Anti-IFNAR1 dosing regimen for hypodermic injection

Abstract

The present disclosure relates to methods and compositions for treating type I IFN mediated diseases. In particular, the disclosure relates to subcutaneous doses of type I IFN receptor inhibitors.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of April 21, 2022, application number 202280029635.7, and invention name “Anti-IFNAR1 dosing regimen for subcutaneous injection”. 1. Background Technology

[0002] To date, clinical studies of the type I IFN receptor (IFNAR1) inhibitor anirumab have primarily focused on treating type 1 interferon-mediated diseases such as systemic lupus erythematosus (SLE) by administering the antibody intravenously (IV). However, IV administration requires patients to visit a hospital or clinic so that the procedure can be performed by a healthcare professional. Therefore, IV administration is inconvenient for patients and places a burden on both patients and the healthcare system.

[0003] Systemic lupus erythematosus (SLE)

[0004] Systemic lupus erythematosus (SLE) is a chronic, multisystemic, disabling autoimmune rheumatic disease of unknown etiology. There is a large unmet medical need in the treatment of SLE, particularly in patients with moderate or severe disease. The long-term prognosis for many patients remains inadequate. Since the approval of hydroxychloroquine for discoid lupus and SLE, only one new treatment for SLE (belimumab) has been approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in approximately 60 years. Many of the agents currently used to treat SLE, such as azathioprine, cyclophosphamide, and mycophenolate mofetil / mycophenolic acid, have not yet been approved for use in the disease. In addition, all of these drugs have well-documented safety issues and are not effective in all patients for all manifestations of lupus. Glucocorticoids remain the mainstay of treatment, with dosages depending on the severity of disease manifestations. A “safe” dose of oral glucocorticoids is not associated with the risk of developing glucocorticoid-induced damage (such as cataracts, osteoporosis, and coronary artery disease), and although increased glucocorticoid exposure is associated with increased cumulative damage overall, relatively low to moderate doses may also be associated with increased damage.

[0005] The clinical manifestations of SLE include, but are not limited to, systemic symptoms such as fatigue and fever, alopecia, rash, serositis, arthritis, nephritis, vasculitis, lymphadenopathy, splenomegaly, hemolytic anemia, cognitive dysfunction and other nervous system involvement. These disease manifestations cause significant disease burden, and can cause permanent organ damage, physical function reduction, unemployment and greater health-related quality of life (QoL) infringement. The increase in hospitalization rate and side effects of drugs including high-dose chronic glucocorticoids and other immunosuppressive therapies has seriously increased the disease burden of SLE. All therapies currently used for the treatment of SLE all have well-known adverse effect spectrums, and therefore there is a medical need to identify new targeted therapies, particularly the medicament that can reduce glucocorticoid and cytotoxic agent demand.

[0006] 1.2. Subcutaneous administration

[0007] An advantage of subcutaneous administration over the intravenous route is that it can be administered at home, thereby reducing the frequency of hospital visits for patients. Therefore, during a global pandemic such as the SARS-CoV2 pandemic, subcutaneous (SC) administration is particularly advantageous because it avoids the need for potentially immune-vulnerable patients to go to the hospital and put themselves at risk of SARS-CoV2 infection.

[0008] Despite the advantages of subcutaneous administration over intravenous injection, switching from intravenous to subcutaneous administration is not straightforward. Conversion to subcutaneous administration may sometimes require the development of new formulations and consideration of various factors, such as differences in bioavailability, pharmacokinetic properties, and immunogenicity of subcutaneous versus intravenous administration [1].

[0009] The pharmacokinetic profiles of subcutaneous and intravenous formulations differ. Direct infusion of monoclonal antibodies into the blood generally results in immediate maximum serum concentrations (C 最大 In contrast, the pharmacokinetic (PK) characteristics of subcutaneous therapeutic proteins are typically characterized by delayed absorption rates and C 最大 levels are lower than those achieved with intravenous administration[2]. In addition, subcutaneous administration results in incomplete bioavailability of the injected molecule, which can vary widely from 50% to 80% for mAbs[2]. Incomplete bioavailability often results in higher doses being required for subcutaneous administration than for intravenous infusion. Therefore, predicting the PK of therapeutically administered SC is challenging[2].

[0010] In heterogeneous autoimmune diseases such as lupus (e.g., SLE), predicting safe and therapeutically effective subcutaneous doses based on intravenous doses is particularly complex. The difficulty in predicting safe and effective subcutaneous doses for SLE based on data from intravenously administered biologics has been demonstrated by previous failed attempts. For example, in a phase I study of SLE, a single intravenous dose of the anti-BAFF monoclonal antibody tabcirumab was administered to five patients with SLE [3]. In the subsequent phase III ILLUMINATE trial (NCT01205438 and NCT01196091), either subcutaneous or intravenous routes of administration were chosen [4,5]. In the phase I trial, SLE patients received a single intravenous dose of tabcirumab, either 0.125 mg / kg or 2.0 mg / kg [3]. In the phase III ILLUMINATE trial, subjects received an initial subcutaneous loading dose of 240 mg, followed by 120 mg subcutaneously every two weeks or monthly. The primary endpoint, SRI-5 response, was not achieved in either dose group. The researchers commented that one possible reason for the trial failure was the selection of an inappropriate SC dose[4] and that even after the trial, the optimal SC dose remained unknown[5].

[0011] Anirudinib

[0012] Anilumab is a human immunoglobulin G1κ (IgG1κ) monoclonal antibody (mAb) directed against subunit 1 of the type 1 interferon receptor (IFNAR1). Although subcutaneous administration has advantages over intravenous administration, a safe and effective subcutaneous dose of anilumab in patients with SLE has not been established.

[0013] The present invention solves one or more of the above problems by providing a dose of an IFNAR1 inhibitor (e.g., aniluomab) for subcutaneous administration. 2. Summary of the Invention

[0014] The present invention relates to a subcutaneous dose of a type I IFN receptor (IFNAR1, also referred to as IFNAR) inhibitor. The present invention also relates to a subcutaneous dose of an IFNAR1 inhibitor used in a method for treating a type I IFN-mediated disease in a subject, such as lupus (e.g., SLE). The present invention is supported by data showing that a common type I IFN gene signature (IFNGS) is elevated in subjects with type I IFN-mediated diseases, including lupus, myositis, scleroderma, and Sjögren's syndrome, and that the IFNGS is associated with disease severity and the identification of safe and effective doses of IFNAR1 inhibitors that neutralize the IFNGS.

[0015] The present invention is supported by, among other things, efficacy, safety, and PK data for an IFNAR1 inhibitor (anirumab) from two Phase 3, multicenter, multinational, randomized, double-blind, placebo-controlled clinical trials in patients with SLE (NCT02446899 and NCT02962960), a Phase 2, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial in patients with SLE (NCT02962960), a Phase I, randomized, placebo-controlled, double-blind clinical trial in healthy subjects (NCT02601625), and a Phase II study to characterize the pharmacokinetics, pharmacodynamics, and safety of anirumab in adult type I interferon-high SLE subjects (NCT02962960), the data analysis of which is presented herein for the first time. The inventors used innovative data modeling to identify the optimal subcutaneous dose of the IFNAR1 inhibitor that would provide safety and efficacy equivalent to the intravenous dose.

[0016] The present invention also relates to the following items:

[0017] 1. A unit dose for subcutaneous administration comprising greater than (>) 105 mg and less than (<) 150 mg of a type I IFN receptor (IFNAR1) inhibitor.

[0018] 2. The unit dose according to item 1, comprising equal to or less than (≤) 135 mg of the IFNAR1 inhibitor.

[0019] 3. The unit dose of item 1 or 2, comprising about 120 mg of the IFNAR1 inhibitor.

[0020] 4. The unit dose of item 1, wherein the unit dose consists essentially of >105 mg and <150 mg of the IFNAR1 inhibitor.

[0021] 5. The unit dose of item 4, which essentially consists of ≤135 mg of the IFNAR1 inhibitor.

[0022] 6. The unit dose of item 5, which consists essentially of about 120 mg of the IFNAR1 inhibitor.

[0023] 7. The unit dose of any of the preceding items, wherein the concentration of the IFNAR1 inhibitor is about 150 mg / ml.

[0024] 8. The unit dose according to any of the preceding items, wherein the volume of the unit dose is about 0.8 ml.

[0025] 9. The unit dose of any of the preceding items, wherein the unit dose comprises a formulation of about 150 mg / ml to 200 mg / ml of the IFNAR1 inhibitor, about 25 mM to 150 mM lysine salt and no loaded excipients.

[0026] 10. The unit dose of item 9, wherein the unit dose comprises a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05% w / v polysorbate 80.

[0027] 11. The unit dose of item 9 or 10, wherein the formulation has a pH of about 5.9.

[0028] 12. The unit dose according to any one of items 1 to 11, wherein the IFNAR1 inhibitor is a human monoclonal antibody specific for IFNAR1, optionally a modified human monoclonal antibody of the IgG1 class.

[0029] 13. The unit dose of item 12, wherein the antibody comprises:

[0030] (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3;

[0031] (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4;

[0032] c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5;

[0033] (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6;

[0034] (e) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; and / or

[0035] (f) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0036] 14. The unit dose of item 12 or 13, wherein the antibody comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.

[0037] 15. The unit dose of any one of items 11 to 14, wherein the antibody comprises an Fc region comprising an amino acid substitution of L234F, as numbered by the EU index as set forth in Kabat, and wherein the antibody exhibits decreased affinity for at least one Fc ligand compared to the unmodified antibody, optionally wherein the antibody comprises an amino acid substitution of L235E and / or P331S in the Fc region, as numbered by the EU index as set forth in Kabat.

[0038] 16. The unit dose of any one of items 12 to 15, wherein the antibody comprises: (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11; and (b) a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0039] 17. The unit dose according to any of the preceding items, wherein the IFNAR1 inhibitor is anirumab or a functional variant thereof.

[0040] 18. A method of treating a type I interferon (IFN)-mediated disease in a subject, the method comprising subcutaneously administering a unit dose of any one of items 1 to 17 to a subject suffering from a type I interferon (IFN)-mediated disease.

[0041] 19. A method of treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering to the subject a dose of an IFNAR1 inhibitor, wherein the dose is greater than (>) 105 mg and less than (<) 150 mg.

[0042] 20. A method of treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering a dose of an IFNAR1 inhibitor, wherein weekly subcutaneous administration of the dose provides a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by intravenous administration of 300 mg of the IFNAR1 inhibitor every four weeks.

[0043] 21. The method of clause 20, wherein weekly subcutaneous administration of the dose provides a plasma concentration in the subject that is greater than the plasma concentration provided by intravenous administration of 300 mg of the IFNAR1 inhibitor every 4 weeks.

[0044] 22. The method of any one of items 18 to 21, wherein the dose is <150 mg of the IFNAR1 inhibitor.

[0045] 23. The method of any one of items 18 to 22, wherein the dose is >105 mg of the IFNAR1 inhibitor.

[0046] 24. The method of any one of items 18 to 23, wherein the dose is administered subcutaneously in a single administration step.

[0047] 25. The method of any one of items 18 to 24, wherein the dose is equal to or less than (≤) 135 mg of the IFNAR1 inhibitor.

[0048] 26. The method of any one of items 18 to 25, wherein the dose is about 120 mg of the IFNAR1 inhibitor.

[0049] 27. The method of any one of items 18 to 26, which comprises administering the dose or unit dose subcutaneously at intervals of 6-8 days.

[0050] 28. The method of any one of items 18 to 27, comprising administering the dose or unit dose subcutaneously once a week (QW).

[0051] 29. The method of any one of items 18 to 28, wherein the dose or unit dose is 120 mg of the IFNAR1 inhibitor, and the method comprises administering the dose subcutaneously once a week (QW) in a single administration step.

[0052] 30. The method of any one of items 18 to 29, wherein the dose or unit dose is administered subcutaneously once a week for at least about 4, 8, 12, 16, 20, 24, 28, or 32 weeks.

[0053] 31. The method of any one of items 18 to 30, wherein the dose or unit dose is administered subcutaneously once a week for at least about 8 weeks.

[0054] 32. The method of any one of items 18 to 31, wherein the volume of the dose or unit dose is about 0.5 ml to about 1 ml.

[0055] 33. The method of any one of items 18 to 32, wherein the volume of the dose or unit dose is about 0.8 ml.

[0056] 34. The method of any one of items 18 to 33, comprising administering a corticosteroid to the patient, optionally wherein the corticosteroid is an oral corticosteroid.

[0057] 35. The method of claim 34, comprising administering a first dose of the corticosteroid and subsequently administering a second dose of the corticosteroid, wherein the second dose of the corticosteroid is lower than the first dose of the corticosteroid.

[0058] 36. The method of claim 35, wherein the second dose of the corticosteroid is about 7.5 mg prednisone equivalents or less; optionally wherein the second dose of the corticosteroid is 5 mg prednisone equivalents or less; optionally wherein the method comprises administering the second dose of the corticosteroid once daily.

[0059] 37. The method of claim 35 or 36, wherein the first dose of the corticosteroid is about 10 mg prednisone equivalent.

[0060] 38. The method of any one of items 35 to 37, wherein the method comprises administering the second dose of the corticosteroid once daily.

[0061] 39. The method of any one of items 35 to 38, wherein the second dose of the corticosteroid is administered for at least 24 weeks, optionally at least 28 weeks.

[0062] 40. The method of any one of items 18 to 39, wherein administration of the dose or unit dose provides a plasma concentration of the IFNAR1 inhibitor in the subject of ≥10 μg anirumab or a functional variant thereof per ml of plasma (≥10 μg / ml).

[0063] 41. The method of any one of items 18 to 40, wherein administration of the dose or unit dose provides a plasma concentration of the IFNAR1 inhibitor in the subject of about 10 μg / ml-100 μg / ml, optionally about 20 μg / ml-80 μg / ml, optionally about 30 μg / ml-70 μg / ml.

[0064] 42. The method of any one of items 18 to 41, wherein administration of the dose or unit dose provides a trough concentration of the IFNAR1 inhibitor in the subject of ≥20 μg / ml, optionally ≥30 μg / ml, optionally ≥40 μg / ml.

[0065] 43. The method of any one of items 18 to 42, wherein administration of the dose or unit dose provides a trough concentration of the IFNAR1 inhibitor in the subject of about 20 μg / ml-100 μg / ml, optionally about 30 μg / ml-80 μg / ml, optionally about 40 μg / ml-70 μg / ml.

[0066] 44. The method of any one of items 18 to 43, wherein the subject is a patient who tests high for a type I interferon-stimulated gene signature (IFNGS) prior to administration of the dose or unit dose, optionally wherein the IFNGS is a 4-gene, 5-gene or 21-gene IFNGS.

[0067] 45. A method as described in any one of items 18 to 44, which comprises identifying the subject as a patient with a high IFNGS test prior to treatment with the dose or unit dose.

[0068] 46. ​​The method of any one of items 18 to 45, wherein the dose or unit dose provides a therapeutic effect in the subject that is at least equivalent to the therapeutic effect provided by administering an intravenous dose of 300 mg of the IFNAR1 inhibitor administered once every 4 weeks (Q4W).

[0069] 47. The method of any one of items 18 to 46, wherein the dose or unit dose provides a trough concentration of the IFNAR1 inhibitor in the subject that is greater than the trough concentration of the IFNAR1 inhibitor provided by an intravenous dose of 300 mg of anirumab or a functional variant thereof administered once every 4 weeks (Q4W).

[0070] 48. The method of any one of items 18 to 47, wherein the IFNAR1 inhibitor is contained in a pharmaceutical composition.

[0071] 49. The method of claim 48, wherein the pharmaceutical composition comprises 150 mg / mL of the IFNAR1 inhibitor, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0072] 50. The method of any one of items 18 to 49, wherein the type I IFN-mediated disease is associated with an elevated IFNGS score compared to a healthy donor, wherein the IFNGS score is a 4-gene, 5-gene and / or 21-gene score.

[0073] 51. The method of any one of items 18 to 50, wherein the type I IFN-mediated disease is an autoimmune disease.

[0074] 52. The method of any one of items 18 to 51, wherein the type I IFN-mediated disease is lupus.

[0075] 53. The method of claim 52, wherein the type I IFN-mediated disease is systemic lupus erythematosus (SLE), optionally wherein the SLE is moderately to severely active autoantibody-positive SLE.

[0076] 54. The method of any one of item 52, wherein the type I IFN-mediated disease is lupus nephritis (LN).

[0077] 55. The method of any one of item 52, wherein the type I IFN-mediated disease is cutaneous lupus erythematosus (CLE).

[0078] 56. The method of any one of items 52 to 55, wherein administration of the dose or unit dose provides an improvement from baseline in the patient's BILAG-based Comprehensive Lupus Assessment (BICLA) response rate.

[0079] 57. The method of any one of items 52 to 56, wherein administration of the dose or unit dose provides an improvement from baseline in the patient's Systemic Lupus Erythematosus Responder Index (SRI) 4 score.

[0080] 58. The method of any one of items 52 to 57, wherein the method reduces SLE disease activity in the subject.

[0081] 59. The method of claim 58, wherein reducing SLE disease activity in the subject comprises:

[0082] a) a BILAG-based Comprehensive Lupus Assessment (BICLA) response in the subject,

[0083] b) SRI(4) response in the subject, and / or

[0084] c) reducing the subject's Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) score as compared to the subject's CLASI score before treatment.

[0085] 60. The method of any one of item 51, wherein the type I IFN-mediated disease is myositis.

[0086] 61. The method of any one of item 51, wherein the type I IFN-mediated disease is scleroderma.

[0087] 62. The method of any one of item 51, wherein the type I IFN-mediated disease is Sjögren's syndrome.

[0088] 63. The method of any one of items 18 to 62, wherein the IFNAR1 inhibitor neutralizes elevated IFNGS in the subject.

[0089] 64. The method of any one of items 18 to 63, wherein the IFNAR1 is a human monoclonal antibody specific for IFNAR1, optionally a modified human monoclonal antibody of the IgG1 class.

[0090] 65. The method of item 64, wherein the antibody comprises:

[0091] (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3;

[0092] (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4;

[0093] c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5;

[0094] (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6;

[0095] (e) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; and / or

[0096] (f) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0097] 66. The method of item 64 or 65, wherein the antibody comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.

[0098] 67. The method of any one of items 64 to 65, wherein the antibody comprises an Fc region comprising an amino acid substitution of L234F, as numbered by the EU index as shown in Kabat, and wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to the unmodified antibody.

[0099] 68. The method of any one of items 64 to 66, wherein the antibody comprises: (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11; and (b) a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0100] 69. The method of any one of items 18 to 68, wherein the IFNAR1 inhibitor is anirumab or a functional variant thereof.

[0101] 70. The method of claim 19, wherein the type I IFN-mediated disease is SLE, wherein the IFNAR1 inhibitor is anirumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises administering the dose subcutaneously weekly.

[0102] 71. The method of claim 19, wherein the type I IFN-mediated disease is LN, wherein the IFNAR1 inhibitor is anirumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises administering the dose subcutaneously weekly.

[0103] 72. The method of claim 19, wherein the type I IFN-mediated disease is CLE, wherein the IFNAR1 inhibitor is anirumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises administering the dose subcutaneously weekly.

[0104] 73. The method of claim 19, wherein the type I IFN-mediated disease is myositis, wherein the IFNAR1 inhibitor is anirumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises administering the dose subcutaneously weekly.

[0105] 74. The method of claim 19, wherein the type I IFN-mediated disease is scleroderma, wherein the IFNAR1 inhibitor is anirumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises administering the dose subcutaneously weekly.

[0106] 75. The method of claim 19, wherein the type I IFN-mediated disease is Sjögren's syndrome, wherein the IFNAR1 inhibitor is anirumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises administering the dose subcutaneously weekly.

[0107] 76. A pharmaceutical composition for use in the method of treatment of any one of items 18 to 75, the method comprising subcutaneously administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a unit dose of any one of items 1 to 17.

[0108] 77. A pharmaceutical composition for use in a method of treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a dose of anirumab or a functional variant thereof, wherein the dose is greater than (>) 105 mg and less than (<) 150 mg.

[0109] 78. The pharmaceutical composition for use according to item 76 or 77, wherein the dose is about 120 mg of anirumab or a functional variant thereof.

[0110] 79. An injection device comprising a unit dose as described in items 1-17, or a pharmaceutical composition for use as described in any one of items 76 to 78.

[0111] 80. The injection device of item 79, wherein the injection device is a pre-filled syringe (PFS).

[0112] 81. The injection device of item 79, wherein the injection device is an attachment-free pre-filled syringe (AFPS).

[0113] 82. The injection device of item 79, wherein the injection device is an autoinjector.

[0114] 83. A kit comprising i) a unit dose as described in any one of items 1 to 17, ii) a pharmaceutical composition as described in item 77 or 78, or iii) an injection device as described in any one of items 79 to 82; and instructions for use, wherein the instructions for use include instructions for subcutaneously administering the unit dose or pharmaceutical composition to a subject.

[0115] 84. The kit of item 83, wherein the instructions for use specify that the unit dose or pharmaceutical composition is for use in any one of the methods of items 18 to 75.

[0116] 85. The kit of item 83 or 84, comprising packaging, wherein the packaging is adapted to contain the injection device and the instructions for use.

[0117] 86. The kit of any one of items 83 to 85, wherein the instructions for use are attached to the injection device.

[0118] 87. The kit of any one of items 83 to 86, wherein the instructions for use comprise instructions for administering 120 mg of anirumab or the functional variant.

[0119] 88. The kit of any one of items 83 to 87, wherein the instructions for use comprise instructions for weekly subcutaneous administration of 120 mg of anirumab or the functional variant.

[0120] 89. The kit of any one of items 83 to 87, wherein the instructions for use comprise instructions for use of the method of any one of items 18 to 75. 3. Description of the Figures

[0121] Figure 1: TULIP-1 and TULIP-2 study designs

[0122] ACR: American College of Rheumatology; ANA: antinuclear antibody; anti-dsDNA: anti-double-stranded DNA; anti-Sm: anti-Smith antibody; BICLA: BILAG-based comprehensive lupus assessment; BILAG: British Isles Lupus Assessment Group; IFNGS: interferon gene signature; IV: intravenous; OCS: oral corticosteroids; PGA: physician global assessment; Q4W: every 4 weeks; SLE: systemic lupus erythematosus; SLEDAI-2K: SLE Disease Activity Index 2000; SRI(4): SLE Responder Index. a Eligible patients met the ACR classification of SLE; b Patients were stratified according to IFNGS status, SLEDAI-2K score, and OCS dose;c For patients with baseline prednisone OCS ≥10 mg / day or equivalent.

[0123] Figure 2 : TULIP-1 and TULIP-2 efficacy results

[0124] Overall efficacy results for TULIP-1, TULIP-2, and MUSE. BICLA: BILAG-based integrated lupus assessment; BILAG: British Isles Lupus Assessment Group; CI: confidence interval; CLASI: Cutaneous Lupus Erythematosus Area and Severity Index; IFNGS: interferon gene signature; OCS: oral corticosteroids; SRI(4): SLE responder index. Analytical methods and definitions varied among the trials. a Published data expressed as odds ratios; b Previously unpublished data.

[0125] Figure 3: Study 05, BICLA response over time and time to first relapse

[0126] Figure 3A The percentage of patients with British Isles Lupus Assessment Group (BILAG) Comprehensive Lupus Assessment (BICLA) responses is shown; vertical bars indicate 95% confidence intervals (CI). Figure 3B The time to first relapse is shown, with relapse defined as at least one new BILAG 2004 index (BILAG-2004) A item or at least two new BILAG-2004B items compared to the previous visit. The BILAG-2004 is an assessment of 97 clinical and laboratory variables covering nine organ systems, with scores for each organ system ranging from A (severe) to E (never involved). The hollow black circles in this panel indicate censored data. The time to first relapse was evaluated using a Cox proportional hazards model, but no adjustment was made for multiple comparisons, so no inferences can be drawn from this result.

[0127] Figure 4 : Relationship between mean anirumab concentration and herpes zoster incidence

[0128] Incidence (%) of Herpes Zoster in Patients Received Placebo, 300 mg IV Anirudumab, or 1000 mg IV Anirudumab in Study 1013.

[0129] Figure 5: Mean Anirumab Serum Concentration-Time Curves

[0130] Figure 5AStudy MI-CP180 in Systemic Sclerosis (SSc) - Mean anirumab serum concentration-time profiles after a single IV dose. Data represent ±SD. Mean data below the LLOQ are not plotted. IV, intravenous; LLOQ, lower limit of quantification; MEDI 546, anirumab; n, number of patients in subgroup; SSc, systemic sclerosis. Figure 5B Study 06 in healthy volunteers - Mean anirumab serum concentration-time profiles after single subcutaneous and intravenous doses. Samples with actual collection times that deviated by >10% from the nominal collection time were excluded from the mean. IV, intravenous; N, number of subjects; SC, subcutaneous.

[0131] Figure 6: Study 08 Research Design and Results

[0132] Figure 6A : Phase II study design of SC anirumab in patients with SLE. Study 08 (NCT02962960) evaluated the effects of two anirumab doses every other week. Figure 6B : Mean serum concentrations of aniluolumab over time. Figure 6C : Anirumab neutralization of type I IFN gene signature.

[0133] Figure 7: Calculated median AUC ratio (SC / IV)

[0134] Figure 7A Figure 3: Median AUC ratios (SC / IV) calculated for different SC doses between weeks 0 and 52. Median AUC ratios (SC / IV) calculated based on estimated bioavailability in Study 06 between weeks 0 and 52, with subcutaneous doses of 75 mg (+ sign), 90 mg (open squares), 105 mg (circles), 120 mg (triangles), or 135 mg (closed squares). Subcutaneous doses here were administered once every 7 days (QW); the IV dose was administered at a dose of 300 mg once every 4 weeks (Q4W). Based on AUC, both 90 mg and 105 mg SC QW appeared similar to 300 mg IV. Figure 7B : Calculated median AUC ratio (SC / IV) for 90 mg and 105 mg SC QW. The median AUC ratio (SC / IV) calculated based on an estimated bioavailability that was approximately 7% lower than the bioavailability calculated from Study 06 between Weeks 0-52, where the subcutaneous dose was 90 mg SC QW or 105 mg SC.

[0135] Figure 8: Anirudin concentrations over time at different doses

[0136] Figure 8A: Graph (straight line) showing the (calculated) trough concentrations of plasma anirumab in patients administered: (i) 105 mg anirumab subcutaneously every 7 days; (ii) 300 mg anirumab intravenously every 4 weeks (lower dashed line); (ii) 1000 mg anirumab intravenously every 4 weeks (upper dashed line). The shaded area represents the region between the 5th and 95th percentiles for the 300 mg IV Q4W dose. Figure 8B Anilumab trough concentrations in IFNGS-high SLE subjects. Calculated trough concentrations of anilumab in plasma of IFNGS-high patients following administration are as follows: (i) 300 mg IV every 4 weeks; (ii) 90 mg subcutaneous (SC) every 4 weeks; (iii) 105 mg subcutaneous (SC) every 4 weeks; (iv) 135 mg subcutaneous (SC) every 4 weeks; and (v) 1000 mg IV every 4 weeks. SC = subcutaneous. Based on trough values, both 90 mg and 105 mg subcutaneous (SC) every 4 weeks are expected to have greater PD suppression than 300 mg IV.

[0137] Figure 9: Exposure observed in TULIP 1 & TULIP 2 in patients with high IFNGS was positively correlated with BICLA

[0138] Figure 9A : TULIP I, versus placebo, 150 mg, and 300 mg anirumab. Figure 9B : TULIP II, versus placebo and 300 mg.

[0139] Figure 10: BICLA dose response

[0140] Figure 10A Figure 3: Dose-response curves showing the predicted mean (grey line) and 95% confidence interval (CI) (dashed area) for the probability of meeting BICLA response criteria (in patients with IFNGS-high) relative to the mean C of aniluolumab within 52 weeks. Patients were grouped by dose (150 mg, n=62; 300 mg, n=242; and 1000 mg). Figure 10B : Predicted PK and efficacy of different SC doses. Probability of meeting BICLA (in patients with high IFNGS) for weekly SC doses starting at 105 mg and up to 150 mg. Assumptions for generating data exclude dose delays / interruptions.

[0141] Figure 11: C after thigh injection compared to abdominal injection 谷

[0142] Compared with abdominal injection, C 谷 Showing a downward trend. Figure 11A : 150mg SC Q2W. Figure 11B: 300mg SC Q2W.

[0143] Figure 12 : Based on 81%-87% bioavailability and exposure predictions from preliminary PK modeling

[0144] Based on preliminary PK modeling and bioavailability assumptions, the predicted C values ​​for anirumab are 90 mg-150 mg SC QW to 300 mg Q4W. 平均 If a bioavailability (F1) of 81%-87% is assumed, 105 mg would initially be expected to provide a C equivalent to 300 mg IV. 平均 .

[0145] Figure 13: C of aniluomab at different SC and IV doses over 52 weeks in patients with IFNGS high dose 平均

[0146] When the estimated bioavailability is reduced to approximately 70% or less, the median C of a 105 mg QW subcutaneous dose is 平均 dropped below 1. Figure 13A : 105mg SC QW. Figure 13B : 120mg SC QW. Figure 13C : Overlap with 1000 mg IV Q4W.

[0147] Figure 14: C of SC QW to 300mg IV Q4W 平均 median ratio

[0148] Doses above 105 mg (preferably 120 mg or higher) are selected to optimize exposure response by minimizing the effects of variability in response onset and bioavailability in lupus (eg, SLE) patients. Figure 14A : Assuming 81% bioavailability. Figure 14B : Assuming 70% bioavailability.

[0149] Figure 15 : Relationship between mean anirumab concentration and herpes zoster incidence

[0150] Incidence (%) of herpes zoster in patients receiving placebo, 300 mg IV anirumab, or 1000 mg IV anirumab in Study 1013. SC doses lower than 150 mg QW also showed promise in reducing the risk of herpes zoster infection.

[0151] Figure 16 :Schematic diagram of the PK / PD model

[0152] Nonlinear mixed-effects model. Ab, anirumab in the central compartment; Abp, anirumab in the peripheral tissue compartment; Ab.R, anirumab-IFNAR1 complex; CL RES , reticuloendothelial clearance; GS IFN,wb , type I IFNPD marker in whole blood; IC 50 Potency, corresponding to the concentration of anirumab that produces half-maximal inhibition of PD markers; IFN, interferon; I 最大 , the maximum graded degree of inhibition of PD markers by anirumab; k deg , degradation rate constant of IFN-αR1; k in,wb , the production rate constant of IFN gene in whole blood; k int , internalization rate constant; k off , dissociation rate constant; k on Binding rate constant; k out , IFN gene elimination rate constant; PD, pharmacodynamics; PK, pharmacokinetics; Q, intracompartmental clearance; wb, whole blood.

[0153] Figure 17 Association between 4-gene IFNGS status (high or low) at screening and 21-gene IFNGS at baseline in pooled data from the TULIP-1 and TULIP-2 trials

[0154] 21-IFNGS, 21-gene pharmacodynamic interferon gene signature; IFNGS, interferon gene signature; SLE, systemic lupus erythematosus. Data points are shown as the fold change in 21-IFNGS in patients with SLE in the TULIP-1 and TULIP-2 trials relative to 30 pooled healthy controls. The numbers shown represent the median for each group. In the TULIP-1 and TULIP-2 trials, 819 patients received at least one dose of aniluomab 300 mg, aniluomab 150 mg, or placebo, of whom 25 patients (18 IFNGS-high and 6 IFNGS-low patients) had missing baseline 21-IFNGS scores, so only 794 patients were included in this analysis.

[0155] Figure 18 IFNGS status at screening and 21-IFNGS score at baseline by age group, pooled data from TULIP-1 and TULIP-2

[0156] An inverse association between age and IFNGS expression was observed for the dichotomous IFNGS test at screening and the median 21-IFNGS score at baseline. 21-IFNGS, 21-gene pharmacodynamic interferon gene signature; IFNGS, interferon gene signature.

[0157] Figure 19 : 21-IFNGS score of IFNGS-high patients relative to IFNGS-low patients in TULIP-1 and TULIP-2 (fold change relative to healthy controls)

[0158] 21-IFNGS, 21-gene pharmacodynamic interferon gene signature; IFNGS, interferon gene signature; SLE, systemic lupus erythematosus. The y-axis represents the median fold change in 21-IFNGS in SLE patients relative to 30 pooled healthy controls. Error bars represent the median absolute deviation. This analysis included 439 patients in TULIP-1 and 355 patients in TULIP-2 who had at least one baseline or postbaseline 21-IFNGS measurement.

[0159] Figure 20 : Median 21-gene IFNGS neutralization according to baseline 21-IFNGS quartiles in pooled data from IFNGS-high patients treated with 300 mg anirumab in TULIP-1 and TULIP-2

[0160] Patients in the lowest baseline 21-IFNGS quartile (those with a baseline 21-IFNGS closest to that observed in patients with low IFNGS) had lower PD neutralization and greater variability than patients in the higher baseline 21-IFNGS quartiles. 21-IFNGS, 21-gene pharmacodynamic interferon gene signature; IFNGS, interferon gene signature; MAD, median absolute deviation; PD, pharmacodynamic; Q, quartile. This analysis included 291 patients with high IFNGS who had a baseline 21-IFNGS measurement and were treated with anirumab 300 mg from TULIP-1 and TULIP-2. Baseline 21-IFNGS quartiles were calculated based on 794 patients (IFNGS-high or IFNGS-low) who received at least one dose of aniluomab 300 mg, aniluomab 150 mg, or placebo in the TULIP-1 and TULIP-2 trials and who had a baseline 21-IFNGS measurement; because the figure includes only patients with high IFNGS, the numbers in each quartile are not equal.

[0161] Figure 21: Over a 52-week treatment duration in TULIP-2 and TULIP-1, the C 平均 PD neutralization of 21-genotype I IFNGS observed in subgroups

[0162] Figure 21A :TULIP-2. Figure 21A :TULIP-1. C 平均, mean anirumab concentration during the treatment period; IFNGS, interferon gene signature; MAD, median absolute deviation; PD, pharmacodynamics; PK, pharmacokinetic. The figure includes patients with a high IFNGS who had ≥1 quantifiable serum PK observation and ≥1 PD measurement before discontinuation; PD measurements collected after discontinuation were not included.

[0163] Figure 22 : Neutralization of 21-IFNGS Pharmacodynamics in Patients with High IFNGS Treated with Anirudumab 300 mg Based on Baseline Disease Characteristics

[0164] The baseline disease activity subgroups (including those based on SLEDAI-2K score (<10 vs ≥10), oral glucocorticoid dose (<10 vs ≥10 mg / day) and the incidence of leukemia were significantly higher in the control group (P<0.05). -1 Substantial and sustained PD neutralization was consistently observed with anirumab 300 mg in patients with lupus erythematosus (SLE) and subgroups with lupus serology (anti-dsDNA antibodies, C3, and C4). 21-IFNGS, 21-gene pharmacodynamic interferon gene signature; anti-dsDNA, anti-double-stranded DNA; C3, complement 3; C4, complement 4; GC, glucocorticoid; IFNGS, interferon gene signature; MAD, median absolute deviation; SLEDAI-2K, systemic lupus erythematosus disease activity index 2000.

[0165] Figure 23 : Visual predictive checking of the PK / PD model for anirumab 150 mg and 300 mg

[0166] This PK / PD model analysis included 646 patients with high IFNGS from the pooled TULIP-1 and TULIP-2 trials who received placebo (n=289), anirumab 150 mg (n=70), or anirumab 300 mg (n=287). As demonstrated by visual predictive inspection, the PK / PD indirect response model adequately captured the observed data with a 95% prediction interval. 21-IFNGS, 21-gene pharmacodynamic interferon gene signature; Obs, observed data; Obs-Med, observed median; PD, pharmacodynamics; PK, pharmacokinetics; PI, prediction interval. The dark line shows the predicted median percentage neutralization of 21-IFNGS expression. The analysis was based on 646 patients with high IFNGS levels in the PK / PD analysis set (289 in the placebo group, 70 in the 150 mg group, and 287 in the 300 mg group).

[0167] Figure 24 : PK / PD model-predicted anirumab trough concentrations at week 24 for anirumab 150 mg and 300 mg

[0168] Due to nonlinearity, the estimated median C at week 24 for anirumab 300 mg was 谷 Higher than anirumab 150 mg (15.6 μg mL -1 Relative to 0.2 μg mL -1 ). 21-IFNGS, 21-type I interferon gene signature; PD, pharmacodynamics; PK, pharmacokinetics. 80 is the approximate anirumab concentration required to produce 80% of the maximal inhibition of 21-IFNGS expression. Predictions based on 5000 simulations of a nonlinear mixed-effects PK / PD model were implemented into the software NONMEM (version 7.3 or higher).

[0169] Figure 25: Diagnostic plots of the PK / PD model

[0170] CWRES, conditional weighted residual; IFN, interferon; PD, pharmacodynamics; PK, pharmacokinetics. The green line represents Figure 25A and Figure 25B The identification line in Figure 25C and Figure 25D LOESS (Locally Weighted Smoothing) line in .

[0171] Figure 26: BICLA and SRI(4) response rates at week 52 according to median type I 21-IFNGS PD neutralization quartiles in patients with type I IFNGS-high

[0172] Figure 26A :BICLA; Figure 26B : SRI(4). BILAG, British Isles Lupus Assessment Group (BICLA)-based comprehensive lupus assessment; IFNGS, interferon gene signature; PD, pharmacodynamic; SRI(4), systemic lupus erythematosus responder index ≥4. Analyses included patients with a high IFNGS who had baseline and at least one postbaseline PD assessment before discontinuation and who received anirumab 150 mg or 300 mg (n=341) or placebo (n=280) in the TULIP-1 and TULIP-2 trials. PD measurements collected after discontinuation were excluded.

[0173] Figure 27 : BICLA response rates for all participants according to baseline 21-IFNGS quartiles in TULIP-1 and TULIP-2

[0174] Anilovib 300 mg resulted in a higher BICLA response relative to placebo across all baseline 21-IFNGS score quartiles in TULIP-1 and TULIP-2. 21-IFNGS, 21-gene pharmacodynamic interferon gene signature; BILAG, British Isles Lupus Assessment Group (BICLA)-based integrated lupus assessment. In the TULIP-1 and TULIP-2 trials, 819 patients received at least one dose of anilovib 300 mg, anilovib 150 mg, or placebo. Of these, 25 patients (18 with IFNGS-high and 7 with IFNGS-low) had missing baseline 21-IFNGS scores, resulting in only 794 patients included in this analysis. Baseline 21-IFNGS quartiles were calculated based on the same population.

[0175] Figure 28 : 21 interferon-α / β-induced genes that constitute a 21-gene pharmacodynamic interferon gene signature

[0176] Figure 29: Interferon gene signature (IFNGS)

[0177] In SLE there is a clear demarcation between patients who are positive and negative for diagnostic tests. Figure 29A : Fold change (RQ) marker. Figure 29B : Distribution of transcript scores for each SLE patient. This test results in a score that is compared to a pre-determined cutoff value that stratifies patients into 2 groups with low or high levels of IFN-inducible gene expression. Figure 29C : A high type I IFN gene signature is associated with increased disease activity and steroid use in SLE.

[0178] Figure 30: IFNGS Neutralization

[0179] Figure 30A : Study CP152 of sifalimumab treatment in patients with SLE. Figure 30B : Changes in type I IFNGS in patients with high baseline IFNGS. IFNGS: interferon gene signature; MAD, median absolute deviation.

[0180] Figure 31: Distribution of IFNs in Type I IFN-mediated diseases

[0181] Figure 31A : Distribution of interferon-glucose nephritis (IFNGS) in patients with systemic lupus nephritis (SLE), lupus nephritis (LN), and Sjögren's syndrome. LN: lupus nephritis; SLE: systemic lupus erythematosus; HD: healthy donor. Figure 31B: Whole blood and skin microarray analysis of patients in study MI-CP180. The IFN score is defined as the median fold change (FC) of five type I IFN-induced genes that are among the most differentially regulated genes in scleroderma patients compared to healthy controls. The baseline (day 0) score is used to determine whether the patient is IFN signature positive or negative. These five genes are a subset of the 21-gene set used to measure PD in SLE patients.

[0182] Figure 32: Baseline Gene Signatures Using 5-Gene IFNGS

[0183] Figure 32A : Type I IFN-induced gene signature scoring in whole blood (WB). Figure 32B : Type I IFN-inducible gene signature score in skin. 5-gene score: (IFI27, RSAD2, IFI44L, IFI44, IFI6).

[0184] Figure 33 Anirudinib in SSc: Phase I Study Design

[0185] Multicenter, open-label, dose-escalation study; 34 patients from 7 US sites (NCT00930683).

[0186] Figure 34: Baseline type I IFN score is associated with disease activity in patients with scleroderma

[0187] Figure 34A : Comparison of the distribution of five gene signatures in SSc and SLE at baseline. Figure 34B IFN scores were determined by calculating the median fold change (FC) of five IFN-inducible genes (IFI27, IFI6, IFI44, IFI44L, and RSAD2). The correlation between peripheral and disease tissues was evaluated. Figure 34C : Baseline IFN score correlates with disease activity score (mRTSS score). RNA was isolated from WB and skin at baseline and IFN score was measured. Modified Rodnan Total Skin Score (mRTSS), an assessment of SSc disease activity, was determined by clinicians. (A) shows the correlation between IFN score and mRTSS in all patients. (B) mRTSS scores in IFN(+) versus IFN(-) patients revealed a significant increase in disease activity in IFN Marker(+) patients. Patients were identified as Marker(+) based on a cutoff of IFN score ≥3 in WB and IFN score ≥2 in skin.

[0188] Figure 35: Dose-dependent neutralization of the (5-gene) IFN score in WB and skin of marker-positive scleroderma patients.

[0189] Patients were given a single aniluomab administration at multiple dose levels. % neutralization was calculated relative to baseline IFN score.

[0190] Figure 36: Therapeutic effect of aniluolumab in patients with SSc.

[0191] Patients were given a single aniluolumab administration at multiple dose levels.

[0192] Figure 37 : A phase Ib trial of sifalimumab, an anti-IFN-α monoclonal antibody, in patients with DM and PM

[0193] Overview of the protocol for study MI-CP151. DM, dermatomyositis; IFN, interferon; IFNGS, interferon gene signature; IV, intravenous; PM, polymyositis; Q2W, every 2 weeks; R, randomization. a According to Bohan and Peter 1975 criteria 2 Make an evaluation. b Represents when performing pharmacodynamic IFNGS measurements.

[0194] Figure 38 : IFNGS in Myositis Patients (Study MI-CP151)

[0195] Baseline type I IFN gene signature (13-gene score) values ​​in muscle and blood of patients with DM and PM were determined, showing elevated IFNGS scores in whole blood and muscle of patients with BM and PM.

[0196] Figure 39 : Neutralization of IFNGS in Myositis Patients (Study MI-CP151)

[0197] In study MI-CP151, sifalimumab was effective in treating DM ( Figure 39 ) or PM( Figure 39 ) Targeted modulation of type I IFN gene signatures in blood and muscle of patients.

[0198] FIG40 : Targeted modulation of type I IFN gene signatures in blood shows correlated trends in disease activity in patients with DM and PM (Study MI-CP151)

[0199] Figure 40A: Stratified targeted neutralization curves represent the proportion of patients with DM or PM treated with sifalimumab who demonstrated suppression of their type I IFN gene signature at the thresholds provided on the x-axis at day 98. Patients who demonstrated at least a 15% improvement in MMT8 score at day 98 (compared to day 0) are represented by the orange line, while patients who did not improve are represented by the blue line. All patients with a positive type I IFN signature (27) were treated with sifalimumab prior to dosing. Figure 40B : Targeted inhibition of the type I IFN gene signature is associated with suppression of important signaling events in muscle tissue.

[0200] Figure 41 : IFNα inhibition reduces the infiltration of immune cells into myositis muscles (DM and PM) (study

[0201] Sifalimumab reduced immune cell infiltration in myositis muscle tissue in patients with DM and PM.

[0202] Figure 42: Sifalimumab improves muscle strength at pharmacologically active doses

[0203] Doses included 1 mg / kg, 3 mg / kg, and 10 mg / kg. The sifalimumab group received 14 doses (Q2W) over 6 months. The placebo group received sifalimumab for 3 months, followed by a switch to sifalimumab for 3 months.

[0204] Figure 43 Comparison of the neutralization effects of aniluolumab and sifalimumab on IFNGS

[0205] Both sifalimumab and aniluomab were tested in phase II clinical trials in SLE (NCT01283139 and Study 1013, respectively, Table 6-1: Clinical Studies). Both therapies had positive results and neutralized type I IFNGS, with aniluomab having a greater effect.

[0206] Figure 44: Conveying device

[0207] Phase III study plan ( Figure 44A ). Through an injection device[1][9] such as a pre-filled syringe (PFS) ( Figure 44B ) or auto-injector ( Figure 44C ) administration of anirumab.

[0208] Figure 45: Autoinjector

[0209] Exploded view ( Figure 45A )、Assembly drawing( Figure 45B ) and filled with drug substance ( Figure 45C ) for administering anirutumab or a functional variant thereof.

[0210] Figure 46: Prefilled syringe with accessories

[0211] A prefilled syringe (APFS) with attachments for aniluomab or its functional variants. The primary tube is in assembled form ( Figure 46A ) and exploded view ( Figure 46B ) is shown. APFS with its additional components is in assembled form ( Figure 46C ) and exploded view ( Figure 46D ) is shown.

[0212] Figure 47 :Packaging for conveying devices

[0213] Figure 48 Anirudumab heavy chain alignment

[0214] Figure 49 Anirudumab light chain alignment 4. Specific Implementation Methods

[0215] 4.1. Subcutaneous Unit Dose

[0216] The present invention relates to a unit dose (pharmaceutical unit dose, unit dosage form, or pharmaceutical unit dosage form) for subcutaneous administration, comprising >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg) of aniluolumab or a functional variant thereof. The unit dose can be packaged or formulated as a unit dose, i.e., administered to a subject in a single administration step.

[0217] The present invention relates to a unit dose (pharmaceutical unit dose, unit dosage form or pharmaceutical unit dosage form) for subcutaneous administration, comprising>105 mg (i.e. greater than 105 mg) and<150 mg (i.e. less than 150 mg) of an IFNAR1 inhibitor. The unit dose can be packaged or formulated as a unit dose, i.e. administered to a subject in a single administration step.

[0218] The unit dose may comprise ≤135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor. The unit dose may comprise approximately 120 mg of the IFNAR1 inhibitor. The unit dose may consist essentially of >105 mg and <150 mg of the IFNAR1 inhibitor. The unit dose may consist essentially of ≤135 mg of the IFNAR1 inhibitor. The unit dose may consist essentially of approximately 120 mg of the IFNAR1 inhibitor. The concentration of the IFNAR1 inhibitor in the unit dose may be approximately 150 mg / ml. The volume of the unit dose may be less than 1 ml. The volume of the dose or unit dose may be 0.5 ml to 1 ml. The concentration of the unit dose may be approximately 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose may comprise a formulation of 150 mg / ml to 200 mg / ml anirumab or its functional variant, 25 mM to 150 mM lysine salt, and an unloaded excipient. The unit dose can consist essentially of a formulation of 150 mg / ml to 200 mg / ml of the IFNAR1 inhibitor, 25 mM to 150 mM lysine salt, and an unloaded excipient. The unit dose comprises a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05% w / v polysorbate 80. The pH of the formulation can be about 5.9.

[0219] The unit dose may contain ≤135 mg (i.e., 135 mg or less) of aniluomab or a functional variant thereof. The unit dose may contain approximately 120 mg of aniluomab or a functional variant thereof. The unit dose may contain 120 mg of aniluomab or a functional variant thereof. The unit dose may consist essentially of >105 mg and <150 mg of aniluomab or a functional variant thereof. The unit dose may consist essentially of ≤135 mg of aniluomab or a functional variant thereof. The unit dose may consist essentially of approximately 120 mg of aniluomab or a functional variant thereof. The concentration of aniluomab or a functional variant thereof in the unit dose may be approximately 150 mg / ml. The volume of the unit dose may be less than 1 ml. The volume of the dose or unit dose may be 0.5 ml to 1 ml. The concentration of the unit dose may be approximately 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose may comprise a formulation of 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, 25 mM to 150 mM lysine salt, and unloaded excipients. The unit dose may comprise a formulation of 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, 25 mM to 150 mM lysine salt, and unloaded excipients. The unit dose comprises a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05% w / v polysorbate 80. The pH of the formulation may be about 5.9.

[0220] 4.2. Methods for treating type I IFN-mediated diseases

[0221] The present invention also relates to a method for treating a type I interferon (IFN)-mediated disease in a subject, the method comprising subcutaneously administering a unit dose of the present invention to a subject suffering from a type I interferon (IFN)-mediated disease. The present invention also relates to a method for treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering a dose of an IFNAR1 inhibitor, wherein the dose is >105 mg and <150 mg. The present invention also relates to a method for treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering a dose of aniluomab or a functional variant thereof, wherein the dose is >105 mg and <150 mg.

[0222] The invention still further relates to a method for treating a disease of type I IFN mediation of a subject, the method comprising administering a certain dose of an IFNAR1 inhibitor subcutaneously, wherein administering the dosage weekly provides the following plasma concentration in the subject, which is at least equivalent to the plasma concentration provided by intravenously administering 300mg IFNAR1 inhibitors per 4 weeks. Administering the dosage weekly can provide the following plasma concentration in the subject, which is at least greater than the plasma concentration provided by intravenously administering 300mg IFNAR1 inhibitors per 4 weeks. Administering the dosage weekly can provide the following plasma concentration in the subject, which is at least equivalent to the plasma concentration provided by intravenously administering 400mg IFNAR1 inhibitors per 4 weeks. The dosage can be administered in a single administration step. The dosage administered to the subject can be the IFNAR1 inhibitor of <150mg (i.e., less than 150mg). The dosage administered to the subject can be the IFNAR1 inhibitor of >105mg (i.e., greater than 105mg). The dosage administered to the subject can be the IFNAR1 inhibitor of ≤135mg (i.e., 135mg or less). The dose administered to the subject can be about 120 mg of the IFNAR1 inhibitor.

[0223] The present invention also relates to a method for treating a type I IFN-mediated disease in a subject, comprising subcutaneously administering a dose of aniluomab or a functional variant thereof, wherein weekly administration of the dose provides a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by 300 mg of aniluomab or a functional variant thereof administered intravenously every four weeks. Weekly administration of the dose can provide a plasma concentration in the subject that is greater than the plasma concentration provided by 300 mg of aniluomab or a functional variant thereof administered intravenously every four weeks. Weekly administration of the dose can provide a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by 400 mg of aniluomab or a functional variant thereof administered intravenously every four weeks. The dose can be administered in a single administration step. The dose administered to the subject can be <150 mg (i.e., less than 150 mg) of aniluomab or a functional variant thereof. The dose administered to the subject can be >105 mg (i.e., greater than 105 mg) of aniluomab or a functional variant thereof. The dose administered to the subject may be ≤135 mg (i.e., 135 mgl or less) aniluomab or a functional variant thereof. The dose administered to the subject may be approximately 120 mg aniluomab or a functional variant thereof.

[0224] The type I IFN-mediated disease may be lupus. The type I IFN-mediated disease may be systemic lupus erythematosus (SLE). Administration of the dose or unit dose may provide an improvement in the patient's BILAG-based comprehensive lupus assessment (BICLA) (BICLA) response rate from baseline. Administration of the dose or unit dose may result in a BICLA response in the subject, wherein a BICLA response is defined as (1) at least one grade improvement in baseline BILAG scores in all body systems with moderate or severe disease activity at enrollment (e.g., all A (severe disease) scores are reduced to B (moderate), C (mild) or D (inactive) and all B scores are reduced to C or D); (2) no new BILAG A or more than one new BILAG B score; (3) no worsening of the total SLEDAI score from baseline; (4) no significant regression (≤10%) in the physician's global assessment; and (5) no treatment failure (start of non-protocol treatment). Administration of the dose or unit dose can provide an improvement from baseline in the patient's Systemic Lupus Erythematosus Responder Index (SRI) 4 score. A subject achieves SRI (4) if all of the following criteria are met: 1. a decrease from baseline of ≥4 points on the SLEDAI-2K; 2. no new organ system involvement compared to baseline using BILAG-2004, as defined by one or more BILAG-2004A or two or more 3. BILAG-2004B items; 4. no worsening of the subject's lupus disease activity from baseline, as defined by an increase of ≥0.30 points on the 3-point PGA VAS. Lupus includes SLE, lupus nephritis, and cutaneous lupus erythematosus (CLE).

[0225] The treatment method can reduce SLE disease activity in the subject. Reducing SLE disease activity in the subject can include a) a BILAG-based comprehensive lupus assessment (BICLA) response in the subject, b) an SRI(4) response in the subject, and / or reducing the subject's Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) score as compared to the subject's CLASI score before treatment.

[0226] The type I IFN-mediated disease may be an autoimmune disease. The type I IFN-mediated disease may be myositis. The type I IFN-mediated disease may be Sjögren's syndrome. The type I IFN-mediated disease may be scleroderma.

[0227] I type IFN mediated disease can be defined as a disease in which the patient has elevated IFNGS compared to a healthy donor. The elevated IFNGS can be in the patient's whole blood and / or diseased tissue (e.g., muscle and / or skin). The elevated IFNGS can be measured as a 4-gene, 5-gene, or 21-gene score.

[0228] Dosage

[0229] Unit dose (also referred to as unit dosage form, drug unit dose or drug unit dosage form) is a dosage formed by a single unit. Unit dose (unit dosage form) is suitable for use in a single administration to a subject. Unit dose (unit dosage form) can be packaged in a single unit container, such as a disposable pre-filled syringe or an automatic syringe. The advantage of unit dose is that they can be ordered, packaged, processed and used as a single dose unit containing a predetermined amount of medicine. Unit dose can reduce administration errors and reduce waste.

[0230] On the other hand, the present invention relates to a unit dose (pharmaceutical unit dose, unit dosage form or pharmaceutical unit dosage form) for subcutaneous administration comprising>105mg (i.e. greater than 105mg) and<150mg (i.e. less than 150mg) of an IFNAR1 inhibitor. The unit dose may comprise 105mg to 149mg of an IFNAR inhibitor.

[0231] In another aspect, the present invention relates to a unit dose (pharmaceutical unit dose, unit dosage form or pharmaceutical unit dosage form) for subcutaneous administration comprising >105 mg (i.e. greater than 105 mg) and <150 mg (i.e. less than 150 mg) anirumab or a functional variant thereof.

[0232] The unit dose may comprise ≤135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor. The unit dose may comprise 105 mg to 135 mg of the IFNAR inhibitor. The unit dose may comprise approximately 120 mg of the IFNAR1 inhibitor. The unit dose may consist essentially of >105 mg and <150 mg of the IFNAR1 inhibitor. The unit dose may consist essentially of ≤135 mg of the IFNAR1 inhibitor. The unit dose may consist essentially of approximately 120 mg of aniluomab or its functional variant. The concentration of the IFNAR1 inhibitor in the unit dose may be approximately 150 mg / ml. The volume of the unit dose may be 1 ml or less. The volume of the dosage or unit dose may be 0.5 ml to 1 ml. The concentration of the unit dose may be approximately 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose can comprise a formulation of 150mg / ml to 200mg / ml of this IFNAR1 inhibitor, 25mM to 150mM lysine salt and an unloaded excipient. The unit dose can comprise a formulation of 150mg / ml to 200mg / ml of this IFNAR1 inhibitor, 25mM to 150mM lysine salt and an unloaded excipient. The unit dose comprises a formulation of 25mM histidine-HCL, 130mM trehalose and 0.05% w / v polysorbate 80. The pH of the formulation can be about 5.9.

[0233] In another aspect, the present invention relates to a method of treating lupus (e.g., SLE) in a subject, the method comprising subcutaneously administering a unit dose of the present invention to a subject suffering from lupus (e.g., SLE). In another aspect, the present invention relates to a method of treating lupus (e.g., SLE) in a subject, the method comprising subcutaneously administering a dose of aniluomab or a functional variant thereof, wherein the dose is >105 mg and <150 mg. In another aspect, the present invention relates to a method of treating lupus (e.g., SLE) in a subject, the method comprising subcutaneously administering a dose of aniluomab or a functional variant thereof, wherein the dose is between 105 mg and 149 mg.

[0234] On the other hand, the present invention relates to a method for treating lupus (such as SLE) of a subject, the method comprising administering a certain dose of IFNAR1 inhibitor subcutaneously, wherein the dosage is administered weekly to provide the following plasma concentration in the subject, which is at least equivalent to the plasma concentration provided by intravenously administering 300mg IFNAR1 inhibitors per 4 weeks. The dosage can be administered weekly to provide the following plasma concentration in the subject, which is greater than the plasma concentration provided by intravenously administering 300mg aniluomab or its functional variants per 4 weeks. The dosage can be administered weekly to provide the following plasma concentration in the subject, which is at least equivalent to the plasma concentration provided by intravenously administering 400mg IFNAR1 inhibitors per 4 weeks. The dosage can be administered in a single administration step. The dosage administered to the subject can be <150mg (i.e., less than 150mg) IFNAR1 inhibitor. The dosage administered to the subject can be >105mg (i.e., greater than 105mg) IFNAR1 inhibitor. The dosage administered to the subject can be <135mg (i.e., 135mg or less) IFNAR1 inhibitor. The dose administered to the subject may be 105 mg to 135 mg of the IFNARl inhibitor. The dose administered to the subject may be about 120 mg of the IFNARl inhibitor.

[0235] In another aspect, the present invention relates to a method for treating lupus (e.g., SLE) in a subject, comprising subcutaneously administering a dose of aniluomab or a functional variant thereof, wherein weekly administration of the dose provides a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by intravenous administration of 300 mg of aniluomab or a functional variant thereof every 4 weeks. Weekly administration of the dose can provide a plasma concentration in the subject that is greater than the plasma concentration provided by intravenous administration of 300 mg of aniluomab or a functional variant thereof every 4 weeks. Weekly administration of the dose can provide a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by intravenous administration of 400 mg of aniluomab or a functional variant thereof every 4 weeks. The dose can be administered in a single administration step. The dose administered to the subject can be <150 mg (i.e., less than 150 mg) of aniluomab or a functional variant thereof. The dose administered to the subject can be >105 mg (i.e., greater than 105 mg) of aniluomab or a functional variant thereof. The dose administered to the subject may be 105 mg to 149 mg of aniluomab or a functional variant thereof. The dose administered to the subject may be 105 mg to 135 mg of aniluomab or a functional variant thereof. The dose administered to the subject may be approximately 120 mg of aniluomab or a functional variant thereof.

[0236] The method of the present invention may include administering the dose or unit dose at intervals of 6 to 8 days. The dose or unit dose may be administered once a week (QW). The dose or unit dose may be 120 mg of aniluomab or a functional variant thereof, wherein the method includes administering the dose once a week (QW) in a single administration step. In other words, the method includes administering 120 mg QW of aniluomab or a functional variant thereof. The dose or unit dose may be administered once a week for at least about 4 weeks. The dose or unit dose may be administered once a week for at least about 8 weeks. The dose or unit dose may be administered once a week for at least about 12 weeks. The dose or unit dose may be administered once a week for at least about 16 weeks. The dose or unit dose may be administered once a week for at least about 20 weeks. The dose or unit dose may be administered once a week for at least about 24 weeks. The dose or unit dose may be administered once a week for at least about 28 weeks. The dose or unit dose may be administered once a week for at least about 32 weeks. The dosage or unit dose can be administered once a week for about 8 weeks. The dosage or unit dose can have a volume that allows it to be suitable for delivery in a single subcutaneous administration step. The volume of the dosage or unit dose can be 0.5 ml to 1 ml. The volume of the dosage or unit dose can be less than 1 ml. The volume of the dosage or unit dose can be about 0.8 ml.

[0237] Administration of the dose or unit dose can provide a plasma concentration of aniluomab or its functional variant in the patient at ≥10 μg (i.e., 10 μg or more) aniluomab or its functional variant per ml of plasma (i.e., a plasma concentration ≥10 μg / ml). Administration of the dose or unit dose can provide aniluomab or its functional variant at a plasma concentration of about 10 μg / ml-100 μg / ml in the subject. Administration of the dose or unit dose can provide aniluomab or its functional variant at a plasma concentration of 20 μg / ml-80 μg / ml in the subject. Administration of the dose or unit dose can provide aniluomab or its functional variant at a plasma concentration of 30 μg / ml-70 μg / ml in the subject. Administration of the dose or unit dose can provide a trough concentration of aniluomab or its functional variant in the subject of ≥20 μg / ml (i.e., 20 μg / ml or higher). Administration of the dose or unit dose can provide anirumab or its functional variant at a trough concentration of ≥30 μg / ml (i.e., 30 μg / ml or higher) in the subject. Administration of the dose or unit dose can provide anirumab or its functional variant at a trough concentration of ≥40 μg / ml (i.e., 40 μg / ml or higher) in the subject. Administration of the dose or unit dose can provide anirumab or its functional variant at a trough concentration of 20 μg / ml-100 μg / ml in the subject. Administration of the dose or unit dose can provide anirumab or its functional variant at a trough concentration of approximately 30 μg / ml-80 μg / ml in the subject. Administration of the dose or unit dose can provide anirumab or its functional variant at a trough concentration of 40 μg / ml-70 μg / ml in the subject.

[0238] The dose or unit dose can provide a therapeutic effect in the subject that is at least equivalent to the therapeutic effect provided by administering a 300 mg intravenous dose of anibovumab or a functional variant thereof administered once every 4 weeks (Q4W). The dose or unit dose can provide a trough concentration of anibovumab or a functional variant thereof in the subject that is greater than the trough concentration of anibovumab or a functional variant thereof provided by administering a 300 mg intravenous dose of anibovumab or a functional variant thereof administered once every 4 weeks (Q4W).

[0239] The method of the present invention may include administering the dose or unit dose at intervals of 6 to 8 days. The dose or unit dose may be administered once a week (QW). The dose or unit dose may be 120 mg of aniluomab or a functional variant thereof, wherein the method comprises administering the dose once a week (QW) in a single administration step. In other words, the method comprises administering 120 mg QW of aniluomab or a functional variant thereof. The dose or unit dose may be administered once a week for at least 4 weeks. The dose or unit dose may be administered once a week for at least 8 weeks. The dose or unit dose may be administered once a week for at least 12 weeks. The dose or unit dose may be administered once a week for at least 16 weeks. The dose or unit dose may be administered once a week for at least 20 weeks. The dose or unit dose may be administered once a week for at least 24 weeks. The dose or unit dose may be administered once a week for at least 28 weeks. The dose or unit dose may be administered once a week for at least 32 weeks. The dose or unit dose may be administered once a week for about 8 weeks. The dose or unit dose can have a volume that allows it to be suitable for delivery in a single subcutaneous administration step. The volume of the dose or unit dose can be 0.5 ml to 1 ml. The volume of the dose or unit dose can be less than 1 ml. The volume of the dose or unit dose can be about 0.8 ml.

[0240] Administration of the dose or unit dose can provide a plasma concentration of aniluomab or its functional variant in the patient at ≥10 μg (i.e., 10 μg or more) aniluomab or its functional variant per ml of plasma (i.e., a plasma concentration ≥10 μg / ml). Administration of the dose or unit dose can provide aniluomab or its functional variant in the subject at a plasma concentration of 10 μg / ml-100 μg / ml. Administration of the dose or unit dose can provide aniluomab or its functional variant in the subject at a plasma concentration of 20 μg / ml-80 μg / ml. Administration of the dose or unit dose can provide aniluomab or its functional variant in the subject at a plasma concentration of 30 μg / ml-70 μg / ml. Administration of the dose or unit dose can provide a trough concentration of aniluomab or its functional variant in the subject of ≥20 μg / ml (i.e., 20 μg / ml or higher). Administration of the dose or unit dose can provide anirumab or its functional variant at a trough concentration of ≥30 μg / ml (i.e., 30 μg / ml or higher) in the subject. Administration of the dose or unit dose can provide anirumab or its functional variant at a trough concentration of ≥40 μg / ml (i.e., 40 μg / ml or higher) in the subject. Administration of the dose or unit dose can provide anirumab or its functional variant at a trough concentration of 20 μg / ml-100 μg / ml in the subject. Administration of the dose or unit dose can provide anirumab or its functional variant at a trough concentration of approximately 30 μg / ml-80 μg / ml in the subject. Administration of the dose or unit dose can provide anirumab or its functional variant at a trough concentration of 40 μg / ml-70 μg / ml in the subject.

[0241] The dose or unit dose can provide a therapeutic effect in the subject that is at least equivalent to the therapeutic effect provided by administering a 300 mg intravenous dose of anibovumab or a functional variant thereof administered once every 4 weeks (Q4W). The dose or unit dose can provide a trough concentration of anibovumab or a functional variant thereof in the subject that is greater than the trough concentration of anibovumab or a functional variant thereof provided by administering a 300 mg intravenous dose of anibovumab or a functional variant thereof administered once every 4 weeks (Q4W).

[0242] The dose or unit dose can be 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg or 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, or 149 mg.

[0243] 4.4. Subjects

[0244] The subject may be a human subject. The subject may be an adult. The subject may have lupus. The subject may have systemic lupus erythematosus (SLE). The subject may have active SLE. The subject may have moderate to severe SLE. The subject may have lupus nephritis (LN). The subject may have CLE. The subject may have myositis. The subject may have scleroderma. The subject may have Sjögren's syndrome.

[0245] The subject may be a patient whose type I IFN gene signature is elevated. The subject may be a patient whose type I interferon-stimulated gene signature (IFNGS) test is high before the dosage or unit dose is administered. The IFNGS may be a 21-gene signature. The IFNGS may be a 4-gene signature. The IFNGS may be a 5-gene signature. The subject may have elevated expression levels of genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood. The subject may have elevated expression levels of genes IFI27, RSAD2, IFI44, IFI44L, and IFI6 in whole blood. The method may include identifying the subject as a patient whose IFNGS test is high before treatment with the dosage or unit dose. The method may include measuring the expression of genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood of the subject. The method may include measuring the expression of genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood of the subject. The method may include measuring the expression of genes IFI27, RSAD2, IFI44, IFI44L, IFI6 in the whole blood of the subject by RT-PCR. Gene expression can be measured in an isolated sample of the subject. Measurement may include a physical measurement step.

[0246] The subject's 21-IFNGS score at baseline (i.e., before treatment with the dose) may be about 13. The subject's 21-IFNGS score at baseline (i.e., before treatment with the dose) may be about 10, 11, 12, 13, 14, 15, or 16. The subject's 21-IFNGS score at baseline (i.e., before treatment with the dose) may be about 13.1.

[0247] 4.5. Pharmaceutical Compositions

[0248] In another aspect, the present invention relates to a pharmaceutical composition for treating SLE in a subject in need thereof, the method comprising subcutaneously administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a unit dose of the present invention.

[0249] In another aspect, the invention relates to a pharmaceutical composition for use in a method of treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a unit dose of the invention.

[0250] In another aspect, the present invention relates to a pharmaceutical composition for use in a method of treating a disease mediated by a functional variant type I IFN in a subject, the method comprising subcutaneously administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a dose of aniluomab or a functional variant thereof, wherein the dose is >105 mg and <150 mg. The dose of aniluomab or a functional variant thereof can be a unit dose (unit dosage form, pharmaceutical unit dosage form, pharmaceutical unit dose). Functional aniluomab variants include antigen-binding fragments of aniluomab and antibody and immunoglobulin derivatives of aniluomab.

[0251] In another aspect, the present invention relates to a pharmaceutical composition for use in a method of treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a dose of aniluomab or a functional variant thereof, wherein weekly administration of the pharmaceutical composition provides a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by 300 mg of aniluomab or a functional variant thereof administered intravenously every four weeks. Weekly administration of the dose can provide a plasma concentration in the subject that is approximately equivalent to the plasma concentration provided by 400 mg of aniluomab or a functional variant thereof administered intravenously every four weeks. The dose can be <150 mg (i.e., less than 150 mg) of aniluomab or a functional variant thereof. The dose can be >105 mg (i.e., greater than 105 mg) of aniluomab or a functional variant thereof. The dose can be ≤135 mg (i.e., 135 mg or less) of aniluomab or a functional variant thereof. The dose can be approximately 120 mg of aniluomab or a functional variant thereof. The dose can be 120 mg of aniluomab or a functional variant thereof.

[0252] Administration of the pharmaceutical composition can provide a plasma concentration of aniluomab or its functional variant in the patient at ≥10 μg (i.e., 10 μg or more) aniluomab or its functional variant per ml of plasma (i.e., a plasma concentration ≥10 μg / ml). Administration of the pharmaceutical composition can provide aniluomab or its functional variant in the subject at a plasma concentration of 10 μg / ml-100 μg / ml. Administration of the pharmaceutical composition can provide aniluomab or its functional variant in the subject at a plasma concentration of 20 μg / ml-80 μg / ml. Administration of the pharmaceutical composition can provide aniluomab or its functional variant in the subject at a plasma concentration of 30 μg / ml-70 μg / ml. Administration of the pharmaceutical composition can provide aniluomab or its functional variant in the subject at a trough concentration of ≥20 μg / ml (i.e., 20 μg / ml or higher). Administration of the pharmaceutical composition can provide aniluomab or its functional variant in the subject at a trough concentration of ≥30 μg / ml (i.e., 30 μg / ml or higher). Administration of the pharmaceutical composition can provide a trough concentration of aniluomab or a functional variant thereof in the subject of ≥40 μg / ml (i.e., 40 μg / ml or higher). Administration of the pharmaceutical composition can provide a trough concentration of aniluomab or a functional variant thereof in the subject of 20 μg / ml-100 μg / ml. Administration of the pharmaceutical composition can provide a trough concentration of aniluomab or a functional variant thereof in the subject of 30 μg / ml-80 μg / ml. Administration of the pharmaceutical composition can provide a trough concentration of aniluomab or a functional variant thereof in the subject of 40 μg / ml-70 μg / ml.

[0253] The pharmaceutical composition can provide a therapeutic effect in the subject that is at least equivalent to the therapeutic effect provided by an intravenous dose of 300 mg anirumab or a functional variant thereof administered once every 4 weeks (Q4W). The pharmaceutical composition can provide a trough concentration of anirumab or a functional variant thereof in the subject that is greater than the trough concentration of anirumab or a functional variant thereof provided by an intravenous dose of 300 mg anirumab or a functional variant thereof administered once every 4 weeks (Q4W). The anirumab or a functional variant thereof can be included in a pharmaceutical composition. The pharmaceutical composition can include approximately 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and an unloaded excipient. The pharmaceutical composition can include 150 mg / mL anirumab or a functional variant thereof. The pharmaceutical composition can include 50 mM lysine HCl. The pharmaceutical composition can include 130 mM trehalose dihydrate. The pharmaceutical composition can include 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL anirumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0254] 4.6. Preparations

[0255] The IFNAR1 inhibitor may be included in a pharmaceutical composition. The pharmaceutical composition may include approximately 150 mg / ml to 200 mg / ml of the IFNAR1 inhibitor, approximately 25 mM to 150 mM lysine salt, and an unloaded excipient. The pharmaceutical composition may include 150 mg / mL anirumab or a functional variant thereof. The pharmaceutical composition may include 50 mM lysine HCl. The pharmaceutical composition may include 130 mM trehalose dihydrate. The pharmaceutical composition may include 0.05% polysorbate 80. The pharmaceutical composition may include 25 mM histidine / histidine HCl. The pharmaceutical composition may include 150 mg / mL of the IFNAR1 inhibitor, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0256] The anirumab or its functional variant may be included in a pharmaceutical composition. The pharmaceutical composition may comprise approximately 150 mg / ml to 200 mg / ml anirumab or its functional variant, approximately 25 mM to 150 mM lysine salt, and an unloaded excipient. The pharmaceutical composition may comprise 150 mg / mL anirumab or its functional variant. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL anirumab or its functional variant, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0257] The unit dose may comprise approximately 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and unloaded excipients. The unit dose may comprise 150 mg / mL anirumab or a functional variant thereof. The unit dose may comprise 50 mM lysine HCl. The unit dose may comprise 130 mM trehalose dihydrate. The unit dose may comprise approximately 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and unloaded excipients. The unit dose may comprise 150 mg / mL anirumab or a functional variant thereof. The unit dose may comprise 50 mM lysine HCl. The unit dose may comprise 130 mM trehalose dihydrate. The unit dose may comprise 0.05% polysorbate 80. The unit dose may comprise 25 mM histidine / histidine HCl. The unit dose may comprise 150 mg / mL anirumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0258] The pharmaceutical composition may comprise approximately 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and unloaded excipients. The pharmaceutical composition may comprise 150 mg / mL anirumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise approximately 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and unloaded excipients. The pharmaceutical composition may comprise 150 mg / mL anirumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL anirumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0259] Stable formulations suitable for administration to a subject and comprising anirumab are described in detail in U.S. Patent 10,125,195 Bl, which is incorporated herein in its entirety.

[0260] 4.7. Steroids

[0261] Many lupus (e.g., SLE) patients receive corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are relevant to organ damage. Aniluomab allows the corticosteroids (glucocorticoids) in lupus (e.g., SLE) patients to be tapered (steroid moderation). The treatment method or method may include administering a corticosteroid to the experimenter, optionally wherein the corticosteroid is an oral corticosteroid. The method may include gradually tapering the dosage (steroid moderation) of the corticosteroid administered to the experimenter. The method may include administering the corticosteroid of a first dose and subsequently administering the corticosteroid of a second dose, wherein the corticosteroid of the second dose is lower than the corticosteroid of the first dose. The corticosteroid of the second dose may be approximately 7.5 mg prednisone equivalent dose or less (see Table 5-4). The corticosteroid of the second dose may be 5 mg prednisone equivalent dose or less. The method or treatment method may include administering the corticosteroid of the second dose once a day. The first dose of the corticosteroid can be about 10 mg prednisone equivalents. The method can include gradually reducing the dose of the corticosteroid administered to the patient from 10 mg or more per day to less than 10 mg per day. The method or treatment method can include administering the second dose of the corticosteroid once a day. The method can allow for administration of a reduced dose of the corticosteroid for several weeks. The second dose of the corticosteroid can be administered for at least 24 weeks. The second dose of the corticosteroid can be administered for at least 28 weeks.

[0262] One or more methods of the present invention may comprise administering a standard of care (SOC) to the subject. One or more methods of the present invention may comprise administering a steroid to the subject. The method or methods of the present invention may comprise performing steroid abstinence in a subject, wherein the dose of the steroid administered to the subject is gradually tapered from a pre-abstinence dose at baseline to a post-abstinence dose.

[0263] The method may include performing steroid abstinence in a subject, wherein the dose of a steroid administered to the subject is gradually reduced from a pre-abstinence dose at baseline to a post-abstinence dose. The post-abstinence dose may be ≤7.5 mg / day of prednisone or a prednisone equivalent. The pre-abstinence dose may be 20 mg / day of prednisone or a prednisone equivalent. The steroid may include a glucocorticoid. The steroid may include an oral glucocorticoid. The steroid may be selected from the group consisting of hydrocortisone, mometasone, fluticasone, fluocinolone acetonide, fluocinolone acetonide, flurandrenolide, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, clocortolone, dihydroxycortisone, alclomethasone, amcinonide, diflucortolone valerate, fluocortolone, fluprednidine, flu Fluandrenolone, fluorometholone, halcinonide, ulbetasol, desonide, diflorasone, flurandrenolide, fluocinolone acetonide, prednicarbate, desoximetasone, fluprednisolone, prednisone, azelastine, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinolone acetonide, halopredasol, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, prednisolone, prednisolone 21-phosphate, clobetasol propionate, triamcinolone acetonide acetate, or a mixture thereof. The steroid may be prednisone.

[0264] 4.8. Device

[0265] The present invention also relates to an injection device comprising a unit dose of the present invention or a pharmaceutical composition for any use of the present invention. The drug in the injection device may comprise >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg) of aniluomab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise approximately 120 mg of aniluomab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise 120 mg of aniluomab or a functional variant thereof. The concentration of aniluomab or a functional variant thereof in the pharmaceutical composition in the injection device may be approximately 150 mg / ml. The volume of the pharmaceutical composition in the injection device may be at least about 0.8 ml. The volume of the pharmaceutical composition may be about 0.8 ml.

[0266] The pharmaceutical composition in the injection device may comprise approximately 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and unloaded excipients. The pharmaceutical composition in the injection device may comprise 150 mg / mL anirumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition in the injection device may comprise approximately 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and unloaded excipients. The pharmaceutical composition in the injection device may comprise 150 mg / mL anirumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition in the injection device may comprise 130 mM trehalose dihydrate. The pharmaceutical composition in the injection device may comprise 0.05% polysorbate 80. The pharmaceutical composition in the injection device may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition in the injection device may comprise 150 mg / mL anirumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0267] In addition to providing subcutaneous administration of antibodies, the ability to self-administer (e.g., at home) can also be further enhanced by subcutaneous administration via a prefilled syringe with an attachment (APFS), an automatic injector (AI), or a combination thereof. Such devices have been found to be well tolerated and reliable for administering subcutaneous doses of antibodies and provide further options for optimizing patient care. In fact, such devices can reduce the burden of frequent patient visits. Examples of suitable APFS devices are described in Ferguson et al. [6], which is incorporated herein by reference in its entirety.

[0268] The doses described by the inventors offer advantages in APFS administration, as APFS devices typically administer a maximum volume of 1 ml. Doses ranging from >105 mg to <155 mg can be readily accommodated in a volume of approximately 0.8 ml, making one or more doses of the present invention particularly suitable for APFS and AI administration. For comparison, due to the viscosity of aniluolumab, larger doses (particularly doses >150 mg) need to be administered in volumes >1 ml, requiring at least two SC injections, which is inconvenient for the patient and requires multiple prefilled devices.

[0269] The delivery device may be a single-use, disposable system designed to enable manual subcutaneous (SC) administration of the dose.

[0270] The present invention also relates to an injection device comprising a unit dose. The unit dose may comprise >105 mg (i.e., at least 105 mg) and <150 mg (i.e., less than 150 mg) of aniluomab or a functional variant thereof. The unit dose may comprise ≤135 mg (i.e., 135 mg or less) of aniluomab or a functional variant thereof. The unit dose may comprise approximately 120 mg of aniluomab or a functional variant thereof. The unit dose in the injection device may comprise 120 mg of aniluomab or a functional variant thereof. The unit dose in the injection device may consist essentially of >105 mg and <150 mg of aniluomab or a functional variant thereof. The unit dose in the injection device may consist essentially of ≤135 mg of aniluomab or a functional variant thereof. The unit dose in the injection device may consist essentially of approximately 120 mg of aniluomab or a functional variant thereof. The concentration of aniluomab or a functional variant thereof in the unit dose in the injection device may be approximately 150 mg / ml. The volume of the unit dose in the injection device may be less than 1 ml. The volume of a unit dose in the injection device can be 0.5 ml to 1 ml. The concentration of the unit dose can be approximately 0.8 ml. The volume of the unit dose can be 0.8 ml. The unit dose in the injection device can comprise a formulation of approximately 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and an unloaded excipient. The unit dose in the injection device can comprise a formulation of 150 mg / ml to 200 mg / ml anirumab or a functional variant thereof, 25 mM to 150 mM lysine salt, and an unloaded excipient. The unit dose comprises a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05% w / v polysorbate 80. The pH of the formulation can be approximately 5.9.

[0271] The injection device may be a prefilled syringe (PFS). The injection device may be a prefilled syringe with attachment (AFPS). The injection device may be an autoinjector (AI).

[0272] 4.9. Kit

[0273] The present invention also relates to a kit comprising a unit dose of the present invention and instructions for use, wherein the instructions for use comprise instructions for subcutaneously administering the unit dose to a subject. The present invention also relates to a kit comprising a pharmaceutical composition for use according to the present invention, wherein the instructions for use comprise instructions for subcutaneously administering the pharmaceutical composition to a subject.

[0274] The present invention also relates to a kit comprising the injection device of any one of the present invention and instructions for use, wherein the instructions for use comprise instructions for use of the injection device for subcutaneously administering the unit dose or pharmaceutical composition to the subject.

[0275] The instructions for use may specify that the injection device, unit dose and / or pharmaceutical composition are for use in treating SLE. The kit of the present invention may comprise packaging, wherein the packaging is adapted to accommodate the injection device and instructions for use. The instructions for use may be attached to the injection device. The instructions for use may include instructions for administering >105 mg and <150 mg of aniluomab or its functional variant. The instructions for use may include instructions for administering ≤135 mg of aniluomab or its functional variant. The instructions for use may include instructions for administering 120 mg of aniluomab or its functional variant. The instructions for use may include instructions for administering 120 mg of aniluomab or its functional variant every 4 weeks. The instructions for use may define the subject as having a type I IFN-mediated disease. The instructions may define the subject as having lupus (e.g., SLE). The instructions for use may be written instructions. The instructions for use may specify that the type I IFN inhibitor is for subcutaneous administration.

[0276] The instructions for use may specify that the injection device, unit dosage, and / or pharmaceutical composition be used in any of the methods of the invention.

[0277] The present invention also relates to a method for producing a kit of the invention, a pharmaceutical composition of the invention or a unit dose of the invention.

[0278] 4.10. Inhibitors of Type I IFN-mediated Signaling

[0279] The inhibitor of type I IFN-mediated signal transduction can be an IFNAR1 inhibitor. The IFNAR1 inhibitor can be a human monoclonal antibody specific for IFNAR1. The IFNAR1 inhibitor can be a modified IgG1 class human monoclonal antibody specific for IFNAR1.

[0280] The antibody may comprise a heavy chain variable region complementary determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3. The antibody may comprise a heavy chain variable region complementary determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4. The antibody may comprise a heavy chain variable region complementary determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5. The antibody may comprise a light chain variable region complementary determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6. The antibody may comprise a light chain variable region complementary determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7. The antibody may comprise a light chain variable region complementary determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0281] The antibody may comprise a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1. The antibody may comprise a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. The antibody may comprise a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 9. The antibody may comprise a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 10. The antibody may comprise an amino acid substitution of L234F in the Fc region, as numbered by the EU index as set forth in Kabat, and wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to the unmodified antibody. The antibody may comprise a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11. The antibody may comprise a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0282] The antibody may comprise: (a) a heavy chain variable region complementary determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3; (b) a heavy chain variable region complementary determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4; c) a heavy chain variable region complementary determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5; (d) a light chain variable region complementary determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6; (b) a light chain variable region complementary determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; c) a light chain variable region complementary determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0283] The antibody may comprise (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO:11; and (b) a human light chain comprising the amino acid sequence of SEQ ID NO:12.

[0284] The IFNAR1 inhibitor can be aniluomab or a functional variant thereof.

[0285] The IC of the IFNAR1 inhibitor 80 Can be about 3.88 μg mL -1 , where the IC 80 The IC of the IFNAR1 inhibitor is defined as the approximate concentration required to produce 80% of the maximal inhibition of 21-IFNGS expression relative to baseline. 50 The IC of the IFNAR1 inhibitor may be about 6. 50 It can be about 6.56 nM.

[0286] 5. Definitions

[0287] 5.1. Inhibitors of Type I IFN Signaling

[0288] Anirudinib

[0289] Anilumab (MEDI-546, anifro, ANI) is a human immunoglobulin G1κ (IgG1κ) monoclonal antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1). Anilumab downregulates IFNAR signaling and inhibits the expression of IFN-inducible genes. Disclosures related to anilumab can be found in U.S. Patent No. 7,662,381 and U.S. Patent No. 9,988,459, which are incorporated herein by reference in their entirety. Sequence information for anilumab is provided in Table 5-1: Sequence, Figure 48 and Figure 49 .

[0290] Table 5-1: Sequence

[0291]

[0292]

[0293] Anilumab is a human immunoglobulin G1κ monoclonal antibody that binds to subunit 1 of the type I interferon receptor (IFNAR1) with high specificity and affinity. This binding inhibits type I IFN signaling, thereby preventing the biological activity of type I IFNs. Anilumab also induces the internalization of IFNAR1, thereby reducing the levels of cell surface IFNAR1 available for receptor assembly. Blocking receptor-mediated type I IFN signaling inhibits IFN-responsive gene expression and downstream inflammatory and immune processes. Inhibition of type I IFN blocks plasma cell differentiation and normalizes peripheral T cell subsets, restoring the balance between adaptive and innate immunity that is dysregulated in SLE.

[0294] In adult patients with SLE, aniluomab, administered at doses ≥300 mg by intravenous infusion every 4 weeks, demonstrated sustained neutralization (≥80%) of 21 type I interferon pharmacodynamic (PD) markers in the blood. This suppression occurred early in the last 4 weeks and was maintained or further suppressed over the 52-week treatment period. After discontinuation of aniluomab at the end of the 52-week treatment period in the SLE clinical trial, the type I IFN PD marker in blood samples returned to baseline levels within 8 to 12 weeks. Aniluomab 150 mg IV showed <20% gene marker suppression at early time points, reaching a maximum of <60% at the end of the treatment period.

[0295] "Anilumab" is an immunoglobulin comprising HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively (or functional variants thereof); and LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively (or functional variants thereof). Annilumab is an immunoglobulin comprising the VH of SEQ ID NO: 1 and the VL of SEQ ID NO: 2.

[0296] The constant region of aniluomab has been modified such that aniluomab exhibits reduced affinity for at least one Fc ligand compared to the unmodified antibody. Aniluomab is a modified IgG monoclonal antibody specific for IFNAR1 that comprises an amino acid substitution of L234F in the Fc region, as numbered by the EU index as set forth in Kabat (1991, NIH publication 91-3242, National Technical Information Service, Springfield, VA). Aniluomab is a modified IgG monoclonal antibody specific for IFNAR1 that comprises an amino acid substitution of L234F, L235E, and / or P331S in the Fc region, as numbered by the EU index as set forth in Kabat (1991, NIH publication 91-3242, National Technical Information Service, Springfield, VA). Aniluomab is an antibody comprising the light chain constant region of SEQ ID NO: 9. Anilumab is an antibody comprising the heavy chain constant region of SEQ ID NO: 10. Anilumab is an antibody comprising the light chain constant region of SEQ ID NO: 9 and the heavy chain constant region of SEQ ID NO: 10. Anilumab is an antibody comprising the heavy chain of SEQ ID NO: 11. Anilumab is an antibody comprising the light chain of SEQ ID NO: 12. Anilumab is an antibody comprising the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO: 12.

[0297] Functional variants of aniluomab are sequence variants that perform the same function as aniluomab. Functional variants of aniluomab are variants that bind to the same target as aniluomab and have the same effector function as aniluomab. Functional aniluomab variants include antigen-binding fragments of aniluomab and antibody and immunoglobulin derivatives of aniluomab. Functional variants include biosimilars and interchangeable products. The terms biosimilars and interchangeable products are defined by the FDA and EMA. The term biosimilar refers to a biological product that is highly similar in structure to an approved (e.g., FDA-approved) biological product (reference product, such as aniluomab) and has no clinically meaningful differences from the reference product in terms of pharmacokinetics, safety, and efficacy. Whether a biosimilar has clinically meaningful differences can be assessed in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and in clinical immunogenicity assessments. An interchangeable product is a biosimilar that is expected to produce the same clinical results as the reference product in any given patient.

[0298] For example, a variant of the reference (anilumab) antibody may comprise: a heavy chain CDR1 having up to 2 amino acid differences when compared to SEQ ID NO:3; a heavy chain CDR2 having up to 2 amino acid differences when compared to SEQ ID NO:4; a heavy chain CDR3 having up to 2 amino acid differences when compared to SEQ ID NO:5; a light chain CDR1 having up to 2 amino acid differences when compared to SEQ ID NO:6; a light chain CDR2 having up to 2 amino acid differences when compared to SEQ ID NO:7; and a light chain CDR3 having up to 2 amino acid differences when compared to SEQ ID NO:8; wherein the variant antibody binds to the target of anilumab (e.g., IFNAR), and preferably binds with the same affinity.

[0299] A variant of the reference (anilumab) antibody may comprise: a heavy chain CDR1 having at most 1 amino acid difference when compared to SEQ ID NO:3; a heavy chain CDR2 having at most 1 amino acid difference when compared to SEQ ID NO:4; a heavy chain CDR3 having at most 1 amino acid difference when compared to SEQ ID NO:5; a light chain CDR1 having at most 1 amino acid difference when compared to SEQ ID NO:6; a light chain CDR2 having at most 1 amino acid difference when compared to SEQ ID NO:7; and a light chain CDR3 having at most 1 amino acid difference when compared to SEQ ID NO:8; wherein the variant antibody binds to the target of anilumab (e.g., IFNAR), optionally with the same affinity.

[0300] When compared to the corresponding reference (anilumab) antibody, the variant antibody may have a total of up to 5, 4 or 3 amino acid differences in its CDRs, provided that there are at most 2 (optionally at most 1) amino acid differences per CDR. When compared to the corresponding reference (anilumab) antibody, the variant antibody may have a total of up to 2 (optionally at most 1) amino acid differences in its CDRs, provided that there are at most 2 amino acid differences per CDR. When compared to the corresponding reference (anilumab) antibody, the variant antibody may have a total of up to 2 (optionally at most 1) amino acid differences in its CDRs, provided that there are at most 1 amino acid difference per CDR.

[0301] The variant antibodies may have a total of up to 5, 4 or 3 amino acid differences in their framework regions when compared to the corresponding reference (anilumab) antibody, provided that there are at most 2 (optionally at most 1) amino acid differences per framework region. Optionally, the variant antibodies have a total of up to 2 (optionally at most 1) amino acid differences in their framework regions when compared to the corresponding reference (anilumab) antibody, provided that there are at most 2 amino acid differences per framework region. Optionally, the variant antibodies have a total of up to 2 (optionally at most 1) amino acid differences in their framework regions when compared to the corresponding reference (anilumab) antibody, provided that there is at most 1 amino acid difference per framework region.

[0302] The variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein: the heavy chain has up to 14 amino acid differences when compared to the heavy chain sequence herein (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region); and the light chain has up to 14 amino acid differences when compared to the light chain sequence herein (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region); wherein the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anirumab) antibody, and preferably binds with the same affinity.

[0303] These variant heavy or light chains can be referred to as "functional equivalents" of the reference heavy or light chain. The variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein: when compared to the heavy chain sequence herein, the heavy chain has a maximum of 7 amino acid differences (a maximum of 1 amino acid difference in each CDR and a maximum of 1 amino acid difference in each framework region); and when compared to the light chain sequence herein, the light chain has a maximum of 7 amino acid differences (a maximum of 1 amino acid difference in each CDR and a maximum of 1 amino acid difference in each framework region); wherein the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anilumab) antibody, and preferably binds with the same affinity.

[0304] Functional variants of aniluomab include the antibodies described in WO 2018 / 023976 A1, which is incorporated herein by reference (Table 5-2).

[0305] Table 5-2: Anti-IFNAR Antibody Sequences

[0306]

[0307] Functional variants include antibodies comprising the VH amino acid sequence of SEQ ID NO: 13. Functional variants include antibodies comprising the VH amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VL amino acid sequence of SEQ ID NO: 14. Functional variants include antibodies comprising the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0308] The IFNAR inhibitor may be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 13. The anti-IFNAR antibody may comprise the VH amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 14. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0309] Functional variants of aniluolumab and anti-IFNAR antibodies include the QX006N antibody described in CN 11327807, which is incorporated herein by reference.

[0310] Table 3: QX006N antibody sequence

[0311]

[0312] The IFNAR inhibitor may be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 17. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO:18.

[0313] QX006N is an immunoglobulin comprising HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively (or functional variants thereof); and LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 23, respectively (or functional variants thereof). QX006N is an immunoglobulin comprising the VH amino acid sequence of SEQ ID NO: 17 and the VL amino acid sequence of SEQ ID NO: 18.

[0314] 5.1.2. Sifalimumab

[0315] Sifalimumab (MEDI-545) is a fully human immunoglobulin G1κ monoclonal antibody that binds to and neutralizes most IFN-α subtypes [7]. Sifalimumab is described in U.S. Patent 7,741,449, which is incorporated herein by reference in its entirety. The efficacy and safety of sifalimumab were evaluated in a Phase IIb, randomized, double-blind, placebo-controlled study (NCT01283139) in adults with moderately to severely active systemic lupus erythematosus (SLE). 431 patients were randomly assigned and received intravenous sifalimumab (200 mg, 600 mg, or 1200 mg) or placebo monthly in addition to standard of care medication. The primary efficacy endpoint was the percentage of patients achieving an SLE Responder Index response at week 52. A greater percentage of patients who received sifalimumab (all doses) achieved the primary endpoint compared to placebo (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg: 59.8%).

[0316] 5.2. Steroids

[0317] Oral corticosteroids (OCS, glucocorticoids) include prednisone, cortisone, hydrocortisone, methylprednisolone, prednisolone and triamcinolone. Examples of equivalent doses of oral prednisone are shown in (Table 5-4).

[0318] Table 5-4: Examples of equivalent doses of oral prednisone

[0319]

[0320] 5.3. Endpoint

[0321] 5.3.1. SRI (Systemic Lupus Erythematosus Responder Index ≥ 4)

[0322] A subject achieves SRI if all of the following criteria are met (4):

[0323] A decrease in SLEDAI-2K from baseline of 4 points or more;

[0324] No new organ system involvement compared to baseline with BILAG-2004, as seen with 1 or more BILAG-2004A or 2 or more

[0325] · as defined in BILAG-2004, item B;

[0326] The subject's lupus disease activity did not worsen from baseline based on the 3-point PGA VAS, defined as an increase of ≥0.30 points.

[0327] SRI(X) (X = 5, 6, 7, or 8) is defined by the proportion of subjects meeting the following criteria:

[0328] A decrease in SLEDAI-2K from baseline of ≥X points;

[0329] No new organ system involvement compared to baseline with BILAG-2004, as seen with 1 or more BILAG-2004A or 2 or more

[0330] More as defined in BILAG-2004B;

[0331] The subject's lupus disease activity did not worsen from baseline based on a 3-point PGA VAS.

[0332] 5.3.2.SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) defined as an increase of ≥0.30 points

[0333] The SLEDAI-2K Disease Activity Index consists of a series of organ-specific manifestations, each with its own definition. A certified investigator or designated physician will complete the SLEDAI-2K assessment and decide whether each manifestation is "present" or "absent" within the past four weeks. This assessment also includes the collection of blood and urine to assess the laboratory categories of the SLEDAI-2K.

[0334] The SLEDAI-2K assessment consists of 24 lupus-related items. It is a weighted tool in which the descriptors are multiplied by the "weight" of the specific organ. For example, the renal descriptor is multiplied by 4, and the central nervous system descriptor is multiplied by 8, and these weighted organ performances are summed up for the final score. The SLEDAI-2K score ranges from 0 to 105, with 0 indicating no active disease. The SLEDAI-2K score is a valid, reliable, and sensitive clinical assessment of lupus disease activity.

[0335] 5.3.3.BILAG-2004 (British Isles Lupus Assessment Group-2004)

[0336] BILAG-2004 is a translational index for 9 organ systems (general condition, mucocutaneous, neuropsychiatric, musculoskeletal, cardiac and pulmonary, gastrointestinal, eye, kidney and blood) that can capture the severity of changes in clinical manifestations in SLE patients. It has an ordinal level by design and no global score; to be precise, it records the disease activity across different organ systems at a glance by comparing the most recent 4 weeks with the 4 weeks before them. It is based on the principle of doctor's intention to treat and divides disease activity into 5 different levels from A to E:

[0337] Grade A indicates very active disease requiring immunosuppressive drugs and / or prednisone doses > 20 mg / day or equivalent

[0338] Grade B indicates moderate disease activity requiring lower doses of corticosteroids, topical steroids, topical immunosuppressants, antimalarials, or NSAIDs

[0339] Grade C indicates mild to stable disease

[0340] Grade D means no disease activity, but the system has been previously affected

[0341] Grade E indicates no current or past disease activity

[0342] Although BILAG-2004 was developed on an intention-to-treat basis, treatment was not associated with the scoring index; only the presence of active manifestations affected the score.

[0343] 5.3.4. BICLA (BILAG-based Comprehensive Lupus Assessment)

[0344] BICLA is a composite index originally derived by expert consensus of disease activity indices. BICLA response is defined as (1) at least one grade improvement in baseline BILAG scores in all body systems with moderate or severe disease activity at enrollment (e.g., all A (severe disease) scores reduced to B (moderate), C (mild), or D (inactive) and all B scores reduced to C or D); (2) no new BILAG A or more than one new BILAG B score; (3) no worsening of the total SLEDAI score from baseline; (4) no significant regression (≤10%) in the physician's global assessment; and (5) no treatment failure (initiation of non-protocol treatment).

[0345] Specifically, a subject is a BICLA responder if the following criteria are met:

[0346] All baseline BILAG-2004A items decreased to B / C / D and all baseline BILAG-2004B items decreased to C / D, and there was no BILAG-2004 exacerbation in other organ systems, as defined by 1 new BILAG-2004A item or more than 1 new BILAG-2004B item;

[0347] No worsening of the SLEDAI-2K from baseline, as defined as an increase of >0 points from baseline in the SLEDAI-2K;

[0348] The subject's lupus disease activity did not worsen from baseline based on the 3-point PGA VAS, defined as an increase of ≥0.30 points;

[0349] The BICLA response is a composite endpoint that requires improvement in all baseline BILAG-2004A and B scores, no worsening as assessed by the SLEDAI-2K and PGA, no IP discontinuation, and no use of restrictive medications beyond protocol-permitted thresholds. BILAG captures relative improvement in organ systems (in contrast to the SLEDAI-2K, which is used to show improvement in SRI and requires complete resolution of an organ system); BILAG-2004, which measures improvement in the BICLA, can detect clinically meaningful relative improvements in organ systems.

[0350] 5.3.5.CLASI (Cutaneous Lupus Erythematosus Area and Severity Index)

[0351] The CLASI is a validated index for evaluating skin lesions in SLE and consists of two separate scores: the first score summarizes the inflammatory activity of the disease; the second score is a measure of the damage caused by the disease. The activity score takes into account erythema, scaling / hypertrophy, mucosal lesions, recent hair loss, and non-scarring alopecia. The damage score represents dyspigmentation, scarring / atrophy / panniculitis, and scalp scarring. Subjects are asked whether their dyspigmentation has persisted for 12 months or longer, in which case the dyspigmentation score is doubled. Each of the above parameters is measured in 13 different anatomical locations that are specifically included because these anatomical locations are most commonly affected in cutaneous lupus erythematosus (CLE). The most severe lesion in each area is measured.

[0352] 5.3.6. Tender and swollen joints

[0353] The swollen and tender joint count can be based on the left and right shoulders, elbows, wrists, metacarpophalangeal (MCP) 1, MCP2, MCP3, MCP4, MCP5, proximal interphalangeal (PIP) 1, PIP2, PIP3, PIP4, PIP5 joints of the upper extremities, and the left and right knees of the lower extremities. Active joints for joint count assessment can be defined as joints with tenderness and swelling.

[0354] 5.4. Pharmacokinetic Glossary

[0355] Area Under the Curve (AUC): The area under the plasma drug concentration-time curve, which is used as a measure of drug exposure.

[0356] C 平均 : Steady-state average concentration.

[0357] C 最大 : Maximum (or peak) concentration of a drug in plasma.

[0358] C 最小 : Minimum plasma drug concentration.

[0359] C 谷 : The drug concentration at steady state in plasma immediately before the next dose is administered. Trough plasma concentration (the concentration measured at the end of the dosing interval at steady state [obtained directly before the next dose]).

[0360] LLOQ: Lower limit of quantification, the lowest amount of analyte in a sample that can be quantitatively determined with appropriate precision and accuracy.

[0361] Linear Pharmacokinetics: When the concentration of a drug in the blood or plasma increases proportionally with increasing doses, and the elimination rate is proportional to the concentration, the drug is said to exhibit linear pharmacokinetics. The clearance and volume of distribution of these drugs are not dose-dependent.

[0362] Nonlinear pharmacokinetics: In contrast to linear pharmacokinetics, the concentration of a drug in the blood or plasma does not increase proportionally with increasing doses. The clearance and volume of distribution of a drug may vary with the administered dose. Nonlinearity may be associated with any component of the absorption, distribution, and / or elimination processes.

[0363] 5.5.PK / PD

[0364] The plasma levels that can be obtained by SC administration and IV administration can be compared based on the plasma drug concentration-time curve (AUC), which reflects the body's exposure to the antibody after the drug dose is administered. For example, during a clinical study, a patient's plasma drug concentration-time curve can be plotted by measuring the plasma concentration at several time points. If a computer simulation modeling approach is used, the plasma drug concentration-time for any given dose can be predicted. The AUC (area under the curve) can then be calculated by integrating the plasma drug concentration-time curve. A suitable method is described in Tummala et al. [8], which is incorporated herein by reference in its entirety. In the examples described herein, the PK parameters were calculated by non-compartmental analysis using Phoenix WinNonlin V / 6.2 (Certara, Princeton, NJ, USA), and included the area under the serum concentration-time curve (AUC), clearance (CL, CL / F), maximum serum concentration (C 最大 ) and the time to reach maximum serum concentration (t 最大 All data were analyzed using SAS System V.9.2 (SAS Institute Inc., Cary, North Carolina, USA).

[0365] Conveniently, the ratio of the AUC obtained by SC administration to the AUC obtained by IV administration can be calculated (AUC SC AUC IV ), thereby providing a numerical comparison of the bioavailability provided by the dosage route. The "AUC ratio" referred to herein refers to the AUC SC AUC IV Ratio. To provide statistical robustness, the AUC ratio is preferably an average, median or mode (e.g., mean) calculated from multiple replicates (or computer simulations). This approach is demonstrated in the reference examples. The average, median or mode (preferably mean) can be derived by aggregating data obtained from multiple patients (or multiple computer simulations). Thus, the AUC ratio can reflect the average, median or mode (preferably mean) AUC of multiple patients.

[0366] Nonlinear PK occurs when clearance is not constant. In other words, nonlinear PK occurs when clearance varies with dose.

[0367] 5.6. Type I IFN-mediated diseases

[0368] A type I IFN-mediated disease can be defined as a disease characterized by dysregulation of type I IFN[9]. The type I IFN disease can be a type I IFN-mediated autoimmune disease. The type I IFN disease can be a type I IFN-mediated systemic autoimmune disease. Type I IFN-mediated diseases include lupus (including SLE, LN, and CLE). Type I IFN-mediated diseases can be lupus nephritis. Type I IFN-mediated diseases include cutaneous lupus erythematosus. Type I IFN-mediated diseases include myositis. Type I IFN-mediated diseases include scleroderma. Type I IFN-mediated diseases include Sjögren's syndrome.

[0369] Type I IFN-mediated diseases include interferonopathies. Compared to healthy subjects, the type I IFN-mediated disease can be characterized by an association with an elevated 21-gene IFNGS. Compared to healthy subjects, the type I IFN-mediated disease can be characterized by an association with an elevated 4-gene IFNGS. Compared to healthy subjects, the type I IFN-mediated disease can be characterized by an association with an elevated 5-gene IFNGS.

[0370] Myositis

[0371] Like SLE, myositis (also known as idiopathic inflammatory myopathy (IMM)) is a connective tissue disease with severe type 1 IFN involvement. Myositis is a rare, progressive, and debilitating disease. Myositis is a type 1 IFN-mediated disease. Specifically, type 1 IFN-inducible genes are overexpressed in the whole blood and muscle of patients with myositis [10,11]. Type 1 IFN gene expression correlates with myositis disease activity [10,11]. Furthermore, plasmacytoid DCs (pDCs) that secrete type 1 IFN are present in target tissues of patients with myositis [12,13]. Furthermore, myositis can be induced de novo or exacerbated by IFN therapy [13,14]. Finally, in DM and PM, the anti-IFN-α monoclonal antibody sifalimumab neutralizes IFN gene expression in muscle, which is associated with improved muscle function (see Examples, Section 11.4). Clinical manifestations of fatigue, rash, photosensitivity, and joint pain are common in both lupus and myositis.

[0372] 5.6.2. Scleroderma

[0373] Like SLE, systemic sclerosis (SSc) is a connective tissue disease with significant involvement of type 1 IFN. Systemic sclerosis is a multisystem autoimmune disease characterized by functional and structural abnormalities of small vessels and fibrosis of the skin and internal organs. The type 1 IFN pathway is a pathogenic driver of SSc. Evidence for a central role for type 1 IFN in the pathogenesis of SSc (inflammatory and fibrotic processes) includes multiple genetic polymorphisms that are associated with the type 1 IFN pathway in SSc

[15] . In addition, SSc autoantibodies have been found to directly amplify type 1 IFN responses

[16] , and there is evidence that type 1 IFN contributes to TGF-β-dependent and -independent fibrosis in the lungs and skin of patients with SSc

[17] . Furthermore, digital ulcers resulting from small vessel vasculopathy in SSc are associated with elevated IFN markers

[18] .

[0374] 5.7. Type I IFN gene signature (IFNGS)

[0375] The interferon gene signature (IFNGS) is defined as a set of specific gene transcripts whose expression increases upon activation of the IFN receptor (IFNAR1) through binding of type I IFN ligands (IFN-α, IFN-β, and IFN-ω). Two interferon gene signatures were used as part of the Saphnelo and sifalimumab trials to provide different readouts: the 4-gene interferon gene signature is a peripheral blood marker derived from genome-wide gene expression studies and further validated using a quantitative PCT test developed to specifically measure IFN gene expression based on four genes. It is further used at baseline to understand whether the disease, or a specific patient's condition, is driven by type I IFNs. The 21-gene interferon gene signature is a peripheral blood marker derived from genome-wide gene expression studies. It is used to study the pharmacodynamic effects of Saphnelo by providing a measure of inhibition of type 1 interferon signaling after treatment.

[0376] The IFN 21-gene signature (IFNGS) is a validated pharmacodynamic marker of type I IFN signaling

[10] ( Figure 28 ), which is elevated in patients with type I IFN-mediated diseases including SLE, lupus nephritis, myositis, Sjögren's disease, and scleroderma ( Figure 31A and Figure 31B ).

[0377] The 4-gene IFNGS score was calculated by measuring the expression of IFI27, IFI44, IFI44L, and RSAD2. The 5-gene IFNGS score was calculated by measuring the expression of IFI27, RSAD2, IFI44, IFI44L, and IFI6. Figure 2821-gene IFNGS scores are calculated by measuring the gene shown in .Gene expression can be measured by detecting the mRNA in the subject's whole blood or tissue.IFNGS gene expression (e.g., mRNA) can be measured by measuring the IFNGS gene expression (e.g., mRNA) in the subject's blood or tissue, and the expression of these gene expression levels and the housekeeping genes (house-keeping) or control genes (e.g., ACTB, GAPDH and 18SrRNA) in the blood or tissue is compared to detect IFNGS (4-gene, 5-gene or 21-gene) scores.

[0378] 6. Example 1: Anirudin in the clinic

[0379] The safety of aniluomab has been evaluated in eight blinded or open-label intravenous (IV) and subcutaneous (SC) studies: six studies in patients with SLE (Study 05, Study 04, Study 1013, Study 1145, and Study 08), one study in patients with systemic sclerosis (SSc) (Study MI-CP180), and one study in healthy volunteers (Study 06) (Table 6-1). Two of these studies (Studies 08 and 06) used SC aniluomab administration. Two studies are ongoing: one study in patients with SLE (Study 09) and one study in patients with lupus nephritis (LN) (Study 07).

[0380] Table 6-1: Clinical studies

[0381]

[0382]

[0383] Study MI-CP151 is described in more detail in Higgs et al. 2013

[10] . Study 1013 is described in more detail in Furie et al. 2017

[19] , which is incorporated herein by reference in its entirety. Study 04 is described in more detail in Furie et al. 2019

[20] , which is incorporated herein by reference in its entirety. The results of Study 05 are presented in Morand et al. 2020

[21] , which is incorporated herein by reference in its entirety. A complete overview of the evidence for the clinical efficacy of intravenous anirumab in SLE is provided in Tanaka et al. 2020

[22] , which is incorporated herein by reference in its entirety.

[0384] 7. Example 2: Safety and Efficacy of Intravenous Anirudumab

[0385] 7.1. Efficacy

[0386] The primary evaluation of aniluomab's efficacy was based on data from three global, randomized, double-blind, placebo-controlled studies (Phase 3 Studies 04 and 05, and Phase 2 Study 1013). These studies were very similar in design, including a 52-week treatment period, and had similar patient characteristics and consistent inclusion / exclusion criteria. The primary objective of all three studies was to evaluate the effect of aniluomab on overall disease activity compared with placebo. Secondary objectives were selected to further characterize the efficacy of aniluomab compared with placebo, such as the ability to reduce glucocorticoid use, effects on organ-specific endpoints (skin SLE activity and joints), and relapse rates.

[0387] In three double-blind, global Phase 2 / 3 studies (Studies 04, 05, and 1013), the efficacy of aniluomab 300 mg IV every 4 weeks in patients with moderate to severe SLE was investigated across a range of key clinical endpoints. Aniluomab had an early and sustained effect on overall disease activity, enabled tapering of steroid use to a clinically beneficial level (≤7.5 mg / day) and maintained that level through Week 52, had an early and sustained benefit on skin activity, and resulted in a clinically meaningful reduction in flare rates.

[0388] 2.1.1: Study 1013 (MUSE, NCT01438489)

[0389] Study 1013 (MUSE, NCT01438489) was a Phase 2b, multicenter, double-blind, randomized, placebo-controlled, 52-week study of anirumab 300 mg and 1000 mg compared with placebo in adult patients with moderately to severely active SLE who were receiving standard of care (SOC) therapy. During the trial, tapering of OCS was encouraged but was at the discretion of the investigators. The primary efficacy endpoint was a reduction in SLE disease activity as measured by the SRI(4), with sustained reductions in OCS use after 24 weeks of treatment.

[0390] At week 24, more patients treated with aniluomab (34.3% and 28.8% for patients receiving 300 mg [n=99] and 1000 mg [n=104], respectively) achieved the primary endpoint of a composite of SRI(4) response with sustained OCS reduction compared with placebo (17.6% [n=102]; p=.014 and p=.063 for 300 mg and 1000 mg versus placebo, respectively). A greater effect was observed in patients with high IFNGS at baseline, with 36.0% (p=.004) and 28.2% (p=.029) of patients treated with aniluomab 300 mg and 1000 mg, respectively, achieving the primary endpoint compared with 13.2% of patients receiving placebo. Among patients with low IFNGS at baseline, the corresponding response rates for patients achieving the primary endpoint were 29.2%, 30.8%, and 30.8% for aniluolumab 300 mg, aniluolumab 1000 mg, and placebo.

[0391] Study 1013 is described in more detail in Furie et al. 2017

[19] , which is incorporated herein by reference in its entirety.

[0392] 7.1.1. Studies 04 and 05 (TULIP I and TULIP II)

[0393] The pivotal TULIP (Treatment of Uncontrolled Lupus via IFN Pathway) program consisted of two phase 3, multinational, randomized, double-blind, placebo-controlled, parallel-group clinical trials, TULIP-1 (Study 04) and TULIP-2 (Study 05). The designs of Study 04 and Study 05 were nearly identical (Figure 1). Both studies consisted of a 52-week treatment period with either anirumab or placebo IV Q4W from Week 0 to Week 48 for a total of 13 doses. The primary endpoint was assessed at Week 52. In both studies, patients receiving baseline oral prednisone ≥10 mg / day or equivalent were mandated to undergo an OCS taper from Week 8 to Week 40 until a dose of ≤7.5 mg / day was achieved, which had to be continued until Week 52. Both studies employed a composite endpoint of clinically meaningful improvement in SLE disease activity: SRI(4) (primary endpoint of TULIP-1) and BICLA (primary endpoint of TULIP-2).

[0394] In these studies, the selection of a 300 mg dose of aniluomab every 4 weeks (Q4W) was based on safety and efficacy results from an interim analysis of the Phase 2b 1013 study, in which two doses of aniluomab (300 mg and 1000 mg) were evaluated relative to placebo, as well as dose-response modeling and simulations (as described in U.S. Patent 9493570, corresponding to PCT Publication WO 2013188494, which is incorporated herein by reference in its entirety). In the interim analysis of the Phase 2b study, a clinically meaningful benefit was observed with the 300 mg dose, while no additional benefit was observed with the 1000 mg dose. In addition, a higher proportion of subjects reported recurrences of herpes zoster in the 1000 mg dose group compared to the 300 mg dose group. Given the comparable efficacy between the 300 mg and 1000 mg aniluomab doses and the increased incidence of herpes zoster events in the 1000 mg dose group compared to the 300 mg dose group, the benefit:risk curve appears to favor the 300 mg dose.

[0395] In TULIP-1 and TULIP-2, patients with moderate to severe SLE who were on standard therapy were randomized to receive aniluomab 300 mg (TULIP-1 and TULIP-2), aniluomab 150 mg (TULIP-1 only), or placebo intravenously every 4 weeks for 48 weeks, along with standard therapy. Patients were randomly assigned ...) or placebo intravenously every 4 weeks, along with standard therapy. Patients were randomly assigned to receive aniluomab 150 mg (TULIP-1 only) or placebo intravenously every 4 weeks, along with standard therapy. Patients were randomly assigned to receive aniluomab 150 mg (TULIP-1 only) or placebo intravenously every 4 weeks, along with standard therapy. Patients were randomly assigned to receive aniluomab 150 mg (TULIP-1 only) or placebo intravenously every 4 weeks, along with standard therapy. Patients were randomly assigned to receive aniluomab 150 mg (TULIP-1 only) or placebo intravenously every 4 weeks -1 Randomization was stratified by prednisone or equivalent. TULIP-1 and TULIP-2 trials had consistent efficacy variables, safety variables, assessment frequency, and inclusion / exclusion criteria ( Figure 1 ).

[0396] Study 04 (TULIP I, NCT02446912)

[0397] Study 04 compared anirumab 150 mg and 300 mg with placebo in adult patients with moderately to severely active SLE who were receiving SOC therapy. Efficacy was assessed by reduction in SLE disease activity as measured by SRI(4) response.

[0398] In Study 04, the proportion of patients achieving the primary outcome of SRI(4) response at Week 52 was comparable between the anirumab 300-mg (84 / 180 [47%]) and placebo groups (79 / 184 [43%]; difference -3.9; 95% CI -6.3, 14.1; p = .45) groups. Figure 2Similarly, in the prespecified analysis (without modified restrictive medication rules), the proportion of patients with an SRI(4) response at week 52 was 65 of 180 (36%) treated with anirutumab 300 mg and 74 of 184 (40%) in the placebo group (difference -4.2; 95% CI -14.2, 5.8; p = .41).

[0399] Study 04 is described in more detail in Furie et al. 2019

[20] , which is incorporated herein by reference in its entirety.

[0400] Study 05 (TULIP II, NCT02446899)

[0401] In Study 05 (TULIP-2), a protocol amendment changed the primary endpoint from SRI (4) to BICLA response before unblinding of the trial data and after completion of TULIP-1. This change was driven by the MUSE and TULIP-1 analyses.

[0402] Study 05 compared anirumab 300 mg with placebo in adult patients with moderately to severely active SLE who were receiving SOC therapy. Efficacy in this trial was assessed by reduction in SLE disease activity as measured by the BILAG-based Comprehensive Lupus Assessment (BICLA) response.

[0403] In Study 05, a greater percentage of patients achieved the primary outcome of a BICLA response at Week 52 in the anirumab group (47.8%) compared with the placebo group (31.5%; adjusted difference 16.3%; 95% CI 6.3, 26.3; p = .001). Figure 2 、 Figure 3A and Figure 3B ). In the IFNGS-test-high subgroup, the percentage of patients with a BICLA response at week 52 was 48.0% (72 / 150) in the anirumab group and 30.7% (46 / 151) in the placebo group (adjusted difference 17.3%; 95% CI 6.5, 28.2; adjusted p = .002). The corresponding results in the IFNGS-test-low subgroup were 46.7% (14 / 30) and 35.5% (11 / 31) of patients in the anirumab group and placebo group, respectively (adjusted difference 11.2; 95% CI -13.5, 35.8). BICLA responses were consistent in favor of anirumab across other protocol-defined patient subgroups of baseline disease severity, race, ethnicity, age, sex, age at onset, and anti-drug antibody status. The overall group HR for time to sustained BICLA response through 52 weeks favored the anirumab 300-mg group compared with placebo (HR 1.55; 95% CI 1.11, 2.18).

[0404] Anillumab also had significant benefits in terms of sustained OCS reduction and reduced skin disease severity (reduced CLASI score). Figure 2 Among patients receiving ≥10 mg / day of prednisone or equivalent at baseline, 51.7% (45 / 87) of patients treated with aniluomab and 30.1% (25 / 83) of patients receiving placebo achieved a sustained reduction to ≤7.5 mg / day (adjusted difference 21.2%; 95% CI 6.8, 35.7; adjusted p = .01). Among patients with at least moderately active skin disease at baseline (CLASI score ≥10), 49.0% (24 / 49) of patients receiving aniluomab and 25.0% (10 / 40) of patients receiving placebo achieved a ≥50% reduction in CLASI score at week 12 (adjusted difference 24.0%; 95% CI 4.3, 43.6; adjusted p = .04). Although treatment responses in organs other than the skin and joints were not part of the prespecified analyses, the BICLA response definition required improvement in all affected organ systems at baseline (reduction of all baseline BILAG-2004A and B domain scores to B / C / D and C / D, respectively) and no new relapses in the remaining BILAG-2004 organ systems. At baseline, the most affected organ domains in enrolled patients were mucocutaneous and musculoskeletal (>80% of patients had BILAG-2004A or B affected). Baseline BILAG-2004A or B scores were less frequent in the cardiopulmonary, constitutional, renal, neuropsychiatric, gastrointestinal, hematologic, and ophthalmic domains. Therefore, by definition, in patients who achieved a BICLA response, responses occurred in all of these affected BILAG-2004 organ systems. The annualized relapse rate based on BILAG-2004 was 0.43 in the anirumab group and 0.64 in the placebo group (adjusted rate ratio 0.67; 95% CI 0.48, 0.94; adjusted p = .08).

[37] Among patients with ≥6 swollen and ≥6 tender joints at baseline, 42.2% (30 / 71) of the anirumab group and 37.5% (34 / 90) of the placebo group had a ≥50% reduction in swollen and tender joint counts at week 52 (adjusted difference 4.7%; 95% CI -10.6, 20.0; adjusted p = .55).

[0405] The results of Study 05 are presented in Morand et al. 2020

[21] , which is incorporated herein by reference in its entirety.

[0406] 7.1.4. Efficacy Conclusion

[0407] Study 05 provides strong evidence for the efficacy of aniluomab in patients with moderately to severely active SLE who were treated with SOC, based on the pre-specified BICLA primary endpoint. The combined data from all three clinical trials further support the efficacy of aniluomab 300 in these patients across a range of clinically meaningful endpoints. Importantly, there was a consistent benefit of aniluomab 300 mg across all studies for BICLA response rates at week 52; treatment differences compared with placebo of >16% were observed in BICLA response rates across all three studies. In addition, aniluomab demonstrated a treatment benefit in SRI(4) responses in both TULIP-2 and MUSE. The consistent, supportive evidence of efficacy of aniluomab 300 across many key secondary endpoints (e.g., reduction in OCS, improvement in CLASI scores, reduction in relapses) is relevant to the full extent of the aniluomab treatment effect, particularly given the heterogeneous presentation of SLE.

[0408] Anilovib demonstrated efficacy in reducing relapses, and the treatment effect in reducing disease activity began to emerge as early as 8–12 weeks after treatment initiation, when a numerical separation of BICLA response rates >10% (favoring anilovib 300 mg) was observed, and was maintained over 52 weeks of treatment. Furthermore, the steroid-sparing effect of anilovib reduced the cumulative risk of long-term organ damage associated with SLE. The improvements seen with anilovib in cutaneous manifestations (CLASI activity score) were also particularly important given their prevalence and the frequent presence of visible lesions on the face, head, and neck.

[0409] A complete overview of the evidence for the clinical efficacy of intravenous anirumab in SLE is provided in Tanaka et al., 2020

[22] , which is incorporated herein by reference in its entirety.

[0410] 7.2. Security

[0411] The safety and tolerability profile of aniluomab was consistent and generally similar across all three efficacy studies. Across all studies, the percentage of patients experiencing any adverse event (AE) ranged from 85% to 89% in the aniluomab-treated group and from 77% to 84% in the placebo-treated group. The most common AEs included upper respiratory tract infection, nasopharyngitis, and infusion-related reactions. Aniluomab infusions were generally well tolerated, with one report of an allergic reaction in a patient receiving 150 mg of aniluomab in TULIP-1. A minority of patients experienced allergic reactions, and most infusion-related AEs were non-serious and mild or moderate in intensity. Serious AEs (SAEs) occurred in 8%-16% of aniluomab-treated patients and in 16%-19% of placebo-treated patients. One death occurred during the treatment period in each of TULIP-1 and TULIP-2 arms; both occurred in the aniluomab-treated arm and were due to pneumonia. There was also one death in MUSE in a patient who received one dose of aniluomab 1000 mg and had acute colitis. The percentage of patients with AEs leading to discontinuation was smaller among patients receiving aniluomab relative to placebo in TULIP-2 and MUSE, but was greater among patients treated with aniluomab in TULIP-1 (6% vs. 3% for placebo).

[0412] The incidence of herpes zoster was increased in the anirumab-treated group (5%-7%) compared with the placebo group (1%-2%); most cases were cutaneous, not severe, and did not lead to discontinuation. All patients responded to SOC treatment, and the disease generally resolved without sequelae. For other AEs of particular interest, the incidence was low and similar across treatment groups.

[0413] A complete overview of the safety and tolerability evidence for anivumab is provided in Tanaka et al., 2020

[22] , which is incorporated herein by reference in its entirety.

[0414] Conclusion

[0415] Anilumab demonstrated clinically relevant benefit in subjects with moderate to severe SLE treated with SOC. This efficacy was supported by a broad range of global (different levels of SRI response, BICLA) and organ-specific clinical measures of disease activity (CLASI, joint counts). A clinically relevant increase in the proportion of subjects achieving pre-specified corticosteroid reduction was also observed in the 300 mg group compared with placebo, whereas no significant difference was observed when the 1000 mg group was compared with placebo.

[0416] Anilovub was generally well tolerated. A dose-related increase in the number of subjects with uncomplicated herpes zoster infection was observed in subjects receiving anilovubub compared with placebo.

[0417] Across all three studies, a greater number of patients receiving aniluomab compared with placebo consistently achieved a BICLA response, as did sustained OCS reductions and CLASI improvements. In MUSE and TULIP-2, a higher percentage of patients also achieved aniluomab (4) responses relative to placebo. In the efficacy studies, the safety profile of aniluomab was similar, with 8%-16% of aniluomab-treated patients and 16%-19% of patients receiving placebo experiencing SAEs. In all three studies, the incidence of herpes zoster was increased in the aniluomab-treated groups compared with the placebo group, but most occurred on the skin and responded to SOC treatment. The clinical trial evidence discussed suggests that in patients with active SLE, aniluomab 300 mg administered IV Q4W is superior to placebo in achieving the composite endpoint of disease activity response, as well as reducing OCS dose, skin disease severity, and relapse rate. Therefore, clinical studies of IV anirumab administration concluded that 300 mg IV Q4W was the optimal dose compared with 150 mg Q4W. Increasing the dose to 1000 mg Q4W was found to provide only incremental benefit, and a dose-related increase in herpes zoster infections was observed ( Figure 4 ).

[0418] 8. Example 3: Subcutaneous administration of aniluolumab

[0419] 8.1. Phase I Study of IV Anirudumab in SSc Patients: MI-CP180

[0420] After a single weight-based dose, mean anirumab serum concentrations were as follows: Figure 5A As shown. After single-dose administration, aniluomab exhibited nonlinear-linear PK at lower dose levels (<10.0 mg / kg) in both IFNGS high-dose and IFNGS low-dose patients. 最大 Anirudinib increased dose-proportionally, but the increase in AUC was more than dose-proportional between 0.1 mg / kg and 10.0 mg / kg. In the high-dose cohort, the t1 / 2 of anirudinib was prolonged. At the highest dose level studied (20.0 mg / kg), the terminal t1 / 2 was approximately 12 days.

[0421] 8.2. Phase I of IV and SC Anirudumab in Healthy Volunteers (Study 06)

[0422] In this Phase I, randomized, placebo-controlled study, 30 healthy adults were assigned to three treatment cohorts (anirumab 300 mg SC (n=6), anirumab 300 mg intravenously (n=6), anirumab 600 mg SC (n=6)) and placebo (n=4 / cohort). After SC administration, exposure to anirumab was escalated proportionally from 300 mg to 600 mg based on the area under the serum concentration-time curve. The arithmetic mean serum anirumab concentration-time curves after single IV and SC administrations are shown in Figure 2. Figure 5B As reported by Tummala et al. 2018[8], which is incorporated herein by reference in its entirety, the bioavailability of anirumab in healthy volunteers was estimated to be 87% of the intravenous exposure.

[0423] 8.3. Phase II of SC Anirumab in SLE Patients (Study 08)

[0424] This study aimed to describe the pharmacokinetics and pharmacodynamics of subcutaneously administered anirutumab ( Figure 6A ).

[0425] This study investigated the clinical pharmacology, safety, and exploratory efficacy of subcutaneous aniluomab. The pharmacokinetics in Study 08 were consistent with the high bioavailability and high CL in patients with high IFNGS in Study 06 (healthy volunteers). Aniluomab administered subcutaneously every 2 weeks to patients with SLE and moderate to severe skin manifestations exhibited nonlinear pharmacokinetics that exceeded dose proportionality and neutralized the type I interferon gene signature ( Figure 6B and Figure 6C In particular, subcutaneous administration of 150 mg or 300 mg of anirumab every 2 weeks for 50 weeks has nonlinear pharmacokinetics, whereby C 谷 Concentrations were more than dose proportional. The number of adverse events with subcutaneous anirumab was similar to that observed after intravenous administration in a large study of patients with SLE.

[0426] The results of Study 08 are fully described in Bruce et al.

[23] , which is incorporated herein by reference in its entirety.

[0427] Study 08 was limited by its small sample size, precluding conclusions about the biologic effects of the study drug (e.g., complement C3 or C4 concentrations) or its clinical efficacy. The inclusion of only patients with a high type I interferon gene signature and active skin disease also limits the generalizability of the study to patients with similar disease characteristics. The study was further limited by the increasing frequency of missing values ​​over time.

[0428] 8.4. Conclusion

[0429] The PK of aniluomab consistently demonstrated target-mediated drug disposition, with concentrations or exposure decreasing more than dose-proportionally at lower dose levels. High bioavailability of aniluomab administered by SC injection was observed in Study 06 (healthy volunteers); the ratio of the AUC of aniluomab SC to aniluomab IV at 300 mg was approximately 87%.

[0430] 9. Example 4: Determining the Optimal Subcutaneous Unit Dose

[0431] 9.1. Objectives

[0432] To examine the optimal dosing regimen for subcutaneous anirumab, the inventors developed population PK and PK / PD models designed to leverage existing human clinical trials. PK data from Phase III studies 04 and 05 and Phase II study 1013 were used to assist in the development of the population PK model.

[0433] The inventors' initial goal was to detect a subcutaneous dose that provided equivalent exposure to the standard 300 mg IV (Q4W) dose while allowing for more conventional dosing at a lower dose. This was based on the understanding that 300 mg IV Q4W provided the best clinical PK profile and clinical efficacy (e.g., achieving a BICLA response), as reported in Furie et al. 2017

[19] , which is incorporated herein by reference in its entirety.

[0434] 9.2. Results

[0435] 9.2.1. Initial Selection of Subcutaneous Anirudin Dose

[0436] In an initial analysis, the inventors identified a specific dose regimen that was predicted to provide equivalent exposure to that achieved with 300 mg Q4WIV. Initially, it was found that a dose regimen of 105 mg subcutaneously weekly (QW) could provide an AUC ratio close to (or slightly greater than) 1 ( Figure 7A ), even though the bioavailability is expected to be reduced by approximately 7% compared to that reported by Tummal et al. 2018[8] (which is incorporated herein by reference in its entirety) to account for the inter-individual variability in bioavailability ( Figure 7B 105 mg subcutaneous QW appeared to provide comparable or improved median trough concentrations and IFNGS suppression compared to the comparative 300 Q4W mg IV dose ( Figure 8A and Figure 8BFrom these initial analyses, it appears that the SC 105 mg QW dose of aniluomab, equivalent to 300 mg Q4W, should be selected to have the best efficacy / risk profile for treating patients with SLE. Importantly, these analyses assumed that the 300 mg IV dose was at or near the plateau of the aniluomab dose-response curve; that is, increasing the dose beyond 300 mg IV Q4W would not provide any meaningful benefit to patients, especially given the increased risk of herpes zoster infection with high doses.

[0437] 9.2.2. Modified Anirumab Subcutaneous Dosage Selection

[0438] Therefore, based on the data available from the MUSE study, Study 06, and Study 08, the inventors initially considered 105 mg QW to be the optimal SC anirumab dose for the treatment of type I IFN-mediated diseases. However, to confirm the selection of the 105 mg SC dose, the inventors conducted further analysis of data from the TULIP I (Study 04) and TULIP II (Study 05) clinical trials.

[0439] Additional data demonstrated a positive correlation between exposure and BICLA in patients with high IFNGS levels. Surprisingly, this relationship was observed even within the 300 mg IV Q4W group ( Figure 9A and Figure 9B ). Therefore, the BICLA response was variable within the 300 mg IV Q4W patient group. Logistic regression of the patient's BILCA response at Week 52 confirmed that PK exposure was a significant covariate in both TULIPI and TULIP II. 平均 Statistically significant results were achieved in all analyses of participants and IFNGS-high in both the independent TULIP I and TULIP II studies as well as in the pooled analysis of TULIP I and TULIP II. In the pooled data from the TULIP I and TULIP II studies, the exposure response demonstrated a higher C 平均 was associated with higher BICLA and SRI(4). In other words, there was exposure-dependent variability in the response to aniluomab in lupus patients receiving 300 mg Q4W IV ( Figure 9A and Figure 9B ).

[0440] Surprisingly, the 300 mg IV Q4W dose was thus found to reside at the beginning of the exposure-response plateau, whereas the suboptimal 150 mg IV dose resided in the step region of the exposure-response curve ( Figure 10AAs a result of these analyses, the inventors determined that a 105 mg QW subcutaneous dose (previously considered equivalent to a 300 mg IV Q4W dose) would not provide the best balance of efficacy and safety for lupus patients. Therefore, the inventors decided to select another dose for SC administration that would mitigate the impact of variability in response in the lupus patient population.

[0441] In summary, from initial analyses, it appeared that administering a 105 mg QW subcutaneous dose of aniluomab would achieve at least similar efficacy to 300 mg IV Q4W. However, surprisingly, upon further analysis of newly available data from further studies, the inventors discovered that concentrations at this weekly (QW) dose could increase without reaching the maximum threshold for bioavailability and efficacy. In other words, the QW dose could be increased to above 105 mg to provide higher plasma concentrations and IFNGS suppression, and to mitigate the response variability observed in SLE patients. Therefore, the 105 mg dose is suboptimal.

[0442] The surprising additional dose-response curve data (Table 9-1) were further validated by demonstrating that the probability of achieving a relevant BICLA response (in patients with high IFNGS) increases with weekly subcutaneous administration of concentrations above 105 mg. These data demonstrate the unexpected location of the dose-response plateau (e.g., subcutaneous administration), with the plateau shifting to the right as the dose is increased above 105 mg ( Figure 10B ), indicating that the maximum BICLA response can actually be achieved at doses exceeding 105 mg and that higher doses are preferred (Table 9-1).

[0443] Table 9-1: Projected SC efficacy assuming no dose delays / interruptions.

[0444]

[0445] 9.2.3. The bioavailability of aniluolumab is highly variable

[0446] After further studying the bioavailability of aniluomab, the inventors demonstrated that there may be surprisingly high levels of variability in the bioavailability of aniluomab among different patients following subcutaneous administration. This high level of variability in aniluomab bioavailability was not appreciated in previous studies that reported a bioavailability of >80% after subcutaneous administration (see Example 3) [8]. In Study 08 (SLE patients, SC), the bioavailability of aniluomab in healthy volunteers (F1) was found to be 81% using a population PK model (Table 9-2).

[0447] Table 9-2: Bioavailability of Anirudinib in healthy volunteers

[0448]

[0449] The inventors performed external validation of Study 08 (Ph2 SC in SLE) using a PPK model developed in healthy volunteers and SLE patients in an IV study to determine bioavailability in the lupus population.

[0450] In-depth analysis of the data from Study 08 showed that the site of SC administration affected bioavailability. Specifically, when the bioavailability of 300 mg was estimated in the abdomen relative to IV, the bioavailability (F1) was estimated to be 85.4%, whereas it was 81% when the injection site was not considered. Thus, C after thigh injection was significantly higher than after abdominal injection. 谷 There is a downward trend ( Figure 11A and Figure 11B ). Therefore, taking into account the variability attributed to the injection site and the higher variability in bioavailability in lupus (SLE) patients compared with healthy volunteers, the surprising conclusion is that bioavailability may actually be as low as 70%. Importantly, if a bioavailability (F1) of 81%-87% is assumed, 105 mg would initially be expected to provide a C equivalent to 300 mg IV. 平均 ( Figure 12 ). In contrast, when the estimated bioavailability is reduced to about 70% or less, the median C of a 105 mg QW subcutaneous dose is 平均 Falling below 1 ( Figure 13A 、 Figure 13B and Table 9-3).

[0451] Table 9-3: Bioavailability of Anirudin

[0452]

[0453] Value = median C for 300 mg IV 平均 SC = subcutaneous

[0454] In addition, between 105 mg SC QW and the suboptimal IV dose of 150 mg Q4W, C 平均 An undesirable 30% overlap was observed in the 2017 PCR assay, whereas only 16% overlap was observed when bioavailability was assumed to be 81%. Figure 13A However, when the SC 120 mg dose was used, the effect was similar to that of the 150 mg IV dose of C 平均 The overlap is less than that with the optimal IV dose of 300 mg IV, even assuming a low bioavailability of 70% ( Figure 13B Furthermore, the 120 mg SC QW dose has minimal overlap with the undesirable 1000 mg IV dose (13C), at which the risk of herpes zoster infection is increased ( Figure 15). There is undesirable overlap between the 150 mg SC QW dose and the 1000 mg IV Q4W dose. Even more surprising, the 120 mg SC dose or above was predicted to have better PD suppression (Table 9-4) than the hypothetical optimal 300 mg IV dose (Table 9-5).

[0455] Therefore, doses higher than 105 mg (preferably 120 mg or higher) are selected to optimize exposure response by minimizing the effects of variability in response onset and bioavailability in lupus (e.g., SLE) patients (Table 9-4, Figure 14A , Figure 14B SC doses lower than 150 mg QW also help reduce the risk of herpes zoster infection ( Figure 15 ).

[0456] Table 9-4: Calculated % PD Inhibition at Week 24, SC Dosage

[0457]

[0458] Table 9-5: Calculated % PD Inhibition at Week 24, IV Dosage

[0459]

[0460] The 120 mg and 135 mg QW doses in particular offer a reasonable benefit-risk profile. At doses of 150 mg QW or above, there are increased safety risks, such as an increased risk of patients developing herpes zoster, because a 150 mg QW SC dose is equivalent to 1000 mg IV Q4W ( Figure 13C , Figure 15 ). Therefore, a subcutaneous dose of less than 150 mg QW and greater than 105 mg QW was determined to be a preferred dose. A subcutaneous dose of less than 150 mg QW and less than or equal to 135 mg was determined to be a more preferred dose. A subcutaneous dose of 120 mg was determined to be the optimal dose.

[0461] In summary, the inventors found that, considering previously available preliminary data, the optimal subcutaneous dose of aniluomab may initially be 105 mg QW ( Figure 15 However, further data and analysis unexpectedly showed that doses of 105 mg QW or lower resulted in underdosing in a significant proportion of patients ( Figure 10B, Table 9-3). Therefore, a particularly advantageous dosing regimen demonstrated by the inventors is a dose higher than 105 mg QW. Based on the estimated bioavailability, a particularly ideal dose was determined to be 120 mg subcutaneously QW, equivalent to approximately 400 mg IV Q4W. Therefore, the optimal SC dose is surprisingly >30% higher than the optimal dose based solely on a comparison of 300 mg IV Q4W and previously known anirumab bioavailability. In other words, the data from Study 06 (300 mg IV versus 300 mg and 600 mg SC (abdomen)) showed that the bioavailability of anirumab was approximately 86% (300 mg SC versus 300 mg IV). However, surprisingly, further analysis of Study 08 (150 mg and 300 mg SC, Q2W) found that the bioavailability of anirumab after thigh injection was significantly higher than that after abdominal injection. 谷 Therefore, when the injection site is not considered based on the model and simulations, the bioavailability is estimated to be approximately 81%, but could be as low as 70%, justifying the selection of a SC dose higher than 105 mg QW (Figure 14).

[0462] Thus, the inventors have surprisingly demonstrated that doses greater than 105 mg SC QW and less than 150 mg SC QW, particularly doses of 120 mg QW, (a) maximize efficacy while maintaining an acceptable safety profile, (b) mitigate the effects of bioavailability variability, and (c) mitigate the effects of variability in the onset of response. Thus, doses greater than 105 mg QW are beneficial in accounting for bioavailability variability, thereby improving treatment outcomes. Doses less than 150 mg QW reduce the risk of herpes zoster infection.

[0463] Pharmacokinetic data from healthy volunteers (Study 06 [IV arm only]) and SLE patients (Studies 1013, 02, 04, and 05) were also pooled to evaluate the effects of covariates such as demographics and renal / liver function tests on PK exposure. Patients with high body weight and high type I IFN tests were found to have significantly higher clearance (CL) and lower concentrations. However, surprisingly, these covariates had no clinically relevant effects on efficacy and safety. Surprisingly, other covariates associated with specific populations evaluated in the population PK model were not significant, including race / ethnicity / region, age, sex, renal / liver function tests, standard of care therapy (e.g., OCS, antimalarial, azathioprine, methotrexate, mycophenolate mofetil, mycophenolic acid, mizoribine, and NSAIDs), and medications commonly used by SLE patients (ACE inhibitors and HMG-CoA reductase inhibitors).

[0464] Conclusion

[0465] The inventors have demonstrated that anibocinib doses <150 mg Q4 and >105 mg Q4W provide at least similar or even higher C values ​​than 300 mg IV Q4W over 52 weeks. 平均 In lupus patients, the 120 mg SC QW dose will specifically provide efficacy at least equivalent to the 300 mg IV Q4W dose. It is further plausible that the 120 mg SC QW dose will provide greater efficacy than that demonstrated with the 300 mg IV Q4W dose.

[0466] Based on the data presented herein, a subcutaneous dose of aniluomab has been selected for a multicenter, randomized, double-blind, placebo-controlled Phase 3 study to evaluate the efficacy and safety of subcutaneous aniluomab in adult patients with SLE. In summary, two doses of SC aniluomab (150 mg and 300 mg every 2 weeks [Q2W]) were evaluated in a completed Phase 2 SC study in SLE patients with high type I IFN test results and active skin disease (Study 06). The primary pharmacokinetic (PK) / pharmacodynamic (PD) endpoints and safety of the Phase 2 SC study were analyzed at Week 12, and the tolerability of SC aniluomab administration was assessed at Week 52. Based on the PK / PD data from the Phase 2 SC study and data from the aniluomab IV study, a dose of 120 mg QW was selected for the current Phase 3 SC study to provide mean concentrations (C 平均 ), therefore 120 mg SC QW is expected to provide at least similar efficacy to 300 mg IV Q4W.

[0467] Taking into account the change in dosing interval from Q4W to QW, and by providing at least similar C 平均 , trough concentrations of 120 mg SC QW are expected to be higher than those of 300 mg IV Q4W, and therefore it is expected to provide non-inferior PD suppression to 300 mg IV. In addition, C 平均 Compared to 1000 mg IV (evaluated in Phase 2b study 1013) 平均 The overlap is minimal, with the latter being shown to be safe and tolerable; therefore, any dose below 1000 mg IV Q4W is considered safe.

[0468] The development of a SC route of administration for anivumab using AI-based APFS is expected to provide greater convenience and dosing flexibility for patients and / or caregivers, reduce the risk of infection associated with clinical visit dosing (including but not limited to influenza or COVID-19), and improve treatment access and compliance.

[0469] 10. Example 5: Relationship between the pharmacokinetics, pharmacodynamics, and efficacy of anirumab in patients with moderate to severe systemic lupus erythematosus

[0470] 10.1. Summary

[0471] This study aimed to elucidate the pharmacokinetic / pharmacodynamic and pharmacodynamic / efficacy relationships of the type I interferon receptor antibody anirabtinib in patients with moderate to severe systemic lupus erythematosus (SLE). Data were pooled from the randomized, 52-week, placebo-controlled TULIP-1 and TULIP-2 trials of intravenous anirabtinib (150 mg / 300 mg every 4 weeks [Q4W] for 48 weeks). Pharmacodynamic neutralization was measured using the 21-gene type I interferon gene signature (21-IFNGS) in patients with high IFNGS. Pharmacokinetic / pharmacodynamic relationships were analyzed graphically and modeled with a nonlinear mixed-effects model. British Isles Lupus Assessment Group-based Integrated Lupus Assessment (BICLA) response rates were compared across 21-IFNGS neutralization quartiles. Overall, 819 patients received ≥1 dose of anirabtinib or placebo, including 676 with high IFNGS. Over 52 weeks, higher mean aniluomab serum concentrations were associated with increases in median 21IFNGS neutralization, which was rapid and sustained with aniluomab 300 mg (>80%, weeks 12-52), decreased and delayed with aniluomab 150 mg (>50%, week 52), and minimal with placebo. 80 The trough concentration of anirumab at week 24 (C 谷 The proportion of patients receiving aniluomab 300 mg was greater than that receiving aniluomab 150 mg (approximately 83% versus approximately 27%) because the estimated median C 谷 The BICLA response rate increased with 21IFNGS neutralization (15.6 μg / mL vs. 0.2 μg / mL). At week 52, more patients had BICLA responses in the highest and lowest neutralization quartiles (58.1% vs. 37.6%). In conclusion, anirumab IV 300 mg Q4W rapidly, extensively, and persistently neutralized 21IFNGS and was associated with clinical efficacy, supporting the 300 mg IV dosing regimen and the corresponding 120 mg SC dose in patients with SLE.

[0472] 10.2. Introduction

[0473] Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by dysregulation of innate and adaptive immune pathways in tissues, hyperinflammatory signaling cascades, and immune deposition, which can cause irreversible damage to vital organs. The type I interferon (IFN) signaling pathway plays an instrumental role in the pathogenesis of SLE. All five types of type I IFNs (α, β, ε, κ, ω) activate type I IFN-α receptors (IFNARs), which mediate downstream signaling to stimulate IFN-regulated gene transcription, measured using IFN gene signatures (IFNGS). In 50%-80% of SLE patients, elevated type I IFNGS occur in the blood or tissues and are associated with increased disease activity. 10-13 Relative to IFNGS-low patients, IFNGS-high patients had more active SLE disease with higher levels of anti-double-stranded DNA (anti-dsDNA) antibodies.

[0474] Anilumab is a human immunoglobulin G1κ (IgG1κ) monoclonal antibody that binds to type I IFNAR subunit 1 (IFNAR1) with high affinity and specificity, sterically inhibiting the formation of a functional IFNAR complex. The subsequent rapid internalization of the antibody-receptor complex prevents IFNAR1-mediated signaling in response to all type I IFNs.

[0475] In the randomized, placebo-controlled, 52-week phase 3 TULIP-1 and TULIP-2 trials of patients with moderate to severe SLE who had received standard therapy, aniluomab 300 mg intravenously every 4 weeks (Q4W) for 48 weeks was well tolerated and more effective than placebo across a range of clinical endpoints, including British Isles Lupus Assessment Group (BILAG) Integrated Lupus Assessment (BICLA) response, skin reactions, oral glucocorticoid dose reduction, and flare rate. According to the proposed mechanism of action, aniluomab 300 mg caused substantial (median >85%) pharmacodynamic (PD) neutralization of 21-genotype I IFNGS (21-IFNGS) in patients with high IFNGS, which was achieved as early as week 4 and sustained through week 52.

[0476] In an analysis of aniluomab pharmacokinetic (PK) exposure across 5 clinical trials, median aniluomab serum concentrations were consistent across the 52-week treatment period (across trials and within each trial) with aniluomab 300 mg Q4W, with few patients experiencing trough concentrations (C 谷) below the limit of quantification. High IFNGS expression was associated with lower systemic anirumab exposure, as patients with high IFNGS had a shorter median time to elimination than those with low IFNGS (57 days vs. 67 days). Anirumab PK concentrations were also inversely correlated with body weight but were not affected by other covariates (race, age, sex, renal and hepatic function, immunogenicity, and use of common SLE medications).

[0477] Higher aniluomab doses are associated with greater PD neutralization in patients with systemic sclerosis and SLE; however, the PK / PD and PD / efficacy relationships, and whether these are influenced by disease characteristics, remain to be fully characterized. Here, we aimed to confirm that a 300 mg intravenous aniluomab dosing regimen, administered quarterly, the recommended dose, provides adequate PK exposure and PD neutralization in patients with SLE with a high IFNGS score. PD neutralization was quantified as the change from baseline in the 21-IFNGS score; therefore, patients with a low IFNGS score were not included in our analysis because their baseline 21-IFNGS expression was insufficient to observe meaningful PD neutralization. To investigate the PK and PD in patients with a high IFNGS score, we used pooled data from the TULIP-1 and TULIP-2 trials to evaluate how varying serum aniluomab exposures affect PD neutralization of 21-IFNGS and how 21-IFNGS neutralization, in turn, relates to clinical efficacy.

[0478] 10.3. Methods

[0479] Study design

[0480] For this analysis, data were pooled from the randomized, double-blind, parallel-group, placebo-controlled, 52-week, phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) ​​trials ( Figure 1 ).

[0481] 10.3.2. Patients

[0482] The TULIP-1 and TULIP-2 trials enrolled adults (18-70 years) who met the American College of Rheumatology classification criteria for SLE. All patients had moderate to severe SLE, defined as a SLEDAI-2K score ≥6 (excluding scores attributable to fever, lupus-related headache, or organic brain syndrome) and a clinical (excluding laboratory results) SLEDAI-2K score ≥4. At screening, patients were seropositive for antinuclear antibodies, anti-dsDNA antibodies, and / or anti-Smith antibodies and received at least one stable standard of care. At screening, patients were categorized as 4-genotype I IFNGS high or low in a central laboratory using an analytically validated 4-gene (IFI27, IFI44, IFI44L, and RSAD2) quantitative polymerase chain reaction (qPCR)-based test of patient whole blood.

[0483] 10.3.3. Efficacy Endpoints

[0484] Both the TULIP-1 and TULIP-2 trials evaluated the proportion of patients in the anirumab 300 mg group relative to the placebo group who had a BICLA response at week 52 (primary endpoint in TULIP-2, secondary endpoint in TULIP-1) or a SLE responder index ≥ 4 (SRI[4]) at week 52 (primary endpoint in TULIP-1, secondary endpoint in TULIP-2). The percentages of patients classified as BICLA or SRI(4) responders, the differences between the anirumab and placebo groups, and the associated 95% confidence intervals (CIs) were adjusted for stratification factors using the Cochran-Mantel-Haenszel method.

[0485] A BICLA response was defined as all of the following: a reduction in all baseline BILAG-2004 domain A and B scores to B / C / D and C / D, respectively, with no worsening in other BILAG-2004 organ systems; no increase in SLEDAI-2K score (from baseline); no increase in Physician's Global Assessment (PGA) score (≥0.3 points from baseline); no discontinuation of study treatment; and no use of restrictive medications.

[0486] An SRI(4) response was defined as all of the following: a ≥4-point decrease in the SLEDAI-2K; <1 new BILAG-2004A or <2 new BILAG-2004B organ domain scores; no increase in the PGA score (≥0.3 points from baseline); no study treatment discontinuation; and no use of restrictive medications.

[0487] PK Metrics and Models

[0488] The PK analysis dataset included all patients who received anirumab 150 mg or anirumab 300 mg and who had at least one quantifiable serum PK observation after the first dose. PK measurements were performed pre-dose at Weeks 0, 12, 24, 36, and 48, post-dose at 15 ± 5 minutes after the end of the infusion at Weeks 0 and 48, and a final anirumab PK measurement at Week 52. Anirumab concentrations were determined using an electrochemiluminescence assay on the Meso Scale Discovery platform (MesoScale Diagnostics, Rockville, MD, USA). The assay measurement range was 20 ng mL for a 1:10 dilution of human serum. -1 to 1280 ng mL -1 The lower limit of quantification is 20 ng mL -1 As previously described, a population PK model developed for SLE was used to estimate predicted aniluomab concentrations at specific time points (e.g., aniluomab trough concentrations at week 24 [C 谷 ]), and the predicted mean anirumab concentration over the duration of treatment (C 平均 ).

[0489] 10.3.5. PD Measurement Indicators

[0490] PD was measured using the 21-IFNGS assay, which consists of 21 type I IFN-α / β-inducible genes, as previously described [24,25]. Figure 28 ), which includes 4 genes in the dichotomous IFNGS test. PD measurements performed at baseline are expressed as median fold changes in 21-IFNGS scores relative to a pooled healthy control sample from 30 healthy volunteers. PD was also measured at weeks 12, 24, 36, and 52, with median PD neutralization expressed as median percentage change from baseline of 21-IFNGS+ / - median absolute deviation (MAD). All PD analyses excluded 25 patients with missing baseline PD measurements.

[0491] PK / PD Analysis

[0492] The baseline 21-IFNGS scores of patients with low IFNGS were similar to those of healthy subjects, which was insufficient to observe meaningful PD neutralization; therefore, patients with low IFNGS were not included in the PK / PD or PD / efficacy analyses.

[0493] 10.3.6.1. Graphical PK / PD Analysis

[0494] Graphical PK / PD analyses included patients with high IFNGS who had at least one PD measurement before discontinuation in all treatment groups and at least one quantifiable serum PK observation in the 150 mg and 300 mg aniluomab groups. Individually predicted mean aniluomab concentrations (C 平均 ) median or tertiles (depending on sample size) to categorize patients treated with anirumab. 平均 The median 21-IFNGS PD neutralization was achieved in the subgroup over the 52-week treatment period.

[0495] PK / PD Model

[0496] The PK / PD model analysis population included patients with high IFNGS who had baseline and at least one post-baseline PD measurement before discontinuation in all groups and at least one quantifiable serum PK observation in the anirumab group. The relationship between anirumab exposure (PK) and PD neutralization of 21-IFNGS was described by an indirect response model in which anirumab inhibits the production of type I IFN-inducible genes. This model is a nonlinear mixed-effects model originally developed to describe the PK / PD relationship of anirumab in patients with systemic sclerosis. The model is shown in the figure below. Figure 16 The PK / PD model was implemented in NONMEM software (version 7.3 or higher, ICON Development Solutions, Ellicott City, MD; 2006) to provide PK / PD parameter estimates. Visual prediction checks were performed to ensure that the observed data were adequately captured using the 95% prediction interval, which was generated based on 5000 model simulations.

[0497] 10.3.7. PD / Efficacy Analysis

[0498] This PD / efficacy analysis included patients with high IFNGS who had baseline and at least one post-baseline PD assessment before discontinuation. Individual median 21-IFNGS neutralization from baseline to steady-state was calculated at Weeks 12, 24, 36, and 52 based on observational data pooled from the anirumab 150 mg and 300 mg treatment groups, excluding PD measurements collected after discontinuation. Patients in the pooled anirumab 150 mg and 300 mg treatment groups were stratified into subgroups based on median percent 21-IFNGS neutralization quartiles. BICLA and SRI(4) response rates were calculated for the fourth quartile subgroups and for the placebo treatment group overall at Week 52.

[0499] 10.4. Results

[0500] 10.4.1. Demographic and Baseline Characteristics of IFNGS

[0501] In the TULIP-1 and TULIP-2 trials, 819 patients received at least one dose of aniluomab 300 mg, aniluomab 150 mg, or placebo; 676 (82.5%) and 143 (17.5%) had 4-gene type I IFNGS-high and IFNGS-low, respectively. Because the four genes tested in the dichotomous 4-gene IFNGS are a subset of the continuous 21-IFNGS, 19,27 The 4-gene IFNGS status (high vs. low) was closely associated with the median 21-IFNGS score, which was 15.1 in patients with high IFNGS and 1.1 in patients with low IFNGS (Table 10-1, Figure 17 Table 10-1: Summary characteristics of patients with IFNGS-high and IFNGS-low at baseline and throughout the TULIP-1 and TULIP-2 trials

[0502]

[0503]

[0504] Anti-dsDNA, anti-double-stranded DNA; BILAG-2004, British Isles Lupus Assessment Group-2004; C3, complement 3; C4, complement 4; CLASI, cutaneous lupus erythematosus area and severity index; IFNGS, interferon gene signature; IQR, interquartile range; SD, standard deviation; SLEDAI-2K, systemic lupus erythematosus disease activity index 2000.

[0505] The table includes all patients who received at least one dose of aniluomab 300 mg, aniluomab 150 mg, or placebo in the TULIP-1 and TULIP-2 trials.

[0506] a The 21-IFNGS score was calculated as expression relative to 30 pooled healthy control samples. There were 25 patients (18 IFNGS high and 7 IFNGS low) with missing baseline 21-IFNGS scores.

[0507] b The percentages shown are the percentages of patients with high or low IFNGS in each geographic region or racial group, including patients treated with 150 mg aniluomab, 300 mg aniluomab, or placebo in TULIP-1 and TULIP-2.

[0508] c Anti-dsDNA antibody levels were classified as positive (>15 U mL -1 ) or negative (≤15 U mL-1 ) and were measured using an automated fluorescent immunoassay in a central laboratory.

[0509] d Complement levels were classified as abnormal (C3 < 0.9 g L -1 ; C4 < 0.1 g L -1 ) or normal (C3 ≥ 0.9 g L -1 ; C4 ≥ 0.1 g L -1 ) and measured in a central laboratory.

[0510] e Discontinuation rates are shown as the number of patients who discontinued (n) relative to the number of patients in each treatment subgroup (N).

[0511] f The rate of restrictive medication use is shown as the number of patients (n) who used any medication in excess of the protocol-allowed limit relative to the number of patients in each treatment subgroup (N).

[0512] Table 10-1 shows the baseline characteristics of type I IFNGS-high and IFNGS-low patients. IFNGS-high patients were younger than IFNGS-low patients (median age 40 years vs. 46 years). For the dichotomous IFNGS test at screening and the median 21-IFNGS score at baseline, an inverse association between age and IFNGS expression was observed ( Figure 18 Compared with other geographic regions, North American patients were slightly older (median age 44 years vs. 40-41 years) and slightly less likely to have a high IFNGS (72.6% vs. 88.5%-90.9%). Black / African American patients (86.1%) and Asian patients (95.2%) had a higher proportion of patients with a high IFNGS than white patients (78.3%), who are the predominant ethnic group in North America.

[0513] Patients with high IFNGS had more severe disease than those with low IFNGS; they had higher rates of anti-dsDNA seropositivity (48.7% vs. 25.9%), abnormal C3 (41.7% vs. 13.3%), and abnormal C4 (26.9% vs. 5.6%) at baseline, and more patients with SLEDAI-2K scores ≥ 10 (71.9% vs. 62.9%) (Table 10-1). The association between disease severity and IFNGS was also reflected in the placebo group, and patients with high IFNGS were treated with the TULIP-1 and TULIP-2 regimens. 16,17 A higher proportion of patients with IFNGS-low had restricted medications (34.1% vs. 18.8%); in contrast, patients with IFNGS-high who received aniluolumab 300 mg had similar restricted medications as those with IFNGS-low at week 52 (approximately 21%).

[0514] PK / PD Analysis

[0515] The baseline 21-IFNGS scores in the IFNGS-low subgroup were similar to those in healthy subjects, which were insufficient to observe meaningful PD neutralization; thus, the median 21-IFNGS neutralization percentage over time was minimal in patients with IFNGS-low therapy with anirumab 300 mg and placebo ( Figure 19 ). Therefore, patients with low IFNGS were not included in the PK / PD or PD / efficacy analyses.

[0516] Table 10-2: Anirudumab C used for graphical PK / PD analysis 平均 Subgroup threshold

[0517]

[0518] C 平均 , mean anirumab concentration over the treatment duration; M, median; PD, pharmacodynamics; PK, pharmacokinetics; T, tertile.

[0519] In contrast, in IFNGS-high patients treated with aniluolumab 300 mg, PD neutralization of 21-IFNGS occurred in all baseline 21-IFNGS groups. However, patients in the lowest baseline 21-IFNGS quartile (those with a baseline 21-IFNGS closest to that observed in IFNGS-low patients) had lower PD neutralization with greater variability than patients in higher baseline 21-IFNGS quartiles ( Figure 20 ).

[0520] 10.4.2.1. PK / PD Graphical Analysis

[0521] The PK / PD graphical analysis included 357 IFNGS-high patients from TULIP-1 who received placebo (n=144), anirumab 150 mg (n=72), or anirumab 300 mg (n=141), and 297 IFNGS-high patients from TULIP-2 who received placebo (n=149) or anirumab 300 mg (n=148) ( Figure 21 ).

[0522] Patients treated with anirumab 300 mg were assigned to C 平均 The tertiles were used for classification, which was generally consistent in TULIP-1 and TULIP-2. 平 The mean is higher or lower than the median (11.5 μg mL -1), patients treated with aniluomab 150 mg were divided into subgroups. As previously reported, patients treated with aniluomab 300 mg generally had higher C values ​​than those treated with aniluomab 150 mg due to nonlinearity of PK exposure. 平均 values, and the observed C 平均 The value overlap is minimal (Table 10-2).

[0523] All anirumab 300mg C 平均 All tertiles achieved ~80% median PD neutralization, which persisted from week 12 to week 52; however, in both trials, the lowest C 平均 The variability of the tertiles was greater than that of the two higher C 平均 The variability of the tertiles ( Figure 21A 、 Figure 21B ). The two highest C 平均 The median PD neutralization across tertiles was stable at approximately 90%. There was no significant difference in baseline disease activity subgroups (including those based on SLEDAI-2K score (<10 vs. ≥10), oral glucocorticoid dose (<10 vs. ≥10 mg / day), and the presence of PD-negative agents (<10 vs. ≥10 mg / day). -1 ) and subgroups of lupus serology (anti-dsDNA antibodies, C3 and C4), substantial and sustained PD neutralization was consistently observed with anirumab 300 mg ( Figure 22 In contrast, in C patients treated with anirumab 150 mg 平均 In the subgroup of patients with values ​​below the median, PD neutralization varied widely (larger MAD values), although it was numerically greater than the mild PD neutralization observed with placebo.

[0524] 10.4.2.2. PK / PD Model Analysis

[0525] This PK / PD model analysis included 646 patients with high IFNGS from the pooled TULIP-1 and TULIP-2 trials who received placebo (n=289), anirumab 150 mg (n=70), or anirumab 300 mg (n=287). As demonstrated by visual predictive inspection, the PK / PD indirect response model adequately captured the observed data with a 95% prediction interval ( Figure 23 ). NONMEM outputs diagnostic graphs such as Figure 25A -D. The estimated values ​​of the PK / PD model parameters are shown in Table 10-3.

[0526] IC 80 is defined as the approximate anirumab concentration required to produce 80% of maximal inhibition of 21-IFNGS expression relative to baseline. The model gives a value of 3.88 μg mL -1 IC 80 Estimated value, based on an IC of 6.56 nM50 Due to nonlinearity, the estimated median C at week 24 for aniluomab 300 mg was 谷 Higher than anirumab 150 mg (15.6 μg mL -1 Relative to 0.2 μg mL -1 )( Figure 24 Thus, a higher proportion of patients treated with anirutumab 300 mg compared with those treated with anirutumab 150 mg had C-terminal changes at week 24. 谷 Exceed IC 80 (Approximately 83% versus approximately 27%). For patients with high IFNGS, the model-estimated baseline 21-IFNGS score was 13.1 (Table 10-3).

[0527] Table 10-3: Anirudin parameters estimated by PK / PD model

[0528]

[0529]

[0530] GS0, baseline gene signature; IC 50 , efficacy, approximate anirumab concentration required to produce 50% of maximal inhibition of 21-IFNGS expression relative to baseline; IFN, interferon; I 最大 , the approximate anirumab concentration required to produce maximal inhibition of 21-IFNGS expression relative to baseline; k out , elimination rate constant; PD, pharmacodynamics; PK, pharmacokinetics; Var(η IC50 ), IC 50 The inter-subject variability of Var(η GS0 ), inter-subject variability of GS0; σ 2 , residual variability.

[0531] 10.4.3. Pooled PD Neutralization in the Anirudin 150 mg and 300 mg Groups

[0532] The 341 patients with high IFNGS who received aniluomab 150 mg or 300 mg were stratified by PD neutralization quartiles (Q1 < 51.7%, Q2 ≥ 51.7%-85.3%, Q3 ≥ 85.3%-92.6%, and Q4 ≥ 92.6%). Patients in the aniluomab 300 mg group primarily resided in the higher PD neutralization quartiles (Q2-Q4); median PD neutralization from week 12 to week 52 was > 86% with aniluomab 300 mg versus < 37% with aniluomab 150 mg.

[0533] Of the 273 patients with high IFNGS from the anirumab 300 mg group included in the PD neutralization analysis, 41 (15.0%) were in the lowest quartile of PD neutralization (<51.7% neutralization). Of these 41 patients, 18 (43.9%) had a baseline 21-IFNGS score in the bottom quartile (Q1 < 3.8), which is associated with lower PD neutralization ( Figure 20 The remaining 23 patients tended to have low PK exposure; 19 were at the lowest anirumab 300 mg PK C 平均 Quartile (C 平均 <27.6 μg mL -1 ), and 4 were in the second quartile (27.6 μg mL -1 -39.2 μg mL -1 )(Pooled TULIP-1 and TULIP-2 anirudin 300mg PK C 平均 Compared with the total IFNGS-high group (n=676), these 23 patients tended to have more active baseline disease, with positive anti-dsDNA antibodies (56.2% vs. 48.7%), low C3 (56.5% vs. 41.7%), low C4 (47.8% vs. 26.9%), SLEDAI-2K score ≥10 (78.2% vs. 71.9%), or higher oral glucocorticoid dose (12.4 mg / day). -1 Relative to 10.2 mg / day -1 ) was numerically higher.

[0534] Table 10-4: C of anirumab 300 mg in the pooled TULIP-1 and TULIP-2 data 平均 PK quartiles

[0535]

[0536] C 平均 , mean anirumab concentration over the duration of treatment; M, median; PK, pharmacokinetics; Q, quartile; Q4W, every 4 weeks.

[0537] Quartiles of mean PK concentrations are based on pooled data from TULIP-1 and TULIP-2 for patients who were treated with 300 mg anirumab and completed treatment.

[0538] 10.4.4. PD / Efficacy Analysis

[0539] The PD / efficacy analysis included 341 patients with high IFNGS who received anirudin 150 mg or 300 mg and 280 patients who received placebo. Figure 26A and Figure 26B As shown. The proportion of patients with BICLA responses at week 52 increased with higher PD neutralization in the anirumab group (Q1 37.6%, Q2 49.4%, Q3 51.8%, Q4 58.1%); the response rate was numerically greater than placebo (30%) across all anirumab quartiles. Similarly, in the anirumab group, the proportion of patients with SRI(4) responses at week 52 increased with higher PD neutralization subgroups (Q1 48.2%, Q2 56.5%, Q3 58.8%, Q4 64.0%); the response rate was numerically greater than placebo (40%) across all anirumab quartiles.

[0540] Next, the inventors investigated whether there was an association between the BICLA response rate at week 52 and the 21-IFNGS score at baseline. In the anirumab 300 mg group, patients with higher baseline 21-IFNGS scores (Q4 ≥ 20.7) had numerically higher BICLA response rates at week 52 compared with patients with lower 21-IFNGS scores (Q1 < 3.8) (TULIP-1: 54% vs. 40%; TULIP-2: 47% vs. 43%). However, across all baseline 21-IFNGS score quartiles in TULIP-1 and TULIP-2, anirumab 300 mg resulted in higher BICLA responses relative to placebo ( Figure 27 ).

[0541] 10.5. Discussion

[0542] Correlating drug concentrations, pharmacodynamics, and efficacy can provide important insights into the relationship between a drug's mechanism of action and clinical response. In this analysis, the inventors evaluated pooled data from the Phase 3 TULIP-1 and TULIP-2 trials in patients with moderate to severe SLE to examine the PK / PD and PD / efficacy relationships of aniluomab. This study identified an association between aniluomab serum concentrations and PD neutralization of the type I IFN-inducible gene (21-IFNGS), which in turn was associated with improved efficacy at week 52 in patients with high IFNGS at screening. These findings support aniluomab's mechanism of action; that is, by blocking the type I IFN pathway and inhibiting downstream expression of genes that propagate SLE disease activity and drive lupus pathogenesis, measures of disease activity and clinical efficacy are improved.

[0543] At screening, PD neutralization was not significant in patients with a low IFNGS score, so only patients with a high IFNGS score were included in this analysis. Furthermore, it is important to specifically consider patients with a high IFNGS score, as these patients have a higher clearance rate of aniluomab than patients with a low IFNGS score. Elevated IFNGS expression is associated with more active, more difficult-to-treat disease, elevated serum concentrations of IFN-α, and serum markers of inflammation and immune dysregulation, including tumor necrosis factor, IL-2, IFN-γ, and IL-1R2. We consistently found that patients with a high IFNGS score had higher baseline disease activity, with more patients seropositive for anti-dsDNA antibodies or abnormal C3 / C4 at baseline relative to patients with a low IFNGS score. In the placebo group, patients with a high IFNGS score were more likely to use restrictive medications throughout the trial compared with patients with a low IFNGS score. However, treatment with aniluomab 300 mg in patients with a high IFNGS score was associated with reduced use of restrictive medications, similar to that observed in patients with a low IFNGS score. In both patients with IFNGS-high and IFNGS-low, the rate of treatment discontinuation was lower with aniluomab 300 mg than with placebo.

[0544] The PK / PD model, IFNAR1 internalization kinetics, and information from the SLE study appear robust, as the estimated values ​​are consistent with the observed data. The model-predicted parameters indicate a strong PK / PD relationship. In the aniluomab 300 mg group, approximately 83% of patients were predicted to have aniluomab trough concentrations that would result in >80% inhibition of 21-IFNGS expression. In fact, in all patients receiving aniluomab 300 mg C 平均 Rapid (at week 12), substantial (~80%), and sustained (through week 52) neutralization of 21-IFNGS was observed across tertiles. In contrast, in the aniluomab 150 mg group, only approximately 27% of patients were predicted to have aniluomab trough concentrations that would result in >80% inhibition of 21-IFNGS. Thus, lower, more variable, and delayed PD neutralization was observed with aniluomab 150 mg, particularly in the C 平均 PD neutralization was minimal in patients below the median and was similar to that observed with placebo. Lower anirumab serum exposure resulted in a more variable PD neutralization profile across trials and dosing regimens.

[0545] Throughout the trial, a small subset (15%) of patients in the aniluomab 300 mg group with IFNGS-high status did not experience high PD neutralization (median baseline 21-IFNGS percentage neutralization was less than 51.7%). Nearly half of these patients had baseline 21-IFNGS scores in the lower quartile (despite being assigned IFNGS-high status due to the dichotomous nature of the 4-gene IFNGS test) and therefore did not require high PD neutralization to achieve 21-IFNGS scores similar to healthy controls. The other half of these patients had low PK exposure, supporting a PK / PD relationship, and tended to have numerically higher disease activity at baseline. However, across the entire pooled population, baseline disease activity measures appeared to have no impact on PD neutralization with aniluomab 300 mg, further supporting the aniluomab 300 mg IV dosing regimen and the corresponding 120 mg subcutaneous dose in patient subgroups, regardless of disease activity.

[0546] Thus, it might be suggested that a subset of patients with low PD neutralization may benefit from anirumab doses higher than 300 mg; however, there is no evidence that BICLA response rates are higher with doses exceeding 300 mg IV. For example, in the Phase 2 MUSE study, the BICLA response rate at week 52 was higher with anirumab 300 mg (53.3%) than with anirumab 1000 mg (41.2%). Furthermore, in an analysis modeling the relationship between PK exposure and BICLA response rate in TULIP-1 and TULIP-2, anirumab 1000 mg was predicted to provide only an incremental benefit compared to anirumab 300 mg due to nonlinearity. However, as shown in Example 4, this variability, combined with variability in bioavailability, justifies surprisingly high subcutaneous doses greater than 105 mg when determining the optimal subcutaneous unit dose.

[0547] PD neutralization of 21-IFNGS was associated with improved clinical efficacy. The proportions of BICLA and SRI(4) responders were numerically higher in all aniluomab PD neutralization quartiles than in the placebo group. However, the absolute BICLA and SRI(4) response rates in the highest aniluomab PD neutralization quartile were approximately 21% and approximately 16% higher, respectively, than in the lowest aniluomab PD neutralization quartile (primarily composed of patients in the aniluomab 150 mg group). These results are consistent with the association analyses between PK and efficacy in the TULIP-1 and TULIP-2 trials, which identified an exposure-efficacy relationship and demonstrated that BICLA / SRI(4) response rates were higher in all aniluomab PK subgroups than in the placebo group.

[0548] Early changes in PD markers that correlate with clinical efficacy at later time points are clinically valuable. This study suggests that the degree of IFNGS neutralization can serve as a definitive PD marker for future anibovizumab trial design in different populations (e.g., pediatric patients or other lupus populations such as lupus nephritis (LN) or cutaneous lupus erythematosus (CLE)) or with different administration methods (e.g., subcutaneous injection).

[0549] In the phase 2 MUSE trial, aniluomab 300 mg IV every 4 weeks was selected as the optimal dosing regimen for patients with moderate to severe SLE because of its favorable benefit-risk profile. 平均 The results were consistent and higher than those elicited by aniluomab 150 mg, with minimal overlap between subgroups, consistent with the nonlinear PK profile of aniluomab. Aniluomab steady-state concentrations, quantified by trough concentrations at week 24, were predicted to be approximately 80-fold higher with aniluomab 300 mg than with aniluomab 150 mg.

[0550] 10.6. Conclusion

[0551] Here, the inventors demonstrate a clear relationship between aniluomab serum exposure and PD neutralization in patients with moderate to severe SLE receiving standard therapy, providing evidence to support the aniluomab IV 300 mg Q4W dosing regimen and the aniluomab SC 120 mg QW dosing regimen. Indeed, aniluomab 300 mg provides sufficient PK exposure in patients with high IFNGS, resulting in rapid, substantial, and sustained neutralization of 21-IFNGS, which in turn is associated with improved clinical efficacy. Therefore, aniluomab SC doses greater than 105 mg (e.g., 120 mg QW) are expected to have the same clinical efficacy.

[0552] 11. Example 7: Treatment of Type I IFN Diseases

[0553] 11.1. Type I IFN Markers

[0554] In order to understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know whether the subject's disease is driven by type I IFN activation. However, directly measuring type I IFN remains a challenge. Therefore, transcript-based markers have been developed to evaluate the effect of target protein overexpression on a specific set of mRNA markers. The expression of these markers is easily detected in whole blood, for example using PCR (e.g., TaqMan) assays.

[0555] The expression of the gene can be measured by RT-PCR. Suitable primers and probes for detecting the gene can be found in WO2011028933. Suitable kits for measuring gene expression for IFNGS testing are QIAGEN The IFIGx RGQ RT-PCR kit (IFIGx kit) was used as described by Brohawn et al.

[26] , which is incorporated herein by reference in its entirety. The 21-IFNGS assay consists of 21 type I IFN-α / β inducible genes ( Figure 28 ), which included 4 genes in the dichotomous IFNGS test.

[0556] The bimodal distribution of transcript scores in SLE subjects supports the definition of IFN-test high and low subpopulations using the 4-gene IFN test ( Figure 29A The type I IFN test is described in WO 2011028933A1, which is incorporated herein by reference in its entirety. The type I IFN gene signature can be used to identify subjects with a high type I IFN gene signature (IFNGS) test or a low IFNGS test. Figure 29B The 4-gene IFNGS test measures the expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subject's whole blood compared to three reference genes: 18S, ACTB, and GAPDH. The test result is a score that is compared to a predetermined cutoff value that categorizes patients into two groups with either low or high levels of IFN-inducible gene expression ( Figure 29B ).

[0557] Type I IFN gene scores were shown to correlate with expression in diseased tissues (e.g., skin) in SLE. In particular, high type I IFN gene signatures were associated with increased disease activity and OCS use in SLE ( Figure 29C ).

[0558] IFNGS can be used to identify other type I IFN-mediated diseases that are amenable to treatment with IFNAR1 inhibitors. Type I IFN-mediated diseases include lupus nephritis (LN) and Sjögren's syndrome, in which patients may be identified with elevated IFNGS ( Figure 31A and Figure 31B A similar core type I IFN signature (5-gene score) was activated in patients with SSc and myositis ( FIG32 ).

[0559] 11.2. Lupus

[0560] The IFNγ gene (21-gene) in systemic lupus erythematosus (SLE) is overexpressed by type I IFN signaling inhibitors such as the anti-IFNα antibody sifalimumab ( Figure 30A) or the type I IFN receptor (IFNAR1) inhibitor anirumab ( Figure 30B )) Neutralization. See also Section 10.

[0561] 11.3. Scleroderma

[0562] Systemic sclerosis (SSc) is a rare autoimmune disease characterized by chronic immune activation and excessive deposition of extracellular matrix components. A phase 1 dose-escalation trial (Study CP180) investigated the safety and tolerability of aniluomab in subjects with SSc. Figure 33 The IFNGS score in SSc patients was determined as the median fold change (FC) of five IFN-inducible genes compared to healthy controls, which were among the most differentially regulated genes in scleroderma patients. These five genes are a subset of the 21-gene IFNGS.

[0563] The 5-gene IFNGS is elevated in whole blood (WB) of scleroderma patients as measured using a 5-gene signature (IFI27, RSAD2, IFI44, IFI44L, IFI6). Figure 31B The 5-gene IFNGS score of SSc patients was comparable to that of SLE patients ( Figure 32A 、 Figure 34A Baseline IFN signatures were highly correlated between affected tissues and the periphery and were highly correlated with baseline disease activity ( Figure 34B There was also a positive correlation between baseline 5-gene IFNGS score and SSc disease activity, as measured by the modified Rodnan Skin Score (mRTSS) ( Figure 34C ).

[0564] As described in WO 2013 / 188494 (incorporated herein by reference in its entirety), a 5-gene IFNGS can be neutralized in patients with scleroderma (SSc) ( Figure 35 In particular, approximately two-thirds of SSc patients in the CP180 study (NCT0093082) were positive for type I IFN signatures at baseline. Following treatment with anirumab, at doses of 1 mg / kg (mpk) or higher (single and multiple doses), the incidence of type I IFN signatures was significantly higher in patients with SSc (P<0.001). Figure 35 ), there was a rapid and nearly complete suppression of IFNGS (day 1), and a clear dose-dependent effect on the time the marker remained suppressed before recovery ( Figure 35 The IFN score used in the CP180 study, similar to scores used in other autoimmune indications, has been shown to be a sensitive marker of PD and correlates with treatment with inhibitors of type I IFN-mediated signaling in SSc.

[0565] Anilumab treatment in SSc patients also inhibited T cell activation (via decreased CXCL10 and CD40L) (Figure 36). Anilumab further inhibited collagen formation markers and upregulated collagen degradation markers (Figure 36), suggesting a mechanism of action that regulates tissue function in SSc patients through inhibition of type I IFN signaling. Skin scores further improved (mRSS at the highest dose).

[0566] In conclusion, anilovib treatment of patients with scleroderma resulted in almost complete suppression of type I IFN scores in WB and skin in a dose-dependent manner. In patients with SSc, treatment with anilovib neutralized the gene signature, resulting in elevations in core IFN scores. Anilovib has also been shown to have therapeutic efficacy in patients with SSc. Therefore, the therapeutic efficacy of anilovib in patients with SSc is similar to that in patients with SLE and LN, with a dose similar to or identical to that shown to be safe and effective in SLE, namely, 300 mg IV every 4 weeks or an equivalent SC dose greater than 105 mg and less than 150 mg every 4 weeks, particularly 120 mg SC every 4 weeks.

[0567] Myositis

[0568] The presence of type I IFNs in myositis muscle biopsies was first observed by immunohistochemistry studies

[27] , and subsequently increased PDCs were reported in dermatomyositis (DM) muscle and skin biopsies [28,29]. DM or polymyositis (PM) has been observed to develop after IFN-α or IFN-β therapy, suggesting that type I IFNs are potential therapeutic targets for both indications [30,31]. IFN-β, but not IFN-α, transcripts are overexpressed in PM and dermatomyositis / JDM7. IFNβ is elevated in the blood of DM patients and correlates with type I IFN-induced genes in the blood

[32] . Gene expression profiling of muscle biopsies from patients with myositis revealed that the most overexpressed transcripts in DM patients compared with normal controls were IFN-α / β-induced genes

[28] .

[0569] Type I IFN-inducible genes (136 genes) are overexpressed in the blood of patients with dermatomyositis (DM) or polymyositis (PM) compared with healthy volunteers (defined as a value < 4)

[11] , particularly IFI44L and RSAD2. Greenberg et al. identified 13 type I IFN signatures of PD markers or elevated expression of IFI27, RSAD2, IFI44L, IFI44, OAS1, IFIT1, ISG15, OAS3, HERC5, MX1, ESPTI1, IFIT3, and IFI6 compared with healthy donors

[11] . In study MI-CP151 (NCT00533091), blood and muscle biopsy specimens were collected from patients. Baseline type I IFN gene signatures (4-gene and 13-gene scores) were determined in muscle and blood of patients with DM and PM, showing elevated IFNGS scores in whole blood and muscle of patients with BM and PM ( Figure 37 、 Figure 31A 、 Figure 38 )

[10] . See also WO 2009 / 011770 and WO 2009 / 011770, both of which are incorporated herein by reference.

[0570] The type I IFN gene signaling inhibitor (sifalimumab) dose-dependently neutralized the 13-gene IFNGS score in blood and muscle of patients with DM and PM (Study MI-CP151, Figure 39 In particular, the median maximum neutralization of the type I IFN gene signature was 91% in the 0.3 mg / kg cohort, with median neutralization of 47%, 33%, and 65% in the sifalimumab-treated cohorts on days 28, 56, and 98, respectively. At day 98, the four sifalimumab-treated cohorts showed a median neutralization range of 54%-91% of the gene signature. Neutralization of the type I IFN signature in muscle was shown to be as high as 80% when sifalimumab was used to treat myositis patients ( Figure 38 Relative to placebo, more IFNα suppression was observed in a dose-dependent manner in all four sifalimumab dose groups (0.3 mg.kg, 1.0 mg.kg, 3.0 mg.kg, and 10 mg.kg). IFNα inhibition reduced the infiltration of immune cells into myositis muscles (DM and PM) ( Figure 41 ). Sifalimumab inhibits the downstream pathway of type I IFN in the muscle of myositis patients, and targeted neutralization is associated with improved muscle function (MMT8) in myositis patients [10,11] (Figure 42). Therefore, it is important that targeted modulation of the type I IFN gene signature in blood shows a trend associated with disease activity in patients with DM and PM ( Figure 40A Furthermore, targeted inhibition of the type I IFN gene signature was associated with inhibition of important disease-associated signaling events in muscle tissue ( Figure 40B ).

[0571] In summary, the core IFNGS was elevated in patients with myositis, and treatment with sifalimumab neutralized this gene signature. Therefore, the IFNGS signature data plausibly suggest that the spectrum of IFN pathway activation in myositis is similar to that in SLE. Similar IFN activation was observed in SLE, DM, and PM (Figure 32). Furthermore, due to the ubiquity of type I IFN receptors, the general availability of receptors is a major driver of dose selection in myositis. The data show that PF / PD is similar across disease states (e.g., comparing SLE to SSc). Furthermore, subcutaneous dosing data from studies 06 and 08 support the selection of a dose of approximately 120 mg SC QW in myositis. Anirumab completely inhibits type I IFN signaling through IFNARs, whereas sifalimumab only targets most IFN-α ( Figure 43 Thus, anilumab has a similar neutralizing effect on IFNGS as sifalimumab in patients with myositis at a dose similar to or the same as that shown to be safe and effective in SLE, i.e., 300 mg IV Q4W or an equivalent SC dose greater than 105 mg and less than 150 mg QW (particularly 120 mg SC QW).

[0572] 12. Example 8: Injection device

[0573] Through injection devices[1][9] such as pre-filled syringes (PFS) ( Figure 44A ) or autoinjector (AI) ( Figure 44B ) administration of anirumab.

[0574] 12.1. Autoinjectors

[0575] Aniluomab can be administered via an autoinjector[1]. The autoinjector is shown in exploded view ( Figure 45A ) and assembly form ( Figure 45B ) is shown. The label [4] is wrapped around and attached to the automatic injector [1] ( Figure 45C The autoinjector comprises an autoinjector housing [3], a cap and cap remover [2], and a drive mechanism [5]. A unit dose of liquid anirutumab formulation [6] is contained in the autoinjector housing [3]. The unit dose [6] can be observed through an observation window [7].

[0576] 12.1.1.1. Prefilled syringes with accessories

[0577] Aniluomab can be administered via an attachment prefilled syringe (APFS) [8]. The APFS [8] comprises a unit dose [6] of aniluomab contained in a primary container [9], such as Figure 46A The assembly state and Figure 46BAs shown in the exploded view in FIG. The main container [9] has a plunger stopper

[16] . The main container has a nominal fill volume

[17] of 0.8 ml, but may contain slightly more than 0.8 ml. The remaining space in the main container [9] is occupied by an air bubble

[18] . The air bubble

[18] may have a size of 3-5 mm, optionally 4 mm. The main container [9] has a defined stopper position

[19] .

[0578] A prefilled syringe (APFS) primary container [9] with attachments is provided in a PFS assembly [8] that includes a needle guard

[12] , a finger flange

[11] , and a plunger rod

[13] . A label

[14] is provided with the primary container [9] in the PFS assembly [8]. The label

[14] is wrapped around the syringe [9] in a label placement location

[15] .

[0579] 12.1.1.2. Packaging

[0580] The injection device [1] [8] is provided in a kit

[20] ( Figure 47 ). The label [4]

[14] is provided with the APFS or autoinjector in the packaging. The label includes instructions for use of the injection device [1], [8]. The packaging includes a tamper seal.

[0581] References

[0582] All publications mentioned in this specification and / or cited below are herein incorporated by reference.

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[0584] [2] B. Bittner, W. Richter, and J. Schmidt, Biodrugs 32, 425 (2018).

[0585] [3] J. Witcher et al., Br. J. Clin. Pharmacol. 81, 908 (2016).

[0586] [4]DAIsenberg et al., Ann.Rheum.Dis.75,323(2016).

[0587] [5]JTMerrill et al., Ann.Rheum.Dis.75,332(2016).

[0588] [6]GTFerguson et al.,J.Asthma Allergy 11.63(2018).

[0589] [7]M.Khamashta et al.,Ann.Rheum.Dec.75,1909(2016).

[0590] [8]R.Tummala et al.,Lupus Sci.Med.5,e000252(2018).

[0591] [9]A.Psarras,P.Emery,and EMVital,Rheumatol.Oxf.Engl.56,1662(2017).

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[10] BWHiggs et al.,Ann.Rheum.Dis.73,256(2014).

[0593]

[11] SAGreenberg et al.,Gene Immun.13,207(2012).

[0594]

[12] JCHall and A.Rosen,Nat.Rev.Rheumatol.6.40(2010).

[0595]

[13] L.Bolko et al.,Brain Pathol.Zurich Switz.31,e12955(2021).

[0596]

[14] A.-K.Somani et al.,Arch.Dermatol.144,1341(2008).

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[15] B.Skaug and S.Assassi,Cytokine 132,154635(2020).

[0598]

[16] BWHiggs et al., Ann.Rheum.Dec.70,2029(2011).

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[17] X.Liu et al., Arthritis Rheum.65,226(2013).

[0600]

[18] X.Guo et al.,J.Invest.Dermatol.135,2402(2015).

[0601]

[19] R.Furie et al.,Arthritis Rheumatol.Hoboken Nj 69,376(2017).

[0602]

[20] RAFurie et al.,Lancet Rheumatol.1,e208(2019).

[0603]

[21] EF Morand et al.,N.Engl.J.Med.382,211(2020).

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[22] Y.Tanaka and R.Tummala,Mod.Rheumatol.0,1(2020).

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[24] Y.Yao et al.,Arthritis Rheum.60,1785(2009).

[0607]

[25] Y.Yao et al.,Hum.Genomics Proteomics HGP 2009,(2009).

[0608]

[26] ACR Meeting Abstracts(nd).

[0609]

[27] DAIsenberg et al.,Clin.Exp.Immunol.63,450(1986).

[0610]

[28] SAGreenberg et al.,Neurology 65,1782(2005).

[0611]

[29] J. Wenzel et al., Clin.Exp.Dermatol.31,576 (2006).

[0612]

[30] L.Dietrich,A.Bridges,and M.Albertini,Med.Oncol.17,64(2000).

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[31] C.Gota and L.Calabrese,Autoimmunity 36,511(2003).

[0614]

[32] A.P.Liao et al.,Ann.Rheum.Dis.70,831(2011).

Claims

1. A unit dose comprising greater than (>) 105 mg and less than (<) 150 mg of a type I IFN receptor (IFNAR1) inhibitor, wherein the IFNAR1 inhibitor is anirumab, and wherein the unit dose is for subcutaneous injection into a subject once a week (QW).

2. The unit dose of claim 1, comprising equal to or less than (≤) 135 mg of the IFNAR1 inhibitor.

3. The unit dose of claim 1 or 2, comprising about 120 mg of the IFNAR1 inhibitor.

4. The unit dose of any one of claims 1 to 3, for use in a method of treating or preventing a disease in a subject, wherein the use comprises subcutaneously administering the unit dose to the subject, wherein the disease is a type I interferon (IFN) mediated disease.

5. A unit dose for use as claimed in claim 4, wherein the disease is an autoimmune disease.

6. A unit dosage for use as claimed in claim 5, wherein the disease is lupus.

7. A unit dose for use as claimed in claim 6, wherein the disease is SLE.

8. The unit dose for use according to claim 7, wherein the disease is moderately to severely active autoantibody-positive SLE.

9. The unit dose for use according to claim 6, wherein the disease is lupus nephritis (LN).

10. The unit dosage for use according to claim 6, wherein the disease is cutaneous lupus erythematosus (CLE).

11. The unit dose for use according to claim 5, wherein the disease is myositis.

12. The unit dosage for use according to claim 5, wherein the disease is scleroderma.

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