Treatment of thyroid eye disease

Abstract

Methods for treating thyroid eye disease in a subject in need thereof, that include orally administering to the subject a twice-daily dose of about 75 mg to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof; testing one or both of the subject's serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels after about six consecutive weeks of administering the twice-daily dose; and testing one or both of the subject's serum ALT and AST levels after about twelve consecutive weeks of administering the twice-daily dose.

Description

ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004TREATMENT OF THYROID EYE DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 743,081, filed January 8, 2025, the disclosure of which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Thyroid eye disease, also known as Graves’ ophthalmopathy, is an autoimmune condition characterized by inflammation and swelling of the tissues surrounding the eyes. Thyroid eye disease is commonly associated with hyperthyroidism and Graves’ disease in particular. Graves’ disease is an autoimmune disorder characterized by the production of antibodies that stimulate the thyroid gland, leading to hyperthyroidism. Thyroid eye disease can occur, however, in people who do not have Graves’ disease.

[0003] Human insulin-like growth factor- 1 receptor (IGF-1R) signaling has been found to be dysregulated in thyroid eye disease. The exact mechanisms are not fully understood, but it is believed that the antibodies bind to and activate IGF-1R, leading to the release of pro-inflammatory cytokines and the recruitment of immune cells to the orbital tissues. This inflammatory response results in the characteristic features of thyroid eye disease, including eyelid retraction, bulging eyes (proptosis), double vision (diplopia), and eye pain. Inhibition of IGF-1R signaling has been explored as a potential approach to modulate the immune response and reduce inflammation in thyroid eye disease. In 2020, the FDA approved teprotumumab, an IGF-1R inhibitor, for the treatment of thyroid eye disease. However, teprotumumab must be administered intravenously and may be associated with severe hearing impairment.

[0004] Linsitinib is a small-molecule inhibitor of IGF-1R and the insulin receptor (IR) and has previously been investigated as an anti-proliferative agent. The preparation of linsitinib in the form of a free base is disclosed in U.S. Patent Nos. 7,534,797 and 8,101,613, which are incorporated herein by reference. For example, linsitinib was granted orphan drug designation for adrenocortical carcinoma and clinical trials have been conducted against a variety of cancers. See, for instance, NCT00889382, NCT00924989, NCT01016860, NCT01101906, NCT01334710, NCT01427205. NCT01533181, NCT01533246, NCT01560260, NCT01600807, NCT02546544, and NCT01186861. More recently, linsitinib has been advanced for the treatment of thyroid eye disease by oral administration. There is a need forATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004new methods of treating thyroid eye disease that include the oral administration of an IGF-1R inhibitor that does not pose a significant risk of severe hearing impairment.SUMMARY

[0005] One aspect of the present disclosure relates to a method of treating thyroid eye disease in a subject in need thereof, the method comprising: orally administering to the subject a twice-daily dose of about 75 mg to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof; testing one or both of the subject’s serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels after about six consecutive weeks of administering the twice-daily dose; and testing one or both of the subject’s serum ALT and AST levels after about twelve consecutive weeks of administering the twice-daily dose. In some embodiments, the twice-daily dose is about 75 mg to about 180 mg of linsitinib. In some embodiments, the twice-daily dose is about 75 mg of linsitinib. In some embodiments, the twice-daily dose is about 150 mg of linsitinib. In some embodiments, the twice-daily dose is the corresponding amount of the pharmaceutically acceptable salt of linsitinib.

[0006] Another aspect of the present disclosure relates to a method of treating thyroid eye disease in a subject in need thereof, the method comprising: orally administering to the subject a twice-daily dose of about 20 to about 300 mg of a pharmaceutically acceptable salt of linsitinib; testing one or both of the subject’s serum ALT and AST levels after about six consecutive weeks of administering the twice-daily dose; and testing one or both of the subject’s serum ALT and AST levels after about twelve consecutive weeks of administering the twice-daily dose. In some embodiments, the twice-daily dose is about 20 mg to about 300 mg of an esylate salt or an (Z)-malate salt of linsitinib. In some embodiments, the twice-daily dose is about 75 mg to about 190 mg of the esylate salt of linsitinib. In some embodiments, the twice-daily dose is about 160 mg to about 185 mg of the esylate salt of linsitinib. In some embodiments, the esylate salt of linsitinib is a crystalline esylate salt of linsitinib.

[0007] In some embodiments, the subject’s serum ALT level is tested after the about six consecutive weeks of administering the twice-daily dose. In some embodiments, if the subject’s serum ALT level is above a value that is three-times the upper limit of normal and below a value that is five-times the upper limit of normal after the about six consecutive weeks of administering the twice-daily dose, the subject’s serum ALT level is tested weekly for theATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004remainder of the treatment or until the subject’s serum ALT level falls below a value that is three-times the upper limit of normal. In some embodiments, if the subject’s serum ALT level is above a value that is five-times the upper limit of normal after the about six consecutive weeks of administering the twice-daily dose, the administration is suspended for a suspension period, wherein the subject’s serum ALT levels are tested weekly during the suspension period, and administration of the twice-daily dose is resumed if the subject’s serum ALT level falls below a value that is three-times the upper limit of normal.

[0008] In some embodiments, the subject’s serum ALT level is tested after the about twelve consecutive weeks of administering the twice-daily dose. In some embodiments, if the subject’s serum ALT level is below a value that is three-times the upper limit of normal after the twelve consecutive weeks of administering the twice-daily dose, the subject’s serum ALT level is not tested for the remainder of the treatment. In some embodiments, if the subject’s serum ALT level is below a value that is three-times the upper limit of normal after 15, 18, 21, or 24 consecutive weeks of administering the twice-daily dose, the subject’s serum ALT level is not tested for the remainder of the treatment. In some embodiments, the method comprises testing the subject’s serum ALT level every three to six consecutive weeks following the about twelve consecutive weeks of administering the twice-daily dose, for the remainder of the treatment.

[0009] In some embodiments, the subject’s serum ALT level is above a value that is three-times the upper limit of normal and below a value five-times the upper limit of normal after the about twelve consecutive weeks of administering the twice-daily dose, the subject’s serum ALT level is tested weekly for the remainder of the treatment or until the subject’s serum ALT level falls below a value that is three-times the upper limit of normal. In some embodiments, if the subject’s serum ALT level is above a value that is five-times the upper limit of normal after the about twelve consecutive weeks of administering the twice-daily dose, the administration is suspended for a suspension period, wherein the subject’s serum ALT levels are tested weekly during the suspension period, and administration of the twice-daily dose is resumed if the subject’s serum ALT level falls below a value that is three-times the upper limit of normal.

[0010] In some embodiments, the subject’s serum AST level is tested after the about six consecutive weeks of administering the twice-daily dose. In some embodiments, if the subject’s serum AST level is above a value that is three-times the upper limit of normal andATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004below a value that is five-times the upper limit of normal after the about six consecutive weeks of administering the twice-daily dose, the subject’s serum AST level is tested weekly for the remainder of the treatment or until the subject’s serum AST level falls below a value that is three-times the upper limit of normal. In some embodiments, if the subject’s serum AST level is above a value that is five-times the upper limit of normal after the about six consecutive weeks of administering the twice-daily dose, the administration is suspended for a suspension period, wherein the subject’s serum AST levels are tested weekly during the suspension period, and administration of the twice-daily dose is resumed if the subject’s serum AST level falls below a value that is three-times the upper limit of normal.

[0011] In some embodiments, the subject’s serum AST level is tested after the about twelve consecutive weeks of administering the twice-daily dose. In some embodiments, the subject’s serum AST level is below a value that is three-times the upper limit of normal after the twelve consecutive weeks of administering the twice-daily dose, the subject’s serum AST level is not tested for the remainder of the treatment. In some embodiments, the subject’s serum AST level is below a value that is three-times the upper limit of normal after 15, 18, 21, or 24 consecutive weeks of administering the twice-daily dose, the subject’s serum AST level is not tested for the remainder of the treatment. In some embodiments, the method comprises testing the subject’s serum AST level every three to six consecutive weeks following the about twelve consecutive weeks of administering the twice-daily dose, for the remainder of the treatment.

[0012] In some embodiments, if the subject’s serum AST level is above a value that is three-times the upper limit of normal and below a value five-times the upper limit of normal after the about twelve consecutive weeks of administering the twice-daily dose, the subject’s serum AST level is tested weekly for the remainder of the treatment or until the subject’s serum AST level falls below a value that is three-times the upper limit of normal. In some embodiments, if the subject’s serum AST level is above a value that is five-times the upper limit of normal after the about twelve consecutive weeks of administering the twice-daily dose, the administration is suspended for a suspension period, wherein the subject’s serum AST levels are tested weekly during the suspension period, and administration of the twice-daily dose is resumed if the subject’s serum AST level falls below a value that is three-times the upper limit of normal.

[0013] In some embodiments, both the subject’s serum ALT and AST levels are tested after the about six consecutive weeks of administering the twice-daily dose. In some embodiments,ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004both the subject’s serum ALT and AST levels are tested after the about twelve consecutive weeks of administering the twice-daily dose.

[0014] Another aspect of the present disclosure relates to a method of treating thyroid eye disease in a subject in need thereof, the method comprising: orally administering to the subject a twice-daily dose of about 75 to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof, wherein the subject does not experience the onset of severe hearing impairment for the duration of the administration of the twice-daily dose. In some embodiments, the twice-daily dose is about 75 mg to about 180 mg of linsitinib. In some embodiments, the twice-daily dose is about 75 mg of linsitinib. In some embodiments, the twice-daily dose is about 150 mg of linsitinib. In some embodiments, the twice-daily dose is the corresponding amount of the pharmaceutically acceptable salt of linsitinib.

[0015] Another aspect of the present disclosure relates to a method of treating thyroid eye disease in a subject in need thereof, the method comprising: orally administering to the subject a twice daily dose of about 20 to about 300 mg of a pharmaceutically acceptable salt of linsitinib, wherein the subject does not experience the onset of severe hearing impairment for the duration of the administration of the twice-daily dose. In some embodiments, the twice-daily dose is about 20 mg to about 300 mg of an esylate salt or an (Z)-malate salt of linsitinib. In some embodiments, the twice-daily dose is about 75 mg to about 190 mg of the esylate salt of linsitinib. In some embodiments, the twice-daily dose is about 160 mg to about 185 mg of the esylate salt of linsitinib. In some embodiments, the esylate salt of linsitinib is a crystalline esylate salt of linsitinib.

[0016] In some embodiments, the subject’s hearing is not tested for the duration of the administration of the twice-daily dose. In some embodiments, the subject’s hearing is not tested immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject’s hearing is not tested immediately after the administration of the final twice-daily dose. In some embodiments, the subject does not experience hearing loss for the duration of the administration of the twice-daily dose.

[0017] In some embodiments, immediately after the administration of the final twice-daily dose, the subject’s proptosis in at least one eye is reduced by 0.5 mm or greater as compared to the subj ect’ s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose, theATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004subject’s proptosis in at least one eye is reduced by 1.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose, the subject’s proptosis in at least one eye is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0018] In some embodiments, the twice-daily dose is administered for at least 24 consecutive weeks.

[0019] In some embodiments, the subject’s thyroid eye disease is active thyroid eye disease having an onset of within the 12 months immediately prior to the initial administration of the twice-daily dose. In some embodiments, wherein the subject’s active thyroid eye disease is associated with one or more selected from (i)-(iv) for the subject’s most severely affected eye:(i) eyelid retraction of 2 mm or more;(ii) moderate or severe soft tissue involvement;(iii) proptosis of 3 mm or more above normal for race and gender; or(iv) inconstant or constant diplopia.

[0020] In some embodiments, the subject’s thyroid eye disease is active moderate-to-severe thyroid eye disease. In some embodiments, the subject’s active moderate-to-severe thyroid eye disease has a Clinical Active Score (CAS) of at least 4 for the most severely affected eye, on a 7-point scale, immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has Graves’ Disease which is associated with the thyroid eye disease. In some embodiments, the subject has autoimmune Hashimoto’s thyroiditis which is associated with the thyroid eye disease.

[0021] In some embodiments, the subject is euthyroid or has mild hypothyroidism or hyperthyroidism immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject does not require an immediate ophthalmological intervention immediately prior to the initial administration of the twice-daily dose and has not scheduled an ophthalmological intervention for the duration of the administration. In some embodiments, the subject does not have decreased best corrected visual acuity due to optic neuropathy immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject does not have corneal decompensation unresponsive to medical management prior to the initial administration of the twice-daily dose. In some embodiments, the subject has notATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004had orbital irradiation or orbital surgery prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken a glucocorticoid with a cumulative dose equivalent to 1 g or more of methylprednisolone within the three months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken an IGF-1R inhibitor prior to the initial administration of the twice-daily dose.

[0022] Other obj ects and advantages of the present disclosure will become apparent from the detailed description that follows.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIG. 1 depicts an X-ray powder diffraction pattern of linsitinib free base Form H. Adapted from FIG. 75 of U.S. Patent No. 11,976,074.

[0024] FIG. 2 depicts an X-ray powder diffraction pattern of linsitinib free base Form I. Adapted from FIG. 78 of U.S. Patent No. 11,976,074.

[0025] FIG. 3 depicts an X-ray powder diffraction pattern of linsitinib free base Form J. Adapted from FIG. 85 of U.S. Patent No. 11,976,074.

[0026] FIG. 4 depicts an X-ray powder diffraction pattern of linsitinib free base Form K. Adapted from FIG. 86 of U.S. Patent No. 11,976,074.

[0027] FIG. 5 depicts an X-ray powder diffraction pattern of linsitinib esylate crystalline Form 1. Adapted from FIG. 5 of U.S. Patent No. 11,976,074.

[0028] FIG. 6 depicts an X-ray powder diffraction pattern of linsitinib esylate crystalline Form 2. Adapted from FIG. 8 of U.S. Patent No. 11,976,074.

[0029] FIG. 7 depicts an X-ray powder diffraction pattern of linsitinib esylate crystalline Form 3. Adapted from FIG. 22 of U.S. Patent No. 11,976,074.

[0030] FIG. 8 depicts an X-ray powder diffraction pattern of linsitinib esylate crystalline Form 4. Adapted from FIG. 25 of U.S. Patent No. 11,976,074.

[0031] FIG. 9 depicts an X-ray powder diffraction pattern of linsitinib esylate crystalline Forms 1, 2, 3, 4, and 5. Adapted from FIG. 4 of U.S. Patent No. 11,976,074.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0032] FIG. 10 depicts an X-ray powder diffraction pattern of linsitinib di-esylate crystalline Form 1. Adapted from FIG. 30 of U.S. Patent No. 11,976,074.

[0033] FIG. 11 depicts an X-ray powder diffraction pattern of linsitinib (Z)-malate crystalline Form 1. Adapted from FIG. 33 of U.S. Patent No. 11,976,074.

[0034] FIG. 12 depicts an X-ray powder diffraction pattern of linsitinib (Z)-malate crystalline Forms 1-9. Adapted from FIG. 36 of U.S. Patent No. 11,976,074.

[0035] FIG. 13 depicts an X-ray powder diffraction pattern of linsitinib edisylate crystalline Form 1. Adapted from FIG. 49 of U.S. Patent No. 11,976,074.

[0036] FIG. 14 depicts an X-ray powder diffraction pattern of linsitinib maleate crystalline Form 1. Adapted from FIG. 53 of U.S. Patent No. 11,976,074.

[0037] FIG. 15 depicts an X-ray powder diffraction pattern of linsitinib napsylate crystalline Form 1. Adapted from FIG. 56 of U.S. Patent No. 11,976,074.

[0038] FIG. 16 depicts an X-ray powder diffraction pattern of linsitinib phosphate crystalline Form 1. Adapted from FIG. 59 of U.S. Patent No. 11,976,074.

[0039] FIG. 17 depicts an X-ray powder diffraction pattern of linsitinib HC1 crystalline Form 1. Adapted from FIG. 62 of U.S. Patent No. 11,976,074.

[0040] FIG. 18 depicts an X-ray powder diffraction pattern of linsitinib fumarate crystalline Form 1. Adapted from FIG. 66 of U.S. Patent No. 11,976,074.

[0041] FIG. 19 depicts an X-ray powder diffraction pattern of linsitinib salicylic cocrystal crystalline Form 1. Adapted from FIG. 70 of U.S. Patent No. 11,976,074.

[0042] FIG. 20 depicts an X-ray powder diffraction pattern of linsitinib gluconic cocrystal crystalline Form 1. Adapted from FIG. 68 of U.S. Patent No. 11,976,074.

[0043] FIG. 21 depicts an X-ray powder diffraction pattern of linsitinib orotic cocrystal crystalline Form 1. Adapted from FIG. 69 of U.S. Patent No. 11,976,074.

[0044] FIG. 22 shows a schematic overview of the study of Example 1, which evaluated the safety, pharmacokinetics and efficacy of linsitinib in subjects with active, moderate to severe thyroid eye disease.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0045] FIGS. 23A-B graphically depict the AUC0-24 ratio for the esylate salt of linsitinib against that of 75 mg of linsitinib free base at three different dose ratios (FIG. 23 A) and the Cmax ratio for the esylate salt of linsitinib against that of 75 mg of linsitinib free base at three different dose ratios (FIG. 23B), as determined from the study described in Example 2.

[0046] FIGS. 24A-B graphically depict the AUC0-24 ratio for the esylate salt of linsitinib at three different doses (FIG. 24A) and the Cmax ratio for the esylate salt of linsitinib against that of 75 mg of linsitinib free base at three different doses (FIG. 24B), as determined from the study described in Example 2.

[0047] FIGS. 25A-B graphically depict the mean pharmacokinetic (PK) traces for 75 mg of the linsitinib free base (FIG. 25 A) and the esylate salt of linsitinib at three different doses (FIG.25B), as determined from the study described in Example 2.DETAILED DESCRIPTION

[0048] The following description sets forth numerous exemplary methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0049] The present disclosure generally provides methods of using an orally active IGF-1R inhibitor, linsitinib ((AS',3k)-3-[8-amino-l-(2-phenyl-7-quinolinyl)imidazo[l,5-a]pyrazin-3-yl]-l-methyl-cyclobutanol), or a pharmaceutically acceptable salt thereof, twice-daily for the treatment of thyroid eye disease (TED). Twice-daily (also referred to as “BID”) dosing means that the dose is administered two times a day. The methods and uses for treating thyroid eye disease provided herein comprise orally administering a twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof. The thyroid eye disease may be active thyroid eye disease, mild thyroid eye disease, mild active thyroid eye disease, moderate-to-severe thyroid eye disease, moderate-to-severe active thyroid eye disease, sight-threatening thyroid eye disease, sight-threatening active thyroid eye disease, thyroid eye disease associated with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis, thyroid eye disease associated with Graves’ Disease and autoimmune Hashimoto’s thyroiditis, thyroid eye disease associated with Graves’ Disease, thyroid eye disease associated with autoimmune Hashimoto’s thyroiditis, active thyroid eye disease associated with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis, active thyroid eye disease associated with Graves’ Disease andATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004autoimmune Hashimoto’s thyroiditis, active thyroid eye disease associated with Graves’ Disease, active thyroid eye disease associated with autoimmune Hashimoto’s thyroiditis, moderate-to-severe active thyroid eye disease associated with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis, moderate-to-severe active thyroid eye disease associated with Graves’ Disease and autoimmune Hashimoto’s thyroiditis, moderate-to-severe active thyroid eye disease associated with Graves’ Disease, or moderate-to-severe active thyroid eye disease associated with autoimmune Hashimoto’s thyroiditis.

[0050] Teprotumumab is a human immunoglobulin G1 (IgGl) monoclonal blocking antibody which binds to the membrane bound IGF-1R, blocks its activation, and results in robust internalization and degradation of receptor. Developed as an anticancer agent, Teprotumumab was repurposed for use in thyroid eye disease based on preclinical data implicating the IGF-1R signaling pathway in the pathogenesis of thyroid eye disease. Two multi-center randomized control trials with similar trial design of 24-week treatment and 48-week Follow-up were completed. The Phase 2 primary endpoint was set as a composite of reduction of at least 2 / 7 points in Clinical Activity Score (CAS, defined below) and a reduction of at least 2 mm in proptosis at week 24. The Phase 3 primary endpoint was set as a reduction in proptosis only. In both studies, approximately 70% of patients treated with teprotumumab (versus -20% in placebo group) showed marked improvement in proptosis, CAS or both. While these results represented robust treatment effects, toxicities such as hearing loss (7%), nausea (20%) and muscle spasms (20%), together with the need to retreat a significant number of relapsing thyroid eye disease patients after 24 weeks of initial treatment, indicate the need for additional therapies and formal comparison to intravenous glucocorticoid therapy. Taylor, et al. Nat. Rev. Endocrinol. 2020, 16(2), 104-116; Douglas, et al. N. Engl. J. Med. 2020, 382, 341-52; Smith, et al. N. Engl. J Med. 2017, 376, 1748-1761.

[0051] Although some IGF-1R inhibitors, such as teprotumumab, are administered intravenously, linsitinib and pharmaceutically acceptable salts thereof may be administered orally, making dose administration easier and more convenient.

[0052] Also provided herein are uses of linsitinib, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment according to any of methods described herein. Also provided herein are uses of linsitinib, or a pharmaceutically acceptable salt thereof, for the treatment of thyroid eye disease according to any of methods describedATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004herein. Also provided are dosage formulations comprising linsitinib, or a pharmaceutically acceptable salt thereof, and their use in any of the methods described herein.

[0053] Further embodiments of the present disclosure are described hereinafter, in which some, but not all, embodiments of the disclosure are illustrated.

[0054] Each embodiment disclosed herein may be used individually or in combination with any other embodiment disclosed herein.

[0055] Publications, patents, and published patent applications referred to in this application are specifically incorporated by reference herein.Linsitinib

[0056] Linsitinib is a compound having the IUPAC name (15,35)-3-[8-amino-l-(2-phenyl-7-quinolinyl)imidazo[l,5-a]pyrazin-3-yl]-l -methyl -cyclobutanol (or cz -3-[8-amino-l-(2-phenyl-7-quinolinyl)imidazo[l,5-a]pyrazin-3-yl]-l-methyl-cyclobutanol) and CAS No.867160-71-2, and is represented by Formula (I):

[0057] Linsitinib is a small-molecule kinase inhibitor of the human insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) and has been investigated as an antiproliferative agent of tumor cells.

[0058] In some embodiments, the methods and uses provided herein comprise the administration of linsitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods and uses provided herein comprise the administration of linsitinib. In some embodiments, the methods and uses provided herein comprise the administration of a pharmaceutically acceptable salt of linsitinib. The preparation of linsitinib in the form of a freeATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004base is disclosed in U.S. Patent Nos. 7,534,797 and 8,101,613, which are incorporated herein by reference.

[0059] In some embodiments, the methods and uses provided herein comprise the administration of linsitinib (i.e., as the free base). In some embodiments, the linsitinib is a crystalline form of linsitinib. In some embodiments, the linsitinib is a polymorphic form of linsitinib.

[0060] In some embodiments, the crystalline form of linsitinib (i.e., the free base of linsitinib) may be any of those disclosed in U.S. Patent No. 11,976,074, which is herein incorporated by reference in its entirety. In some embodiments, the crystalline form of the free base of linsitinib is Form H of U.S. Patent No. 11,976,074. In some embodiments, linsitinib Form H exhibits an X-ray powder diffraction (XRPD) pattern substantially resembling that of linsitinib FIG. 1 (FIG. 75 of U.S. Patent No. 11,976,074). All XRPD patterns disclosed herein were determined on a diffractometer using Cu Ka radiation ( = 1.54178 A). In some embodiments, the crystalline form of the free base of linsitinib is Form I of U.S. Patent No. 11,976,074. In some embodiments, linsitinib Form I exhibits an XRPD pattern substantially resembling that of FIG.2 (FIG. 78 of U.S. Patent No. 11,976,074). In some embodiments, the crystalline form of the free base of linsitinib is Form J of U.S. Patent No. 11,976,074. In some embodiments, linsitinib Form J exhibits an XRPD pattern substantially resembling that of FIG. 3 (FIG. 85 of U.S. Patent No. 11, 976, 074). In some embodiments, the crystalline form of the free base of linsitinib is Form K of U.S. Patent No. 11,976,074. In some embodiments, linsitinib Form K exhibits an XRPD pattern substantially resembling that of FIG. 4 (FIG. 86 of U.S. Patent No.11,976,074).

[0061] In some embodiments, the methods and uses provided herein comprise the administration of a pharmaceutically acceptable salt of linsitinib. “Pharmaceutically acceptable” compounds, components, and compositions are those which are not biologically, or otherwise, undesirable. For example, a pharmaceutically acceptable material may be administered to a subject without causing any substantially undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. In some such embodiments, the pharmaceutically acceptable salt of linsitinib is a pharmaceutically acceptable acid addition salt. Such salts include, but are not limited to, salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like), and salts with organic acids (e.g., formic acid, acetic acid,ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like).

[0062] One of skill in the art will appreciate that a number of acids can be used to prepare pharmaceutically acceptable salts of linsitinib. Such acids include, but are not limited to, hydrochloric, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic (esylic), ethanedisulfonic (edisylic), formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, napsylic, and the like. In some embodiments, the pharmaceutically acceptable linsitinib salt comprises an anion derived from edisylic acid, esylic acid, hydrochloric acid, maleic acid, (Z)-malic acid, napsylic acid, and phosphoric acid. In some embodiments, the pharmaceutically acceptable salt of linsitinib is selected from an edisylate salt of linsitinib, an esylate salt of linsitinib, a hydrochloride salt of linsitinib, a maleate salt of linsitinib, (Z)-maleate salt of linsitinib, a napsylate salt of linsitinib, or a phosphate salt of linsitinib.

[0063] In some embodiments, the pharmaceutically acceptable salt of linsitinib may be any of those disclosed in U.S. Patent No. 11,976,074, which is herein incorporated by reference.

[0064] In some embodiments, the pharmaceutically acceptable salt of linsitinib is an esylate salt of linsitinib. Ethanesulfonic acid is a monoprotic acid with the conjugate base ethanesulfonate. As used herein, “esylate” refers to ethanesulfonate. As used herein, an “esylate salt” of linsitinib is a salt containing at least about one ethanesulfonate anion per cation of protonated linsitinib. In some embodiments, the esylate salt of linsitinib is a salt containing about one ethanesulfonate anion per cation of protonated linsitinib. In some embodiments, the esylate salt of linsitinib is a salt according to Formula II:(II).ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0065] In some embodiments, the esylate salt of linsitinib is a crystalline esylate salt of linsitinib. In some embodiments, the esylate salt of linsitinib is linsitinib esylate crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib esylate crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 5 (FIG. 5 of U.S. Patent No. 11,976,074). In some embodiments, the esylate salt of linsitinib is linsitinib esylate crystalline Form 2 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib esylate crystalline Form 2 exhibits an XRPD pattern substantially resembling that of FIG. 6 (FIG. 8 of U.S. Patent No. 11,976,074). In some embodiments, the esylate salt of linsitinib is linsitinib esylate crystalline Form 3 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib esylate crystalline Form 3 exhibits an XRPD pattern substantially resembling that of FIG. 7 (FIG. 22 of U.S. Patent No. 11,976,074). In some embodiments, the esylate salt of linsitinib is linsitinib esylate crystalline Form 4 U.S. Patent No. 11,976,074. In some embodiments, linsitinib esylate crystalline Form 4 exhibits an XRPD pattern substantially resembling that of FIG. 8 (FIG. 25 of U.S. Patent No. 11,976,074). In some embodiments, the esylate salt of linsitinib is linsitinib esylate crystalline Form 5 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib esylate crystalline Form 5 exhibits an XRPD pattern substantially resembling that of FIG. 9 (FIG. 4 of U.S. Patent No. 11,976,074).

[0066] In some embodiments, the pharmaceutically acceptable salt of linsitinib is a di-esylate salt of linsitinib. As used herein, a “di-esylate salt” of linsitinib is a salt containing about two ethanesulfonate anions per cation of protonated linsitinib. In some embodiments, the di-esylate salt of linsitinib is a crystalline di-esylate salt of linsitinib. In some embodiments, the di-esylate salt of linsitinib is linsitinib di-esylate crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib di-esylate crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 10 (FIG. 30 of U.S. Patent No. 11,976,074).

[0067] In some embodiments, the pharmaceutically acceptable salt of linsitinib is an (Z)-malate salt of linsitinib. (Z)-malic acid may be referred to by synonyms such as fS')-hydroxybutanedioic acid and fS')-2-hydroxysuccinic acid. (Z)-malic acid is a diprotic acid with conjugate bases including (5)-3-carboxy-2-hydroxypropanoate, (S)-3-carboxy-3-hydroxypropanoate, and (5)-hydroxysuccinate. As used herein, a “Z-malic acid salt” or “Z-malate salt” of linsitinib refers to a salt containing about one fS')-3-carboxy-2-hydroxypropanoate, fS')-3-carboxy-3 -hydroxy propanoate anion, or fS')-hydroxy succinate anionATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004per cation of protonated linsitinib. In some embodiments, the (Z)-malate salt of linsitinib is a salt containing about one fS')-3-carboxy-2-hydroxypropanoate, fS')-3-carboxy-3-hydroxypropanoate anion, or fS')-hydroxy succinate anion per cation of protonated linsitinib. In some embodiments, the (Z)-malate salt of linsitinib is a salt according to Formula III:

[0068] In some embodiments, the (Z)-malate salt of linsitinib is a crystalline esylate salt of linsitinib. In some embodiments, the (Z)-malate salt of linsitinib is crystalline Form 1 of linsitinib (Z)-malate salt of U.S. Patent No. 11,976,074. In some embodiments, linsitinib (Z)-malate crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 11 (FIG. 33 of U.S. Patent No. 11,976,074). In some embodiments, the (Z)-malate salt of linsitinib is crystalline Form 2 of linsitinib (Z)-malate salt of U.S. Patent No. 11,976,074. In some embodiments, linsitinib (Z)-malate crystalline Form 2 exhibits an XRPD pattern substantially resembling that of FIG. 12 (FIG. 36 of U.S. Patent No. 11,976,074). In some embodiments, the (Z)-malate salt of linsitinib is crystalline Form 3 of linsitinib (Z)-malate salt of U.S. Patent No. 11,976,074. In some embodiments, linsitinib (Z)-malate crystalline Form 3 exhibits an XRPD pattern substantially resembling that of FIG. 12 (FIG. 36 of U.S. Patent No.11,976,074). In some embodiments, the (Z)-malate salt of linsitinib is crystalline Form 4 of linsitinib esylate salt of U.S. Patent No. 11,976,074. In some embodiments, linsitinib (Z)-malate crystalline Form 4 exhibits an XRPD pattern substantially resembling that of FIG. 12 (FIG. 36 of U.S. Patent No. 11,976,074). In some embodiments, the esylate salt of linsitinib is esylate crystalline Form 5 of linsitinib esylate salt of U.S. Patent No. 11,976,074. In some embodiments, linsitinib (Z)-malate crystalline Form 5 exhibits an XRPD pattern substantially resembling that of FIG. 12 (FIG. 36 of U.S. Patent No. 11,976,074). In some embodiments, the esylate salt of linsitinib is esylate crystalline Form 6 of linsitinib esylate salt of U.S. Patent No.11,976,074. In some embodiments, linsitinib (Z)-malate crystalline Form 6 exhibits an XRPD pattern substantially resembling that of FIG. 12 (FIG. 36 of U.S. Patent No. 11,976,074). In some embodiments, the esylate salt of linsitinib is esylate crystalline Form 7 of linsitinib esylateATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004salt of U.S. Patent No. 11,976,074. In some embodiments, linsitinib (Z)-malate crystalline Form 7 exhibits an XRPD pattern substantially resembling that of FIG. 12 (FIG. 36 of U.S. Patent No. 11,976,074). In some embodiments, the esylate salt of linsitinib is esylate crystalline Form 8 of linsitinib esylate salt of U.S. PatentNo. 11,976,074. In some embodiments, linsitinib (Z)-malate crystalline Form 8 exhibits an XRPD pattern substantially resembling that of FIG.12 (FIG. 36 of U.S. PatentNo. 11,976,074). In some embodiments, the esylate salt of linsitinib is esylate crystalline Form 9 of linsitinib esylate salt of U.S. PatentNo. 11,976,074. In some embodiments, linsitinib (Z)-malate crystalline Form 9 exhibits an XRPD pattern substantially resembling that of FIG. 12 (FIG. 36 of U.S. PatentNo. 11,976,074).

[0069] In some embodiments, the pharmaceutically acceptable salt of linsitinib is an edisylate salt of linsitinib. Ethane-l,2-disulfonic acid is a diprotic acid with conjugate bases 2-sulfoethane-l -sulfonate and ethane- 1,2-di sulfonate, corresponding to each dissociation of the diprotic acid. As used herein, “edisylate” refers to either 2-sulfoethane-l -sulfonate or ethane-1,2-disulfonate. As used herein, an “edisylate salt” of linsitinib refers to a salt containing at least about one 2-sulfoethane-l -sulfonate or ethane- 1,2-disulfonate anion per cation of protonated linsitinib. In some embodiments, the edisylate salt of linsitinib is a salt containing about one 2-sulfoethane-l -sulfonate or ethane-l,2-disulfonate anion per cation of protonated linsitinib. In some embodiments, the edisylate salt of linsitinib is a salt according to Formula IV:

[0070] In some embodiments, the edisylate salt of linsitinib is a crystalline edisylate salt of linsitinib. In some embodiments, the edisylate salt of linsitinib is linsitinib edisylate crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib edisylate crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 13 (FIG. 49 of U.S. PatentNo. 11,976,074).ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0071] In some embodiments, the pharmaceutically acceptable salt of linsitinib is a maleate salt of linsitinib. Maleic acid (also known as cv.s-butenedioic acid) is a diprotic acid with conjugate bases (Z)-3-carboxyacrylate and maleate, corresponding to each dissociation of the diprotic acid. As used herein, a “maleic acid salt” or “maleate salt” of linsitinib refers to a salt containing at least about one (Z)-3 -carboxyacrylate anion or maleate anion per cation of protonated linsitinib. In some embodiments, the maleate salt of linsitinib is a salt containing about one (Z)-3-carboxyacrylate anion or maleate anion per cation of protonated linsitinib. In some embodiments, the maleate salt of linsitinib is a salt according to Formula V:

[0072] In some embodiments, the maleate salt of linsitinib is a crystalline maleate salt of linsitinib. In some embodiments, the maleate salt of linsitinib is linsitinib maleate crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib maleate crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 14 (FIG. 53 of U.S. Patent No. 11,976,074).

[0073] In some embodiments, the pharmaceutically acceptable salt of linsitinib is a napsylate salt of linsitinib. Napthalene-2-sulfonic acid is a monoprotic acid with the conjugate base naphthalene-2-sulfonate. As used herein, “napsylate” refers to a naphthalene-2-sulfonate anion. As used herein, a “napsylate salt” of linsitinib refers to a salt containing at least about one naphthal ene-2-sulfonate anion per cation of protonated linsitinib. In some embodiments, the napsylate salt of linsitinib is a salt about one naphthalene-2-sulfonate anion per cation of protonated linsitinib. In some embodiments, the napsylate salt of linsitinib is a salt according to Formula VI:ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0074] In some embodiments, the napsylate salt of linsitinib is a crystalline napsylate salt of linsitinib. In some embodiments, the napsylate salt of linsitinib is linsitinib napsylate crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib napsylate crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 15 (FIG. 56 of U.S. Patent No. 11,976,074).

[0075] In some embodiments, the pharmaceutically acceptable salt of linsitinib is a phosphate salt of linsitinib. Phosphoric acid is a triprotic acid with conjugate bases including dihydrogen phosphate, hydrogen phosphate, and phosphate. As used herein, a “phosphoric acid salt” or “phosphate salt” of linsitinib refers to a salt containing at least about one dihydrogen phosphate anion, hydrogen phosphate anion, or phosphate anion per cation of protonated linsitinib. In some embodiments, the phosphate salt of linsitinib is a salt according to Formula VII:(VII).

[0076] In some embodiments, the phosphate salt of linsitinib is a crystalline phosphate salt of linsitinib. In some embodiments, the phosphate salt of linsitinib is linsitinib phosphate crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib phosphate crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 16 (FIG. 59 of U.S. Patent No. 11,976,074).ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0077] In some embodiments, the pharmaceutically acceptable salt of linsitinib is a hydrochloride salt of linsitinib. As used herein, “hydrochloride salt,” “hydrochloric acid salt” or “HC1 salt” of linsitinib refers to a salt containing at least about one chloride anion per linsitinib molecule. In some embodiments, the hydrochloride salt of linsitinib contains about one chloride anion per linsitinib molecule. In some embodiments, the hydrochloride salt of Linsitinib is a salt according to Formula VIII:(VIII).

[0078] In some embodiments, the hydrochloride salt of linsitinib is a crystalline hydrochloride salt of linsitinib. In some embodiments, the hydrochloride salt of linsitinib is linsitinib HC1 crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib HC1 crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 17 (FIG. 62 of U.S. Patent No. 11,976,074).

[0079] In some embodiments, the pharmaceutically acceptable salt of linsitinib is a fumarate salt of linsitinib. Fumaric acid, also known as / ra / z.s-butenedioic acid is a diprotic acid with conjugate bases (E)-3-carboxyacrylate and fumarate, corresponding to each dissociation of the diprotic acid. As used herein, a “fumaric acid salt” or “fumarate salt” of linsitinib refers to a salt containing at least about one (E)-3-carboxyacrylate anion or fumarate anion per cation of protonated linsitinib. In some embodiments, the fumarate salt of linsitinib contains about one ( / ■fl-S -carboxy aery late anion or fumarate anion per cation of protonated linsitinib. In some embodiments, the fumarate salt of linsitinib is a salt according to Formula IXATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0080] In some embodiments, the fumarate salt of linsitinib is a crystalline fumerate salt of linsitinib. In some embodiments, the fumarate salt of linsitinib is linsitinib fumarate crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib fumarate crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 18 (FIG. 66 of U.S. Patent No. 11,976,074).

[0081] In some embodiments, the methods and uses provided herein comprise the administration of pharmaceutically acceptable cocrystals of linsitinib. One of skill in the art will appreciate that a number of pharmaceutically acceptable coformers can be used to prepare linsitinib cocrystals. The coformers represent various different hydrogen bond donating and accepting groups that may pair with the donors and acceptors in the structure of linsitinib — including some weaker acids not acidic enough to fully protonate linsitinib but able to participate in hydrogen bonding. Pharmaceutically acceptable coformers include, but are not limited to, acesulfame K, adenine, adipic acid, 4-aminosalicylic acid, (Z)-arginine, (Z)-ascorbic acid, benzamide, benzoic acid, betaine HC1, caffeine, cinnamic acid, creatinine, D-fructose, D-gluconic acid, glucosamine HC1, D-glucose, ( / .(-glutamine, glutaric acid, glycine, hippuric acid, isonicotinamide, ( / .(-lactic acid, lactose, (Z)-leucine, malonic acid, maltol, D-mannitol, methyl paraben, monosodium glutamate, nicotinamide, orotic acid, propyl gallate, saccharin, salicylic acid, sebacic acid, sodium lauryl sulfate, sorbic acid, stearic acid, succinic acid, sucrose, taurine, thiamine chloride HC1, ( / .(-threonine, tromethamine HC1, ( / .(-tryptophan, urea, (Z)-valine, vanillin, xanthine, xylitol, and the like. In some embodiments, the pharmaceutically acceptable cocrystal of linsitinib is a cocrystal derived from gluconic acid, orotic acid, or salicylic acid.

[0082] In some embodiments, the pharmaceutically acceptable cocrystals of linsitinib may be any of those disclosed in U.S. Patent No. 11,976,074, which is herein incorporated by reference, in its entirety.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0083] In some embodiments, the pharmaceutically acceptable cocrystal of linsitinib is a salicylic cocrystal of linsitinib. Salicylic acid is a weak acid. As used herein, a “salicylic cocrystal” or “salicylic salt” of linsitinib refers to a cocrystal containing at least about one salicylic acid molecule per molecule of linsitinib. In some embodiments, the salicylic cocrystal of linsitinib contains about one molecule of salicylic acid per molecule of linsitinib. In some embodiments, the salicylic acid cocrystal of linsitinib is a cocrystal according to Formula X:(X).

[0084] In some embodiments, the salicylic cocrystal of linsitinib is a crystalline salicylic cocrystal of linsitinib. In some embodiments, the salicylic cocrystal of linsitinib is linsitinib salicylic cocrystal crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib salicylic cocrystal crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 19 (FIG. 70 of U.S. Patent No. 11,976,074).

[0085] In some embodiments, the pharmaceutically acceptable cocrystal of linsitinib is a gluconic cocrystal of linsitinib. Gluconic acid is a weak acid. As used herein, a “gluconic cocrystal” or “gluconic salt” of linsitinib refers to a cocrystal containing at least about one gluconic acid molecule per molecule of linsitinib. In some embodiments, a gluconic cocrystal of linsitinib contains about one molecule of gluconic acid per molecule of linsitinib. In some embodiments, the gluconic acid cocrystal of Linsitinib is a cocrystal according to Formula XI:ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0086] In some embodiments, the gluconic cocrystal of linsitinib is a crystalline gluconic cocrystal of linsitinib. In some embodiments, the gluconic cocrystal of linsitinib is linsitinib gluconic cocrystal crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib gluconic cocrystal crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 20 (FIG. 68 of U.S. Patent No. 11,976,074).

[0087] In some embodiments, the pharmaceutically acceptable cocrystal of linsitinib is an orotic cocrystal of linsitinib. Orotic acid is a weak acid. As used herein, an “orotic cocrystal” or “orotic salt” of linsitinib refers to a cocrystal containing at least about one orotic acid molecule per molecule of linsitinib. In some embodiments, an orotic cocrystal of linsitinib contains about one molecule of orotic acid per molecule of linsitinib. In some embodiments, the orotic acid cocrystal of Linsitinib is a cocrystal according to Formula XII:(XII).

[0088] In some embodiments, the orotic cocrystal of linsitinib is a crystalline orotic cocrystal of linsitinib. In some embodiments, the orotic cocrystal of linsitinib is linsitinib orotic cocrystal crystalline Form 1 of U.S. Patent No. 11,976,074. In some embodiments, linsitinib orotic cocrystal crystalline Form 1 exhibits an XRPD pattern substantially resembling that of FIG. 21 (FIG. 69 of U.S. Patent No. 11,976,074).Therapeutic Uses and Methods of Treatment

[0089] Disclosed herein are methods of using an orally active, twice-daily administered, IGF-1R inhibitor, linsitinib, or a pharmaceutically acceptable salt thereof, for the treatment of thyroid eye disease.

[0090] The present disclosure provides methods and uses of linsitinib, or a pharmaceutically acceptable salt thereof, for the treatment of thyroid eye disease in a subject in need thereof.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004The present disclosure provides methods and uses of dosage formulations comprising linsitinib, or a pharmaceutically acceptable salt thereof, for the treatment of thyroid eye disease in a subject in need thereof. “Thyroid eye disease” may capture any form of the disease, such as those described herein. Thyroid eye disease is most commonly associated with Graves’ Disease — though it may occur in subjects not having Graves’ Disease. As used herein, a “patient” or a “subject” may refer to a mammal. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In some embodiments of the present disclosure, the mammal is a human. In some embodiments, the subject is an adult who is of at least 18 years of age. In some embodiments, the subject is of at least 18 years of age immediately prior to the initial administration of the twice-daily dose.

[0091] In some embodiments of the methods and uses described herein, the thyroid eye disease may be active thyroid disease. A subject having “active thyroid eye disease” is a subject with thyroid eye disease who, at presentation, has a Clinical Active Score (CAS) of > 3 (out of 7) or, after presentation, has a CAS of >4 (out of 10) for the most severely affected eye. Moledina, et al., Eye 2024, 38, 1425-1437. As used herein in relation to thyroid eye disease, the term “Clinical Active Score” refers to a binary scoring system developed by Mouritis et al. for assessing the activity of thyroid eye disease in a patient. Mourits et al., Clin. Endocrinol. 1997, 47, 9-14. As used herein the “most severely affected eye” is the eye with the most significant proptosis. If both eyes have the same proptosis, the most severely affected eye is the one with the higher CAS score. If both eyes have the same proptosis and the same CAS score, then either may be considered the most severely affected eye.

[0092] In some embodiments of the methods and uses described herein, the thyroid eye disease may be active moderate-to-severe thyroid eye disease. Moderate-to- severe thyroid eye disease may be non-sight-threatening and have an appreciable impact on daily life. In some embodiments, a subject having moderate-to-severe thyroid eye disease has proptosis of 3 mm or greater in the most severely affected eye. In some embodiments of the methods and uses described herein, the thyroid eye disease may be active moderate-to-severe thyroid disease. In some embodiments, a subject having moderate-to-severe thyroid eye disease has one or more selected from a lid retraction of 2 mm or more, moderate or severe soft tissue involvement,ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004proptosis of 3 mm or more above normal for race and gender, or inconstant or constant diplopia in the subject’s most severely affected eye.

[0093] In some embodiments of the methods and uses described herein, the thyroid eye disease may be active moderate-to-severe thyroid disease. In some embodiments, a subject having active moderate-to-severe thyroid eye disease has a CAS of > 4 (out of 7) for the most severely affected eye.

[0094] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with Graves’ Disease. In some embodiments of the methods and uses described herein, the thyroid eye disease is not associated with Graves’ Disease. In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with autoimmune Hashimoto’s thyroiditis. In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis. In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with both Graves’ Disease and autoimmune Hashimoto’s thyroiditis. In some embodiments, the subject has been clinically diagnosed with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis associated with thyroid eye disease. In some embodiments, the subject has been clinically diagnosed with both Graves’ Disease and autoimmune Hashimoto’s thyroiditis associated with thyroid eye disease. In some embodiments, the subject has been clinically diagnosed with Graves’ Disease associated with thyroid eye disease. In some embodiments, the subject has been clinically diagnosed with autoimmune Hashimoto’s thyroiditis associated with thyroid eye disease.

[0095] In some embodiments of the methods and uses described herein, the thyroid eye disease is active thyroid eye disease associated with Graves’ Disease. In some embodiments of the methods and uses described herein, the thyroid eye disease is active thyroid eye disease associated with autoimmune Hashimoto’s thyroiditis. In some embodiments of the methods and uses described herein, the thyroid eye disease is active thyroid eye disease associated with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis. In some embodiments of the methods and uses described herein, the thyroid eye disease is active thyroid eye disease associated with both Graves’ Disease and autoimmune Hashimoto’s thyroiditis. In some embodiments, the subject has been clinically diagnosed with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis associated with active thyroid eye disease. In some embodiments, the subject has been clinically diagnosed with both Graves’ Disease andATTORNEY DOCKET No.: SLTH-OOl / OIWO 353890-2004autoimmune Hashimoto’s thyroiditis associated with active thyroid eye disease. In some embodiments, the subject has been clinically diagnosed with Graves’ Disease associated with active thyroid eye disease. In some embodiments, the subject has been clinically diagnosed with autoimmune Hashimoto’s thyroiditis associated with active thyroid eye disease.

[0096] In some embodiments of the methods and uses described herein, the thyroid eye disease is active moderate-to-severe thyroid eye disease associated with Graves’ Disease. In some embodiments of the methods and uses described herein, the thyroid eye disease is active moderate-to-severe thyroid eye disease associated with autoimmune Hashimoto’s thyroiditis. In some embodiments of the methods and uses described herein, the thyroid eye disease is active moderate-to-severe thyroid eye disease associated with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis. In some embodiments of the methods and uses described herein, the thyroid eye disease is active moderate-to-severe thyroid eye disease associated with both Graves’ Disease and autoimmune Hashimoto’s thyroiditis. In some embodiments, the subject has been clinically diagnosed with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis associated with active moderate-to-severe thyroid eye disease. In some embodiments, the subject has been clinically diagnosed with both Graves’ Disease and autoimmune Hashimoto’s thyroiditis associated with active moderate-to-severe thyroid eye disease. In some embodiments, the subject has been clinically diagnosed with Graves’ Disease associated with active moderate-to-severe thyroid eye disease. In some embodiments, the subject has been clinically diagnosed with autoimmune Hashimoto’s thyroiditis associated with active moderate-to-severe thyroid eye disease.

[0097] In some embodiments, the thyroid eye disease may be active thyroid eye disease, mild thyroid eye disease, mild active thyroid eye disease, moderate-to-severe thyroid eye disease, moderate-to-severe active thyroid eye disease, sight-threatening thyroid eye disease, sightthreatening active thyroid eye disease, thyroid eye disease associated with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis, thyroid eye disease associated with Graves’ Disease and autoimmune Hashimoto’s thyroiditis, thyroid eye disease associated with Graves’ Disease, thyroid eye disease associated with autoimmune Hashimoto’s thyroiditis, active thyroid eye disease associated with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis, active thyroid eye disease associated with Graves’ Disease and autoimmune Hashimoto’s thyroiditis, active thyroid eye disease associated with Graves’ Disease, active thyroid eye disease associated with autoimmune Hashimoto’s thyroiditis, moderate-to-severeATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004active thyroid eye disease associated with Graves’ Disease and / or autoimmune Hashimoto’s thyroiditis, moderate-to-severe active thyroid eye disease associated with Graves’ Disease and autoimmune Hashimoto’s thyroiditis, moderate-to-severe active thyroid eye disease associated with Graves’ Disease, or moderate-to-severe active thyroid eye disease associated with autoimmune Hashimoto’s thyroiditis.

[0098] The methods and uses described herein include treating thyroid eye disease in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof. A “therapeutically effective amount” may refer to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and / or to prevent the occurrence of the disease or disorder. For example, a therapeutically effective dose for treatment of thyroid eye disease includes where the treatment brings about an amelioration of one or more symptoms of the thyroid eye disease, slows the progression of the thyroid eye disease, etc. The methods and uses described herein include treating thyroid eye disease in a subject in need thereof, the method comprising orally administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib, or a pharmaceutically acceptable salt thereof.

[0099] The methods and uses described herein include treating thyroid eye disease in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of about 50 mg to about 250 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 50 mg to about 225 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 50 mg to about 200 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 75 mg to about 250 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 75 mg to about 225 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 75 mg to about 200 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of aboutATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-200475 mg to about 190 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 75 mg to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 75 mg to about 170 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 75 mg to about 160 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 75 mg to about 150 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 50 mg to about 100 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 50 mg to about 80 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 100 mg to about 200 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 100 mg to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 100 mg to about 175 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 100 mg to about 150 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 125 mg to about 200 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 125 mg to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 125 mg to about 175 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 125 mg to about 150 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In someATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004embodiments, the method comprises administering to the subject a twice-daily dose of about 150 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a twice-daily dose of about 75 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof.

[0100] Throughout the present disclosure, amounts of linsitinib disclosed refer to the amount of linsitinib free form to be administered. The term “corresponding amount” as used herein refers to the amount of a pharmaceutically acceptable salt or cocrystal of linsitinib required to obtain the amount of linsitinib free form recited in the formulation. It would be clear to one of skill in the art how to calculate the “corresponding amount” of the salt or cocrystal of a compound, such as the corresponding amount of the pharmaceutically acceptable salt of linsitinib, by taking into account the difference in molecular weight between the free base of a compound and a salt or cocrystal form. For example, about 100 mg of linsitinib would correspond to about 126 mg of the esylate salt of linsitinib.

[0101] Further dosages of the present disclosure applicable to all methods and uses disclosed herein are described in the section entitled “Dosing and Administration.”

[0102] The methods and uses described herein include treating active thyroid eye disease in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0103] The methods and uses described herein include treating active moderate-to-severe thyroid eye disease in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0104] The methods and uses described herein include treating active moderate-to-severe thyroid eye disease associated with Graves’ Disease or autoimmune Hashimoto thyroiditis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0105] The methods and uses described herein include treating active moderate-to-severe thyroid eye disease associated with Graves’ Disease and autoimmune Hashimoto thyroiditis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0106] The methods and uses described herein include treating active moderate-to-severe thyroid eye disease associated with Graves’ Disease in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0107] The methods and uses described herein include treating active moderate-to-severe thyroid eye disease associated with autoimmune Hashimoto thyroiditis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0108] The methods and uses provided herein may treat thyroid eye disease by reducing proptosis. The present disclosure also provides methods and uses of linsitinib, or a pharmaceutically acceptable salt thereof, for reducing proptosis in a subject in need thereof. As used herein “proptosis” refers to the protrusion of the eyeball from the orbit and is also commonly referred to as “exophthalmos.” Increased proptosis is a symptom associated with a variety of ocular conditions — including thyroid eye disease. The increased proptosis may be unilateral (i.e., affecting one eye) or bilateral (i.e., affecting both eyes). For bilateral cases, the proptosis of each eye may be the same or different.

[0109] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in at least one eye is reduced by 0.5 mm or greater, 0.6 mm or greater, 0.7 mm or greater, 0.8 mm or greater, 0.9 mm or greater, 1.0 mm or greater, 1.1 mm or greater, 1.2 mm or greater, 1.3 mm or greater, 1.4 mm or greater, 1.5 mm or greater, 1.6 mm or greater, 1.7 mm or greater, 1.8 mm or greater, 1.9 mm or greater, 2.0 mm or greater, 2.1 mm or greater, 2.2 mm or greater, 2.3 mm or greater, 2.4 mm or greater, 2.5 mm or greater, 2.6 mm or greater, 2.7 mm or greater, 2.8 mm or greater, 2.9 mm or greater, 3.0 mm or greater, 3.1 mm or greater, 3.2 mm or greater, 3.3 mm or greater, 3.4 mm or greater, or 3.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments,ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in at least one eye is reduced by 0.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in at least one eye is reduced by 1.0 mm or greater as compared to the subj ect’ s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in at least one eye is reduced by 1.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in at least one eye is reduced by 2.0 mm or greater as compared to the subj ect’ s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in at least one eye is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0110] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in one eye is reduced by 0.5 mm or greater, 0.6 mm or greater, 0.7 mm or greater, 0.8 mm or greater, 0.9 mm or greater, 1.0 mm or greater, 1.1 mm or greater, 1.2 mm or greater, 1.3 mm or greater, 1.4 mm or greater, 1.5 mm or greater, 1.6 mm or greater, 1.7 mm or greater, 1.8 mm or greater, 1.9 mm or greater, 2.0 mm or greater, 2.1 mm or greater, 2.2 mm or greater, 2.3 mm or greater, 2.4 mm or greater, 2.5 mm or greater, 2.6 mm or greater, 2.7 mm or greater, 2.8 mm or greater, 2.9 mm or greater, 3.0 mm or greater, 3.1 mm or greater, 3.2 mm or greater, 3.3 mm or greater, 3.4 mm or greater, or 3.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in one eye is reduced by 0.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in one eye isATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004reduced by 1.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in one eye is reduced by 1.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in one eye is reduced by 2.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in one eye is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0111] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in both eyes is reduced by 0.5 mm or greater, 0.6 mm or greater, 0.7 mm or greater, 0.8 mm or greater, 0.9 mm or greater, 1.0 mm or greater, 1.1 mm or greater, 1.2 mm or greater, 1.3 mm or greater, 1.4 mm or greater, 1.5 mm or greater, 1.6 mm or greater, 1.7 mm or greater, 1.8 mm or greater, 1.9 mm or greater, 2.0 mm or greater, 2.1 mm or greater, 2.2 mm or greater, 2.3 mm or greater, 2.4 mm or greater, 2.5 mm or greater, 2.6 mm or greater, 2.7 mm or greater, 2.8 mm or greater, 2.9 mm or greater, 3.0 mm or greater, 3.1 mm or greater, 3.2 mm or greater, 3.3 mm or greater, 3.4 mm or greater, 3.5 mm or greater, or 4.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in both eyes is reduced by 0.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in both eyes is reduced by 1.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in both eyes is reduced by 1.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after theATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in both eyes is reduced by 2.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in both eyes is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0112] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in at least one eye is reduced by 0.5 mm to 4.0 mm, 0.5 mm to 3.5 mm, 0.5 mm to 3.4 mm, 0.5 mm to 3.2 mm, 0.5 mm to 3.0 mm, 0.5 mm to 2.9 mm, 0.5 mm to 2.8 mm, 0.5 mm to 2.7 mm, 0.5 mm to 2.6 mm, 0.5 mm to 2.5 mm, 0.5 mm to 2.4 mm, 0.5 mm to 2.3 mm, 0.5 mm to 2.2 mm, 0.5 mm to 2.1 mm, 0.5 mm to 2.0 mm, 0.7 mm to 4.0 mm, 0.7 mm to 3.5 mm, 0.7 mm to 3.4 mm, 0.7 mm to 3.2 mm, 0.7 mm to 3.0 mm, 0.7 mm to 2.9 mm, 0.7 mm to 2.8 mm, 0.7 mm to 2.7 mm, 0.7 mm to 2.6 mm, 0.7 mm to 2.5 mm, 0.7 mm to 2.4 mm, 0.7 mm to 2.3 mm, 0.7 mm to 2.2 mm, 0.7 mm to 2.1 mm, 0.7 mm to 2.0 mm, 0.9 mm to 4.0 mm, 0.9 mm to 3.5 mm, 0.9 mm to 3.4 mm, 0.9 mm to 3.2 mm, 0.9 mm to 3.0 mm, 0.9 mm to 2.9 mm, 0.9 mm to 2.8 mm, 0.9 mm to 2.7 mm, 0.9 mm to 2.6 mm, 0.9 mm to 2.5 mm, 0.9 mm to 2.4 mm, 0.9 mm to 2.3 mm, 0.9 mm to 2.2 mm, 0.9 mm to 2.1 mm, 0.9 mm to 2.0 mm, 1.0 mm to 4.0 mm, 1.0 mm to 3.5 mm, 1.0 mm to 3.4 mm, 1.0 mm to 3.2 mm, 1.0 mm to 3.0 mm, 1.0 mm to 2.9 mm, 1.0 mm to 2.8 mm, 1.0 mm to 2.7 mm, 1.0 mm to 2.6 mm, 1.0 mm to 2.5 mm, 1.0 mm to 2.4 mm, 1.0 mm to 2.3 mm, 1.0 mm to 2.2 mm, 1.0 mm to 2.1 mm, 1.0 mm to 2.0 mm, 1.1 mm to 4.0 mm, 1.1 mm to 3.5 mm, 1.1 mm to 3.4 mm, 1.1 mm to 3.2 mm, 1.1 mm to 3.0 mm, 1.1 mm to 2.9 mm, 1.1 mm to 2.8 mm, 1.1 mm to 2.7 mm, 1.1 mm to 2.6 mm, 1.1 mm to 2.5 mm, 1.1 mm to 2.4 mm, 1.1 mm to 2.3 mm, 1.1 mm to 2.2 mm, 1.1 mm to 2.1 mm, 1.1 mm to 2.0 mm, 1.3 mm to 4.0 mm, 1.3 mm to 3.5 mm, 1.3 mm to 3.4 mm, 1.3 mm to 3.2 mm, 1.3 mm to 3.0 mm, 1.3 mm to 2.9 mm, 1.3 mm to 2.8 mm, 1.3 mm to 2.7 mm, 1.3 mm to 2.6 mm, 1.3 mm to 2.5 mm, 1.3 mm to 2.4 mm, 1.3 mm to 2.3 mm, 1.3 mm to 2.2 mm, 1.3 mm to 2.1 mm, 1.3 mm to 2.0 mm, 1.5 mm to 4.0 mm, 1.5 mm to 3.5 mm, 1.5 mm to 3.4 mm, 1.5 mm to 3.2 mm, 1.5 mm to 3.0 mm, 1.5 mm to 2.9 mm, 1.5 mm to 2.8 mm, 1.5 mm to 2.7 mm, 1.5 mm to 2.6 mm, 1.5 mm to 2.5 mm, 1.5 mm to 2.4 mm, 1.5 mm to 2.3 mm, 1.5 mm to 2.2 mm, 1.5 mm to 2.1 mm, 1.5 mm to 2.0 mm, 1.7 mm to 4.0 mm, 1.7 mm to 3.5 mm, 1.7 mm to 3.4 mm, 1.7 mm to 3.2 mm, 1.7 mm to 3.0 mm, 1.7 mm to 2.9 mm, 1.7 mm to 2.8 mm, 1.7 mm to 2.7 mm, 1.7 mm to 2.6 mm,ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-20041.7 mm to 2.5 mm, 1.7 mm to 2.4 mm, 1.7 mm to 2.3 mm, 1.7 mm to 2.2 mm, 1.7 mm to 2.1 mm, 1.7 mm to 2.0 mm, 1.9 mm to 4.0 mm, 1.9 mm to 3.5 mm, 1.9 mm to 3.4 mm, 1.9 mm to 3.2 mm, 1.9 mm to 3.0 mm, 1.9 mm to 2.9 mm, 1.9 mm to 2.8 mm, 1.9 mm to 2.7 mm, 1.9 mm to 2.6 mm, 1.9 mm to 2.5 mm, 1.9 mm to 2.4 mm, 1.9 mm to 2.3 mm, 1.9 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.9 mm to 2.0 mm, 2.0 mm to 4.0 mm, 2.0 mm to 3.5 mm, 2.0 mm to 3.4 mm, 2.0 mm to 3.2 mm, 2.0 mm to 3.0 mm, 2.0 mm to 2.9 mm, 2.0 mm to 2.8 mm, 2.0 mm to 2.7 mm, 2.0 mm to 2.6 mm, 2.0 mm to 2.5 mm, 2.0 mm to 2.4 mm, 2.0 mm to 2.3 mm, 2.0 mm to 2.2 mm, 2.0 mm to 2.1 mm, 2.2 mm to 4.0 mm, 2.2 mm to 3.5 mm, 2.2 mm to 3.4 mm, 2.2 mm to 3.2 mm, 2.2 mm to 3.0 mm, 2.2 mm to 2.9 mm, 2.2 mm to 2.8 mm, 2.2 mm to 2.7 mm, 2.2 mm to 2.6 mm, 2.2 mm to 2.5 mm, 2.2 mm to 2.4 mm, 2.2 mm to 2.3 mm, 2.3 mm to 4.0 mm, 2.3 mm to 3.5 mm, 2.3 mm to 3.4 mm, 2.3 mm to 3.2 mm, 2.3 mm to 3.0 mm, 2.3 mm to 2.9 mm, 2.3 mm to 2.8 mm, 2.3 mm to 2.7 mm, 2.3 mm to 2.6 mm, 2.3 mm to 2.5 mm, 2.3 mm to 2.4 mm, 2.4 mm to 4.0 mm, 2.4 mm to 3.5 mm, 2.4 mm to 3.4 mm, 2.4 mm to 3.2 mm, 2.4 mm to 3.0 mm, 2.4 mm to 2.9 mm, 2.4 mm to 2.8 mm, 2.4 mm to 2.7 mm, 2.4 mm to 2.6 mm, 2.4 mm to 2.5 mm, 2.5 mm to 4.0 mm, 2.5 mm to 3.5 mm, 2.5 mm to 3.4 mm, 2.5 mm to 3.2 mm, 2.5 mm to 3.0 mm, 2.5 mm to 2.9 mm, 2.5 mm to 2.8 mm, 2.5 mm to 2.7 mm, 2.5 mm to 2.6 mm, 2.6 mm to 4.0 mm, 2.6 mm to 3.5 mm, 2.6 mm to 3.4 mm, 2.6 mm to 3.2 mm, 2.6 mm to 3.0 mm, 2.6 mm to 2.9 mm, 2.6 mm to 2.8 mm, 2.6 mm to 2.7 mm, 2.7 mm to 4.0 mm, 2.7 mm to 3.5 mm, 2.7 mm to 3.4 mm, 2.7 mm to 3.2 mm, 2.7 mm to 3.0 mm, 2.7 mm to 2.9 mm, 2.7 mm to 2.8 mm, 2.8 mm to 4.0 mm, 2.8 mm to 3.5 mm, 2.8 mm to 3.4 mm, 2.8 mm to 3.2 mm, 2.8 mm to 3.0 mm, 2.8 mm to 2.9 mm, 2.9 mm to 4.0 mm, 2.9 mm to 3.5 mm, 2.9 mm to 3.4 mm, 2.9 mm to 3.2 mm, 2.9 mm to 3.0 mm, 3.0 mm to 4.0 mm, 3.0 mm to 3.5 mm, 3.0 mm to 3.4 mm, 3.0 mm to 3.2 mm, 3.2 mm to 4.0 mm, 3.2 mm to 3.5 mm, 3.2 mm to 3.4 mm, 3.4 mm to 4.0 mm, 3.4 mm to 3.5 mm, or 3.5 mm to 4.0 mm as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0113] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in one eye is reduced by 0.5 mm to 4.0 mm, 0.5 mm to 3.5 mm, 0.5 mm to 3.4 mm, 0.5 mm to 3.2 mm, 0.5 mm to 3.0 mm, 0.5 mm to 2.9 mm, 0.5 mm to 2.8 mm, 0.5 mm to 2.7 mm, 0.5 mm to 2.6 mm, 0.5 mm to 2.5 mm, 0.5 mm to 2.4 mm, 0.5 mm to 2.3 mm, 0.5 mm to 2.2 mm, 0.5 mm to 2.1 mm, 0.5 mm to 2.0 mm, 0.7 mm to 4.0 mm, 0.7 mm to 3.5 mm, 0.7 mm to 3.4 mm, 0.7 mm to 3.2 mm, 0.7 mm to 3.0 mm, 0.7 mm to 2.9 mm, 0.7 mm to 2.8 mm, 0.7 mm to 2.7 mm, 0.7 mm to 2.6 mm, 0.7 mm to 2.5 mm, 0.7 mm to 2.4 mm, 0.7 mm to 2.3 mm, 0.7 mm to 2.2 mm,ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-20040.7 mm to 2.1 mm, 0.7 mm to 2.0 mm, 0.9 mm to 4.0 mm, 0.9 mm to 3.5 mm, 0.9 mm to 3.4 mm, 0.9 mm to 3.2 mm, 0.9 mm to 3.0 mm, 0.9 mm to 2.9 mm, 0.9 mm to 2.8 mm, 0.9 mm to 2.7 mm, 0.9 mm to 2.6 mm, 0.9 mm to 2.5 mm, 0.9 mm to 2.4 mm, 0.9 mm to 2.3 mm, 0.9 mm to 2.2 mm, 0.9 mm to 2.1 mm, 0.9 mm to 2.0 mm, 1.0 mm to 4.0 mm, 1.0 mm to 3.5 mm, 1.0 mm to 3.4 mm, 1.0 mm to 3.2 mm, 1.0 mm to 3.0 mm, 1.0 mm to 2.9 mm, 1.0 mm to 2.8 mm, 1.0 mm to 2.7 mm, 1.0 mm to 2.6 mm, 1.0 mm to 2.5 mm, 1.0 mm to 2.4 mm, 1.0 mm to 2.3 mm, 1.0 mm to 2.2 mm, 1.0 mm to 2.1 mm, 1.0 mm to 2.0 mm, 1.1 mm to 4.0 mm, 1.1 mm to 3.5 mm, 1.1 mm to 3.4 mm, 1.1 mm to 3.2 mm, 1.1 mm to 3.0 mm, 1.1 mm to 2.9 mm, 1.1 mm to 2.8 mm, 1.1 mm to 2.7 mm, 1.1 mm to 2.6 mm, 1.1 mm to 2.5 mm, 1.1 mm to 2.4 mm, 1.1 mm to 2.3 mm, 1.1 mm to 2.2 mm, 1.1 mm to 2.1 mm, 1.1 mm to 2.0 mm, 1.3 mm to 4.0 mm, 1.3 mm to 3.5 mm, 1.3 mm to 3.4 mm, 1.3 mm to 3.2 mm, 1.3 mm to 3.0 mm, 1.3 mm to 2.9 mm, 1.3 mm to 2.8 mm, 1.3 mm to 2.7 mm, 1.3 mm to 2.6 mm, 1.3 mm to 2.5 mm, 1.3 mm to 2.4 mm, 1.3 mm to 2.3 mm, 1.3 mm to 2.2 mm, 1.3 mm to 2.1 mm, 1.3 mm to 2.0 mm, 1.5 mm to 4.0 mm, 1.5 mm to 3.5 mm, 1.5 mm to 3.4 mm, 1.5 mm to 3.2 mm, 1.5 mm to 3.0 mm, 1.5 mm to 2.9 mm, 1.5 mm to 2.8 mm, 1.5 mm to 2.7 mm, 1.5 mm to 2.6 mm, 1.5 mm to 2.5 mm, 1.5 mm to 2.4 mm, 1.5 mm to 2.3 mm, 1.5 mm to 2.2 mm, 1.5 mm to 2.1 mm, 1.5 mm to 2.0 mm, 1.7 mm to 4.0 mm, 1.7 mm to 3.5 mm, 1.7 mm to 3.4 mm, 1.7 mm to 3.2 mm, 1.7 mm to 3.0 mm, 1.7 mm to 2.9 mm, 1.7 mm to 2.8 mm, 1.7 mm to 2.7 mm, 1.7 mm to 2.6 mm, 1.7 mm to 2.5 mm, 1.7 mm to 2.4 mm, 1.7 mm to 2.3 mm, 1.7 mm to 2.2 mm, 1.7 mm to 2.1 mm, 1.7 mm to 2.0 mm, 1.9 mm to 4.0 mm, 1.9 mm to 3.5 mm, 1.9 mm to 3.4 mm, 1.9 mm to 3.2 mm, 1.9 mm to 3.0 mm, 1.9 mm to 2.9 mm, 1.9 mm to 2.8 mm, 1.9 mm to 2.7 mm, 1.9 mm to 2.6 mm, 1.9 mm to 2.5 mm, 1.9 mm to 2.4 mm, 1.9 mm to 2.3 mm, 1.9 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.9 mm to 2.0 mm, 2.0 mm to 4.0 mm, 2.0 mm to 3.5 mm, 2.0 mm to 3.4 mm, 2.0 mm to 3.2 mm, 2.0 mm to 3.0 mm, 2.0 mm to 2.9 mm, 2.0 mm to 2.8 mm, 2.0 mm to 2.7 mm, 2.0 mm to 2.6 mm, 2.0 mm to 2.5 mm, 2.0 mm to 2.4 mm, 2.0 mm to 2.3 mm, 2.0 mm to 2.2 mm, 2.0 mm to 2.1 mm, 2.2 mm to 4.0 mm, 2.2 mm to 3.5 mm, 2.2 mm to 3.4 mm, 2.2 mm to 3.2 mm, 2.2 mm to 3.0 mm, 2.2 mm to 2.9 mm, 2.2 mm to 2.8 mm, 2.2 mm to 2.7 mm, 2.2 mm to 2.6 mm, 2.2 mm to 2.5 mm, 2.2 mm to 2.4 mm, 2.2 mm to 2.3 mm, 2.3 mm to 4.0 mm, 2.3 mm to 3.5 mm, 2.3 mm to 3.4 mm, 2.3 mm to 3.2 mm, 2.3 mm to 3.0 mm, 2.3 mm to 2.9 mm, 2.3 mm to 2.8 mm, 2.3 mm to 2.7 mm, 2.3 mm to 2.6 mm, 2.3 mm to 2.5 mm, 2.3 mm to 2.4 mm, 2.4 mm to 4.0 mm, 2.4 mm to 3.5 mm, 2.4 mm to 3.4 mm, 2.4 mm to 3.2 mm, 2.4 mm to 3.0 mm, 2.4 mm to 2.9 mm, 2.4 mm to 2.8 mm, 2.4 mm to 2.7 mm, 2.4 mm to 2.6 mm, 2.4 mm to 2.5 mm, 2.5 mm to 4.0 mm, 2.5 mm to 3.5 mm, 2.5 mm to 3.4 mm, 2.5 mm to 3.2 mm, 2.5 mm to 3.0 mm, 2.5 mm to 2.9 mm, 2.5 mm to 2.8 mm, 2.5 mm to 2.7 mm, 2.5 mm to 2.6 mm, 2.6ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004mm to 4.0 mm, 2.6 mm to 3.5 mm, 2.6 mm to 3.4 mm, 2.6 mm to 3.2 mm, 2.6 mm to 3.0 mm, 2.6 mm to 2.9 mm, 2.6 mm to 2.8 mm, 2.6 mm to 2.7 mm, 2.7 mm to 4.0 mm, 2.7 mm to 3.5 mm, 2.7 mm to 3.4 mm, 2.7 mm to 3.2 mm, 2.7 mm to 3.0 mm, 2.7 mm to 2.9 mm, 2.7 mm to 2.8 mm, 2.8 mm to 4.0 mm, 2.8 mm to 3.5 mm, 2.8 mm to 3.4 mm, 2.8 mm to 3.2 mm, 2.8 mm to 3.0 mm, 2.8 mm to 2.9 mm, 2.9 mm to 4.0 mm, 2.9 mm to 3.5 mm, 2.9 mm to 3.4 mm, 2.9 mm to 3.2 mm, 2.9 mm to 3.0 mm, 3.0 mm to 4.0 mm, 3.0 mm to 3.5 mm, 3.0 mm to 3.4 mm, 3.0 mm to 3.2 mm, 3.2 mm to 4.0 mm, 3.2 mm to 3.5 mm, 3.2 mm to 3.4 mm, 3.4 mm to 4.0 mm, 3.4 mm to 3.5 mm, or 3.5 mm to 4.0 mm as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. .

[0114] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in both eyes is reduced by 0.5 mm to 4.0 mm, 0.5 mm to 3.5 mm, 0.5 mm to 3.4 mm, 0.5 mm to 3.2 mm, 0.5 mm to 3.0 mm, 0.5 mm to 2.9 mm, 0.5 mm to 2.8 mm, 0.5 mm to 2.7 mm, 0.5 mm to 2.6 mm, 0.5 mm to 2.5 mm, 0.5 mm to 2.4 mm, 0.5 mm to 2.3 mm, 0.5 mm to 2.2 mm, 0.5 mm to 2.1 mm, 0.5 mm to 2.0 mm, 0.7 mm to 4.0 mm, 0.7 mm to 3.5 mm, 0.7 mm to 3.4 mm, 0.7 mm to 3.2 mm, 0.7 mm to 3.0 mm, 0.7 mm to 2.9 mm, 0.7 mm to 2.8 mm, 0.7 mm to 2.7 mm, 0.7 mm to 2.6 mm, 0.7 mm to 2.5 mm, 0.7 mm to 2.4 mm, 0.7 mm to 2.3 mm, 0.7 mm to 2.2 mm, 0.7 mm to 2.1 mm, 0.7 mm to 2.0 mm, 0.9 mm to 4.0 mm, 0.9 mm to 3.5 mm, 0.9 mm to 3.4 mm, 0.9 mm to 3.2 mm, 0.9 mm to 3.0 mm, 0.9 mm to 2.9 mm, 0.9 mm to 2.8 mm, 0.9 mm to 2.7 mm, 0.9 mm to 2.6 mm, 0.9 mm to 2.5 mm, 0.9 mm to 2.4 mm, 0.9 mm to 2.3 mm, 0.9 mm to 2.2 mm, 0.9 mm to 2.1 mm, 0.9 mm to 2.0 mm, 1.0 mm to 4.0 mm, 1.0 mm to 3.5 mm, 1.0 mm to 3.4 mm, 1.0 mm to 3.2 mm, 1.0 mm to 3.0 mm, 1.0 mm to 2.9 mm, 1.0 mm to 2.8 mm, 1.0 mm to 2.7 mm, 1.0 mm to 2.6 mm, 1.0 mm to 2.5 mm, 1.0 mm to 2.4 mm, 1.0 mm to 2.3 mm, 1.0 mm to 2.2 mm, 1.0 mm to 2.1 mm, 1.0 mm to 2.0 mm, 1.1 mm to 4.0 mm, 1.1 mm to 3.5 mm, 1.1 mm to 3.4 mm, 1.1 mm to 3.2 mm, 1.1 mm to 3.0 mm, 1.1 mm to 2.9 mm, 1.1 mm to 2.8 mm, 1.1 mm to 2.7 mm, 1.1 mm to 2.6 mm, 1.1 mm to 2.5 mm, 1.1 mm to 2.4 mm, 1.1 mm to 2.3 mm, 1.1 mm to 2.2 mm, 1.1 mm to 2.1 mm, 1.1 mm to 2.0 mm, 1.3 mm to 4.0 mm, 1.3 mm to 3.5 mm, 1.3 mm to 3.4 mm, 1.3 mm to 3.2 mm, 1.3 mm to 3.0 mm, 1.3 mm to 2.9 mm, 1.3 mm to 2.8 mm, 1.3 mm to 2.7 mm, 1.3 mm to 2.6 mm, 1.3 mm to 2.5 mm, 1.3 mm to 2.4 mm, 1.3 mm to 2.3 mm, 1.3 mm to 2.2 mm, 1.3 mm to 2.1 mm, 1.3 mm to 2.0 mm, 1.5 mm to 4.0 mm, 1.5 mm to 3.5 mm, 1.5 mm to 3.4 mm, 1.5 mm to 3.2 mm, 1.5 mm to 3.0 mm, 1.5 mm to 2.9 mm, 1.5 mm to 2.8 mm, 1.5 mm to 2.7 mm, 1.5 mm to 2.6 mm, 1.5 mm to 2.5 mm, 1.5 mm to 2.4 mm, 1.5 mm to 2.3 mm, 1.5 mm to 2.2 mm, 1.5 mm to 2.1 mm, 1.5 mm toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-20042.0 mm, 1.7 mm to 4.0 mm, 1.7 mm to 3.5 mm, 1.7 mm to 3.4 mm, 1.7 mm to 3.2 mm, 1.7 mm to 3.0 mm, 1.7 mm to 2.9 mm, 1.7 mm to 2.8 mm, 1.7 mm to 2.7 mm, 1.7 mm to 2.6 mm, 1.7 mm to 2.5 mm, 1.7 mm to 2.4 mm, 1.7 mm to 2.3 mm, 1.7 mm to 2.2 mm, 1.7 mm to 2.1 mm, 1.7 mm to 2.0 mm, 1.9 mm to 4.0 mm, 1.9 mm to 3.5 mm, 1.9 mm to 3.4 mm, 1.9 mm to 3.2 mm, 1.9 mm to 3.0 mm, 1.9 mm to 2.9 mm, 1.9 mm to 2.8 mm, 1.9 mm to 2.7 mm, 1.9 mm to 2.6 mm, 1.9 mm to 2.5 mm, 1.9 mm to 2.4 mm, 1.9 mm to 2.3 mm, 1.9 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.9 mm to 2.0 mm, 2.0 mm to 4.0 mm, 2.0 mm to 3.5 mm, 2.0 mm to 3.4 mm, 2.0 mm to 3.2 mm, 2.0 mm to 3.0 mm, 2.0 mm to 2.9 mm, 2.0 mm to 2.8 mm, 2.0 mm to 2.7 mm, 2.0 mm to 2.6 mm, 2.0 mm to 2.5 mm, 2.0 mm to 2.4 mm, 2.0 mm to 2.3 mm, 2.0 mm to 2.2 mm, 2.0 mm to 2.1 mm, 2.2 mm to 4.0 mm, 2.2 mm to 3.5 mm, 2.2 mm to 3.4 mm, 2.2 mm to 3.2 mm, 2.2 mm to 3.0 mm, 2.2 mm to 2.9 mm, 2.2 mm to 2.8 mm, 2.2 mm to 2.7 mm, 2.2 mm to 2.6 mm, 2.2 mm to 2.5 mm, 2.2 mm to 2.4 mm, 2.2 mm to 2.3 mm, 2.3 mm to 4.0 mm, 2.3 mm to 3.5 mm, 2.3 mm to 3.4 mm, 2.3 mm to 3.2 mm, 2.3 mm to 3.0 mm, 2.3 mm to 2.9 mm, 2.3 mm to 2.8 mm, 2.3 mm to 2.7 mm, 2.3 mm to 2.6 mm, 2.3 mm to 2.5 mm, 2.3 mm to 2.4 mm, 2.4 mm to 4.0 mm, 2.4 mm to 3.5 mm, 2.4 mm to 3.4 mm, 2.4 mm to 3.2 mm, 2.4 mm to 3.0 mm, 2.4 mm to 2.9 mm, 2.4 mm to 2.8 mm, 2.4 mm to 2.7 mm, 2.4 mm to 2.6 mm, 2.4 mm to 2.5 mm, 2.5 mm to 4.0 mm, 2.5 mm to 3.5 mm, 2.5 mm to 3.4 mm, 2.5 mm to 3.2 mm, 2.5 mm to 3.0 mm, 2.5 mm to 2.9 mm, 2.5 mm to 2.8 mm, 2.5 mm to 2.7 mm, 2.5 mm to 2.6 mm, 2.6 mm to 4.0 mm, 2.6 mm to 3.5 mm, 2.6 mm to 3.4 mm, 2.6 mm to 3.2 mm, 2.6 mm to 3.0 mm, 2.6 mm to 2.9 mm, 2.6 mm to 2.8 mm, 2.6 mm to 2.7 mm, 2.7 mm to 4.0 mm, 2.7 mm to 3.5 mm, 2.7 mm to 3.4 mm, 2.7 mm to 3.2 mm, 2.7 mm to 3.0 mm, 2.7 mm to 2.9 mm, 2.7 mm to 2.8 mm, 2.8 mm to 4.0 mm, 2.8 mm to 3.5 mm, 2.8 mm to 3.4 mm, 2.8 mm to 3.2 mm, 2.8 mm to 3.0 mm, 2.8 mm to 2.9 mm, 2.9 mm to 4.0 mm, 2.9 mm to 3.5 mm, 2.9 mm to 3.4 mm, 2.9 mm to 3.2 mm, 2.9 mm to 3.0 mm, 3.0 mm to 4.0 mm, 3.0 mm to 3.5 mm, 3.0 mm to 3.4 mm, 3.0 mm to 3.2 mm, 3.2 mm to 4.0 mm, 3.2 mm to 3.5 mm, 3.2 mm to 3.4 mm, 3.4 mm to 4.0 mm, 3.4 mm to 3.5 mm, or 3.5 mm to 4.0 mm as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. .

[0115] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 0.5 mm or greater, 0.6 mm or greater, 0.7 mm or greater, 0.8 mm or greater, 0.9 mm or greater, 1.0 mm or greater, 1.1 mm or greater, 1.2 mm or greater, 1.3 mm or greater, 1.4 mm or greater, 1.5 mm or greater, 1.6 mm or greater, 1.7 mm or greater, 1.8 mmATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004or greater, 1.9 mm or greater, 2.0 mm or greater, 2.1 mm or greater, 2.2 mm or greater, 2.3 mm or greater, 2.4 mm or greater, 2.5 mm or greater, 2.6 mm or greater, 2.7 mm or greater, 2.8 mm or greater, 2.9 mm or greater, 3.0 mm or greater, 3.1 mm or greater, 3.2 mm or greater, 3.3 mm or greater, 3.4 mm or greater, or 3.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 0.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 1.0 mm or greater as compared to the subj ect’ s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 1.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 2.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 0.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 1.0 mm or greater as comparedATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004to the subj ect’ s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 1.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 2.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in at least one eye is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0116] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 0.5 mm or greater, 0.6 mm or greater, 0.7 mm or greater, 0.8 mm or greater, 0.9 mm or greater, 1.0 mm or greater, 1.1 mm or greater, 1.2 mm or greater, 1.3 mm or greater, 1.4 mm or greater, 1.5 mm or greater, 1.6 mm or greater, 1.7 mm or greater, 1.8 mm or greater, 1.9 mm or greater, 2.0 mm or greater, 2.1 mm or greater, 2.2 mm or greater, 2.3 mm or greater, 2.4 mm or greater, 2.5 mm or greater, 2.6 mm or greater, 2.7 mm or greater, 2.8 mm or greater, 2.9 mm or greater, 3.0 mm or greater, 3.1 mm or greater, 3.2 mm or greater, 3.3 mm or greater, 3.4 mm or greater, or 3.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 0.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 1.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 1.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 2.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 0.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 1.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 1.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 2.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in one eye is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0117] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in bothATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004eyes is reduced by 0.5 mm or greater, 0.6 mm or greater, 0.7 mm or greater, 0.8 mm or greater, 0.9 mm or greater, 1.0 mm or greater, 1.1 mm or greater, 1.2 mm or greater, 1.3 mm or greater, 1.4 mm or greater, 1.5 mm or greater, 1.6 mm or greater, 1.7 mm or greater, 1.8 mm or greater, 1.9 mm or greater, 2.0 mm or greater, 2.1 mm or greater, 2.2 mm or greater, 2.3 mm or greater, 2.4 mm or greater, 2.5 mm or greater, 2.6 mm or greater, 2.7 mm or greater, 2.8 mm or greater, 2.9 mm or greater, 3.0 mm or greater, 3.1 mm or greater, 3.2 mm or greater, 3.3 mm or greater, 3.4 mm or greater, or 3.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in both eyes is reduced by 0.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in both eyes is reduced by 1.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in both eyes is reduced by 1.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in both eyes is reduced by 2.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in both eyes is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in both eyes is reduced by 0.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediatelyATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in both eyes is reduced by 1.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in both eyes is reduced by 1.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in both eyes is reduced by 2.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s proptosis in both eyes is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0118] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in at least one eye is reduced by 0.5 mm to 4.0 mm, 0.5 mm to 3.5 mm, 0.5 mm to 3.4 mm, 0.5 mm to 3.2 mm, 0.5 mm to 3.0 mm, 0.5 mm to 2.9 mm, 0.5 mm to 2.8 mm, 0.5 mm to 2.7 mm, 0.5 mm to 2.6 mm, 0.5 mm to 2.5 mm, 0.5 mm to 2.4 mm, 0.5 mm to 2.3 mm, 0.5 mm to 2.2 mm, 0.5 mm to 2.1 mm, 0.5 mm to 2.0 mm, 0.7 mm to 4.0 mm, 0.7 mm to 3.5 mm, 0.7 mm to 3.4 mm, 0.7 mm to 3.2 mm, 0.7 mm to 3.0 mm, 0.7 mm to 2.9 mm, 0.7 mm to 2.8 mm, 0.7 mm to 2.7 mm, 0.7 mm to 2.6 mm, 0.7 mm to 2.5 mm, 0.7 mm to 2.4 mm, 0.7 mm to 2.3 mm, 0.7 mm to 2.2 mm, 0.7 mm to 2.1 mm, 0.7 mm to 2.0 mm, 0.9 mm to 4.0 mm, 0.9 mm to 3.5 mm, 0.9 mm to 3.4 mm, 0.9 mm to 3.2 mm, 0.9 mm to 3.0 mm, 0.9 mm to 2.9 mm, 0.9 mm to 2.8 mm, 0.9 mm to 2.7 mm, 0.9 mm to 2.6 mm, 0.9 mm to 2.5 mm, 0.9 mm to 2.4 mm, 0.9 mm to 2.3 mm, 0.9 mm to 2.2 mm, 0.9 mm to 2.1 mm, 0.9 mm to 2.0 mm, 1.0 mm to 4.0 mm, 1.0 mm to 3.5 mm, 1.0 mm to 3.4 mm, 1.0 mm to 3.2 mm, 1.0 mm to 3.0 mm, 1.0 mm to 2.9 mm, 1.0 mm to 2.8 mm, 1.0 mm to 2.7 mm, 1.0 mm to 2.6 mm, 1.0 mm to 2.5 mm, 1.0 mm to 2.4 mm, 1.0 mm to 2.3 mm, 1.0 mm to 2.2 mm, 1.0 mm to 2.1 mm, 1.0 mm to 2.0 mm, 1.1 mm to 4.0 mm, 1.1 mm to 3.5 mm, 1.1 mm to 3.4 mm, 1.1 mm to 3.2 mm, 1.1 mm to 3.0 mm, 1.1 mm to 2.9 mm, 1.1 mm to 2.8 mm, 1.1 mm to 2.7 mm, 1.1 mm to 2.6 mm, 1.1 mm to 2.5 mm, 1.1 mm to 2.4 mm, 1.1 mm to 2.3 mm, 1.1 mm to 2.2 mm, 1.1 mm to 2.1 mm, 1.1 mm to 2.0 mm, 1.3 mm toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-20044.0 mm, 1.3 mm to 3.5 mm, 1.3 mm to 3.4 mm, 1.3 mm to 3.2 mm, 1.3 mm to 3.0 mm, 1.3 mm to 2.9 mm, 1.3 mm to 2.8 mm, 1.3 mm to 2.7 mm, 1.3 mm to 2.6 mm, 1.3 mm to 2.5 mm, 1.3 mm to 2.4 mm, 1.3 mm to 2.3 mm, 1.3 mm to 2.2 mm, 1.3 mm to 2.1 mm, 1.3 mm to 2.0 mm, 1.5 mm to 4.0 mm, 1.5 mm to 3.5 mm, 1.5 mm to 3.4 mm, 1.5 mm to 3.2 mm, 1.5 mm to 3.0 mm, 1.5 mm to 2.9 mm, 1.5 mm to 2.8 mm, 1.5 mm to 2.7 mm, 1.5 mm to 2.6 mm, 1.5 mm to 2.5 mm, 1.5 mm to 2.4 mm, 1.5 mm to 2.3 mm, 1.5 mm to 2.2 mm, 1.5 mm to 2.1 mm, 1.5 mm to 2.0 mm, 1.7 mm to 4.0 mm, 1.7 mm to 3.5 mm, 1.7 mm to 3.4 mm, 1.7 mm to 3.2 mm, 1.7 mm to 3.0 mm, 1.7 mm to 2.9 mm, 1.7 mm to 2.8 mm, 1.7 mm to 2.7 mm, 1.7 mm to 2.6 mm, 1.7 mm to 2.5 mm, 1.7 mm to 2.4 mm, 1.7 mm to 2.3 mm, 1.7 mm to 2.2 mm, 1.7 mm to 2.1 mm, 1.7 mm to 2.0 mm, 1.9 mm to 4.0 mm, 1.9 mm to 3.5 mm, 1.9 mm to 3.4 mm, 1.9 mm to 3.2 mm, 1.9 mm to 3.0 mm, 1.9 mm to 2.9 mm, 1.9 mm to 2.8 mm, 1.9 mm to 2.7 mm, 1.9 mm to 2.6 mm, 1.9 mm to 2.5 mm, 1.9 mm to 2.4 mm, 1.9 mm to 2.3 mm, 1.9 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.9 mm to 2.0 mm, 2.0 mm to 4.0 mm, 2.0 mm to 3.5 mm, 2.0 mm to 3.4 mm, 2.0 mm to 3.2 mm, 2.0 mm to 3.0 mm, 2.0 mm to 2.9 mm, 2.0 mm to 2.8 mm, 2.0 mm to 2.7 mm, 2.0 mm to 2.6 mm, 2.0 mm to 2.5 mm, 2.0 mm to 2.4 mm, 2.0 mm to 2.3 mm, 2.0 mm to 2.2 mm, 2.0 mm to 2.1 mm, 2.2 mm to 4.0 mm, 2.2 mm to 3.5 mm, 2.2 mm to 3.4 mm, 2.2 mm to 3.2 mm, 2.2 mm to 3.0 mm, 2.2 mm to 2.9 mm, 2.2 mm to 2.8 mm, 2.2 mm to 2.7 mm, 2.2 mm to 2.6 mm, 2.2 mm to 2.5 mm, 2.2 mm to 2.4 mm, 2.2 mm to 2.3 mm, 2.3 mm to 4.0 mm, 2.3 mm to 3.5 mm, 2.3 mm to 3.4 mm, 2.3 mm to 3.2 mm, 2.3 mm to 3.0 mm, 2.3 mm to 2.9 mm, 2.3 mm to 2.8 mm, 2.3 mm to 2.7 mm, 2.3 mm to 2.6 mm, 2.3 mm to 2.5 mm, 2.3 mm to 2.4 mm, 2.4 mm to 4.0 mm, 2.4 mm to 3.5 mm, 2.4 mm to 3.4 mm, 2.4 mm to 3.2 mm, 2.4 mm to 3.0 mm, 2.4 mm to 2.9 mm, 2.4 mm to 2.8 mm, 2.4 mm to 2.7 mm, 2.4 mm to 2.6 mm, 2.4 mm to 2.5 mm, 2.5 mm to 4.0 mm, 2.5 mm to 3.5 mm, 2.5 mm to 3.4 mm, 2.5 mm to 3.2 mm, 2.5 mm to 3.0 mm, 2.5 mm to 2.9 mm, 2.5 mm to 2.8 mm, 2.5 mm to 2.7 mm, 2.5 mm to 2.6 mm, 2.6 mm to 4.0 mm, 2.6 mm to 3.5 mm, 2.6 mm to 3.4 mm, 2.6 mm to 3.2 mm, 2.6 mm to 3.0 mm, 2.6 mm to 2.9 mm, 2.6 mm to 2.8 mm, 2.6 mm to 2.7 mm, 2.7 mm to 4.0 mm, 2.7 mm to 3.5 mm, 2.7 mm to 3.4 mm, 2.7 mm to 3.2 mm, 2.7 mm to 3.0 mm, 2.7 mm to 2.9 mm, 2.7 mm to 2.8 mm, 2.8 mm to 4.0 mm, 2.8 mm to 3.5 mm, 2.8 mm to 3.4 mm, 2.8 mm to 3.2 mm, 2.8 mm to 3.0 mm, 2.8 mm to 2.9 mm, 2.9 mm to 4.0 mm, 2.9 mm to 3.5 mm, 2.9 mm to 3.4 mm, 2.9 mm to 3.2 mm, 2.9 mm to 3.0 mm, 3.0 mm to 4.0 mm, 3.0 mm to 3.5 mm, 3.0 mm to 3.4 mm, 3.0 mm to 3.2 mm, 3.2 mm to 4.0 mm, 3.2 mm to 3.5 mm, 3.2 mm to 3.4 mm, 3.4 mm to 4.0 mm, 3.4 mm to 3.5 mm, or 3.5 mm to 4.0 mm as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0119] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in one eye is reduced by 0.5 mm to 4.0 mm, 0.5 mm to 3.5 mm, 0.5 mm to 3.4 mm, 0.5 mm to 3.2 mm, 0.5 mm to 3.0 mm, 0.5 mm to 2.9 mm, 0.5 mm to 2.8 mm, 0.5 mm to 2.7 mm, 0.5 mm to 2.6 mm, 0.5 mm to 2.5 mm, 0.5 mm to 2.4 mm, 0.5 mm to 2.3 mm, 0.5 mm to 2.2 mm, 0.5 mm to 2.1 mm, 0.5 mm to 2.0 mm, 0.7 mm to 4.0 mm, 0.7 mm to 3.5 mm, 0.7 mm to 3.4 mm, 0.7 mm to 3.2 mm, 0.7 mm to 3.0 mm, 0.7 mm to 2.9 mm, 0.7 mm to 2.8 mm, 0.7 mm to 2.7 mm, 0.7 mm to 2.6 mm, 0.7 mm to 2.5 mm, 0.7 mm to 2.4 mm, 0.7 mm to 2.3 mm, 0.7 mm to 2.2 mm, 0.7 mm to 2.1 mm, 0.7 mm to 2.0 mm, 0.9 mm to 4.0 mm, 0.9 mm to 3.5 mm, 0.9 mm to 3.4 mm, 0.9 mm to 3.2 mm, 0.9 mm to 3.0 mm, 0.9 mm to 2.9 mm, 0.9 mm to 2.8 mm, 0.9 mm to 2.7 mm, 0.9 mm to 2.6 mm, 0.9 mm to 2.5 mm, 0.9 mm to 2.4 mm, 0.9 mm to 2.3 mm, 0.9 mm to 2.2 mm, 0.9 mm to 2.1 mm, 0.9 mm to 2.0 mm, 1.0 mm to 4.0 mm, 1.0 mm to 3.5 mm, 1.0 mm to 3.4 mm, 1.0 mm to 3.2 mm, 1.0 mm to 3.0 mm, 1.0 mm to 2.9 mm, 1.0 mm to 2.8 mm, 1.0 mm to 2.7 mm, 1.0 mm to 2.6 mm, 1.0 mm to 2.5 mm, 1.0 mm to 2.4 mm, 1.0 mm to 2.3 mm, 1.0 mm to 2.2 mm, 1.0 mm to 2.1 mm, 1.0 mm to 2.0 mm, 1.1 mm to 4.0 mm, 1.1 mm to 3.5 mm, 1.1 mm to 3.4 mm, 1.1 mm to 3.2 mm, 1.1 mm to 3.0 mm, 1.1 mm to 2.9 mm, 1.1 mm to 2.8 mm, 1.1 mm to 2.7 mm, 1.1 mm to 2.6 mm, 1.1 mm to 2.5 mm, 1.1 mm to 2.4 mm, 1.1 mm to 2.3 mm, 1.1 mm to 2.2 mm, 1.1 mm to 2.1 mm, 1.1 mm to 2.0 mm, 1.3 mm to 4.0 mm, 1.3 mm to 3.5 mm, 1.3 mm to 3.4 mm, 1.3 mm to 3.2 mm, 1.3 mm to 3.0 mm, 1.3 mm to 2.9 mm, 1.3 mm to 2.8 mm, 1.3 mm to 2.7 mm, 1.3 mm to 2.6 mm, 1.3 mm to 2.5 mm, 1.3 mm to 2.4 mm, 1.3 mm to 2.3 mm, 1.3 mm to 2.2 mm, 1.3 mm to 2.1 mm, 1.3 mm to 2.0 mm, 1.5 mm to 4.0 mm, 1.5 mm to 3.5 mm, 1.5 mm to 3.4 mm, 1.5 mm to 3.2 mm, 1.5 mm to 3.0 mm, 1.5 mm to 2.9 mm, 1.5 mm to 2.8 mm, 1.5 mm to 2.7 mm, 1.5 mm to 2.6 mm, 1.5 mm to 2.5 mm, 1.5 mm to 2.4 mm, 1.5 mm to 2.3 mm, 1.5 mm to 2.2 mm, 1.5 mm to 2.1 mm, 1.5 mm to 2.0 mm, 1.7 mm to 4.0 mm, 1.7 mm to 3.5 mm, 1.7 mm to 3.4 mm, 1.7 mm to 3.2 mm, 1.7 mm to 3.0 mm, 1.7 mm to 2.9 mm, 1.7 mm to 2.8 mm, 1.7 mm to 2.7 mm, 1.7 mm to 2.6 mm, 1.7 mm to 2.5 mm, 1.7 mm to 2.4 mm, 1.7 mm to 2.3 mm, 1.7 mm to 2.2 mm, 1.7 mm to 2.1 mm, 1.7 mm to 2.0 mm, 1.9 mm to 4.0 mm, 1.9 mm to 3.5 mm, 1.9 mm to 3.4 mm, 1.9 mm to 3.2 mm, 1.9 mm to 3.0 mm, 1.9 mm to 2.9 mm, 1.9 mm to 2.8 mm, 1.9 mm to 2.7 mm, 1.9 mm to 2.6 mm, 1.9 mm to 2.5 mm, 1.9 mm to 2.4 mm, 1.9 mm to 2.3 mm, 1.9 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.9 mm to 2.0 mm, 2.0 mm to 4.0 mm, 2.0 mm to 3.5 mm, 2.0 mm to 3.4 mm, 2.0 mm to 3.2 mm, 2.0 mm to 3.0 mm, 2.0 mm to 2.9 mm, 2.0 mm to 2.8 mm, 2.0 mm to 2.7 mm, 2.0 mm to 2.6 mm, 2.0 mm to 2.5 mm, 2.0 mm to 2.4 mm, 2.0 mm to 2.3 mm, 2.0 mm to 2.2 mm,ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-20042.0 mm to 2.1 mm, 2.2 mm to 4.0 mm, 2.2 mm to 3.5 mm, 2.2 mm to 3.4 mm, 2.2 mm to 3.2 mm, 2.2 mm to 3.0 mm, 2.2 mm to 2.9 mm, 2.2 mm to 2.8 mm, 2.2 mm to 2.7 mm, 2.2 mm to 2.6 mm, 2.2 mm to 2.5 mm, 2.2 mm to 2.4 mm, 2.2 mm to 2.3 mm, 2.3 mm to 4.0 mm, 2.3 mm to 3.5 mm, 2.3 mm to 3.4 mm, 2.3 mm to 3.2 mm, 2.3 mm to 3.0 mm, 2.3 mm to 2.9 mm, 2.3 mm to 2.8 mm, 2.3 mm to 2.7 mm, 2.3 mm to 2.6 mm, 2.3 mm to 2.5 mm, 2.3 mm to 2.4 mm, 2.4 mm to 4.0 mm, 2.4 mm to 3.5 mm, 2.4 mm to 3.4 mm, 2.4 mm to 3.2 mm, 2.4 mm to 3.0 mm, 2.4 mm to 2.9 mm, 2.4 mm to 2.8 mm, 2.4 mm to 2.7 mm, 2.4 mm to 2.6 mm, 2.4 mm to 2.5 mm, 2.5 mm to 4.0 mm, 2.5 mm to 3.5 mm, 2.5 mm to 3.4 mm, 2.5 mm to 3.2 mm, 2.5 mm to 3.0 mm, 2.5 mm to 2.9 mm, 2.5 mm to 2.8 mm, 2.5 mm to 2.7 mm, 2.5 mm to 2.6 mm, 2.6 mm to 4.0 mm, 2.6 mm to 3.5 mm, 2.6 mm to 3.4 mm, 2.6 mm to 3.2 mm, 2.6 mm to 3.0 mm, 2.6 mm to 2.9 mm, 2.6 mm to 2.8 mm, 2.6 mm to 2.7 mm, 2.7 mm to 4.0 mm, 2.7 mm to 3.5 mm, 2.7 mm to 3.4 mm, 2.7 mm to 3.2 mm, 2.7 mm to 3.0 mm, 2.7 mm to 2.9 mm, 2.7 mm to 2.8 mm, 2.8 mm to 4.0 mm, 2.8 mm to 3.5 mm, 2.8 mm to 3.4 mm, 2.8 mm to 3.2 mm, 2.8 mm to 3.0 mm, 2.8 mm to 2.9 mm, 2.9 mm to 4.0 mm, 2.9 mm to 3.5 mm, 2.9 mm to 3.4 mm, 2.9 mm to 3.2 mm, 2.9 mm to 3.0 mm, 3.0 mm to 4.0 mm, 3.0 mm to 3.5 mm, 3.0 mm to 3.4 mm, 3.0 mm to 3.2 mm, 3.2 mm to 4.0 mm, 3.2 mm to 3.5 mm, 3.2 mm to 3.4 mm, 3.4 mm to 4.0 mm, 3.4 mm to 3.5 mm, or 3.5 mm to 4.0 mm as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose. .

[0120] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s proptosis in both eyes is reduced by 0.5 mm to 4.0 mm, 0.5 mm to 3.5 mm, 0.5 mm to 3.4 mm, 0.5 mm to 3.2 mm, 0.5 mm to 3.0 mm, 0.5 mm to 2.9 mm, 0.5 mm to 2.8 mm, 0.5 mm to 2.7 mm, 0.5 mm to 2.6 mm, 0.5 mm to 2.5 mm, 0.5 mm to 2.4 mm, 0.5 mm to 2.3 mm, 0.5 mm to 2.2 mm, 0.5 mm to 2.1 mm, 0.5 mm to 2.0 mm, 0.7 mm to 4.0 mm, 0.7 mm to 3.5 mm, 0.7 mm to 3.4 mm, 0.7 mm to 3.2 mm, 0.7 mm to 3.0 mm, 0.7 mm to 2.9 mm, 0.7 mm to 2.8 mm, 0.7 mm to 2.7 mm, 0.7 mm to 2.6 mm, 0.7 mm to 2.5 mm, 0.7 mm to 2.4 mm, 0.7 mm to 2.3 mm, 0.7 mm to 2.2 mm, 0.7 mm to 2.1 mm, 0.7 mm to 2.0 mm, 0.9 mm to 4.0 mm, 0.9 mm to 3.5 mm, 0.9 mm to 3.4 mm, 0.9 mm to 3.2 mm, 0.9 mm to 3.0 mm, 0.9 mm to 2.9 mm, 0.9 mm to 2.8 mm, 0.9 mm to 2.7 mm, 0.9 mm to 2.6 mm, 0.9 mm to 2.5 mm, 0.9 mm to 2.4 mm, 0.9 mm to 2.3 mm, 0.9 mm to 2.2 mm, 0.9 mm to 2.1 mm, 0.9 mm to 2.0 mm, 1.0 mm to 4.0 mm, 1.0 mm to 3.5 mm, 1.0 mm to 3.4 mm, 1.0 mm to 3.2 mm, 1.0 mm to 3.0 mm, 1.0 mm to 2.9 mm, 1.0 mm to 2.8 mm, 1.0 mm to 2.7 mm, 1.0 mm to 2.6 mm, 1.0 mm to 2.5 mm, 1.0 mm to 2.4 mm, 1.0 mm toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-20042.3 mm, 1.0 mm to 2.2 mm, 1.0 mm to 2.1 mm, 1.0 mm to 2.0 mm, 1.1 mm to 4.0 mm, 1.1 mm to 3.5 mm, 1.1 mm to 3.4 mm, 1.1 mm to 3.2 mm, 1.1 mm to 3.0 mm, 1.1 mm to 2.9 mm, 1.1 mm to 2.8 mm, 1.1 mm to 2.7 mm, 1.1 mm to 2.6 mm, 1.1 mm to 2.5 mm, 1.1 mm to 2.4 mm, 1.1 mm to 2.3 mm, 1.1 mm to 2.2 mm, 1.1 mm to 2.1 mm, 1.1 mm to 2.0 mm, 1.3 mm to 4.0 mm, 1.3 mm to 3.5 mm, 1.3 mm to 3.4 mm, 1.3 mm to 3.2 mm, 1.3 mm to 3.0 mm, 1.3 mm to 2.9 mm, 1.3 mm to 2.8 mm, 1.3 mm to 2.7 mm, 1.3 mm to 2.6 mm, 1.3 mm to 2.5 mm, 1.3 mm to 2.4 mm, 1.3 mm to 2.3 mm, 1.3 mm to 2.2 mm, 1.3 mm to 2.1 mm, 1.3 mm to 2.0 mm, 1.5 mm to 4.0 mm, 1.5 mm to 3.5 mm, 1.5 mm to 3.4 mm, 1.5 mm to 3.2 mm, 1.5 mm to 3.0 mm, 1.5 mm to 2.9 mm, 1.5 mm to 2.8 mm, 1.5 mm to 2.7 mm, 1.5 mm to 2.6 mm, 1.5 mm to 2.5 mm, 1.5 mm to 2.4 mm, 1.5 mm to 2.3 mm, 1.5 mm to 2.2 mm, 1.5 mm to 2.1 mm, 1.5 mm to 2.0 mm, 1.7 mm to 4.0 mm, 1.7 mm to 3.5 mm, 1.7 mm to 3.4 mm, 1.7 mm to 3.2 mm, 1.7 mm to 3.0 mm, 1.7 mm to 2.9 mm, 1.7 mm to 2.8 mm, 1.7 mm to 2.7 mm, 1.7 mm to 2.6 mm, 1.7 mm to 2.5 mm, 1.7 mm to 2.4 mm, 1.7 mm to 2.3 mm, 1.7 mm to 2.2 mm, 1.7 mm to 2.1 mm, 1.7 mm to 2.0 mm, 1.9 mm to 4.0 mm, 1.9 mm to 3.5 mm, 1.9 mm to 3.4 mm, 1.9 mm to 3.2 mm, 1.9 mm to 3.0 mm, 1.9 mm to 2.9 mm, 1.9 mm to 2.8 mm, 1.9 mm to 2.7 mm, 1.9 mm to 2.6 mm, 1.9 mm to 2.5 mm, 1.9 mm to 2.4 mm, 1.9 mm to 2.3 mm, 1.9 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.9 mm to 2.0 mm, 2.0 mm to 4.0 mm, 2.0 mm to 3.5 mm, 2.0 mm to 3.4 mm, 2.0 mm to 3.2 mm, 2.0 mm to 3.0 mm, 2.0 mm to 2.9 mm, 2.0 mm to 2.8 mm, 2.0 mm to 2.7 mm, 2.0 mm to 2.6 mm, 2.0 mm to 2.5 mm, 2.0 mm to 2.4 mm, 2.0 mm to 2.3 mm, 2.0 mm to 2.2 mm, 2.0 mm to 2.1 mm, 2.2 mm to 4.0 mm, 2.2 mm to 3.5 mm, 2.2 mm to 3.4 mm, 2.2 mm to 3.2 mm, 2.2 mm to 3.0 mm, 2.2 mm to 2.9 mm, 2.2 mm to 2.8 mm, 2.2 mm to 2.7 mm, 2.2 mm to 2.6 mm, 2.2 mm to 2.5 mm, 2.2 mm to 2.4 mm, 2.2 mm to 2.3 mm, 2.3 mm to 4.0 mm, 2.3 mm to 3.5 mm, 2.3 mm to 3.4 mm, 2.3 mm to 3.2 mm, 2.3 mm to 3.0 mm, 2.3 mm to 2.9 mm, 2.3 mm to 2.8 mm, 2.3 mm to 2.7 mm, 2.3 mm to 2.6 mm, 2.3 mm to 2.5 mm, 2.3 mm to 2.4 mm, 2.4 mm to 4.0 mm, 2.4 mm to 3.5 mm, 2.4 mm to 3.4 mm, 2.4 mm to 3.2 mm, 2.4 mm to 3.0 mm, 2.4 mm to 2.9 mm, 2.4 mm to 2.8 mm, 2.4 mm to 2.7 mm, 2.4 mm to 2.6 mm, 2.4 mm to 2.5 mm, 2.5 mm to 4.0 mm, 2.5 mm to 3.5 mm, 2.5 mm to 3.4 mm, 2.5 mm to 3.2 mm, 2.5 mm to 3.0 mm, 2.5 mm to 2.9 mm, 2.5 mm to 2.8 mm, 2.5 mm to 2.7 mm, 2.5 mm to 2.6 mm, 2.6 mm to 4.0 mm, 2.6 mm to 3.5 mm, 2.6 mm to 3.4 mm, 2.6 mm to 3.2 mm, 2.6 mm to 3.0 mm, 2.6 mm to 2.9 mm, 2.6 mm to 2.8 mm, 2.6 mm to 2.7 mm, 2.7 mm to 4.0 mm, 2.7 mm to 3.5 mm, 2.7 mm to 3.4 mm, 2.7 mm to 3.2 mm, 2.7 mm to 3.0 mm, 2.7 mm to 2.9 mm, 2.7 mm to 2.8 mm, 2.8 mm to 4.0 mm, 2.8 mm to 3.5 mm, 2.8 mm to 3.4 mm, 2.8 mm to 3.2 mm, 2.8 mm to 3.0 mm, 2.8 mm to 2.9 mm, 2.9 mm to 4.0 mm, 2.9 mm to 3.5 mm, 2.9 mm to 3.4 mm, 2.9 mm to 3.2 mm, 2.9 mm to 3.0 mm, 3.0 mm to 4.0 mm, 3.0 mm to 3.5 mm, 3.0 mm to 3.4ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004mm, 3.0 mm to 3.2 mm, 3.2 mm to 4.0 mm, 3.2 mm to 3.5 mm, 3.2 mm to 3.4 mm, 3.4 mm to 4.0 mm, 3.4 mm to 3.5 mm, or 3.5 mm to 4.0 mm as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0121] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, was administered, the subject’s proptosis in at least one eye is reduced by 0.5 mm or greater, 0.6 mm or greater, 0.7 mm or greater, 0.8 mm or greater, 0.9 mm or greater, 1.0 mm or greater, 1.1 mm or greater, 1.2 mm or greater, 1.3 mm or greater, 1.4 mm or greater, 1.5 mm or greater, 1.6 mm or greater, 1.7 mm or greater, 1.8 mm or greater, 1.9 mm or greater, 2.0 mm or greater, 2.1 mm or greater, 2.2 mm or greater, 2.3 mm or greater, 2.4 mm or greater, 2.5 mm or greater, 2.6 mm or greater, 2.7 mm or greater, 2.8 mm or greater, 2.9 mm or greater, 3.0 mm or greater, 3.1 mm or greater, 3.2 mm or greater, 3.3 mm or greater, 3.4 mm or greater, or 3.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0122] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, a subject’s proptosis in at least one eye is reduced by 0.5 mm to 4.0 mm, 0.5 mm to 3.5 mm, 0.5 mm to 3.4 mm, 0.5 mm to 3.2 mm, 0.5 mm to 3.0 mm, 0.5 mm to 2.9 mm, 0.5 mm to 2.8 mm, 0.5 mm to 2.7 mm, 0.5 mm to 2.6 mm, 0.5 mm to 2.5 mm, 0.5 mm to 2.4 mm, 0.5 mm to 2.3 mm, 0.5 mm to 2.2 mm, 0.5 mm to 2.1 mm, 0.5 mm to 2.0 mm, 0.7 mm to 4.0 mm, 0.7 mm to 3.5 mm, 0.7 mm to 3.4 mm, 0.7 mm to 3.2 mm, 0.7 mm to 3.0 mm, 0.7 mm to 2.9 mm, 0.7 mm to 2.8 mm, 0.7 mm to 2.7 mm, 0.7 mm to 2.6 mm, 0.7 mm to 2.5 mm, 0.7 mm to 2.4 mm, 0.7 mm to 2.3 mm, 0.7 mm to 2.2 mm, 0.7 mm to 2.1 mm, 0.7 mm to 2.0 mm, 0.9 mm to 4.0 mm, 0.9 mm to 3.5 mm, 0.9 mm to 3.4 mm, 0.9 mm to 3.2 mm, 0.9 mm to 3.0 mm, 0.9 mm to 2.9 mm, 0.9 mm to 2.8 mm, 0.9 mm to 2.7 mm, 0.9 mm to 2.6 mm, 0.9 mm to 2.5 mm, 0.9 mm to 2.4 mm, 0.9 mm to 2.3 mm, 0.9 mm to 2.2 mm, 0.9 mm to 2.1 mm, 0.9 mm to 2.0 mm, 1.0 mm to 4.0 mm, 1.0 mm to 3.5 mm, 1.0 mm to 3.4 mm, 1.0 mm to 3.2 mm, 1.0 mm to 3.0 mm, 1.0 mm to 2.9 mm, 1.0 mm to 2.8 mm, 1.0 mm to 2.7 mm, 1.0 mm to 2.6 mm, 1.0 mm to 2.5 mm, 1.0 mm to 2.4 mm, 1.0 mm to 2.3 mm, 1.0 mm to 2.2 mm, 1.0 mm to 2.1 mm, 1.0 mm to 2.0 mm, 1.1 mm to 4.0 mm, 1.1 mm to 3.5 mm, 1.1 mm to 3.4 mm, 1.1 mm to 3.2 mm, 1.1 mm to 3.0 mm, 1.1 mm to 2.9 mm, 1.1 mm to 2.8 mm, 1.1 mm to 2.7 mm, 1.1 mm to 2.6 mm, 1.1 mm to 2.5 mm, 1.1 mm to 2.4 mm,ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-20041.1 mm to 2.3 mm, 1.1 mm to 2.2 mm, 1.1 mm to 2.1 mm, 1.1 mm to 2.0 mm, 1.3 mm to 4.0 mm, 1.3 mm to 3.5 mm, 1.3 mm to 3.4 mm, 1.3 mm to 3.2 mm, 1.3 mm to 3.0 mm, 1.3 mm to 2.9 mm, 1.3 mm to 2.8 mm, 1.3 mm to 2.7 mm, 1.3 mm to 2.6 mm, 1.3 mm to 2.5 mm, 1.3 mm to 2.4 mm, 1.3 mm to 2.3 mm, 1.3 mm to 2.2 mm, 1.3 mm to 2.1 mm, 1.3 mm to 2.0 mm, 1.5 mm to 4.0 mm, 1.5 mm to 3.5 mm, 1.5 mm to 3.4 mm, 1.5 mm to 3.2 mm, 1.5 mm to 3.0 mm, 1.5 mm to 2.9 mm, 1.5 mm to 2.8 mm, 1.5 mm to 2.7 mm, 1.5 mm to 2.6 mm, 1.5 mm to 2.5 mm, 1.5 mm to 2.4 mm, 1.5 mm to 2.3 mm, 1.5 mm to 2.2 mm, 1.5 mm to 2.1 mm, 1.5 mm to 2.0 mm, 1.7 mm to 4.0 mm, 1.7 mm to 3.5 mm, 1.7 mm to 3.4 mm, 1.7 mm to 3.2 mm, 1.7 mm to 3.0 mm, 1.7 mm to 2.9 mm, 1.7 mm to 2.8 mm, 1.7 mm to 2.7 mm, 1.7 mm to 2.6 mm, 1.7 mm to 2.5 mm, 1.7 mm to 2.4 mm, 1.7 mm to 2.3 mm, 1.7 mm to 2.2 mm, 1.7 mm to 2.1 mm, 1.7 mm to 2.0 mm, 1.9 mm to 4.0 mm, 1.9 mm to 3.5 mm, 1.9 mm to 3.4 mm, 1.9 mm to 3.2 mm, 1.9 mm to 3.0 mm, 1.9 mm to 2.9 mm, 1.9 mm to 2.8 mm, 1.9 mm to 2.7 mm, 1.9 mm to 2.6 mm, 1.9 mm to 2.5 mm, 1.9 mm to 2.4 mm, 1.9 mm to 2.3 mm, 1.9 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.9 mm to 2.0 mm, 2.0 mm to 4.0 mm, 2.0 mm to 3.5 mm, 2.0 mm to 3.4 mm, 2.0 mm to 3.2 mm, 2.0 mm to 3.0 mm, 2.0 mm to 2.9 mm, 2.0 mm to 2.8 mm, 2.0 mm to 2.7 mm, 2.0 mm to 2.6 mm, 2.0 mm to 2.5 mm, 2.0 mm to 2.4 mm, 2.0 mm to 2.3 mm, 2.0 mm to 2.2 mm, 2.0 mm to 2.1 mm, 2.2 mm to 4.0 mm, 2.2 mm to 3.5 mm, 2.2 mm to 3.4 mm, 2.2 mm to 3.2 mm, 2.2 mm to 3.0 mm, 2.2 mm to 2.9 mm, 2.2 mm to 2.8 mm, 2.2 mm to 2.7 mm, 2.2 mm to 2.6 mm, 2.2 mm to 2.5 mm, 2.2 mm to 2.4 mm, 2.2 mm to 2.3 mm, 2.3 mm to 4.0 mm, 2.3 mm to 3.5 mm, 2.3 mm to 3.4 mm, 2.3 mm to 3.2 mm, 2.3 mm to 3.0 mm, 2.3 mm to 2.9 mm, 2.3 mm to 2.8 mm, 2.3 mm to 2.7 mm, 2.3 mm to 2.6 mm, 2.3 mm to 2.5 mm, 2.3 mm to 2.4 mm, 2.4 mm to 4.0 mm, 2.4 mm to 3.5 mm, 2.4 mm to 3.4 mm, 2.4 mm to 3.2 mm, 2.4 mm to 3.0 mm, 2.4 mm to 2.9 mm, 2.4 mm to 2.8 mm, 2.4 mm to 2.7 mm, 2.4 mm to 2.6 mm, 2.4 mm to 2.5 mm, 2.5 mm to 4.0 mm, 2.5 mm to 3.5 mm, 2.5 mm to 3.4 mm, 2.5 mm to 3.2 mm, 2.5 mm to 3.0 mm, 2.5 mm to 2.9 mm, 2.5 mm to 2.8 mm, 2.5 mm to 2.7 mm, 2.5 mm to 2.6 mm, 2.6 mm to 4.0 mm, 2.6 mm to 3.5 mm, 2.6 mm to 3.4 mm, 2.6 mm to 3.2 mm, 2.6 mm to 3.0 mm, 2.6 mm to 2.9 mm, 2.6 mm to 2.8 mm, 2.6 mm to 2.7 mm, 2.7 mm to 4.0 mm, 2.7 mm to 3.5 mm, 2.7 mm to 3.4 mm, 2.7 mm to 3.2 mm, 2.7 mm to 3.0 mm, 2.7 mm to 2.9 mm, 2.7 mm to 2.8 mm, 2.8 mm to 4.0 mm, 2.8 mm to 3.5 mm, 2.8 mm to 3.4 mm, 2.8 mm to 3.2 mm, 2.8 mm to 3.0 mm, 2.8 mm to 2.9 mm, 2.9 mm to 4.0 mm, 2.9 mm to 3.5 mm, 2.9 mm to 3.4 mm, 2.9 mm to 3.2 mm, 2.9 mm to 3.0 mm, 3.0 mm to 4.0 mm, 3.0 mm to 3.5 mm, 3.0 mm to 3.4 mm, 3.0 mm to 3.2 mm, 3.2 mm to 4.0 mm, 3.2 mm to 3.5 mm, 3.2 mm to 3.4 mm, 3.4 mm to 4.0 mm, 3.4 mm to 3.5 mm, or 3.5 mm to 4.0 mm as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0123] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, was administered, the subject’s proptosis in one eye is reduced by 0.5 mm or greater, 0.6 mm or greater, 0.7 mm or greater, 0.8 mm or greater, 0.9 mm or greater, 1.0 mm or greater, 1.1 mm or greater, 1.2 mm or greater, 1.3 mm or greater, 1.4 mm or greater, 1.5 mm or greater, 1.6 mm or greater, 1.7 mm or greater, 1.8 mm or greater, 1.9 mm or greater, 2.0 mm or greater, 2.1 mm or greater, 2.2 mm or greater, 2.3 mm or greater, 2.4 mm or greater, 2.5 mm or greater, 2.6 mm or greater, 2.7 mm or greater, 2.8 mm or greater, 2.9 mm or greater, 3.0 mm or greater, 3.1 mm or greater, 3.2 mm or greater, 3.3 mm or greater, 3.4 mm or greater, or 3.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0124] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, a subject’s proptosis in one eye is reduced by 0.5 mm to 4.0 mm, 0.5 mm to 3.5 mm, 0.5 mm to 3.4 mm, 0.5 mm to 3.2 mm, 0.5 mm to 3.0 mm, 0.5 mm to 2.9 mm, 0.5 mm to 2.8 mm, 0.5 mm to 2.7 mm, 0.5 mm to 2.6 mm, 0.5 mm to 2.5 mm, 0.5 mm to 2.4 mm, 0.5 mm to 2.3 mm, 0.5 mm to 2.2 mm, 0.5 mm to 2.1 mm, 0.5 mm to 2.0 mm, 0.7 mm to 4.0 mm, 0.7 mm to 3.5 mm, 0.7 mm to 3.4 mm, 0.7 mm to 3.2 mm, 0.7 mm to 3.0 mm, 0.7 mm to 2.9 mm, 0.7 mm to 2.8 mm, 0.7 mm to 2.7 mm, 0.7 mm to 2.6 mm, 0.7 mm to 2.5 mm, 0.7 mm to 2.4 mm, 0.7 mm to 2.3 mm, 0.7 mm to 2.2 mm, 0.7 mm to 2.1 mm, 0.7 mm to 2.0 mm, 0.9 mm to 4.0 mm, 0.9 mm to 3.5 mm, 0.9 mm to 3.4 mm, 0.9 mm to 3.2 mm, 0.9 mm to 3.0 mm, 0.9 mm to 2.9 mm, 0.9 mm to 2.8 mm, 0.9 mm to 2.7 mm, 0.9 mm to 2.6 mm, 0.9 mm to 2.5 mm, 0.9 mm to 2.4 mm, 0.9 mm to 2.3 mm, 0.9 mm to 2.2 mm, 0.9 mm to 2.1 mm, 0.9 mm to 2.0 mm, 1.0 mm to 4.0 mm, 1.0 mm to 3.5 mm, 1.0 mm to 3.4 mm, 1.0 mm to 3.2 mm, 1.0 mm to 3.0 mm, 1.0 mm to 2.9 mm, 1.0 mm to 2.8 mm, 1.0 mm to 2.7 mm, 1.0 mm to 2.6 mm, 1.0 mm to 2.5 mm, 1.0 mm to 2.4 mm, 1.0 mm to 2.3 mm, 1.0 mm to 2.2 mm, 1.0 mm to 2.1 mm, 1.0 mm to 2.0 mm, 1.1 mm to 4.0 mm, 1.1 mm to 3.5 mm, 1.1 mm to 3.4 mm, 1.1 mm to 3.2 mm, 1.1 mm to 3.0 mm, 1.1 mm to 2.9 mm, 1.1 mm to 2.8 mm, 1.1 mm to 2.7 mm, 1.1 mm to 2.6 mm, 1.1 mm to 2.5 mm, 1.1 mm to 2.4 mm, 1.1 mm to 2.3 mm, 1.1 mm to 2.2 mm, 1.1 mm to 2.1 mm, 1.1 mm to 2.0 mm, 1.3 mm to 4.0 mm, 1.3 mm to 3.5 mm, 1.3 mm to 3.4 mm, 1.3 mm to 3.2 mm, 1.3 mm to 3.0 mm, 1.3 mm to 2.9 mm, 1.3 mm to 2.8 mm, 1.3 mm to 2.7 mm, 1.3 mm to 2.6 mm, 1.3 mm to 2.5 mm, 1.3 mm to 2.4 mm, 1.3 mm to 2.3 mm, 1.3 mm to 2.2 mm, 1.3 mm to 2.1 mm, 1.3 mm to 2.0 mm, 1.5 mm toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-20044.0 mm, 1.5 mm to 3.5 mm, 1.5 mm to 3.4 mm, 1.5 mm to 3.2 mm, 1.5 mm to 3.0 mm, 1.5 mm to 2.9 mm, 1.5 mm to 2.8 mm, 1.5 mm to 2.7 mm, 1.5 mm to 2.6 mm, 1.5 mm to 2.5 mm, 1.5 mm to 2.4 mm, 1.5 mm to 2.3 mm, 1.5 mm to 2.2 mm, 1.5 mm to 2.1 mm, 1.5 mm to 2.0 mm, 1.7 mm to 4.0 mm, 1.7 mm to 3.5 mm, 1.7 mm to 3.4 mm, 1.7 mm to 3.2 mm, 1.7 mm to 3.0 mm, 1.7 mm to 2.9 mm, 1.7 mm to 2.8 mm, 1.7 mm to 2.7 mm, 1.7 mm to 2.6 mm, 1.7 mm to 2.5 mm, 1.7 mm to 2.4 mm, 1.7 mm to 2.3 mm, 1.7 mm to 2.2 mm, 1.7 mm to 2.1 mm, 1.7 mm to 2.0 mm, 1.9 mm to 4.0 mm, 1.9 mm to 3.5 mm, 1.9 mm to 3.4 mm, 1.9 mm to 3.2 mm, 1.9 mm to 3.0 mm, 1.9 mm to 2.9 mm, 1.9 mm to 2.8 mm, 1.9 mm to 2.7 mm, 1.9 mm to 2.6 mm, 1.9 mm to 2.5 mm, 1.9 mm to 2.4 mm, 1.9 mm to 2.3 mm, 1.9 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.9 mm to 2.0 mm, 2.0 mm to 4.0 mm, 2.0 mm to 3.5 mm, 2.0 mm to 3.4 mm, 2.0 mm to 3.2 mm, 2.0 mm to 3.0 mm, 2.0 mm to 2.9 mm, 2.0 mm to 2.8 mm, 2.0 mm to 2.7 mm, 2.0 mm to 2.6 mm, 2.0 mm to 2.5 mm, 2.0 mm to 2.4 mm, 2.0 mm to 2.3 mm, 2.0 mm to 2.2 mm, 2.0 mm to 2.1 mm, 2.2 mm to 4.0 mm, 2.2 mm to 3.5 mm, 2.2 mm to 3.4 mm, 2.2 mm to 3.2 mm, 2.2 mm to 3.0 mm, 2.2 mm to 2.9 mm, 2.2 mm to 2.8 mm, 2.2 mm to 2.7 mm, 2.2 mm to 2.6 mm, 2.2 mm to 2.5 mm, 2.2 mm to 2.4 mm, 2.2 mm to 2.3 mm, 2.3 mm to 4.0 mm, 2.3 mm to 3.5 mm, 2.3 mm to 3.4 mm, 2.3 mm to 3.2 mm, 2.3 mm to 3.0 mm, 2.3 mm to 2.9 mm, 2.3 mm to 2.8 mm, 2.3 mm to 2.7 mm, 2.3 mm to 2.6 mm, 2.3 mm to 2.5 mm, 2.3 mm to 2.4 mm, 2.4 mm to 4.0 mm, 2.4 mm to 3.5 mm, 2.4 mm to 3.4 mm, 2.4 mm to 3.2 mm, 2.4 mm to 3.0 mm, 2.4 mm to 2.9 mm, 2.4 mm to 2.8 mm, 2.4 mm to 2.7 mm, 2.4 mm to 2.6 mm, 2.4 mm to 2.5 mm, 2.5 mm to 4.0 mm, 2.5 mm to 3.5 mm, 2.5 mm to 3.4 mm, 2.5 mm to 3.2 mm, 2.5 mm to 3.0 mm, 2.5 mm to 2.9 mm, 2.5 mm to 2.8 mm, 2.5 mm to 2.7 mm, 2.5 mm to 2.6 mm, 2.6 mm to 4.0 mm, 2.6 mm to 3.5 mm, 2.6 mm to 3.4 mm, 2.6 mm to 3.2 mm, 2.6 mm to 3.0 mm, 2.6 mm to 2.9 mm, 2.6 mm to 2.8 mm, 2.6 mm to 2.7 mm, 2.7 mm to 4.0 mm, 2.7 mm to 3.5 mm, 2.7 mm to 3.4 mm, 2.7 mm to 3.2 mm, 2.7 mm to 3.0 mm, 2.7 mm to 2.9 mm, 2.7 mm to 2.8 mm, 2.8 mm to 4.0 mm, 2.8 mm to 3.5 mm, 2.8 mm to 3.4 mm, 2.8 mm to 3.2 mm, 2.8 mm to 3.0 mm, 2.8 mm to 2.9 mm, 2.9 mm to 4.0 mm, 2.9 mm to 3.5 mm, 2.9 mm to 3.4 mm, 2.9 mm to 3.2 mm, 2.9 mm to 3.0 mm, 3.0 mm to 4.0 mm, 3.0 mm to 3.5 mm, 3.0 mm to 3.4 mm, 3.0 mm to 3.2 mm, 3.2 mm to 4.0 mm, 3.2 mm to 3.5 mm, 3.2 mm to 3.4 mm, 3.4 mm to 4.0 mm, 3.4 mm to 3.5 mm, or 3.5 mm to 4.0 mm as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0125] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, the subject’s proptosis in both eyesATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004is reduced by 0.5 mm or greater, 0.6 mm or greater, 0.7 mm or greater, 0.8 mm or greater, 0.9 mm or greater, 1.0 mm or greater, 1.1 mm or greater, 1.2 mm or greater, 1.3 mm or greater, 1.4 mm or greater, 1.5 mm or greater, 1.6 mm or greater, 1.7 mm or greater, 1.8 mm or greater, 1.9 mm or greater, 2.0 mm or greater, 2.1 mm or greater, 2.2 mm or greater, 2.3 mm or greater, 2.4 mm or greater, 2.5 mm or greater, 2.6 mm or greater, 2.7 mm or greater, 2.8 mm or greater, 2.9 mm or greater, 3.0 mm or greater, 3.1 mm or greater, 3.2 mm or greater, 3.3 mm or greater, 3.4 mm or greater, or 3.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0126] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, a subject’s proptosis in both eyes is reduced by 0.5 mm to 4.0 mm, 0.5 mm to 3.5 mm, 0.5 mm to 3.4 mm, 0.5 mm to 3.2 mm, 0.5 mm to 3.0 mm, 0.5 mm to 2.9 mm, 0.5 mm to 2.8 mm, 0.5 mm to 2.7 mm, 0.5 mm to 2.6 mm, 0.5 mm to 2.5 mm, 0.5 mm to 2.4 mm, 0.5 mm to 2.3 mm, 0.5 mm to 2.2 mm, 0.5 mm to 2.1 mm, 0.5 mm to 2.0 mm, 0.7 mm to 4.0 mm, 0.7 mm to 3.5 mm, 0.7 mm to 3.4 mm, 0.7 mm to 3.2 mm, 0.7 mm to 3.0 mm, 0.7 mm to 2.9 mm, 0.7 mm to 2.8 mm, 0.7 mm to 2.7 mm, 0.7 mm to 2.6 mm, 0.7 mm to 2.5 mm, 0.7 mm to 2.4 mm, 0.7 mm to 2.3 mm, 0.7 mm to 2.2 mm, 0.7 mm to 2.1 mm, 0.7 mm to 2.0 mm, 0.9 mm to 4.0 mm, 0.9 mm to 3.5 mm, 0.9 mm to 3.4 mm, 0.9 mm to 3.2 mm, 0.9 mm to 3.0 mm, 0.9 mm to 2.9 mm, 0.9 mm to 2.8 mm, 0.9 mm to 2.7 mm, 0.9 mm to 2.6 mm, 0.9 mm to 2.5 mm, 0.9 mm to 2.4 mm, 0.9 mm to 2.3 mm, 0.9 mm to 2.2 mm, 0.9 mm to 2.1 mm, 0.9 mm to 2.0 mm, 1.0 mm to 4.0 mm, 1.0 mm to 3.5 mm, 1.0 mm to 3.4 mm, 1.0 mm to 3.2 mm, 1.0 mm to 3.0 mm, 1.0 mm to 2.9 mm, 1.0 mm to 2.8 mm, 1.0 mm to 2.7 mm, 1.0 mm to 2.6 mm, 1.0 mm to 2.5 mm, 1.0 mm to 2.4 mm, 1.0 mm to 2.3 mm, 1.0 mm to 2.2 mm, 1.0 mm to 2.1 mm, 1.0 mm to 2.0 mm, 1.1 mm to 4.0 mm, 1.1 mm to 3.5 mm, 1.1 mm to 3.4 mm, 1.1 mm to 3.2 mm, 1.1 mm to 3.0 mm, 1.1 mm to 2.9 mm, 1.1 mm to 2.8 mm, 1.1 mm to 2.7 mm, 1.1 mm to 2.6 mm, 1.1 mm to 2.5 mm, 1.1 mm to 2.4 mm, 1.1 mm to 2.3 mm, 1.1 mm to 2.2 mm, 1.1 mm to 2.1 mm, 1.1 mm to 2.0 mm, 1.3 mm to 4.0 mm, 1.3 mm to 3.5 mm, 1.3 mm to 3.4 mm, 1.3 mm to 3.2 mm, 1.3 mm to 3.0 mm, 1.3 mm to 2.9 mm, 1.3 mm to 2.8 mm, 1.3 mm to 2.7 mm, 1.3 mm to 2.6 mm, 1.3 mm to 2.5 mm, 1.3 mm to 2.4 mm, 1.3 mm to 2.3 mm, 1.3 mm to 2.2 mm, 1.3 mm to 2.1 mm, 1.3 mm to 2.0 mm, 1.5 mm to 4.0 mm, 1.5 mm to 3.5 mm, 1.5 mm to 3.4 mm, 1.5 mm to 3.2 mm, 1.5 mm to 3.0 mm, 1.5 mm to 2.9 mm, 1.5 mm to 2.8 mm, 1.5 mm to 2.7 mm, 1.5 mm to 2.6 mm, 1.5 mm to 2.5 mm, 1.5 mm to 2.4 mm, 1.5 mm to 2.3 mm, 1.5 mm to 2.2 mm, 1.5 mm to 2.1 mm, 1.5 mm to 2.0ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004mm, 1.7 mm to 4.0 mm, 1.7 mm to 3.5 mm, 1.7 mm to 3.4 mm, 1.7 mm to 3.2 mm, 1.7 mm to 3.0 mm, 1.7 mm to 2.9 mm, 1.7 mm to 2.8 mm, 1.7 mm to 2.7 mm, 1.7 mm to 2.6 mm, 1.7 mm to 2.5 mm, 1.7 mm to 2.4 mm, 1.7 mm to 2.3 mm, 1.7 mm to 2.2 mm, 1.7 mm to 2.1 mm, 1.7 mm to 2.0 mm, 1.9 mm to 4.0 mm, 1.9 mm to 3.5 mm, 1.9 mm to 3.4 mm, 1.9 mm to 3.2 mm, 1.9 mm to 3.0 mm, 1.9 mm to 2.9 mm, 1.9 mm to 2.8 mm, 1.9 mm to 2.7 mm, 1.9 mm to 2.6 mm, 1.9 mm to 2.5 mm, 1.9 mm to 2.4 mm, 1.9 mm to 2.3 mm, 1.9 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.9 mm to 2.0 mm, 2.0 mm to 4.0 mm, 2.0 mm to 3.5 mm, 2.0 mm to 3.4 mm, 2.0 mm to 3.2 mm, 2.0 mm to 3.0 mm, 2.0 mm to 2.9 mm, 2.0 mm to 2.8 mm, 2.0 mm to 2.7 mm, 2.0 mm to 2.6 mm, 2.0 mm to 2.5 mm, 2.0 mm to 2.4 mm, 2.0 mm to 2.3 mm, 2.0 mm to 2.2 mm, 2.0 mm to 2.1 mm, 2.2 mm to 4.0 mm, 2.2 mm to 3.5 mm, 2.2 mm to 3.4 mm, 2.2 mm to 3.2 mm, 2.2 mm to 3.0 mm, 2.2 mm to 2.9 mm, 2.2 mm to 2.8 mm, 2.2 mm to 2.7 mm, 2.2 mm to 2.6 mm, 2.2 mm to 2.5 mm, 2.2 mm to 2.4 mm, 2.2 mm to 2.3 mm, 2.3 mm to 4.0 mm, 2.3 mm to 3.5 mm, 2.3 mm to 3.4 mm, 2.3 mm to 3.2 mm, 2.3 mm to 3.0 mm, 2.3 mm to 2.9 mm, 2.3 mm to 2.8 mm, 2.3 mm to 2.7 mm, 2.3 mm to 2.6 mm, 2.3 mm to 2.5 mm, 2.3 mm to 2.4 mm, 2.4 mm to 4.0 mm, 2.4 mm to 3.5 mm, 2.4 mm to 3.4 mm, 2.4 mm to 3.2 mm, 2.4 mm to 3.0 mm, 2.4 mm to 2.9 mm, 2.4 mm to 2.8 mm, 2.4 mm to 2.7 mm, 2.4 mm to 2.6 mm, 2.4 mm to 2.5 mm, 2.5 mm to 4.0 mm, 2.5 mm to 3.5 mm, 2.5 mm to 3.4 mm, 2.5 mm to 3.2 mm, 2.5 mm to 3.0 mm, 2.5 mm to 2.9 mm, 2.5 mm to 2.8 mm, 2.5 mm to 2.7 mm, 2.5 mm to 2.6 mm, 2.6 mm to 4.0 mm, 2.6 mm to 3.5 mm, 2.6 mm to 3.4 mm, 2.6 mm to 3.2 mm, 2.6 mm to 3.0 mm, 2.6 mm to 2.9 mm, 2.6 mm to 2.8 mm, 2.6 mm to 2.7 mm, 2.7 mm to 4.0 mm, 2.7 mm to 3.5 mm, 2.7 mm to 3.4 mm, 2.7 mm to 3.2 mm, 2.7 mm to 3.0 mm, 2.7 mm to 2.9 mm, 2.7 mm to 2.8 mm, 2.8 mm to 4.0 mm, 2.8 mm to 3.5 mm, 2.8 mm to 3.4 mm, 2.8 mm to 3.2 mm, 2.8 mm to 3.0 mm, 2.8 mm to 2.9 mm, 2.9 mm to 4.0 mm, 2.9 mm to 3.5 mm, 2.9 mm to 3.4 mm, 2.9 mm to 3.2 mm, 2.9 mm to 3.0 mm, 3.0 mm to 4.0 mm, 3.0 mm to 3.5 mm, 3.0 mm to 3.4 mm, 3.0 mm to 3.2 mm, 3.2 mm to 4.0 mm, 3.2 mm to 3.5 mm, 3.2 mm to 3.4 mm, 3.4 mm to 4.0 mm, 3.4 mm to 3.5 mm, or 3.5 mm to 4.0 mm as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.

[0127] The methods and uses described herein include reducing proptosis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0128] The methods and uses described herein include reducing proptosis in a subject having thyroid eye disease, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0129] The methods and uses described herein include reducing proptosis in a subject having active thyroid eye disease, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0130] The methods and uses described herein include reducing proptosis in a subject having active moderate-to-severe thyroid eye disease, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0131] The methods and uses described herein include reducing proptosis in a subject having active moderate-to-severe thyroid eye disease associated with Graves’ Disease or autoimmune Hashimoto thyroiditis, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0132] The methods and uses described herein include reducing proptosis in a subject having active moderate-to-severe thyroid eye disease associated with Graves’ Disease and autoimmune Hashimoto thyroiditis, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0133] The methods and uses described herein include reducing proptosis in a subject having active moderate-to-severe thyroid eye disease associated with Graves’ Disease, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0134] The methods and uses described herein include reducing proptosis in a subject having active moderate-to-severe thyroid eye disease associated with autoimmune Hashimoto thyroiditis, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0135] The methods and uses described herein include reducing proptosis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof, wherein the subject has thyroid eye disease.

[0136] The methods and uses described herein include reducing proptosis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof, wherein the subject has active moderate-to-severe thyroid eye disease.

[0137] The methods and uses described herein include reducing proptosis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof.

[0138] The methods and uses described herein include reducing proptosis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof, wherein the subject has active moderate-to-severe thyroid eye disease associated with Graves’ Disease or autoimmune Hashimoto thyroiditis.

[0139] The methods and uses described herein include reducing proptosis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof, wherein the subject has active moderate-to-severe thyroid eye disease associated with Graves’ Disease and autoimmune Hashimoto thyroiditis.

[0140] The methods and uses described herein include reducing proptosis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof, wherein the subject has active moderate-to-severe thyroid eye disease associated with Graves’ Disease.

[0141] The methods and uses described herein include reducing proptosis in a subject in need thereof, the method comprising administering to the subject a twice-daily dose of a therapeutically effective amount of linsitinib or a pharmaceutically acceptable salt thereof,ATTORNEY DOCKET No.: SLTH-OOl / OIWO 353890-2004wherein the subject has active moderate-to-severe thyroid eye disease associated with autoimmune Hashimoto thyroiditis.

[0142] The methods and uses provided herein may treat thyroid eye disease by reducing the subject’s CAS. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, or at least 7 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by at least 1 point as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by at least 2 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by at least 3 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by at least 4 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by at least 5 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by at least 6 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by at least 7 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0143] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, or 7 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by 1 point as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by 2 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by 3 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by 4 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by 5 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by 6 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is reduced by 7 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose.

[0144] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, or at least 7 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by at least 1 point as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by at least 2 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by at least 3 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by at least 4 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by at least 5 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by at least 6 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by at least 7 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose.

[0145] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, or 7 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In someATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by 1 point as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by 2 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by 3 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by 4 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by 5 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by 6 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 24 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is reduced by 7 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose.

[0146] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 0, 1 or less, 2 or less, 3 or less, or 4 or less on a 7-point scale. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 0 on a 7-point scale. In some embodiments, immediately after theATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 1 or less on a 7-point scale. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 2 or less on a 7-point scale. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 3 or less on a 7-point scale. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 4 or less on a 7-point scale.

[0147] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 0, 1, 2, 3, or 4 on a 7-point scale. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 0 on a 7-point scale. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 1 on a 7-point scale. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 2 on a 7-point scale. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 3 on a 7-point scale. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s CAS is 4 on a 7-point scale.

[0148] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 0, 1 or less, 2 or less, 3 or less, or 4 or less on a 7-point scale. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 0 on a 7-point scale. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 1 or less on a 7-point scale. InATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 2 or less on a 7-point scale. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 3 or less on a 7-point scale. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 4 or less on a 7-point scale.

[0149] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 0, 1, 2, 3, or 4 on a 7-point scale. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 0 on a 7-point scale. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 1 on a 7-point scale. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 2 on a 7-point scale. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 3 on a 7-point scale. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s CAS is 4 on a 7-point scale.

[0150] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, the subject’s CAS is reduced by atATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, or at least 7 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose.

[0151] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, the subject’s CAS is reduced by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, or 7 points as compared to the subject’s CAS immediately prior to the initial administration of the twice-daily dose.

[0152] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, the subject’s CAS is 0, 1 or less, 2 or less, 3 or less, or 4 or less on a 7-point scale.

[0153] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, the subject’s CAS is 0, 1, 2, 3, or 4 on a 7-point scale.

[0154] The methods and uses provided herein may treat thyroid eye disease by improving the subject’s quality of life. The present disclosure also provides methods and uses of linsitinib, or a pharmaceutically acceptable salt thereof, for improving the quality of life in a subject having thyroid eye disease. Quality of life assessments may utilize the Graves’ Ophthalmology Quality of Life Questionnaire (GO-QoL) questionnaire, which is a questionnaire with 8 questions on visual functioning and 8 questions on appearance — answers on each subscale are transformed to scores ranging from 0 (worst) to 100 (best). Terwee, et al., Br. J. Ophthalmol.1998, 82, 773-779; Terwee, et al., J. Clin. Epidemiol. 1999, 52(9), 875-884.

[0155] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on one or both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose ofATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on the visual functioning subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on the appearance subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s scores immediately prior to the initial administration of the twice-daily dose.

[0156] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points on one or both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 15 points on one or both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 20 points on one or both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 25 points on one or both ofATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 30 points on one or both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 35 points on one or both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 40 points on one or both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose.

[0157] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points on both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s scores immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 15 points on both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s scores immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 20 points on both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s scores immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life isATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004improved as measured by an increase of at least 25 points on both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s scores immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 30 points on both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s scores immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 35 points on both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s scores immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 40 points on both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s scores immediately prior to the initial administration of the twice-daily dose

[0158] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points on the visual functioning subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 15 points on the visual functioning subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 20 points on the visual functioning subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 25 points on the visual functioningATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 30 points on the visual functioning subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 35 points on the visual functioning subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 40 points on the visual functioning subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose

[0159] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points on the appearance subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 15 points on the appearance subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 20 points on the appearance subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 25 points on the appearance subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after theATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 30 points on the appearance subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 35 points on the appearance subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 40 points on the appearance subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose

[0160] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on one or both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s scores immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on the visual functioning subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initialATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on the appearance subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose.

[0161] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on one or both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose.

[0162] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on both of the visual functioning and appearance subscales of the GO-QOL questionnaire as compared to the subject’s scores immediately prior to the initial administration of the twice-daily dose.

[0163] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, a subject’s quality of life is improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on the visual functioning subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose.

[0164] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, a subject’s quality of life isATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004improved as measured by an increase of at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points on the appearance subscale of the GO-QOL questionnaire as compared to the subject’s score immediately prior to the initial administration of the twice-daily dose.

[0165] The methods and uses provided herein may treat thyroid eye disease by reducing diplopia. The present disclosure also provides methods and uses of linsitinib, or a pharmaceutically acceptable salt thereof, for reducing diplopia in a subject having thyroid eye disease. In some embodiments, diplopia may be measured using the Bahn-Gorman scale, which uses the following subjective scores to assess the severity of diplopia: 0 = no diplopia; 1 = intermittent (diplopia in primary position of gaze, when tired or when first awakening); 2 = inconstant (diplopia at extremes of gaze); and 3 = constant (continuous diplopia in primary or reading position). Bahn R.S., Gorman C.A, Endocrinol. Metab. Clin. North Am. 1987, 16(2), 391-407. In some embodiments, the diplopia is monocular. In some embodiments, the diplopia is binocular.

[0166] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia is reduced by at least 1 point, at least 2 points, or at least 3 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia is reduced by at least 1 point according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia is reduced by at least 2 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia is reduced by at least 3 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose.

[0167] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia is reducedATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004by 1 point, 2 points, or 3 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia is reduced by 1 point according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia is reduced by 2 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia is reduced by 3 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose.

[0168] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia is reduced by at least 1 point, at least 2 points, or at least 3 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia is reduced by at least 1 point according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia is reduced by at least 2 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia is reduced by at least 3 pointsATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose.

[0169] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia is reduced by 1 point, 2 points, or 3 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia is reduced by 1 point according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia is reduced by 2 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia is reduced by 3 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose.

[0170] In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia has a Bahn-Gorman value of 0 or 1. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia has a Bahn-Gorman value of 0. In some embodiments, immediately after the administration of the final twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, a subject’s diplopia has a Bahn-Gorman value of 1.

[0171] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia has aATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004Bahn-Gorman value of 0 or 1. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia has a Bahn-Gorman value of 0. In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia has a Bahn-Gorman value of 1.

[0172] In some embodiments, immediately after 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 30 weeks, 36 weeks, or 52 weeks of administering the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, the subject’s diplopia is reduced by at least 1 point, at least 2 points, or at least 3 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose.

[0173] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, the subject’s diplopia is reduced by 1 point, 2 points, or 3 points according to the Bahn-Gorman scale as compared to the subject’s diplopia immediately prior to the initial administration of the twice-daily dose.

[0174] In some embodiments, immediately after 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 72 weeks, or 96 weeks since the final twice-daily dose of linsitinib or a pharmaceutically acceptable salt thereof, was administered, the subject’s diplopia has a Bahn-Gorman value of 0 or 1.

[0175] In some embodiments of the methods and uses described herein, the thyroid eye disease had an onset within the 24 months, 18 months, 15 months, 12 months, 9 months, or 6 months immediately prior to the initial administration of the twice-daily dose. In some embodiments of the methods and uses described herein, the thyroid eye disease had an onset within the 12 months immediately prior to the initial administration of the twice-daily dose. In some embodiments of the methods and uses described herein, the thyroid eye disease is active thyroid eye disease having an onset within the 12 months immediately prior to the initial administration of the twice-daily dose. In some embodiments of the methods and uses described herein, the thyroid eye disease is active moderate-to-severe thyroid eye diseaseATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004having an onset within the 12 months immediately prior to the initial administration of the twice-daily dose.

[0176] In some embodiments of the methods and uses described herein, the subject was diagnosed with thyroid eye disease within the 24 months, 18 months, 15 months, 12 months, 9 months, or 6 months immediately prior to the initial administration of the twice-daily dose. In some embodiments of the methods and uses described herein, the subject was diagnosed with thyroid eye disease within the 12 months immediately prior to the initial administration of the twice-daily dose. In some embodiments of the methods and uses described herein, the and the subject was diagnosed with active thyroid eye disease within the 12 months immediately prior to the initial administration of the twice-daily dose. In some embodiments of the methods and uses described herein, the and the subject was diagnosed with active moderate-to-severe thyroid eye disease within the 12 months immediately prior to the initial administration of the twice-daily dose.

[0177] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with a lid retraction in the subject’s most severely affected eye of 1 mm or more, 1.5 mm or more, 2 mm or more, 2.5 mm or more, or 3 mm or more immediately prior to the initial administration of the twice-daily dose. In some embodiments, the thyroid eye disease is associated with a lid retraction in the subject’s most severely affected eye of 2 mm or more immediately prior to the initial administration of the twice-daily dose.

[0178] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with an upper lid retraction in the subject’s most severely affected eye of 1 mm or more, 1.5 mm or more, 2 mm or more, 2.5 mm or more, or 3 mm or more immediately prior to the initial administration of the twice-daily dose. In some embodiments, the thyroid eye disease is associated with an upper lid retraction in the subject’s most severely affected eye of 2 mm or more immediately prior to the initial administration of the twice-daily dose.

[0179] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with a lower lid retraction in the subject’s most severely affected eye of 1 mm or more, 1.5 mm or more, 2 mm or more, 2.5 mm or more, or 3 mm or more immediately prior to the initial administration of the twice-daily dose. In some embodiments, the thyroid eye disease is associated with a lower lid retraction in the subject’s most severely affected eye of 2 mm or more immediately prior to the initial administration of the twice-daily dose.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0180] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with soft tissue involvement in the subject’s most severely affected eye immediately prior to the initial administration of the twice-daily dose. As used herein, “soft tissue involvement,” as relates to thyroid eye disease, refers to inflammation of soft tissues around the eyes and may include periorbital edema, conjunctival hyperemia, chemosis, superior limbic keratoconjunctivitis, and the like. In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with moderate or severe soft tissue involvement in the subject’s most severely affected eye immediately prior to the initial administration of the twice-daily dose. In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with moderate soft tissue involvement in the subject’s most severely affected eye immediately prior to the initial administration of the twice-daily dose. In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with severe soft tissue involvement in the subject’s most severely affected eye immediately prior to the initial administration of the twice-daily dose.

[0181] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with proptosis in the subject’s most severely affected eye of 2 mm or more, 2.5 mm or more, 3 mm or more, 3.5 mm or more, or 4 mm or more above normal for the subject’s race and gender. In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with proptosis in the subject’s most severely affected eye of 3 mm or more above normal for the subject’s race and gender.

[0182] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with inconstant or constant diplopia. In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with inconstant diplopia. In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with constant diplopia.

[0183] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with one or more selected from (i)-(iv) for the subject’s most severely affected eye immediately prior to the initial administration of the twice-daily dose:(i) lid retraction of 2 mm or more;(ii) moderate or severe soft tissue involvement;ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004(iii) proptosis of 3 mm or more above normal for race and gender; or(iv) inconstant or constant diplopia.

[0184] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with two or more selected from (i)-(iv) for the subject’s most severely affected eye immediately prior to the initial administration of the twice-daily dose:(i) lid retraction of 2 mm or more;(ii) moderate or severe soft tissue involvement;(iii) proptosis of 3 mm or more above normal for race and gender; or(iv) inconstant or constant diplopia.

[0185] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with three or more selected from (i)— (iv) for the subject’s most severely affected eye immediately prior to the initial administration of the twice-daily dose:(i) lid retraction of 2 mm or more;(ii) moderate or severe soft tissue involvement;(iii) proptosis of 3 mm or more above normal for race and gender; or(iv) inconstant or constant diplopia.

[0186] In some embodiments of the methods and uses described herein, the thyroid eye disease is associated with each of (i)— (iv) for the subject’s most severely affected eye immediately prior to the initial administration of the twice-daily dose:(i) lid retraction of 2 mm or more;(ii) moderate or severe soft tissue involvement;(iii) proptosis of 3 mm or more above normal for race and gender; and(iv) inconstant or constant diplopia.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0187] In some embodiments, the subject is euthyroid or has mild hypothyroidism or hyperthyroidism immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is euthyroid or has mild hypothyroidism or hyperthyroidism within the 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month immediately prior to the initial administration of the twice-daily dose. As used herein, the term “euthyroid” means a subject having free thyroxine (T3) and free triiodothyronine (T4) levels within the normal reference range. A euthyroid subject is neither hypothyroidic nor hyperthyroidic. In some embodiments, a euthyroid subject has a thyroxine (T3) level of between about 0.9 and about 1.7 ng / dL. In some embodiments, a euthyroid subject has a triiodothyronine (T4) level of between about 2.0 and about 4.4 pg / mL. In some embodiments, a euthyroid subject has a thyroid stimulating hormone level of between about 0.270 and 4.200 mcIU / mL. As used herein, the term “mild hypothyroidism” refers to hypothyroidism where the subject’s free thyroxine (T3) and free triiodothyronine (T4) levels are below the lower limit of normal but above a value 50% below the lower limit of normal. In some embodiments, a mildly hypothyroidic subject has a thyroxine (T3) level of between about 0.45 and about 0.9 ng / dL. In some embodiments, a mildly hypothyroidic subject has a triiodothyronine (T4) level of between about 1.0 and about 2.0 pg / mL. As used herein, the term “mild hyperthyroidism” refers to hyperthyroidism where the subject’s free thyroxine (T3) and free triiodothyronine (T4) levels are above the upper limit of normal but below a value 50% above the upper limit of normal. In some embodiments, a mildly hyperthyroidic subject has a thyroxine (T3) level of between about 1.7 and about 2.55 ng / dL. In some embodiments, a mildly hypothyroidic subject has a triiodothyronine (T4) level of between about 4.4 and about 6.6 pg / mL.

[0188] In some embodiments, the subject is euthyroid immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is euthyroid within the 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month immediately prior to the initial administration of the twice-daily dose.

[0189] In some embodiments, the subject has mild hypothyroidism or hyperthyroidism immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has mild hypothyroidism or hyperthyroidism within the 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month immediately prior to the initial administration of the twice-daily dose.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0190] In some embodiments, the subject has mild hypothyroidism immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has mild hypothyroidism within the 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month immediately prior to the initial administration of the twice-daily dose.

[0191] In some embodiments, the subject has mild hyperthyroidism immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has mild hyperthyroidism within the 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month immediately prior to the initial administration of the twice-daily dose.

[0192] In some embodiments, the subject does not require an immediate ophthalmological intervention immediately prior to the initial administration of the twice-daily dose and has not scheduled an ophthalmological intervention for the duration of the administration. As used herein, a condition requiring “immediate ophthalmological intervention” is an eye condition that poses a significant risk of vision loss if it is not treated in a timely manner. One example of a condition requiring immediate ophthalmological intervention is dystrophic optic nephropathy with impending vision loss. In some embodiments, the subject does not require an immediate ophthalmological intervention immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject does not require an immediate ophthalmological intervention within the 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month immediately prior to the initial administration of the twice-daily dose and has not scheduled an ophthalmological intervention for the duration of the administration. In some embodiments, the subject does not require an immediate ophthalmological intervention within the 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not scheduled an ophthalmological intervention for the duration of the administration.

[0193] In some embodiments, the subject is not diabetic. In some embodiments, the subject is diabetic. In some embodiments, the subject is diabetic and has a serum HbAlc level of less than 9.0% immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is diabetic and has a serum HbAlc level of less than 9.0% within the 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is a Type 2 diabetic who is not on insulin and was not prescribed insulin within the 1 day, 2 days, 3 days, 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 30 days, 1 month, 45 days, 60 days, 2 months, 90ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004days, or three months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is a Type 2 diabetic who is not on insulin and was not prescribed insulin within the 60 days immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is a diabetic who is on insulin whose prescribed total daily insulin dose has not changed by more than 20% or more than 10 units (whichever is greater) in the 1 day, 2 days, 3 days, 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 30 days, 1 month, 45 days, 60 days, 2 months, 90 days, or three months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is a diabetic who is on insulin whose prescribed total daily insulin dose has not changed by more than 20% or more than 10 units (whichever is greater) in the 60 days immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is a diabetic who has not had a severe hypoglycemic event in the 1 day, 2 days, 3 days, 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 30 days, 1 month, 45 days, 60 days, 2 months, 90 days, or three months immediately prior to the initial administration of the twice-daily dose. As used herein, a “severe hypoglycemic event” is an event for which the subject received medical care by a health care professional. In some embodiments, the subject is a diabetic who has not had a severe hypoglycemic event in the 60 days immediately prior to the initial administration of the twice-daily dose.

[0194] In some embodiments, the subject is a woman of childbearing potential who is not pregnant or lactating immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is a woman of childbearing potential who is not pregnant immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is a woman of childbearing potential who is not lactating immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject is a woman of childbearing potential who provided a negative pregnancy test immediately prior to the initial administration of the twice-daily dose. As used herein, women of “childbearing potential” includes women with an onset of menopause less than two years prior to the initial administration of the twice-daily dose, women having non-therapy-induced amenorrhea for less than twelve months prior to the initial administration of the twice-daily dose, and women who are considered infertile (sterile) from non-surgical conditions. In some embodiments, a woman of childbearing potential who is sexually active with a non-vasectomized male partner uses two reliable forms of contraception from immediately prior to the initial administration of the twice-daily dose until at least 28 days following the final administration of the twice-dailyATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004dose. In embodiments where hormonal contraception is one of the two reliable forms of contraception, it must have been initiated at least 21 days immediately prior to the initial administration of the twice-daily dose and continue for at least 28 days following the final administration of the twice-daily dose.

[0195] In some embodiments, the subject is a man who is sexually active with a woman of childbearing potential and is either vasectomized or uses a barrier contraceptive immediately prior to the initial administration of the twice-daily dose and continue for 75 days following the final administration of the twice-daily dose.

[0196] In some embodiments, the subject does not have decreased best corrected visual acuity due to optic neuropathy immediately prior to the initial administration of the twice-daily dose. As used herein, a subject having “decreased best corrected visual acuity due to optic neuropathy” refers to a subject having (i) a decrease in vision of 2 lines on the Snellen chart, (ii) a new visual field defect, or (iii) a color defect, where each of (i)-(iii) are secondary to optic nerve involvement. In some embodiments, the subject has not had decreased best corrected visual acuity due to optic neuropathy within the 12 months, 24 months, 36 months, 48 months, or 60 immediately months prior to the initial administration of the twice-daily dose.

[0197] In some embodiments, the subject does not have corneal decompensation unresponsive to medical management prior to the initial administration of the twice-daily dose. As used herein, a subject having “corneal decompensation unresponsive to medical management” means the subject has corneal decompensation that has been unsuccessfully treated with one or more medical interventions. In some embodiments, the subject has not had corneal decompensation unresponsive to medical management within the 12 months, 24 months, 36 months, 48 months, or 60 months immediately prior to the initial administration of the twice-daily dose.

[0198] In some embodiments, the subject has not had orbital irradiation or orbital surgery prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not had orbital irradiation prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not had orbital surgery prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not had orbital irradiation or orbital surgery within the 12 months, 24 months, 36 months, 48 months, or 60 months immediately prior to the initial administration of the twice-daily dose.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0199] In some embodiments, the subject has not had ocular surgery other than routine cataract surgery, subsequent yttrium aluminum garnet (YAG) laser capsulotomy, or corneal refractive surgery prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not had ocular surgery other than routine cataract surgery or subsequent YAG laser capsulotomy prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not had ocular surgery other than corneal refractive surgery prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not had ocular surgery other than routine cataract surgery, subsequent YAG laser capsulotomy, or corneal refractive surgery within the 12 months, 24 months, 36 months, 48 months, or 60 months immediately prior to the initial administration of the twice-daily dose.

[0200] In some embodiments, the subject has not had routine cataract surgery, subsequent YAG laser capsulotomy, or corneal refractive surgery within the 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 12 months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not had routine cataract surgery, subsequent YAG laser capsulotomy, or corneal refractive surgery within the 3 months immediately prior to the initial administration of the twice-daily dose.

[0201] In some embodiments, the subject has not taken a glucocorticoid with a cumulative dose equivalent to 1 g or more of methylprednisolone or equivalent for the treatment of thyroid eye disease within the four weeks immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken a glucocorticoid with a cumulative dose equivalent to 1 g or more of methylprednisolone or equivalent for the treatment of thyroid eye disease within the two months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken a glucocorticoid with a cumulative dose equivalent to 1 g or more of methylprednisolone or equivalent for the treatment of thyroid eye disease within the three months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken a glucocorticoid with a cumulative dose equivalent to 1 g or more of methylprednisolone or equivalent for the treatment of thyroid eye disease within the six months immediately prior to the initial administration of the twice-daily dose.

[0202] In some embodiments, the subject has not taken a glucocorticoid, other than a topical steroid for a dermatological condition or an inhaled steroid, with a cumulative dose equivalent to 1 g or more of methylprednisolone or equivalent for the treatment of a condition other thanATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004thyroid eye disease within the two weeks immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken a glucocorticoid, other than a topical steroid for a dermatological condition or an inhaled steroid, with a cumulative dose equivalent to 1 g or more of methylprednisolone or equivalent for the treatment of a condition other than thyroid eye disease within the four weeks immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken a glucocorticoid, other than a topical steroid for a dermatological condition or an inhaled steroid, with a cumulative dose equivalent to 1 g or more of methylprednisolone or equivalent for the treatment of a condition other than thyroid eye disease within the two months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken a glucocorticoid, other than a topical steroid for a dermatological condition or an inhaled steroid, with a cumulative dose equivalent to 1 g or more of methylprednisolone or equivalent for the treatment of a condition other than thyroid eye disease within the three months immediately prior to the initial administration of the twice-daily dose.

[0203] In some embodiments, the subject has not taken an IGF-1R inhibitor, for any condition, prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken an IGF-1R inhibitor, for any condition, within the 12 months, 24 months, 36 months, 48 months, or 60 months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken an IGF-1R inhibitor for treating thyroid eye disease prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken an IGF-1R inhibitor for treating thyroid eye disease within the 12 months, 24 months, 36 months, 48 months, or 60 months immediately prior to the initial administration of the twice-daily dose.

[0204] In some embodiments, the subject has not taken a non-steroidal immunosuppressive agent within the 4 weeks immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken a non-steroidal immunosuppressive agent within the 2 months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken a non-steroidal immunosuppressive agent within the 3 months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken a non-steroidal immunosuppressive agent within the 6 months immediately prior to the initial administration of the twice-daily dose.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0205] In some embodiments, the subject has not taken anti-IL6 receptor or anti-CD20 antibodies or monoclonal antibodies for immunomodulation prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken anti-IL6 receptor or anti-CD20 antibodies or monoclonal antibodies for immunomodulation within the 12 months, 24 months, 36 months, 48 months, or 60 months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken anti-IL6 receptor or anti-CD20 antibodies or monoclonal antibodies for immunomodulation prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken anti-IL6 receptor or anti-CD20 antibodies or monoclonal antibodies for immunomodulation within the 12 months, 24 months, 36 months, 48 months, or 60 months immediately prior to the initial administration of the twice-daily dose.

[0206] In some embodiments, the subject has not had biopsy-proven or clinically suspected inflammatory bowel disease prior to the initial administration of the twice-daily dose. In some embodiments, the clinically suspected inflammatory bowel disease may include: diarrhea with or without blood; rectal bleeding associated with abdominal pain or cramping / colic; urgency, tenesmus, or incontinence for more than 4 weeks without a confirmed alternative diagnosis; or endoscopic or radiologic evidence of enteritis / colitis without a confirmed alternative diagnosis.

[0207] In some embodiments, the subject has not taken selenium or biotin, other than in a multivitamin, within the 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 12 months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not taken selenium or biotin, other than in a multivitamin, within the 3 weeks, immediately prior to the initial administration of the twice-daily dose.

[0208] In some embodiments, the subject has not had QTcF prolongation prior to the initial administration of the twice-daily dose. In some embodiments, the subject has not had QTcF prolongation within the 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 12 months immediately prior to the initial administration of the twice-daily dose. As used herein, the term “QTcF prolongation” refers to a QT interval of greater than 450 ms for a male subject or a QT interval of greater than 470 ms for a female subject, as corrected with the Fridericia algorithm.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0209] In some embodiments, the subject has not taken a drug commonly associated with QT prolongation within the 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 12 months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the drug commonly associated with QT prolongation may be selected from amiodarone, solatol, quinidine, procainamide, dofetilide, ibutilide, levofloxacin, ciprofloxacin, gatifloxacin, moxifloxacin, clarithromycin, erythromycin, ketoconazole, itraconazole, amitriptyline, desipramine, imipramine, doxepin, fluoxetine, sertraline, venlafaxine, haloperidol, droperidol, quetiapine, thioridazine, ziprasidone, cisapride, sumatriptan, zolmitriptan, arsenic, dolasetron, or methadone. In some embodiments, the subject has not taken a drug commonly associated with QT prolongation within the 14 days immediately prior to the initial administration of the twice-daily dose.

[0210] In some embodiments, the subject does not have a serum alanine transferase (ALT) level or a serum aspartate aminotransferase (AST) level greater than three-times the upper limit of normal immediately prior to the initial administration of the twice-daily dose. The term “upper limit of normal” (also referred to as “ULN”) means the value of a particular measurement that is two standard deviations above the mean for a reference population. A skilled clinician is able to determine the upper limit of normal for a particular measurement and particular subject. For example, for serum AST levels, the upper limit of normal may be about 43 U / L for males and about 36 U / L for females. For example, for serum ALT levels, the upper limit of normal may be about 40 U / L for males and about 33 U / L for females. In some embodiments, the subject does not have a serum alanine transferase (ALT) level or a serum aspartate aminotransferase (AST) level greater than three-times the upper limit of normal within the 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 12 months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject does not have a serum ALT level greater than three-times the upper limit of normal immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject does not have a serum ALT level greater than three-times the upper limit of normal within the 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 12 months immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject does not have a serum AST level greater than three-times the upper limit of normal immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject does not have a serum AST level greater than three-times the upper limit of normal within the 1ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 12 months immediately prior to the initial administration of the twice-daily dose.

[0211] In some embodiments, the subject does not have a serum creatinine level greater than two-times the upper limit of normal immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject does not have a serum creatinine level greater than two-times the upper limit of normal within the 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 12 months immediately prior to the initial administration of the twice-daily dose.

[0212] In some embodiments, the subject does not have uncontrolled human immunodeficiency virus (HIV), hepatitis C, or hepatitis B immediately prior to the initial administration of the twice-daily dose. In some embodiments, the subject does not have uncontrolled human immunodeficiency virus (HIV), hepatitis C, or hepatitis within the 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 12 months immediately prior to the initial administration of the twice-daily dose.Dosins and Administration

[0213] Although some IGF-1R inhibitors, such as teprotumumab, may be administered intravenously, linsitinib and pharmaceutically acceptable salts thereof may be administered orally, making dose administration easier and more convenient.

[0214] For treatment of thyroid eye disease, a twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, may be administered orally. In some embodiments, the linsitinib, or a pharmaceutically acceptable salt thereof, is formulated with a pharmaceutically acceptable carrier or excipients and administered as a dosage formulation. In some embodiments, the dosage formulation is a solid preparation, such as a tablet, capsule, granule, or powder, for oral administration.

[0215] In some embodiments, the dosage formulations comprising linsitinib, or a pharmaceutically acceptable salt thereof, have an immediate release profile. However, the dosage formulation may have other release profiles including, for example, delayed release and extended release. As used herein, a “delayed release” dosage form is a dosage form that does not release the medication quickly after administration. For example, in some embodiments, a delayed release dosage form may not release the medication until after passage through the gut.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004As used herein, an “extended release” (which can also be referred to as a “sustained release”) dosage form is a dosage form that is designed to release the medication in a slower, controlled manner over an extended period of time following administration.

[0216] In the methods and uses described herein, the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, may be administered for at least 4 consecutive weeks, at least 8 consecutive weeks, at least 12 consecutive weeks, at least 16 consecutive weeks, at least 20 consecutive weeks, at least 24 consecutive weeks, at least 30 consecutive weeks, at least 36 consecutive weeks, at least 48 consecutive weeks, at least 52 consecutive weeks, at least 72 consecutive weeks, at least 96 consecutive weeks, or at least 104 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 4 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 8 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 12 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 16 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 20 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 24 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 30 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 36 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 48 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 52 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 72 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 96 consecutive weeks. In some embodiments, the twice-daily dose is administered for at least 104 consecutive weeks.

[0217] In the methods and uses described herein, the twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, may be administered for 4 consecutive weeks, 8 consecutive weeks, 12 consecutive weeks, 16 consecutive weeks, 20 consecutive weeks, 24 consecutive weeks, 30 consecutive weeks, 36 consecutive weeks, 48 consecutive weeks, 52 consecutive weeks, 72 consecutive weeks, 96 consecutive weeks, or 104 consecutive weeks. In some embodiments, the twice-daily dose is administered for 4 consecutive weeks. In some embodiments, the twice-daily dose is administered for 8 consecutive weeks. In some embodiments, the twice-daily dose is administered for 12 consecutive weeks. In some embodiments, the twice-daily dose is administered for 16 consecutive weeks. In some embodiments, the twice-daily dose is administered for 20 consecutive weeks. In someATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004embodiments, the twice-daily dose is administered for 24 consecutive weeks. In some embodiments, the twice-daily dose is administered for 30 consecutive weeks. In some embodiments, the twice-daily dose is administered for 36 consecutive weeks. In some embodiments, the twice-daily dose is administered for 48 consecutive weeks. In some embodiments, the twice-daily dose is administered for 52 consecutive weeks. In some embodiments, the twice-daily dose is administered for 72 consecutive weeks. In some embodiments, the twice-daily dose is administered for 96 consecutive weeks. In some embodiments, the twice-daily dose is administered for 104 consecutive weeks.

[0218] The methods and uses described herein include chronic administration. For example, the administration of linsitinib, or a pharmaceutically acceptable salt thereof, for treating thyroid eye disease may be of a long duration, such as, twice-daily administration for a consecutive day period of 24 weeks or greater, twice-daily administration for a consecutive day period of 36 weeks or greater, twice-daily administration for a consecutive day period of 48 weeks or greater, twice-daily administration for a consecutive day period of 52 consecutive weeks or greater, twice-daily administration for a consecutive day period of 72 consecutive weeks or greater, twice-daily administration for a consecutive day period of 76 weeks or greater, twice-daily administration for a consecutive day period of 96 weeks or greater, twice-daily administration for a consecutive day period of 104 weeks or greater, or twice-daily administration for a consecutive day period of 128 weeks or greater. In some embodiments, the treatment period is twice-daily administration for a consecutive day period of 48 weeks or greater.

[0219] The methods and uses described herein include administering a twice-daily dose of linsitinib, or a pharmaceutically acceptable salt thereof, to a subject in need thereof for the treatment of thyroid eye disease. In some embodiments, the twice-daily dose comprises about 20 mg to about 300 mg, about 20 mg to about 275 mg, about 20 mg to about 250 mg, about 20 mg to about 240 mg, about 20 mg to about 230 mg, about 20 mg to about 225 mg, about 20 mg to about 220 mg, about 20 mg to about 210 mg, about 20 mg to about 200 mg, about 20 mg to about 190 mg, about 20 mg to about 180 mg, about 20 mg to about 175 mg, about 20 mg to about 170 mg, about 20 mg to about 160 mg, about 20 mg to about 150 mg, about 20 mg to about 140 mg, about 20 mg to about 130 mg, about 20 mg to about 125 mg, about 20 mg to about 120 mg, about 20 mg to about 110 mg, about 20 mg to about 100 mg, about 20 mg to about 90 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg , about 20 mg to aboutATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-200470 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 300 mg, about 30 mg to about 275 mg, about 30 mg to about 250 mg, about 30 mg to about 240 mg, about 30 mg to about 230 mg, about 30 mg to about 225 mg, about 30 mg to about 220 mg, about 30 mg to about 210 mg, about 30 mg to about 200 mg, about 30 mg to about 190 mg, about 30 mg to about 180 mg, about 30 mg to about 175 mg, about 30 mg to about 170 mg, about 30 mg to about 160 mg, about 30 mg to about 150 mg, about 30 mg to about 140 mg, about 30 mg to about 130 mg, about 30 mg to about 125 mg, about 30 mg to about 120 mg, about 30 mg to about 110 mg, about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg , about 30 mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, about 30 mg to about 40 mg, about 40 mg to about 300 mg, about 40 mg to about 275 mg, about 40 mg to about 250 mg, about 40 mg to about 240 mg, about 40 mg to about 230 mg, about 40 mg to about 225 mg, about 40 mg to about 220 mg, about 40 mg to about 210 mg, about 40 mg to about 200 mg, about 40 mg to about 190 mg, about 40 mg to about 180 mg, about 40 mg to about 175 mg, about 40 mg to about 170 mg, about 40 mg to about 160 mg, about 40 mg to about 150 mg, about 40 mg to about 140 mg, about 40 mg to about 130 mg, about 40 mg to about 125 mg, about 40 mg to about 120 mg, about 40 mg to about 110 mg, about 40 mg to about 100 mg, about 40 mg to about 90 mg, about 40 mg to about 80 mg, about 40 mg to about 75 mg , about 40 mg to about 70 mg, about 40 mg to about 60 mg, about 40 mg to about 50 mg, about 50 mg to about 300 mg, about 50 mg to about 275 mg, about 50 mg to about 250 mg, about 50 mg to about 240 mg, about 50 mg to about 230 mg, about 50 mg to about 225 mg, about 50 mg to about 220 mg, about 50 mg to about 210 mg, about 50 mg to about 200 mg, about 50 mg to about 190 mg, about 50 mg to about 180 mg, about 50 mg to about 175 mg, about 50 mg to about 170 mg, about 50 mg to about 160 mg, about 50 mg to about 150 mg, about 50 mg to about 140 mg, about 50 mg to about 130 mg, about 50 mg to about 125 mg, about 50 mg to about 120 mg, about 50 mg to about 110 mg, about 50 mg to about 100 mg, about 50 mg to about 90 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg , about 50 mg to about 70 mg, about 50 mg to about 60 mg, about 60 mg to about 300 mg, about 60 mg to about 275 mg, about 60 mg to about 250 mg, about 60 mg to about 240 mg, about 60 mg to about 230 mg, about 60 mg to about 225 mg, about 60 mg to about 220 mg, about 60 mg to about 210 mg, about 6 Omg to about 200 mg, about 60 mg to about 190 mg, about 60 mg to about 180 mg, about 60 mg to about 175 mg, about 60 mg to about 170 mg, about 60 mg to about 160 mg, about 60mg to about 150 mg, about 60 mg to about 140 mg, about 60 mg to about 130 mg, about 60 mg to about 125 mg, about 60 mg toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004about 120 mg , about 60 mg to about 110 mg, about 60 mg to about 100 mg, about 60 mg to about 90 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 70 mg to about 300 mg, about 70 mg to about 275 mg, about 70 mg to about 250 mg, about 70 mg to about 240 mg, about 70 mg to about 230 mg, about 70 mg to about 225 mg, about 70 mg to about 220 mg, about 70 mg to about 210 mg, about 70 mg to about 200 mg, about 70 mg to about 190 mg, about 70 mg to about 180 mg, about 70 mg to about 175 mg, about 70 mg to about 170 mg, about 70 mg to about 160 mg , about 70 mg to about 150 mg, about 70 mg to about 140 mg, about 70 mg to about 130 mg, about 70 mg to about 125 mg, about 70 mg to about 120 mg , about 70 mg to about 110 mg, about 70 mg to about 100 mg, about 70 mg to about 90 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 300 mg, about 75 mg to about 275 mg, about 75 mg to about 250 mg, about 75 mg to about 240 mg, about 75 mg to about 230 mg, about 75 mg to about 225 mg, about 75 mg to about 220 mg, about 75 mg to about 210 mg, about 75 mg to about 200 mg, about 75 mg to about 190 mg, about 75 mg to about 180 mg, about 75 mg to about 175 mg, about 75 mg to about 170 mg, about 75 mg to about 160 mg, about 75 mg to about 150 mg, about 75 mg to about 140 mg, about 75 mg to about 130 mg, about 75 mg to about 125 mg, about 75 mg to about 120 mg , about 75 mg to about 110 mg, about 75 mg to about 100 mg, about 75 mg to about 90 mg, about 75 mg to about 80 mg, about 80 mg to about 300 mg, about 80 mg to about 275 mg, about 80 mg to about 250 mg, about 80 mg to about 240 mg, about 80 mg to about 230 mg, about 80 mg to about 225 mg, about 80 mg to about 220 mg, about 80 mg to about 210 mg, about 80 mg to about 200 mg, about 80 mg to about 190 mg, about 80 mg to about 180 mg, about 80 mg to about 175 mg, about 80 mg to about 170 mg, about 80 mg to about 160 mg, about 80 mg to about 150 mg, about 80 mg to about 140 mg, about 80 mg to about 130 mg, about 80 mg to about 125 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 100 mg, about 80 mg to about 90 mg, about 90 mg to about 300 mg, about 90 mg to about 275 mg, about 90 mg to about 250 mg, about 90 mg to about 240 mg, about 90 mg to about 230 mg, about 90 mg to about 225 mg, about 90 mg to about 220 mg, about 90 mg to about 210 mg, about 90 mg to about 200 mg, about 90 mg to about 190 mg, about 90 mg to about 180 mg, about 90 mg to about 175 mg, about 90 mg to about 170 mg, about 90 mg to about 160 mg, about 90 mg to about 150 mg, about 90 mg to about 140 mg, about 90 mg to about 130 mg, about 90 mg to about 125 mg, about 90 mg to about 120 mg, about 90 mg to about 110 mg, about 90 mg to about 100 mg, about 100 mg to about 300 mg, about 100 mg to about 275 mg, about 100 mg to about 250 mg, about 100 mg to about 240 mg, about 100 mg to about 230 mg, about 100 mg to about 225 mg, about 100 mgATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004out 210 mg, about 100 mg to about 200 mg, about 100 mg out 180 mg, about 100 mg to about 175 mg, about 100 mg out 160 mg, about 100 mg to about 150 mg, about 100 mg out 130 mg, about 100 mg to about 125 mg, about 100 mg out 110 mg, about 110 mg to about 300 mg, about 110 mg out 250 mg, about 110 mg to about 240 mg, about 110 mg out 225 mg, about 110 mg to about 220 mg, about 110 mg out 200 mg, about 110 mg to about 190 mg, about 110 mg out 175 mg, about 110 mg to about 170 mg, about 110 mg out 150 mg, about 110 mg to about 140 mg, about 110 mg out 125 mg, about 110 mg to about 120 mg, about 120 mg out 275 mg, about 120 mg to about 250 mg, about 120 mg out 230 mg, about 120 mg to about 225 mg, about 120 mg out 210 mg, about 120 mg to about 200 mg, about 120 mg out 180 mg, about 120 mg to about 175 mg, about 120 mg out 160 mg, about 120 mg to about 150 mg, about 120 mg out 130 mg, about 120 mg to about 125 mg, about 125 mg out 275 mg, about 125 mg to about 250 mg, about 125 mg out 230 mg, about 125 mg to about 225 mg, about 125 mg out 210 mg, about 125 mg to about 200 mg, about 125 mg out 180 mg, about 125 mg to about 175 mg, about 125 mg out 160 mg, about 125 mg to about 150 mg, about 125 mg out 130 mg, about 130 mg to about 300 mg, about 130 mg out 250 mg, about 130 mg to about 240 mg, about 130 mg out 225 mg, about 130 mg to about 220 mg, about 130 mg out 200 mg, about 130 mg to about 190 mg, about 130 mg out 175 mg, about 130 mg to about 170 mg, about 130 mg out 150 mg, about 130 mg to about 140 mg, about 140 mg ut 275 mg, about 140 mg to about 250 mg, about 140 mg out 230 mg, about 140 mg to about 225 mg, about 140 mg out 210 mg, about 140 mg to about 200 mg, about 140 mg out 180 mg, about 140 mg to about 175 mg, about 140 mg out 160 mg, about 140 mg to about 150 mg, about 150 mg out 275 mg, about 150 mg to about 250 mg, about 150 mgATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004out 230 mg, about 150 mg to about 225 mg, about 150 mg out 210 mg, about 150 mg to about 200 mg, about 150 mg out 180 mg, about 150 mg to about 175 mg, about 150 mg out 160 mg, about 160 mg to about 300 mg, about 160 mg out 250 mg, about 160 mg to about 240 mg, about 160 mg out 225 mg, about 160 mg to about 220 mg, about 160 mg out 200 mg, about 160 mg to about 190 mg, about 160 mg out 175 mg, about 160 mg to about 170 mg, about 170 mg out 275 mg, about 170 mg to about 250 mg, about 170 mg out 230 mg, about 170 mg to about 225 mg, about 170 mg out 210 mg, about 170 mg to about 200 mg, about 170 mg out 180 mg, about 170 mg to about 175 mg, about 175 mg out 275 mg, about 175 mg to about 250 mg, about 175 mg out 230 mg, about 175 mg to about 225 mg, about 175 mg out 210 mg, about 175 mg to about 200 mg, about 175 mg out 180 mg, about 180 mg to about 300 mg, about 180 mg out 250 mg, about 180 mg to about 240 mg, about 180 mg out 225 mg, about 180 mg to about 220 mg, about 180 mg out 200 mg, about 180 mg to about 190 mg, about 190 mg out 275 mg, about 190 mg to about 250 mg, about 190 mg out 230 mg, about 190 mg to about 225 mg, about 190 mg out 210 mg, about 190 mg to about 200 mg, about 200 mg out 275 mg, about 200 mg to about 250 mg, about 200 mg out 230 mg, about 200 mg to about 225 mg, about 200 mg out 210 mg, about 210 mg to about 300 mg, about 210 mg out 250 mg, about 210 mg to about 240 mg, about 210 mg out 225 mg, about 210 mg to about 220 mg, about 220 mg out 275 mg, about 220 mg to about 250 mg, about 220 mg out 230 mg, about 220 mg to about 225 mg, about 225 mg out 275 mg, about 225 mg to about 250 mg, about 225 mg out 230 mg, about 230 mg to about 300 mg, about 230 mg out 250 mg, about 230 mg to about 240 mg, about 240 mg out 275 mg, about 240 mg to about 250 mg, about 250 mgATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004to about 300 mg, about 250 mg to about 275 mg, or about 275 mg to about 300 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the twice-daily dose comprises about 20 mg to about 300 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 50 mg to about 250 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 50 mg to about 225 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 75 mg to about 250 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 75 mg to about 225 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 75 mg to about 200 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 75 mg to about 190 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 75 mg to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 75 mg to about 170 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 75 mg to about 160 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 75 mg to about 150 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 50 mg to about 100 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 50 mg to about 80 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 100 mg to about 200 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 100 mg to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 100 mg to about 175 mg of linsitinib, or a corresponding amount of aATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 100 mg to about 150 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 125 mg to about 200 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 125 mg to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 125 mg to about 175 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 125 mg to about 150 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, the twice-daily dose comprises about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, or about 300 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 20 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 30 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 40 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 50 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 55 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 60 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 65 mg of linsitinib, or a corresponding amount of a pharmaceuticallyATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 70 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 75 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 80 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 85 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 90 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 95 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 100 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 105 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 110 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 115 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 120 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 125 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 130 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 135 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 140 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 145 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 150 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 155 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 160 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 165 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-dailyATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004dose comprises about 170 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 175 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 185 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 190 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 195 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 200 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 205 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 210 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 215 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 220 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 225 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 230 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 235 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 240 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 245 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 250 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 275 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the twice-daily dose comprises about 300 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004

[0222] In some embodiments, the methods and uses described herein include administering a twice-daily dose of linsitinib (i.e., as the free form) to a subject in need thereof for the treatment of thyroid eye disease. In some embodiments, the twice-daily dose comprises about 20 mg to about 300 mg, about 20 mg to about 275 mg, about 20 mg to about 250 mg, about 20 mg to about 240 mg, about 20 mg to about 230 mg, about 20 mg to about 225 mg, about 20 mg to about 220 mg, about 20 mg to about 210 mg, about 20 mg to about 200 mg, about 20 mg to about 190 mg, about 20 mg to about 180 mg, about 20 mg to about 175 mg, about 20 mg to about 170 mg, about 20 mg to about 160 mg, about 20 mg to about 150 mg, about 20 mg to about 140 mg, about 20 mg to about 130 mg, about 20 mg to about 125 mg, about 20 mg to about 120 mg, about 20 mg to about 110 mg, about 20 mg to about 100 mg, about 20 mg to about 90 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg , about 20 mg to about 70 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 300 mg, about 30 mg to about 275 mg, about 30 mg to about 250 mg, about 30 mg to about 240 mg, about 30 mg to about 230 mg, about 30 mg to about 225 mg, about 30 mg to about 220 mg, about 30 mg to about 210 mg, about 30 mg to about 200 mg, about 30 mg to about 190 mg, about 30 mg to about 180 mg, about 30 mg to about 175 mg, about 30 mg to about 170 mg, about 30 mg to about 160 mg, about 30 mg to about 150 mg, about 30 mg to about 140 mg, about 30 mg to about 130 mg, about 30 mg to about 125 mg, about 30 mg to about 120 mg, about 30 mg to about 110 mg, about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg , about 30 mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, about 30 mg to about 40 mg, about 40 mg to about 300 mg, about 40 mg to about 275 mg, about 40 mg to about 250 mg, about 40 mg to about 240 mg, about 40 mg to about 230 mg, about 40 mg to about 225 mg, about 40 mg to about 220 mg, about 40 mg to about 210 mg, about 40 mg to about 200 mg, about 40 mg to about 190 mg, about 40 mg to about 180 mg, about 40 mg to about 175 mg, about 40 mg to about 170 mg, about 40 mg to about 160 mg, about 40 mg to about 150 mg, about 40 mg to about 140 mg, about 40 mg to about 130 mg, about 40 mg to about 125 mg, about 40 mg to about 120 mg, about 40 mg to about 110 mg, about 40 mg to about 100 mg, about 40 mg to about 90 mg, about 40 mg to about 80 mg, about 40 mg to about 75 mg , about 40 mg to about 70 mg, about 40 mg to about 60 mg, about 40 mg to about 50 mg, about 50 mg to about 300 mg, about 50 mg to about 275 mg, about 50 mg to about 250 mg, about 50 mg to about 240 mg, about 50 mg to about 230 mg, about 50 mg to about 225 mg, about 50 mg to about 220 mg, about 50 mg to about 210 mg, about 50 mg to about 200 mg, about 50 mg to about 190 mg, about 50 mg to about 180ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004mg, about 50 mg to about 175 mg, about 50 mg to about 170 mg, about 50 mg to about 160 mg, about 50 mg to about 150 mg, about 50 mg to about 140 mg, about 50 mg to about 130 mg, about 50 mg to about 125 mg, about 50 mg to about 120 mg, about 50 mg to about 110 mg, about 50 mg to about 100 mg, about 50 mg to about 90 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg , about 50 mg to about 70 mg, about 50 mg to about 60 mg, about 60 mg to about 300 mg, about 60 mg to about 275 mg, about 60 mg to about 250 mg, about 60 mg to about 240 mg, about 60 mg to about 230 mg, about 60 mg to about 225 mg, about 60 mg to about 220 mg, about 60 mg to about 210 mg, about 6 Omg to about 200 mg, about 60 mg to about 190 mg, about 60 mg to about 180 mg, about 60 mg to about 175 mg, about 60 mg to about 170 mg, about 60 mg to about 160 mg, about 60mg to about 150 mg, about 60 mg to about 140 mg, about 60 mg to about 130 mg, about 60 mg to about 125 mg, about 60 mg to about 120 mg , about 60 mg to about 110 mg, about 60 mg to about 100 mg, about 60 mg to about 90 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 70 mg to about 300 mg, about 70 mg to about 275 mg, about 70 mg to about 250 mg, about 70 mg to about 240 mg, about 70 mg to about 230 mg, about 70 mg to about 225 mg, about 70 mg to about 220 mg, about 70 mg to about 210 mg, about 70 mg to about 200 mg, about 70 mg to about 190 mg, about 70 mg to about 180 mg, about 70 mg to about 175 mg, about 70 mg to about 170 mg, about 70 mg to about 160 mg , about 70 mg to about 150 mg, about 70 mg to about 140 mg, about 70 mg to about 130 mg, about 70 mg to about 125 mg, about 70 mg to about 120 mg , about 70 mg to about 110 mg, about 70 mg to about 100 mg, about 70 mg to about 90 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 300 mg, about 75 mg to about 275 mg, about 75 mg to about 250 mg, about 75 mg to about 240 mg, about 75 mg to about 230 mg, about 75 mg to about 225 mg, about 75 mg to about 220 mg, about 75 mg to about 210 mg, about 75 mg to about 200 mg, about 75 mg to about 190 mg, about 75 mg to about 180 mg, about 75 mg to about 175 mg, about 75 mg to about 170 mg, about 75 mg to about 160 mg, about 75 mg to about 150 mg, about 75 mg to about 140 mg, about 75 mg to about 130 mg, about 75 mg to about 125 mg, about 75 mg to about 120 mg , about 75 mg to about 110 mg, about 75 mg to about 100 mg, about 75 mg to about 90 mg, about 75 mg to about 80 mg, about 80 mg to about 300 mg, about 80 mg to about 275 mg, about 80 mg to about 250 mg, about 80 mg to about 240 mg, about 80 mg to about 230 mg, about 80 mg to about 225 mg, about 80 mg to about 220 mg, about 80 mg to about 210 mg, about 80 mg to about 200 mg, about 80 mg to about 190 mg, about 80 mg to about 180 mg, about 80 mg to about 175 mg, about 80 mg to about 170 mg, about 80 mg to about 160 mg, about 80 mg to about 150 mg, about 80 mg to about 140 mg, about 80 mg toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004about 130 mg, about 80 mg to about 125 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 100 mg, about 80 mg to about 90 mg, about 90 mg to about 300 mg, about 90 mg to about 275 mg, about 90 mg to about 250 mg, about 90 mg to about 240 mg, about 90 mg to about 230 mg, about 90 mg to about 225 mg, about 90 mg to about 220 mg, about 90 mg to about 210 mg, about 90 mg to about 200 mg, about 90 mg to about 190 mg, about 90 mg to about 180 mg, about 90 mg to about 175 mg, about 90 mg to about 170 mg, about 90 mg to about 160 mg, about 90 mg to about 150 mg, about 90 mg to about 140 mg, about 90 mg to about 130 mg, about 90 mg to about 125 mg, about 90 mg to about 120 mg, about 90 mg to about 110 mg, about 90 mg to about 100 mg, about 100 mg to about 300 mg, about 100 mg to about 275 mg, about 100 mg to about 250 mg, about 100 mg to about 240 mg, about 100 mg to about 230 mg, about 100 mg to about 225 mg, about 100 mg to about 220 mg, about 100 mg to about 210 mg, about 100 mg to about 200 mg, about 100 mg to about 190 mg, about 100 mg to about 180 mg, about 100 mg to about 175 mg, about 100 mg to about 170 mg, about 100 mg to about 160 mg, about 100 mg to about 150 mg, about 100 mg to about 140 mg, about 100 mg to about 130 mg, about 100 mg to about 125 mg, about 100 mg to about 120 mg, about 100 mg to about 110 mg, about 110 mg to about 300 mg, about 110 mg to about 275 mg, about 110 mg to about 250 mg, about 110 mg to about 240 mg, about 110 mg to about 230 mg, about 110 mg to about 225 mg, about 110 mg to about 220 mg, about 110 mg to about 210 mg, about 110 mg to about 200 mg, about 110 mg to about 190 mg, about 110 mg to about 180 mg, about 110 mg to about 175 mg, about 110 mg to about 170 mg, about 110 mg to about 160 mg, about 110 mg to about 150 mg, about 110 mg to about 140 mg, about 110 mg to about 130 mg, about 110 mg to about 125 mg, about 110 mg to about 120 mg, about 120 mg to about 300 mg, about 120 mg to about 275 mg, about 120 mg to about 250 mg, about 120 mg to about 240 mg, about 120 mg to about 230 mg, about 120 mg to about 225 mg, about 120 mg to about 220 mg, about 120 mg to about 210 mg, about 120 mg to about 200 mg, about 120 mg to about 190 mg, about 120 mg to about 180 mg, about 120 mg to about 175 mg, about 120 mg to about 170 mg, about 120 mg to about 160 mg, about 120 mg to about 150 mg, about 120 mg to about 140 mg, about 120 mg to about 130 mg, about 120 mg to about 125 mg, about 125 mg to about 300 mg, about 125 mg to about 275 mg, about 125 mg to about 250 mg, about 125 mg to about 240 mg, about 125 mg to about 230 mg, about 125 mg to about 225 mg, about 125 mg to about 220 mg, about 125 mg to about 210 mg, about 125 mg to about 200 mg, about 125 mg to about 190 mg, about 125 mg to about 180 mg, about 125 mg to about 175 mg, about 125 mg to about 170 mg, about 125 mg to about 160 mg, about 125 mg to about 150 mg, about 125 mg to about 140 mg, about 125 mg to about 130 mg, about 130 mg to about 300 mg, about 130 mgATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004out 250 mg, about 130 mg to about 240 mg, about 130 mg out 225 mg, about 130 mg to about 220 mg, about 130 mg out 200 mg, about 130 mg to about 190 mg, about 130 mg out 175 mg, about 130 mg to about 170 mg, about 130 mg out 150 mg, about 130 mg to about 140 mg, about 140 mg ut 275 mg, about 140 mg to about 250 mg, about 140 mg out 230 mg, about 140 mg to about 225 mg, about 140 mg out 210 mg, about 140 mg to about 200 mg, about 140 mg out 180 mg, about 140 mg to about 175 mg, about 140 mg out 160 mg, about 140 mg to about 150 mg, about 150 mg out 275 mg, about 150 mg to about 250 mg, about 150 mg out 230 mg, about 150 mg to about 225 mg, about 150 mg out 210 mg, about 150 mg to about 200 mg, about 150 mg out 180 mg, about 150 mg to about 175 mg, about 150 mg out 160 mg, about 160 mg to about 300 mg, about 160 mg out 250 mg, about 160 mg to about 240 mg, about 160 mg out 225 mg, about 160 mg to about 220 mg, about 160 mg out 200 mg, about 160 mg to about 190 mg, about 160 mg out 175 mg, about 160 mg to about 170 mg, about 170 mg out 275 mg, about 170 mg to about 250 mg, about 170 mg out 230 mg, about 170 mg to about 225 mg, about 170 mg out 210 mg, about 170 mg to about 200 mg, about 170 mg out 180 mg, about 170 mg to about 175 mg, about 175 mg out 275 mg, about 175 mg to about 250 mg, about 175 mg out 230 mg, about 175 mg to about 225 mg, about 175 mg out 210 mg, about 175 mg to about 200 mg, about 175 mg out 180 mg, about 180 mg to about 300 mg, about 180 mg out 250 mg, about 180 mg to about 240 mg, about 180 mg out 225 mg, about 180 mg to about 220 mg, about 180 mg out 200 mg, about 180 mg to about 190 mg, about 190 mg out 275 mg, about 190 mg to about 250 mg, about 190 mg out 230 mg, about 190 mg to about 225 mg, about 190 mg out 210 mg, about 190 mg to about 200 mg, about 200 mg out 275 mg, about 200 mg to about 250 mg, about 200 mgATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004to about 240 mg, about 200 mg to about 230 mg, about 200 mg to about 225 mg, about 200 mg to about 220 mg, about 200 mg to about 210 mg, about 210 mg to about 300 mg, about 210 mg to about 275 mg, about 210 mg to about 250 mg, about 210 mg to about 240 mg, about 210 mg to about 230 mg, about 210 mg to about 225 mg, about 210 mg to about 220 mg, about 220 mg to about 300 mg, about 220 mg to about 275 mg, about 220 mg to about 250 mg, about 220 mg to about 240 mg, about 220 mg to about 230 mg, about 220 mg to about 225 mg, about 225 mg to about 300 mg, about 225 mg to about 275 mg, about 225 mg to about 250 mg, about 225 mg to about 240 mg, about 225 mg to about 230 mg, about 230 mg to about 300 mg, about 230 mg to about 275 mg, about 230 mg to about 250 mg, about 230 mg to about 240 mg, about 240 mg to about 300 mg, about 240 mg to about 275 mg, about 240 mg to about 250 mg, about 250 mg to about 300 mg, about 250 mg to about 275 mg, or about 275 mg to about 300 mg of linsitinib.

[0223] In some embodiments, the twice-daily dose comprises about 20 mg to about 300 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 50 mg to about 250 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 50 mg to about 225 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 75 mg to about 250 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 75 mg to about 225 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 75 mg to about 200 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 75 mg to about 190 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 75 mg to about 180 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 75 mg to about 170 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 75 mg to about 160 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 75 mg to about 150 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 50 mg to about 100 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 50 mg to about 80 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 100 mg to about 200 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 100 mg to about 180 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 100 mg to about 175 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 100 mg to about 150 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 125 mg to about 200 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 125 mg to about 180 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 125 mg toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004about 175 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 125 mg to about 150 mg of linsitinib.

[0224] In some embodiments, the twice-daily dose comprises about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, or about 300 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 20 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 30 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 40 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 50 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 55 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 60 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 65 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 70 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 75 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 80 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 85 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 90 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 95 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 100 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 105 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 110 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 115 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 120 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 125 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 130 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 135 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 140 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 145 mg of linsitinib. In someATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004embodiments, the twice-daily dose comprises about 150 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 155 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 160 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 165 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 170 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 175 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 180 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 185 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 190 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 195 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 200 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 205 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 210 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 215 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 220 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 225 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 230 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 235 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 240 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 245 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 250 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 275 mg of linsitinib. In some embodiments, the twice-daily dose comprises about 300 mg of linsitinib.

[0225] In some embodiments, the methods and uses described herein include administering a twice-daily dose of a pharmaceutically acceptable salt of linsitinib to a subject in need thereof for the treatment of thyroid eye disease. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 20 mg to about 300 mg, about 20 mg to about 275 mg, about 20 mg to about 250 mg, about 20 mg to about 240 mg, about 20 mg to about 230 mg, about 20 mg to about 225 mg, about 20 mg to about 220 mg, about 20 mg to about 210 mg, about 20 mg to about 200 mg, about 20 mg to about 190 mg, about 20 mg to about 180 mg, about 20 mg to about 175 mg, about 20 mg to about 170 mg, about 20 mg to about 160 mg, about 20 mg to about 150 mg, about 20 mg to about 140 mg, about 20 mg to about 130 mg, about 20 mg to about 125 mg, about 20 mg toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004about 120 mg, about 20 mg to about 110 mg, about 20 mg to about 100 mg, about 20 mg to about 90 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg , about 20 mg to about 70 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 300 mg, about 30 mg to about 275 mg, about 30 mg to about 250 mg, about 30 mg to about 240 mg, about 30 mg to about 230 mg, about 30 mg to about 225 mg, about 30 mg to about 220 mg, about 30 mg to about 210 mg, about 30 mg to about 200 mg, about 30 mg to about 190 mg, about 30 mg to about 180 mg, about 30 mg to about 175 mg, about 30 mg to about 170 mg, about 30 mg to about 160 mg, about 30 mg to about 150 mg, about 30 mg to about 140 mg, about 30 mg to about 130 mg, about 30 mg to about 125 mg, about 30 mg to about 120 mg, about 30 mg to about 110 mg, about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg , about 30 mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, about 30 mg to about 40 mg, about 40 mg to about 300 mg, about 40 mg to about 275 mg, about 40 mg to about 250 mg, about 40 mg to about 240 mg, about 40 mg to about 230 mg, about 40 mg to about 225 mg, about 40 mg to about 220 mg, about 40 mg to about 210 mg, about 40 mg to about 200 mg, about 40 mg to about 190 mg, about 40 mg to about 180 mg, about 40 mg to about 175 mg, about 40 mg to about 170 mg, about 40 mg to about 160 mg, about 40 mg to about 150 mg, about 40 mg to about 140 mg, about 40 mg to about 130 mg, about 40 mg to about 125 mg, about 40 mg to about 120 mg, about 40 mg to about 110 mg, about 40 mg to about 100 mg, about 40 mg to about 90 mg, about 40 mg to about 80 mg, about 40 mg to about 75 mg , about 40 mg to about 70 mg, about 40 mg to about 60 mg, about 40 mg to about 50 mg, about 50 mg to about 300 mg, about 50 mg to about 275 mg, about 50 mg to about 250 mg, about 50 mg to about 240 mg, about 50 mg to about 230 mg, about 50 mg to about 225 mg, about 50 mg to about 220 mg, about 50 mg to about 210 mg, about 50 mg to about 200 mg, about 50 mg to about 190 mg, about 50 mg to about 180 mg, about 50 mg to about 175 mg, about 50 mg to about 170 mg, about 50 mg to about 160 mg, about 50 mg to about 150 mg, about 50 mg to about 140 mg, about 50 mg to about 130 mg, about 50 mg to about 125 mg, about 50 mg to about 120 mg, about 50 mg to about 110 mg, about 50 mg to about 100 mg, about 50 mg to about 90 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg , about 50 mg to about 70 mg, about 50 mg to about 60 mg, about 60 mg to about 300 mg, about 60 mg to about 275 mg, about 60 mg to about 250 mg, about 60 mg to about 240 mg, about 60 mg to about 230 mg, about 60 mg to about 225 mg, about 60 mg to about 220 mg, about 60 mg to about 210 mg, about 6 Omg to about 200 mg, about 60 mg to about 190 mg, about 60 mg to about 180 mg, about 60 mg to about 175 mg, about 60 mg toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004about 170 mg, about 60 mg to about 160 mg, about 60mg to about 150 mg, about 60 mg to about 140 mg, about 60 mg to about 130 mg, about 60 mg to about 125 mg, about 60 mg to about 120 mg , about 60 mg to about 110 mg, about 60 mg to about 100 mg, about 60 mg to about 90 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 70 mg to about 300 mg, about 70 mg to about 275 mg, about 70 mg to about 250 mg, about 70 mg to about 240 mg, about 70 mg to about 230 mg, about 70 mg to about 225 mg, about 70 mg to about 220 mg, about 70 mg to about 210 mg, about 70 mg to about 200 mg, about 70 mg to about 190 mg, about 70 mg to about 180 mg, about 70 mg to about 175 mg, about 70 mg to about 170 mg, about 70 mg to about 160 mg , about 70 mg to about 150 mg, about 70 mg to about 140 mg, about 70 mg to about 130 mg, about 70 mg to about 125 mg, about 70 mg to about 120 mg , about 70 mg to about 110 mg, about 70 mg to about 100 mg, about 70 mg to about 90 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 300 mg, about 75 mg to about 275 mg, about 75 mg to about 250 mg, about 75 mg to about 240 mg, about 75 mg to about 230 mg, about 75 mg to about 225 mg, about 75 mg to about 220 mg, about 75 mg to about 210 mg, about 75 mg to about 200 mg, about 75 mg to about 190 mg, about 75 mg to about 180 mg, about 75 mg to about 175 mg, about 75 mg to about 170 mg, about 75 mg to about 160 mg, about 75 mg to about 150 mg, about 75 mg to about 140 mg, about 75 mg to about 130 mg, about 75 mg to about 125 mg, about 75 mg to about 120 mg , about 75 mg to about 110 mg, about 75 mg to about 100 mg, about 75 mg to about 90 mg, about 75 mg to about 80 mg, about 80 mg to about 300 mg, about 80 mg to about 275 mg, about 80 mg to about 250 mg, about 80 mg to about 240 mg, about 80 mg to about 230 mg, about 80 mg to about 225 mg, about 80 mg to about 220 mg, about 80 mg to about 210 mg, about 80 mg to about 200 mg, about 80 mg to about 190 mg, about 80 mg to about 180 mg, about 80 mg to about 175 mg, about 80 mg to about 170 mg, about 80 mg to about 160 mg, about 80 mg to about 150 mg, about 80 mg to about 140 mg, about 80 mg to about 130 mg, about 80 mg to about 125 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 100 mg, about 80 mg to about 90 mg, about 90 mg to about 300 mg, about 90 mg to about 275 mg, about 90 mg to about 250 mg, about 90 mg to about 240 mg, about 90 mg to about 230 mg, about 90 mg to about 225 mg, about 90 mg to about 220 mg, about 90 mg to about 210 mg, about 90 mg to about 200 mg, about 90 mg to about 190 mg, about 90 mg to about 180 mg, about 90 mg to about 175 mg, about 90 mg to about 170 mg, about 90 mg to about 160 mg, about 90 mg to about 150 mg, about 90 mg to about 140 mg, about 90 mg to about 130 mg, about 90 mg to about 125 mg, about 90 mg to about 120 mg, about 90 mg to about 110 mg, about 90 mg to about 100 mg, about 100 mg toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004about 300 mg, about 100 mg to about 275 mg, about 100 mg to about 250 mg, about 100 mg to about 240 mg, about 100 mg to about 230 mg, about 100 mg to about 225 mg, about 100 mg to about 220 mg, about 100 mg to about 210 mg, about 100 mg to about 200 mg, about 100 mg to about 190 mg, about 100 mg to about 180 mg, about 100 mg to about 175 mg, about 100 mg to about 170 mg, about 100 mg to about 160 mg, about 100 mg to about 150 mg, about 100 mg to about 140 mg, about 100 mg to about 130 mg, about 100 mg to about 125 mg, about 100 mg to about 120 mg, about 100 mg to about 110 mg, about 110 mg to about 300 mg, about 110 mg to about 275 mg, about 110 mg to about 250 mg, about 110 mg to about 240 mg, about 110 mg to about 230 mg, about 110 mg to about 225 mg, about 110 mg to about 220 mg, about 110 mg to about 210 mg, about 110 mg to about 200 mg, about 110 mg to about 190 mg, about 110 mg to about 180 mg, about 110 mg to about 175 mg, about 110 mg to about 170 mg, about 110 mg to about 160 mg, about 110 mg to about 150 mg, about 110 mg to about 140 mg, about 110 mg to about 130 mg, about 110 mg to about 125 mg, about 110 mg to about 120 mg, about 120 mg to about 300 mg, about 120 mg to about 275 mg, about 120 mg to about 250 mg, about 120 mg to about 240 mg, about 120 mg to about 230 mg, about 120 mg to about 225 mg, about 120 mg to about 220 mg, about 120 mg to about 210 mg, about 120 mg to about 200 mg, about 120 mg to about 190 mg, about 120 mg to about 180 mg, about 120 mg to about 175 mg, about 120 mg to about 170 mg, about 120 mg to about 160 mg, about 120 mg to about 150 mg, about 120 mg to about 140 mg, about 120 mg to about 130 mg, about 120 mg to about 125 mg, about 125 mg to about 300 mg, about 125 mg to about 275 mg, about 125 mg to about 250 mg, about 125 mg to about 240 mg, about 125 mg to about 230 mg, about 125 mg to about 225 mg, about 125 mg to about 220 mg, about 125 mg to about 210 mg, about 125 mg to about 200 mg, about 125 mg to about 190 mg, about 125 mg to about 180 mg, about 125 mg to about 175 mg, about 125 mg to about 170 mg, about 125 mg to about 160 mg, about 125 mg to about 150 mg, about 125 mg to about 140 mg, about 125 mg to about 130 mg, about 130 mg to about 300 mg, about 130 mg to about 275 mg, about 130 mg to about 250 mg, about 130 mg to about 240 mg, about 130 mg to about 230 mg, about 130 mg to about 225 mg, about 130 mg to about 220 mg, about 130 mg to about 210 mg, about 130 mg to about 200 mg, about 130 mg to about 190 mg, about 130 mg to about 180 mg, about 130 mg to about 175 mg, about 130 mg to about 170 mg, about 130 mg to about 160 mg, about 130 mg to about 150 mg, about 130 mg to about 140 mg, about 140 mg to about 300 mg, about 10 mg to about 275 mg, about 140 mg to about 250 mg, about 140 mg to about 240 mg, about 140 mg to about 230 mg, about 140 mg to about 225 mg, about 140 mg to about 220 mg, about 140 mg to about 210 mg, about 140 mg to about 200 mg, about 140 mg to about 190 mg, about 140 mg to about 180 mg, about 140 mg to about 175 mg, about 140 mgATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004out 160 mg, about 140 mg to about 150 mg, about 150 mg out 275 mg, about 150 mg to about 250 mg, about 150 mg out 230 mg, about 150 mg to about 225 mg, about 150 mg out 210 mg, about 150 mg to about 200 mg, about 150 mg out 180 mg, about 150 mg to about 175 mg, about 150 mg out 160 mg, about 160 mg to about 300 mg, about 160 mg out 250 mg, about 160 mg to about 240 mg, about 160 mg out 225 mg, about 160 mg to about 220 mg, about 160 mg out 200 mg, about 160 mg to about 190 mg, about 160 mg out 175 mg, about 160 mg to about 170 mg, about 170 mg out 275 mg, about 170 mg to about 250 mg, about 170 mg out 230 mg, about 170 mg to about 225 mg, about 170 mg out 210 mg, about 170 mg to about 200 mg, about 170 mg out 180 mg, about 170 mg to about 175 mg, about 175 mg out 275 mg, about 175 mg to about 250 mg, about 175 mg out 230 mg, about 175 mg to about 225 mg, about 175 mg out 210 mg, about 175 mg to about 200 mg, about 175 mg out 180 mg, about 180 mg to about 300 mg, about 180 mg out 250 mg, about 180 mg to about 240 mg, about 180 mg out 225 mg, about 180 mg to about 220 mg, about 180 mg out 200 mg, about 180 mg to about 190 mg, about 190 mg out 275 mg, about 190 mg to about 250 mg, about 190 mg out 230 mg, about 190 mg to about 225 mg, about 190 mg out 210 mg, about 190 mg to about 200 mg, about 200 mg out 275 mg, about 200 mg to about 250 mg, about 200 mg out 230 mg, about 200 mg to about 225 mg, about 200 mg out 210 mg, about 210 mg to about 300 mg, about 210 mg out 250 mg, about 210 mg to about 240 mg, about 210 mg out 225 mg, about 210 mg to about 220 mg, about 220 mg out 275 mg, about 220 mg to about 250 mg, about 220 mg out 230 mg, about 220 mg to about 225 mg, about 225 mg out 275 mg, about 225 mg to about 250 mg, about 225 mg out 230 mg, about 230 mg to about 300 mg, about 230 mg out 250 mg, about 230 mg to about 240 mg, about 240 mgATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004to about 300 mg, about 240 mg to about 275 mg, about 240 mg to about 250 mg, about 250 mg to about 300 mg, about 250 mg to about 275 mg, or about 275 mg to about 300 mg of linsitinib.

[0226] In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 20 mg to about 300 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 50 mg to about 250 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 50 mg to about 225 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 75 mg to about 250 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 75 mg to about 225 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 75 mg to about 200 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 75 mg to about 190 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 75 mg to about 180 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 75 mg to about 170 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 75 mg to about 160 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 75 mg to about 150 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 50 mg to about 100 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 50 mg to about 80 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 100 mg to about 200 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 100 mg to about 180 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of aATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004pharmaceutically acceptable salt of linsitinib that corresponds to about 100 mg to about 175 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 100 mg to about 150 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 125 mg to about 200 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 125 mg to about 180 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 125 mg to about 175 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 125 mg to about 150 mg of linsitinib.

[0227] In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, or about 300 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 20 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 30 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 40 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 50 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 55 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib thatATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004corresponds to about 60 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 65 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 70 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 75 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 80 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 85 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 90 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 95 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 100 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 105 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 110 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 115 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 120 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 125 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 130 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 135 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 140 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 145 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 150 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable saltATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004of linsitinib that corresponds to about 155 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 160 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 165 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 170 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 175 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 180 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 185 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 190 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 195 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 200 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 205 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 210 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 215 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 220 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 225 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 230 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 235 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 240 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 245 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceuticallyATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004acceptable salt of linsitinib that corresponds to about 250 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 275 mg of linsitinib. In some embodiments, the twice-daily dose comprises an amount of a pharmaceutically acceptable salt of linsitinib that corresponds to about 300 mg of linsitinib.

[0228] In some embodiments, the methods and uses described herein include administering a twice-daily dose of an esylate salt of linsitinib to a subject in need thereof for the treatment of thyroid eye disease. In some embodiments, the twice-daily dose comprises about 20 mg to about 300 mg, about 20 mg to about 275 mg, about 20 mg to about 250 mg, about 20 mg to about 240 mg, about 20 mg to about 230 mg, about 20 mg to about 225 mg, about 20 mg to about 220 mg, about 20 mg to about 210 mg, about 20 mg to about 200 mg, about 20 mg to about 190 mg, about 20 mg to about 180 mg, about 20 mg to about 175 mg, about 20 mg to about 170 mg, about 20 mg to about 160 mg, about 20 mg to about 150 mg, about 20 mg to about 140 mg, about 20 mg to about 130 mg, about 20 mg to about 125 mg, about 20 mg to about 120 mg, about 20 mg to about 110 mg, about 20 mg to about 100 mg, about 20 mg to about 90 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg , about 20 mg to about 70 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 30 mg to about 300 mg, about 30 mg to about 275 mg, about 30 mg to about 250 mg, about 30 mg to about 240 mg, about 30 mg to about 230 mg, about 30 mg to about 225 mg, about 30 mg to about 220 mg, about 30 mg to about 210 mg, about 30 mg to about 200 mg, about 30 mg to about 190 mg, about 30 mg to about 180 mg, about 30 mg to about 175 mg, about 30 mg to about 170 mg, about 30 mg to about 160 mg, about 30 mg to about 150 mg, about 30 mg to about 140 mg, about 30 mg to about 130 mg, about 30 mg to about 125 mg, about 30 mg to about 120 mg, about 30 mg to about 110 mg, about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg , about 30 mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, about 30 mg to about 40 mg, about 40 mg to about 300 mg, about 40 mg to about 275 mg, about 40 mg to about 250 mg, about 40 mg to about 240 mg, about 40 mg to about 230 mg, about 40 mg to about 225 mg, about 40 mg to about 220 mg, about 40 mg to about 210 mg, about 40 mg to about 200 mg, about 40 mg to about 190 mg, about 40 mg to about 180 mg, about 40 mg to about 175 mg, about 40 mg to about 170 mg, about 40 mg to about 160 mg, about 40 mg to about 150 mg, about 40 mg to about 140 mg, about 40 mg to about 130 mg, about 40 mg to about 125 mg, about 40 mg to about 120 mg, about 40 mg toATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004about 110 mg, about 40 mg to about 100 mg, about 40 mg to about 90 mg, about 40 mg to about 80 mg, about 40 mg to about 75 mg , about 40 mg to about 70 mg, about 40 mg to about 60 mg, about 40 mg to about 50 mg, about 50 mg to about 300 mg, about 50 mg to about 275 mg, about 50 mg to about 250 mg, about 50 mg to about 240 mg, about 50 mg to about 230 mg, about 50 mg to about 225 mg, about 50 mg to about 220 mg, about 50 mg to about 210 mg, about 50 mg to about 200 mg, about 50 mg to about 190 mg, about 50 mg to about 180 mg, about 50 mg to about 175 mg, about 50 mg to about 170 mg, about 50 mg to about 160 mg, about 50 mg to about 150 mg, about 50 mg to about 140 mg, about 50 mg to about 130 mg, about 50 mg to about 125 mg, about 50 mg to about 120 mg, about 50 mg to about 110 mg, about 50 mg to about 100 mg, about 50 mg to about 90 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg , about 50 mg to about 70 mg, about 50 mg to about 60 mg, about 60 mg to about 300 mg, about 60 mg to about 275 mg, about 60 mg to about 250 mg, about 60 mg to about 240 mg, about 60 mg to about 230 mg, about 60 mg to about 225 mg, about 60 mg to about 220 mg, about 60 mg to about 210 mg, about 6 Omg to about 200 mg, about 60 mg to about 190 mg, about 60 mg to about 180 mg, about 60 mg to about 175 mg, about 60 mg to about 170 mg, about 60 mg to about 160 mg, about 60mg to about 150 mg, about 60 mg to about 140 mg, about 60 mg to about 130 mg, about 60 mg to about 125 mg, about 60 mg to about 120 mg , about 60 mg to about 110 mg, about 60 mg to about 100 mg, about 60 mg to about 90 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 70 mg to about 300 mg, about 70 mg to about 275 mg, about 70 mg to about 250 mg, about 70 mg to about 240 mg, about 70 mg to about 230 mg, about 70 mg to about 225 mg, about 70 mg to about 220 mg, about 70 mg to about 210 mg, about 70 mg to about 200 mg, about 70 mg to about 190 mg, about 70 mg to about 180 mg, about 70 mg to about 175 mg, about 70 mg to about 170 mg, about 70 mg to about 160 mg , about 70 mg to about 150 mg, about 70 mg to about 140 mg, about 70 mg to about 130 mg, about 70 mg to about 125 mg, about 70 mg to about 120 mg , about 70 mg to about 110 mg, about 70 mg to about 100 mg, about 70 mg to about 90 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 300 mg, about 75 mg to about 275 mg, about 75 mg to about 250 mg, about 75 mg to about 240 mg, about 75 mg to about 230 mg, about 75 mg to about 225 mg, about 75 mg to about 220 mg, about 75 mg to about 210 mg, about 75 mg to about 200 mg, about 75 mg to about 190 mg, about 75 mg to about 180 mg, about 75 mg to about 175 mg, about 75 mg to about 170 mg, about 75 mg to about 160 mg, about 75 mg to about 150 mg, about 75 mg to about 140 mg, about 75 mg to about 130 mg, about 75 mg to about 125 mg, about 75 mg to about 120 mg , about 75 mg to about 110 mg, about 75 mg to about 100 mg,ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004about 75 mg to about 90 mg, about 75 mg to about 80 mg, about 80 mg to about 300 mg, about 80 mg to about 275 mg, about 80 mg to about 250 mg, about 80 mg to about 240 mg, about 80 mg to about 230 mg, about 80 mg to about 225 mg, about 80 mg to about 220 mg, about 80 mg to about 210 mg, about 80 mg to about 200 mg, about 80 mg to about 190 mg, about 80 mg to about 180 mg, about 80 mg to about 175 mg, about 80 mg to about 170 mg, about 80 mg to about 160 mg, about 80 mg to about 150 mg, about 80 mg to about 140 mg, about 80 mg to about 130 mg, about 80 mg to about 125 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 100 mg, about 80 mg to about 90 mg, about 90 mg to about 300 mg, about 90 mg to about 275 mg, about 90 mg to about 250 mg, about 90 mg to about 240 mg, about 90 mg to about 230 mg, about 90 mg to about 225 mg, about 90 mg to about 220 mg, about 90 mg to about 210 mg, about 90 mg to about 200 mg, about 90 mg to about 190 mg, about 90 mg to about 180 mg, about 90 mg to about 175 mg, about 90 mg to about 170 mg, about 90 mg to about 160 mg, about 90 mg to about 150 mg, about 90 mg to about 140 mg, about 90 mg to about 130 mg, about 90 mg to about 125 mg, about 90 mg to about 120 mg, about 90 mg to about 110 mg, ; ibout 90 mg to about 100 mg, about 100 mg to about 300 mg, about 100 mg to about 275 mg , about 1...

Claims

1.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004CLAIMSWhat is claimed is:Claim 1. A method of treating thyroid eye disease in a subj ect in need thereof, the method comprising:orally administering to the subject a twice-daily dose of about 75 mg to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof;testing one or both of the subject’s serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels after about six consecutive weeks of administering the twice-daily dose; andtesting one or both of the subject’s serum ALT and AST levels after about twelve consecutive weeks of administering the twice-daily dose.Claim 2. The method of claim 1, wherein the twice-daily dose is about 75 mg to about 180 mg of linsitinib.Claim 3. The method of claim 1 or 2, wherein the twice-daily dose is about 75 mg of linsitinib.Claim 4. The method of claim 1 or 2, wherein the twice-daily dose is about 150 mg of linsitinib.Claim 5. The method of claim 1, wherein the twice-daily dose is the corresponding amount of the pharmaceutically acceptable salt of linsitinib.Claim 6. A method of treating thyroid eye disease in a subj ect in need thereof, the method comprising:orally administering to the subject a twice-daily dose of about 20 to about 300 mg of a pharmaceutically acceptable salt of linsitinib;testing one or both of the subject’s serum ALT and AST levels after about six consecutive weeks of administering the twice-daily dose; andtesting one or both of the subject’s serum ALT and AST levels after about twelve consecutive weeks of administering the twice-daily dose.Claim 7. The method of claim 6, wherein the twice-daily dose is about 20 mg to about 300 mg of an esylate salt or an (Z)-malate salt of linsitinib.ATTORNEY DOCKET No.: SLTH-OOl / OIWO 353890-2004Claim 8. The method of claim 7, wherein the twice-daily dose is about 75 mg to about 190 mg of the esylate salt of linsitinib.Claim 9. The method of claim 7 or 8, wherein the twice-daily dose is about 160 mg to about 185 mg of the esylate salt of linsitinib.Claim 10. The method of any one of claims 7 to 9, wherein the esylate salt of linsitinib is a crystalline esylate salt of linsitinib.Claim 11. The method of any one of claims claim 1 to 10, wherein the subject’s serum ALT level is tested after the about six consecutive weeks of administering the twice-daily dose.Claim 12. The method of claim 11, wherein if the subject’s serum ALT level is above a value that is three-times the upper limit of normal and below a value that is five-times the upper limit of normal after the about six consecutive weeks of administering the twice-daily dose, the subject’s serum ALT level is tested weekly for the remainder of the treatment or until the subject’s serum ALT level falls below a value that is three-times the upper limit of normal.Claim 13. The method of claim 11, wherein, if the subject’s serum ALT level is above a value that is five-times the upper limit of normal after the about six consecutive weeks of administering the twice-daily dose, the administration is suspended for a suspension period, wherein the subject’s serum ALT levels are tested weekly during the suspension period, and wherein administration of the twice-daily dose is resumed if the subject’s serum ALT level falls below a value that is three-times the upper limit of normal.Claim 14. The method of any one of claims 1 to 13, wherein the subject’s serum ALT level is tested after the about twelve consecutive weeks of administering the twice-daily dose.Claim 15. The method of claim 14, wherein if the subject’s serum ALT level is below a value that is three-times the upper limit of normal after the twelve consecutive weeks of administering the twice-daily dose, the subject’s serum ALT level is not tested for the remainder of the treatment.Claim 16. The method of claim 14, wherein if the subject’s serum ALT level is below a value that is three-times the upper limit of normal after 15, 18, 21, or 24 consecutive weeks of administering the twice-daily dose, the subject’s serum ALT level is not tested for the remainder of the treatment.ATTORNEY DOCKET No.: SLTH-OOl / OIWO 353890-2004Claim 17. The method of claim 14, further comprising testing the subject’s serum ALT level every three to six consecutive weeks following the about twelve consecutive weeks of administering the twice-daily dose, for the remainder of the treatment.Claim 18. The method of claim 14, wherein if the subject’s serum ALT level is above a value that is three-times the upper limit of normal and below a value five-times the upper limit of normal after the about twelve consecutive weeks of administering the twice-daily dose, the subject’s serum ALT level is tested weekly for the remainder of the treatment or until the subject’s serum ALT level falls below a value that is three-times the upper limit of normal.Claim 19. The method of claim 14, wherein if the subject’s serum ALT level is above a value that is five-times the upper limit of normal after the about twelve consecutive weeks of administering the twice-daily dose, the administration is suspended for a suspension period, wherein the subject’s serum ALT levels are tested weekly during the suspension period, and wherein administration of the twice-daily dose is resumed if the subject’s serum ALT level falls below a value that is three-times the upper limit of normal.Claim 20. The method of any one of claims claim 1 to 19, wherein the subject’s serum AST level is tested after the about six consecutive weeks of administering the twice-daily dose.Claim 21. The method of claim 20, wherein if the subject’s serum AST level is above a value that is three-times the upper limit of normal and below a value that is five-times the upper limit of normal after the about six consecutive weeks of administering the twice-daily dose, the subject’s serum AST level is tested weekly for the remainder of the treatment or until the subject’s serum AST level falls below a value that is three-times the upper limit of normal.Claim 22. The method of claim 21, wherein if the subject’s serum AST level is above a value that is five-times the upper limit of normal after the about six consecutive weeks of administering the twice-daily dose, the administration is suspended for a suspension period, wherein the subject’s serum AST levels are tested weekly during the suspension period, and wherein administration of the twice-daily dose is resumed if the subject’s serum AST level falls below a value that is three-times the upper limit of normal.Claim 23. The method of any one of claims 1 to 22, wherein the subj ect’ s serum AST level is tested after the about twelve consecutive weeks of administering the twice-daily dose.ATTORNEY DOCKET No.: SLTH-OOl / OIWO 353890-2004Claim 24. The method of claim 23, wherein if the subject’s serum AST level is below a value that is three-times the upper limit of normal after the twelve consecutive weeks of administering the twice-daily dose, the subject’s serum AST level is not tested for the remainder of the treatment.Claim 25. The method of claim 23, wherein if the subject’s serum AST level is below a value that is three-times the upper limit of normal after 15, 18, 21, or 24 consecutive weeks of administering the twice-daily dose, the subject’s serum AST level is not tested for the remainder of the treatment.Claim 26. The method of claim 23, further comprising testing the subject’s serum AST level every three to six consecutive weeks following the about twelve consecutive weeks of administering the twice-daily dose, for the remainder of the treatment.Claim 27. The method of claim 23, wherein if the subject’s serum AST level is above a value that is three-times the upper limit of normal and below a value five-times the upper limit of normal after the about twelve consecutive weeks of administering the twice-daily dose, the subject’s serum AST level is tested weekly for the remainder of the treatment or until the subject’s serum AST level falls below a value that is three-times the upper limit of normal.Claim 28. The method of claim 23, wherein if the subject’s serum AST level is above a value that is five-times the upper limit of normal after the about twelve consecutive weeks of administering the twice-daily dose, the administration is suspended for a suspension period, wherein the subject’s serum AST levels are tested weekly during the suspension period, and wherein administration of the twice-daily dose is resumed if the subject’s serum AST level falls below a value that is three-times the upper limit of normal.Claim 29. The method of any one of claims 1 to 28, wherein both the subject’s serum ALT and AST levels are tested after the about six consecutive weeks of administering the twice-daily dose.Claim 30. The method of any one of claims 1 to 29, wherein both the subject’s serum ALT and AST levels are tested after the about twelve consecutive weeks of administering the twice-daily dose.ATTORNEY DOCKET No.: SLTH-001 / 01WO 353890-2004Claim 31. A method of treating thyroid eye disease in a subj ect in need thereof, the method comprising:orally administering to the subject a twice-daily dose of about 75 to about 180 mg of linsitinib, or a corresponding amount of a pharmaceutically acceptable salt thereof, wherein the subject does not experience the onset of severe hearing impairment for the duration of the administration of the twice-daily dose.Claim 32. The method of claim 31, wherein the twice-daily dose is about 75 mg to about 180 mg of linsitinib.Claim 33. The method of claim 31 or 32, wherein the twice-daily dose is about 75 mg of linsitinib.Claim 34. The method of claim 31 or 32, wherein the twice-daily dose is about 150 mg of linsitinib.Claim 35. The method of claim 31, wherein the twice-daily dose is the corresponding amount of the pharmaceutically acceptable salt of linsitinib.Claim 36. A method of treating thyroid eye disease in a subject in need thereof, the method comprising:orally administering to the subject a twice daily dose of about 20 to about 300 mg of a pharmaceutically acceptable salt of linsitinib,wherein the subject does not experience the onset of severe hearing impairment for the duration of the administration of the twice-daily dose.Claim 37. The method of claim 36, wherein the twice-daily dose is about 20 mg to about 300 mg of an esylate salt or an (Z)-malate salt of linsitinib.Claim 38. The method of claim 37, wherein the twice-daily dose is about 75 mg to about 190 mg of the esylate salt of linsitinib.Claim 39. The method of claim 37 or 38, wherein the twice-daily dose is about 160 mg to about 185 mg of the esylate salt of linisitnib.Claim 40. The method of any one of claims 37 to 39, wherein the esylate salt of linsitinib is a crystalline esylate salt of linsitinib.ATTORNEY DOCKET No.: SLTH-OOl / OIWO 353890-2004Claim 41. The method of any one of claims 31 to 40, wherein the subject’s hearing is not tested for the duration of the administration of the twice-daily dose.Claim 42. The method of any one of claims 31 to 41, wherein the subject’s hearing is not tested immediately prior to the initial administration of the twice-daily dose.Claim 43. The method of any one of claims 31 to 42, wherein the subject’s hearing is not tested immediately after the administration of the final twice-daily dose.Claim 44. The method of any one of claims 31 to 43, wherein the subject does not experience hearing loss for the duration of the administration of the twice-daily dose.Claim 45. The method of any one of claims 1 to 44, wherein, immediately after the administration of the final twice-daily dose, the subject’s proptosis in at least one eye is reduced by 0.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.Claim 46. The method of any one of claims 1 to 45, wherein, immediately after the administration of the final twice-daily dose, the subject’s proptosis in at least one eye is reduced by 1.0 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.Claim 47. The method of any one of claims 1 to 46, wherein, immediately after the administration of the final twice-daily dose, the subject’s proptosis in at least one eye is reduced by 2.5 mm or greater as compared to the subject’s proptosis immediately prior to the initial administration of the twice-daily dose.Claim 48. The method of any one of claims 1 to 47 wherein the twice-daily dose is administered for at least 24 consecutive weeks.Claim 49. The method of any one of claims 1 to 48, wherein the subject’s thyroid eye disease is active thyroid eye disease having an onset of within the 12 months immediately prior to the initial administration of the twice-daily dose.Claim 50. The method of claim 49, wherein the subject’s active thyroid eye disease is associated with one or more selected from (i)-(iv) for the subject’s most severely affected eye:(i) eyelid retraction of 2 mm or more;ATTORNEY DOCKET No.: SLTH-OOl / OIWO 353890-2004(ii) moderate or severe soft tissue involvement;(iii) proptosis of 3 mm or more above normal for race and gender; or(iv) inconstant or constant diplopia.Claim 51. The method of any one of claims 1 to 50, wherein the subject’s thyroid eye disease is active moderate-to-severe thyroid eye disease.Claim 52. The method of claim 51, wherein the subject’s active moderate-to-severe thyroid eye disease has a Clinical Active Score (CAS) of at least 4 for the most severely affected eye, on a 7-point scale, immediately prior to the initial administration of the twice-daily dose.Claim 53. The method of any one of claims 1 to 52, wherein the subject has Graves’ Disease which is associated with the thyroid eye disease.Claim 54. The method of any one of claims 1 to 53, wherein the subject has autoimmune Hashimoto’s thyroiditis which is associated with the thyroid eye disease.Claim 55. The method of any one of claims 1 to 54, wherein the subject is euthyroid or has mild hypothyroidism or hyperthyroidism immediately prior to the initial administration of the twice-daily dose.Claim 56. The method of any one of claims 1 to 55, wherein the subject does not require an immediate ophthalmological intervention immediately prior to the initial administration of the twice-daily dose and has not scheduled an ophthalmological intervention for the duration of the administration.Claim 57. The method of any one of claims 1 to 56 wherein, the subject does not have decreased best corrected visual acuity due to optic neuropathy immediately prior to the initial administration of the twice-daily dose.Claim 58. The method of any one of claims 1 to 57, wherein the subject does not have corneal decompensation unresponsive to medical management prior to the initial administration of the twice-daily dose.Claim 59. The method of any one of claims 1 to 58, wherein the subject has not had orbital irradiation or orbital surgery prior to the initial administration of the twice-daily dose.ATTORNEY DOCKET No.: SLTH-OOl / OIWO 353890-2004Claim 60. The method of any one of claims 1 to 59, wherein the subject has not taken a glucocorticoid with a cumulative dose equivalent to 1 g or more of methylprednisolone within the three months immediately prior to the initial administration of the twice-daily dose.Claim 61. The method of any one of claims 1 to 60, wherein, the subject has not taken an IGF-1R inhibitor prior to the initial administration of the twice-daily dose.

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