mg per kilogram of body weight to 25 mg per kilogram of body weight will be used. In one embodiment, a Src kinase inhibitor, such as saracatinib, is administered orally, for example, in the form of tablets or capsules.

[0107] 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. Suitably, the therapeutically effective amount is administered once a day. Conveniently, the therapeutically effective amount is administered once a day for at least two consecutive days, suitably at least or equal to 4 weeks, suitably at least or equal to 14 weeks, suitably at least or equal to 26 weeks, suitably at least or equal to 52 weeks, suitably at least or equal to 2 years or more.

[0108] The appropriate dosage can be determined by reference to the severity of the disease and the body size of the subject. Typical dosage ranges are 0.01 mg to 500 mg (such as 0.1 mg to 175 mg, such as 1 mg to 125 mg) per person, delivered at least once a day (such as once or twice a day). For example, the dosage of a Src kinase inhibitor (such as saracatinib) can be 100 mg, 125 mg or up to 250 mg per day.

[0109] In one embodiment, the therapeutically effective amount of a Src kinase inhibitor is between 5 mg and 500 mg per day, suitably between 10 mg and 400 mg per day, suitably between 20 mg and 300 mg per day, suitably between 30 mg and 200 mg per day, suitably between 75 mg and 150 mg per day, suitably between 100 mg and 150 mg per day, suitably between 110 mg and 140 mg per day, suitably between 120 mg and 130 mg, or suitably about 125 mg.

[0110] Combination therapy

[0111] In one embodiment, the method for treating fibrosis further comprises administering to a human patient a therapeutically effective amount of a Src kinase inhibitor or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective dose of at least one other therapeutic agent. The combined administration may be separate, simultaneous or sequential. In one embodiment, fibrosis is characterized by increased expression of collagen I and / or MMP-9 and / or TIMP-1.

[0112] Therapeutic agents refer to chemical or biological molecules that can produce a therapeutic effect in human patients, such as compounds, peptides, nucleic acids, proteins, and antibodies, or fragments thereof. In one embodiment, the therapeutic agent is a pharmaceutically active compound. In another embodiment, the therapeutic agent is an anti-fibrotic drug.

[0113] Such pharmaceutically active compounds may be, for example, compounds which are also pharmaceutically active in the treatment of fibrosis, such as pirfenidone or nintedanib. Such pharmaceutically active compounds may also be substances having secretolytic, broncholytic and / or anti-inflammatory activity, such as anticholinergic agents, 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, TGFβ inhibitors, LPA1 antagonists, LOXL2 inhibitors, CTGF inhibitors, pentoxifylline, N-acetylcysteine, anti-IL13 agents, anti-IL4 agents, αV integrin inhibitors (including inhibitors of αVβ1, αVβ2, αVβ3, αVβ4, αVβ5, αVβ6, αVβ7, αVβ8 and any combination thereof), IGF inhibitors, PI3K inhibitors, mTOR inhibitors, JNK inhibitors, penetrant 2 and / or endothelin antagonists.

[0114] Other pharmaceutically active compounds combined with Src kinase inhibitors include compounds with anti-fibrotic 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 (α and / or β), FGR inhibitors, and / or VEGFR inhibitors. In one embodiment, the anti-fibrotic drug is selected from pirfenidone or a pharmaceutically acceptable salt thereof, or nintedanib or a pharmaceutically acceptable salt thereof.

[0115] 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 pharmaceutically acceptable salt thereof, and a therapeutically effective dose of at least one anti-fibrotic, either alone, simultaneously, sequentially or in the form of a pharmaceutical composition comprising a Src kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-fibrotic. An anti-fibrotic drug is a drug as defined herein that, when administered to a human patient, reduces and / or inhibits fibrosis.

[0116] In one embodiment, one anti-fibrotic drug is administered in combination with a Src inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, two anti-fibrotic drugs are administered in combination with a Src inhibitor or a pharmaceutically acceptable salt thereof.

[0117] It should be understood that the anti-fibrotic drug may be in free form (ie, free acid or free base) or in the form of a pharmaceutically acceptable salt.

[0118] In a specific embodiment, the anti-fibrotic drug is selected from nintedanib or a pharmaceutically acceptable salt thereof; pirfenidone or a pharmaceutically acceptable salt thereof; and combinations thereof. In one embodiment, the anti-fibrotic drug is nintedanib or a pharmaceutically acceptable salt thereof. In one embodiment, the anti-fibrotic drug is pirfenidone or a pharmaceutically acceptable salt thereof. Surprisingly, the present disclosure has shown that Src kinase inhibitors, such as sacatinib, when combined with anti-fibrotic drugs such as nintedanib or pirfenidone, provide a synergistic effect in the treatment of fibrosis.

[0119] In one embodiment, a pharmaceutical composition is provided, comprising a Src kinase inhibitor or a pharmaceutically acceptable salt thereof as defined herein, and at least a pharmaceutically active compound or a pharmaceutically acceptable salt thereof. In one embodiment, a pharmaceutical composition is provided, comprising a Src kinase inhibitor or a pharmaceutically acceptable salt thereof, and at least one anti-fibrotic drug or a pharmaceutically acceptable salt thereof. In one embodiment, a pharmaceutical composition is provided, comprising a Src kinase inhibitor or a pharmaceutically acceptable salt thereof, and nintedanib or a pharmaceutically acceptable salt thereof, and / or pirfenidone or a pharmaceutically acceptable salt thereof. In one embodiment, a pharmaceutical composition is provided, comprising sacatinib or a pharmaceutically acceptable salt thereof, and nintedanib or a pharmaceutically acceptable salt thereof, and / or pirfenidone or a pharmaceutically acceptable salt thereof. In one embodiment, there is between 0.5 mg and 0.5 g, such as 0.5 mg to 200 mg, 1 mg to 150 mg, 75 mg to 150 mg, 90 mg to 135 mg or 100 mg to 125 mg of a Src kinase inhibitor in the pharmaceutical composition.

[0120] Reagent test kit

[0121] In another aspect, a pharmaceutical combination is provided, comprising (a) salacartinib or a pharmaceutically acceptable salt thereof, and (b) a therapeutically effective amount of at least one additional therapeutic agent; wherein salacartinib is present in an amount of 75 mg to 500 mg, such as 90 mg to 135 mg, such as 100 mg to 125 mg, such as about 100 mg, or about 125 mg. In one embodiment, salacartinib or a pharmaceutically acceptable salt thereof is administered once daily in an oral dosage form. In one embodiment, the additional therapeutic agent is selected from nintedanib or a pharmaceutically acceptable salt thereof, pirfenidone or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0122] In one embodiment, the pharmaceutical combination is a kit of parts. The kit comprises instructions for use and a Src kinase inhibitor as defined herein or a pharmaceutically acceptable salt thereof.

[0123] In another aspect, there is provided a kit of parts comprising instructions for use, a Src kinase inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and at least one other pharmaceutically active compound, or a pharmaceutically acceptable salt thereof.

[0124] In one embodiment, a kit is provided, the kit comprising instructions for use, a Src kinase inhibitor as defined herein or a pharmaceutically acceptable salt thereof, and at least one anti-fibrotic drug as defined herein or a pharmaceutically acceptable salt thereof.

[0125] In another aspect, a kit is provided, the kit comprising instructions for use and a pharmaceutical composition as defined herein. In one embodiment, the pharmaceutical composition comprises a Src kinase inhibitor or a pharmaceutically acceptable salt thereof, and an anti-fibrotic drug or a pharmaceutically acceptable salt thereof.

[0126] Examples

[0127] Example 1 - Kinase Selectivity

[0128] The IC50 values ​​of sacatinib, nintedanib and 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2) against c-Src, c-Yes, Lck, Lyn, c-Fyn and EGFR kinases, as well as PGFRTKα and PGFRTKβ are shown in Table 1 below.

[0129] The IC of sacatinib and PP2 was disclosed in Hennequin 2006 DOI: 10.1021 / jm060434q 50 Measured value. IC of nintedanib 50 The measured values ​​are disclosed in "Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy" published by Hilberg et al. in June 2008, Cancer Res 2008; 68: (12). 2008-06-15 DOI: 10.1158 / 0008-5472.CAN-07-6307.

[0130] Table 1: IC 50 Measurement results

[0131]

[0132] The ICs shown in Table 1 50 The assay values ​​indicate that sacatinib 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.

[0133] Example 2 - Bleomycin Model

[0134] Bleomycin sulfate was obtained from Sigma-Aldrich. IU is converted to enzyme units (U) of approximately 1.5-2U / mg. A 2mg / mL solution was prepared in 0.9% NaCl for delivery of 4U / kg in 50 μL. Bleomycin or vehicle was administered intranasally on day 0. Starting 7 days after bleomycin induction, the compound was administered orally by gavage twice daily, at a time consistent with the historical onset of fibrosis (pirfenidone at 200mg / kg BID, nintedanib at 30mg / kg BID, and sacatinib at 1, 3 or 10mg / kg BID). Body weight 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 hydroxyproline levels were analyzed as an indicator of local collagen deposition, and another lung was fixed with formalin for histopathological examination (quantitative staining with Sirius red). Half of the animals in each group were dosed 1 hour before terminal blood draw (see below) on day 21 (for C max ); the other half of the animals were not given medication (Cmin) (Table 2).

[0135] Table 2. Pharmacokinetics (PK) of Saracatinib

[0136] Dosage (mg / kg BID) Cmax(nM)+ / -SD Cmin(nM)+ / -SD 10 390+ / -224 31.8+ / -15.9 3 139+ / -75 8.41+ / -2.9 1 71.5+ / -24 2.52+ / -0.8

[0137] The results are as follows Figure 1 The observed effects indicate that salacartinib is superior to pirfenidone (at much lower doses) and may be superior to nintedanib at clinically relevant doses.

[0138] Example 3 - Effects on TGF-β-induced changes in primary human lung fibroblasts from healthy donors

[0139] Normal human lung fibroblasts from healthy donors (passage 5) were seeded in 96-well culture plates in DMEM medium containing 10% FBS and 1% penicillin-streptomycin. 2 50,000 cells were cultured. They were cultured at 37°C for 24 hours and then washed twice with DPBS and serum starved for 24 hours before adding the following treatments: salactinib, nintedanib, pirfenidone or positive control SB-525334, Alk-5 inhibitor or 0.1% DMSO (as vehicle control). The cells were incubated for 1 hour, then 0.123ng / ml TGF-β1 was added on top of the compound / vehicle treatment and the cells were incubated for 24 hours.

[0140] After 24 hours, the culture medium was collected and analyzed for IL-6, and the cells were lysed for RNA isolation, DNA synthesis and TaqMan quantitative PCR, or the cells were fixed and stained for α-smooth muscle actin (αSMA) and Hoechst nuclear stain. The percentage of cells that stained positive for αSMA was determined by high-content image analysis, and the myofibroblast phenotype was thus displayed. The Ct values ​​from quantitative PCR were normalized for the geometric Ct values ​​of the two reference genes and presented as fold expression relative to these reference genes (2^-ΔCt).

[0141] The dose required to inhibit 50% of the TGF-β1-induced response (IC50) was determined for different compounds by fitting dose-response curves to the data using a four-parameter nonlinear regression model.

[0142] Table 3: Mean IC generated from NHLF experiments stimulated by TGFβ using healthy donor 197 (n=3) 50 value

[0143]

[0144] Saracatinib showed superior efficacy at therapeutic concentrations (Table 3, Figure 2 and Figure 3 ). Indeed, saracutinib caused a dose-dependent inhibition of αSMA without affecting cell viability. Nintedanib and pirfenidone inhibited αSMA, however at supratherapeutic concentrations and with some evidence of cell death.

[0145] Example 4 - Organoid formation assay

[0146] Airway basal cells (ABC) from IPF patients have been described as "cancer-like" in terms of their proliferation, migration and anti-apoptosis. They are rich in bronchialized areas, where they extend into fibroblast foci; the structure is 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 forms 3D organoids in culture. After observing success in oncology, IPF-ABC organoid formation is being developed as a tool for screening therapeutic activity (A Prasse et al., European Respiratory Journal [European Respiratory Journal] 2017; 50; and A Prasse et al., Am J Respir Crit Care Med. [American Respiratory and Critical Care Medicine] August 24, 2018. doi: 10.1164 / rccm.201712-2551OC).

[0147] ABC is thought to be involved in the pathology of IPF, and the observed signals are associated with the severity of the disease (decline in FVC, need for lung transplantation, and risk of death). In fact, the ABC model reproduces the abnormal wound healing in IPF (such as the formation of fibroblast tubules, 3D organoid architecture, and production of ECM components). Human IPF ABC-transplanted mice recapitulate a broad spectrum of IPF pathology, including a strong fibrotic response, migration, invasion of alveolar compartments, cystic structures, etc.

[0148] Airway basal cells (ABC) derived from IPF patients or healthy volunteers (HV) The cells were cultured in a transwell system (Corning, in a transwell system with or without lung fibroblasts derived from IPF patients or normal lungs) in an incubator (5% CO2, 37°C) for up to 35 days. Medium exchange (BEGM (Lonza, Basel, Switzerland, #CC-3170) / DMEM (Dulbecco's Modified Eagle Medium (Gibco, Fisher Scientific / Germany); ratio 1:1) was performed every 7 days. The conditioned medium was used for the Sircol assay (Scientific-Biocolor / UK, #S1000) performed according to the manufacturer's recommendations (https: / / www.biocolor.co.uk / product / sircol-soluble-collagen-assay / ). Organoids were treated with 8 nM, 25 nM, 75 nM, 210 nM or 600 nM salactinib or 1 mM pirfenidone or 1 μM nintedanib (pirfenidone and nintedanib served as positive controls). Spheroid formation was performed by Axio Vert.A1 / Zeiss / Germany and Axio Observer Z1 / Zeiss / Germany records.

[0149] The results are shown in Figure 4 , 5 and 6 in. Figure 4 and Figure 5Spheroid formation of ABC treated with salactinib, pirfenidone, or nintedanib is shown at different magnification levels. Salactinib was non-cytotoxic at the concentrations tested. Nintedanib and pirfenidone had little or no effect on organoid formation at artificially high, supratherapeutic doses. These data in a mouse model of human IPFABC suggest that salactinib is distinct and uniquely effective relative to nintedanib or pirfenidone.

[0150] Example 5 - DiscoverX

[0151] The BioMAP panel consists of human primary cell-based systems designed to mimic different aspects of the human body in an in vitro format. The 12 systems available in the Diversity PLUS panel allow for the characterization of test agents in an unbiased manner across a broad set of systems that model various human disease states. BioMAP systems are constructed with one or more primary cell types from healthy human donors and stimuli (such as cytokines or growth factors) are added to capture relevant signaling networks that occur naturally in human tissues or pathological conditions. The systems recapitulate aspects of the systemic immune response, including monocyte-driven Th1 inflammation (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 the BF4T system (Th2) represent airway inflammation of the lung, while the MyoF system models myofibroblast-lung tissue remodeling.

[0152] Each test agent generates a signature BioMAP profile created from changes in readouts of protein biomarkers within the context of a single system. Biomarker readouts (7-17 per system) are selected for therapeutic and biological relevance, predictive of disease outcome or specific drug action, and validated using agents with known mechanisms of action (MoA). Each readout is quantitatively measured by either immunological-based methods that detect proteins (such as ELISA) or functional assays that measure proliferation and viability. BioMAP readouts are diverse and include cell surface receptors, cytokines, chemokines, matrix molecules, and enzymes.

[0153] Using custom designed software with data mining tools, BioMAP profiles can be compared to a proprietary reference database of >4,000 BioMAP profiles of biologically active agents (biologics, approved drugs, chemicals, and experimental agents) to classify and identify the most similar profiles. This powerful data platform allows for rapid evaluation and interpretation of BioMAP profiles through unbiased mathematical identification of similar activities. Specific BioMAP activities are correlated with in vivo biology, and multiparametric BioMAP profiles have been used to discriminate compounds based on MoA and target selectivity, and can provide predictive signatures for in vivo toxicological outcomes (e.g., vascular toxicity, developmental toxicity, etc.) in different physiological systems.

[0154] Saracatinib and Nintedanib were prepared as stock solutions at 10mM concentration in 100% DMSO. In the ComboELECT panel, a 4x4 combinatorial array was created to test all mixtures of two serial dilutions of a single test agent / drug. Test agents / drugs were screened in triplicate at 4 concentrations (3-fold dilutions: Saracatinib at 3.3μM, 1.1μM, 0.367μM, and 0.123μM; Nintedanib at 1μM, 330μM, 110μM, and 37μM) in selected BioMAP systems (50+ human biological and disease model systems available through BioMAP Combo ELECT).

[0155] The results are shown in Figure 7 , 8 and 9.

[0156] Figure 7 It was shown that saracutinib caused a decrease in N-cadherin expression and an increase in α-SMA expression; both are associated with myofibroblast activation. Saracutinib also caused a decrease in TIMP-1 and MMP-9 expression; both are associated with fibrosis-related matrix. Saracutinib caused a decrease in the expression of sVEGF. The expression of sVEGF is associated with tissue remodeling and / or wound healing. In addition, saracutinib caused a decrease in the expression of sIL-8 and sIL-6, and an increase in the expression of VCAM-1 protein. These are associated with inflammation.

[0157] Figure 8 showed that nintedanib caused a decrease in the expression of TIMP-1 and MMP-9, both of which are associated with fibrosis-associated stroma.

[0158] Fig. 9 The combination of saracutinib and nintedanib resulted in novel inhibition of collagen I and greater inhibition of MMP-9 and TIMP-1 relative to saracutinib or nintedanib alone.

[0159] Example 6 - Safety and Tolerability

[0160] Saracatinib (100 mg or 125 mg daily) has been tested in double-blind placebo-controlled clinical trials in human patients with Alzheimer's disease (AD). For the treatment of idiopathic pulmonary fibrosis (IPF), the safety and tolerability profiles were compared with those 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), and the safety and tolerability results are summarized in Tables 4, 5, and 6 below.

[0161] Table 4. Gastrointestinal disorders

[0162]

[0163] As shown in Table 4, sacatinib has a better gastrointestinal tolerability profile than nintedanib.

[0164] Table 5. Common barriers

[0165]

[0166] 1 Nobel et al. 2016

[0167] 2 Richeldi et al. 2016

[0168] 3 Pirfenidone Medical Review (Pirfenidone n=345; Placebo n=347)

[0169] As shown in Table 5, sacatinib had a similar or better general tolerability profile than nintedanib and pirfenidone.

[0170] Table 6. Treatment discontinuation

[0171]

[0172] As shown in Table 6, saracatinib treatment resulted in fewer discontinuations.

[0173] This written description uses examples to disclose the invention and enable those skilled in the art to practice the invention, including making and using any salt, substance or composition disclosed herein, and performing any method or process disclosed herein. The patentable scope of the invention is defined by the claims and may include other examples that occur to those skilled in the art. If such other examples have elements that are indistinguishable from the literal language of the claims, or if they include equivalent elements that are insubstantially different from the literal language of the claims, these examples are intended to be included within the scope of the claims. Although preferred embodiments of the invention are shown and described in this specification, 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 embodiments of the invention may be employed when implementing the invention. The section headings used in this section and throughout the disclosure are not intended to be limiting.

[0174] All of the above references (patent and non-patent) are incorporated into this patent application by reference. The discussion of these references is intended only to summarize the assertions made by their authors. No admission is made that any reference (or part of any reference) is relevant prior art (or is prior art). Applicants reserve the right to question the accuracy and relevance of the cited references.

Claims

1. Use of saracatinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating idiopathic pulmonary fibrosis (IPF) in a human patient, wherein the IPF is characterized by abnormal collagen deposition, or by abnormal formation of persistent, debilitating lesions or scars as determined by high-resolution computed tomography (HRCT) or biopsy.

2. The method according to claim 1, wherein the IPF is further characterized by epithelial-mesenchymal transition (EMT).

3. The use according to claim 1 or 2, wherein the IPF is further characterized by increased expression of collagen I and / or MMP-9 and / or TIMP-1.

4. The use according to claim 1 or 2, wherein the IPF is further characterized by increased expression of sVEGF and / or sIL-8 and / or sIL-6.

5. The use according to claim 1 or 2, wherein the IPF is further characterized by decreased expression of VCAM-1.

6. The use according to claim 1 or 2, wherein the IPF is further characterized by the formation of extracellular matrix (ECM).

7. Use of sacatinib or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating idiopathic pulmonary fibrosis in a human patient.

8. The use according to claim 7, wherein the IPF is characterized by increased expression of collagen I and / or MMP-9 and / or TIMP-1.

9. A drug combination comprising: a. saracatinib or a pharmaceutically acceptable salt thereof; and b. a therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof; Wherein saracatinib is present in an amount of 75 mg to 500 mg.

10. The pharmaceutical combination according to claim 9, wherein saracatinib is present in an amount of 90 mg to 135 mg.

11. The pharmaceutical combination according to claim 10, wherein saracatinib is present in an amount of 100 mg to 125 mg.

12. The pharmaceutical combination according to claim 11, wherein saracatinib is present in an amount of 100 mg.

13. The pharmaceutical combination according to claim 11, wherein saracatinib is present in an amount of 125 mg.

14. The pharmaceutical combination according to any one of claims 9 to 13, wherein saracatinib or a pharmaceutically acceptable salt thereof is administered once daily in an oral dosage form.

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