Methods for treatment of chronic thyroid eye disease

Abstract

The present invention provides, among other things, a method of treating chronic thyroid eye disease (TED) comprising administering an anti-IGF-1R antibody to a patient at a dosing regimen for a treatment period sufficient to reduce one or more symptoms associated with TED with low adverse events, such as hearing impairment.

Description

Attorney Docket No. VRD-025WO1METHODS FOR TREATMENT OF CHRONIC THYROID EYE DISEASECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 734,154, filed December 15, 2024, U.S. Provisional Application No. 63 / 735,188, filed December 17, 2024, and U.S. Provisional Application No. 63 / 763,093, filed February 25, 2025, each of which is hereby incorporated by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on December 15, 2025, is named “VRD-025WOl_SL” and is 50,619 bytes.BACKGROUND

[0003] Thyroid Eye Disease (TED) is an autoimmune condition most commonly associated with Graves’ disease and hyperthyroidism but can also be found in patients who are euthyroid or hypothyroid. Pathological remodeling of the orbit and periorbital tissues results in varied presentations which include dry eyes, increased lacrimation, local irritation and eyelid retraction. As the pathophysiology progresses, signs and symptoms increase to include proptosis, diplopia, restriction of ductions and versions and optic nerve compression, with ensuing vision loss. The disease course has historically been said to transition from a first active and progressive phase (“active TED”), which is characterized by inflammation of orbital and external periorbital tissues, to a more stabilized and fibrotic phase. Active TED can be characterized by local inflammation of conjunctivae, superficial vasculature, orbital fat, lids, and extraocular muscles. The second phase of TED can be characterized by a dampened autoimmune inflammation of the first phase, leaving sequelae of expanded, fibrotic orbital tissues and dysfunctional, tethered extraocular muscles, though evidence exists that these TED patients may also exhibit an underlying inflammatory component. Accordingly, the onset of this non-active phase may be indicated by the duration, severity,Attorney Docket No. VRD-025WO1 and / or nature of disease symptoms. In view of the different natures of the two disease phases, there remains a need for effective therapies for TED.SUMMARY OF INVENTION

[0004] The present invention provides, among other things, a safer and more potent method for treating chronic thyroid eye disease (TED) based on VRDN-001 and other anti- IGF-1R antibodies using dosing regimens described herein. The present invention is, in part, based on the superior clinical results in chronic TED patients receiving VRDN-001 treatment resulting in particularly high diplopia response (e.g., > 50% rate; > 30% placebo-adjusted rate), the first demonstration of complete diplopia resolution (e.g., > 30% rate; > 15% placebo-adjusted rate), and high proptosis responder rate (e.g., > 55% rate; > 45% placebo- adjusted rate), while keeping the hearing impairment incidence low (e.g., < 15% rate; < 10% placebo adjusted rate).

[0005] In one aspect, the present invention provides, among other things, a method of treating thyroid eye disease (TED) comprising administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months, and, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0006] In some embodiments, method comprises administering a total dose of no more than 70 mg / kg. In some embodiments, method comprises administering a total dose of no more than 60 mg / kg. In some embodiments, method comprises administering a total dose of no more than 50 mg / kg. In some embodiments, method comprises administering a total dose of no more than 40 mg / kg. In some embodiments, method comprises administering a total dose of no more than 30 mg / kg. In some embodiments, method comprises administering a total dose of no more than 20 mg / kg. In some embodiments, method comprises administering a total dose of no more than 15 mg / kg. In some embodiments, method comprises administering a total dose of no more than 10 mg / kg.Attorney Docket No. VRD-025WO1

[0007] In some embodiments, the method comprises administering a total dose of 80 mg / kg. In some embodiments, the method comprises administering a total dose of 70 mg / kg. In some embodiments, the method comprises administering a total dose of 60 mg / kg. In some embodiments, the method comprises administering a total dose of 50 mg / kg. In some embodiments, the method comprises administering a total dose of 40 mg / kg. In some embodiments, the method comprises administering a total dose of 30 mg / kg. In some embodiments, the method comprises administering a total dose of 20 mg / kg. In some embodiments, the method comprises administering a total dose of 10 mg / kg.

[0008] In one aspect, the present invention provides, among other things, a method of treating chronic thyroid eye disease (TED) comprising administering an anti-IGF-lR antibody to a patient at a total dose of 50 mg / kg, wherein the total dose of 50 mg is administered by the first dose of 10 mg / kg followed by four subsequent doses of 10 mg / kg every three weeks, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6.

[0009] In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of >0. In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of 1. In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of 2. In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of 3.

[0010] In some embodiments, the treatment is sufficient to result in a reduction of diplopia in the patient. In some embodiments, the treatment is sufficient to result in a reduction of Gorman Subject Diplopia Score by at least 1. In some embodiments, the treatment is sufficient to result in a reduction of Gorman Subject Diplopia Score by at least 2. In some embodiments, the treatment is sufficient to result in a reduction of Gorman Subject Diplopia Score by at least 3. In some embodiments, the diplopia is resolved in the treated patient. In some embodiments, the reduction of Gorman Subject Diplopia Score is achieved within 15 weeks from first administering the anti-IGF-lR antibody.

[0011] In some embodiments, the treatment results in at least 15% diplopia response rate. In some embodiments, the treatment is sufficient to result in at least 20% diplopiaAttorney Docket No. VRD-025WO1 response rate. In some embodiments, the treatment is sufficient to result in at least 25% diplopia response rate. In some embodiments, the treatment is sufficient to result in at least 30% diplopia response rate. In some embodiments, the treatment results in at least 31% diplopia response rate. In some embodiments, the treatment is sufficient to result in at least 35% diplopia response rate. In some embodiments, the treatment is sufficient to result in at least 40% diplopia response rate. In some embodiments, the treatment is sufficient to result in at least 45% diplopia response rate. In some embodiments, the treatment is sufficient to result in at least 50% diplopia response rate. In some embodiments, the treatment is sufficient to result in at least 55% diplopia response rate. In some embodiments, a treatment period is sufficient to result in at least 56% diplopia response. In some embodiments, the treatment is sufficient to result in at least 60% diplopia response rate. In some embodiments, diplopia response is determined by a reduction of Gorman Subject Diplopia Score by at least 1 as compared to baseline score of at least 1. In some embodiments, the percentage diplopia response is a placebo-adjusted value.

[0012] In some embodiments, the diplopia response is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 12 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 21 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 30 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 4 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 5 months from firstAttorney Docket No. VRD-025WO1 administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 6 months. In some embodiments, the diplopia response is maintained for at least 7 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 10 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia response is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0013] In some embodiments, the at least 30% diplopia response rate is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 12 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 21 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 30 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 4 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 6 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30%Attorney Docket No. VRD-025WO1 diplopia response rate is maintained for at least 7 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 10 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia response rate is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0014] In some embodiments, the at least 55% diplopia response rate is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 12 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 21 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody' . In some embodiments, the at least 55% diplopia response rate is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 30 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 4 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 6 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 7 months from first administering the antiAttorney Docket No. VRD-025WO1IGF-1R antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 10 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 55% diplopia response rate is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0015] In some embodiments, at least 30% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 24. In some embodiments, at least 40% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 24. In some embodiments, at least 50% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 24. In some embodiments, at least 60% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 24. In some embodiments, at least 70% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 24. In some embodiments, at least 80% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 24. In some embodiments, at least 90% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 24.

[0016] In some embodiments, at least 30% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 36. In some embodiments, at least 40% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 36. In some embodiments, at least 50% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 36. In some embodiments, at least 60% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 36. In some embodiments, at least 70% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 36. In some embodiments, at least 80% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 36. In someAttorney Docket No. VRD-025WO1 embodiments, at least 90% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 36.

[0017] In some embodiments, at least 30% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 52. In some embodiments, at least 40% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 52. In some embodiments, at least 50% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 52. In some embodiments, at least 60% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 52. In some embodiments, at least 70% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 52. In some embodiments, at least 80% of patients achieving diplopia response at week 15 from first administering the anti-IGF-lR antibody maintain diplopia response at week 52.

[0018] In some embodiments, a method achieves a diplopia response within 3 weeks from the first administration. In some embodiments, a method achieves a diplopia response within 6 weeks from the first administration. In some embodiments, a method achieves a diplopia response within 9 weeks from the first administration.

[0019] In some embodiments, the treatment is sufficient to result in diplopia resolution, wherein diplopia resolution is determined by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline score of at least 1.

[0020] In some embodiments, a treatment period is sufficient to result in at least 5% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 10% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 15% diplopia resolution rate. In some embodiments, the treatment results in at least 18% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 20% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 25% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 30% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 32% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 35% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 40% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at leastAttorney Docket No. VRD-025WO145% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 50% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 55% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 60% diplopia resolution rate.

[0021] In some embodiments, a method achieves diplopia resolution within 3 weeks from the first administration. In some embodiments, a method achieves diplopia resolution within 6 weeks from the first administration. In some embodiments, a method achieves diplopia resolution within 9 weeks from the first administration.

[0022] In some embodiments, the percentage diplopia resolution is a placebo-adjusted value.

[0023] In some embodiments, the diplopia resolution is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 12 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 21 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 30 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 4 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 6 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 7 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopiaAttorney Docket No. VRD-025WO1 resolution is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 10 months from first administering the anti-IGF-lR antibody. In some embodiments, the diplopia resolution is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0024] In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 12 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 21 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 30 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 4 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 6 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 7 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In someAttorney Docket No. VRD-025WO1 embodiments, the at least 15% diplopia resolution rate is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 10 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 15% diplopia resolution rate is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0025] In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 12 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 21 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 30 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 4 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 6 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 7 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 9 monthsAttorney Docket No. VRD-025WO1 from first administering the anti-IGF-lR antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 10 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 30% diplopia resolution rate is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0026] In some embodiments, at least 30% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 24. In some embodiments, at least 40% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 24. In some embodiments, at least 50% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 24. In some embodiments, at least 60% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 24. In some embodiments, at least 70% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 24. In some embodiments, at least 80% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 24. In some embodiments, at least 90% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 24.

[0027] In some embodiments, at least 30% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 36. In some embodiments, at least 40% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 36. In some embodiments, at least 50% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 36. In some embodiments, at least 60% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 36. In some embodiments, at least 70% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 36. In some embodiments, at least 80% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 36. In some embodiments, at least 90% of patients achieving diplopia resolution atAttorney Docket No. VRD-025WO1 week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 36.

[0028] In some embodiments, at least 30% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 52. In some embodiments, at least 40% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 52. In some embodiments, at least 50% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 52. In some embodiments, at least 60% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 52. In some embodiments, at least 70% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 52. In some embodiments, at least 80% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 52. In some embodiments, at least 90% of patients achieving diplopia resolution at week 15 from first administering the anti-IGF-lR antibody maintain diplopia resolution at week 52.

[0029] In some embodiments, the treatment is sufficient to result in at least 30% proptosis responder rate. In some embodiments, the treatment is sufficient to result in at least 35% proptosis responder rate. In some embodiments, the treatment results in at least 40% proptosis responder rate. In some embodiments, the treatment results in at least 45% proptosis responder rate. In some embodiments, the treatment results in at least 48% proptosis responder rate. In some embodiments, the treatment results in at least 50% proptosis responder rate. In some embodiments, the treatment results in at least 55% proptosis responder rate. In some embodiments, the treatment results in at least 56% proptosis responder rate. In some embodiments, the treatment results in at least 60% proptosis responder rate. In some embodiments, the treatment results in at least 65% proptosis responder rate. In some embodiments, the treatment results in at least 70% proptosis responder rate.

[0030] In some embodiments, proptosis responder rate is determined by a reduction of proptosis of >1 mm from baseline. In some embodiments, proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, proptosis responder rate is determined by a reduction of proptosis of >3 mm from baseline.Attorney Docket No. VRD-025WO1

[0031] In some embodiments, the treatment is sufficient to result in at least 30% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 40% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 45% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 48% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 50% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 55% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 56% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 60% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 65% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 70% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline.

[0032] In some embodiments, the reduction of proptosis is measured by Hertel exophthalmometer. In some embodiments, the reduction of proptosis is measured by magnetic resonance imaging (MRI) or computed tomography (CT). In some embodiments, the reduction of proptosis is measured by Hertel exophthalmometer, MRI, or CT.

[0033] In some embodiments, the percentage proptosis responder rate is a placebo- adjusted value.

[0034] In some embodiments, the proptosis responder rate is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the proptosis responder rate is maintained for at least 9 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the proptosis responder rate is maintained for at least 12 weeks from first administering the anti-IGF-lR antibody. In some embodiments, theAttorney Docket No. VRD-025WO1 proptosis responder rate is maintained for at least 15 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the proptosis responder rate is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the proptosis responder rate is maintained for at least 21 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the proptosis responder rate is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the proptosis responder rate is maintained for at least 27 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the proptosis responder rate is maintained for at least 30 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the proptosis responder rate is maintained for at least 36 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the proptosis responder rate is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the proptosis responder rate is maintained for at least 4 months from first administering the anti- IGF-1R antibody. In some embodiments, the proptosis responder rate is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the proptosis responder rate is maintained for at least 6 months from first administering the anti- IGF-1R antibody. In some embodiments, the proptosis responder rate is maintained for at least 7 months from first administering the anti-IGF-lR antibody. In some embodiments, the proptosis responder rate is maintained for at least 8 months from first administering the anti- IGF-1R antibody. In some embodiments, the proptosis responder rate is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the proptosis responder rate is maintained for at least 10 months from first administering the anti- IGF-1R antibody. In some embodiments, the proptosis responder rate is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0035] In some embodiments, the at least 45% proptosis responder rate is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 12 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45%Attorney Docket No. VRD-025WO1 proptosis responder rate is maintained for at least 21 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 30 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 4 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 6 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 7 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 10 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 45% proptosis responder rate is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0036] In some embodiments, the at least 55% proptosis responder rate is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 12 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 21 weeks from first administering the antiAttorney Docket No. VRD-025WO1IGF-1R antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 30 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 4 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 6 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 7 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 10 months from first administering the anti- IGF-1R antibody. In some embodiments, the at least 55% proptosis responder rate is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0037] In some embodiments, the baseline proptosis is the proptosis measurement prior to the first administration.

[0038] In some embodiments, the patient had a baseline proptosis of > 15 mm. In some embodiments, the patient had a baseline proptosis of > 16 mm. In some embodiments, the patient had a baseline proptosis of > 17 mm. In some embodiments, the patient had a baseline proptosis of between 17 mm and 33 mm. In some embodiments, the patient had a baseline proptosis of between 15 mm and 35 mm. In some embodiments, the patient had a baseline proptosis of between 16 mm and 30 mm. In some embodiments, the patient had a baseline proptosis of between 15 mm and 28 mm.

[0039] In some embodiments, the patient had a baseline proptosis of 20 mm. In some embodiments, the patient had a baseline proptosis of 21 mm. In some embodiments, theAttorney Docket No. VRD-025WO1 patient had a baseline proptosis of 22 mm. In some embodiments, the patient had baseline proptosis of 23 mm. In some embodiments, the patient had a baseline proptosis of 24 mm. In some embodiments, the patient had a baseline proptosis of 25 mm.

[0040] In some embodiments, the patient had a baseline proptosis of at least 15 mm. In some embodiments, the patient had a baseline proptosis of at least 20 mm. In some embodiments, the patient had a baseline proptosis of less than 20 mm.

[0041] In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 1.0 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 1.5 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 2.0 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 2.3 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 2.5 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 3.0 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 3.5 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 4.0 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 4.5 mm as compared to baseline.

[0042] In some embodiments, a reduction in proptosis is measured by Hertel exophthalmometer. In some embodiments, a reduction in proptosis is measured by MRI or CT. In some embodiments, a reduction in proptosis is measured by Hertel exophthalmometer, MRI, or CT.

[0043] In some embodiments, the reduction in proptosis is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in proptosis is maintained for at least 9 weeks from first administering the anti-IGF- 1R antibody. In some embodiments, the reduction in proptosis is maintained for at least 12 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in proptosis is maintained for at least 15 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the reduction in proptosis is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in proptosis is maintained for at least 21 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the reduction in proptosis is maintained for at leastAttorney Docket No. VRD-025WO124 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in proptosis is maintained for at least 27 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the reduction in proptosis is maintained for at least 30 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in proptosis is maintained for at least 36 weeks from first administering the anti- IGF-1R antibody. In some embodiments, the reduction in proptosis is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in proptosis is maintained for at least 4 months from first administering the anti- IGF-1R antibody. In some embodiments, the reduction in proptosis is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in proptosis is maintained for at least 6 months from first administering the anti- IGF-1R antibody. In some embodiments, the reduction in proptosis is maintained for at least 7 months from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in proptosis is maintained for at least 8 months from first administering the anti- IGF-1R antibody. In some embodiments, the reduction in proptosis is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in proptosis is maintained for at least 10 months from first administering the anti- IGF-1R antibody. In some embodiments, the reduction in proptosis is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0044] In some embodiments, at least 30% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 24. In some embodiments, at least 40% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 24. In some embodiments, at least 50% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 24. In some embodiments, at least 60% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 24. In some embodiments, at least 70% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 24. In some embodiments, at least 80% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 24. In some embodiments, at least 90% of patients achieving proptosis response atAttorney Docket No. VRD-025WO1 week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 24.

[0045] In some embodiments, at least 30% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 36. In some embodiments, at least 40% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 36. In some embodiments, at least 50% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 36. In some embodiments, at least 60% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 36. In some embodiments, at least 70% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 36. In some embodiments, at least 80% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 36. In some embodiments, at least 90% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 36.

[0046] In some embodiments, at least 30% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 52. In some embodiments, at least 40% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 52. In some embodiments, at least 50% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 52. In some embodiments, at least 60% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 52. In some embodiments, at least 70% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 52. In some embodiments, at least 80% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 52. In some embodiments, at least 90% of patients achieving proptosis response at week 15 from first administering the anti-IGF-lR antibody maintain proptosis response at week 52.Attorney Docket No. VRD-025WO1

[0047] In some embodiments, a patient has a baseline CAS of 0 to 7. In some embodiments, a patient has a baseline CAS <1. In some embodiments, a patient has a baseline CAS <2. In some embodiments, a patient has a baseline CAS <3. In some embodiments, a patient has a baseline CAS <4. In some embodiments, a patient has a baseline CAS <5. In some embodiments, a patient has a baseline CAS <6. In some embodiments, a patient has a baseline CAS <7. In some embodiments, a patient has a baseline CAS >3.

[0048] In some embodiments, a patient exhibits fibrosis.

[0049] In some embodiments, administration of an anti-IGF-lR antibody is sufficient to result in the treatment of fibrosis.

[0050] In some embodiments, fibrosis is reduced post-treatment with an anti-IGF-lR antibody. In some embodiments, fibrosis is alleviated post-treatment with an anti-IGF-lR antibody. In some embodiments, fibrosis is reversed post-treatment with an anti-IGF-lR antibody.

[0051] In some embodiments, the treatment is sufficient to result in a reduction of CAS of >1 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >2 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >2.5 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >2.9 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >3 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >4 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >5 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >6 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >7 from baseline.

[0052] In some embodiments, the patient has no worsening of Clinical Activity Score (CAS) post-treatment.

[0053] In some embodiments, the treatment is sufficient to result in a CAS of 0 or 1. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 10%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 15%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 20%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 25%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 30%. In some embodiments, the rate of achieving a CAS of 0 or 1 isAttorney Docket No. VRD-025WO1 at least 35%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 40%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 45%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 50%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 55%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 60%.

[0054] In some embodiments, the percentage rate of achieving a CAS of 0 or 1 is a placebo-adjusted value.

[0055] In some embodiments, a CAS of 0 or 1 is maintained for at least is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 12 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 21 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 30 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 4 months from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 6 months from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 7 months from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, a CAS of 0 or 1 is maintained for at least 10Attorney Docket No. VRD-025WO1 months. In some embodiments, a CAS of 0 or 1 is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0056] In some embodiments, at least 50% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 55% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 60% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 65% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 70% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 75% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 80% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 85% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 90% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 24.

[0057] In some embodiments, at least 50% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 55% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 60% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 65% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 70% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 75% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 80% of patients achieving a CAS of 0 or 1 at week 15 from firstAttorney Docket No. VRD-025WO1 administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 85% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 90% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 36.

[0058] In some embodiments, at least 50% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 55% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 60% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 65% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 70% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 75% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 80% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 85% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 90% of patients achieving a CAS of 0 or 1 at week 15 from first administering the anti-IGF-lR antibody maintain a CAS of 0 or 1 at week 52.

[0059] In some embodiments, the treatment results in hearing impairment incidence of less than 20%. In some embodiments, the treatment results in hearing impairment incidence of less than 18%. In some embodiments, the treatment results in hearing impairment incidence of less than 16%. In some embodiments, the treatment results in hearing impairment incidence of less than 15%. In some embodiments, the treatment results in hearing impairment incidence of less than 12%. In some embodiments, the treatment results in hearing impairment incidence of less than 10%. In some embodiments, the treatment results in hearing impairment incidence of less than 8%. In some embodiments, the treatment results in hearing impairment incidence of less than 6%. In some embodiments, the treatment results in hearing impairment incidence of less than 5.5%. In some embodiments,Attorney Docket No. VRD-025WO1 the treatment results in hearing impairment incidence of less than 5%. In some embodiments, the treatment results in hearing impairment incidence of less than 4%. In some embodiments, the treatment does not result in hearing impairment incidence.

[0060] In some embodiments, the hearing impairment incidence of less than 10% is maintained for the treatment period. In some embodiments, the hearing impairment incidence is placebo-adjusted value.

[0061] In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 12 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, hearing impairment incidence of less than 14% is maintained for at least 21 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 30 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 4 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 6 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 7 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairmentAttorney Docket No. VRD-025WO1 incidence of less than 14% is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 10 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 14% is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0062] In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 12 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, hearing impairment incidence of less than 10% is maintained for at least 21 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 30 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 4 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 5 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 6 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 7 months from firstAttorney Docket No. VRD-025WO1 administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 8 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 9 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 10 months from first administering the anti-IGF-lR antibody. In some embodiments, the hearing impairment incidence of less than 10% is maintained for at least 12 months from first administering the anti-IGF-lR antibody.

[0063] In some embodiments, the patient does not have hearing impairment prior to the treatment. In some embodiments, the patient has hearing impairment prior to treatment.

[0064] In some embodiments, the treatment period is at least 6 weeks. In some embodiments, the treatment period is at least 9 weeks. In some embodiments, the treatment period is at least 12 weeks. In some embodiments, the treatment period is at least 15 weeks. In some embodiments, the treatment period is at least 18 weeks. In some embodiments, the treatment period is at least 21 weeks. In some embodiments, the treatment period is at least 24 weeks. In some embodiments, the treatment period is at least 27 weeks.

[0065] In some embodiments, the treatment period is 6 weeks. In some embodiments, the treatment period is 9 weeks. In some embodiments, the treatment period is 12 weeks. In some embodiments, the treatment period is 15 weeks. In some embodiments, the treatment period is 18 weeks. In some embodiments, the treatment period is 21 weeks. In some embodiments, the treatment period is 24 weeks. In some embodiments, the treatment period is 27 weeks. In some embodiments, the treatment period is 36 weeks. In some embodiments, the treatment period is 52 weeks.

[0066] In some embodiments, the treatment period is no more than 52 weeks. In some embodiments, the treatment period is no more than 36 weeks. In some embodiments, the treatment period is no more than 27 weeks. In some embodiments, the treatment period is no more than 24 weeks. In some embodiments, the treatment period is no more than 21 weeks. In some embodiments, the treatment period is no more than 18 weeks. In some embodiments, the treatment period is no more than 15 weeks.

[0067] In some embodiments, the method comprises administering three subsequent doses. In some embodiments, the method comprises administering four subsequent doses. In some embodiments, the method comprises administering five subsequent doses. In some embodiments, the method comprises administering six subsequent doses. In someAttorney Docket No. VRD-025WO1 embodiments, the method comprises administering seven subsequent doses. In some embodiments, the method comprises administering eight subsequent doses. In some embodiments, the method comprises administering more than eight subsequent doses.

[0068] In some embodiments, the patient, prior to treatment, had proptosis of >1 mm above normal values for race and gender. In some embodiments, the e patient, prior to treatment, had proptosis of >2 mm above normal values for race and gender. In some embodiments, the e patient, prior to treatment, had proptosis of >3 mm above normal values for race and gender. In some embodiments, the e patient, prior to treatment, had proptosis of >4 mm above normal values for race and gender. In some embodiments, the e patient, prior to treatment, had proptosis of >5 mm above normal values for race and gender.

[0069] In some embodiments, the patient, prior to treatment, had lid retraction of >1 mm. In some embodiments, the patient, prior to treatment, had lid retraction of >2 mm. In some embodiments, the patient, prior to treatment, had lid retraction of >3 mm. In some embodiments, the patient, prior to treatment, had lid retraction of >4 mm. In some embodiments, the patient, prior to treatment, had lid retraction of >5 mm. In some embodiments, the patient, prior to treatment, had lid retraction of >6 mm.

[0070] In some embodiments, the patient, prior to treatment, had moderate or severe soft tissue involvement. In some embodiments, the patient, prior to treatment, had soft tissue involvement. In some embodiments, the patient, prior to treatment, had severe soft tissue involvement.

[0071] In some embodiments, patient, prior to treatment, had periodic or constant diplopia.

[0072] In some embodiments, the treatment results in substantially no incidence of anti-drug antibody (ADA) as compared to placebo.

[0073] In some embodiments, the anti-IGF-lR antibody comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3, and a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0074] In some embodiments, the anti-IGF-lR antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO: 10, and a light chain having an amino acid sequence of SEQ ID NO: 11.

[0075] In some embodiments, the anti-IGF-lR antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO: 14, and a light chain having an amino acid sequence of SEQ ID NO: 15.Attorney Docket No. VRD-025WO1

[0076] In some embodiments, the patient is at least 18 years of age or older.

[0077] In some embodiments, the patient had not received prior treatment with another anti-IGF-lR therapy. In some embodiments, the patient has received prior treatment with another anti-IGF-lR therapy.

[0078] In some embodiments, the patient, prior to the treatment, did not have a compressive optic neuropathy of TED that is expected to require surgical decompression in the immediate future.

[0079] In some embodiments, the patient, prior to the treatment, did not have corneal decompensation in the study eye unresponsive to medical management.

[0080] In some embodiments, the patient did not have a decrease in CAS of >2 points in the study eye between screening assessment and Day -1

[0081] In some embodiments, the patient did not a decrease in proptosis of >2 mm in the study eye between screening assessment and Day -1.

[0082] In some embodiments, the patient, prior to the treatment, have not had previous orbital irradiation or decompression surgery involving excision of fat for TED to the study eye’s orbit.

[0083] In some embodiments, a patient receives additional doses of anti-IGF-lR antibody upon return of one or more symptoms of thyroid eye disease. In some embodiments, the return of one or more symptoms is worsening of a CAS score. In some embodiments, the return of one or more symptoms is an increase in proptosis. In some embodiments, the return of one or more symptoms is a decrease in diplopia resolution.

[0084] In some embodiments, a treatment further comprises administering magnesium to the subject. In some embodiments, the magnesium is administered prior to the administration of the anti-IGF-lR antibody. In some embodiments, the magnesium is administered during the administration of the anti-IGF-lR antibody. In some embodiments, the magnesium is administered after the administration of the anti-IGF-lR antibody. In some embodiments, the magnesium is administered 1-2 days prior to subsequent administration of the anti-IGF-lR antibody.

[0085] In some embodiments, the magnesium is administered at a dose of 100-1000 mg. In some embodiments, the magnesium is administered at a dose of 200-800 mg. In some embodiments, the magnesium is administered at a dose of 200-600 mg. In some embodiments, the magnesium is administered at a dose of 300-500 mg. In some embodiments, the magnesium is administered at a dose of 300 mg. In some embodiments,Attorney Docket No. VRD-025WO1 the magnesium is administered at a dose of 400 mg. In some embodiments, the magnesium is administered at a dose of 500 mg. In some embodiments, the magnesium is administered orally.

[0086] In one aspect, the present invention provides, among other things, a method of treating chronic TED comprising administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months, wherein the treatment is sufficient to result in at least 55% diplopia response, wherein diplopia resolution is measured by a reduction of Gorman Subjective Diplopia Score by at least 1, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0087] In one aspect, the present invention provides, among other things, a method of treating chronic TED comprising administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months, wherein the treatment is sufficient to result in at least 30% placebo adjusted diplopia response, wherein diplopia resolution is measured by a reduction of Gorman Subjective Diplopia Score by at least 1, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0088] In one aspect, the present invention provides, among other things, a method of treating chronic TED comprising administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months, wherein the treatment is sufficient to result in at least 30% diplopia resolution, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline score of at least 1, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.Attorney Docket No. VRD-025WO1

[0089] In one aspect, the present invention provides, among other things, a method of treating chronic TED comprising administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months, wherein the treatment is sufficient to result in at least 17% placebo adjusted diplopia resolution, wherein diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline score of at least 1, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0090] In one aspect, the present invention provides, among other things, a method of treating chronic TED comprising administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months, wherein the treatment is sufficient to result in at least 56% proptosis response, wherein a proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0091] In one aspect, the present invention provides, among other things, a method of treating chronic TED comprising administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months, wherein the treatment is sufficient to result in at least 48% placebo adjusted proptosis response, wherein a proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3 and the light chain comprises a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

[0092] In some embodiments, administering an anti-IGF-lR antibody results in a reduction in orbital fat volume as compared to a baseline. In some embodiments, theAttorney Docket No. VRD-025WO1 administering an anti-IGF-lR antibody results in a reduction in extraocular muscle volume. In some embodiments, orbital fat volume is determined using MRI or CT. In some embodiments, extraocular muscle volume is determined using MRI or CT.

[0093] In some embodiments, the orbital fat volume is reduced by at least 500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 2000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 2500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 3000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 3500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 4000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 4500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 5000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 5500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 6000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 6500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 7000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 7500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 8000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 8500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 9000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 9500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 10,000 pL as compared to a baseline.

[0094] In some embodiments, the reduction in orbital fat volume is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in orbital fat volume is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in orbital fat volume is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody.

[0095] In some embodiments, the extraocular muscle volume is reduced by at least 500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 1000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 1500 pL as compared to a baseline. In someAttorney Docket No. VRD-025WO1 embodiments, the extraocular muscle volume is reduced by at least 2000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 2500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 3000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 3500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 4000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 4500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 5000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 5500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 6000 pL as compared to a baseline.

[0096] In some embodiments, the reduction in extraocular muscle volume is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in extraocular muscle volume is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, the reduction in extraocular muscle volume is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody.

[0097] In some embodiments, administering an anti-IGF-lR antibody results in an improvement in GO-QOL score as compared to baseline. In some embodiments, the improvement in GO-QOL score is in GO-QOL combined score. In some embodiments, the improvement in GO-QOL score is in GO-QOL activity subscale score. In some embodiments, the improvement in GO-QOL score is in GO-QOL appearance subscale score. In some embodiments, the improvement in GO-QOL score is in GO-QOL combined score, activity subscale score, and appearance subscale score. In some embodiments, a patient has a GO-QOL combined score of <92 at baseline. In some embodiments, a method results in a >8 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >10 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >12 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >14 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >16 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >18 point improvement inAttorney Docket No. VRD-025WO1GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >20 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >30 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >40 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >50 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >60 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >70 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >80 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >90 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL combined score as compared to baseline.

[0098] In some embodiments, a patient has a GO-QOL activity subscale score of <92 at baseline. In some embodiments, a method results in a >8 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >10 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >12 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >14 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >16 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >18 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >20 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >30 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >40 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >50 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >60 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >70 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >80 point improvement in GO-QOL activity subscaleAttorney Docket No. VRD-025WO1 score as compared to baseline. In some embodiments, a method results in a >90 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL activity subscale score as compared to baseline.

[0099] In some embodiments, a patient has a GO-QOL appearance subscale score of <92 at baseline. In some embodiments, a method results in a >8 point improvement in GO- QOL appearance subscale score. In some embodiments, a method results in a >10 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >12 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >14 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >16 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >18 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >20 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >30 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >40 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >50 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >60 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >70 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >80 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >90 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL appearance subscale score as compared to baseline.

[0100] In some embodiments, a method results in a >8 point improvement in GO- QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >10 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >12 point improvement in GO-QOLAttorney Docket No. VRD-025WO1 combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >14 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >16 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >18 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >20 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >30 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >40 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >50 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >60 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >70 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >80 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >90 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline.

[0101] In some embodiments, an improvement in GO-QOL is achieved within 3 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is achieved within 6 weeks from first administering the anti-IGF- 1R antibody. In some embodiments, an improvement in GO-QOL is achieved within 9 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is achieved within 12 weeks from first administering the anti-IGF-lR antibody. InAttorney Docket No. VRD-025WO1 some embodiments, an improvement in GO-QOL is achieved within 15 weeks from first administering the anti-IGF-lR antibody.

[0102] In some embodiments, an improvement in GO-QOL is maintained for at least 6 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is maintained for at least 9 weeks from first administering the anti- IGF-1R antibody. In some embodiments, an improvement in GO-QOL is maintained for at least 12 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is maintained for at least 15 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is maintained for at least 18 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is maintained for at least 21 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is maintained for at least 24 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is maintained for at least 27 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is maintained for at least 30 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is maintained for at least 36 weeks from first administering the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is maintained for at least 52 weeks from first administering the anti-IGF-lR antibody.

[0103] In some embodiments, the baseline is a value prior to the administration of the anti-IGF-lR antibody. In some embodiments, the baseline is a patient without the administration of the anti-IGF-lR antibody. In some embodiments, the baseline is a historical data of the same disease condition.BRIEF DESCRIPTION OF THE DRAWINGS

[0104] FIG. 1 is an exemplary graphing showing proptosis responder rate (reduction of >2 mm from baseline in the most proptotic eye, without deterioration in the fellow eye of > 2 mm), as assessed by Hertel exophthalmometer, in chronic TED patients treated with VRDN-001 compared to placebo.

[0105] FIG. 2 is an exemplary graph showing mean change from baseline in proptosis, as assessed by Hertel exophthalmometer, in chronic TED patients treated with VRDN-001 compared to placebo.Attorney Docket No. VRD-025WO1

[0106] FIG. 3 is an exemplary graph showing diplopia responder % in chronic TED patients treated with VRDN-001 compared to placebo.

[0107] FIG. 4 is an exemplary graph showing diplopia complete resolution % in chronic TED patients treated with VRDN-001 as compared to placebo.DETAILED DESCRIPTION

[0108] The present invention provides, among other things, a safer and more potent method for treating thyroid eye disease (TED) based on VRDN-001 and other anti-IGF-lR antibodies using dosing regimens described herein. The present invention is, in part, based on the superior clinical results in TED patients receiving VRDN-001 treatment resulting in particularly high diplopia response (e.g., > 30% placebo adjusted rate), the first demonstration of diplopia resolution (e.g., >18% placebo-adjusted rate), high proptosis responder rate (e.g., > 48% placebo adjusted rate), while keeping the hearing impairment incidence low (e.g., < 10% placebo adjusted rate).

[0109] Any numerical values used in this application are meant to cover any variations within the standard deviation or normal fluctuations appreciated by one of ordinary skill in the relevant art.Thyroid Eye Disease (TED)

[0110] Provided herein are antibodies that bind and modulate the activity of IGF-1R. The antibodies can be used, for example, to treat thyroid-associated ophthalmopathy (TAO), also known as thyroid eye disease (TED), Graves’ ophthalmopathy or orbitopathy (GO), thyrotoxic exophthalmos, dysthyroid ophthalmopathy, autoimmune associated eye disorders associated with IGF-1R signaling, inflammatory orbital disorder associated with IGF-1R signaling, and other thyroid eye disorders associated with IGF-1R signaling.

[0111] Thyroid Eye Disease (TED) is an autoimmune condition most commonly associated with Graves’ disease and hyperthyroidism but can also be found in patients who are euthyroid or hypothyroid. Pathological remodeling of the orbit and periorbital tissues results in varied presentations which include dry eyes, increased lacrimation, local irritation and eyelid retraction. As the pathophysiology progresses, signs and symptoms increase to include proptosis, diplopia, restriction of ductions and versions and optic nerve compression, with ensuing vision loss.Attorney Docket No. VRD-025WO1

[0112] The pathophysiology of TED is incompletely understood. Stimulation of inflammatory cytokines causes proliferation of the orbital fibroblasts which in turn produce collagen and glycosaminoglycans in the extracellular matrix. The polyanionic charge and the high osmotic pressure of this matrix substance cause swelling of the extraocular muscles. In addition, a subgroup of orbital fibroblasts differentiates into new mature fat cells (adipogenesis), which adds to increased orbital tissue volume. There is also a role for the humoral-mediated immune response in which thyrotropin receptor autoantibodies and immunoglobulins targeting insulin-like growth factor- 1 receptors contribute to fibroblast activation and glycosaminoglycan secretion. Levator and Muller muscle inflammation and fibrosis account for upper eyelid retraction, which is seen in up to 90% of affected patients. Proptosis is caused by the expansion of orbital fat (type 1 orbitopathy), extraocular muscles (type 2 orbitopathy), or both. Blindness is caused by compression of the optic nerve, presumably within the apex of the orbit. Dramatic proptosis itself can lead to visual loss via exposure keratopathy and corneal ulceration. This constellation of signs and symptoms causes difficulty with working, driving, reading and other activities of daily living, and leads to psychosocial distress and social withdrawal.

[0113] Ultimately, the alterations in the extracellular matrix lead to proptosis, strabismus, diplopia and disfigurement of facial and periorbital anatomy. Many patients with TED endure at least 5 to 7 years of medical and surgical therapy before reaching a point of stability, transformed physically, emotionally and visually, with overwhelming dysfunction in their quality of life.

[0114] The disease course has historically been said to transition from an active and progressive phase (characterized by inflammation of orbital and external periorbital tissues) to a more stabilized and fibrotic, inactive phase, though this nomenclature is inexact and changing. Active TED has been characterized by local inflammation of conjunctiva, orbital fat and extraocular muscles, and is said to last between 1-3 years. Chronic, TED occurs when the autoimmune inflammation dampens, leaving sequelae of expanded, fibrotic orbital tissues and dysfunctional, tethered extraocular muscles, though evidence exists that even chronic TED patients may exhibit an underlying inflammatory component that needs to be further understood.

[0115] The present invention provides, among other things, a safer and more effective therapy for TED, particularly chronic TED.Attorney Docket No. VRD-025WO1Chronic Thyroid Eye Disease

[0116] Thyroid Eye Disease has historically been said to transition from an active and progressive phase (characterized by inflammation of orbital and external periorbital tissues) to a more stabilized and fibrotic, chronic phase. Active TED has been characterized by local inflammation of conjunctivae, superficial vasculature, orbital fat, lids, and extraocular muscles. Active TED may be of variable duration and may last between 1-3 years. Chronic TED occurs when the autoimmune inflammation dampens, leaving sequelae of expanded, fibrotic orbital tissues and dysfunctional, tethered extraocular muscles, though evidence exists that even chronic TED patients may exhibit an underlying inflammatory component. Chronic TED may therefore be characterized either by the duration of symptoms (e.g., the time since first onset of symptoms) and / or by the severity of disease. Further, chronic TED may be characterized by a fibrotic component to disease. However, a patient with chronic TED may still experience inflammatory episodes. Thus, a patient suffering from chronic TED may be further categorized based on the underlying disease activity into active chronic TED (e.g., Clinical Activity Score >3) or inactive chronic TED (e.g., Clinical Activity Score <3).

[0117] In some embodiments, a patient suffers from chronic thyroid eye disease (TED). In some embodiments, a patient suffers from fibrosis associated with thyroid eye disease (TED).

[0118] In some embodiments, methods of treating a patient with chronic thyroid eye disease are provided. In some embodiments, a patient with chronic thyroid eye disease, prior to treatment, has had one or more symptoms for at least 12 months. In some embodiments, a patient with chronic thyroid eye disease, prior to treatment, has had one or more symptoms for at least 1 year. In some embodiments, a patient with chronic thyroid eye disease, prior to treatment, has had one or more symptoms for more than one year. In some embodiments, a patient with chronic thyroid eye disease, prior to treatment, has had one or more symptoms for at least 15 months. In some embodiments, a patient with chronic thyroid eye disease, prior to treatment, has had one or more symptoms for longer than 15 months. In some embodiments, a patient with chronic thyroid eye disease, prior to treatment, has had one or more symptoms for at least 2 years.

[0119] In some embodiments, a patient, prior to administration of a first dose of a pharmaceutical composition provided for herein, has had one or more symptoms of thyroid eye disease more than 2, 3, 4, 5, 6, or 7 years, or 1 to about 8 years, about 1 to about 7 years,Attorney Docket No. VRD-025WO1 about 1 to about 6 years, about 1 to about 5 years, about 1 to about 4 years, about 1 to about 3 years, about 1 to about 2 years, about 2 to about 8 years, about 2 to about 7 years, about 2 to about 6 years, about 2 to about 5 years, about 2 to about 4 years, about 2 to about 3 years, about 3 to about 8 years, about 3 to about 7 years, about 3 to about 5 years, about 3 to about 4 years, about 4 to about 8 years, about 4 to about 7 years, about 4 to about 6 years, about 4 to about 5 years, about 5 to about 8 years, about 5 to about 7 years, about 5 to about 6 years, about 6 to about 8 years, about 6 to about 7 years, or about 7 to about 8 years.

[0120] In some embodiments, a patient suffers from inactive chronic TED. In some embodiments, a patient suffering from inactive chronic TED, prior to treatment, had a Clinical Activity Score (CAS) of <2. In some embodiments, a patient suffering from inactive chronic TED, prior to treatment, had a Clinical Activity Score (CAS) <1. In some embodiments, a patient suffering from inactive chronic TED, prior to treatment, had a Clinical Activity Score (CAS) of 0 or 1.

[0121] In some embodiments, a patient has a baseline CAS <1 and / or documented signs and symptoms that have persisted more than 12 months (one year) prior to commencement of treatment according to methods described herein. In some embodiments, a patient has a baseline CAS <1 and documented signs and symptoms that have persisted more than 12 months (one year) prior to commencement of treatment according to methods described herein.

[0122] In some embodiments, a patient has a baseline CAS <1 and / or documented signs and symptoms that have persisted more than 15 months prior to commencement of treatment according to methods described herein. In some embodiments, a patient has a baseline CAS <1 and documented signs and symptoms that have persisted more than 15 months prior to commencement of treatment according to methods described herein.

[0123] In some embodiments, a patient has a baseline CAS <1 and / or documented signs and symptoms that have persisted more than two years prior to commencement of treatment according to methods described herein. In some embodiments, a patient has a baseline CAS <1 and documented signs and symptoms that have persisted more than two years prior to commencement of treatment according to methods described herein.

[0124] In some embodiments, a patient suffers from active chronic TED. In some embodiments, a patient suffering from active chronic TED, prior to treatment, had a Clinical Activity Score (CAS) of >2. In some embodiments, a patient suffering from active chronic TED, prior to treatment, had a Clinical Activity Score (CAS) >3. In some embodiments, aAttorney Docket No. VRD-025WO1 patient suffering from active chronic TED, prior to treatment, had a Clinical Activity Score (CAS) of >4.

[0125] In some embodiments, a patient has a baseline CAS >2 and / or documented signs and symptoms that have persisted more than 12 months (one year) prior to commencement of treatment according to methods described herein. In some embodiments, a patient has a baseline CAS >2 and documented signs and symptoms that have persisted more than 12 months (one year) prior to commencement of treatment according to methods described herein.

[0126] In some embodiments, a patient has a baseline CAS >2 and / or documented signs and symptoms that have persisted more than 15 months prior to commencement of treatment according to methods described herein. In some embodiments, a patient has a baseline CAS >2 and documented signs and symptoms that have persisted more than 15 months prior to commencement of treatment according to methods described herein. In some embodiments, a patient has a baseline CAS >2 and / or documented signs and symptoms that have persisted more than two years prior to commencement of treatment according to methods described herein. In some embodiments, a patient has a baseline CAS >2 and documented signs and symptoms that have persisted more than two years prior to commencement of treatment according to methods described herein.Patient Population

[0127] As used herein, the terms “a patient” or “the patient” encompasses a single patent and a patient population.

[0128] In some embodiments, a patient has documented evidence of ocular symptoms or signs associated with TED that began at least 15 months prior to commencing treatment. In some embodiments, a patient has documented evidence of ocular symptoms or signs associated with TED that began more than 15 months prior to commencing treatment.

[0129] In some embodiments, a patient with TED is at least 18 years old. In some embodiments, a patient with TED is 18 to 34 years old. In some embodiments, a patient with TED is 35 to 65 years old. In some embodiments, a patient with TED is >65 years old.

[0130] As used herein, the term Clinical Activity Score (CAS) refers to the protocol described and scored according to Table 1. According to this protocol, one point is given for the presence of each of the parameters assessed in the Table below. The sum of all pointsAttorney Docket No. VRD-025WO1 defines clinical activity and provides the CAS, where 0 or 1 constitutes inactive disease and 7 severe active ophthalmopathy.

[0131] As provided in Table 1, the CAS consists of seven components: spontaneous retrobulbar pain, pain on attempted eye movements (upward, side-to-side, and downward gazes), conjunctival redness, redness of the eyelids, chemosis, swelling of the caruncle / plica, and swelling of the eyelids. Each component is scored as present (1 point) or absent (0 points). The score at each efficacy assessment is the sum of all items present; giving a range of 0-7, where 0 or 1 constitutes inactive disease and 7 severe active ophthalmopathy. A change of >2 points is considered clinically meaningful. In some embodiments, the subject’s score improves by at least 2, 3, or 4 points. In some embodiments, the subject’s score improves within 3 weeks of the first dose. In some embodiments, the subject’s score improves within 6 weeks of the first dose.

[0132] Item 1, spontaneous orbital pain could be a painful, or oppressive feeling on, or behind, the globe. This pain may be caused by the rise in intraorbital pressure, when the orbital tissues volume increases through excess synthesis of extracellular matrix, fluid accumulation, and cellular infiltration and expansion. Item 2, gaze evoked orbital pain, could be pain in the eyes when looking, or attempting to look, up, down or sideways, i.e., pain withAttorney Docket No. VRD-025WO1 upward, downward, or lateral eye movement, or when attempting eye movement. This kind of pain could arise from the stretching of the inflamed muscle(s), especially on attempted upgaze. The ' stretching pain' cannot be provoked by digital pressing on the eyeball, as would be expected if it were a manifestation of the raised intraorbital pressure. Both kinds of pain can be reduced after anti-inflammatory treatment. These kinds of pain are therefore considered to be directly related to autoimmune inflammation in the orbit and thus useful in assessing TAO activity.

[0133] Swelling in TED is seen as chemosis (edema of the conjunctiva), item no. 6 in Table 1, and swelling of the caruncle and / or plica semilunaris. Both are signs of TAO activity. Swollen eyelids can be caused by edema, fat prolapse through the orbital septum, or fibrotic degeneration. In addition to swelling, other symptoms indicative of active TAO include redness and / or pain of the conjunctiva, eyelid, caruncle and / or plica semilunaris.

[0134] In some embodiments, a patient has a baseline CAS of 0-7. In some embodiments, a patient has a baseline CAS of 0 or 1. In some embodiments, a patient has a baseline CAS of <2. In some embodiments, a patient has a baseline CAS of >3. In some embodiments, a patient has a baseline CAS of >4. In some embodiments, a patient has a baseline CAS of >2 and <4. In some embodiments, a patient has a baseline CAS >3 and documented signs or symptoms that began within 15 months of commencing treatment. In some embodiments, a patient has a baseline CAS >3 and documented signs or symptoms that began within 12 months of commencing treatment. In some embodiments, a patient has a baseline CAS >3 and documented signs or symptoms that began within 9 months of commencing treatment.

[0135] In some embodiments, a patient with TED has proptosis of >3 mm above normal values for race and gender at baseline. In some embodiments, a patient with TED has proptosis of >20mm at baseline. In some embodiments, a patient with TED has proptosis of <20mm at baseline.

[0136] In some embodiments, a patient with TED has diplopia at baseline. In some embodiments, diplopia is assessed using Gorman Grading of Diplopia. The Gorman assessment of subjective diplopia includes four categories: no diplopia (absent), diplopia when the patient is tired or awakening (intermittent), diplopia at extremes of gaze (inconstant), and continuous diplopia in the primary or reading position (constant). Patients are scored according to which grade of diplopia they are experiencing. In some embodiments, diplopia is scored from 0 to 3 (0=no diplopia; 1 intermittent, i.e., diplopia inAttorney Docket No. VRD-025WO1 primary position of gaze, when tired or when first awakening; 2=inconstant, i.e., diplopia at extremes of gaze; 3=constant, i.e., continuous diplopia in primary or reading position). In some embodiments, the diplopia is constant diplopia. In some embodiments, the diplopia is inconstant diplopia. In some embodiments, the diplopia is intermittent diplopia.

[0137] In some embodiments, the present invention provides a method of treating TED in patients with moderate to severe TED. Those skilled in the art will appreciate that the disease severity of TED can be assessed in a variety of ways, e.g., based on one or more of the following criteria: (i) minor lid retraction < 2mm (mild) or lid retraction > 2 mm (moderate to severe), (ii) mild soft tissue involvement (mild) or moderate / severe soft-tissue involvement (mod to severe), (iii) exophthalmos < 3mm above normal for race and gender (mild) or > 3 mm above normal for race and gender (mod to severe), (iv) no or intermittent diplopia and corneal exposure responsive to lubricants (mild) or inconstant or constant diplopia (mod to severe); or sight-threatening dysthyroid optic neuropathy and or corneal breakdown (very severe). In some embodiments, a patient with moderate to severe TED has proptosis of >3 mm above normal values for race and gender at baseline and one or more of: (i) lid retraction of >2 mm; (ii) moderate or severe soft tissue involvement; (iii) inconstant or constant diplopia; (iv) spontaneous retrobulbar pain or pain on eye movement; (v) swelling of the conjunctiva, eyelids or plica; or (vi) redness of the eyelids or plica. In some embodiments, a patient at baseline has one or more of (i) minor lid retraction < 2mm, (ii) mild soft tissue involvement, (iii) exophthalmos < 3mm above normal for race and gender, (iv) no or intermittent diplopia and corneal exposure responsive to lubricants. In some embodiments, a patient at baseline has one or more of (i) lid retraction > 2 mm, (ii) moderate / severe soft-tissue involvement, (iii) > 3 mm above normal for race and gender, (iv) inconstant or constant diplopia. In some embodiments, at patient at baseline has sight-threatening dysthyroid optic neuropathy and or corneal breakdown.

[0138] In some embodiments, the patient had a baseline proptosis of > 15 mm. In some embodiments, the patient had a baseline proptosis of > 16 mm. In some embodiments, the patient had a baseline proptosis of > 17 mm. In some embodiments, the patient had a baseline proptosis of between 17 mm and 33 mm. In some embodiments, the patient had a baseline proptosis of between 15 mm and 35 mm. In some embodiments, the patient had a baseline proptosis of between 16 mm and 30 mm. In some embodiments, the patient had a baseline proptosis of between 15 mm and 28 mm.Attorney Docket No. VRD-025WO1

[0139] In some embodiments, the patient had a baseline proptosis of 20 mm. In some embodiments, the patient had a baseline proptosis of 21 mm. In some embodiments, the patient had a baseline proptosis of 22 mm. In some embodiments, the patient had baseline proptosis of 23 mm. In some embodiments, the patient had a baseline proptosis of 24 mm. In some embodiments, the patient had a baseline proptosis of 25 mm.

[0140] In some embodiments, the patient had a baseline proptosis of at least 15 mm. In some embodiments, the patient had a baseline proptosis of at least 20 mm. In some embodiments, the patient had a baseline proptosis of less than 20 mm.IGF-1R Antibodies

[0141] The anti-IGF-lR antibodies described below, particularly VRDN-001, VRDN- 002, and VRDN-003 (shown in Tables 2-7) are suitable for treating TED according to methods described in the present invention.

[0142] As used herein, the term “antibody” refers to any form of antibody that exhibits the desired biological activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies and camelized single domain antibodies. “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic antibody.

[0143] As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment” refers to antigen binding fragments of antibodies, i.e. antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g. fragments that retain one or more CDR regions. Examples of antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; nanobodies and multispecific antibodies formed from antibody fragments.

[0144] In some embodiments, the antibody comprises one or more peptides having the following sequences, or a variant thereof:Attorney Docket No. VRD-025WO1Attorney Docket No. VRD-025WO1Attorney Docket No. VRD-025WO1

[0145] The VH and the VL sequences can be in any format, including, but not limited to a scFv format where the VH and VL regions are linked with a peptide linker. Examples of peptide linkers that can be used to link various peptides provided for herein include, but are not limited to: (GGGGS)n (SEQ ID NO: 12); (GGGGA)n (SEQ ID NO: 13), or any combination thereof, wherein each n is independently 1-5. In some embodiments, the peptide linker comprises (GGGGS)n (SEQ ID NO: 12), (GGGGA)n (SEQ ID NO: 13), (GSTSGSGKPGSGEGSTKG)n (SEQ ID NO: 26) or any combination thereof, wherein each n is independently 1-8. In some embodiments, the variable regions are not linked with a peptide linker. In some embodiments, the antibody comprises or consists of a polypeptide set forth in SEQ ID NOS: 10 and 11. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOS: 3, 4, 5, 6, 7, 8, and 9. In some embodiments, theAttorney Docket No. VRD-025WO1 antibody comprises a polypeptide comprising SEQ ID NOS: 27, 28, 6, 29, 30, and 31. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOS: 4, 5, 6, 32, 33, and 9. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOS: 4, 34, 6, 35, 36, and 31. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOS: 18, 19, 20, 21, 22, and 23. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOS: 37, 28, 20, 38, 39, and 40. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOS: 18, 19, 20, 41, 42, and 23. In some embodiments, the antibody comprises a polypeptide comprising SEQ ID NOS: 18, 43, 20, 44, 45, and 40.

[0146] In some embodiments, an antibody, or antigen binding fragment thereof is provided, wherein the antibody or antibody fragment comprises a peptide selected from the following tables.Attorney Docket No. VRD-025WO1Attorney Docket No. VRD-025WO1

[0147] In some embodiments, the antibody comprises one or more peptides having the following sequences, or a variant thereof comprising one or more variable domain (italicized) CDRs (italics and bold, according to Kabat numbering scheme) and a human IgGl / Kappa constant domain (underlined):Attorney Docket No. VRD-025WO1

[0148] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy or light chain having an amino acid sequence of SEQ ID NOs: 10 and 11. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having an amino acid sequence of SEQ ID NO: 10. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having a sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10. In some embodiments, an antibody, or an antibody binding fragmentAttorney Docket No. VRD-025WO1 thereof, comprises a heavy chain having an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10. In some embodiments, the sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10 comprises the CDRs having an amino acid sequence of SEQ ID NO: 7, 8, and / or 9 as set forth above. In some embodiments, the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10 comprises the CDRs of SEQ ID NO: 7, 8, and / or 9 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10 comprises the CDRs having an amino acid sequence of SEQ ID NO: 29, 30, and / or 31 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10 comprises the CDRs having an amino acid sequence of SEQ ID NO: 32, 33, and / or 9 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 10 comprises the CDRs having an amino acid sequence of SEQ ID NO: 35, 36, and / or 31 as set forth above.

[0149] In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having an amino acid sequence of SEQ ID NO: 11. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having an amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11 In some embodiments, the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11 comprises the CDRs having an amino acid sequence of SEQ ID NO: 4, 5, and / or 6 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%,Attorney Docket No. VRD-025WO199.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11 comprises the CDRs having an amino acid sequence of SEQ ID NO: 4, 5, and / or 6 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11 comprises the CDRs having an amino acid sequence of SEQ ID NO: 27, 28, and / or 6 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 11 comprises the CDRs having an amino acid sequence of SEQ ID NO: 4, 34 and / or 6 as set forth above.

[0150] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having an amino acid sequence of SEQ ID NO: 4, 5, or 6. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having an amino acid sequence of SEQ ID NO: 7, 8, or 9.

[0151] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 4 the LCDR2 has an amino acid sequence of SEQ ID NO: 5 and the LCDR3 has an amino acid sequence of SEQ ID NO: 6.

[0152] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 7 the HCDR2 has an amino acid sequence of SEQ ID NO: 8 and the HCDR3 has an amino acid sequence of SEQ ID NO: 9.

[0153] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having an amino acid sequence of SEQ ID NO: 27, 28, or 6. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having an amino acid sequence of SEQ ID NO: 29, 30, or 31.

[0154] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 27 the LCDR2 has an amino acid sequence of SEQ ID NO: 28 and the LCDR3 has an amino acid sequence of SEQ ID NO: 6.

[0155] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1Attorney Docket No. VRD-025WO1 has an amino acid sequence of SEQ ID NO: 29 the HCDR2 has an amino acid sequence of SEQ ID NO: 30 and the HCDR3 has an amino acid sequence of SEQ ID NO: 31.

[0156] In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having an amino acid sequence of SEQ ID NO: 32, 33, or 9.

[0157] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 32 the HCDR2 has an amino acid sequence of SEQ ID NO: 33 and the HCDR3 has an amino acid sequence of SEQ ID NO: 9.

[0158] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having an amino acid sequence of SEQ ID NO: 4, 34, or 6. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having an amino acid sequence of SEQ ID NO: 35, 36, or 31.

[0159] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 4 the LCDR2 has an amino acid sequence of SEQ ID NO: 34 and the LCDR3 has an amino acid sequence of SEQ ID NO: 6.

[0160] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 35 the HCDR2 has an amino acid sequence of SEQ ID NO: 36 and the HCDR3 has an amino acid sequence of SEQ ID NO: 31.

[0161] The different CDR motifs can be combined in any combination including those not depicted in the table above. For example, the following embodiments are provided as non-limiting examples of such combinations.

[0162] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 5; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 7; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 8; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 9; or variants of any of the foregoing.Attorney Docket No. VRD-025WO1

[0163] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 27; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 28; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 29; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 30; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 31; or variants of any of the foregoing.

[0164] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 5; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 32; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 33; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 9; or variants of any of the foregoing.

[0165] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 34; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 35; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 36; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 31; or variants of any of the foregoing.

[0166] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 95%,Attorney Docket No. VRD-025WO196%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 5; and the light chain CDR3 sequence has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 7; the heavy chain CDR2 sequence has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 8; and the heavy chain CDR3 sequence has the amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 9; or variants of any of the foregoing.

[0167] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 5; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 7; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 8; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 9; or variants of any of the foregoing.Attorney Docket No. VRD-025WO1

[0168] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 27; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 28; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 29; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 30; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 31; or variants of any of the foregoing.

[0169] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 5; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequenceAttorney Docket No. VRD-025WO1 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 32; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 33; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 9; or variants of any of the foregoing.

[0170] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 4; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 34; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 6; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 35; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 36; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 31; or variants of any of the foregoing.

[0171] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy or light chain having an amino acid sequence of SEQ ID NOs: 14 and 15. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises aAttorney Docket No. VRD-025WO1 heavy chain having an amino acid sequence of SEQ ID NO: 14. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having an amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 14. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 14 comprises the CDRs of SEQ ID NO: 7, 8, and / or 9 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 14 comprises the CDRs of SEQ ID NO: 29, 30, and / or 31 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 14 comprises the CDRs of SEQ ID NO: 32, 33, and / or 9 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 14 comprises the CDRs of SEQ ID NO:35, 36, and / or 31 as set forth above.

[0172] In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having an amino acid sequence of SEQ ID NO: 15. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having an amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 15. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 15 comprises the CDRs of SEQ ID NO: 4, 5, and / or 6 as set forth above.

[0173] In some embodiments, the antibody, or antigen binding fragment thereof, or protein is provided that comprises a peptide having an amino acid sequence as set forth in any of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 27, 28, 29, 30, 31, 32, 33, 34, 35, or36.Attorney Docket No. VRD-025WO1

[0174] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy or light chain having an amino acid sequence of SEQ ID NOs: 24 and 25. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having an amino acid sequence of SEQ ID NO: 24. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a heavy chain having an amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 24. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 24 comprises the CDRs of SEQ ID NO: 21, 22, and / or 23 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 24 comprises the CDRs of SEQ ID NO: 38, 39, and / or 40 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 24 comprises the CDRs of SEQ ID NO: 41, 42, and / or 23 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 24 comprises the CDRs of SEQ ID NO: 44, 45, and / or 40 as set forth above.

[0175] In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having an amino acid sequence of SEQ ID NO: 25. In some embodiments, an antibody, or an antibody binding fragment thereof, comprises a light chain having an amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 25. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 25 comprises the CDRs of SEQ ID NO: 18, 19, and / or 20 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%,Attorney Docket No. VRD-025WO199.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 25 comprises the CDRs of SEQ ID NO: 37, 28, and / or 20 as set forth above. In some embodiments, the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 25 comprises the CDRs of SEQ ID NO: 18, 43, and / or 20 as set forth above.

[0176] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having an amino acid sequence of SEQ ID NO: 18, 19, or 20. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having an amino acid sequence of SEQ ID NO: 21, 22, or 23.

[0177] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 18 the LCDR2 has an amino acid sequence of SEQ ID NO: 19 and the LCDR3 has an amino acid sequence of SEQ ID NO: 20.

[0178] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 21 the HCDR2 has an amino acid sequence of SEQ ID NO: 22 and the HCDR3 has an amino acid sequence of SEQ ID NO: 23.

[0179] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having an amino acid sequence of SEQ ID NO: 18, 19, or 20. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having an amino acid sequence of SEQ ID NO: 21, 22, or 23.

[0180] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 37 the LCDR2 has an amino acid sequence of SEQ ID NO: 28 and the LCDR3 has an amino acid sequence of SEQ ID NO: 20.

[0181] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 38 the HCDR2 has an amino acid sequence of SEQ ID NO: 39 and the HCDR3 has an amino acid sequence of SEQ ID NO: 40.

[0182] In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having an amino acid sequence of SEQ ID NO: 41, 42, or 23.

[0183] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1Attorney Docket No. VRD-025WO1 has an amino acid sequence of SEQ ID NO: 41 the HCDR2 has an amino acid sequence of SEQ ID NO: 42 and the HCDR3 has an amino acid sequence of SEQ ID NO: 23.

[0184] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain CDR having a sequence of SEQ ID NO: 18, 43, or 20. In some embodiments, an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having an amino acid sequence of SEQ ID NO: 44, 45, or 40.

[0185] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 18 the LCDR2 has an amino acid sequence of SEQ ID NO: 43 and the LCDR3 has an amino acid sequence of SEQ ID NO: 20.

[0186] In some embodiments, an antibody, or antibody binding fragment thereof, comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 44 the HCDR2 has an amino acid sequence of SEQ ID NO: 45 and the HCDR3 has an amino acid sequence of SEQ ID NO: 40.

[0187] The different CDR motifs can be combined in any combination including those not depicted in the table above. For example, the following embodiments are provided as non-limiting examples of such combinations.

[0188] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 18; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 19; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 21; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:22; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 23; or variants of any of the foregoing.

[0189] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 28; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein theAttorney Docket No. VRD-025WO1 heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 38; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 39; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 40; or variants of any of the foregoing.

[0190] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 18; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 19; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 41; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:42; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 23; or variants of any of the foregoing.

[0191] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 18; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 43; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 44; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:45; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 40; or variants of any of the foregoing.

[0192] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 18; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 19; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%,Attorney Docket No. VRD-025WO190%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 21; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 22; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 23; or variants of any of the foregoing.

[0193] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 37; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 28; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 38; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 39; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 40; or variants of any of the foregoing.Attorney Docket No. VRD-025WO1

[0194] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 37; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 28; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 41; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 42; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 23; or variants of any of the foregoing.

[0195] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 53; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 54; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 55; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO:51; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52; or variants of any of the foregoing.

[0196] In some embodiments, an antibody, or antigen binding fragment thereof, comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3Attorney Docket No. VRD-025WO1 sequences, wherein the light chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 18; the light chain CDR2 has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 43; and the light chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 20; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 44; the heavy chain CDR2 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 45; and the heavy chain CDR3 sequence has the amino acid sequence that is 80%, 81%, 82%, 83% 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or substantially 100% identical to that of SEQ ID NO: 40; or variants of any of the foregoing.

[0197] In some embodiments, the antibody, or antigen binding fragment thereof, or protein is provided that comprises a peptide having a sequence as set forth in any of SEQ ID NOs: 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 28, 37, 38, 39, 40, 41, 42, 43, 44, or 45.

[0198] In some embodiments, methods described herein comprise use or administration of an anti-IGF-lR antibody, and antigen binding fragments thereof, including any forms, variants, or derivatives thereof of the anti-IGF-lR antibody, and antigen binding fragments.

[0199] In some embodiments, the antibody, or antigen binding fragment thereof, comprises a sequence of, or a variant of any of the foregoing.

[0200] In some embodiments, the reference anti-IGF-lR antibody is used for comparing the efficacy and safety. In some embodiments, the reference antibody is shown in Table 8Attorney Docket No. VRD-025WO1Dosing Regimens

[0201] The present invention provides, among other things, a more efficacious and safer dosing regimens for treating TED. The dosing regimens disclosed herein results in particularly high diplopia response (e.g., > 50% rate; > 30% placebo-adjusted rate), high diplopia resolution (e.g., > 30% rate; > 15% placebo-adjusted rate), and high proptosis responder rate (e.g., > 55% rate; > 45% placebo-adjusted rate), while keeping the hearing impairment incidence low (e.g., < 15% rate; < 10% placebo adjusted rate).Attorney Docket No. VRD-025WO1Dose

[0202] In some embodiments, a method comprises administering an IGF-1R to a patient at a therapeutically effective dose.

[0203] In some embodiments, an IGF-1R antibody is administered at a dose of 3-20 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 3-15 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 3-10 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 5-15 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 8-12 mg / kg.

[0204] In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 5 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 10 mg / kg. In some embodiments, an IGF-1R antibody is administered at a dose of 20 mg / kg.

[0205] In some embodiments, an antibody is administered at a dose of 3 mg / kg or less. In some embodiments, an antibody is administered at a dose of 5 mg / kg or less. In some embodiments, an antibody is administered at a dose of 10 mg / kg or less. In some embodiments, an antibody is administered at a dose of 20 mg / kg or less.

[0206] In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg to 20 mg / kg antibody as a first dose. In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg to 15 mg / kg antibody as a first dose. In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg to 10 mg / kg antibody as a first dose. In some embodiments, an IGF-1R antibody is administered at a dose of 5 mg / kg to 15 mg / kg antibody as a first dose. In some embodiments, an IGF-1R antibody is administered at a dose of 8 mg / kg to 12 mg / kg antibody as a first dose.

[0207] As used herein, the term “first dose” is used interchangeably with “first administration.” In some embodiments, a first dose that is administered intravenously is referred to herein as “the first infusion.”

[0208] In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg to 20 mg / kg antibody in subsequent doses. In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg to 15 mg / kg antibody in subsequent doses. In some embodiments, an IGF-1R antibody is administered at a dose of 3 mg / kg to 10 mg / kgAttorney Docket No. VRD-025WO1 antibody in subsequent doses. In some embodiments, an IGF-1R antibody is administered at a dose of 5 mg / kg to 15 mg / kg antibody in subsequent doses. In some embodiments, an IGF- 1R antibody is administered at a dose of 8 mg / kg to 12 mg / kg antibody in subsequent doses.Administration Interval

[0209] In some embodiments, a therapeutically effective dosage regimen comprises administration of one or more doses to a patient (e.g., one or more doses of an antibody as described herein).

[0210] In some embodiments, a therapeutically effective dosage regimen comprises administration of a first dose (e.g., any dose amount of an antibody described herein) to a patient. In some embodiments, a therapeutically effective dosage regimen comprises administration of subsequent dose(s) (e.g., any dose amount of an antibody described herein) to a patient. In some embodiments, a first dose is the same amount as a subsequent dose. In some embodiments, a first dose is different amount as a subsequent dose. In some embodiments, a first dose is a higher amount than a subsequent dose. In some embodiments, a first dose is a lower amount than a subsequent dose.

[0211] In some embodiments, a subsequent dose (e.g., of an antibody as described herein) is administered to a patient once every 1-8 weeks. In some embodiments, a subsequent dose is administered to a patient once every week. In some embodiments, a subsequent dose is administered to a patient once every two weeks. In some embodiments, a subsequent dose is administered to a patient once every three weeks. In some embodiments, a subsequent dose is administered to a patient once every four weeks. In some embodiments, a subsequent dose is administered to a patient once every five weeks. In some embodiments, a subsequent dose is administered to a patient once every six weeks. In some embodiments, a subsequent dose is administered to a patient once every seven weeks. In some embodiments, a subsequent dose is administered to a patient once every eight weeks. In some embodiments, a subsequent dose is administered to a patient once every nine weeks. In some embodiments, a subsequent dose is administered to a patient once every ten weeks.

[0212] In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 3 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administering an anti- IGF-1R antibody to a patient at a dose of 5 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administeringAttorney Docket No. VRD-025WO1 an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 12 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 15 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 20 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg once every three weeks.

[0213] In some embodiments, an equivalent dosing regimen comprises administering an anti-IGFIR antibody at a dose at an administration interval sufficient to reduce one or more symptoms associated with TED. For example, an equivalent dosing regimen of 10 mg / kg or less every three weeks is 5 mg / kg or less every 10 days, or 20 mg / kg or less every six weeks.

[0214] In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 2 mg / kg or less once every 4 days. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 5 mg / kg or less once every 10 days. In some embodiments, a method comprises administering an anti- IGF-1R antibody to a patient at a dose of 20 mg / kg or less once every six weeks. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 30 mg / kg or less once every nine weeks.

[0215] Doses described herein can be administered according to methods known in the art. Exemplary routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal, or intra-arterial.

[0216] In some embodiments, a dose is administered by infusion, intravenously, or subcutaneously. In some embodiments, a dose is administered intravenously, such as by infusion.Attorney Docket No. VRD-025WO1Treatment Period

[0217] The present invention provides, among other things, a method comprising administering an anti-IGF-lR antibody for a treatment period sufficient to result in high diplopia response (e.g., > 30%), complete diplopia resolution (e.g., >18%), and high proptosis responder rate (e.g., > 29%), while keeping hearing impairment incidence low (e.g., < 10%).

[0218] In some embodiments, diplopia response is determined by a reduction of Gorman Subject Diplopia Score by at least 1 as compared to baseline score of at least 1. In some embodiments, a treatment period is sufficient to result in at least 15% diplopia response. In some embodiments, a treatment period is sufficient to result in at least 20% diplopia response. In some embodiments, a treatment period is sufficient to result in at least 25% diplopia response. In some embodiments, a treatment period is sufficient to result in at least 30% diplopia response. In some embodiments, the treatment results in at least 31% diplopia response. In some embodiments, a treatment period is sufficient to result in at least 35% diplopia response. In some embodiments, a treatment period is sufficient to result in at least 40% diplopia response. In some embodiments, a treatment period is sufficient to result in at least 45% diplopia response. In some embodiments, a treatment period is sufficient to result in at least 50% diplopia response. In some embodiments, a treatment period is sufficient to result in at least 55% diplopia response. In some embodiments, a treatment period is sufficient to result in at least 56% diplopia response. In some embodiments, a treatment period is sufficient to result in at least 60% diplopia response.

[0219] In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 6 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 10 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 11 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 14 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 15 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopiaAttorney Docket No. VRD-025WO1 response for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 27 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 30 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 33 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 36 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 39 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 42 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 45 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 48 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 51 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia response for at least 52 weeks.

[0220] In some embodiments, a treatment period is sufficient to result in at least 5% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 10% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 15% diplopia resolution. In some embodiments, the treatment results in at least 18% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 20% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 25% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 30% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 32% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 35% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 40% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 45% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 50% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 55% diplopia resolution. In some embodiments, a treatment period is sufficient to result in at least 60% diplopia resolution.

[0221] In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 6 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 10 weeks. In someAttorney Docket No. VRD-025WO1 embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 11 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 14 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 15 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 27 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 30 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 33 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 36 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 39 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 42 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 45 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 48 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 51 weeks. In some embodiments, a treatment period is sufficient to maintain the diplopia resolution for at least 52 weeks.

[0222] In some embodiments, the treatment period is sufficient to result in at least 30% proptosis responder rate. In some embodiments, the treatment period is sufficient to result in at least 35% proptosis responder rate. In some embodiments, the treatment period is sufficient to result in at least 40% proptosis responder rate. In some embodiments, the treatment period is sufficient to result in at least 45% proptosis responder rate. In some embodiments, the treatment period is sufficient to result in at least 48% proptosis responder rate. In some embodiments, the treatment period is sufficient to result in at least 50% proptosis responder rate. In some embodiments, the treatment period is sufficient to result in at least 55% proptosis responder rate. In some embodiments, the treatment period is sufficient to result in at least 56% proptosis responder rate. In some embodiments, the treatment period is sufficient to result in at least 60% proptosis responder rate. In someAttorney Docket No. VRD-025WO1 embodiments, the treatment period is sufficient to result in at least 65% proptosis responder rate. In some embodiments, the treatment period is sufficient to result in at least 70% proptosis responder rate.

[0223] In some embodiments, the treatment period is sufficient to result in at least 30% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment period is sufficient to result in at least 35% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment period is sufficient to result in at least 40% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment period is sufficient to result in at least 45% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment period is sufficient to result in at least 48% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment period is sufficient to result in at least 50% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment period is sufficient to result in at least 55% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment period is sufficient to result in at least 56% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment period is sufficient to result in at least 60% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment period is sufficient to result in at least 65% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment period is sufficient to result in at least 70% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline.

[0224] In some embodiments, the reduction of proptosis is measured by Hertel exophthalmometer. In some embodiments, the reduction of proptosis is measured by magnetic resonance imaging (MRI) or computed tomography (CT). In some embodiments, the reduction of proptosis is measured by Hertel exophthalmometer, MRI, or CT.Attorney Docket No. VRD-025WO1

[0225] In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 6 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 10 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 11 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 14 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 15 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 27 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 30 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 33 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 36 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 39 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 42 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 45 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 48 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 51 weeks. In some embodiments, a treatment period is sufficient to maintain the proptosis response for at least 52 weeks.

[0226] In some embodiments, the baseline proptosis is the proptosis measurement prior to the first administration.

[0227] In some embodiments, a treatment period is sufficient to result in a reduction of proptosis of at least 1.0 mm as compared to baseline. In some embodiments, a treatment period is sufficient to result in a reduction of proptosis of at least 1.5 mm as compared to baseline. In some embodiments, a treatment is sufficient to result in a reduction of proptosis of at least 2.0 mm as compared to baseline. In some embodiments, a treatment period isAttorney Docket No. VRD-025WO1 sufficient to result in a reduction of proptosis of at least 2.3 mm as compared to baseline. In some embodiments, a treatment period is sufficient to result in a reduction of proptosis of at least 2.5 mm as compared to baseline. In some embodiments, a treatment period is sufficient to result in a reduction of proptosis of at least 3.0 mm as compared to baseline. In some embodiments, a treatment period is sufficient to result in a reduction of proptosis of at least3.5 mm as compared to baseline. In some embodiments, a treatment period is sufficient to result in a reduction of proptosis of at least 4.0 mm as compared to baseline. In some embodiments, a treatment period is sufficient to result in a reduction of proptosis of at least4.5 mm as compared to baseline.

[0228] In some embodiments, a reduction in proptosis is measured by Hertel exophthalmometer. In some embodiments, a reduction in proptosis is measured by MRI or CT. In some embodiments, a reduction in proptosis is measured by Hertel exophthalmometer, MRI, or CT.

[0229] In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 6 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 15 weeks. In some embodiments, the treatment period is sufficient to maintain a reduction in proptosis for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 27 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 30 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 4 months. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 5 months. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 6 months. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 7 months. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 8 months. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 9 months. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis forAttorney Docket No. VRD-025WO1 at least 10 months. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 11 months. In some embodiments, a treatment period is sufficient to maintain the reduction in proptosis for at least 12 months.

[0230] In some embodiments, a treatment period is sufficient to result in a CAS of 0 or 1 for patients with a baseline CAS of >1. In some embodiments, a treatment period is sufficient to result in a CAS of 0 or 1 for patients with a baseline CAS of >3. In some embodiments, a treatment period is sufficient to maintain a at least 10% rate of CAS of 0 or 1. In some embodiments, a treatment period is sufficient to maintain a at least 15% rate of CAS of 0 or 1. In some embodiments, a treatment period is sufficient to maintain a at least 20% rate of CAS of 0 or 1. In some embodiments, a treatment period is sufficient to maintain a at least 25% rate of CAS of 0 or 1. In some embodiments, a treatment period is sufficient to maintain a at least 30% rate of CAS of 0 or 1. In some embodiments, a treatment period is sufficient to maintain a at least 35% rate of CAS of 0 or 1. In some embodiments, a treatment period is sufficient to maintain a at least 40% rate of CAS of 0 or 1. In some embodiments, a treatment period is sufficient to maintain a at least 45% rate of CAS of 0 or 1. In some embodiments, a treatment period is sufficient to maintain a at least 50% rate of CAS of 0 or 1. In some embodiments, a treatment period is sufficient to maintain a at least 55% rate of CAS of 0 or 1. In some embodiments, a treatment period is sufficient to maintain a at least 60% rate of CAS of 0 or 1. In some embodiments, the % rate of achieving a CAS of 0 or 1 is a placebo-adjusted value.

[0231] In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 6 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 10 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 11 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 14 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 15 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 27 weeks. In someAttorney Docket No. VRD-025WO1 embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 30 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 33 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 36 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 39 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 42 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 45 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 48 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 51 weeks. In some embodiments, a treatment period is sufficient to maintain a CAS of 0 or 1 for at least 52 weeks.

[0232] In some embodiments, a treatment period is sufficient to result in a reduction of CAS from baseline for patients with a baseline CAS of >1. In some embodiments, a treatment period is sufficient to result in a reduction of CAS from baseline for patients with a baseline CAS of >3. In some embodiments, a treatment period is sufficient to result in a reduction of CAS of >1 from baseline. In some embodiments, a treatment period is sufficient to result in a reduction of CAS of >2 from baseline. In some embodiments, a treatment period is sufficient to result in a reduction of CAS of >2.5 from baseline. In some embodiments, a treatment period is sufficient to result in a reduction of CAS of >2.9 from baseline. In some embodiments, a treatment period is sufficient to result in a reduction of CAS of >3 from baseline. In some embodiments, a treatment period is sufficient to result in a reduction of CAS of >4 from baseline. In some embodiments, a treatment period is sufficient to result in a reduction of CAS of >5 from baseline. In some embodiments, a treatment period is sufficient to result in a reduction of CAS of >6 from baseline. In some embodiments, a treatment period is sufficient to result in a reduction of CAS of >7 from baseline.

[0233] In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 6 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 15 weeks. In some embodiments, the treatment period is sufficient to maintain a reduction in fibrosis for at least 18 weeks. In some embodiments, a treatment period isAttorney Docket No. VRD-025WO1 sufficient to maintain the reduction in fibrosis for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 27 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 30 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 4 months. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 5 months. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 6 months. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 7 months. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 8 months. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 9 months. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 10 months. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 11 months. In some embodiments, a treatment period is sufficient to maintain the reduction in fibrosis for at least 12 months.

[0234] In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 6 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 15 weeks. In some embodiments, the treatment period is sufficient to maintain the reduction in orbital fat volume for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 27 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 30 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 4 months. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 5 months. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 6 months. In some embodiments, a treatmentAttorney Docket No. VRD-025WO1 period is sufficient to maintain the reduction in orbital fat volume for at least 7 months. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 8 months. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 9 months. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 10 months. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 11 months. In some embodiments, a treatment period is sufficient to maintain the reduction in orbital fat volume for at least 12 months.

[0235] In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 1,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 1,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 2,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 2,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 3,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 3,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 4,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 4,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 5,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 5,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 6,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 6,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 7,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 7,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction ofAttorney Docket No. VRD-025WO1 orbital fat volume by at least 8,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 8,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 9,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 9,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 10,000 pL as compared to a baseline.

[0236] In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 5% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 10% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 15% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 20% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 25% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 30% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 35% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 40% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 45% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of orbital fat volume by at least 50% as compared to a baseline.

[0237] In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 6 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 15 weeks. In some embodiments, the treatment period is sufficient to maintain a reduction in reduction in extraocular muscleAttorney Docket No. VRD-025WO1 volume for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 27 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 30 weeks. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 4 months. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 5 months. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 6 months. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 7 months. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 8 months. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 9 months. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 10 months. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 11 months. In some embodiments, a treatment period is sufficient to maintain the reduction in reduction in extraocular muscle volume for at least 12 months.

[0238] In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 1,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 1,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 2,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 2,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 3,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient toAttorney Docket No. VRD-025WO1 result in a reduction of extraocular muscle volume by at least 3,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 4,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 4,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 5,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 5,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 6,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 6,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 7,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 7,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 8,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 8,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 9,000 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 9,500 pL as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 10,000 pL as compared to a baseline.

[0239] In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 5% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 10% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 15% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 20% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 25% as compared to a baseline. In some embodiments, a treatment periodAttorney Docket No. VRD-025WO1 is sufficient to result in a reduction of extraocular muscle volume by at least 30% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 35% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 40% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 45% as compared to a baseline. In some embodiments, a treatment period is sufficient to result in a reduction of extraocular muscle volume by at least 50% as compared to a baseline.

[0240] In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 20%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 18%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 16%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 15%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 12%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 10%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 8%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 6%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 5.5%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 5%. In some embodiments, a treatment period is sufficient to result in the hearing impairment incidence of less than 4%.

[0241] In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 9 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 10 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 11 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 12 weeks. In some embodiments, a treatment period is sufficient to maintain hearing impairment incidence of less than 10% for at least 14 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 15 weeks. In some embodiments, a treatment period is sufficient to maintain theAttorney Docket No. VRD-025WO1 hearing impairment incidence of less than 10% for at least 16 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 18 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 20 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 21 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 24 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 25 weeks. In some embodiments, a treatment period is sufficient to maintain the hearing impairment incidence of less than 10% for at least 30 weeks.

[0242] In some embodiments, a treatment period is 12 weeks. In some embodiments, a treatment period is 15 weeks. In some embodiments, a treatment period is 18 weeks. In some embodiments, a treatment period is 21 weeks. In some embodiments, a treatment period is 24 weeks. In some embodiments, a treatment period is 27 weeks.

[0243] In some embodiments, a treatment period is at least 12 weeks. In some embodiments, a treatment period is at least 15 weeks. In some embodiments, a treatment period is at least 18 weeks. In some embodiments, a treatment period is at least 21 weeks. In some embodiments, a treatment period is at least 24 weeks. In some embodiments, a treatment period is at least 27 weeks.

[0244] In some embodiments, a treatment period is 12 weeks or less. In some embodiments, a treatment period is 15 weeks or less. In some embodiments, a treatment period is 18 weeks. In some embodiments, a treatment period is 21 weeks or less. In some embodiments, a treatment period is 24 weeks. In some embodiments, a treatment period is 27 weeks or less.

[0245] In some embodiments, a patient is administered 5 doses of an anti-IGF-lR antibody. In some embodiments, a patient is administered 6 doses of an anti-IGF-lR antibody. In some embodiments, a patient is administered 7 doses of an anti-IGF-lR antibody. In some embodiments, a patient is administered 8 doses of an anti-IGF-lR antibody. In some embodiments, a patient is administered 9 doses of an anti-IGF-lR antibody. In some embodiments, a patient is administered 10 doses of an anti-IGF-lR antibody.

[0246] In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalentAttorney Docket No. VRD-025WO1 dosing regimen thereof, for 12 weeks. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 15 weeks. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 18 weeks. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 21 weeks. In some embodiments, a method comprises administering an anti-IGF- 1R antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 24 weeks.

[0247] In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 12 weeks or less. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 15 weeks or less. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 18 weeks or less. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 21 weeks or less. In some embodiments, a method comprises administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, for 24 weeks or less.

[0248] In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient for 3 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient for 4 infusions or less. In some embodiments, an anti- IGF-1R antibody is intravenously administered to a patient for 5 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient for 6 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient for 7 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient for 8 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient for 9 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient for 10 infusions or less.Attorney Docket No. VRD-025WO1

[0249] In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 3 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 4 infusions or less. In some embodiments, an anti -IGF - 1R antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 5 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 6 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 7 infusions or less. In some embodiments, an anti -IGF - 1R antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 8 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 9 infusions or less. In some embodiments, an anti-IGF-lR antibody is intravenously administered to a patient at 10 mg / kg or less every three weeks, for 10 infusions or less.Clinical Efficacy Metrics / Endpoints

[0250] TED is an autoimmune condition characterized by inflammation, and enlargement of extraocular muscles, orbital fat and connective tissue. These changes lead to pain, redness and swelling of the eyelids and conjunctiva, as well as eye bulging (proptosis), double vision (diplopia), and these symptoms and signs form the basis of clinically relevant efficacy endpoints

[0251] In some embodiments, the clinical efficacy metrics achieved are placebo- adjusted rates. Those skilled in the art will appreciate that a placebo adjusted rate adjusts the efficacy results based on a placebo response rate.Diplopia

[0252] In some embodiments, diplopia Resolution is a reduction in Gorman Subjective Diplopia Score to 0 from baseline for participants with baseline Gorman Subjective Diplopia Score >0. In some embodiments, Diplopia Responder is a decrease of Gorman Subjective Diplopia Score by at least 1 from baseline for participants with baseline Gorman Subjective Diplopia Score >0.

[0253] In one aspect, the present invention provides, among other things, a method of treating TED comprising alleviating diplopia in a patient with TED. In some embodiments, aAttorney Docket No. VRD-025WO1 patient has a baseline Gorman Subjective Diplopia Score of >0, 1, 2, or 3. In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of 1. In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of 2. In some embodiments, the patient has a baseline Gorman Subjective Diplopia Score of 3.

[0254] In some embodiments, a method comprises achieving a reduction in Gorman Subjective Diplopia Score. In some embodiments, a method comprises achieving a reduction in Gorman Subjective Diplopia Score by at least 1. In some embodiments, a method comprises achieving a reduction in Gorman Subjective Diplopia Score by at least 2. In some embodiments, a method comprises achieving a reduction in Gorman Subjective Diplopia Score by at least 3.

[0255] In some embodiments, a method comprises achieving diplopia resolution. In some embodiments, diplopia resolution is measured by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline score of at least 1. In some embodiments, a method achieves at least 10% diplopia resolution rate. In some embodiments, a method achieves at least 15% diplopia resolution rate. In some embodiments, the treatment results in at least 18% diplopia resolution rate. In some embodiments, a method achieves at least 20% diplopia resolution rate. In some embodiments, a method achieves at least 25% diplopia resolution rate. In some embodiments, a method achieves at least 30% diplopia resolution rate. In some embodiments, a treatment period is sufficient to result in at least 32% diplopia resolution rate. In some embodiments, a method results in at least 35% diplopia resolution rate. In some embodiments, a method results in at least 40% diplopia resolution rate. In some embodiments, a method results in at least 40% diplopia resolution rate. In some embodiments, a method results in at least 45% diplopia resolution rate. In some embodiments, a method results in at least 50% diplopia resolution rate. In some embodiments, a method results in at least 55% diplopia resolution rate. In some embodiments, a method results in at least 60% diplopia resolution rate. In some embodiments, a method results in at least 65% diplopia resolution rate. In some embodiments, a method results in at least 70% diplopia resolution rate.

[0256] In some embodiments, a method achieves diplopia resolution within 3 weeks from the first administration. In some embodiments, a method achieves diplopia resolution within 6 weeks from the first administration. In some embodiments, a method achieves diplopia resolution within 9 weeks from the first administration.Attorney Docket No. VRD-025WO1

[0257] In some embodiments, diplopia resolution is maintained for at least 15 weeks. In some embodiments, diplopia resolution is maintained for at least 24 weeks. In some embodiments, diplopia resolution is maintained for at least 36 weeks. In some embodiments, diplopia resolution is maintained for at least 52 weeks.

[0258] In some embodiments, a method comprises achieving a diplopia response. In some embodiments, a diplopia response is a reduction in Gorman Subjective Diplopia score from a baseline of >0. In some embodiments, the treatment results in at least 15% diplopia response rate. In some embodiments, the treatment is sufficient to result in at least 20% diplopia response rate. In some embodiments, the treatment is sufficient to result in at least 25% diplopia response rate. In some embodiments, the treatment is sufficient to result in at least 30% diplopia response rate. In some embodiments, a method results in at least 30% diplopia response rate. In some embodiments, the treatment results in at least 31% diplopia response rate. In some embodiments, a method results in at least 35% diplopia response rate. In some embodiments, a method results in at least 40% diplopia response rate. In some embodiments, a method results in at least 40% diplopia response rate. In some embodiments, a method results in at least 42% diplopia response rate. In some embodiments, a method results in at least 45% diplopia response rate. In some embodiments, a method results in at least 50% diplopia response rate. In some embodiments, a method results in at least 55% diplopia response rate. In some embodiments, a treatment period is sufficient to result in at least 56% diplopia response rate. In some embodiments, a method results in at least 60% diplopia response rate. In some embodiments, a method results in at least 65% diplopia response rate. In some embodiments, a method results in at least 70% diplopia response rate.

[0259] In some embodiments, a method achieves diplopia response within 3 weeks from the first administration.

[0260] In some embodiments, a method achieves diplopia response within 6 weeks from the first administration. In some embodiments, a method achieves diplopia response within 9 weeks from the first administration.

[0261] In some embodiments, diplopia responder rate is maintained for at least 15 weeks. In some embodiments, diplopia responder rate is maintained for at least 24 weeks. In some embodiments, diplopia responder rate is maintained for at least 36 weeks. In some embodiments, diplopia responder rate is maintained for at least 52 weeks.

[0262] In some embodiments, at least 30% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 40% ofAttorney Docket No. VRD-025WO1 patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 50% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 60% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 70% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 80% of patients achieving diplopia response at week 15 maintain diplopia response at week 24. In some embodiments, at least 90% of patients achieving diplopia response at week 15 maintain diplopia response at week 24.

[0263] In some embodiments, at least 30% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 40% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 50% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 60% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 70% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 80% of patients achieving diplopia response at week 15 maintain diplopia response at week 36. In some embodiments, at least 90% of patients achieving diplopia response at week 15 maintain diplopia response at week 36.

[0264] In some embodiments, at least 30% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 40% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 50% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 60% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 70% of patients achieving diplopia response at week 15 maintain diplopia response at week 52. In some embodiments, at least 80% of patients achieving diplopia response at week 15 maintain diplopia response at week 52.Proptosis

[0265] As used herein, the term “proptosis” refers to the forward projection, displacement, bulging, or protrusion of the eye anteriorly out of the orbit. Owing to the rigid bony structure of the orbit with only anterior opening for expansion, any increase in orbital soft tissue contents taking place from the side or from behind will displace the eyeballAttorney Docket No. VRD-025WO1 forward, inflammations, tumors, trauma, metastases, endocrine lesions, vascular diseases & extra orbital lesions.

[0266] In some embodiments, a method comprises achieving a proptosis response. In some embodiments, a proptosis responder is a reduction of proptosis of > 2 mm from baseline in the study eye (without a corresponding increase of > 2 mm in the fellow eye). In some embodiments, proptosis responder rate is determined by a reduction of proptosis of >1 mm from baseline. In some embodiments, proptosis responder rate is determined by a reduction of proptosis of >3 mm from baseline.

[0267] In some embodiments, a patient had baseline proptosis of > 16 mm. In some embodiments, a patient had baseline proptosis of > 20 mm. In some embodiments, a patient had baseline proptosis of <20 mm. In some embodiments, a method results in at least 30% proptosis response. I n some embodiments, the treatment is sufficient to result in at least 35% proptosis responder rate. In some embodiments, a method results in at least 40% proptosis response. In some embodiments, a method results in at least 45% proptosis response. In some embodiments, the treatment results in at least 48% proptosis responder rate. In some embodiments, a method results in at least 50% proptosis response. In some embodiments, a method results in at least 55% proptosis response. In some embodiments, the treatment results in at least 56% proptosis responder rate. In some embodiments, a method results in at least 60% proptosis response. In some embodiments, a method results in at least 65% proptosis response. In some embodiments, a method results in at least 70% proptosis response. In some embodiments, a method results in at least 75% proptosis response.

[0268] In some embodiments, a method achieves proptosis response within 3 weeks from the first administration. In some embodiments, a method achieves proptosis response within 6 weeks from the first administration. In some embodiments, a method achieves proptosis response within 9 weeks from the first administration. In some embodiments, proptosis responder rate is maintained for at least 15 weeks. In some embodiments, proptosis responder rate is maintained for at least 24 weeks. In some embodiments, proptosis responder rate is maintained for at least 36 weeks. In some embodiments, proptosis responder rate is maintained for at least 52 weeks. In some embodiments, the percentage proptosis responder rate is a placebo-adjusted value.

[0269] In some embodiments, the treatment is sufficient to result in at least 30% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at leastAttorney Docket No. VRD-025WO140% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 45% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 48% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 50% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 55% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 56% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 60% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 65% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline. In some embodiments, the treatment results in at least 70% proptosis responder rate, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline.

[0270] In some embodiments, at least 30% of patients achieving proptosis response at week 15 maintain proptosis response at week 24. In some embodiments, at least 40% of patients achieving proptosis response at week 15 maintain proptosis response at week 24. In some embodiments, at least 50% of patients achieving proptosis response at week 15 maintain proptosis response at week 24. In some embodiments, at least 60% of patients achieving proptosis response at week 15 maintain proptosis response at week 24. In some embodiments, at least 70% of patients achieving proptosis response at week 15 maintain proptosis response at week 24. In some embodiments, at least 80% of patients achieving proptosis response at week 15 maintain proptosis response at week 24. In some embodiments, at least 90% of patients achieving proptosis response at week 15 maintain proptosis response at week 24.

[0271] In some embodiments, at least 30% of patients achieving proptosis response at week 15 maintain proptosis response at week 36. In some embodiments, at least 40% of patients achieving proptosis response at week 15 maintain proptosis response at week 36. InAttorney Docket No. VRD-025WO1 some embodiments, at least 50% of patients achieving proptosis response at week 15 maintain proptosis response at week 36. In some embodiments, at least 60% of patients achieving proptosis response at week 15 maintain proptosis response at week 36. In some embodiments, at least 70% of patients achieving proptosis response at week 15 maintain proptosis response at week 36. In some embodiments, at least 80% of patients achieving proptosis response at week 15 maintain proptosis response at week 36. In some embodiments, at least 90% of patients achieving proptosis response at week 15 maintain proptosis response at week 36.

[0272] In some embodiments, at least 30% of patients achieving proptosis response at week 15 maintain proptosis response at week 52. In some embodiments, at least 40% of patients achieving proptosis response at week 15 maintain proptosis response at week 52. In some embodiments, at least 50% of patients achieving proptosis response at week 15 maintain proptosis response at week 52. In some embodiments, at least 60% of patients achieving proptosis response at week 15 maintain proptosis response at week 52. In some embodiments, at least 70% of patients achieving proptosis response at week 15 maintain proptosis response at week 52. In some embodiments, at least 80% of patients achieving proptosis response at week 15 maintain proptosis response at week 52. In some embodiments, at least 90% of patients achieving proptosis response at week 15 maintain proptosis response at week 52.

[0273] In some embodiments, the treatment is sufficient to achieve an overall response, wherein the overall response is determined by achieving a >2 mm reduction in proptosis and >2-point reduction in CAS from baseline in the study eye. In some embodiments, the treatment is sufficient to result in at least 30% overall responder rate. In some embodiments, the treatment is sufficient to result in at least 35% overall responder rate. In some embodiments, the treatment is sufficient to result in at least 40% overall responder rate. In some embodiments, the treatment is sufficient to result in at least 45% overall responder rate. In some embodiments, the treatment is sufficient to result in at least 49% overall responder rate. In some embodiments, the treatment is sufficient to result in at least 50% overall responder rate. In some embodiments, the treatment is sufficient to result in at least 55% overall responder rate. In some embodiments, the treatment is sufficient to result in at least 60% overall responder rate. In some embodiments, the reduction in proptosis of overall responder rate is measured by Hertel exophthalmometer. In some embodiments, the reduction in proptosis of overall responder rate is measured by MRI or CT. In someAttorney Docket No. VRD-025WO1 embodiments, the reduction in proptosis of overall responder rate is measured by Hertel exophthalmometer, MRI, or CT. In some embodiments, a patient achieves an overall response without a corresponding deterioration >2 mm increase in proptosis or 2 point increase in CAS in the fellow eye. In some embodiments, the percentage overall responder rate is a placebo adjusted value.

[0274] In some embodiments, a method comprises achieving a reduction in proptosis as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 1.0 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 1.5 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 2.0 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 2.3 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 2.5 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 3.0 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 3.5 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 4.0 mm as compared to baseline. In some embodiments, the treatment is sufficient to result in a reduction of proptosis of at least 4.5 mm as compared to baseline. In some embodiments, a method achieves a reduction in proptosis within 3 weeks from the first administration. In some embodiments, a method achieves a reduction in proptosis within 6 weeks from the first administration. In some embodiments, a method achieves a reduction in proptosis within 9 weeks from the first administration. In some embodiments, proptosis reduction is maintained for at least 15 weeks.

[0275] In some embodiments, the reduction of proptosis is measured by Hertel exophthalmometer. In some embodiments, the reduction of proptosis is measured by magnetic resonance imaging (MRI) or computed tomography (CT). In some embodiments, the reduction of proptosis is measured by Hertel exophthalmometer, MRI, or CT.Clinical Activity Score (CAS)

[0276] The Clinical Activity Score (CAS) was devised as a measure of disease activity and a potential predictor of response to anti-inflammatory treatment. The CAS is based on seven components. Each component is scored as present or absent (scored as 1 or 0,Attorney Docket No. VRD-025WO1 respectively), and the CAS is given as the sum of the scores (range, 0 to 7, with higher scores indicating greater level of inflammation).

[0277] In some embodiments, the treatment is sufficient to result in a reduction of CAS of >1 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >2 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >2.5 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >2.9 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >3 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >4 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >5 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >6 from baseline. In some embodiments, the treatment is sufficient to result in a reduction of CAS of >7 from baseline.

[0278] In some embodiments, change from baseline is the post-baseline value - baseline value.

[0279] In some embodiments, a method comprises reducing CAS score as compared to baseline. In some embodiments, a method results in a reduction of CAS of >1. In some embodiments, a method results in a reduction of CAS of >2. In some embodiments, a method results in a reduction of CAS of >2.5. In some embodiments, a method results in a reduction of CAS of >2.9. In some embodiments, a method results in a reduction of CAS of >3. In some embodiments, a method results in a reduction of CAS of >4. In some embodiments, a method results in a reduction in CAS within 3 weeks of the first administration. In some embodiments, a method results in a reduction in CAS within 6 weeks of the first administration. In some embodiments, a method results in a reduction in CAS within 9 weeks of the first administration. In some embodiments, CAS reduction is maintained for at least 15 weeks. In some embodiments, a method comprises result in a CAS score of 0 or 1, wherein the patient at baseline has a CAS score of >1.

[0280] In some embodiments, the treatment is sufficient to result in a CAS of 0 or 1 for patients with a baseline CAS of >1. In some embodiments, the treatment is sufficient to result in a CAS of 0 or 1 for patients with a baseline CAS of >3. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 10%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 15%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 20%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 25%.Attorney Docket No. VRD-025WO1In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 30%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 35%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 40%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 45%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 50%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 55%. In some embodiments, the rate of achieving a CAS of 0 or 1 is at least 60%.

[0281] In some embodiments, a CAS of 0 or 1 is maintained for at least is maintained for at least 6 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 9 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 12 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 15 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 18 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 21 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 24 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 27 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 30 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 36 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 52 weeks. In some embodiments, a CAS of 0 or 1 is maintained for at least 4 months. In some embodiments, a CAS of 0 or 1 is maintained for at least 5 months. In some embodiments, a CAS of 0 or 1 is maintained for at least 6 months. In some embodiments, a CAS of 0 or 1 is maintained for at least 7 months. In some embodiments, a CAS of 0 or 1 is maintained for at least 8 months. In some embodiments, a CAS of 0 or 1 is maintained for at least 9 months. In some embodiments, a CAS of 0 or 1 is maintained for at least 10 months. In some embodiments, a CAS of 0 or 1 is maintained for at least 12 months.

[0282] In some embodiments, at least 50% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 55% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 60% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 65% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 70% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 75% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 80% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 85% ofAttorney Docket No. VRD-025WO1 patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 24. In some embodiments, at least 90% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 24.

[0283] In some embodiments, at least 50% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 55% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 60% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 65% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 70% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 75% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 80% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 85% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 36. In some embodiments, at least 90% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 36.

[0284] In some embodiments, at least 50% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 55% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 60% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 65% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 70% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 75% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 80% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 85% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 52. In some embodiments, at least 90% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 52.Fibrosis

[0285] In some embodiments, methods described herein can treat fibrosis (e.g., ocular fibrosis). In some embodiments, the treatment is sufficient to result in an alleviation ofAttorney Docket No. VRD-025WO1 fibrosis (e.g., ocular fibrosis). In some embodiments, the treatment is sufficient to result in a reversal in fibrosis (e.g., ocular fibrosis). In some embodiments, the treatment is sufficient to prevent fibrosis or prevent further fibrosis (e.g., ocular fibrosis). In some embodiments, the alleviation and / or reversal in ocular fibrosis results in an improvement in vision. In some embodiments, the alleviation and / or reversal in ocular fibrosis is sufficient to result in no further deterioration in vision or no worsening of symptoms (e.g., preservation of vision or no further vision loss or impairment). In some embodiments, the treatment of ocular fibrosis is sufficient to result in improvements in diplopia and / or proptosis (e.g., as described herein). In some embodiments, the fibrosis (e.g., ocular fibrosis) is associated with or results from inflammation. In some embodiments, the fibrosis (e.g., ocular fibrosis) is associated with or results from an autoimmune disorder. In some embodiments, the fibrosis (e.g., ocular fibrosis) is associated with or results from thyroid eye disease. In some embodiments, ocular fibrosis is fibrosis that develops around the extraocular muscles. In some embodiments, the fibrosis (e.g., ocular fibrosis) follows an inflammatory period of TED (e.g., fibrosis following active TED or following an inflammatory flare-up in a patient having chronic and / or inactive TED). One skilled in the art will appreciate that a variety of methods well-known in the art nay be used to assess changes in fibrosis (e.g., ocular fibrosis), including biopsy followed by staining or via imaging techniques (e.g., computed tomography (CT) or magnetic resonance imaging (MRI)). Still other methods of diagnosing and / or characterizing fibrosis (e.g., ocular fibrosis) include dye-based angiography, optical coherence tomography (OCT), and OCT angiography (OCTA). Fibrosis may also be assessed using levels of inflammatory or fibrotic factors. In some embodiments, the fibrosis is assessed through one or more of analysis of adenosine monophosphate-activated protein kinase (AMPK), fibronectin, alpha- SM A, and collagen staining.Orbital Fat

[0286] Orbital fat volume can be measured by imaging of the head to facilitate three- dimensional volumetric calculations. Images can be taken at baseline and various timepoints post treatment to assess the change in volume. Imaging may utilize T1 / T2 high resolution with 1 mm slices and thickness of orbits, face and ears without contrast. In some embodiments, orbital fat is measured from MRI and CT scans. In some embodiments, orbital fat is measured from an MRI. In some embodiments, orbital fat is measured from CT scans.Attorney Docket No. VRD-025WO1

[0287] In some embodiments, administrating an anti-IGF-lR antibody results in an improvement in orbital fat volume as compared to a baseline.

[0288] In some embodiments, the orbital fat volume is reduced by 2000-15,000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by 5000-10,000 pL as compared to a baseline.

[0289] In some embodiments, the orbital fat volume is reduced by at least 2000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 2500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 3000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 3500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 4000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 4500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 5000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 5500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 6000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least6500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 7000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 7500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 8000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 8500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 9000 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 9500 pL as compared to a baseline. In some embodiments, the orbital fat volume is reduced by at least 10,000 pL as compared to a baseline.

[0290] In some embodiments, an improvement in orbital fat volume is a reduction in volume as compared to baseline. In some embodiments, a method results in at least a 5% reduction in orbital fat volume. In some embodiments, a method results in at least a 10% reduction in orbital fat volume. In some embodiments, a method results in at least a 15% reduction in orbital fat volume. In some embodiments, a method results in at least a 20% reduction in orbital fat volume. In some embodiments, a method results in at least a 25% reduction in orbital fat volume. In some embodiments, a method results in at least a 30% reduction in orbital fat volume. In some embodiments, a method results in at least a 35%Attorney Docket No. VRD-025WO1 reduction in orbital fat volume. In some embodiments, a method results in at least a 40% reduction in orbital fat volume. In some embodiments, a method results in at least a 45% reduction in orbital fat volume. In some embodiments, a method results in at least a 50% reduction in orbital fat volume.

[0291] In some embodiments, a reduction in orbital fat volume is achieved within 3 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, a reduction in orbital fat volume is achieved within 6 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, a reduction in orbital fat volume is achieved within 9 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, a reduction in orbital fat volume is achieved within 12 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, a reduction in orbital fat volume is achieved within 15 weeks from the first administration of the anti-IGF-lR antibody.

[0292] In some embodiments, a reduction in orbital fat volume is maintained for at least 6 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 9 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 12 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 15 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 18 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 21 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 24 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 27 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 30 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 36 weeks. In some embodiments, a reduction in orbital fat volume is maintained for at least 52 weeks.Extraocular Muscles

[0293] Proptosis caused by expansion of extraocular muscles is type 2 orbitopathy. Extraocular muscle volume can be measured by imaging of the head to facilitate three- dimensional volumetric calculations. Images can be taken at baseline and various timepoints post treatment to assess the change in volume. Imaging may utilize T1 / T2 high resolution with 1 mm slices and thickness of orbits, face and ears without contrast. In some embodiments, extraocular muscle volume is assessed as the total rectus muscle volumes. In someAttorney Docket No. VRD-025WO1 embodiments, extraocular muscles are measured from MRI and CT scans. In some embodiments, extraocular muscles are measured from an MRI. In some embodiments, extraocular muscles are measured from CT scans.

[0294] In some embodiments, administrating an anti-IGF-lR antibody results in an improvement in extraocular muscle volume as compared to a baseline.

[0295] In some embodiments, the extraocular muscle volume is reduced by 1000- 5000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by 1500-3000 pL as compared to a baseline.

[0296] In some embodiments, the extraocular muscle volume is reduced by at least 500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 1,000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 1,500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 2,000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 2,500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 3,000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 3,500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 4,000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 4,500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 5,000 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 5,500 pL as compared to a baseline. In some embodiments, the extraocular muscle volume is reduced by at least 6,000 pL as compared to a baseline.

[0297] In some embodiments, a method results in at least a 5% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 10% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 15% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 20% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 25% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 30% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 35% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 40% reduction in extraocular muscle volume. InAttorney Docket No. VRD-025WO1 some embodiments, a method results in at least a 45% reduction in extraocular muscle volume. In some embodiments, a method results in at least a 50% reduction in extraocular muscle volume.

[0298] In some embodiments, a reduction in extraocular muscle volume is achieved within 3 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, a reduction in extraocular muscle volume is achieved within 6 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, a reduction in extraocular muscle volume is achieved within 9 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, a reduction in extraocular muscle volume is achieved within 12 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, a reduction in extraocular muscle volume is achieved within 15 weeks from the first administration of the anti-IGF-lR antibody.

[0299] In some embodiments, a reduction in extraocular muscle volume is maintained for at least 6 weeks. In some embodiments, a reduction in extraocular muscle volume is maintained for at least 9 weeks. In some embodiments, a reduction in extraocular muscle volume is maintained for at least 12 weeks. In some embodiments, a reduction in extraocular muscle volume is maintained for at least 15 weeks. In some embodiments, a reduction in extraocular muscle volume is maintained for at least 18 weeks. In some embodiments, a reduction in extraocular muscle volume is maintained for at least 21 weeks. In some embodiments, a reduction in extraocular muscle volume is maintained for at least 24 weeks. In some embodiments, a reduction in extraocular muscle volume is maintained for at least 27 weeks. In some embodiments, a reduction in extraocular muscle volume is maintained for at least 30 weeks. In some embodiments, a reduction in extraocular muscle volume is maintained for at least 36 weeks. In some embodiments, a reduction in extraocular muscle volume is maintained for at least 52 weeks.Quality of Life

[0300] In some embodiments, patient quality of life is improved following administration of the anti-IGF-lR antibody.

[0301] In some embodiments, patient quality of life is assessed using the Graves’ Orbitopathy - Quality of Life Measurement (GO-QoL). GO-QoL can be assessed via a questionnaire. The questionnaire has two self-assessment subscales; one covering the impact of visual function on daily activities (activity subscale score), and the other assessing theAttorney Docket No. VRD-025WO1 impact of self-perceived appearance (appearance subscale score). Each subscale has 8 questions on visual functioning / activity and appearance (i.e., psychosocial functioning related to changed physical appearance) which are scored 1-3 and the total raw score is then mathematically transformed to a 0-100 scale, where 0 represents the most negative impact on quality of life, and 100 represents no impact. The combined score takes raw scores from both subscales and again transforms them to a single 0-100 scale. A change of 8 points or greater on an individual subscale or the combined score on the 0-100 scale has been shown to be clinically meaningful.

[0302] In some embodiments, a patient has a GO-QOL combined score of <92 at baseline. In some embodiments, a method results in a >8 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >10 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >12 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >14 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >16 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >18 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >20 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >30 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >40 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >50 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >60 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >70 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >80 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a >90 point improvement in GO-QOL combined score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL combined score as compared to baseline.

[0303] In some embodiments, a patient has a GO-QOL activity subscale score of <92 at baseline. In some embodiments, a method results in a >8 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in aAttorney Docket No. VRD-025WO1>10 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >12 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >14 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >16 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >18 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >20 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >30 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >40 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >50 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >60 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >70 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >80 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a >90 point improvement in GO-QOL activity subscale score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL activity subscale score as compared to baseline.

[0304] In some embodiments, a patient has a GO-QOL appearance subscore score of <92 at baseline. In some embodiments, a method results in a >8 point improvement in GO- QOL appearance subscale score. In some embodiments, a method results in a >10 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >12 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >14 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >16 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >18 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >20 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >30 pointAttorney Docket No. VRD-025WO1 improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >40 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >50 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >60 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >70 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >80 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a >90 point improvement in GO-QOL appearance subscale score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL appearance subscale score as compared to baseline.

[0305] In some embodiments, a method results in a >8 point improvement in GO- QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >10 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >12 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >14 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >16 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >18 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >20 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >30 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >40 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >50 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >60 point improvement in GO-QOLAttorney Docket No. VRD-025WO1 combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >70 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >80 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a >90 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline. In some embodiments, a method results in a 100 point improvement in GO-QOL combined score, activity subscale score, and appearance subscale score as compared to baseline.

[0306] In some embodiments, an improvement in GO-QOL is achieved within 3 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is achieved within 6 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is achieved within 9 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, an improvement in GO-QOL is achieved within 12 weeks from the first administration of the anti-IGF-lR antibody. In some embodiments, an improvement in GO- QOL is achieved within 15 weeks from the first administration of the anti-IGF-lR antibody.

[0307] In some embodiments, an improvement in GO-QOL is maintained for at least 6 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 9 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 12 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 15 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 18 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 21 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 24 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 27 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 30 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 36 weeks. In some embodiments, an improvement in GO-QOL is maintained for at least 52 weeks.

[0308] In some embodiments, patient quality of life is assessed using the EUROQOL Questionnaire Version EQ-5D-5L. The EQ-5D-5L is a 5-level version which is made up of a 2 page questionnaire that consists of the EQ-5D descriptive system and the EQ visualAttorney Docket No. VRD-025WO1 analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self- care, usual activities, pain / discomfort and anxiety / depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient may assess his / her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1 -digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient’s health state. The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale, where the endpoints are labelled ‘The best health you can imagine’ and ‘The worst health you can imagine’. The VAS can be used as a quantitative measure of health outcome that reflect the patient’s own judgement. In some embodiments, a method results in an improvement in EQ-5D-5L assessment as compared to baseline.Adverse Events

[0309] In some embodiments, a method of the present invention provides a safer method of treating TED in a patient by minimizing adverse events. In some embodiments, a method of treating TED described herein results in a low incidence rate of severe adverse events. In some embodiments, a method of treating TED described herein results in a low incidence rate of adverse events. In some embodiments, a method of treating TED described herein results in substantially no adverse events.

[0310] In some embodiments, the administration of the anti-IGF-lR antibody does not result in hyperglycemia. In some embodiments, the administrating of the anti-IGF-lR antibody results in a hyperglycemia incidence of less than 15%. In some embodiments, the administrating of the anti-IGF-lR antibody results in a hyperglycemia incidence of less than 12%. In some embodiments, the administrating of the anti-IGF-lR antibody results in a hyperglycemia incidence of less than 10%. In some embodiments, the administrating of the anti-IGF-lR antibody results in a hyperglycemia incidence of less than 8%. In some embodiments, the administrating of the anti-IGF-lR antibody results in a hyperglycemia incidence of less than 7%. In some embodiments, the administrating of the anti-IGF-lR antibody results in a hyperglycemia incidence of less than 6%. In some embodiments, the administrating of the anti-IGF-lR antibody results in a hyperglycemia incidence of less than 5.5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in a hyperglycemia incidence of less than 5%. In some embodiments, the administrating of theAttorney Docket No. VRD-025WO1 anti-IGF-lR antibody results in a hyperglycemia incidence of less than 4%. In some embodiments, the administrating of the anti-IGF-lR antibody results in a hyperglycemia incidence of less than 3%.

[0311] In some embodiments, the treatment results in no incidence of anti-drug antibody (ADA). In some embodiments, the treatment results in no incidence of anti-drug antibody (ADA) after at least 15 weeks. In some embodiments, the treatment results in substantially no incidence of anti -drug antibody (ADA). In some embodiments, the treatment results in substantially no incidence of anti-drug antibody (ADA) after at least 15 weeks. In some embodiments, the treatment results in substantially no incidence of anti-drug antibody (ADA) as compared to placebo. In some embodiments, the treatment results in substantially no incidence of anti -drug antibody (ADA) as compared to placebo after at least 15 weeks.Hearing Impairment

[0312] Hearing impairment or loss is a common side effect of therapies with the IGF- 1R inhibitors or antibodies. Particularly, according to public information, a treatment with the reference anti-IGF-lR antibody shown in Table 8 resulted in hearing loss (n=6, 23 percent), tinnitus, or ringing in the ears (n=7, 27 percent), ear plugging sensation (n=3, 12 percent), and autophony, an unusually loud hearing of a person’s own voice (29 percent). Kossler, A. L. March 20, 2021, Increased risk of hearing impairment with new thyroid eye disease treatment. Endocrine Society.

[0313] The present invention is based, in part, on a finding that the dosing regimen and the treatment period disclosed herein is effective in reducing one or more symptoms associated with TED while keeping the hearing impairment incidence low.

[0314] In some embodiments, the administrating of the anti-IGF-lR antibody results in the hearing impairment incidence of less than 15%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hearing impairment incidence of less than 12%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hearing impairment incidence of less than 10%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hearing impairment incidence of less than 8%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hearing impairment incidence of less than 7%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hearing impairment incidence ofAttorney Docket No. VRD-025WO1 less than 6%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hearing impairment incidence of less than 5.5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hearing impairment incidence of less than 5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hearing impairment incidence of less than 4%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hearing impairment incidence of less than 3%.

[0315] In some embodiments, the percentage of hearing impairment incidence is a placebo-adjusted value. In some embodiments, a placebo-adjusted value is determined by the difference between the value from the treatment arm and the value from the placebo arm.

[0316] In some embodiments, the percentage hearing impairment is measured by number of patients with at least one of the following hearing impairments: autophony, deafness neurosensory, hypoacusis, or tinnitus.

[0317] In some embodiments, the administrating of the anti-IGF-lR antibody results in the autophony incidence of less than 10%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the autophony incidence of less than 8%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the autophony incidence of less than 6%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the autophony incidence of less than 5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the autophony incidence of less than 4%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the autophony incidence of less than 3%. In some embodiments, the administrating of the anti- IGF-1R antibody results in the autophony incidence of less than 2.5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the autophony incidence of less than 2%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the autophony incidence of less than 1.5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the autophony incidence of less than 1%. In some embodiments, the administrating of the anti-IGF-lR antibody results in substantially 0% of the autophony incidence.

[0318] In some embodiments, the administrating of the anti-IGF-lR antibody results in the deafness neurosensory incidence of less than 10%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the deafness neurosensory incidence of less than 8%. In some embodiments, the administrating of the anti-IGF-lR antibody resultsAttorney Docket No. VRD-025WO1 in the deafness neurosensory incidence of less than 6%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the deafness neurosensory incidence of less than 5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the deafness neurosensory incidence of less than 4%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the deafness neurosensory incidence of less than 3%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the deafness neurosensory incidence of less than 2.5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the deafness neurosensory incidence of less than 2%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the deafness neurosensory incidence of less than 1.5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the deafness neurosensory incidence of less than 1%. In some embodiments, the administrating of the anti-IGF-lR antibody results in substantially 0% of the deafness neurosensory incidence.

[0319] In some embodiments, the administrating of the anti-IGF-lR antibody results in the hypoacusis incidence of less than 10%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hypoacusis incidence of less than 8%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hypoacusis incidence of less than 6%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hypoacusis incidence of less than 5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hypoacusis incidence of less than 4%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hypoacusis incidence of less than 3%. In some embodiments, the administrating of the anti- IGF-1R antibody results in the hypoacusis incidence of less than 2.5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hypoacusis incidence of less than 2%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hypoacusis incidence of less than 1.5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the hypoacusis incidence of less than 1%. In some embodiments, the administrating of the anti-IGF-lR antibody results in substantially 0% of the hypoacusis incidence.

[0320] In some embodiments, the administrating of the anti-IGF-lR antibody results in the tinnitus incidence of less than 10%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the tinnitus incidence of less than 8%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the tinnitus incidence of less thanAttorney Docket No. VRD-025WO16%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the tinnitus incidence of less than 5%. In some embodiments, the administrating of the anti-IGF- 1R antibody results in the tinnitus incidence of less than 4%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the tinnitus incidence of less than 3%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the tinnitus incidence of less than 2.5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the tinnitus incidence of less than 2%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the tinnitus incidence of less than 1.5%. In some embodiments, the administrating of the anti-IGF-lR antibody results in the tinnitus incidence of less than 1%. In some embodiments, the administrating of the anti-IGF-lR antibody results in substantially 0% of the tinnitus incidence.

[0321] In some embodiments, a hearing impairment incidence in a patient is resolved by week 12. In some embodiments, a hearing impairment incidence in a patient is resolved by week 15. In some embodiments, a hearing impairment incidence in a patient is resolved by week 18. In some embodiments, a hearing impairment incidence in a patient is resolved by week 21. In some embodiments, a hearing impairment incidence in a patient is resolved by week 24.

[0322] In some embodiments, hearing impairment is measured by audiometry. In some embodiments, a hearing impairment is measured by air conduction audiometry with the addition of extended high frequency testing (10,000 - 16,000 Hz). In some embodiments, hearing impairment is measured by hearX® hearTest. In some embodiments, hearing impairment is determined by measuring pure tone average (PTA) at 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz. In some embodiments, hearing impairment is determined by measuring pure tone average (PTA) at 500 Hz. In some embodiments, hearing impairment is determined by measuring pure tone average (PTA) at 1000 Hz. In some embodiments, hearing impairment is determined by measuring pure tone average (PTA) at 2000 Hz. In some embodiments, hearing impairment is determined by measuring pure tone average (PTA) at 4000 Hz. In some embodiments, PTA is determined by the average of hearing thresholds at frequencies of 500 to 4000 Hz. In some embodiments, PTA is determined by the average of hearing thresholds at 500, 1000, 2000, and 4000 Hz.

[0323] In some embodiments, the administrating of the anti-IGF-lR antibody does not increase PTA of a patient. In some embodiments, the administrating of the anti-IGF-lR antibody results in PTA of 25dB or less, which is considered normal for speech.Attorney Docket No. VRD-025WO1

[0324] In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 15 dB. In some embodiments, the administrating of the anti-IGF- 1R antibody results in a PTA shift by less than 14 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 13 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 12 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 11 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 10 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 9 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 8 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 7 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 6 dB. In some embodiments, the administrating of the anti-IGF- 1R antibody results in a PTA shift by less than 5 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 4 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 3 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 2 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in a PTA shift by less than 1 dB. In some embodiments, the administrating of the anti-IGF-lR antibody results in substantially no PTA shift.

[0325] In some embodiments, hearing impairment is measured at base line. In some embodiments, hearing impairment is measured every week. In some embodiments, hearing impairment is measured every two weeks. In some embodiments, hearing impairment is measured every three weeks. In some embodiments, hearing impairment is measured every four weeks. In some embodiments, hearing impairment is measured every five weeks. In some embodiments, hearing impairment is measured every six weeks. In some embodiments, hearing impairment is measured every seven weeks. In some embodiments, hearing impairment is measured every eight weeks. In some embodiments, hearing impairment is measured every nine weeks. In some embodiments, hearing impairment is measured every ten weeks.Attorney Docket No. VRD-025WO1Enumerated Embodiments

[0326] Embodiment 1. A method of treating chronic thyroid eye disease (TED) comprising administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

[0327] Embodiment 2. The method of embodiment 1, wherein the patient has a baseline Gorman Subjective Diplopia Score of >0, 1, 2, or 3.

[0328] Embodiment 3. The method of embodiment 2, wherein the treatment is sufficient to result in a reduction of diplopia in the patient.

[0329] Embodiment 4. The method of embodiment 2 or 3, wherein the treatment is sufficient to result in a reduction of Gorman Subject Diplopia Score as compared to baseline.

[0330] Embodiment 5. The method of any one of embodiments 2-4, wherein the treatment is sufficient to result in a reduction of Gorman Subject Diplopia Score of at least 1, at least 2, or at least 3 compared to baseline.

[0331] Embodiment 6. The method of embodiment 1 or 2, wherein the diplopia is resolved in the treated patient.

[0332] Embodiment 7. The method of any one of embodiments 2-6, wherein the treatment is sufficient to result in at least 20% diplopia response rate, wherein diplopia response is determined by a reduction of Gorman Subject Diplopia Score by at least 1.

[0333] Embodiment 8. The method of any one of embodiments 2-7, wherein the treatment is sufficient to result in at least 30% diplopia response rate, wherein diplopia response is determined by a reduction of Gorman Subject Diplopia Score by at least 1.

[0334] Embodiment 9. The method of embodiment 7 or 8, wherein the percentage diplopia response rate is a placebo-adjusted value.

[0335] Embodiment 10. The method of any one of embodiments 3-9, wherein the diplopia reduction is maintained for a least 12 weeks, or at least 15 weeks.Attorney Docket No. VRD-025WO1

[0336] Embodiment 11. The method of any one of embodiments 3-10, wherein at least 30% of patients achieving diplopia response at week 15 maintain diplopia response at week 52.

[0337] Embodiment 12. The method of any one of embodiments 2-11, wherein the anti-IGF-lR antibody is administered for a treatment period sufficient to result in diplopia resolution, wherein diplopia resolution is determined by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline score of at least 1.

[0338] Embodiment 13. The method of embodiment 12, wherein the anti-IGF-lR antibody is administered for a treatment period sufficient to result in at least 15% diplopia resolution rate, wherein diplopia resolution is determined by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline score of at least 1.

[0339] Embodiment 14. The method of embodiment 13, wherein the percentage diplopia resolution rate is a placebo-adjusted value.

[0340] Embodiment 15. The method of any one of embodiments 12-14, wherein the diplopia resolution is maintained for least 12 weeks, or at least 15 weeks.

[0341] Embodiment 16. The method of any one of embodiments 12-15, wherein the diplopia resolution is maintained for at least 15 weeks.

[0342] Embodiment 17. The method of any one of embodiments 12-16, wherein at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 24.

[0343] Embodiment 18. The method of any one of embodiments 12-16, wherein at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 36.

[0344] Embodiment 19. The method of any one of embodiments 12-16, wherein at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 52.

[0345] Embodiment 20. The method of any one of embodiments 12-19, wherein at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 52.

[0346] Embodiment 21. The method of embodiment 1, wherein the treatment is sufficient to result in at least 35% proptosis responder rate.

[0347] Embodiment 22. The method of embodiment 1 or 21, wherein the treatment is sufficient to result in at least 40% proptosis responder rate.Attorney Docket No. VRD-025WO1

[0348] Embodiment 23. The method of any one of embodiments 1 and 21-22, wherein the treatment is sufficient to result in at least 45% proptosis responder rate.

[0349] Embodiment 24. The method of any one of embodiments 1 and 21-23, wherein the treatment is sufficient to result in at least 48% proptosis responder rate.

[0350] Embodiment 25. The method of any one of embodiments 1 and 21-24, wherein the treatment is sufficient to result in at least 55% proptosis responder rate.

[0351] Embodiment 26. The method of any one of embodiments 21-25, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline.

[0352] Embodiment 27. The method of embodiment 26, wherein the reduction of proptosis is measured by Hertel exophthalmometer.

[0353] Embodiment 28. The method of embodiment 26, wherein the reduction of proptosis is measured by magnetic resonance imaging (MRI) or computed tomography (CT).

[0354] Embodiment 29. The method of any one of embodiments 21-28, wherein the percentage proptosis responder rate is a placebo-adjusted value.

[0355] Embodiment 30. The method of any one of embodiments 21-29, wherein the proptosis response is maintained for at least 12 weeks, or at least 15 weeks.

[0356] Embodiment 31. The method of any one of embodiments 21-30, wherein the proptosis response is maintained for at least 15 weeks.

[0357] Embodiment 32. The method of any one of embodiments 21-31, wherein at least 30% of patients achieving proptosis response at week 15 maintain proptosis response at week 24.

[0358] Embodiment 33. The method of any one of embodiments 21-32, wherein at least 30% of patients achieving proptosis response at week 15 maintain proptosis response at week 36.

[0359] Embodiment 34. The method of any one of embodiments 21-33, wherein at least 30% of patients achieving proptosis response at week 15 maintain proptosis response at week 52.

[0360] Embodiment 35. The method of embodiment 1, wherein the treatment is sufficient to result in a reduction in proptosis of at least 1.0 mm as compared to baseline.

[0361] Embodiment 36. The method of embodiment 1 or 35, wherein the treatment is sufficient to result in a reduction in proptosi...

Claims

Attorney Docket No. VRD-025WO1CLAIMS1. A method of treating chronic thyroid eye disease (TED) comprising administering an anti-IGF-lR antibody to a patient at a dose of 10 mg / kg or less once every three weeks, or an equivalent dosing regimen thereof, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months, and wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 7, a HCDR2 having an amino acid sequence of SEQ ID NO: 8, and a HCDR3 having an amino acid sequence of SEQ ID NO: 9 and the light chain comprises a LCDR1 having an amino acid sequence of SEQ ID NO: 4, a LCDR2 having an amino acid sequence of SEQ ID NO: 5 and a LCDR3 having an amino acid sequence of SEQ ID NO: 6.

2. The method of claim 1, wherein the patient has a baseline Gorman Subjective Diplopia Score of >0, 1, 2, or 3.

3. The method of claim 2, wherein the treatment is sufficient to result in a reduction of diplopia in the patient.

4. The method of claim 2 or 3, wherein the treatment is sufficient to result in a reduction of Gorman Subject Diplopia Score as compared to baseline.

5. The method of any one of claims 2-4, wherein the treatment is sufficient to result in a reduction of Gorman Subject Diplopia Score of at least 1, at least 2, or at least 3 compared to baseline.

6. The method of claim 1 or 2, wherein the diplopia is resolved in the treated patient.

7. The method of any one of claims 2-6, wherein the treatment is sufficient to result in at least 20% diplopia response rate, wherein diplopia response is determined by a reduction of Gorman Subject Diplopia Score by at least 1.

8. The method of any one of claims 2-7, wherein the treatment is sufficient to result in at least 30% diplopia response rate, wherein diplopia response is determined by a reduction of Gorman Subject Diplopia Score by at least 1.

9. The method of claim 7 or 8, wherein the percentage diplopia response rate is a placebo-adjusted value.Attorney Docket No. VRD-025WO110. The method of any one of claims 3-9, wherein the diplopia reduction is maintained for a least 12 weeks, or at least 15 weeks.

11. The method of any one of claims 3-10, wherein at least 30% of patients achieving diplopia response at week 15 maintain diplopia response at week 52.

12. The method of any one of claims 2-11, wherein the anti-IGF-lR antibody is administered for a treatment period sufficient to result in diplopia resolution, wherein diplopia resolution is determined by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline score of at least 1.

13. The method of claim 12, wherein the anti-IGF-lR antibody is administered for a treatment period sufficient to result in at least 15% diplopia resolution rate, wherein diplopia resolution is determined by a reduction to a Gorman Subjective Diplopia Score of 0 compared to a baseline score of at least 1.

14. The method of claim 13, wherein the percentage diplopia resolution rate is a placebo- adjusted value.

15. The method of any one of claims 12-14, wherein the diplopia resolution is maintained for least 12 weeks, or at least 15 weeks.

16. The method of any one of claims 12-15, wherein the diplopia resolution is maintained for at least 15 weeks.

17. The method of any one of claims 12-16, wherein at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 24.

18. The method of any one of claims 12-16, wherein at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 36.

19. The method of any one of claims 12-16, wherein at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 52.

20. The method of any one of claims 12-19, wherein at least 30% of patients achieving diplopia resolution at week 15 maintain diplopia resolution at week 52.Attorney Docket No. VRD-025WO121. The method of claim 1, wherein the treatment is sufficient to result in at least 35% proptosis responder rate.

22. The method of claim 1 or 21, wherein the treatment is sufficient to result in at least 40% proptosis responder rate.

23. The method of any one of claims 1 and 21-22, wherein the treatment is sufficient to result in at least 45% proptosis responder rate.

24. The method of any one of claims 1 and 21-23, wherein the treatment is sufficient to result in at least 48% proptosis responder rate.

25. The method of any one of claims 1 and 21-24, wherein the treatment is sufficient to result in at least 55% proptosis responder rate.

26. The method of any one of claims 21-25, wherein the proptosis responder rate is determined by a reduction of proptosis of >2 mm from baseline.

27. The method of claim 26, wherein the reduction of proptosis is measured by Hertel exophthalmometer.

28. The method of claim 26, wherein the reduction of proptosis is measured by magnetic resonance imaging (MRI) or computed tomography (CT).

29. The method of any one of claims 21-28, wherein the percentage proptosis responder rate is a placebo-adjusted value.

30. The method of any one of claims 21-29, wherein the proptosis response is maintained for at least 12 weeks, or at least 15 weeks.

31. The method of any one of claims 21-30, wherein the proptosis response is maintained for at least 15 weeks.

32. The method of any one of claims 21-31, wherein at least 30% of patients achieving proptosis response at week 15 maintain proptosis response at week 24.

33. The method of any one of claims 21-32, wherein at least 30% of patients achieving proptosis response at week 15 maintain proptosis response at week 36.Attorney Docket No. VRD-025WO134. The method of any one of claims 21-33, wherein at least 30% of patients achieving proptosis response at week 15 maintain proptosis response at week 52.

35. The method of claim 1, wherein the treatment is sufficient to result in a reduction in proptosis of at least 1.0 mm as compared to baseline.

36. The method of claim 1 or 35, wherein the treatment is sufficient to result in a reduction in proptosis of at least 1.5 mm as compared to baseline.

37. The method of any one of claims 1 or 35-36, wherein the treatment is sufficient to result in a reduction in proptosis of at least 2.3 mm as compared to baseline.

38. The method of any one of claims 35-37, wherein the reduction of proptosis is measured by Hertel exophthalmometer.

39. The method of any one of claims 35-37, wherein the reduction of proptosis is measured by magnetic resonance imaging (MRI) or computed tomography (CT).

40. The method of any one of claims 29-39, wherein the reduction of proptosis is maintained for at least 12 week, or at least 15 weeks.

41. The method of any one of claims 29-40, wherein the reduction of proptosis is maintained for at least 15 weeks.

42. The method of any one of claims 29-40, wherein the reduction of proptosis is maintained for at least 24 weeks.

43. The method of any one of claims 29-40, wherein the reduction of proptosis is maintained for at least 36 weeks.

44. The method of any one of claims 29-40, wherein the reduction of proptosis is maintained for at least 52 weeks.

45. The method of any one of claims 1-44, wherein the patient has a baseline CAS <1.

46. The method of any one of claims 1-44, wherein the patient has a baseline CAS >3.Attorney Docket No. VRD-025WO147. The method of any one of claims 1 and 45-46, wherein the treatment is sufficient to result in a reduction in CAS of >1 from baseline.

48. The method of any one of claim 1 and 46-47, wherein the treatment is sufficient to result in a CAS of 0 or 1.

49. The method of claim 48, wherein the rate of achieving a CAS of 0 or 1 is at least 20%.

50. The method of claim 48, wherein the rate of achieving a CAS of 0 or 1 is at least 30%.

51. The method of any one of claims 48-50, wherein a CAS of 0 or 1 is maintained for at least 12 weeks, or at least 15 weeks.

52. The method of any one of claims 48-50, wherein a CAS of 0 or 1 is maintained for at least 15 weeks.

53. The method of any one of claims 48-50, wherein a CAS of 0 or 1 is maintained for at least 24 weeks.

54. The method of any one of claims 48-50, wherein a CAS of 0 or 1 is maintained for at least 36 weeks.

55. The method of any one of claims 48-50, wherein a CAS of 0 or 1 is maintained for at least 52 weeks.

56. The method of any one of claims 48-55, wherein at least 50% of patients achieving a CAS of 0 or 1 at week 15 maintain a CAS of 0 or 1 at week 52.

57. The method of any one of the preceding claims, wherein the patient has no worsening of Clinical Activity (CAS) post-treatment.

58. The method of any one of the preceding claims, wherein the treatment results in hearing impairment incidence of less than 10%.

59. The method of claim 58, wherein the hearing impairment incidence of less than 10% is maintained for the treatment period.Attorney Docket No. VRD-025WO160. The method of claim 59, wherein the hearing impairment incidence of less than 10% is maintained for at least 12 weeks, or at least 15 weeks.

61. The method of any one of the preceding claims, wherein the treatment does not result in hearing impairment incidence.

62. The method of any one of claims 58-61, wherein the percentage of hearing impairment incidence is a placebo-adjusted value.

63. The method of any one of the preceding claims, wherein the patient does not have hearing impairment prior to the treatment.

64. The method of any one of the preceding claims, wherein the treatment period is at least 12 weeks or at least 15 weeks.

65. The method of any one of the preceding claims, wherein the patient, prior to treatment, had proptosis of >3 mm above normal values for race and gender.

66. The method of any one of the preceding claims, wherein the patient, prior to treatment, had lid retraction of >2 mm.

67. The method of claim 65 or 66, wherein the reduction of proptosis is measured by Hertel exophthalmometer.

68. The method of any one of the preceding claims, wherein the treatment results in substantially no incidence of anti-drug antibody (ADA) as compared to placebo.

69. The method of any one of the preceding claims, wherein the anti-IGF-lR antibody comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3, and a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 2.

70. The method of any one of the preceding claims, wherein the anti-IGF-lR antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO: 10, and a light chain having an amino acid sequence of SEQ ID NO: 11.Attorney Docket No. VRD-025WO171. The method of any one of claims 1-69, wherein the anti-IGF-lR antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO: 14, and a light chain having an amino acid sequence of SEQ ID NO: 15.

72. The method of any one of the preceding claims, wherein the patient is at least 18 years of age or older.

73. The method of any one of the preceding claims, wherein the patient had not received prior treatment with another anti-IGF-lR therapy.

74. The method of any one of claims 1-72, wherein the patient has received prior treatment with another anti-IGF-lR therapy.

75. The method of any one of the preceding claims, wherein the patient, prior to the treatment, did not have a compressive optic neuropathy of TED that is expected to require surgical decompression in the immediate future.

76. The method of any one of the preceding claims, wherein the patient, prior to the treatment, did not have corneal decompensation in the study eye unresponsive to medical management.

77. The method of any one of the preceding claims, wherein the patent, prior to the treatment, have not had previous orbital irradiation or decompression surgery involving excision of fat for TED to the study eye’s orbit.

78. The method of any one of the preceding claims, wherein the patient receives additional doses of anti-IGF-lR antibody upon return of one or more symptoms of thyroid eye disease.

79. The method of claim 78, wherein the return of one or more symptoms is worsening of a CAS score.

80. The method of claim 78, wherein the return of one or more symptoms is an increase in proptosis.

81. The method of claim 78, wherein the return of one or more symptoms is a decrease in diplopia resolution.Attorney Docket No. VRD-025WO182. The method of any one of the preceding claims, wherein the patient exhibits fibrosis.

83. The method of claim 82, wherein the administration of the anti-IGF-lR antibody results in the treatment of fibrosis.

84. The method of claim 83, wherein fibrosis is reduced, alleviated, or reversed in the subject.

85. The method of any one of the preceding claims, wherein the method further comprises administering magnesium to the subject.

86. The method of claim 85, wherein the magnesium is administered prior to, during, or after the administration of the anti-IGF-lR antibody.

87. The method of claim 86, wherein the magnesium is administered 1-2 days prior to subsequent administration of the anti-IGF-lR antibody.

88. The method of any one of claims 85-87, wherein the magnesium is administered at a dose of 200-600 mg.

89. The method of claim 88, wherein the magnesium is administered at a dose of 400 mg.

90. The method of any one of claims 85-89, wherein the magnesium is administered orally.

91. The method of any one of the preceding claims, wherein the administering an anti- IGF-1R antibody results in a reduction in orbital fat volume as compared to a baseline.

92. The method of claim 91, wherein the orbital fat volume is reduced by at least 500 pl as compared to a baseline.

93. The method of claim 91, wherein the orbital fat volume is reduced by at least 3000 pl as compared to a baseline.

94. The method of claim 91, wherein the orbital fat volume is reduced by at least 7000 pl as compared to a baseline.Attorney Docket No. VRD-025WO195. The method of any one of claims 91-94, wherein the reduction in orbital fat volume is maintained for at least 15 weeks, at least 24 weeks, at least 36 weeks, or at least 52 weeks.

96. The method of any one of claims 91-95, wherein the orbital fat volume is determined using MRI or CT.

97. The method of any one of the preceding claims, wherein the administering an anti- IGF-1R antibody results in a reduction in extraocular muscle volume as compared to a baseline.

98. The method of claim 97, wherein the extraocular muscle volume is reduced by at least 500 pl as compared to a baseline.

99. The method of claim 97, wherein the extraocular muscle volume is reduced by at least 1500 pl as compared to a baseline.

100. The method of claim 97, wherein the extraocular muscle volume is reduced by at least 2500 pl as compared to a baseline.

101. The method of any one of claims 97-100, wherein the reduction in extraocular muscle volume is maintained for at least 24 weeks, at least 36 weeks, or at least 52 weeks.

102. The method of any one of claims 97-101, wherein the extraocular fat volume is determined using MRI or CT.

103. The method of any one of claims 91-102, wherein the baseline is a value prior to the administration of the anti-IGF-lR antibody.

104. The method of any one of the claims 91-102, wherein the baseline is a patient without the administration of the anti-IGF-lR antibody.

105. The method of any one of claims 91-102, wherein the baseline is a historical data of the same disease condition.

106. The method of any one of the preceding claims, wherein the treatment results in an improvement in Graves’ Orbitopathy-Quality of Life (GO-QOL) score.Attorney Docket No. VRD-025WO1107. The method of claim 106, wherein the treatment results in an at least 8 point improvement in GO-QOL score.

108. The method of any one of claims 106-107, wherein the improvement in GO-QOL score is in GO-QOL combined score.

109. The method of any one of claims 106-107, wherein the improvement in GO-QOL score is in GO-QOL activity subscale score.

110. The method of any one of claims 106-107, wherein the improvement in GO-QOL score is in GO-QOL appearance subscale score.

111. The method of any one of claims 106-110, where the improvement in GO-QOL score is maintained for at least 24 weeks, at least 36 weeks, or at least 52 weeks.

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