Use of inhibitors of insulin-like growth factor receptor-1 for fibrotic diseases

Abstract

Provided are methods of treating a fibrotic disorder comprising administering one or more compounds that inhibit IGF-1R.

Description

USE OF INHIBITORS OF INSULIN-LIKE GROWTH FACTOR RECEPTOR- 1 FOR FIBROTIC DISEASESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 623,051 filed on January 19, 2024, the disclosure of which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Fibrotic diseases encompass a wide spectrum of entities including multisystem diseases such as systemic sclerosis and nephrogenic systemic fibrosis as well as organspecific disorders such as pulmonary, liver, and kidney fibrosis. Collectively, given the wide variety of affected organs, the chronic nature of the fibrotic processes, and the large number of individuals suffering from their devastating effects, fibrotic disease pose a serious health problem and economic burden.

[0003] An effective treatment for fibrotic diseases is still required.BRIEF SUMMARY OF THE INVENTION

[0004] In certain aspects, the present disclosure provides methods of treating a subject having a fibrotic disease, comprising administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibits insulin-like growth factor receptor-1 (IGF-1R). In certain aspects, the fibrotic diseases is idiopathic pulmonary fibrosis, progressive systemic sclerosis, scleroderma, Sjogren’s syndrome, arthrofibrosis, rheumatoid arthritis, juvenile idiopathic arthritis, diffuse idiopathic skeletal hyperostosis, ossification of posterior longitudinal ligament, fibrous dysplasia, cystic fibrosis bone disease obliterative bronchiolitis, pulmonary fibrosis, asbestosis, silicosis, chronic pulmonary hypertension, primary biliary cirrhosis, schistosomal liver disease, liver cirrhosis, primary sclerosing cholangitis, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial fibrosis, pericardial fibrosis, myocardial infarction, arrhythmogenic right ventricular cardiomyopathy, fibrotic vascular disease, tubulointerstitial fibrosis, glomerular fibrosis, nephrogenic systemic fibrosis, polycystickidney disease, diabetic nephropathy, chronic glomerulonephritis, lupus erythematosus, systemic lupus nephritis, cerebral gliosis, muscular dystrophy, diabetes type 1, Grave’s disease, mediastinal fibrosis, retroperitoneal fibrosis, myelofibrosis, adhesive capsulitis, Crohn's disease, keloid, chronic graft versus host disease, epiretinal fibrosis, retinal fibrosis, subretinal fibrosis, diabetic retinopathy, glaucoma, corneal fibrosis, conjunctival fibrosis, sub-conjunctival fibrosis, fibrotic neoplastic disease, fibrotic Riedel thyroiditis, or fibrosis induced by chemical or environmental insult. In certain aspects, the fibrotic disease is idiopathic pulmonary fibrosis.

[0005] In other aspects, the present disclose provides methods of treating a fibroma in a subject, comprising: administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that insulin-like growth factor receptor- 1 (IGF-1R).

[0006] In still other aspects, the present disclosure provides methods of treating a sarcoma in a subject, comprising: administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibit insulin-like growth factor receptor- 1 (IGF-1R). In some aspects, the sarcoma comprises an IGF-1R amplification. In some aspects, wherein the sarcoma is breast sarcoma, uterine carcinosarcoma, dedifferentiated liposarcoma, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, Ewing sarcoma, or other sarcoma.

[0007] In these aspects, the one or more compounds is an antibody, or an antigen binding fragment thereof, or a small molecule or a salt or polymorph thereof. The one or more compounds can be selected from the group consisting of teprotumumab, ganitumab, figitumumab, MED 1-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS- 536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, INSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A-928605, or a salt or polymorph of any of the foregoing. The one or more compounds can be an antibody, or an antigen binding fragment thereof. The one or more compounds can be a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy. The one or more compounds can be a small molecule.

[0008] In these aspects, the one or more compounds that inhibits IGF-1R also inhibits insulin receptor (IR). The one of more compounds that inhibit IGF-1R and IR can be selected from the group consisting of linsitinib, or a pharmaceutically acceptable salt thereof, GSK1904529A, or a pharmaceutically acceptable salt thereof, BMS-536924, or a pharmaceutically acceptable salt thereof, GSK1838705A, or a pharmaceutically acceptable salt thereof, AG- 1024, or a pharmaceutically acceptable salt thereof, certinib, or a pharmaceutically acceptable salt thereof, and BMS-754807, or a pharmaceutically acceptable salt thereof. The compound that inhibits IGF-1R and IR can be linsitinib, or a pharmaceutically acceptable salt thereof.

[0009] In these aspects, the one or more compounds is administered orally, intradermally, subcutaneously (SC), intravenously (IV), or by inhalation.

[0010] In these aspects, the one or more compounds that inhibit IGF-1R is administered one or more times per day. In these aspects, the one or more compounds that inhibit IGF- 1R is administered orally four times per day, three times per day, twice per day or once per day.DETAILED DESCRIPTION OF THE INVENTIONI. Definitions

[0011] So that the present disclosure can be more readily understood, certain terms are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0013] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more," and "at least one" can be used interchangeably herein. In certain aspects, the term "a" or "an" means "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple."

[0014] Furthermore, "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B,""A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0015] The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” can modify a numerical value above and below the stated value by a variance of, e.g., 10 percent, up or down (higher or lower). In some aspects of the disclosure, the term “about” encompasses a deviation from the recited value of between 0.001% and 10%, inclusive of the endpoints. In some aspects, the term “about” encompasses an increase from the recited value of between 0.001% and 10%, inclusive of the endpoints. In some aspects, the term “about” encompasses a decrease from the recited value of between 0.001% and 10%, inclusive of the endpoints.

[0016] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form.

[0017] Numeric ranges are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values.

[0018] The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the disclosure. Thus, ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0019] Any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective measurements. Additionally, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range "1 to 10" should be considered to include any and all subranges between (and inclusive of) the minimum value of 1 and the maximum value of10; that is, all subranges beginning with a minimum value of 1 or more, such as 1 to 6.1, and ending with a maximum value of 10 or less, such as 5.5 to 10.

[0020] Where a value is explicitly recited, it is to be understood that values, which are about the same quantity or amount as the recited value are also within the scope of the disclosure. Where a combination is disclosed, each sub-combination of the elements of that combination is also specifically disclosed and is within the scope of the disclosure. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of a disclosure is disclosed as having a plurality of alternatives, examples of that disclosure in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of a disclosure can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed.

[0021] An IGF-1R inhibitor is a compound that interferes with, either directly or indirectly, and reduces or blocks IGF-1R signaling. Preferably, an IGF-1R inhibitor is a compound that reduces or blocks the tyrosine kinase activity of the IGF-1R. By blocking tyrosine kinase activity of the receptor downstream signaling through the IGF-1R is reduced or blocked. In some aspects, the IGF-1R inhibitor neutralizes the growth promoting properties of the insulin-like growth factors, IGF-1 and IGF-2.

[0022] A “pharmaceutical composition” comprises an IGF-1R inhibitor (e.g., linsitinib), or a pharmaceutically acceptable salt thereof, having a desired degree of purity in a physiologically acceptable carrier, excipient or stabilizer. Pharmaceutically acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0023] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible withthe other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0024] The term "pharmaceutically-acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of an IGF-1R inhibitor (e.g., linsitinib). These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

[0025] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.

[0026] The terms “fibrotic,” “fibrosis, ’’fibrotic action,” “fibrotic change,” or their lexical variants refer to chronic and progressive processes characterized by an excessivedeposition of extracellular matrix (ECM) leading to overgrowth, hardening, scarring of tissues and / or replacement of normal parenchymal tissue with connective tissue. Fibroses can be caused by a failure to control abnormal wound healing responses, repeated injuries, chronic inflammation and repair and can lead to considerable tissue remodeling and organ malfunction. The deposition of connective tissue can interfere with or totally inhibit the normal architecture and function of the underlying tissue or organ. Fibrosis is initiated when immune cells such as macrophages release soluble factors such as TGF-P, connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), and interleukin- 10 (IL-10) that stimulate fibroblast. These signals initiate signal transduction pathways such as the Akt / mTOR and the SMAD pathways that ultimately lead to the proliferation and activation of fibroblasts, which deposit extracellular matrix into the surrounding connective tissue.

[0027] Fibrotic changes may affect almost all tissues and organs, including skin, kidney lung, and liver as well as the vascular system. Aberrant fibrotic tissue remodeling can also be involved in the initiation and progression of tumorous growth.

[0028] Non-limiting examples of fibrotic diseases that may be treated with the compositions of the invention include, but are not limited to idiopathic pulmonary fibrosis, systemic sclerosis, progressive systemic sclerosis, scleroderma, ossification of posterior longitudinal ligament, fibrous dysplasia, cystic fibrosis bone disease, obliterative bronchiolitis, pulmonary fibrosis, asbestosis, silicosis, chronic pulmonary hypertension, primary biliary cirrhosis, schistosomal liver disease, liver cirrhosis, primary sclerosing cholangitis, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial fibrosis, pericardial fibrosis, myocardial infarction, arrhythmogenic right ventricular cardiomyopathy, fibrotic vascular disease, tubulointerstitial fibrosis, glomerular fibrosis, nephrogenic systemic fibrosis, polycystic kidney disease, diabetic nephropathy, chronic glomerulonephritis, systemic lupus nephritis, cerebral gliosis, muscular dystrophy, arthrofibrosis, arthritis, mediastinal fibrosis, retroperitoneal fibrosis, myelofibrosis, adhesive capsulitis, Crohn's disease, keloid, chronic graft versus host disease, epiretinal fibrosis, retinal fibrosis, subretinal fibrosis, diabetic retinopathy, glaucoma, corneal fibrosis, conjunctival fibrosis, sub-conjunctival fibrosis, fibrotic neoplastic disease, fibrotic Riedel thyroiditis, or fibrosis induced by chemical or environmental insult.

[0029] The terms "tumor" and "neoplasm" as used herein refer to any mass of tissue that result from excessive cell growth or proliferation, either benign (non-tumor) or malignant (tumor) including pre-tumor lesions.

[0030] The terms "sarcoma" as used herein refer to or describe the physiological condition in mammals in which a population of cells are characterized by uncontrolled or unregulated cell growth. Non-limiting examples of sarcomas include, but are not limited to breast sarcoma, uterine carcinosarcoma, dedifferentiated liposarcoma, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, Ewing sarcoma, or other sarcoma.

[0031] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.

[0032] As used herein, the terms "treat," "treated," and "treating" mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Thus, those in need of treatment include those already diagnosed with or suspected of having the disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0033] The term "administering," as used herein, refers to any mode of transferring, delivering, introducing, or transporting a therapeutic agent to a subject in need of treatment with such an agent. Such modes of administration include, but are not limited to, oral, topical, intravenous, intraperitoneal, intramuscular, intradermal, intranasal, andsubcutaneous, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions.

[0034] The term “therapeutically effective amount” refer to an amount of an agent (e.g., linsitinib) that provides beneficial or desired therapeutic and / or prophylactic results. For prophylactic use, beneficial or desired results can include, for example, one or more results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results can include, for example, one or more clinical results such as decreasing one or more symptoms and pathological conditions resulting from or associated with the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing the effect of other medication such as via targeting, delaying the progression of the disease, and / or prolonging survival. An effective amount can be, for example, an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As it is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an effective amount may be considered in the context of administering one or more therapeutic agents. An effective amount can be administered in one dosage or can be divided into multiple dosages, the total of such dosages being the effective amount. For example, an effective amount can be provided in two separate administrations over a period of time, that in aggregate, provide the effective amount of the formulation.

[0035] In the case of a fibrotic disease, the therapeutically effective amount of the agent or drug can reduce the number of fibrosis causing cells; reduce the deposit of extracellular matrix and / or fibers; inhibit (i.e., slow to some extent and in some aspects, stop) fibroblast infiltration into tissues; inhibit (i.e., slow to some extent and in some aspects, stop) deposition of extracellular matrix proteins; inhibit, to some extent, fibrous scar tissue development; and / or relieve to some extent one or more of the symptoms associated with the fibrosis. The therapeutically effective amount can have the effect ofreducing one or more of tissue constriction, organ dysfunction, improving constitutional symptoms (such as fatigue, night sweats, cough, pruritus, muscle, joint, bone pain).

[0036] A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0037] In the case of sarcoma, the therapeutically effective amount of the agent or drug can reduce the number of sarcoma cells; reduce the tumor size; inhibit (i.e., slow to some extent and in a certain aspect, stop) sarcoma cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and in a certain aspect, stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the sarcoma. To the extent the compounds of the invention can prevent growth and / or kill existing sarcoma cells, they can be cytostatic and / or cytotoxic. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, but not necessarily, since a prophylactic dose is used in subjects prior to the presence of a sarcoma, at a stage of a pre-sarcoma lesion, and / or at an earlier stage of sarcoma the prophylactically effective amount will be less than the therapeutically effective amount.

[0038] The term “pharmaceutical composition” as used herein refers to a mixture of compound and / or additional therapeutic agent with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. Pharmaceutically acceptable carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients are nontoxic to recipients at the dosages and concentrations employed and include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.II. Methods of Treatment

[0039] In certain aspects, the present disclosure provides methods of treating a subject having a fibrotic disease, comprising administering to the subject, in need thereof, atherapeutically effective amount of one or more compounds that inhibits insulin-like growth factor receptor-1 (IGF-1R) (e.g., linsitinib).

[0040] In some aspects, the method comprises treating a subject having an idiopathic pulmonary fibrosis, progressive systemic sclerosis, scleroderma, Sjogren’s syndrome, arthrofibrosis, rheumatoid arthritis, juvenile idiopathic arthritis, diffuse idiopathic skeletal hyperostosis, ossification of posterior longitudinal ligament, fibrous dysplasia, cystic fibrosis bone disease obliterative bronchiolitis, pulmonary fibrosis, asbestosis, silicosis, chronic pulmonary hypertension, primary biliary cirrhosis, schistosomal liver disease, liver cirrhosis, primary sclerosing cholangitis, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial fibrosis, pericardial fibrosis, myocardial infarction, arrhythmogenic right ventricular cardiomyopathy, fibrotic vascular disease, tubulointerstitial fibrosis, glomerular fibrosis, nephrogenic systemic fibrosis, polycystic kidney disease, diabetic nephropathy, chronic glomerulonephritis, lupus erythematosus, systemic lupus nephritis, cerebral gliosis, muscular dystrophy, diabetes type 1, Grave’s disease, mediastinal fibrosis, retroperitoneal fibrosis, myelofibrosis, adhesive capsulitis, Crohn's disease, keloid, chronic graft versus host disease, epiretinal fibrosis, retinal fibrosis, subretinal fibrosis, diabetic retinopathy, glaucoma, corneal fibrosis, conjunctival fibrosis, sub-conjunctival fibrosis, fibrotic neoplastic disease, fibrotic Riedel thyroiditis, or fibrosis induced by chemical or environmental insult. In some aspects, the subject suffers from idiopathic pulmonary fibrosis. In some aspects, the subject suffers from a Ewing sarcoma.

[0041] Methods of treating a fibroma in a subject, comprising: administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that insulin-like growth factor receptor- 1 (IGF-1R) are also disclosed herein.

[0042] Methods of treating a sarcoma in a subject, comprising: administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibit insulin-like growth factor receptor-1 (IGF-1R) are also disclosed herein. In some aspects, the sarcoma comprises an IGF-1R amplification. In some aspects, wherein the sarcoma is breast sarcoma, uterine carcinosarcoma, dedifferentiated liposarcoma, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, Ewing sarcoma, or other sarcoma.

[0043] In some aspects, the one or more compounds that inhibit IGF-1R is an antibody, or an antigen binding fragment thereof, or a small molecule or a salt or polymorph thereof. The one or more compounds that inhibit IGF-1R can be selected from the group consisting of teprotumumab, ganitumab, figitumumab, MED 1-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, B MS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL- 2258, INSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A- 928605, or a salt or polymorph of any of the foregoing. The one or more compounds that inhibit IGF-1R can be an antibody, or an antigen binding fragment thereof. The one or more compounds can be a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy. The one or more compounds that inhibit IGF-1R can be a small molecule.

[0044] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) is administered one or more times per day. For example, in some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) is administered four times per day, three times per day, twice per day or once per day.

[0045] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib), is administered orally. In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) is administered intravenously, intraperitoneally, subcutaneously, and / or intramuscular.

[0046] In some aspects the method further comprises co-administering the one or more compounds that inhibit IGF-1R and an additional anti-fibrotic and / or anti -neoplastic therapeutic to the subject in need thereof.

[0047] In some aspects, the methods comprise administering to the subject a therapeutically effect amount of one or more compounds that inhibit IGF-1R and IR. In some aspects, the one or more compounds that inhibit IGF-1R and IR can be selected from the group consisting of linsitinib, or a pharmaceutically acceptable salt thereof, GSK1904529A, or a pharmaceutically acceptable salt thereof, BMS-536924, or a pharmaceutically acceptable salt thereof, GSK1838705A, or a pharmaceutically acceptable salt thereof, AG- 1024, or a pharmaceutically acceptable salt thereof, ceritinib, or a pharmaceutically acceptable salt thereof, or BMS-754807, or a pharmaceuticallyacceptable salt thereof. In some aspects, the method comprises administering to the subject a therapeutically effective amount of a compound that inhibits IGF-1R and IR that is linsitinib, or a pharmaceutically acceptable salt thereof.

[0048] In some aspects, the IGF-1R and IR receptor inhibitor (e.g., linsitinib), or a pharmaceutically acceptable salt thereof, is administered one or more times per day. For example, in some aspects, the IGF-1R and IR receptor inhibitor (e.g., linsitinib), or a pharmaceutically acceptable salt thereof, is administered orally four times per day, three times per day, twice per day or once per day.

[0049] In some aspects, the IGF-1R and IR receptor inhibitor (e.g., linsitinib), or a pharmaceutically acceptable salt thereof, is administered orally. In some aspects, the IGF- 1R and IR receptor inhibitor (e.g., linsitinib), or pharmaceutically acceptable salt thereof, is administered intravenously, intraperitoneally, subcutaneously, and / or intramuscular.

[0050] In some aspects, the IGF-1R and IR inhibitor (e.g., linsitinib), or pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount. In some aspects the method further comprises co-administering the IGF-1R and IR receptor inhibitor and an additional anti-fibrotic and / or anti -neoplastic therapeutic to the subject in need thereof.

[0051] The dosage of the one or more compounds that inhibit the IGF-1R receptor may further vary between patients, based on different factors such as the age, gender, race, and body weight of each patient. In some embodiments, the dosage varies by body weight of the patient. The dosage could range from about 1 mg of the antibody, or an antigen binding fragment thereof, per kilogram of body weight to about 100 mg of the antibody, or an antigen binding fragment thereof, per kilogram of body weight.

[0052] Small molecule compounds may be administered orally, via injection, etc. at a dose of from 0.01 to 500 mg / kg per day and / or from 0.1 mg to 5 g per day. The dose range for adult humans is generally from 5 mg to 2 g / day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of the one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, for example around 10 mg to 200 mg.III. Pharmaceutical Compositions

[0053] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) and / or additional therapeutic agent described herein are formulated as compositions for oral, intravenously, intraperitoneal, subcutaneous, and / or intramuscular administration.

[0054] The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0055] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) and / or additional therapeutic agent described herein are formulated by combining the components with, e.g., pharmaceutically acceptable carriers or excipients. In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib) and / or additional therapeutic agent described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0056] In some aspects, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with the compound and / or additional therapeutic agent described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.IV. Kits

[0057] In some aspect, the present disclosure relates to a kit comprising a pharmaceutical composition comprising the one or more compounds that inhibit IGF-1R (e.g., linsitinib) packaged in a manner that facilitates its use to practice methods of the present disclosure.

[0058] In some aspects, the kit further comprises instructions for administering the pharmaceutical composition comprising the one or more compounds that inhibit IGF-1R (e.g., linsitinib) to treat a fibrotic disease and / or a sarcoma.

[0059] All of the references cited herein are incorporated herein by reference in their entireties.

[0060] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.EXAMPLE

[0061] Pilot studies of the effects of a compound that inhibits IGF-1R on human lung fibroblasts (HLFs) will be conducted. Specficially, the ability of the compound to dedifferentiate (a.k.a. to phenotypically reverse) established myofibroblasts - as defined by the loss of expression of alpha-smooth muscle actin (a-SMA) will be investigated. The established myofibroblasts to be employed can either be 1) normal HLFs differentiated to myofibroblasts via 48 h treatment with TGF-b, or 2) cells isolated from lungs of patients with IPF.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a subject having a fibrotic disease, comprising administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibits insulin-like growth factor receptor- 1 (IGF-1R).

2. The method of claim 1, wherein the one or more compounds is an antibody, or an antigen binding fragment thereof, or a small molecule or a salt or polymorph thereof.

3. The method of claim 2, wherein the one or more compounds is selected from the group consisting of teprotumumab, ganitumab, figitumumab, MED 1-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, B MS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL- 2258, INSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A- 928605, or a salt or polymorph of any of the foregoing.

4. The method of claim 3, wherein the one or more compounds is an antibody, or an antigen binding fragment thereof.

5. The method of claim 4, wherein the one or more compounds is a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy.

6. The method of claim 3, wherein the one or more compounds is a small molecule.

7. The method of any one of claims 1-6, wherein the one or more compounds that inhibits IGF-1R also inhibits insulin receptor (IR).

8. The method of claim 7, wherein the one or more compounds that inhibits IGF-1R and IR is selected from the group consisting of linsitinib, or a pharmaceutically acceptable salt thereof, GSK1904529A, or a pharmaceutically acceptable salt thereof, BMS-536924, or apharmaceutically acceptable salt thereof, GSK1838705A, or a pharmaceutically acceptable salt thereof, AG- 1024, or a pharmaceutically acceptable salt thereof, certinib, or a pharmaceutically acceptable salt thereof, and BMS-754807, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the inhibitor of IGF-1R and IR is linsitinib, or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1-9, wherein the one or more compounds is administered orally, intradermally, subcutaneously (SC), intravenously (IV), or by inhalation.

11. The method of any one of claims 1-10, wherein the one or more compounds that inhibit IGF-1R is administered one or more times per day.

12. The method of any one of claims 1-10, wherein the one or more compounds that inhibit IGF-1R is administered orally four times per day, three times per day, twice per day or once per day.

13. The method of any one of claims 1-12, wherein the fibrotic diseases is idiopathic pulmonary fibrosis, progressive systemic sclerosis, scleroderma, Sjogren’s syndrome, arthrofibrosis, rheumatoid arthritis, juvenile idiopathic arthritis, diffuse idiopathic skeletal hyperostosis, ossification of posterior longitudinal ligament, fibrous dysplasia, cystic fibrosis bone disease obliterative bronchiolitis, pulmonary fibrosis, asbestosis, silicosis, chronic pulmonary hypertension, primary biliary cirrhosis, schistosomal liver disease, liver cirrhosis, primary sclerosing cholangitis, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial fibrosis, pericardial fibrosis, myocardial infarction, arrhythmogenic right ventricular cardiomyopathy, fibrotic vascular disease, tubulointerstitial fibrosis, glomerular fibrosis, nephrogenic systemic fibrosis, polycystic kidney disease, diabetic nephropathy, chronic glomerulonephritis, lupus erythematosus, systemic lupus nephritis, cerebral gliosis, muscular dystrophy, diabetes type 1, Grave’s disease, mediastinal fibrosis, retroperitoneal fibrosis, myelofibrosis, adhesive capsulitis,Crohn's disease, keloid, chronic graft versus host disease, epiretinal fibrosis, , retinal fibrosis, subretinal fibrosis, diabetic retinopathy, glaucoma, corneal fibrosis, conjunctival fibrosis, sub-conjunctival fibrosis, fibrotic neoplastic disease, fibrotic Riedel thyroiditis, or fibrosis induced by chemical or environmental insult.

14. The method of any one of claims 1-12, wherein the fibrotic disease is idiopathic pulmonary fibrosis.

15. A method of treating a fibroma in a subject, comprising: administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that insulinlike growth factor receptor- 1 (IGF-1R).

16. A method of treating a sarcoma in a subject, comprising: administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibit insulin-like growth factor receptor-1 (IGF-1R).

17. The method of claim 16, wherein the sarcoma comprises an IGF-1R amplification.

18. The method of any one of claims 16 or 17, wherein the sarcoma is breast sarcoma, uterine carcinosarcoma, dedifferentiated liposarcoma, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, Ewing sarcoma, or other sarcoma.

19. The method of any one of claims 15-18, wherein the one or more compounds is an antibody, or an antigen binding fragment thereof, or a small molecule or a salt or polymorph thereof.

20. The method of claim 19, wherein the one or more compounds is selected from the group consisting of teprotumumab, ganitumab, figitumumab, MED 1-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A,GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL- 2258, INSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A- 928605, or a salt or polymorph of any of the foregoing.

21. The method of claim 20, wherein the one or more compounds is an antibody, or an antigen binding fragment thereof.

22. The method of claim 21, wherein the one or more compounds is a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy.

23. The method of claim 20, wherein the one or more compounds is a small molecule.

24. The method of any one of claims 15-23, wherein the one or more compounds that inhibits IGF-1R also inhibits insulin receptor (IR).

25. The method of claim 24, wherein the one or more compounds that inhibits IGF-1R and IR is selected from the group consisting of linsitinib, or a pharmaceutically acceptable salt thereof, GSK1904529A, or a pharmaceutically acceptable salt thereof, BMS-536924, or a pharmaceutically acceptable salt thereof, GSK1838705A, or a pharmaceutically acceptable salt thereof, AG- 1024, or a pharmaceutically acceptable salt thereof, certinib, or a pharmaceutically acceptable salt thereof, and BMS-754807, or a pharmaceutically acceptable salt thereof.

26. The method of claim 25, wherein the inhibitor of IGF-1R and IR is linsitinib, or a pharmaceutically acceptable salt thereof.

27. The method of any one of claims 15-26, wherein the one or more compounds is administered orally, intradermally, subcutaneously (SC), intravenously (IV), or by inhalation.

28. The method of any one of claims 15-27, wherein the one or more compounds that inhibit IGF-1R is administered one or more times per day.

29. The method of any one of claims 15-27 wherein the one or more compounds that inhibit IGF-1R is administered orally four times per day, three times per day, twice per day or once per day.