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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

• Thyroid eye disease also known as thyroid-associated ophthalmopathy (TAO), Graves' ophthalmopathy or orbitopathy (GO), thyrotoxic exophthalmos, dysthyroid ophthalmopathy, and several other terms, is orbitopathy associated with thyroid dysfunction.
• TAO thyroid-associated ophthalmopathy
• GO Graves' ophthalmopathy or orbitopathy
• thyrotoxic exophthalmos dysthyroid ophthalmopathy
• dysthyroid ophthalmopathy is orbitopathy associated with thyroid dysfunction.
• TAO is divided into two types. Active TED, which typically lasts 1-3 years, is characterized by an ongoing autoimmune/inflammatory response in the soft tissues of the orbit. Active TED is responsible for the expansion and remodeling of the ocular soft tissues. The autoimmune/inflammatory response of active, or acute, TED spontaneously resolves and the condition transitions into inactive TED. Inactive, or chronic, TED is the term used to describe the long-term/permanent sequelae of active TED.
• TED is typically associated with Graves' hyperthyroidism but can also occur as part of other autoimmune conditions that affect the thyroid gland and produce pathology in orbital and periorbital tissue, and, rarely, the pretibial skin (pretibial myxedema) or digits (thyroid acropachy).
• TED is an autoimmune orbitopathy in which the orbital and periocular soft tissues are primarily affected with secondary effects on the eye and vision.
• TED as a result of inflammation and expansion of orbital soft tissues, primarily eye muscles and adipose, the eyes are forced forward (bulge) out of their sockets—a phenomenon termed proptosis or exophthalmos.
• the annual incidence rate of TED has been estimated at 16 cases per 100,000 women and 2.9 cases per 100,000 men from a study based in one largely rural Minnesota community. There appears to be a female preponderance in which women are affected 2.5-6 times more frequently than men; however, severe cases occur more often in men than in women. In addition, most patients are aged 30-50 years, with severe cases appearing to be more frequent in those older than 50 years. Although most cases of TED do not result in loss of vision, this condition can cause vision-threatening exposure keratopathy, troublesome diplopia (double vision), and compressive dysthyroid optic neuropathy.
• TED may precede, coincide with, or follow the systemic complications of dysthyroidism.
• the ocular manifestations of TED include upper eyelid retraction, lid lag, swelling, redness (erythema), conjunctivitis, and bulging eyes (exophthalmos or proptosis), chemosis, periorbital edema, and altered ocular motility with significant functional, social, and cosmetic consequences.
• Hyaluronic acid is produced by fibroblasts residing within the orbital fat and extraocular muscles, and its synthesis in vitro is stimulated by several cytokines and growth factors, including IL-1 ⁇ , interferon- ⁇ , platelet-derived growth factor, thyroid stimulating hormone (TSH) and insulin-like growth factor I (IGF-I).
• cytokines and growth factors including IL-1 ⁇ , interferon- ⁇ , platelet-derived growth factor, thyroid stimulating hormone (TSH) and insulin-like growth factor I (IGF-I).
• TED is commonly considered to be the autoimmune orbital manifestation of Graves' Disease (GD).
• GD Graves' Disease
• TSHR thyroid-stimulating hormone receptor
• TED active TED
• autoantibodies trigger connective tissue and fat to expand, in part from stimulating excessive synthesis of hyaluronan.
• the expanded tissues are infiltrated with T and B cells, become inflamed, and are extensively remodeled.
• TSHR might have some pathogenic role in the development of active TED. Indeed, a positive correlation has been found between anti-TSHR antibodies and the degree of TED activity. However, no definitive link has been established, and a proportion of TED patients remain euthyroid throughout the course of their disease.
• IGF-IR insulin-like growth factor I receptor
• IGF-IR is a widely expressed heterotetrameric protein involved in the regulation of proliferation and metabolic function of many cell types. It is a tyrosine kinase receptor comprising two subunits. IGF-IR ⁇ contains a ligand-binding domain while IGF-IR ⁇ is involved in signaling and contains tyrosine phosphorylation sites. Monoclonal antibodies directed against IGF-IR have been developed and assessed as a therapeutic strategy for several types of solid tumors and lymphomas.
• IGF-IR a membrane-spanning tyrosine kinase receptor with roles in development and metabolism, also stimulates immune function and thus might be targeted therapeutically in autoimmune diseases.
• IGF-IR is overexpressed by orbital fibroblasts and by T cells and B cells in persons with GD and TED. It forms a signaling complex with TSHR through which it is transactivated.
• IGF-IR-inhibitory antibodies can attenuate the actions of IGF-I, thyrotropin, thyroid-stimulating immunoglobulins, and immunoglobulins isolated from patients with GD and TED. These observations prompted a trial of teprotumumab, a fully human IGF-IR-inhibitory monoclonal antibody, in patients with active, moderate-to-severe TED.
• TED thyroid eye disease
• IGF 1R insulin like growth factor-I receptor
• IGF-1R inhibitors are able to decrease TSHR and IGF-IR display by orbital fibroblasts and fibrocytes and attenuate the actions of IGF-I, TSH, thyroid-stimulating immunoglobulins, and immunoglobulins isolated from patients with TED (TAO or GO).
• TED As described above, TED (TAO or GO) remains inadequately treated.
• TEPEZZATM teprotumumab
• medical therapies which primarily consisted of glucocorticoids, had limited efficacy and presented safety concerns.
• broad immunosuppressive treatments for ED e.g. glucocorticoids and rituximab, cause a limited reduction in exophthalmos.
• ivGCs 2.25 g, 4.98 g. 7.47 g of methylprednisolone
• results were not different using rituximab.
• TED advanced cases of TED (TAO or GO) usually called for more invasive surgical treatment such as orbital decompression.
• Teprotumumab an IGF-1R inhibiting monoclonal antibody, has proven to be effective in the treatment of TED.
• teprotumumab is effective for the treatment of TED, for various reasons, not all patients benefit from treatment with teprotumumab. There is still unmet medical need for alternate therapies for TED, e.g. for different drugs that may be administered via alternate modes and on alternate schedules.
• Embodiment 1 A method of treating thyroid eye disease (TED), comprising administering to the subject an effective amount of an insulin like growth factor-I receptor (IGF-1R) inhibitor.
• IGF-1R insulin like growth factor-I receptor
• Embodiment 2 A method of reducing proptosis by at least 2 mm in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an IGF-IR inhibitor.
• TED thyroid eye disease
• Embodiment 3 The method of Embodiment 2, wherein proptosis is reduced by at least 3 mm.
• Embodiment 4 The method of Embodiment 3, wherein proptosis is reduced by at least 4 mm.
• Embodiment 5 The method of Embodiment 2, wherein the method additionally comprises reducing the clinical activity score (CAS) in the subject with TED.
• CAS clinical activity score
• Embodiment 6 The method of Embodiment 5, wherein CAS is reduced by at least 2 points.
• Embodiment 7 The method of Embodiment 6, wherein CAS is reduced by at least 3 points.
• Embodiment 8 The method of Embodiment 7, wherein proptosis is reduced by at least 3 mm and CAS is reduced by at least 3 points.
• Embodiment 9 A method of treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an insulin like growth factor-I receptor (IGF-1R) inhibitor.
• IGF-1R insulin like growth factor-I receptor
• Embodiment 10 The method of Embodiment 9, wherein the diplopia is constant diplopia.
• Embodiment 11 The method of Embodiment 9, wherein the diplopia is intermittent diplopia.
• Embodiment 12 The method of Embodiment 9, wherein the diplopia is inconstant diplopia
• Embodiment 13 The method of any of Embodiments 9-12, wherein the improvement in or reduction in severity of diplopia is sustained at least 20 weeks after discontinuation of inhibitor administration.
• Embodiment 14 The method of any of Embodiments 9-12, wherein the improvement in or reduction in severity of diplopia is sustained at least 50 weeks after discontinuation of inhibitor administration.
• Embodiment 15 A method of treating or reducing the severity of thyroid eye disease (TED), or a symptom thereof, in a subject with TED, comprising administering to the subject an effective amount of an insulin like growth factor-I receptor (IGF-1R) inhibitor.
• TED thyroid eye disease
• IGF-1R insulin like growth factor-I receptor
• Embodiment 16 A method of reducing proptosis in an eye in a subject with thyroid eye disease (TED) in a subject with TED, comprising administering to the subject an effective amount of an insulin like growth factor-I receptor (IGF-1R) inhibitor.
• IGF-1R insulin like growth factor-I receptor
• Embodiment 17 A method of reducing Clinical Activity Score (CAS) of thyroid eye disease (TED) in a subject with TED, comprising administering to the subject an effective amount of an insulin like growth factor-I receptor (IGF-1R) inhibitor.
• CAS Clinical Activity Score
• IGF-1R insulin like growth factor-I receptor
• Embodiment 18 A method of a) reducing proptosis by at least 2 mm and b) reducing the clinical activity score (CAS) in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an insulin like growth factor-I receptor (IGF-1R) inhibitor.
• CAS clinical activity score
• IGF-1R insulin like growth factor-I receptor
• Embodiment 19 The method of any of Embodiments 15, 16, and 18, wherein proptosis is reduced by at least 2 mm.
• Embodiment 20 The method of Embodiment 19, wherein proptosis is reduced by at least 3 mm.
• Embodiment 21 The method of Embodiment 20, wherein proptosis is reduced by at least 4 mm.
• Embodiment 22 The method of any of Embodiments 15-21, wherein the clinical activity score (CAS) of the subject is reduced by at least 2 points.
• CAS clinical activity score
• Embodiment 23 The method of Embodiment 22, wherein the clinical activity score (CAS) of the subject is reduced to one (1).
• CAS clinical activity score
• Embodiment 24 The method of Embodiment 23, wherein the clinical activity score (CAS) of the subject is reduced to zero (0).
• CAS clinical activity score
• Embodiment 25 A method of improving the quality of life in a subject with thyroid eye disease (TED) comprising administering to the subject an effective amount of an insulin like growth factor-I receptor (IGF-1R) inhibitor.
• IGF-1R insulin like growth factor-I receptor
• Embodiment 26 The method of Embodiment 25, wherein the quality of life is measured by the Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment, or either the Visual Functioning or Appearance subscale thereof.
• GO-QoL Graves' Ophthalmopathy Quality of Life
• Embodiment 27 The method of Embodiment 26, wherein the treatment results in an improvement of ⁇ 8 points on the GO-QoL.
• Embodiment 28 The method of Embodiment 26, wherein the treatment results in an improvement on the Functioning subscale of the GO-QoL.
• Embodiment 29 The method of Embodiment 26, wherein the treatment results in an improvement on the Appearance subscale of the GO-QoL.
• Embodiment 30 The method of any of Embodiments 1-29, wherein the TED is moderate-to-severe TED.
• Embodiment 31 The method of any of Embodiments 1-30, wherein the TED is active/acute TED.
• Embodiment 32 The method of any of Embodiments 1-30, wherein the TED is inactive/chronic TED.
• Embodiment 33 The method of any of Embodiments 1-32, wherein the subject is a subject who has undergone prior treatment with an IGF-1R inhibitor and either did not respond to said prior treatment or relapsed after said prior treatment.
• Embodiment 34 The method of any of Embodiments 1-33, wherein the treatment is efficacious for at least 20 weeks beyond the last administered dose.
• Embodiment 35 The method of Embodiment 34, wherein the treatment is efficacious for at least 50 weeks beyond the last administered dose.
• Embodiment 36 The method of any of Embodiments 1-35 wherein said IGF-1R inhibitor is an antibody or small molecule, with the proviso that the antibody is not teprotumumab.
• Embodiment 37 The method of Embodiment 36 wherein said IGF-1R inhibitor is chosen from ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A-928605.
• said IGF-1R inhibitor is chosen from ganitumab, figitumumab
• Embodiment 38 The method of Embodiment 36 wherein said IGF-1R inhibitor is an antibody.
• Embodiment 39 The method of Embodiment 37 wherein said IGF-1R inhibitor is a human, chimeric human, or humanized monoclonal antibody suitable for human therapy.
• Embodiment 40 The method of Embodiment 38 wherein the antibody is administered intravenously (IV) or subcutaneously (SC).
• IV intravenously
• SC subcutaneously
• Embodiment 41 The method of Embodiment 39 wherein the antibody is administered IV.
• Embodiment 42 The method of Embodiment 40 wherein said antibody is chosen from ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, B IIB 022, xentuzumab, and istiratumab.
• Embodiment 43 The method of Embodiment 42 wherein the antibody is ganitumab.
• Embodiment 44 The method of Embodiment 43 wherein the ganitumab is dosed at:
• Embodiment 45 The method of Embodiment 42 wherein the antibody is figitumumab.
• Embodiment 46 The method of Embodiment 45 wherein the figitumumab is dosed at:
• Embodiment 47 The method of Embodiment 42 wherein the antibody is cixutumumab.
• Embodiment 48 The method of Embodiment 47 wherein the cixutumumab is dosed at:
• Embodiment 49 The method of Embodiment 42 wherein the antibody is dalotuzumab.
• Embodiment 50 The method of Embodiment 49 wherein the dalotuzumab is dosed at:
• Embodiment 51 The method of Embodiment 42 wherein the antibody is robatumumab.
• Embodiment 52 The method of Embodiment 51 wherein the robatumumab is dosed at:
• Embodiment 53 The method of Embodiment 42 wherein the antibody is xentuzumab.
• Embodiment 54 The method of Embodiment 53 wherein the xentuzumab is dosed at:
• Embodiment 55 The method of Embodiment 42 wherein the antibody is istiratumab.
• Embodiment 56 The method of Embodiment 55 wherein the istiratumab is dosed at:
• Embodiment 57 The method of Embodiment 42 wherein the antibody is AVE1642.
• Embodiment 58 The method of Embodiment 57 wherein the AVE1642 is dosed at:
• Embodiment 59 The method of Embodiment 42 wherein the antibody is BIIB022.
• Embodiment 60 The method of Embodiment 59 wherein the BIIB022 is dosed at:
• Embodiment 61 The method of Embodiment 48 wherein said IGF-1R inhibitor antibody comprises at least one heavy chain and at least one light chain selected from the selected from the group consisting of:
• Embodiment 62 The method of Embodiment 36 wherein said IGF-1R inhibitor is a small molecule.
• Embodiment 63 The method of Embodiment 61 wherein said IGF-1R inhibitor is dosed orally.
• Embodiment 64 The method of Embodiment 63 wherein said IGF-1R inhibitor is chosen from linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A-928605.
• said IGF-1R inhibitor is chosen from linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-22
• Embodiment 65 The method of Embodiment 64 wherein the IGF-1R inhibitor is linsitinib.
• Embodiment 66 The method of Embodiment 65 wherein the linsitinib is dosed at:
• Embodiment 67 The method of Embodiment 64 wherein the IGF-1R inhibitor is picropodophyllin.
• Embodiment 68 The method of Embodiment 67 wherein the picropodophyllin is dosed:
• Embodiment 69 The method of Embodiment 64 wherein the IGF-1R inhibitor is BMS-754807.
• Embodiment 70 The method of Embodiment 69 wherein the BMS-754807 is dosed:
• Embodiment 71 The method of Embodiment 64 wherein the IGF-1R inhibitor is BMS-536924.
• Embodiment 72 The method of Embodiment 64 wherein the IGF-1R inhibitor is BMS-554417.
• Embodiment 73 The method of Embodiment 64 wherein the IGF-1R inhibitor is GSK1838705A.
• Embodiment 74 The method of Embodiment 64 wherein the IGF-1R inhibitor is GSK1904529A.
• Embodiment 75 The method of Embodiment 64 wherein the IGF-1R inhibitor is NVP-AEW541.
• Embodiment 76 The method of Embodiment 64 wherein the IGF-1R inhibitor is NVP-ADW742.
• Embodiment 77 The method of Embodiment 64 wherein the IGF-1R inhibitor is GTx-134.
• Embodiment 78 The method of Embodiment 64 wherein the IGF-1R inhibitor is AG1024.
• Embodiment 79 The method of Embodiment 64 wherein the IGF-1R inhibitor is PL-2258.
• Embodiment 80 The method of Embodiment 64 wherein the IGF-1R inhibitor is NVP-AEW541.
• Embodiment 81 The method of Embodiment 64 wherein the IGF-1R inhibitor is NSM-18.
• Embodiment 82 The method of Embodiment 64 wherein the IGF-1R inhibitor is AZD3463.
• Embodiment 83 The method of Embodiment 64 wherein the IGF-1R inhibitor is AZD9362.
• Embodiment 84 The method of Embodiment 64 wherein the IGF-1R inhibitor is BI885578.
• Embodiment 85 The method of Embodiment 64 wherein the IGF-1R inhibitor is BI893923.
• Embodiment 86 The method of Embodiment 64 wherein the IGF-1R inhibitor is TT-100.
• Embodiment 87 The method of Embodiment 64 wherein the IGF-1R inhibitor is XL-228.
• Embodiment 80 The method of Embodiment 64 wherein the IGF-1R inhibitor is A-928605.
• Embodiment 88 The method of any of Embodiments 71-88 wherein the IGF-1R inhibitor is dosed:
• Embodiment 89 The method of Embodiment 64 wherein the IGF-1R inhibitor is KW-2450.
• Embodiment 90 The method of Embodiment 90 wherein the KW-2450 is dosed:
• Embodiment 91 The method of any of Embodiments 1-30 and 33-35, wherein the TED is inactive/chronic TED, and wherein the IGF-1R inhibitor is teprotumumab.
• compositions for the treatment of TED comprising an IGF-1R inhibitor.
• Embodiment 92 A pharmaceutical composition comprising an amount of an insulin like growth factor-I receptor (IGF-1R) inhibitor that is therapeutically effective:
• IGF-1R insulin like growth factor-I receptor
• Embodiment 93 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is ganitumab, formulated for administration:
• Embodiment 94 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is figitumumab, formulated for administration:
• Embodiment 95 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is cixutumumab, formulated for administration:
• Embodiment 96 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is dalotuzumab, formulated for administration:
• Embodiment 97 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is robatumumab, formulated for administration:
• Embodiment 98 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is xentuzumab, formulated for administration:
• Embodiment 99 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is istiratumab, formulated for administration:
• Embodiment 100 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is AVE1642, formulated for administration:
• Embodiment 101 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is BIIB022, formulated for administration at:
• Embodiment 102 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is linsitinib, formulated for administration at:
• Embodiment 103 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is picropodophyllin, formulated for administration:
• Embodiment 104 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is BMS-754807, formulated for administration:
• Embodiment 105 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is chosen from BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, and A-928605, formulated for administration:
• Embodiment 106 The pharmaceutical composition of Embodiment 92, wherein the IGF-1R inhibitor is KW-2450, formulated for administration;
• Embodiment 107 The method of Embodiment 57, wherein the AVE1642 antibody comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO:25, a HCDR2 comprising the amino acid sequence of SEQ ID NO:76, a HCDR3 comprising the amino acid sequence of SEQ ID NO:27, a LCDR1 comprising the amino acid sequence of SEQ ID NO:28, a LCDR2 comprising the amino acid sequence of SEQ ID NO:29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:30.
• Embodiment 108 The method of Embodiment 107, wherein the antibody comprises a heavy chain variable domain comprising SEQ ID NO:31 or 78 or 79, and a light chain variable domain comprising SEQ ID NO:32 or 80 or 81 or 82 or 83.
• Embodiment 109 The method of Embodiment 108, wherein the antibody comprises a heavy chain variable domain comprising SEQ ID NO:78 and a light chain variable domain comprising SEQ ID NO:80 or 81 or 82 or 83.
• Embodiment 110 The method of Embodiment 109, wherein the antibody comprises the light chain variable domain comprising SEQ ID NO:80.
• Embodiment 111 The method of Embodiment 109, wherein the antibody comprises the light chain variable domain comprising SEQ ID NO:81.
• Embodiment 112. The method of Embodiment 109, wherein the antibody comprises the light chain variable domain comprising SEQ ID NO:82.
• Embodiment 113 The method of Embodiment 109, wherein the antibody comprises the light chain variable domain comprising SEQ ID NO:83.
• Embodiment 114 The method of any of Embodiments 107-113, wherein the therapeutically effective amount of the AVE1642 antibody comprises a dosage of 1-60 mg/kg or 75-4500 mg IV Q3W; or 0.6-40 mg/kg or 45-3000 mg IV Q2W; or 0.3-20 mg/kg or 22-1500 mg IV QW.
• Embodiment 115 The method of any of Embodiments of 107-113, wherein the therapeutically effective amount of the AVE1642 antibody comprises a dosage of 1-10 mg/kg.
• Embodiment 116 The method of Embodiment 115, wherein the therapeutically effective amount of the AVE1642 antibody comprises a dosage of 1-5 mg/kg.
• Embodiment 117 The method of Embodiment 116, wherein the therapeutically effective amount of the AVE1642 antibody comprises a dosage of about 1 mg/kg, or about 2 mg/kg, or about 3 mg/kg, or about 4 mg/kg, or about 5 mg/kg.
• Embodiment 118 The method of any of Embodiments 115-117, wherein the therapeutically effective amount of the AVE1642 antibody is administered every 1, 2, 3, 4, or 5 weeks (i.e., QW, Q2W, Q3W, Q4W, or Q5W).
• Embodiment 119 The method of Embodiment 118, wherein the AVE1642 antibody is administered intravenously (IV) or subcutaneously (SC).
• IV intravenously
• SC subcutaneously
• Embodiment 120 The method of any of Embodiments 107-113, wherein the therapeutically effective amount of the AVE1642 antibody comprises a dosage of 1-5 mg/kg or 75-375 mg IV Q3W; or 0.6-4 mg/kg or 45-300 mg IV Q2W; or 0.3-3 mg/kg or 22-225 mg IV QW.
• Embodiment 121 The method of any of Embodiments 107-120, wherein the AVE1642 antibody further comprises a variant Fc region comprising mutations that substitute a methionine at position 428 with a leucine (Met428Leu) and substitute an asparagine at position 434 with a serine (Asn434Ser), wherein the amino acid substitution numbering is EU as in Kabat.
• a variant Fc region comprising mutations that substitute a methionine at position 428 with a leucine (Met428Leu) and substitute an asparagine at position 434 with a serine (Asn434Ser), wherein the amino acid substitution numbering is EU as in Kabat.
• Embodiment 122 The method of any Embodiments 115-117, wherein the AVE1642 antibody further comprises a variant Fc region comprising mutations that substitute a methionine at position 428 with a leucine (Met428Leu) and substitute an asparagine at position 434 with a serine (Asn434Ser), wherein the amino acid substitution numbering is EU as in Kabat.
• a variant Fc region comprising mutations that substitute a methionine at position 428 with a leucine (Met428Leu) and substitute an asparagine at position 434 with a serine (Asn434Ser), wherein the amino acid substitution numbering is EU as in Kabat.
• Embodiment 123 The method of Embodiment 122, wherein the therapeutically effective amount of the AVE1642 antibody is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks (i.e., QW, Q2W, Q3W, Q4W, Q5W, Q6W, Q7W, Q8W, Q9W, Q10W, Q11W, or Q12W).
• Embodiment 124 The method of Embodiment 123, wherein the AVE1642 antibody is administered intravenously (IV) or subcutaneously (SC).
• IV intravenously
• SC subcutaneously
• TED thyroid eye disease
• methods of treating or reducing the severity of thyroid eye disease comprising administering to the subject an effective amount of an insulin like growth factor-I receptor (IGF 1R) inhibitor.
• IGF 1R insulin like growth factor-I receptor
• said IGF-1R inhibitor is an antibody.
• said antibody IGF-1R inhibitor is chosen from ganitumab, figitumumab, dusigitumab, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, and xentuzumab.
• said IGF-1R inhibitor is a small molecule.
• said small molecule IGF-1R inhibitor is chosen from linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, NVP-AEW541, GTx-134, and AG1024.
• Also provided herein is a method of reducing proptosis (e.g., by at least 2 mm) in a subject with thyroid-associated ophthalmopathy thyroid eye disease (TED) comprising administering to the subject an effective amount of an IGF-1R inhibitor.
• TED thyroid-associated ophthalmopathy thyroid eye disease
• Also provided herein is a method of reducing proptosis (e.g., by at least 2 mm) and reducing the clinical activity score (CAS) in a subject with thyroid-associated ophthalmopathy thyroid eye disease (TED) comprising administering to the subject an effective amount of an IGF-1R inhibitor.
• CAS clinical activity score
• TED thyroid-associated ophthalmopathy thyroid eye disease
• Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED) comprising administering to a subject in need thereof, an effective amount of an IGF-1R inhibitor, and wherein the IGF-1R inhibitor (i) reduces proptosis by at least 2 mm; and (ii) reduces the CAS in the subject by at least 2 points (on the 7-point version of the scale—as described below).
• TED thyroid eye disease
• Also provided herein is a method of reducing proptosis by at least 4 mm in a subject with thyroid eye disease (TED) comprising administering to the subject an effective amount of an IGF-1R inhibitor.
• TED thyroid eye disease
• Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED) comprising administering to a subject in need thereof an effective amount of an IGF-1R inhibitor, and wherein the IGF-1R inhibitor reduces proptosis by at least 4 mm.
• TED thyroid eye disease
• Also provided herein is a method of treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an IGF-1R inhibitor.
• TED thyroid eye disease
• Also provided herein is a method of reducing the severity of thyroid eye disease (TED) comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an IGF-1R inhibitor, and a pharmaceutically acceptable excipient or diluent or carrier.
• TED thyroid eye disease
• a method of reducing proptosis by at least 2 mm in a subject with TED comprises administering to the subject an effective amount of an IGF-1R inhibitor.
• Also provided herein is a method of reducing proptosis by at least 2 mm and reducing the clinical activity score (CAS) in a subject with TED (TAO or GO), comprising administering to the subject an effective amount of an IGF-1R inhibitor.
• CAS clinical activity score
• Also provided herein is a method of treating or reducing the severity of TED (TAO or GO).
• the method comprises administering to a subject in need thereof, an effective amount of an IGF-1R inhibitor, and wherein the IGF-1R inhibitor (i) reduces proptosis by at least 2 mm; and (ii) reduces the CAS in the subject by at least 2 points (on the 7-point version of the scale).
• the reduction in proptosis or exophthalmos could be greater than 2 mm, for example, 2.2 mm, 2.4 mm, 2.5 mm, 2.6 mm 2.8 mm, 3 mm, 3.2 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.8 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5 mm or more than 5 mm.
• the reduction in CAS is by 2 points or more, for example, by 3, 4, 5, 6, or 7 points. In one embodiment, the reduction in CAS is by 2 or more points. In another embodiment, it is by 3 or more points. In yet another embodiment, the reduction in CAS is by 4 or more points.
• Also provided herein is a method of reducing proptosis by at least 4 mm in a subject with TED (TAO or GO).
• the method comprises administering to the subject an effective amount of an IGF-1R inhibitor.
• the method comprises administering to a subject in need thereof an effective amount of an IGF-1R inhibitor, and wherein the IGF-1R inhibitor reduces proptosis or exophthalmos by at least 3 mm.
• a method of treating or reducing the severity of TED comprises administering to a subject in need thereof, an effective amount of an IGF-1R inhibitor, and wherein the IGF-1R inhibitor reduces proptosis or exophthalmos by at least 4 mm.
• Also provided herein is a method of treating or reducing the severity of diplopia associated with TED (in a subject with TED and diplopia), comprising administering to the subject, an effective amount of an IGF-1R inhibitor.
• Also provided herein is a method of treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED), comprising administering to the subject an effective amount of an IGF-1R inhibitor.
• TED thyroid eye disease
• Also provided herein is a method of treating or reducing the severity of constant diplopia (CD) in a subject with thyroid eye disease (TED), comprising administering to the subject, an effective amount of an IGF-1R inhibitor. Also provided herein is a method of treatment of diplopia comprising administering to the subject, an effective amount of an IGF-1R inhibitor, that results in improved diplopia relative to placebo.
• CD constant diplopia
• TED thyroid eye disease
• the IGF-1R inhibitor When administered to a population of patients, about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the patients may respond with a reduction in proptosis or exophthalmos by at least 2 mm and a reduction in the CAS by at least 2 points. In some embodiments, the response is seen in at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 80% of the patients.
• the IGF-1R inhibitor reduces proptosis by at least 3 mm in at least 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of the subjects. In some embodiments, the IGF-1R inhibitor reduces proptosis by at least 3.5 mm in at least 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of the subjects. In some embodiments, the IGF-1R inhibitor reduces proptosis by at least 4 mm in at least 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of the subjects. In some embodiments, the IGF-1R inhibitor reduces proptosis by at least 4 mm in about 40% of the subjects.
• Also provided herein is a method of reducing proptosis in an eye in a subject with thyroid eye disease (TED), thyroid-associated ophthalmopathy (TAO), or Graves' ophthalmopathy (GO) who has previously undergone prior treatment with an IGF-1R inhibitor and either did not respond to said prior treatment or responded to said prior treatment and later relapsed, comprising administering to said subject an effective amount of the IGF-1R inhibitor.
• TED thyroid eye disease
• TEO thyroid-associated ophthalmopathy
• GO Graves' ophthalmopathy
• Also provided herein is a method of reducing proptosis by at least 2 mm in an eye without a deterioration of 2 mm or more in the other (or fellow eye) in a subject with TED comprising administering to said subject an effective amount of an IGF-1R inhibitor.
• the subject is one who has undergone prior treatment with said IGF-1R inhibitor, and either did not respond to said prior treatment or relapsed after said prior treatment.
• the reduction in proptosis or exophthalmos could be greater than 2 mm, for example, 2.2 mm, 2.4 mm, 2.5 mm, 2.6 mm 2.8 mm, 3 mm, 3.2 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.8 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5 mm or more than 5 mm.
• Also provided herein is a method of reducing Clinical Activity Score (CAS) of thyroid eye disease (TED) in a subject who has undergone prior treatment with an IGF-1R inhibitor, and either did not respond to said prior treatment or relapsed after said prior treatment, comprising administering to a subject in need thereof an effective amount of an IGF-1R inhibitor.
• CAS Clinical Activity Score
• TED thyroid eye disease
• CAS is reduced in said subject to either one (1) or zero (0) (on the 7-point version of the CAS scale—as described below).
• the reduction in CAS is by 2 points or more, for example, by 3, 4, 5, 6, or 7 points. In one embodiment, the reduction in CAS is by 2 or more points. In another embodiment, it is by 3 or more points. In yet another embodiment, the reduction in CAS is by 4 or more points. In yet another embodiment, the reduction in CAS is by 5 or more points.
• the CAS is reduced to one (1). In another embodiment, as a result of the treatment, the CAS is reduced to zero (0).
• Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED) comprising administering to a subject who has undergone prior treatment with an IGF-1R inhibitor, and either did not respond to said prior treatment or responded to said prior treatment and later relapsed, IGF-1R inhibitor.
• TED thyroid eye disease
• Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED) in a subject who has undergone prior treatment with an IGF-1R inhibitor and either did not respond to said prior treatment or relapsed after said prior treatment comprising administering to a subject in need thereof an effective amount of an IGF-1R inhibitor, and wherein said IGF-1R inhibitor (i) reduces proptosis by at least 2 mm in an eye; (ii) is not accompanied by a deterioration of 2 mm or more in the other (or fellow eye); and (iii) reduces the CAS in said subject to either one (1) or zero (0) (on the 7-point version of the scale—as described below.
• TED thyroid eye disease
• Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED; TAO or GO) comprising administering to a subject in need thereof an effective amount of an IGF-1R inhibitor, wherein said antibody reduces proptosis by at least 2 mm as well as reduces the CAS to either one (1) or zero (0).
• the subject is one who has undergone prior treatment with said IGF-1R inhibitor, and either did not respond to said prior treatment or relapsed after said prior treatment.
• Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED; TAO or GO) in a subject with TED who has previously undergone prior treatment with an IGF-1R inhibitor and either did not respond to said prior treatment or responded to said prior treatment and later relapsed, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an IGF-1R inhibitor and a pharmaceutically acceptable excipient or diluent or carrier.
• TED thyroid eye disease
• Also provided herein is a method of reducing proptosis in an eye in a subject with thyroid eye disease (TED; TAO or GO) who has previously undergone prior treatment with an IGF-1R inhibitor and either did not respond to said prior treatment or responded to said prior treatment and later relapsed, comprising administering to said subject an effective amount of the IGF-1R inhibitor.
• TED thyroid eye disease
• Also provided herein is a method of treating or reducing the severity of thyroid eye disease (TED; TAO or GO) comprising administering to a subject who has undergone prior treatment with an IGF-1R inhibitor, and either did not respond to said prior treatment or responded to said prior treatment and later relapsed, the IGF-1R inhibitor.
• TED thyroid eye disease
• Also provided herein is a method of improving the quality of life in a subject with thyroid eye disease (TED; TAO or GO) who has undergone prior treatment with an IGF-1R inhibitor, and either did not respond to said prior treatment or responded to said prior treatment and later relapsed, comprising administering to the subject an effective amount of an IGF-1R inhibitor.
• TED thyroid eye disease
• Also provided herein is a method of treating or reducing diplopia or the severity of diplopia in a subject with thyroid eye disease (TED; TAO or GO) who has undergone prior treatment with an IGF-1R inhibitor, and either did not respond to said prior treatment or responded to said prior treatment and later relapsed, comprising administering to the subject an effective amount of an IGF-1R inhibitor.
• TED thyroid eye disease
• the diplopia is constant diplopia. In some embodiments, the diplopia is inconstant diplopia. In some embodiments, the diplopia is intermittent diplopia.
• the improvement in or reduction in severity of diplopia is sustained at least 20, 30, 40, or 50 weeks after discontinuation of IGF-1R inhibitor administration. In some embodiments, the improvement in or reduction in severity of diplopia is sustained 20-30, 30-40, 40-50, or 50-60 weeks after discontinuation of IGF-1R inhibitor administration. In some embodiments, the improvement in or reduction in severity of diplopia is sustained at least 20 weeks after discontinuation of IGF-1R inhibitor administration. In some embodiments, the improvement in or reduction in severity of diplopia is sustained at least 50 weeks after discontinuation of IGF-1R inhibitor administration.
• Also provided herein is a method of treating or reducing the severity of constant diplopia (CD) in a subject with thyroid eye disease (TED; TAO or GO) who has undergone prior treatment with an IGF-1R inhibitor, and either did not respond to said prior treatment or responded to said prior treatment and later relapsed, comprising administering to the subject an effective amount of an IGF-1R inhibitor.
• the treatment with the IGF-1R inhibitor improves the CD QoL in patients with severe TED.
• Also provided herein is a method of treating or reducing the severity of diplopia in a subject with thyroid eye disease (TED; TAO or GO) who has undergone prior treatment with an IGF-1R inhibitor, and either did not respond to said prior treatment or responded to said prior treatment and later relapsed, comprising administering to the subject an effective amount of an IGF-1R inhibitor, that results in improved diplopia relative to placebo which is sustained out to 51 weeks after drug discontinuation.
• TED thyroid eye disease
• the IGF-1R inhibitor can be administered in a single dose or in multiple doses. In one embodiment, the IGF-1R inhibitor is administered to the subject in a single dose. In another embodiment, the IGF-1R inhibitor is administered to the subject in multiple doses, spread out over the course of a few days, weeks or months. In some embodiments the IGF-1R inhibitor is administered every week or every 2 weeks or every 3 weeks or every 4 weeks or every 5 weeks or every 6 weeks or every 7 weeks or every 8 weeks or every month or every 2 months or every 3 months.
• the IGF-1R inhibitor is administered in multiple doses and the dosage is the same each time. In some embodiments the IGF-1R inhibitor is administered in multiple doses and the dosage at the time of first administration is different (could be higher or lower) from those at subsequent times. In some embodiments the IGF-1R inhibitor is administered in multiple doses and the dosage is adjusted at each administration based on the subject's response to the therapy.
• the dosage may further vary between patients, based on different factors such as the age, gender, race, and body weight of each patient.
• the dosage varies by body weight of the patient.
• the dosage could range from about 1 mg of the IGF-1R inhibitor per kilogram of body weight to about 100 mg of the IGF-1R inhibitor per kilogram of body weight.
• the dosage could for example, be 1 mg, 2 mg, 3 mg, 5 mg, 7 mg, 10 mg, 12 mg, 15 mg, 17 mg, 20 mg, 22 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg, of the IGF-1R inhibitor per kilogram of body weight.
• the dosage is about 1 mg/kg to about 5 mg/kg of the IGF-1R inhibitor. In some embodiments, the dosage is about 5 mg/kg to about 10 mg/kg of the IGF-1R inhibitor. In some embodiments, the dosage is about 10 mg/kg to about 15 mg/kg of the IGF-1R inhibitor. In some embodiments, the dosage is about 15 mg/kg to about 20 mg/kg of the IGF-1R inhibitor.
• the dosage at the time of first administration is about 1 mg/kg to about 5 mg/kg of the IGF-1R inhibitor; or about 5 mg/kg to about 10 mg/kg of the IGF-1R inhibitor; or about 10 mg/kg to about 15 mg/kg of the IGF-1R inhibitor; or about 15 mg/kg to about 20 mg/kg of the IGF-1R inhibitor; or about 20 mg/kg to about 25 mg/kg of the IGF-1R inhibitor.
• the subsequent dose(s) could be higher or lower than the first dose.
• the subsequent dose is about 1 mg/kg to about 5 mg/kg of the IGF-1R inhibitor; or about 5 mg/kg to about 10 mg/kg of the IGF-1R inhibitor; or about 10 mg/kg to about 15 mg/kg of IGF-1R inhibitor; or about 15 mg/kg to about 20 mg/kg of the IGF-1R inhibitor; or about 20 mg/kg to about 25 mg/kg of the IGF-1R inhibitor.
• the duration of the treatment would depend on the subject's response to the therapy and can range from about one month or 4 weeks to about 2 years or 100 weeks.
• the treatment may be provided over a total duration of about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 14 months, 16 months, 18 months, 20 months, 22 months or 2 years.
• the treatment may be provided over a total duration of 4, 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52 weeks, or extended to 56, 64, 72, 80, 88, 96 or 104 weeks.
• the IGF-1R inhibitor may be administered by any suitable route including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intraperitoneal, intrathecal, intraventricular, transdermal, transcutaneous, topical, subcutaneous, intranasal, enteral, sublingual, intravaginal or rectal routes. Hyposprays may also be used to administer the pharmaceutical compositions disclosed herein. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be used.
• any embodiment above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
• two embodiments are “mutually exclusive” when one is defined to be something which is different than the other.
• antibody encompasses the various forms of antibodies including but not being limited to whole antibodies, monoclonal antibodies, antibody fragments, human antibodies, humanized antibodies, chimeric antibodies and genetically engineered antibodies as long as the characteristic properties such as specificity and IGF-IR inhibitory are retained.
• antibody fragment As used herein, the terms “antigen binding fragment,” “fragment,” and “antibody fragment” are used interchangeably to refer to any fragment that comprises a portion of a full length antibody, generally at least the antigen binding portion or the variable region thereof. Examples of antibody fragments include, but are not limited to, diabodies, single-chain antibody molecules, multispecific antibodies, Fab, Fab′, F(ab′) 2 , Fv or scFv. Further, the term “antibody” as used herein includes both antibodies and antigen binding fragments thereof.
• antibody fragments comprise single chain polypeptides having the characteristics of a VH chain, namely being able to assemble together with a VL chain or of a VL chain binding to IGF-IR, namely being able to assemble together with a VH chain to a functional antigen binding pocket and thereby providing the property of inhibiting the binding of IGF-I and IGF-II to IGF-IR.
• the terms “monoclonal antibody” or “monoclonal antibody composition,” as used herein refer to a preparation of antibody molecules of a single amino acid composition. Accordingly, the term “human monoclonal antibody” refers to antibodies displaying a single binding specificity which have variable and constant regions derived from human germline immunoglobulin sequences. In one embodiment, the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light human chain transgene fused to an immortalized cell.
• a transgenic non-human animal e.g., a transgenic mouse
• human antibody as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
• humanized antibody refers to antibodies in which the framework or “complementarity determining regions” (CDR) have been modified to comprise the CDR of an immunoglobulin of different specificity as compared to that of the parent immunoglobulin.
• CDR complementarity determining regions
• a murine CDR is grafted into the framework region of a human antibody to prepare the “humanized antibody.”
• recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from a host cell such as an SP2-0, NS0 or CHO cell or from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes or antibodies expressed using a recombinant expression vector transfected into a host cell.
• recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences in a rearranged form.
• variable region denotes each of the pair of light and heavy chains which is involved directly in binding the antibody to the antigen.
• the domains of variable human light and heavy chains have the same general structure and each domain comprises four framework (FR) regions whose sequences are widely conserved, connected by three “hypervariable regions” (or complementarity determining regions, CDRs).
• the framework regions adopt a ⁇ -sheet conformation and the CDRs may form loops connecting the ⁇ -sheet structure.
• the CDRs in each chain are held in their three-dimensional structure by the framework regions and form together with the CDRs from the other chain the antigen binding site.
• the antibody heavy and light chain CDR3 regions play an important role in the binding specificity/affinity of antibodies.
• CDR complementarity determining region
• hypervariable region comprises amino acid residues from the complementarity determining regions or CDRs.
• “Framework” or “FR” regions are those variable domain regions other than the hypervariable region residues as herein defined. Therefore, the light and heavy chains of an antibody comprise from N- to C-terminus the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and 1-R4. Especially, CDR3 of the heavy chain is the region which contributes most to antigen binding.
• CDR and FR regions are determined according to the standard definition of Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)) and/or those residues from a “hypervariable loop.”
• binding to IGF-IR or “specific binding to IGF-IR” are used interchangeably herein and mean the binding of the antibody to IGF-IR in an in vitro assay, preferably in a binding assay in which the antibody is bound to a surface and binding of IGF-IR is measured by Surface Plasmon Resonance (SPR).
• Binding means a binding affinity (K D ) of 10 ⁇ 8 M or less, preferably 10 ⁇ 13 to 10 ⁇ 9 M. Binding to IGF-IR can be investigated by a BIAcore assay (Pharmacia Biosensor AB, Uppsala, Sweden).
• the affinity of the binding is defined by the terms ka (rate constant for the association of the antibody from the antibody/antigen complex), kd (dissociation constant), and K D (kd/ka).
• the antibodies used in the methods disclose herein typically show a K D of about 10 ⁇ 9 M or less.
• the antibodies, or antigen binding fragments thereof, used in the methods disclosed herein inhibit the binding of IGF-I and IGF-II to IGF-IR.
• the inhibition is measured as IC 50 in an assay for binding of IGF-I/IGF-II to IGF-IR on cells.
• Such an assay is known to one of skill in the art and is described, for example, U.S. Pat. No. 7,579,157, which is incorporated herein in its entirety.
• the IC 50 values of the antibodies used in the methods disclosed herein for the binding of IGF-I and IGF-II to IGF-IR typically are no more than 2 nM. IC 50 values are measured as average or median values of at least three independent measurements. Single IC 50 values may be excluded from the scope.
• inhibiting the binding of IGF-I and IGF-II to IGF-IR refers to inhibiting the binding of I 125 -labeled IGF-I or IGF-II to IGF-IR presented on the surface of cells in an in vitro assay. Inhibiting means an IC 50 value of 2 nM or lower.
• terapéuticaally effective is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.
• terapéuticaally acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
• treatment of a subject or patient is intended to include prevention, prophylaxis, attenuation, amelioration and therapy. Treatment may also include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression. For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease.
• subject and “patient” are used interchangeably herein to mean all mammals including humans Examples of subjects include, but are not limited to, humans, monkeys, dogs, cats, horses, cows, goats, sheep, pigs, and rabbits. In one embodiment, the subject or patient is a human.
• the terms “affected with a disease or disorder,” “afflicted with a disease or disorder,” or “having a disease or disorder” are used interchangeably herein and refer to a subject or patient with any disease, disorder, syndrome or condition. No increased or decreased level of severity of the disorder is implied by the use of one the terms as compared to the other.
• disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
• combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
• any one of the listed items can be employed by itself or in combination with any one or more of the listed items.
• the expression “A and/or B” is intended to mean either or both of A and B, i.e., A alone, B alone or A and B in combination.
• the expression “A, B and/or C” is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination or A, B, and C in combination.
• composition “comprising” encompasses “including” as well as “consisting” e.g., a composition “comprising” X may consist exclusively of X or may include something additional e.g., X+Y.
• ITT intention-to-treat
• Per-protocol population is defined as a subset of the ITT population who completed the study without any major protocol violations. See, e.g., Gupta S K, Intention-to-treat concept: A review, Perspect Clin Res. 2011 July-September; 2(3): 109-112.
• thyroid Eye Disease TED
• Thyroid-associated Ophthalmopathy TEO
• Thyroid Inflammatory Eye Disease TIED
• GO Graves' Ophthalmopathy
• GO Graves' Orbitopathy
• proptosis and exophthalmos refer to the forward projection, displacement, bulging, or protrusion of an organ. As used herein, the terms refer to the forward projection, displacement, bulging, or protrusion of the eye anteriorly out of the orbit.
• Proptosis and exophthalmos are considered by some of skill in the art to have the same meaning and are often used interchangeably, while others attribute subtle differences to their meanings. Exophthalmos is used by some to refer to severe proptosis; or to refer to endocrine-related proptosis. Yet others use the term exophthalmos when describing proptosis associated with the eye, in, for example, subjects with TED (TAO or GO).
• Proptosis and exophthalmos are used interchangeably and refer 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 eyeball forward.
• Proptosis or exophthalmos can be the result of a several disease processes including infections, inflammations, tumors, trauma, metastases, endocrine lesions, vascular diseases & extra orbital lesions.
• TED TEO or GO
• Exophthalmos can be either bilateral, as is often seen in TED (TAO or GO), or unilateral (as is often seen in an orbital tumor).
• Measurement of the degree of exophthalmos can be performed using an exophthalmometer, an instrument used for measuring the degree of forward displacement of the eye.
• the device allows measurement of the forward distance of the lateral orbital rim to the front of the cornea.
• Computed tomography (CT) scanning and Magnetic resonance imaging (MRI) may also be used in evaluating the degree of exophthalmos or proptosis.
• CT scanning is an excellent imaging modality for the diagnosis of TED (TAO or GO).
• TEO Magnetic resonance imaging
• CT scans provide the surgeon or clinician with depictions of the bony anatomy of the orbit when an orbital decompression is required.
• MRI with its multi-planar and inherent contrast capabilities, provides excellent imaging of the orbital contents without the radiation exposure associated with CT scan studies. MRI provides better imaging of the optic nerve, orbital fat, and extraocular muscle, but CT scans provide better views of the bony architecture of the orbit.
• Orbital ultrasonography can also be a used for the diagnosis and evaluation of TED (TAO or GO), because it can be performed quickly and with a high degree of confidence. High reflectivity and enlargement of the extraocular muscles are assessed easily, and serial ultrasonographic examinations can also be used to assess progression or stability of the ophthalmopathy.
• the normal range of proptosis is 12-21 mm, it must be noted that the value for a normal person varies by age, gender and race. For example, in normal adult white males, the average distance of globe protrusion is 16.5 mm, with the upper limit of normal at 21.7 mm. In adult African Americans it averages 18.2 mm, with an upper normal limit of 24.1 mm in males and 22.7 mm in females. In Mexican adults, males averaged 15.2 mm and females averaged 14.8 mm and in Iran, for the age group of 20-70 years, the average was 14.7 mm. In Taiwanese adults, comparing normal subjects to those with Graves' Ophthalmopathy, the normal group had an average reading of 13.9 mm versus 18.3 mm for the TED group.
• CAS refers to the protocol described and scored as disclosed below. According to this protocol, one point is given for the presence of each of the parameters assessed in the list below. The sum of all points defines clinical activity and provides the CAS. For patients assessed for the first time only items 1-7 are scored. A CAS ⁇ 3/7 indicates active GO. For patients that are assessed for the second or subsequent time (typically, 1-3 months later), items 8-10 are also scored; and a CAS ⁇ 4/10 indicates active disease. A ten-item CAS scale exists as well, but in clinical trials, the 7-item scale is generally used, being more amenable to longitudinal studies involving multiple assessments.
• the CAS consists of seven components:
• 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.
• 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 with upward, downward, or lateral eye movement, or when attempting upward, downward, or lateral gaze. This kind of pain could arise from the stretching of the inflamed muscle(s), especially on attempted up-gaze.
• 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 TED activity.
• TED TED
• chemosis edema of the conjunctiva
• swelling of the caruncule and/or plica semilunaris Both are signs of TED activity.
• Swollen eyelids can be caused by edema, fat prolapse through the orbital septum, or fibrotic degeneration.
• other symptoms indicative of active TED include redness and/or pain of the conjunctiva, eyelid, caruncule and/or plica semilunaris.
• VISA is more commonly used in North America and Canada while EUGOGO is in Europe. Since the VISA and EUGOGO protocols are not interchangeable, only one of them should be employed as a reference in a specific patient.
• QoL quality of life
• GO-QoL Graves' ophthalmopathy quality of life
• the GO-QoL questionnaire has two self-assessment subscales. The first relates to the impact of visual function on daily activities, while the second relates to the impact of self-perceived appearance.
• Each subscale has 8 questions which are answered with: (i) yes—very much so; (ii) yes—a little; or (iii) no—not at all.
• Each question is scored 0-2, respectively, 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. A change of >8 points on the 0-100 scale is considered to be clinically meaningful.
• the combined score takes raw scores from both subscales and again transforms them to a single 0-100 scale.
• the distance between the lid margins are measured (in mm) with the patient looking in the primary position, sitting relaxed, and with distant fixation.
• the measure/evaluation is either “absent/equivocal,” “moderate,” or “severe.” Redness of the eyelids is either absent or present. Redness of the conjunctivae is either absent or present.
• Conjunctival edema is either absent or present.
• Inflammation of the caruncle or plica is either absent or present.
• Exophthalmos was measured in millimeter using the same Hertel exophthalmometer and same intercanthal distance for an individual patient.
• eye muscle involvement the ductions are measured in degrees. Corneal involvement is either absent/punctate or keratopathy/ulcer.
• optic nerve involvement i.e., best-corrected visual acuity, color vision, optic disc, relative afferent pupillary defect, the condition is either absent or present.
• visual fields are checked if optic nerve compression was suspected.
• Sight-threatening thyroid eye disease Patients with dysthyroid optic neuropathy (DON) and/or corneal breakdown. This category warranted immediate intervention.
• DON dysthyroid optic neuropathy
• corneal breakdown This category warranted immediate intervention.
• Moderate-to-severe thyroid eye disease Patients without sight-threatening disease whose eye disease had sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate-to-severe thyroid eye disease usually had any one or more of the following: lid retraction ⁇ 2 mm, moderate or severe soft tissue involvement, exophthalmos ⁇ 3 mm above normal for race and gender, inconstant or constant diplopia.
• Mild thyroid eye disease Patients whose features of thyroid eye disease have only a minor impact on daily life insufficient to justify immunosuppressive or surgical treatment. They usually have only one or more of the following: minor lid retraction ( ⁇ 2 mm), mild soft tissue involvement, exophthalmos ⁇ 3 mm above normal for race and gender, transient or no diplopia, and corneal exposure responsive to lubricants.
• 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. An improvement of ⁇ 1 grade is considered clinically meaningful.
• IGR-1R inhibitors described herein may be useful for the treatment of TED in subjects who were either proptosis non-responders ( ⁇ 2 mm reduction in proptosis in the study eye) in the lead-in study or were proptosis responders in the lead-in study but meet the criteria for re-treatment due to relapse.
• the sequences of the heavy chains and light chains of examples of antibodies that may be used in the methods disclosed herein, each comprising three CDRs on the heavy chain and three CDRs on the light chain are provided below.
• the sequences of the CDRs, heavy chains, light chains as well as the sequences of the nucleic acid molecules encoding the CDRs, heavy chains and light chains of the antibodies are disclosed in the sequence listing.
• the CDRs of the antibody heavy chains are referred to as CDRH1 (or HCDR1), CDRH2 (or HCDR2) and CDRH3 (or HCDR3), respectively.
• the CDRs of the antibody light chains are referred to as CDRL1 (or LCDR1), CDRL2 (or LCDR2) and CDRL3 (or LCDR3), respectively.
• variants of the sequences recited in the application are also included within the scope of the disclosure.
• variants include natural variants generated by somatic mutation in vivo during the immune response or in vitro upon culture of immortalized B cell clones.
• variants may arise due to the degeneracy of the genetic code or may be produced due to errors in transcription or translation.
• antibody sequences having improved affinity and/or potency may be obtained using methods known in the art and are included within the scope of the disclosure.
• amino acid substitutions may be used to obtain antibodies with further improved affinity.
• codon optimization of the nucleotide sequence may be used to improve the efficiency of translation in expression systems for the production of the antibody.
• polynucleotides comprising a sequence optimized for antibody specificity or neutralizing activity by the application of a directed evolution method to any of the nucleic acid sequences disclosed herein are also within the scope of the disclosure.
• variant antibody sequences may share 70% or more (i.e. 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or more) amino acid sequence identity with the sequences recited in the application.
• sequence identity is calculated with regard to the full length of the reference sequence (i.e. the sequence recited in the application).
• Antibodies, or antigen binding fragments thereof, used with the methods disclosed herein can be of any isotype (e.g., IgA, IgG, IgM; i.e., an ⁇ , ⁇ or ⁇ heavy chain).
• the antibody is IgG.
• antibodies may be IgG1, IgG2, IgG3 or IgG4 subclass.
• the antibodies may have a ⁇ or a ⁇ light chain.
• the antibodies, or an antigen binding fragments thereof, used with the methods disclosed herein can be administered by any route known to one of skill in the art.
• FcRn neonatal receptor
• the antibody may determine its clearance rate (e.g. stability and half-life) in vivo.
• clearance rate e.g. stability and half-life
• factors that contribute to clearance and half-life are serum aggregation, enzymatic degradation in the serum, inherent immunogenicity of the antibody leading to clearing by the immune system, antigen-mediated uptake, FcR (non-FcRn) mediated uptake and non-serum distribution (e.g. in different tissue compartments).
• PK pharmacokinetics
• PD pharmacodynamics
• substitutions in the Fc domains are chosen such that the resultant proteins show improved serum half-life in vivo as compared to the wild type protein.
• the increase in binding affinity must be at around pH 6 while maintaining lower affinity at around pH 7.4.
• Fc regions are believed to have longer half-lives in vivo because binding to FcRn at pH 6 in an endosome sequesters the Fc.
• the endosomal compartment then recycles the Fc to the cell surface. Once the compartment opens to the extracellular space, the higher pH ( ⁇ 7.4) induces the release of Fc back into the blood.
• Fc mutations that increase Fc's half-life in vivo generally increase FcRn binding at the lower pH while still allowing release of Fc at higher pH.
• the amino acid histidine changes its charge state in the pH range of 6.0 to 7.4. Therefore, it is not surprising to find histidine residues at important positions in the Fc/FcRn complex.
• the increase in FcRn binding over wild type specifically at lower pH ( ⁇ 6.0) facilitates Fc/FcRn binding in the endosome.
• Fc variants with altered FcRn binding can have altered binding to another class of Fc receptors, the Fc ⁇ R's (FcgammaR's) as differential binding to Fc ⁇ R5, particularly increased binding to Fc ⁇ RIIIb and decreased binding to Fc ⁇ RIIb, has been shown to result in increased efficacy.
• IgG1 is a common isotype for therapeutic antibodies for a variety of reasons, including high effector function.
• IgG2 residues at particular positions can be introduced into the IgG1 backbone to result in a protein that exhibits longer serum half-life.
• non-isotypic amino acid changes are made, to improve binding to FcRn and/or to increase in vivo serum half-life, and/or to allow accommodations in structure for stability, etc.
• the FcRn variants described herein can transfer to different ligands to give the same trends of increasing half-life. That is, in general, the relative “order” of the FcRn binding/half-life increases will track to antibodies with the same variants of antibodies with different Fvs as is discussed herein.
• Fc variants within a therapeutic antibody are made by introducing amino acid mutations into the parent molecule. “Mutations” in this context are usually amino acid substitutions, although as shown herein, deletions and insertions of amino acids can also be done and thus are defined as mutations.
• FcRn or “neonatal Fc Receptor” as used herein is meant a protein that binds the IgG antibody Fc region and is encoded at least in part by an FcRn gene.
• the FcRn may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys.
• the functional FcRn protein comprises two polypeptides, often referred to as the heavy chain and light chain.
• the light chain is beta-2-microglobulin and the heavy chain is encoded by the FcRn gene.
• FcRn or an FcRn protein refers to the complex of FcRn heavy chain with beta-2-microglobulin.
• the FcRn variants bind to the human FcRn receptor, or it may be desirable to design variants that bind to rodent or primate receptors in addition, to facilitate clinical trials.
• the present disclosure provides compositions and methods of administering an antibody to a subject, where the antibody comprises a variant Fc region as compared to a parent Fc region, wherein the variant Fc region comprises a first mutation that is a leucine at position 428 and a second mutation that is a serine at position 434, where the antibody has increased serum half-life as compared to an antibody comprising the parent Fc region, and wherein numbering is according to the EU index.
• the antibody disclosed herein comprises a variant Fc region comprising mutations that substitute a methionine at position 428 with a leucine (Met428Leu) and substitutes an asparagine at position 434 with a serine (Asn434Ser).
• the present disclosure includes variants of Fc domains, including those found in antibodies, Fc fusions, and immuno-adhesions, which have an increased binding to the FcRn receptor. As noted herein, binding to FcRn results in longer serum retention in vivo.
• substitutions including those related to M428L/N434S—are known and described in U.S. Pat. Nos. 7,317,091; 8,084,582; and 8,101,720; 8,188,231; 8,367,805; and 8,546,543, each of which is incorporated herein by reference in their entirety.
• the compound, antibody, or an antigen binding fragment thereof can be administered in a single dose or in multiple doses.
• the therapeutic antibody is administered to the subject in a single dose.
• the therapeutic antibody is administered to the subject in multiple doses, spread out over the course of a few days, weeks or months.
• the antibody, or an antigen binding fragment thereof is administered every week or every 2 weeks or every 3 weeks or every 4 weeks or every 5 weeks or every 6 weeks or every 7 weeks or every 8 weeks or every month or every 2 months or every 3 months.
• the antibody, or an antigen binding fragment thereof is administered in multiple doses and the dosage is the same each time. In some embodiments the antibody, or an antigen binding fragment thereof, is administered in multiple doses and the dosage at the time of first administration is different (could be higher or lower) from those at subsequent times. In some embodiments the antibody, or an antigen binding fragment thereof, is administered in multiple doses and the dosage is adjusted at each administration based on the subject's response to the therapy.
• the dosage may further vary between patients, based on different factors such as the age, gender, race, and body weight of each patient. In some embodiments, the dosage varies by body weight of the patient. The dosage could range from about 1 mg of the antibody, or an antigen binding fragment thereof, per kilogram of body weight to about 100 mg of the antibody, or an antigen binding fragment thereof, per kilogram of body weight.
• the dosage could for example, be 1 mg, 2 mg, 3 mg, 5 mg, 7 mg, 10 mg, 12 mg, 15 mg, 17 mg, 20 mg, 22 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg, of the antibody, or an antigen binding fragment thereof, per kilogram of body weight.
• the dose is about 0.3 mg/kg to about 10 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dosage is about 0.3 mg/kg to about 5 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dosage is about 0.3 mg/kg to about 1 mg/kg of the antibody, or an antigen binding fragment thereof.
• the dosage could for example, be about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 8.5 mg/kg, about 9 mg/kg, about 9.5 mg/kg, or about 10 mg/kg, or any number of tenths of a mg/kg in between the foregoing, of the antibody
• the dose is about 0.6 mg/kg to about 20 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dosage is about 0.6 mg/kg to about 5 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dosage is about 0.6 mg/kg to about 10 mg/kg of the antibody, or an antigen binding fragment thereof.
• the dosage could for example, be about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 8.5 mg/kg, about 9 mg/kg, about 9.5 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/
• the dose is about 1 mg/kg to about 30 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dose is about 5 mg/kg to about 30 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dose is about 10 mg/kg to about 30 mg/kg of the antibody, or an antigen binding fragment thereof.
• the dosage could for example, be about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 5 mg/kg, about 7 mg/kg, about 10 mg/kg, about 12 mg/kg, about 15 mg/kg, about 17 mg/kg, about 20 mg/kg, about 22 mg/kg, about 25 mg/kg, or about 30 mg/kg, or any integer and/or number of tenths of a mg/kg in between the foregoing, of the antibody, or an antigen binding fragment thereof.
• the dose is administered every three weeks.
• the dose is about 1.2 mg/kg to about 40 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dose is about 5 mg/kg to about 40 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dose is about 10 mg/kg to about 40 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dose is about 20 mg/kg to about 40 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dose is about 25 mg/kg to about 40 mg/kg of the antibody, or an antigen binding fragment thereof.
• the dosage could for example, be about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 5 mg/kg, about 7 mg/kg, about 10 mg/kg, about 12 mg/kg, about 15 mg/kg, about 17 mg/kg, about 20 mg/kg, about 22 mg/kg, about 25 mg/kg, about 27 mg/kg, about 30 mg/kg, about 32 mg/kg, about 35 mg/kg, about 37 mg/kg, or about 40 mg/kg, or any integer and/or number of tenths of a mg/kg in between the foregoing, of the antibody, or an antigen binding fragment thereof.
• the dose is administered every four weeks.
• the dosage is about 1 mg/kg to about 5 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dosage is about 5 mg/kg to about 10 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dosage is about 10 mg/kg to about 15 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dosage is about 15 mg/kg to about 20 mg/kg of the antibody, or an antigen binding fragment thereof.
• the dosage is about 1 mg/kg to about 5 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dosage is about 5 mg/kg to about 10 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dosage is about 10 mg/kg to about 15 mg/kg of the antibody, or an antigen binding fragment thereof. In some embodiments, the dosage is about 15 mg/kg to about 20 mg/kg of the antibody, or an antigen binding fragment thereof.
• the antibody, or an antigen binding fragment thereof is administered in multiple doses and the dosage at the time of first administration is different from those at subsequent times, the dosage at the time of first administration is about 1 mg/kg to about 5 mg/kg of the antibody, or an antigen binding fragment thereof; or about 5 mg/kg to about 10 mg/kg of the antibody, or an antigen binding fragment thereof; or about 10 mg/kg to about 15 mg/kg of the antibody, or an antigen binding fragment thereof; or about 15 mg/kg to about 20 mg/kg of the antibody, or an antigen binding fragment thereof; or about 20 mg/kg to about 25 mg/kg of the antibody, or an antigen binding fragment thereof.
• the subsequent dose(s) could be higher or lower than the first dose.
• the subsequent dose is about 1 mg/kg to about 5 mg/kg of the antibody, or an antigen binding fragment thereof; or about 5 mg/kg to about 10 mg/kg of the antibody, or an antigen binding fragment thereof; or about 10 mg/kg to about 15 mg/kg of the antibody, or an antigen binding fragment thereof; or about 15 mg/kg to about 20 mg/kg of the antibody, or an antigen binding fragment thereof; or about 20 mg/kg to about 25 mg/kg of the antibody, or an antigen binding fragment thereof.
• Small molecule compounds may be administered orally, via injection, etc. at a dose of from 0.01 to 500 mg/kg per day and/or from 0.1 mg to 5 g per day.
• the dose range for adult humans is generally from 5 mg to 2 g/day.
• Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, for example around 10 mg to 200 mg.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated.
• the route of administration may vary depending on the condition and its severity.
• the duration of the treatment depends on the subject's response to the therapy and can range from about one month or 4 weeks to about 2 years or 100 weeks.
• the treatment may be provided over a total duration of about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 14 months, 16 months, 18 months, 20 months, 22 months or 2 years.
• the treatment may be provided over a total duration of 4, 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52 weeks, or extended to 56, 64, 72, 80, 88, 96 or 104 weeks.
• the antibody, or an antigen binding fragment thereof is administered for a duration of 24 weeks at intervals of 3 weeks starting with an initial dose of 10 mg per kilogram of body weight, followed by 20 mg per kilogram for seven additional treatments.
• the slam molecule compound is administered daily (QD), twice daily, (BID) or thrice daily (TID) for an appropriate duration, e.g., 24 weeks.
• the compound, antibody, or an antigen binding fragment thereof may be administered by any suitable route including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intraperitoneal, intrathecal, intraventricular, transdermal, transcutaneous, topical, subcutaneous, intranasal, enteral, sublingual, intravaginal or rectal routes. Hyposprays may also be used to administer the pharmaceutical compositions disclosed herein.
• the therapeutic antibody may be prepared as a freeze-dried (lyophilized) powder or as an injectable, either as a liquid solution or suspension. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be used.
• compositions used in the methods disclosed herein comprise one or more of: the antibodies or antibody fragments described above and a pharmaceutically acceptable carrier or excipient.
• a pharmaceutically acceptable carrier or excipient may facilitate administration, it should not itself induce the production of antibodies harmful to the subject or individual receiving the composition; nor should it be toxic.
• Suitable carriers may be large, slowly metabolized macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers and inactive virus particles, and are known to one of skill in the art.
• the antibodies, or an antigen binding fragments thereof, or pharmaceutical compositions used with the methods disclosed herein may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intraperitoneal, intrathecal, intraventricular, transdermal, transcutaneous, topical, subcutaneous, intranasal, enteral, sublingual, intravaginal or rectal routes. Hyposprays may also be used to administer the pharmaceutical compositions disclosed herein.
• the therapeutic compositions may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
• the antibody, or an antigen binding fragment thereof, or pharmaceutical composition is administered intravenously. In another embodiment, the antibody, or an antigen binding fragment thereof, or pharmaceutical composition is administered by intravenous infusion.
• Direct delivery of the compositions will generally be accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivered to the interstitial space of a tissue.
• the compositions can also be administered into a lesion.
• Dosage treatment may be a single dose schedule or a multiple dose schedule.
• Known antibody-based pharmaceuticals provide guidance relating to frequency of administration e.g., whether a pharmaceutical should be delivered daily, weekly, monthly, etc. Frequency and dosage may also depend on the severity of symptoms.
• the active ingredient in the composition will be an antibody molecule, an antibody fragment or variants and derivatives thereof. As such, it will be susceptible to degradation in the gastrointestinal tract. Thus, if the composition is to be administered by a route using the gastrointestinal tract, the composition will need to contain agents which protect the antibody from degradation, but which release the antibody once it has been absorbed from the gastrointestinal tract.
• the SC capillaries have low passive permeability; absorption of mAbs into systemic circulation occurs via lymphatic uptake from the interstitial space, as well as via active transport by the neonatal Fc receptor (FcRn) across the capillary endothelia.
• FcRn neonatal Fc receptor
• the extracellular matrix of the subcutaneous tissue also limits the injection of larger volumes (>1-2 mL) SC generally; coformulation with a recombinant hyaluronidase or soluble fragment thereof such as rHuPH20 can permit higher bioavailability.
• physiochemical properties of mAbs including charge, hydrophobicity, and stability, affect the rate and extent of their SC absorption; for example, the combination of high positive charge and hydrophobic interaction can reduce the rate absorption.
• compositions suitable for use in the methods disclosed herein are formulated for subcutaneous administration.
• formulations suitable for subcutaneous administration include, but are not limited to, solutions, suspensions, emulsions, and dry products that can be dissolved or suspended in a pharmaceutically acceptable carrier for injection.
• Antibodies have been, and may be, formulated for subcutaneous administration using methods known in the art.
• compositions suitable for use in the methods disclose herein comprise one or more pharmaceutically acceptable carriers, such as those widely employed in the art of drug manufacturing, and particularly antibody drug manufacturing.
• Pharmaceutically acceptable carriers in particular are non-toxic and should not interfere with the efficacy of the active ingredient.
• the carrier may be a diluent, adjuvant, excipient, or vehicle with which the antibodies are administered.
• Such vehicles may be liquids, such as aqueous fluids, oils, and emulsions. For example, 0.4% saline and 0.3% glycine may be used.
• the solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration).
• compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, stabilizing, thickening, lubricating and coloring agents, etc.
• concentration of the antibodies in such pharmaceutical formulation may vary and will be selected primarily based on required dose, fluid volumes, viscosities, etc., according to the particular mode of administration selected, and other concerns, such as protein aggregation.
• Examples of pharmaceutically acceptable carriers are solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible, such as salts, buffers, antioxidants, saccharides, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifying agents, permeation enhancers, or combinations thereof.
• buffers examples include acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffers, HEPPSO and HEPES.
• antioxidants examples include ascorbic acid, methionine, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, lecithin, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol and tartaric acid.
• amino acids examples include histidine, isoleucine, methionine, glycine, arginine, lysine, L-leucine, tri-leucine, alanine, glutamic acid, L-threonine, and 2-phenylamine.
• surfactants examples include polysorbates (e.g., polysorbate-20 or polysorbate-80); polyoxamers (e.g, poloxamer 188); Triton; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g, lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl
• preservatives examples include phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof.
• saccharides examples include monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, nonreducing sugars such as glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, dextran, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, mellibiose, melezitose, raffmose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol or iso-maltulose.
• permeation enhancers examples include recombinant hyaluronidase or soluble fragment thereof such as rHuPH20 (Halozyme).
• Liquid formulations for subcutaneous administration may comprise rHuPH20 or another soluble human hyaluronidase enzyme.
• rHuPH20 may be present in an amount sufficient to result in an increase in the dispersion of the antibodies contained in the same liquid formulation during subcutaneous administration.
• the amounts of pharmaceutically acceptable carrier(s) in the pharmaceutical compositions may be determined experimentally based on the activities of the carrier(s) and the desired characteristics of the formulation, such as stability, bioavailability, and/or minimal oxidation.
• the methods of the present disclosure can use an antibody, or an antigen binding fragment thereof, as described above, alone or in combination with other pharmaceutically active compounds, to treat conditions such as those disclosed hereinabove.
• the additional pharmaceutically active compound(s) can be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.
• the present disclosure comprises methods for treating a condition by administering to the subject a therapeutically-effective amount of an antibody, or an antigen binding fragment thereof, of the present disclosure and one or more additional pharmaceutically active compounds.
• the antibody, or an antigen binding fragment thereof, of the present disclosure is used in combination with existing therapies, including, but not limited to, corticosteroids; rituximab and other anti-CD20 antibodies; tocilizumab and other anti-IL-6 antibodies; or selenium, infliximab and other anti-TNF-alpha antibodies.
• the antibody, or an antigen binding fragment thereof, of the present disclosure is used in combination with TSHR inhibitors.
• said IGF-1R inhibitor is an antibody or a subset of antibodies chosen from amongst the Examples below.
• said IGF-1R inhibitor is a small molecule or a subset of small molecules chosen from amongst the Examples below.
• teprotumumab (TEPEZZA), an IGF-1R inhibitor approved for the treatment of TED.
• Teprotumumab and other related IGF-1R inhibitor antibodies and their methods of preparation can be found in U.S. Pat. No. 7,572,897, US20190225696, and US20190270820, which are hereby incorporated by reference in their entireties.
• teprotumumab may be used as an active control in clinical trials of other IGF-1R inhibitors, e.g. as in Example 31.
• Dalotuzumab and other related IGF-1R inhibitor antibodies and their methods of preparation can be found in WO 2005/058967, which is hereby incorporated by reference in its entirety.
• Heavy Chain CDRs - Dalotuzumab HCDR 1 HCDR2 HCDR3 GGYLWN YISYDGTNNYKPSLKD YGRVFFDY (SEQ ID NO: 1) (SEQ ID NO: 2) (SEQ ID NO: 3) Light Chain CDRs - Dalotuzumab LCDR 1 LCDR2 LCDR3 RSSQSIVHSNGNTYLQ KVSNRLY FQGSHVPWT (SEQ ID NO: 4) (SEQ ID NO: 5) (SEQ ID NO: 6) Heavy Chain QVQLQESGPGLVKPSETLSLTCTVSGYSIT GGYLWN WIRQPPGKGLE (HC) WIG YISYDGTNNYKPSLKD RVTISRDTSKNQFSLKLSSVTAADTAVYY CAR YGRVFFDY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS
• anti-IGF-1R inhibitor mAbs or antigen binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises an amino acid sequence SEQ ID NO:1, the variable heavy chain CDR2 comprises an amino acid sequence SEQ ID NO:2; and the variable heavy chain CDR3 comprises an amino acid sequence SEQ ID NO:3 or at least a CDR with at least 80% of sequence identity after optimal alignment with SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3.
• the anti-IGF-1R inhibitor mAbs or antibody or antigen binding fragment thereof may additionally comprise a light chain which is paired with the heavy chain to form an antigen binding domain.
• the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises an amino acid sequence SEQ ID NO:4, the variable light chain CDR2 comprises an amino acid sequence SEQ ID NO:5; and the variable light chain CDR3 comprises an amino acid sequence SEQ ID NO:6 or at least a CDR with at least 80% of homology after optimal alignment with SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO:7 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:7.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof may comprise a light chain having an amino acid sequence of SEQ ID NO:8 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:8.
• Heavy Chain CDRs - Ganitumab HCDR1 HCDR2 HCDR3 SSNWWS EIYHSGSTNYNPSLKS WTGRTDAFDI (SEQ ID NO: 9) (SEQ ID NO: 10) (SEQ ID NO: 11)
• Light Chain CDRs - Ganitumab LCDR1 LCDR2 LCDR3 ISCRSSQSLLHSNGYNYLD LGSNRAS MQGTHWPLT (SEQ ID NO: 12) (SEQ ID NO: 13) (SEQ ID NO: 14) Heavy Chain QVQLQESGPGLVKPSGTLSLTCAVSGGSIS SSNWWS WVRQPPGKGLE (HC) WIG EIYHSGSTNYNPSLKS RVTSVDKSKNQFSLKLSSVTAAD TAVYYCAR WTGRTDAFDI WGQGTMVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSV
• anti-IGF-1R inhibitor mAbs or antigen binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises an amino acid sequence SEQ ID NO:9, the variable heavy chain CDR2 comprises an amino acid sequence SEQ ID NO:10; and the variable heavy chain CDR3 comprises an amino acid sequence SEQ ID NO:11 or at least a CDR with at least 80% of sequence identity after optimal alignment with SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11.
• the anti-IGF-1R inhibitor mAbs or antibody or antigen binding fragment thereof may additionally comprise a light chain which is paired with the heavy chain to form an antigen binding domain.
• the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises an amino acid sequence SEQ ID NO:12, the variable light chain CDR2 comprises an amino acid sequence SEQ ID NO:13; and the variable light chain CDR3 comprises an amino acid sequence SEQ ID NO:14 or at least a CDR with at least 80% of homology after optimal alignment with SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO:15 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:15.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof may comprise a light chain having an amino acid sequence of SEQ ID NO:16 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:16.
• Xentuzumab and other related IGF-1R inhibitor antibodies and their methods of preparation can be found in WO 2014/135611, which is hereby incorporated by reference in its entirety.
• Heavy Chain CDRs - Xentuzumab HCDR1 HCDR2 HCDR3 SYWMS SITSYGSFTYADSVK NMYTHFDS (SEQ ID NO: 17) (SEQ ID NO: 18) (SEQ ID NO: 19)
• Light Chain CDRs - Xentuzumab LCDR1 LCDR2 LCDR3 SGSSSNIGSNSVS DNSKRPS QSRDTYGYYWV (SEQ ID NO: 20) (SEQ ID NO: 21) (SEQ ID NO: 22) QSRDTYGYYWV Heavy Chain QVELVESGGGLVQPGGSLRLSCAASGFTFTSYWM (HC) SWVRQAPGKGLELVSSITSYGSFTYYADSVKGRF TISRDNSKNTLYLQMNSLRAEDTAVYYCARNMYT HFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLY
• anti-IGF-1R inhibitor mAbs or antigen binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises an amino acid sequence SEQ ID NO:17, the variable heavy chain CDR2 comprises an amino acid sequence SEQ ID NO:18; and the variable heavy chain CDR3 comprises an amino acid sequence SEQ ID NO:19 or at least a CDR with at least 80% of sequence identity after optimal alignment with SEQ ID NO:17, SEQ ID NO:18, and SEQ ID NO:19.
• the anti-IGF-1R inhibitor mAbs or antibody or antigen binding fragment thereof may additionally comprise a light chain which is paired with the heavy chain to form an antigen binding domain.
• the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises an amino acid sequence SEQ ID NO:20, the variable light chain CDR2 comprises an amino acid sequence SEQ ID NO:21; and the variable light chain CDR3 comprises an amino acid sequence SEQ ID NO:22 or at least a CDR with at least 80% of homology after optimal alignment with SEQ ID NO:20, SEQ ID NO:21, and SEQ ID NO:22.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO:23 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:23.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof may comprise a light chain having an amino acid sequence of SEQ ID NO:24 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:24.
• anti-IGF-1R inhibitor mAbs or antigen binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises an amino acid sequence SEQ ID NO:25, the variable heavy chain CDR2 comprises an amino acid sequence SEQ ID NO:26; and the variable heavy chain CDR3 comprises an amino acid sequence SEQ ID NO:27 or at least a CDR with at least 80% of sequence identity after optimal alignment with SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27.
• the anti-IGF-1R inhibitor mAbs or antibody or antigen binding fragment thereof may additionally comprise a light chain which is paired with the heavy chain to form an antigen binding domain.
• the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises an amino acid sequence SEQ ID NO:28, the variable light chain CDR2 comprises an amino acid sequence SEQ ID NO:29; and the variable light chain CDR3 comprises an amino acid sequence SEQ ID NO:30 or at least a CDR with at least 80% of homology after optimal alignment with SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO:31 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NOs:31, 78, or 79.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof may comprise a light chain having an amino acid sequence of SEQ ID NO:32 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NOs:32, 80, 81, 82, or 83.
• Figitumumab and other related IGF-1R inhibitor antibodies and their methods of preparation can be found in U.S. Pat. No. 7,037,498 which is hereby incorporated by reference in its entirety.
• anti-IGF-1R inhibitor mAbs or antigen binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises an amino acid sequence SEQ ID NO:33, the variable heavy chain CDR2 comprises an amino acid sequence SEQ ID NO:34; and the variable heavy chain CDR3 comprises an amino acid sequence SEQ ID NO:35 or at least a CDR with at least 80% of sequence identity after optimal alignment with SEQ ID NO:33, SEQ ID NO:34, and SEQ ID NO:35.
• the anti-IGF-1R inhibitor mAbs or antibody or antigen binding fragment thereof may additionally comprise a light chain which is paired with the heavy chain to form an antigen binding domain.
• the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises an amino acid sequence SEQ ID NO:36, the variable light chain CDR2 comprises an amino acid sequence SEQ ID NO:37; and the variable light chain CDR3 comprises an amino acid sequence SEQ ID NO:38 or at least a CDR with at least 80% of homology after optimal alignment with SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO:39 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:39.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof may comprise a light chain having an amino acid sequence of SEQ ID NO:40 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:40.
• Dusigitumab (MEDI-573) and other related IGF-1R inhibitor antibodies and their methods of preparation can be found in U.S. Pat. No. 7,939,637 which is hereby incorporated by reference in its entirety.
• anti-IGF-1R inhibitor mAbs or antigen binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises an amino acid sequence SEQ ID NO:41, the variable heavy chain CDR2 comprises an amino acid sequence SEQ ID NO:42; and the variable heavy chain CDR3 comprises an amino acid sequence SEQ ID NO:43 or at least a CDR with at least 80% of sequence identity after optimal alignment with SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43.
• the anti-IGF-1R inhibitor mAbs or antibody or antigen binding fragment thereof may additionally comprise a light chain which is paired with the heavy chain to form an antigen binding domain.
• the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises an amino acid sequence SEQ ID NO:44, the variable light chain CDR2 comprises an amino acid sequence SEQ ID NO:45; and the variable light chain CDR3 comprises an amino acid sequence SEQ ID NO:46 or at least a CDR with at least 80% of homology after optimal alignment with SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO:39 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:47.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof may comprise a light chain having an amino acid sequence of SEQ ID NO:40 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:48.
• anti-IGF-1R inhibitor mAbs or antigen binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises an amino acid sequence SEQ ID NO:49, the variable heavy chain CDR2 comprises an amino acid sequence SEQ ID NO:50; and the variable heavy chain CDR3 comprises an amino acid sequence SEQ ID NO:51 or at least a CDR with at least 80% of sequence identity after optimal alignment with SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51.
• the anti-IGF-1R inhibitor mAbs or antibody or antigen binding fragment thereof may additionally comprise a light chain which is paired with the heavy chain to form an antigen binding domain.
• the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises an amino acid sequence SEQ ID NO:52, the variable light chain CDR2 comprises an amino acid sequence SEQ ID NO:53; and the variable light chain CDR3 comprises an amino acid sequence SEQ ID NO:54 or at least a CDR with at least 80% of homology after optimal alignment with SEQ ID NO:52, SEQ ID NO:53, and SEQ ID NO:54.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO:55 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:55.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof may comprise a light chain having an amino acid sequence of SEQ ID NO:56 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:56.
• BIIB022 and other related IGF-1R inhibitor antibodies and their methods of preparation can be found in U.S. Pat. No. 7,612,178 which is hereby incorporated by reference in its entirety.
• Heavy Chain CDRs - B11B022 HCDR1 HCDR2 HCDR3 IYRMQ GISPSGGTTWYADSVKG WSGGSGYAFDI (SEQ ID NO: 57) (SEQ ID NO: 58) (SEQ ID NO: 59) Light Chain CDRs - B11B022 LCDR1 LCDR2 LCDR3 QASRDIRNYN DASSLQT QQFDSLPHT (SEQ ID NO: 60) (SEQ ID NO: 61) (SEQ ID NO: 62) Heavy Chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYRMQWVRQAPGKGLEW (HC) VSGISPSGGTTWYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCARWSGGSGYAFDIWGQGTMVTVSS (SEQ ID NO: 63) Light Chain DIQMTQSPLSLSASVGDRVTITCQASRDIRNYLNWYQQKPGKAPKLLI
• anti-IGF-1R inhibitor mAbs or antigen binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises an amino acid sequence SEQ ID NO:57, the variable heavy chain CDR2 comprises an amino acid sequence SEQ ID NO:58; and the variable heavy chain CDR3 comprises an amino acid sequence SEQ ID NO:59 or at least a CDR with at least 80% of sequence identity after optimal alignment with SEQ ID NO:57, SEQ ID NO:58, and SEQ ID NO:59.
• the anti-IGF-1R inhibitor mAbs or antibody or antigen binding fragment thereof may additionally comprise a light chain which is paired with the heavy chain to form an antigen binding domain.
• the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises an amino acid sequence SEQ ID NO:60, the variable light chain CDR2 comprises an amino acid sequence SEQ ID NO:61; and the variable light chain CDR3 comprises an amino acid sequence SEQ ID NO:62 or at least a CDR with at least 80% of homology after optimal alignment with SEQ ID NO:60, SEQ ID NO:61, and SEQ ID NO:62.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO:63 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:63.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof may comprise a light chain having an amino acid sequence of SEQ ID NO:64 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:64.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO:65 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:65.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof may comprise a light chain having an amino acid sequence of SEQ ID NO:66 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:66.
• said IGF-1R inhibitor is a small molecule.
• Linsitinib and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 8,101,613, which is hereby incorporated by reference in its entirety. Linsitinib and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• Picropodophyllin (AXL1717) and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in US U.S. Pat. No. 4,567,253, which is hereby incorporated by reference in its entirety. Picropodophyllin and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• GTX-134 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 8,063,225, which is hereby incorporated by reference in its entirety.
• GTX-134 and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• AG1024 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in WO1995024190, which is hereby incorporated by reference in its entirety.
• AG1024 and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• BMS-536924 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 7,081,454, which is hereby incorporated by reference in its entirety.
• BMS-536924 and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• NVP-AEW541 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 7,326,699, which is hereby incorporated by reference in its entirety.
• NVP-AEW541 and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• BMS-754807 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 7,534,792, which is hereby incorporated by reference in its entirety.
• BMS-754807 and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• GSK1838705A and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 7,981,903, which is hereby incorporated by reference in its entirety.
• GSK1838705A and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• BMS-554417 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 7,081,454, which is hereby incorporated by reference in its entirety.
• BMS-554417 and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• NVP-ADW742 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 7,326,699, which is hereby incorporated by reference in its entirety.
• NVP-ADW742 and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• GSK1904529A and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 8,093,239, which is hereby incorporated by reference in its entirety.
• GSK1904529A and the other IGF-1R inhibitors described therein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• KW-2450 shown above as the tosylate salt but not limited thereto, and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in WO2006080450, U.S. Pat. No. 7,605,272, and WO2011158931, which are hereby incorporated by reference in their entireties.
• KW-2450 and the other IGF-1R inhibitors described herein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• PL-225B and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in WO2012145471 and WO2012007926, which is hereby incorporated by reference in its entirety.
• PL225B selectively inhibits IGF-1 R, resulting in inhibition of tumor cell proliferation and the induction of tumor cell apoptosis in IGF-1 R-overexpressing tumor cells.
• PL-225B and the other IGF-1R inhibitors described herein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• INSM-18 nordihydroguaiaretic acid (NDGA) (shown above with relative stereochemistry, in which case it is also referred to as Masoprocol or Actinex, but not limited thereto) referred to in this Example as INSM-18, and other related IGF-1R inhibitor small molecules and their methods of preparation can be found at least in U.S. Pat. No. 2,373,192, which is hereby incorporated by reference in its entirety.
• INSM-18 directly inhibits activation of IGF-1 R and the c-erbB2/HER2/neu receptor, resulting in decreased proliferation of susceptible tumor cell populations.
• INSM-18 and the other IGF-1R inhibitors described herein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• AZD3463 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 8,461,170, which is hereby incorporated by reference in its entirety.
• AZD3463 is a potent ALK/IGF-1 R inhibitor, resulting in inhibition of neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis.
• AZD3463 and the other IGF-1R inhibitors described herein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• AZD9362 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in Degorce, S L et al., “Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R),” J Med Chem (2016), 59(10), 4859-4866, which is hereby incorporated by reference in its entirety.
• IGF-1R Insulin-like Growth Factor-1 Receptor
• BI885578 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Ser. No. 10/414,769, U.S. Pat. No. 9,150,578, and Sanderson M P et al., “BI 885578, a Novel IGF1R/INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis,” Mol Cancer Ther 2015 December; 14(12):2762-72, which are hereby incorporated by reference in its entirety.
• BI885578 is an IGF1R/INSR tyrosine kinase inhibitor distinguished by rapid intestinal absorption and a short in vivo half-life as a result of rapid metabolic clearance, resulting in inhibition of cell proliferation and induction of apoptosis in tumors.
• BI885578 and the other IGF-1R inhibitors described herein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• BI893923 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 8,546,443 and Titze M I et al., “An allometric pharmacokinetic/pharmacodynamics model for BI 893923, a novel IGF-1 receptor inhibitor,” Cancer Chemother Pharmacol 2017 March; 79(3):545-558, which is hereby incorporated by reference in its entirety.
• BI893923 is an IGF1R/INSR tyrosine kinase inhibitor demonstrating anti-tumor efficacy and good tolerability.
• BI893923 and the other IGF-1R inhibitors described herein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• XL-228 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in US20090232828, which is hereby incorporated by reference in its entirety.
• XL-228 is a broad protein kinase inhibitor that contributes to cell proliferation, cell survival, and resistance to cytotoxic agents.
• XL-228 and the other IGF-1R inhibitors described herein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• A-928605 and other related IGF-1R inhibitor small molecules and their methods of preparation can be found in U.S. Pat. No. 7,772,231 and WO2007079164, which are hereby incorporated by reference in its entirety.
• A-928605 is a potent inhibitor of IGF-IR both on the purified enzyme and intracellular IGF-IR phosphorylation.
• A-928605 and the other IGF-1R inhibitors described herein are predicted to have activity in the activity measures or assessments for the treatment of TED described herein.
• Istiratumab and other related IGF-1R inhibitor antibodies and their methods of preparation can be found in U.S. Pat. No. 8,476,409, which is hereby incorporated by reference in its entirety.
• Heavy Chain CDRs - Istiratumab HCDR1 HCDR2 HCDR3 GFMFSRYPMH ISGSGGATPYADSVKG DFYQILTGNAFDY (SEQ ID NO: 67) (SEQ ID NO: 68) (SEQ ID NO: 69)
• Light Chain CDRs - Istiratumab LCDR1 LCDR2 LCDR3 RASQGISSYLA AKSTLQS QQYWTFPLT (SEQ ID NO: 70) (SEQ ID NO: 71) (SEQ ID NO: 72)
• Heavy Chain EVQLLQSGGGLVQPGGSLRLSCAASGFMFSRYPMHWVRQAPGKGLE (HC) WVGSISGSGGATPYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAV YYCAKDFYQILTGNAFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
• anti-IGF-1R inhibitor mAbs or antigen binding fragments thereof comprising a heavy chain comprising a variable heavy chain CDR1, a variable heavy chain CDR2, and a variable heavy chain CDR3, wherein the variable heavy chain CDR1 comprises an amino acid sequence SEQ ID NO:67, the variable heavy chain CDR2 comprises an amino acid sequence SEQ ID NO:68; and the variable heavy chain CDR3 comprises an amino acid sequence SEQ ID NO:69 or at least a CDR with at least 80% of sequence identity after optimal alignment with SEQ ID NO:67, SEQ ID NO:68, and SEQ ID NO:69.
• the anti-IGF-1R inhibitor mAbs or antibody or antigen binding fragment thereof may additionally comprise a light chain which is paired with the heavy chain to form an antigen binding domain.
• the light chain comprises a variable light chain CDR1, a variable light chain CDR2, and a variable light chain CDR3, wherein the variable light chain CDR1 comprises an amino acid sequence SEQ ID NO:70, the variable light chain CDR2 comprises an amino acid sequence SEQ ID NO:71; and the variable light chain CDR3 comprises an amino acid sequence SEQ ID NO:72 or at least a CDR with at least 80% of homology after optimal alignment with SEQ ID NO:70, SEQ ID NO:71, and SEQ ID NO:72.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof comprises a heavy chain amino acid sequence of SEQ ID NO:73 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:73.
• the anti-IGF-1R inhibitor mAbs or antigen binding fragment thereof may comprise a light chain having an amino acid sequence of SEQ ID NO:74 or at least a heavy chain with at least 85%, 90%, 95%, 97%, 98%, or 99% of sequence identity after optimal alignment with SEQ ID NO:74.
• Multicenter optionally double-masked, randomized, parallel-group, placebo- and/or active- (e.g., teprotumumab-) controlled clinical trials may be conducted to determine the efficacy and safety of any Study Drug disclosed herein in patients with either active/acute, or inactive/chronic, moderate-to-severe TED.
• the study may be conducted in male and non-pregnant female patients between the ages of 18 and 80 years, inclusive. Patients will be enrolled and randomly assigned on Day 1 in an appropriate ratio, (e.g., 1:1, 2:1, or 3:1) to receive placebo or active control or Study Drug administered as described herein.
• Subjects will be screened for the study within 4 weeks prior to the Baseline (Day 1) Visit. Subjects may be stratified by duration of disease, ⁇ 2 years or >2 years.
• Moderate to severe acute disease may be defined as: i) ⁇ 3 mm proptosis beyond race/gender norms or beyond patient's pre-TED, ii) clinical activity score of at least 3, and iii) within 15 months of symptom onset.
• Moderate to severe chronic disease may be defined as: i) ⁇ 3 mm proptosis beyond race/gender norms or beyond patient's pre-TED, ii) clinical activity score of 0 or 1, and iii) no significant progression or inflammatory symptoms within 1 year.
• the planned duration of the Treatment Period may be, e.g., 12, 24, or 48 weeks (3, 6, or 12 months), with an optional open-label extension study period.
• the End of the Treatment Period Wide 12, Week 24, or week 48, as appropriate—primary endpoint responders, as well as non-responders who choose not to enroll in the open-label extension study, or will enter a safety Follow-Up Period.
• Subjects who are considered non-responders at the end of the treatment period may enroll in the open-label extension study.
• All subjects will enter a Treatment Period of, e.g., 12-week or 24-week or 48-week. All study drug dosing or initial study drug dosing will be performed at the clinic under the supervision of clinic staff. On each dosing day, scheduled assessments (except for AE and concomitant medication use monitoring, which will be monitored throughout the clinic visit) will be completed prior to study drug dosing. Additional phone/email contacts and clinic visits may also be conducted for any subject experiencing a drug-related adverse event.
• the primary end point may be either proptosis or diplopia, e.g. in the study eye.
• Proptosis may be assessed either as proportion of responders (where a responder is defined as a patient experiencing a ⁇ 2 mm reduction from Baseline in the study eye without deterioration— ⁇ 2 mm increase—of proptosis in the fellow eye) or assessed as a continuous variable (i.e., average or median change from baseline), measured using a standardized exophthalmometer (e.g., Hertel).
• Diplopia may be assessed using any of the subject Gorman scale, the Goldman perimeter, or the cervical range of motion method, as long as the same assessment is used for all patients.
• Secondary end points may include: proptosis, diplopia, orbital pain, MDI and PVR for inferior rectus, superior rectus, the medial rectus, lateral rectus and orbital fat, clinical activity score (CAS), circumference of calf and area of the lesion, inflammatory and fibrotic biomarkers, transcriptomics associated with IGF-1R inhibition, and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire (GO-QoL) or appearance and functioning subscales thereof. Adverse events will also be assessed.
• GO-QoL Graves' ophthalmopathy-specific quality-of-life questionnaire
• the overall objective of the study will be to investigate the efficacy, safety, and tolerability of a monoclonal antibody (mAb) or small molecule inhibitor of the insulin-like growth factor-1 receptor (IGF-1R), in the treatment of subjects with acute or chronic TED.
• mAb monoclonal antibody
• IGF-1R insulin-like growth factor-1 receptor
• the primary objective is to evaluate the effect of Study Drug versus placebo or teprotumumab on the mean change from Baseline to End of the Treatment Period (Week 12, Week 24, or Week 48) in proptosis measurement or diplopia (measured by improvement in subjective Gorman scale, Goldmann perimeter, or Cervical range of motion method) in the study eye in subjects with Chronic/inactive TED.
• ADA Pharmacokinetic and Anti-drug Antibody
• the trial will comprise three phases: screening (28 days prior to Day 1), treatment or intervention period (Day 1 to Week 12, Week 24, and/or Week 48), and follow-up for, e.g., 6 weeks of more after the nd of the treatment period. Screening involves one to three visits. During the treatment period, patients will be assessed at Day 1/Baseline and every 3 weeks for 12, 24, or 48 weeks. Efficacy may be assessed throughout the Treatment Period, e.g.:
• Data from the end of the Treatment Period i.e. week 12, 24, or 48, will be used to assess the primary and secondary end points.
• a change of 2 points in the 7-component CAS will be considered to be clinically relevant, as will achievement of a CAS of 0 or 1 in acute/active TED patients.
• Proptosis will be assessed with the use of a Hertel exophthalmometer.
• a change of 2 mm will be considered to be clinically relevant.
• GO-QoL Graves' ophthalmopathy-specific quality-of-life questionnaire
• scores on each subscale as well as the score on the overall GO-QoL scale have a range of 0 to 100 points, with a change of 8 points being considered to be clinically relevant.
• Subjective diplopia will be assessed by improvement in subjective Gorman scale or Goldmann perimeter or Cervical range of motion method.
• Drugs for evaluation in TED in the present study may include any of the biologic or small molecule drugs listed in Examples 1-22.
• Teprotumumab may be provided according to its marketed formulation.
• Other study drugs will be provided as given below or as appropriate.
• the placebo will be appropriate to the given Study Drug, e.g. IV saline or buffer solution or matching placebo tablet/capsule.
• Patients will receive equivalent types and numbers of administrations of either a Study Drug listed in Table 1, or teprotumumab, or placebo. Dosages are provided below. For example, for subjects assigned to the teprotumumab group, the drug may be administered every 3 weeks starting with an initial dose of 10 mg per kilogram of body weight, followed by 20 mg per kilogram for the remaining infusions. Dosages or frequency of administration can be altered as deemed appropriate by a clinician or study coordinator.
• the lower end of the dose range appropriate for use in TED were estimated from the minimum concentration (C min ) that would achieve an in vitro IC 50 as disclosed in the art.
• the higher end of the dose range appropriate for use in TED was estimated as three-fold of the recommended phase 2 dose (RP2D) if it is not the maximum tolerated dose (MTD), or 2.5-fold of the RP2D if it is the MTD.
• RP2D recommended phase 2 dose
• MTD maximum tolerated dose
• the lower end of the dose range appropriate for use in TED were estimated from the maximum concentration (C max ) that would achieve an in vitro IC 50 as disclosed in the art.
• C max the maximum concentration
• the higher end of the dose range appropriate for use in TED was estimated as three-fold of the recommended phase 2 dose (RP2D) if it is not the maximum tolerated dose (MTD), or 2.5-fold of the RP2D if it is the MTD.
• RP2D recommended phase 2 dose
• MTD maximum tolerated dose
• Dose ranges in Table 1 are given as total dose for a 3-week interval (antibodies) or daily (small molecules) unless otherwise specified.
• (AXL1717) molecule BID BID 13-1400 mg; susp. (tested in or TID: 6-700 mg Ph2 NSCLC) 12 GTx-134 small ** 1-2000 mg QD; or 0.6-1400 mg oral molecule BID; or 0.3-700 mg TID. 13 AG1024 small ** 1-2000 mg QD; or 0.6-1400 mg oral molecule BID; or 0.3-700 mg TID. 14 BMS-536924 small ** 1-2000 mg QD; or 0.6-1400 mg oral molecule BID; or 0.3-700 mg TID. 15 NVP-AEW541 small ** 1-2000 mg QD; or 0.6-1400 mg oral molecule BID; or 0.3-700 mg TID.
• 21 KW-2450 small ** 1-100 mg QD; 0.7-70 mg oral molecule BID; 0.3-30 mg TID 22 PL-2258/ small ** 1-2000 mg QD; or 0.6-1400 mg Oral; PL-225B molecule BID; or 0.3-700 mg TID. 21d 23 INSM-18, small ** 1-2000 mg QD; or 0.6-1400 mg oral nordihydroguaiar molecule BID; or 0.3-700 mg TID.
• etic acid (NDGA)/ Masoprocol, Actinex, TT-100 24 AZD3463 small ** 1-2000 mg QD; or 0.6-1400 mg oral molecule BID; or 0.3-700 mg TID.
• 28 XL-228 small ** 1-2000 mg QD; or 0.6-1400 mg oral molecule BID; or 0.3-700 mg TID.
• Istiratumab antibody 2.8 g 1-112 mg/kg or 75-8400 mg Q3W; IV (MM-141) IV q2w or 0.7-75 mg/kg or 45-5700 mg Q2W; or 0.3-38 mg/kg or 22-2900 mg QW
• IGF-1R antibodies may be useful as described herein and are encompassed within the present disclosure.
• a dosage appropriate for use for the present disclosure may be 1-112 mg/kg or 75-8400 mg every 3 weeks (Q3W); or 0.6-75 mg/kg or 45-5700 mg every 2 weeks (Q2W); or 0.3-38 mg/kg or 22-2900 mg weekly (QW).
• IGF-1R small molecule drugs may be useful as described herein and are encompassed within the present disclosure.
• a dosage appropriate for use for the present disclosure may be 1-2000 mg for once daily administration (QD); or 0.6-1400 mg for twice daily administration (BID); or 0.3-700 mg for three-times daily administration (TID).
• Placebo doses IV saline or buffer solution or matching placebo tablet/capsule
• Placebo doses will be used to maintain the blind due to differing administration schedules and/or methods of administration with the active comparator.
• the eye with the more significant proptosis may be defined as the “study eye.” If both eyes are affected equally, the Investigator may choose the “study eye.” Both eyes will be assessed for efficacy but the study eye may be used to assess the primary outcome measure.
• Efficacy will be assessed by proptosis (measured as exophthalmos evaluation of the Clinical Measures of Severity using a Hertel instrument provided by the Sponsor for consistency in measurement), quality of life (using GO-QoL questionnaire), diplopia (measured as part of the Clinical Measures of Severity or using Goldmann perimeter or cervical range of motion method), CAS (7-item or 10-item scale), orbital pain (using a 10-cm VAS), orbital MRI, and/or PTM (calf circumference and area of lesion).
• Blood samples for Study Drug PK assessment will be collected prior to dosing on Day 1 and at End of Treatment Period, e.g., Week 12, Week 24, or Week 48. Blood samples may be collected and analyzed for inflammatory and fibrotic biomarkers and evaluated for transcriptomics associated with IGF-1R inhibition prior to treatment on Day 1 and after treatment throughout the study, e.g. for a 24-week treatment period, at Weeks 3, 12, and 24.
• Safety will be assessed via AE and concomitant medication use monitoring, immunogenicity testing, ophthalmic examinations, vital signs, clinical safety laboratory evaluations (complete blood count and chemistry (including thyroid panel and HbA1c), pregnancy testing (if applicable), and ECGs.
• Informed Consent Informed consent will be obtained from each subject during Screening.
• Inclusion/Exclusion Criteria will be reviewed with each subject at Screening and on the Day 1/Baseline visit.
• Demographic data may be obtained from each subject during Screening.
• Medical History Medical history, including thyroid disease history and treatment, TED history and treatment, and tobacco use history, will be obtained from each subject at Screening and on the Day 1/Baseline visit.
• TED must be either i) acute/active TED (onset of symptoms within 9 months prior to Baseline) or ii) stable, chronic/inactive (not progressing, non-sight threatening but appreciable impact on daily life) with TED diagnosed >2 years, but no longer than 7 years prior to Screening.
• Weight may be recorded at Screening, and throughout the study, e.g. for a 24-week treatment period, Week 12/Month 3, and Week 24/Month 6. Dosing may be adjusted if there is a change in weight during the Treatment Period. The weight obtained mid-study can be used in dose calculations for later doses.
• Randomization On Day 1 (Baseline), subjects will be randomized and receive the first dose of study drug. Baseline assessments will be performed prior to dosing.
• Subjects will be randomized as described herein to receive: (a) Study Drug; or (b) placebo or (c) teprotumumab—i.e., the study may be designed with two arms to compare Study Drug to either placebo or teprotumumab, or may be designed with three arms to compare Study Drug, placebo, and teprotumumab.
• Study Drug will be given as described herein.
• Teprotumumab Infusion Infusions will take place on Day 1 (Baseline), and per marketed dosing thereafter. Placebo administration will match that of Study Drug or teprotumumab as appropriate.
• CAS Clinical Activity Score: CAS will be obtained from each subject at Screening, Day 1/Baseline, and throughout the study, e.g. for a 24-week treatment period, Week 12/Month 3, and Week 24/Month 6. For patients entering a chronic/inactive study, CAS must be ⁇ 1 in both eyes at the Screening and Baseline visits.
• Clinical Measures of Severity includes proptosis and diplopia: Clinical measures of severity will be obtained at Screening; at Day 1/Baseline, and throughout the study, e.g. for a 24-week treatment period, Week 3, Week 6, Week 12/Month 3, Week 18, and Week 24/Month 6 of the Treatment Period; and Week 30 of the Follow-up Period.
• Subjects who have a ⁇ 2 mm decrease in proptosis in the study eye from Screening are not eligible for randomization.
• Pretibial myxedema (PTM) assessment may optionally be performed at Day 1/Baseline and throughout the study, e.g. for a 24-week treatment period, Week 12/Month 3, and Week 24/Month 6.
• Orbital pain by 10 cm visual analog scale Orbital pain may be assessed on Day 1/Baseline and throughout the study, e.g. for a 24-week treatment period, Week 3, Week 6, Week 12/Month 3, Week 18, and Week 24/Month 6.
• Pregnancy tests will be administered at all visits. Serum pregnancy test at Screening and Week 48 (or 6 months after last infusion if withdrawn early from treatment). Urine pregnancy tests prior to dosing at all other visits, as applicable. Perform for female subjects of childbearing potential (including those with an onset of menopause ⁇ 2 years prior to Screening, non-therapy-induced amenorrhea for ⁇ 12 months prior to Screening, or not surgically sterile [absence of ovaries and/or uterus]).
• Ophthalmic exam will be performed at Screening, Day 1/Baseline, and throughout the study, e.g. for a 24-week treatment period, Week 6, Week 12/Month 3, Week 18, and Week 24/Month 6.
• Best corrected visual acuity, pupil exam, color vision assessment, Ishihara color plates (or equivalent) or related red desaturation, intraocular pressure, and slit lamp exam If significant abnormalities are noted compared to previous visits, including a loss of 2 lines or more of vision, development of pupil abnormalities including afferent pupillary defect, rise in intraocular pressure, development of corneal infiltrates or other abnormalities not here specified but of concern to the ophthalmologist, further investigations of visual function will be conducted according to the ophthalmologist decision.
• Subjects who have decreased best-corrected visual acuity due to optic neuropathy are not eligible for randomization.
• Vital signs blood pressure, heart rate, respiratory rate, temperature
• Vital signs will be measured at all clinic visits. Vital signs will be measured pre- and post-dose on Day 1, and pre-dose on other dose/infusion days. Additional vital signs will be monitored if infusion-associated AEs occur.
• ECG Electrocardiogram
• Chemistry may be assessed at Screening, Day 1/Baseline, and throughout the study, e.g. for a 24-week treatment period, Week 3, Week 6, Week 12/Month 3, Week 18, Week 24/Month 6, Week 30, and Week 36.
• Thyroid Thyroid levels may be assessed at Screening, Day 1/Baseline, and throughout the study, e.g. for a 24-week treatment period, Week 3, Week 6, Week 12/Month 3, Week 18, Week 24/Month 6, Week 30, and Week 36. Subjects must be euthyroid with the baseline disease under control or have mild hypo- or hyperthyroidism (defined as FT4 and FT3 levels ⁇ 50% above or below the normal limits). Every effort should be made to correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid state for the full duration of the clinical trial.
• Hematology may be assessed at Screening, Day 1/Baseline, and throughout the study, e.g. for a 24-week treatment period, Week 3, Week 6, Week 12/Month 3, Week 18, Week 24/Month 6, Week 30, and Week 36.
• HbA1c levels may be assessed at Screening, and throughout the study, e.g. for a 24-week treatment period, Week 12/Month 3, and Week 24/Month 6. HbA1c must be ⁇ 8.0% for randomization. If the HbA1c is elevated and considered clinically significant at any time point after Screening, it will be repeated approximately every 90 days until it returns to normal or baseline value.
• ADA/Nab samples Anti-drug antibody (ADA)/neutralizing antibody (Nab) levels may be obtained on Day 1/Baseline, and throughout the study, e.g. for a 24-week treatment period, Week 3, Week 12/Month 3, and Week 24/Month 6. If a sample is positive in the ADA test, after confirmatory and reactive titer testing, the sample will then be tested for NAb. If the subject tests positive for NAb, he/she may be followed until levels either revert to Baseline or the subject's value decreases or remains stable. Any subject with a positive NAb test at the end of the Treatment Period (or PW) may continue to be followed until the subject's value decreases or remains stable.
• ADA Anti-drug antibody
• Nab neutralizing antibody
• AE/SAE Assessment AEs/SAEs will be assessed periodically, up to and including at every visit. AEs that occur within 2 weeks prior to Day 1 and prior to dosing on Day 1 will be considered baseline signs/symptoms. AEs occurring or worsening after the dose on Day 1 through the end of the Treatment Period will be considered treatment-emergent AEs (TEAEs). AEs occurring or worsening during the Follow-Up Period will be considered post-dose AEs. All SAEs that occur from the signing of informed consent through 30 days after study discontinuation will be recorded.
• Concomitant medications will be assessed periodically, up to and including at every visit.
• GO-QoL Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire: GO-QoL may be assessed at Day 1/Baseline, and periodically throughout the study, e.g. for a 24-week treatment period, Week 6, Week 12/Month 3, and Week 24/Month 6.
• PK samples may be collected prior to, and at the end of, the dosing or infusion on Day 1, and periodically throughout the study, e.g. for a 24-week treatment period, Week 3 and Week 12/Month 3 of the Treatment Period, and a single sample may be collected at the end of the Treatment Period. PK samples will not be collected for subjects who prematurely discontinue from the Treatment Period.
• Biomarker samples may be collected on Day 1 and throughout the study, e.g. for a 24-week treatment period, Week 3 and Week 12/Month 3 of the Treatment Period, and a single sample may be collected at the end of the Treatment Period.
• Magnetic Resonance Imaging Subjects may undergo MRI on Day 1 and at the visit at the end of the Treatment Period.
• the randomized trial is designed to assess efficacy and safety.
• patients will be randomly assigned in the (optionally) double-masked Treatment Period to one of three treatment groups in, e.g., a 1:1, 2:1, or 3:1 ratio in blocks of two, stratified by duration of chronic/inactive disease, ⁇ 2 years or >2 years.
• Study pharmacists who are aware of the trial-group assignments may prepare masked doses and/or infusions if needed.
• the on-site principal investigators will identify a patient's intervention or Treatment Group (Study Drug, active control, or placebo) only in the case of an emergency.
• the clinical activity score 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 will be scored as present or absent, 1 or 0.
• the score at each efficacy assessment will be the sum of all items present to give a range of 0-7, where 0 or 1 constitutes inactive disease and 7 constitutes severe active ophthalmopathy.
• a change of ⁇ 2 points will be considered clinically meaningful, as would achievement of a CAS score of 0 or 1 in patients with acute/active disease.
• the questionnaire has two self-assessment subscales; one covering impact of visual function on daily activities, the other assesses the impact of self-perceived appearance.
• the visual function subscale covers activities such as driving, walking outdoors, reading, watching television, etc.
• the appearance subscale asks the subject questions such as whether ophthalmopathy has altered the subject's appearance, caused other people to have a negative reaction to the subject, caused social isolation, and caused the subject to try to mask his or her appearance.
• Each subscale has 8 questions which are answered with: yes—very much so; yes—a little; or no—not at all.
• Each question is scored 0-2, respectively, 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.
• 0 represents the most negative impact on quality of life
• 100 represents no impact.
• a change of ⁇ 8 points on the 0-100 scale has been shown to be clinically meaningful.
• the combined score takes raw scores from both subscales and again transforms them to a single 0-100 scale.
• 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. An improvement of ⁇ 1 grade is considered clinically meaningful.
• a 12-lead ECG may be performed as described in the Schedule of Events (Table 2) for all subjects or at the discretion of the Investigator. When a subject experiences an AE suspected to be an IR, a 12-lead ECG may also be performed.
• Single 12-lead ECG recordings may be made at Screening, Baseline (Day 1), and periodically throughout the study, e.g. for a 24-week treatment period, Week 3, Week 6, Week 12/Month 3, and Week 24/Month 6, after the subject has been in the supine position for at least 5 minutes.
• a single repeat measurement is permitted at Screening for eligibility determination. Measurements of the following intervals may be recorded and reported: RR interval, PR interval, QRS width, QT interval, and QTcF.
• Assessments should include comments on clinical significance, whether the tracings are normal or abnormal; rhythm; presence of arrhythmia or conduction defects; morphology; any evidence of myocardial infarction; or ST-segment, T-Wave, and U-Wave abnormalities.
• Blood for hematology, clinical chemistry, thyroid measurements
• Blood may be collected at Screening; at Day 1, and periodically throughout the study, e.g. for a 24-week treatment period, Week 3, Week 6, Week 12/Month 3, Week 18, and Week 24/Month 6 of the Treatment Period, and Week 30 and Week 36 of the Follow-up Period.
• HbA1c may be measured at Screening and periodically throughout the study, e.g. for a 24-week treatment period, Week 12/Month 3 of the Treatment Period, and Week 24/Month 6 of the Follow-up Period. HbA1c must be ⁇ 8.0% for randomization. If the HbA1c is elevated and considered clinically significant at any time point after Screening, it will be repeated approximately every 90 days until it returns to normal or baseline value.
• Anti-drug antibodies (ADA)/neutralizing antibodies (Nab) may be measured at Day 1, and periodically throughout the study, e.g. for a 24-week treatment period, Week 3, Week 12/Month 3, and Week 24/Month 6 of the Treatment Period. If a sample is positive in the ADA test, after confirmatory and reactive titer testing, the sample will then be tested for NAb. If the subject tests positive for NAb, he/she may be followed until levels either revert to Baseline or the subject's value decreases or remains stable. Any subject with a positive NAb test at the end of the Treatment Period (or PW) may continue to be followed until the subject's value decreases or remains stable.
• Safety laboratory assessments may include:
• Pregnancy Test Serum pregnancy test at Screening and Week 48 (or 6 months after last dose or infusion). Urine pregnancy tests prior to dosing at all other visits, as applicable. Perform for female subjects of childbearing potential (including those with an onset of menopause ⁇ 2 years prior to Screening, non-therapy-induced amenorrhea for ⁇ 12 months prior to Screening, or not surgically sterile [absence of ovaries and/or uterus]).
• Ophthalmic exam best corrected visual acuity, pupil exam, color vision assessment, Ishihara color plates (or equivalent) or related red desaturation, intraocular pressure, and slit lamp exam. If significant abnormalities are noted compared to previous visits, including a loss of 2 lines or more of vision, development of pupil abnormalities including afferent pupillary defect, rise in intraocular pressure, development of corneal infiltrates or other abnormalities not here specified but of concern to the ophthalmologist, further investigations of visual function will be conducted according to the ophthalmologist decision
• vital Signs blood pressure, heart rate, respiratory rate, and temperature will be measured at all clinic visits. Vital signs will be measured pre- and post-infusion on Day 1 and Week 3, and pre-dose on all other infusion days. Additional vital signs will be monitored if infusion-associated AEs occur.
• Patients who have a response may be defined as those who meet the primary end point at week 24.
• This end point may comprise a reduction of 2 mm or more in proptosis in the study eye in the absence of a corresponding amount of worsening in the non-study eye, or average or median change from baseline in proptosis, or a reduction in diplopia of ⁇ 1 grade in subjects with baseline diplopia >0.
• Secondary end points may include proptosis, diplopia, and the CAS (both measured as continuous variables over time), orbital pain, MDI and PVR for the inferior rectus, superior rectus, the medial rectus, lateral rectus and orbital fat, circumference of calf and area of the lesion in subjects with baseline PTM, inflammatory and fibrotic biomarkers, transcriptomics associated with IGF-1R inhibition, and assessment of the patient's quality of life with the use of the GO-QOL instrument (which includes two subscales that measure limitations in visual functioning and psychosocial functioning as a consequence of changed physical appearance). Patients may also be categorized according to their level of response. Safety will be assessed according to the incidence of adverse events, serious adverse events, and withdrawals due to adverse events.
• IGF-1R inhibitors described herein will, when tested as Study Drugs in a clinical study as disclosed herein for either acute/active or chronic/inactive TED, have efficacy in the outcome measures of TED described herein or as modified by one of skill in the art.
• Table 2 sets forth an example of a schedule of assessments assuming a 24-week Treatment Period and either using teprotumumab as an active control or mimicking it, i.e., dosing on a 3-week cycle by infusion. This table is presented as an example for illustrative purposes, and is not mean to be inconsistent with the guidance above. Those of skill in the art will understand how to modify such a schedule in the event of a different dosing schedule or route of administration ad might be expected with, e.g., a study of an orally bioavailable small molecule drug dosed QD and compared to placebo as opposed to active teprotumumab control.
• Footnotes 1 Screening procedures can take place over more than 1 day/clinic visit provided consent is obtained first and all assessments are completed within the designated window.
• Subjects will be encouraged to continue study participation in the Follow-Up Period. 5 If a subject prematurely discontinues from the study between Week 24 and Week 30 of the Follow-Up Period, they will return for a clinic visit and undergo the Week 30 assessments prior to discharge. 6 All subjects will be contacted via phone or email at Week 36, except subjects who have an ongoing SAE or AESI at the Week 30 visit. Subjects who have an ongoing SAE or AESI at the Week 30 visit will return to the clinic at Week 36. 7 Women of childbearing potential will be contacted via phone or email at Week 48 to inquire if they have missed a menstrual cycle and will return to the clinic for a serum pregnancy test if required.
• Subjects will be randomized in a 1:1 ratio (stratified by duration of chronic/inactive disease) to receive either: a) Study Drug (10 mg/kg on Day 1 followed by 20 mg/kg q3W for the remaining 7 infusions) or b) placebo or teprotumumab (q3W for all 8 infusions).
• 13 Phone (or email) contact by research staff focusing on safety and tolerability aspects will be made the day after infusion for the first and second infusions, and thereafter as deemed appropriate.
• subjects who experience an infusion-associated event after any subsequent infusion will also be contacted by phone (or email) by research staff the day after the infusion, and thereafter as deemed appropriate.
• Ophthalmic exam best corrected visual acuity, pupil exam, color vision assessment, Ishihara color plates (or equivalent) or related red desaturation, intraocular pressure, and slit lamp exam.
• HbA1c must be ⁇ 8.0% for randomization. If the HbA1c is elevated and considered clinically significant at any time point after Screening, it will be repeated approximately every 90 days until it returns to normal or baseline value.
• a sample is positive in the ADA test, after confirmatory and reactive titer testing, the sample will then be tested for NAb. If the subject tests positive for NAb, he/she may be followed until levels either revert to Baseline or the subject's value decreases or remains stable. Any subject with a positive NAb test at Week 24 (or PW) may continue to be followed until the subject's value decreases or remains stable. 24 Not collected for subjects who prematurely discontinue from the Treatment Period. 25 AEs that occur within 2 weeks prior to Day 1 and prior to dosing on Day 1 will be considered baseline signs/symptoms. AEs occurring or worsening after the dose on Day 1 through the end of the Treatment Period will be considered treatment-emergent AEs (TEAEs).
• TEAEs treatment-emergent AEs
• AEs occurring or worsening during the Follow-Up Period will be considered postdose AEs. All SAEs that occur from the signing of informed consent through 30 days after study discontinuation will be recorded. 26 PK samples will be collected prior to, and at the end of, the infusion on Day 1 and Weeks 3 and 12 of the Treatment Period and a single sample will be collected at Week 24. 27 Subjects at one clinical investigative site will undergo MRI on Day 1 and at the Week 24 visit.
• the AVE1642 monoclonal antibody (humanized form of murine antibody EM164) is described in Example 4.
• a half-life extended version, using amino acid substitutions in the Fc portion of the antibody i.e., an Fc variant
• Such a half-life extended AVE1642 antibody comprising M428L/N434S substitutions, would be expected to be effective at a reduced dose and/or frequency than similar antibodies described in Example 4 alone.
• treatment of a subject with TED and/or symptoms of proptosis and/or diplopia would be expected to be treated at a dose of about 1-5 mg/kg, or about 1-10 mg/kg, or about 1-20 mg/kg, or about 1-50 mg/kg.
• treatment of TED with this half-life extended antibody would be expected to occur as described herein at a dose of 1 mg/kg, or 2 mg/kg, or 3 mg/kg, or 4 mg/kg, or 5 mg/kg, or 6 mg/kg, or 7 mg/kg, or 8 mg/kg, or 9 mg/kg, or 10 mg/kg.
• the AVE1642 half-life extended antibody comprising the above CDRs and M428L/N434S Fc variant would also be expected to be suitable for administration via intravenous (IV) or even subcutaneous (SC) injection.

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