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 a Chinese patent application with an application date of April 21, 2022, an application number of 202280029635.7, and an invention title of "Anti-IFNAR1 Administration Regimen for Subcutaneous Injection". 1. Background Art

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

[0003] 1.1. 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, especially in patients with moderate or severe disease. The long-term prognosis for many patients remains inadequate. Since hydroxychloroquine was approved for discoid lupus and SLE, only one new treatment for SLE (belimumab) has been approved by the US 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 been approved for 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 the dose depending on the severity of the disease manifestations. The "safe" dose of oral glucocorticoids is not independent of the risk of developing glucocorticoid-induced damage (such as cataracts, osteoporosis, and coronary artery disease), and although increased glucocorticoid exposure is associated with an increased cumulative overall damage, even 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 a safe and therapeutically effective subcutaneous dose based on an intravenous dose is particularly complex. The difficulty of predicting a safe and effective subcutaneous dose for treating SLE using data from intravenous administration of 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 tabalumab was administered to a total of 5 SLE patients [3]. In the subsequent phase III ILLUMINATE trials (NCT01205438 and NCT01196091), a subcutaneous or intravenous route was chosen [4, 5]. In the phase I trial, SLE patients received a single intravenous dose of tabalumab, 0.125 mg / kg or 2.0 mg / kg [3]. In the phase III ILLUMINATE trials, the initial subcutaneous loading dose for subjects was 240 mg, followed by 120 mg subcutaneously every two weeks or monthly. The primary endpoint of 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] 1.3. Anifrolumab

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

[0013] The present invention solves one or more of the above problems by providing a dose of an IFNAR1 inhibitor (e.g., anifrolumab) 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 known as IFNAR) inhibitor. The present invention also relates to a subcutaneous dose of an IFNAR1 inhibitor for use in a method of 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 in subjects with a type I IFN-mediated disease (including lupus, myositis, scleroderma, and Sjögren's syndrome), a common type I IFN gene signature (IFNGS) is elevated, and this IFNGS is related to the severity of the disease and the identification of a safe and effective dose of an IFNAR1 inhibitor that neutralizes the IFNGS.

[0015] Among other things, the present invention is supported by two Phase 3, multicenter, multinational, randomized, double-blind, placebo-controlled clinical trials in SLE patients (NCT02446899 and NCT02962960), a Phase 2, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial in SLE patients (NCT02962960), a Phase 1, randomized, placebo-controlled, double-blind clinical trial in healthy subjects (NCT02601625), and IFNAR1 inhibitor (anifrolumab)-related efficacy, safety, and PK data from a Phase 2 study characterizing the pharmacokinetics, pharmacodynamics, and safety of anifrolumab in SLE subjects with high type I interferon testing (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, the unit dose comprising equal to or less than (≤) 135 mg of the IFNAR1 inhibitor.

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

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

[0021] 5. The unit dose according to item 4, the unit dose consisting essentially of ≤ 135 mg of the IFNAR1 inhibitor.

[0022] 6. The unit dose according to item 5, the unit dose consisting essentially of approximately 120 mg of the IFNAR1 inhibitor.

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

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

[0025] 9. A unit dose as described in any one of the foregoing 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 a carrier-free excipient.

[0026] 10. The unit dose as described in 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 as described in item 9 or 10, wherein the formulation has a pH of about 5.9.

[0028] 12. The unit dose as described in 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 as described in 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 as described in 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. A unit dose as described in any one of items 11 to 14, wherein the antibody comprises an Fc region containing an amino acid substitution of L234F, numbered as shown by the EU index in Kabat, and wherein the antibody exhibits a reduced affinity for at least one Fc ligand as compared to the unmodified antibody, optionally wherein the antibody comprises an amino acid substitution of L235E and / or P331S in the Fc region, numbered as shown by the EU index in Kabat.

[0038] 16. A unit dose as described in 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. A unit dose as described in any one of the foregoing items, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof.

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

[0041] 19. A method of treating a subject with a type I IFN-mediated disease, 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 subject with a type I IFN-mediated disease, the method comprising subcutaneously administering a dose of an IFNAR1 inhibitor, wherein administering the dose subcutaneously weekly provides in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 300 mg of the IFNAR1 inhibitor every 4 weeks.

[0043] 21. The method as described in item 20, wherein administering the dose subcutaneously weekly provides in the subject a plasma concentration that is greater than the plasma concentration provided by intravenously administering 300 mg of the IFNAR1 inhibitor every 4 weeks.

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

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

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

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

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

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

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

[0051] 29. The method according to 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 according to 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 according to 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 according to 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 according to 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 according to any one of items 18 to 33, the method comprising administering a corticosteroid to the patient, optionally wherein the corticosteroid is an oral corticosteroid.

[0057] 35. The method according to item 34, the method 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 as described in item 35, wherein the second dose of corticosteroid is about 7.5 mg prednisone equivalent or less; optionally wherein the second dose of corticosteroid is 5 mg prednisone equivalent or less; optionally wherein the method comprises administering the second dose of corticosteroid once daily.

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

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

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

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

[0063] 41. The method as described in any one of items 18 to 40, wherein the 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 as described in any one of items 18 to 41, wherein the 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 as described in any one of items 18 to 42, wherein the 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 as described in any one of items 18 to 43, wherein the subject is a patient who tests high for type I interferon-stimulated gene markers (IFNGS) before administration of the dose or unit dose, optionally wherein the IFNGS is a 4-gene, 5-gene or 21-gene IFNGS.

[0067] 45. The method according to any one of items 18 to 44, the method comprising identifying the subject as a patient who is high in the IFNGS test before treatment with the dose or unit dose.

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

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

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

[0071] 49. The method according to item 48, wherein the pharmaceutical composition contains 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 according to any one of items 18 to 49, wherein the type I IFN-mediated disease is associated with an elevated IFNGS score compared to healthy donors, wherein the IFNGS score is a 4-gene, 5-gene, and / or 21-gene score.

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

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

[0075] 53. The method according to item 52, wherein the type I IFN-mediated disease is systemic lupus erythematosus (SLE), optionally wherein the SLE is moderate to severe active autoantibody-positive SLE.

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

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

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

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

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

[0081] 59. The method according to item 58, wherein reducing the SLE disease activity in the subject includes:

[0082] a) a BILAG-based integrated lupus assessment (BICLA) response in the subject,

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

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

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

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

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

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

[0089] 64. The method according to 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 according to 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) Heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:4;

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

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

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

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

[0097] 66. The method according to 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 according to any one of items 64 to 65, wherein the antibody comprises an Fc region with an amino acid substitution of L234F, numbered according to the EU index as shown in Kabat, and wherein the antibody exhibits a reduced affinity for at least one Fc ligand compared to the unmodified antibody.

[0099] 68. The method according to 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 according to any one of items 18 to 68, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof.

[0101] 70. The method according to item 19, wherein the type I IFN-mediated disease is SLE, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises subcutaneous administration of the dose once a week.

[0102] 71. The method according to item 19, wherein the type I IFN-mediated disease is LN, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises subcutaneous administration of the dose once a week.

[0103] 72. The method according to item 19, wherein the type I IFN-mediated disease is CLE, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises subcutaneous administration of the dose weekly.

[0104] 73. The method according to item 19, wherein the type I IFN-mediated disease is myositis, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises subcutaneous administration of the dose weekly.

[0105] 74. The method according to item 19, wherein the type I IFN-mediated disease is scleroderma, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises subcutaneous administration of the dose weekly.

[0106] 75. The method according to item 19, wherein the type I IFN-mediated disease is Sjogren's syndrome, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, wherein the dose is 120 mg, and wherein the method comprises subcutaneous administration of the dose weekly.

[0107] 76. A pharmaceutical composition for use in a treatment method according to any one of items 18 to 75, the method comprising subcutaneous administration of the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a unit dose according to 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 subcutaneous administration of the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a dose of anifrolumab 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 anifrolumab or a functional variant thereof.

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

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

[0112] 81. The injection device according to item 79, wherein the injection device is an attached pre-filled syringe (AFPS).

[0113] 82. The injection device as described in 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 subcutaneous administration of the unit dose or the pharmaceutical composition to a subject.

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

[0116] 85. The kit as described in item 83 or 84, the kit comprising a package, wherein the package is adapted to accommodate the injection device and the instructions for use.

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

[0118] 87. The kit as described in any one of items 83 to 86, wherein the instructions for use include instructions for administering 120 mg of anifrolumab or a functional variant thereof.

[0119] 88. The kit as described in any one of items 83 to 87, wherein the instructions for use include instructions for subcutaneous administration of 120 mg of anifrolumab or a functional variant thereof once a week.

[0120] 89. The kit as described in any one of items 83 to 87, wherein the instructions for use include instructions for use of the method as described in any one of items 18 to 75. 3. DESCRIPTION OF THE DRAWINGS

[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 Composite Lupus Assessment; BILAG: British Isles Lupus Assessment Group; IFNGS: interferon gene signature; IV: intravenous; OCS: oral corticosteroid; 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 meet the ACR classification for SLE; bPatients were stratified according to IFNGS status, SLEDAI-2K score, and OCS dose; c For patients with a prednisone baseline OCS ≥ 10 mg / day or equivalent.

[0123] Figure 2 : Efficacy results of TULIP-1 and TULIP-2

[0124] Overall efficacy results of TULIP-1, TULIP-2, and MUSE. BICLA: BILAG-based Composite Lupus Assessment; BILAG: British Isles Lupus Assessment Group; CI: Confidence Interval; CLASI: Cutaneous Lupus Erythematosus Disease Area and Severity Index; IFNGS: Interferon Gene Signature; OCS: Oral Corticosteroids; SRI(4): SLE Responder Index. Analysis methods and definitions vary across trials. a Published data presented as odds ratios; b Previously unpublished data.

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

[0126] Figure 3A Shows the percentage of patients with a BILAG-based Composite Lupus Assessment (BICLA) response of the British Isles Lupus Assessment Group (BILAG); vertical bars indicate the 95% confidence interval (CI). Figure 3B Shows the time to first recurrence, defined as at least one new BILAG 2004 Index (BILAG-2004) item A or at least two new BILAG-2004 item B compared to the previous visit. 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). Open black circles in this panel indicate censored data. The time to first recurrence was evaluated using the Cox proportional hazards model but not adjusted for multiple comparisons, so no inferences can be drawn from this result.

[0127] Figure 4 : Relationship of anifrolumab mean concentration to herpes zoster incidence

[0128] Herpes zoster incidence (%) in patients in Study 1013 who received placebo, 300 mg IV anifrolumab, or 1000 mg IV anifrolumab.

[0129] Figure 5: Mean anifrolumab serum concentration-time curve

[0130] Figure 5A: Study conducted in SSc MI-CP180 - Mean anifrolumab serum concentration-time curve after a single IV dose. Data represent + / - SD. Mean data below the LLOQ were not plotted. IV, intravenous; LLOQ, lower limit of quantification; MEDI 546, anifrolumab; n, number of patients in the subgroup; SSc, systemic sclerosis. Figure 5B : Study 06 conducted in healthy volunteers - Mean anifrolumab serum concentration-time curve after single SC and IV doses. Samples with an actual collection time deviation > 10% from the nominal collection time were excluded from the mean. IV, intravenous; N, number of subjects; SC, subcutaneous.

[0131] Figure 6: Study 08 study design and results

[0132] Figure 6A : Study design of the SC anifrolumab phase II in SLE patients. Study 08 (NCT02962960) evaluated the effects of two anifrolumab doses every other week. Figure 6B : Mean serum concentration of anifrolumab over time. Figure 6C : Anifrolumab neutralization of type I IFN gene signature.

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

[0134] Figure 7A : Median AUC ratio (SC / IV) calculated for different SC doses between week 0 - 52. Median AUC ratio (SC / IV) calculated based on the estimated bioavailability in study 06 between week 0 - 52, where the subcutaneous dose was 75 mg (+ symbol), 90 mg (hollow square), 105 mg (circle), 120 mg (triangle), or 135 mg (solid square). The subcutaneous doses here were administered once every 7 days (QW); the IV dose was administered once every 4 weeks (Q4W) at a dose of 300 mg. Based on AUC, both 90 mg and 105 mg SC QW showed similar to 300 mg IV. Figure 7B : Calculated median AUC ratio (SC / IV) for 90 mg and 105 mg SC QW. Median AUC ratio (SC / IV) calculated based on an estimated bioavailability approximately 7% lower than the bioavailability calculated in study 06 between week 0 - 52 cycles, where the subcutaneous dose was 90 mg SC QW or 105 mg SC.

[0135] Figure 8: Anifrolumab concentration over time at different doses

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

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

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

[0139] Figure 10: BICLA dose response

[0140] Figure 10A : Dose-response curve for the probability of meeting the BICLA response criteria relative to mean anifrolumab C (in IFNGS-high patients) over 52 weeks, showing the predicted mean (gray line) and 95% confidence interval (CI) (dashed area). Patients were grouped by dose (150 mg, n = 62; 300 mg, n = 242; and 1000 mg). Figure 10B : Predicted PK and efficacy for different SC doses. Probability of meeting BICLA (in IFNGS-high patients) for weekly subcutaneous injection doses from 105 mg up to 150 mg. The assumptions used to generate the data did not include dose delays / interruptions.

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

[0142] C after thigh injection compared to abdominal injection 谷 showed a decreasing trend. Figure 11A : 150 mg SC Q2W. Figure 11B: 300 mg SC Q2W.

[0143] Figure 12 : Exposure predictions based on 81%-87% bioavailability and a preliminary PK model

[0144] Anifrolumab C predicted for 90 mg - 150 mg SC QW to 300 mg Q4W based on PK preliminary modeling and bioavailability assumptions 平均 Median ratio. If the bioavailability (F1) is assumed to be 81%-87%, 105 mg was initially expected to provide a C equivalent to 300 mg IV 平均 .

[0145] Figure 13: Anifrolumab C for different SC and IV doses over 52 weeks in patients with high IFNGS doses 平均

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

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

[0148] Doses above 105 mg (preferably 120 mg or higher) were selected to optimize the exposure-response by minimizing the impact of variability in response onset and bioavailability in patients with lupus (e.g., SLE). Figure 14A : Assume 81% bioavailability. Figure 14B : Assume 70% bioavailability.

[0149] Figure 15 : Relationship of anifrolumab mean concentration to herpes zoster incidence

[0150] Herpes zoster incidence (%) in patients in Study 1013 receiving placebo, 300 mg IV anifrolumab, or 1000 mg IV anifrolumab. SC doses below 150 mg QW are also promising for reducing the risk of herpes zoster infection.

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

[0152] Nonlinear mixed-effects model. Ab, anifrolumab in the central compartment; Abp, anifrolumab in the peripheral tissue compartment; Ab.R, anifrolumab-IFNAR1 complex; CL RES , reticuloendothelial system clearance rate; GS IFN,wb , type I IFN PD marker in whole blood; IC 50 Potency, anifrolumab concentration corresponding to half-maximal inhibition of the PD marker; IFN, interferon; I 最大 , maximum graded degree of inhibition of the PD marker by anifrolumab; k deg , degradation rate constant of IFN-αR1; k in,wb , 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, inter-compartment clearance rate; wb, whole blood.

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

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

[0155] Figure 18 : IFNGS status at screening and baseline 21-IFNGS scores by age group in pooled data from the TULIP-1 and TULIP-2 trials

[0156] For the dichotomous IFNGS test at screening and the median 21-IFNGS score at baseline, a negative association was observed between age and IFNGS expression. 21-IFNGS, 21-gene pharmacodynamic interferon gene marker; IFNGS, interferon gene marker.

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

[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 of 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 post-baseline 21-IFNGS measurement.

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

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

[0161] Figure 21: PD neutralization of 21-gene type I IFNGS observed according to C 平均 subgroups over 52 weeks of treatment duration in TULIP-2 and TULIP-1

[0162] Figure 21A : TULIP-2. Figure 21A : TULIP-1. C 平均, mean anifrolumab concentration during the treatment period; IFNGS, interferon gene signature; MAD, median absolute deviation; PD, pharmacodynamics; PK, pharmacokinetics. Figures include IFNGS-high patients who had ≥1 quantifiable serum PK observation and ≥1 PD measurement prior to discontinuation; PD measurements collected after discontinuation were not included.

[0163] Figure 22 : 21-IFNGS pharmacodynamic neutralization in IFNGS-high patients treated with anifrolumab 300 mg according to baseline disease characteristics

[0164] In baseline disease activity subgroups (including subgroups based on SLEDAI-2K score (<10 vs. ≥10), oral glucocorticoid dose (<10 vs. ≥10 mg per day -1 ), and lupus serology (anti-dsDNA antibody, C3, and C4)), substantial and sustained PD neutralization was consistently observed with anifrolumab 300 mg. 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 checks for the PK / PD models for anifrolumab 150 mg and 300 mg

[0166] This PK / PD model analysis included 646 IFNGS-high patients from the pooled TULIP-1 and TULIP-2 trials who received placebo (n = 289), anifrolumab 150 mg (n = 70), or anifrolumab 300 mg (n = 287). As demonstrated by the visual predictive checks, the PK / PD indirect response model adequately captured the observed data through the 95% prediction intervals. 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 IFNGS-high-level patients 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 : Predicted trough anifrolumab concentration at week 24 for the PK / PD models for anifrolumab 150 mg and 300 mg

[0168] Due to the non-linearity, the estimated median week 24 C of anifrolumab 300 mg 谷 was higher than that of anifrolumab 150 mg (15.6 μg / mL -1 relative to 0.2 μg / mL -1 ). 21-IFNGS, 21-gene type I interferon gene signature; PD, pharmacodynamics; PK, pharmacokinetics. IC 80 is the approximate anifrolumab concentration required to achieve 80% of the maximum inhibition of 21-IFNGS expression. The predicted values based on 5000 simulations of the non-linear mixed-effect PK / PD model were implemented into the software NONMEM (version 7.3 or higher).

[0169] Figure 25: Diagnostic plot 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 and the LOESS (locally weighted scatterplot smoothing) line in

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

[0172] Figure 26A : BICLA; Figure 26B : SRI(4). BILAG, British Isles Lupus Assessment Group (BICLA)-based composite lupus assessment; IFNGS, interferon gene signature; PD, pharmacodynamics; SRI(4), Systemic Lupus Erythematosus Responder Index ≥ 4. Analyses included high IFNGS patients who had a baseline and at least one post-baseline PD assessment before discontinuation and who received anifrolumab 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 randomized participants according to baseline 21-IFNGS quartiles in TULIP-1 and TULIP-2

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

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

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

[0177] There is a clear boundary between patients with positive and negative diagnostic tests in SLE. Figure 29A : Fold change (RQ) signature. Figure 29B : Transcript score distribution for each SLE patient. The test result is a score compared to a pre-determined cut-off value that divides patients into 2 groups with low or high levels of IFN-induced gene expression. Figure 29C : 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 rituximab treatment in SLE patients. 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 IFNGS in type I IFN-mediated diseases

[0181] Figure 31A : Distribution of IFNGS in SLE, LN, and Sjogren's syndrome patients. LN: Lupus nephritis; SLE: Systemic lupus erythematosus; HD: Healthy donor. Figure 31B: Whole blood and skin microarray analysis of patients in MI-CP180. IFN score was defined as the median fold change (FC) of 5 type I IFN-induced genes, which were among the most differentially regulated genes in scleroderma patients compared to healthy controls. The baseline (day 0) score was used to determine whether patients were IFN signature positive or negative. These 5 genes are a subset of the 21-gene set used to measure PD in SLE patients.

[0182] Figure 32: Baseline gene signature using the 5-gene IFNGS

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

[0184] Figure 33 : Anifrolumab 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 scleroderma patients

[0187] Figure 34A : Comparison of the distribution of 5 gene signatures in SSc and SLE at baseline. Figure 34B : The IFNGS in the periphery is correlated with the IFNGS in diseased tissue. At baseline, RNA was isolated from WB and skin, and the IFN score was determined by calculating the median fold change (FC) of 5 IFN-induced genes (IFI27, IFI6, IFI44, IFI44L, and RSAD2). The correlation between the periphery and diseased tissue was evaluated. Figure 34C : Baseline IFNGS is correlated with disease activity score (mRTSS score). RNA was isolated from WB and skin at baseline and the IFN score was measured. The modified Rodnan total skin score (mRTSS), an assessment of SSc disease activity, was determined by a clinician. (A) shows the correlation between IFN score and mRTSS in all patients. (B) The mRTSS score in IFN(+) vs. IFN(-) patients reveals a significant increase in disease activity in IFN signature (+) patients. Based on cut-off values of IFN score ≥3 in WB and IFN score ≥2 in skin, patients were determined to be signature (+).

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

[0189] Single-dose anifrolumab administration was given to patients at multiple dose levels. % neutralization was calculated relative to the baseline IFN score.

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

[0191] Single-dose anifrolumab administration was given to patients at multiple dose levels.

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

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

[0194] Figure 38 : IFNGS in patients with myositis (study MI-CP151)

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

[0196] Figure 39 : Neutralization of IFNGS in patients with myositis (study MI-CP151)

[0197] In study MI-CP151, siltuximab's targeted regulation of type I IFN gene signatures in the blood and muscle of DM ( Figure 39 ) or PM ( Figure 39 ) patients.

[0198] Figure 40: Targeted regulation of type I IFN gene signatures in the blood shows a related trend of disease activity in DM and PM patients (study MI-CP151)

[0199] Figure 40A: The stratified targeting neutralization curve represents the proportion of DM or PM patients treated with siltuximab who demonstrate suppression of their type I IFN gene signature at the thresholds provided on the x-axis at day 98. At day 98 (compared to day 0), patients demonstrating at least a 15% improvement in the MMT8 score are represented by the orange line, while those without improvement are represented by the blue line. All type I IFN signature positive patients (27) were treated with siltuximab prior to dosing. Figure 40B : Targeted suppression of the type I IFN gene signature is associated with suppression of important signaling events in muscle tissue.

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

[0201] Siltuximab reduces infiltration of immune cells in the myositis muscle tissue of DM and PM patients.

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

[0203] Doses include 1 mg / kg, 3 mg / kg, and 10 mg / kg. Siltuximab group: 14 doses over 6 months (Q2W). Placebo group: dosed for 3 months then switched to siltuximab for 3 months.

[0204] Figure 43 : Comparison of the effects of anifrolumab and siltuximab on IFNGS neutralization

[0205] Both siltuximab and anifrolumab 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 a greater effect on anifrolumab.

[0206] Figure 44: Delivery device

[0207] Phase III study protocol ( Figure 44A ). Anifrolumab is administered by an injection device [1][9] such as a prefilled syringe (PFS) ( Figure 44B ) or an autoinjector ( Figure 44C ).

[0208] Figure 45: Autoinjector

[0209] Exploded view ( Figure 45A ), assembly view ( Figure 45B ) and autoinjector for administering anifrolumab or a functional variant thereof filled with a pharmaceutical substance ( Figure 45C ).

[0210] Figure 46: Prefilled syringe with attachment

[0211] Prefilled syringe with attachment (APFS) for anifrolumab or a functional variant thereof. The primary tube is shown in assembled form ( Figure 46A ) and exploded view ( Figure 46B ). The APFS with its additional components is shown in assembled form ( Figure 46C ) and exploded view ( Figure 46D ).

[0212] Figure 47 : Packaging for the delivery device

[0213] Figure 48 . Alignment of anifrolumab heavy chain

[0214] Figure 49 . Alignment of anifrolumab light chain 4. Detailed description

[0215] 4.1. Subcutaneous unit dose

[0216] The present invention relates to a unit dose (pharmaceutical unit dose, unit dose form or pharmaceutical unit dose form) for subcutaneous administration, which comprises > 105 mg (i.e., greater than 105 mg) and < 150 mg (i.e., less than 150 mg) of anifrolumab 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 dose form or pharmaceutical unit dose form) for subcutaneous administration, which comprises > 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 about 120 mg of the IFNAR1 inhibitor. The unit dose may comprise 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 about 120 mg of the IFNAR1 inhibitor. The concentration of the IFNAR1 inhibitor in the unit dose may be about 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 from 0.5 ml to 1 ml. The concentration of the unit dose may be about 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 anifrolumab or a functional variant thereof, 25 mM to 150 mM lysine salt, and a vehicle-free excipient. The unit dose may 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 a vehicle-free 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 may be about 5.9.

[0219] The unit dose may comprise ≤135 mg (i.e., 135 mg or less) anifrolumab or a functional variant thereof. The unit dose may comprise about 120 mg anifrolumab or a functional variant thereof. The unit dose may comprise 120 mg anifrolumab or a functional variant thereof. The unit dose may consist essentially of >105 mg and <150 mg anifrolumab or a functional variant thereof. The unit dose may consist essentially of ≤135 mg anifrolumab or a functional variant thereof. The unit dose may consist essentially of about 120 mg anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the unit dose may be about 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 from 0.5 ml to 1 ml. The concentration of the unit dose may be about 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 anifrolumab or a functional variant thereof, 25 mM to 150 mM lysine salt, and a vehicle-free excipient. The unit dose may comprise a formulation of 150 mg / ml to 200 mg / ml anifrolumab or a functional variant thereof, 25 mM to 150 mM lysine salt, and a vehicle-free 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 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 treatment 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 > 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 anifrolumab or a functional variant thereof, wherein the dose > 105 mg and < 150 mg.

[0222] 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 administering the dose weekly provides in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 300 mg of the IFNAR1 inhibitor every 4 weeks. Administering the dose weekly can provide in the subject a plasma concentration that is at least greater than the plasma concentration provided by intravenously administering 300 mg of the IFNAR1 inhibitor every 4 weeks. Administering the dose weekly can provide in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 400 mg of the IFNAR1 inhibitor 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 the IFNAR1 inhibitor. The dose administered to the subject can be > 105 mg (i.e., greater than 105 mg) of the IFNAR1 inhibitor. The dose administered to the subject can be ≤ 135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor. The dose administered to the subject can be approximately 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, the method comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, wherein administering the dose weekly provides in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. Administering the dose weekly can provide in the subject a plasma concentration that is greater than the plasma concentration provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. Administering the dose weekly can provide in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 400 mg of anifrolumab 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 anifrolumab or a functional variant thereof. The dose administered to the subject can be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject can be ≤135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. The dose administered to the subject can be about 120 mg of anifrolumab or a functional variant thereof.

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

[0225] The treatment method can reduce the SLE disease activity in the subject. Reducing the SLE disease activity in the subject can include a) the BILAG-based integrated lupus assessment (BICLA) response in the subject, b) the SRI(4) response in the subject, and / or a reduction in the subject's CLASI score as compared to the subject's cutaneous lupus erythematosus area and severity index (CLASI) score before treatment.

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

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

[0228] 4.3. Dosage

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

[0230] 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, which contains an IFNAR1 inhibitor of >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg). The unit dose can contain 105 mg to 149 mg of the 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, which contains >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg) of anifrolumab 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 from 105 mg to 135 mg of the IFNAR inhibitor. The unit dose may comprise about 120 mg of the IFNAR1 inhibitor. The unit dose may comprise 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 about 120 mg of anifrolumab or a functional variant thereof. The concentration of the IFNAR1 inhibitor in the unit dose may be about 150 mg / ml. The volume of the unit dose may be 1 ml or less. The volume of the dose or unit dose may be from 0.5 ml to 1 ml. The concentration of the unit dose may be about 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 of the IFNAR1 inhibitor, 25 mM to 150 mM lysine salt, and a load-free excipient. The unit dose may comprise a formulation of 150 mg / ml to 200 mg / ml of the IFNAR1 inhibitor, 25 mM to 150 mM lysine salt, and a load-free 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 may be about 5.9.

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

[0234] In another aspect, the present invention relates to a method of treating lupus (such as SLE) in a subject, the method comprising subcutaneously administering a dose of an IFNAR1 inhibitor, wherein administering the dose weekly provides in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 300 mg of the IFNAR1 inhibitor every 4 weeks. Administering the dose weekly can provide in the subject a plasma concentration that is greater than the plasma concentration provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. Administering the dose weekly can provide in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 400 mg of the IFNAR1 inhibitor 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 the IFNAR1 inhibitor. The dose administered to the subject can be >105 mg (i.e., greater than 105 mg) of the IFNAR1 inhibitor. The dose administered to the subject can be ≤135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor. The dose administered to the subject can be 105 mg to 135 mg of the IFNAR1 inhibitor. The dose administered to the subject can be about 120 mg of the IFNAR1 inhibitor.

[0235] In another aspect, the present invention relates to a method of treating lupus (such as SLE) in a subject, the method comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, wherein administering the dose weekly provides in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. Administering the dose weekly can provide in the subject a plasma concentration that is greater than the plasma concentration provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. Administering the dose weekly can provide in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 400 mg of anifrolumab 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 anifrolumab or a functional variant thereof. The dose administered to the subject can be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject can be 105 mg to 149 mg of anifrolumab or a functional variant thereof. The dose administered to the subject can be 105 mg to 135 mg of anifrolumab or a functional variant thereof. The dose administered to the subject can be about 120 mg of anifrolumab 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 anifrolumab 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 anifrolumab 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 dose or unit dose may be administered once a week for about 8 weeks. The dose or unit dose may have a volume that permits its delivery in a single subcutaneous administration step. The volume of the dose or unit dose may be 0.5 ml to 1 ml. The volume of the dose or unit dose may be less than 1 ml. The volume of the dose or unit dose may be about 0.8 ml.

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

[0238] The dose or unit dose can provide the following therapeutic effect in the subject, which is at least equivalent to the therapeutic effect provided by an intravenous dose of 300 mg of anifrolumab or a functional variant thereof administered once every 4 weeks (Q4W). The dose or unit dose can provide the following trough concentration of anifrolumab or a functional variant thereof in the subject, which is greater than the trough concentration of anifrolumab or a functional variant thereof provided by an intravenous dose of 300 mg of anifrolumab 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 anifrolumab 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 anifrolumab 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 approximately 8 weeks. The dose or unit dose may have a volume that permits its delivery in a single subcutaneous administration step. The volume of the dose or unit dose may be 0.5 ml to 1 ml. The volume of the dose or unit dose may be less than 1 ml. The volume of the dose or unit dose may be approximately 0.8 ml.

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

[0241] The dose or unit dose can provide the following therapeutic effect in the subject, which is at least equivalent to the therapeutic effect provided by an intravenous dose of 300 mg of anifrolumab or a functional variant thereof administered once every four weeks (Q4W). The dose or unit dose can provide the following trough concentration of anifrolumab or a functional variant thereof in the subject, which is greater than the trough concentration of anifrolumab or a functional variant thereof provided by an intravenous dose of 300 mg of anifrolumab or a functional variant thereof administered once every four 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 can be a human subject. The subject can be an adult. The subject may have lupus. The subject may have 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 Sjogren's syndrome.

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

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

[0247] 4.5. Pharmaceutical composition

[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 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 unit dose of the present invention.

[0250] In another aspect, the present invention relates to a pharmaceutical composition for use in a method of treating a functional variant 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 anifrolumab or a functional variant thereof, wherein the dose > 105 mg and < 150 mg. The dose of anifrolumab or a functional variant thereof can be a unit dose (unit dose form, pharmaceutical unit dose form, pharmaceutical unit dose). Functional anifrolumab variants include antigen-binding fragments of anifrolumab and antibody and immunoglobulin derivatives of anifrolumab.

[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 anifrolumab or a functional variant thereof, wherein weekly administration of the pharmaceutical composition provides in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenous administration of 300 mg of anifrolumab or a functional variant thereof every 4 weeks. Weekly administration of the dose can provide in the subject a plasma concentration that is approximately equivalent to the plasma concentration provided by intravenous administration of 400 mg of anifrolumab or a functional variant thereof every 4 weeks. The dose can be <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The dose can be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose can be ≤135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. The dose can be approximately 120 mg of anifrolumab or a functional variant thereof. The dose can be 120 mg of anifrolumab or a functional variant thereof.

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

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

[0254] 4.6. Formulation

[0255] The IFNAR1 inhibitor can be included in the pharmaceutical composition. The pharmaceutical composition can comprise from about 150 mg / ml to 200 mg / ml of the IFNAR1 inhibitor, from about 25 mM to 150 mM of a lysine salt, and a carrier-free excipient. The pharmaceutical composition can comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition can comprise 50 mM of lysine HCl. The pharmaceutical composition can comprise 130 mM of trehalose dihydrate. The pharmaceutical composition can comprise 0.05% of polysorbate 80. The pharmaceutical composition can comprise 25 mM of histidine / histidine HCl. The pharmaceutical composition can comprise 150 mg / mL of the IFNAR1 inhibitor, 50 mM of lysine HCl, 130 mM of trehalose dihydrate, 0.05% of polysorbate 80, and 25 mM of histidine / histidine HCl.

[0256] The anifrolumab or its functional variant can be included in a pharmaceutical composition. The pharmaceutical composition may comprise from about 150 mg / ml to 200 mg / ml of anifrolumab or its functional variant, from about 25 mM to 150 mM of lysine salt, and a carrier-free excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or its functional variant. The pharmaceutical composition may comprise 50 mM of lysine HCl. The pharmaceutical composition may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition may comprise 0.05% of polysorbate 80. The pharmaceutical composition may comprise 25 mM of histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or its functional variant, 50 mM of lysine HCl, 130 mM of trehalose dihydrate, 0.05% of polysorbate 80, and 25 mM of histidine / histidine HCl.

[0257] The unit dose may comprise from about 150 mg / ml to 200 mg / ml of anifrolumab or its functional variant, from about 25 mM to 150 mM of lysine salt, and a carrier-free excipient. The unit dose may comprise 150 mg / mL of anifrolumab or its functional variant. The unit dose may comprise 50 mM of lysine HCl. The unit dose may comprise 130 mM of trehalose dihydrate. The unit dose may comprise from about 150 mg / ml to 200 mg / ml of anifrolumab or its functional variant, from about 25 mM to 150 mM of lysine salt, and a carrier-free excipient. The unit dose may comprise 150 mg / mL of anifrolumab or its functional variant. The unit dose may comprise 50 mM of lysine HCl. The unit dose may comprise 130 mM of trehalose dihydrate. The unit dose may comprise 0.05% of polysorbate 80. The unit dose may comprise 25 mM of histidine / histidine HCl. The unit dose may comprise 150 mg / mL of anifrolumab or its functional variant, 50 mM of lysine HCl, 130 mM of trehalose dihydrate, 0.05% of polysorbate 80, and 25 mM of histidine / histidine HCl.

[0258] The pharmaceutical composition may comprise from about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, from about 25 mM to 150 mM of a lysine salt, and a vehicle-free excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM of lysine HCl. The pharmaceutical composition may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition may comprise from about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, from about 25 mM to 150 mM of a lysine salt, and a vehicle-free excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM of lysine HCl. The pharmaceutical composition may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition may comprise 0.05% of polysorbate 80. The pharmaceutical composition may comprise 25 mM of histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof, 50 mM of lysine HCl, 130 mM of trehalose dihydrate, 0.05% of polysorbate 80, and 25 mM of histidine / histidine HCl.

[0259] A stable formulation suitable for administration to a subject and comprising anifrolumab is described in detail in U.S. Patent 10125195 B1, which is incorporated herein by reference in its entirety.

[0260] 4.7. Steroids

[0261] Many patients with lupus (e.g., SLE) receive corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Anifrolumab allows for the tapering (steroid sparing) of corticosteroids (glucocorticoids) in patients with lupus (e.g., SLE). The treatment method or method may include administering a corticosteroid to the subject, optionally wherein the corticosteroid is an oral corticosteroid. The method may include tapering the dose of the corticosteroid administered to the subject (steroid sparing). The method may include 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. The second dose of the corticosteroid may be about 7.5 mg prednisone equivalent or less (see Table 5-4). The second dose of the corticosteroid may be 5 mg prednisone equivalent or less. The method or treatment method may include administering the second dose of the corticosteroid once daily. The first dose of the corticosteroid may be about 10 mg prednisone equivalent. The method may include tapering 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 may include administering the second dose of the corticosteroid once daily. The method may allow for the administration of a reduced dose of the corticosteroid for several weeks. The second dose of the corticosteroid may be administered for at least 24 weeks. The second dose of the corticosteroid may be administered for at least 28 weeks.

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

[0263] The method may include steroid tapering in a subject, wherein the dose of steroid administered to the subject is tapered from a pre-tapering dose at baseline to a post-tapering dose. The post-tapering dose may be ≤ 7.5 mg / day of prednisone or prednisone equivalent. The pre-tapering dose may be 20 mg / day of prednisone or prednisone equivalent. The steroid may include glucocorticoids. The steroid may include oral glucocorticoids. The steroid may be selected from the group consisting of: hydrocortisone, mometasone, fluticasone, fluocinonide, fluocinolone, acetonide fluocinolone, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, clocortolone, dihydrocortisone, alclometasone, amcinonide, diflucortolone valerate, flucortolone, fluprednidene, fluandrenolone, fluorometholone, halcinonide, ultrabetasol, desonide, diflorasone, flurandrenolide, fluocinonide acetate, prednicarbate, desoxymethasone, fluprednisolone, prednisone, azelastine, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide acetate, halopredone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, prednisolone, prednisolone 21-phosphate, clobetasol propionate, triamcinolone acetonide, or a mixture thereof. The steroid may be prednisone.

[0264] 4.8. Device

[0265] The invention also relates to an injection device comprising a unit dose of the invention or a pharmaceutical composition for any use of the 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 anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise about 120 mg of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the pharmaceutical composition in the injection device may be about 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 from about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, from about 25 mM to 150 mM of a lysine salt, and a load-free excipient. The pharmaceutical composition in the injection device may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise 50 mM of lysine HCl. The pharmaceutical composition may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition in the injection device may comprise from about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, from about 25 mM to 150 mM of a lysine salt, and a load-free excipient. The pharmaceutical composition in the injection device may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM of lysine HCl. The pharmaceutical composition in the injection device may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition in the injection device may comprise 0.05% of polysorbate 80. The pharmaceutical composition in the injection device may comprise 25 mM of histidine / histidine HCl. The pharmaceutical composition in the injection device may comprise 150 mg / mL of anifrolumab or a functional variant thereof, 50 mM of lysine HCl, 130 mM of trehalose dihydrate, 0.05% of polysorbate 80, and 25 mM of histidine / histidine HCl.

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

[0268] The doses elucidated by the inventors provide an advantage in terms of APFS administration because the maximum volume typically administered by an APFS device is 1 ml. Doses in the range of >105 mg to <155 mg can be easily accommodated in a volume of about 0.8 ml, making one or more of the doses of the present invention particularly suitable for APFS and AI administration. For comparison, due to the viscosity of anifrolumab, larger doses (especially doses >150 mg) need to be administered in a volume >1 ml and require at least two SC injections, which is inconvenient for the patient and requires multiple prefilled devices.

[0269] The delivery device can be a single-use disposable system that is designed to be able to manually administer a dose subcutaneously (SC).

[0270] The present invention also relates to an injection device comprising a unit dose. The unit dose may comprise anifrolumab or a functional variant thereof that is > 105 mg (i.e., at least 105 mg) and < 150 mg (i.e., less than 150 mg). The unit dose may comprise anifrolumab or a functional variant thereof that is ≤ 135 mg (i.e., 135 mg or less). The unit dose may comprise about 120 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device may comprise 120 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device may consist essentially of anifrolumab or a functional variant thereof that is > 105 mg and < 150 mg. The unit dose in the injection device may consist essentially of anifrolumab or a functional variant thereof that is ≤ 135 mg. The unit dose in the injection device may consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the unit dose in the injection device may be about 150 mg / ml. The volume of the unit dose in the injection device may be less than 1 ml. The volume of the unit dose in the injection device may be from 0.5 ml to 1 ml. The concentration of the unit dose may be about 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose in the injection device may comprise a formulation of about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, about 25 mM to 150 mM lysine salt, and a carrier-free excipient. The unit dose in the injection device may comprise a formulation of 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, 25 mM to 150 mM lysine salt, and a carrier-free 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 may be about 5.9.

[0271] The injection device may be a pre-filled syringe (PFS). The injection device may be an attached pre-filled syringe (AFPS). The injection device may be an auto-injector (AI).

[0272] 4.9. Kit

[0273] The present invention also relates to a kit comprising the unit dose of the present invention and instructions for use, wherein the instructions for use comprise instructions for subcutaneous administration of the unit dose to a subject. The present invention also relates to a kit comprising a pharmaceutical composition for use in the uses of the present invention, wherein the instructions for use comprise instructions for subcutaneous administration of 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 subcutaneous administration of the unit dose or pharmaceutical composition to the subject.

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

[0276] The instruction manual may specify the injection device, unit dose, and / or pharmaceutical composition for use in any method of the present invention.

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

[0278] 4.10. Inhibitors of type I IFN-mediated signaling

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

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

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

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

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

[0284] The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

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

[0286] 5. Definition

[0287] 5.1. Inhibitor of type I IFN signaling

[0288] 5.1.1. Anifrolumab

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

[0290] Table 5-1: Sequences

[0291]

[0292]

[0293] Anifrolumab 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 IFN. Anifrolumab also induces the internalization of IFNAR1, thereby reducing the level 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. Inhibiting type I IFN blocks plasma cell differentiation and normalizes peripheral T cell subsets, restoring the balance between adaptive and innate immunity disrupted in SLE.

[0294] In adult patients with SLE, anifrolumab administered at a dose of ≥300 mg by intravenous infusion every 4 weeks demonstrated sustained neutralization (≥80%) of the 21-gene type I interferon pharmacodynamic (PD) marker in the blood. This inhibition occurred early in the later 4 weeks and was maintained or further inhibited during the 52-week treatment period. After discontinuation of anifrolumab 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. Anifrolumab 150 mg IV showed <20% gene marker inhibition at early time points and reached a maximum of <60% at the end of the treatment period.

[0295] “Anifrolumab” is an immunoglobulin that comprises HCDR1, HCDR2, and HCDR3 (or functional variants thereof) that are SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, respectively; and LCDR1, LCDR2, and LCDR3 (or functional variants thereof) that are SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively. Anifrolumab is an immunoglobulin that comprises VH of SEQ ID NO:1 and VL of SEQ ID NO:2.

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

[0297] Functional variants of anifrolumab are sequence variants that perform the same functions as anifrolumab. Functional variants of anifrolumab are variants that bind to the same targets as anifrolumab and have the same effector functions as anifrolumab. Functional anifrolumab variants include antigen-binding fragments of anifrolumab, as well as antibodies and immunoglobulin derivatives of anifrolumab. Functional variants include biosimilars and interchangeable products. The terms biosimilar and interchangeable product 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, e.g., anifrolumab) and has no clinically meaningful differences from the reference product in terms of pharmacokinetics, safety, and efficacy. Whether there are clinically meaningful differences in a biosimilar can be evaluated in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and in the assessment of clinical immunogenicity. An interchangeable product is a biosimilar that is expected to produce the same clinical outcome as the reference product in any given patient.

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

[0299] Variants of a reference (anifrolumab) antibody may include: 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 anifrolumab (e.g., IFNAR) and optionally binds with the same affinity.

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

[0301] When compared to the corresponding reference (anifrolumab) antibody, the variant antibody can have up to a total of 5, 4, or 3 amino acid differences in its framework regions, provided that there are at most 2 (optionally at most 1) amino acid differences in each framework region. Optionally, when compared to the corresponding reference (anifrolumab) antibody, the variant antibody has up to a total of 2 (optionally at most 1) amino acid differences in its framework regions, provided that there are at most 2 amino acid differences in each framework region. Optionally, when compared to the corresponding reference (anifrolumab) antibody, the variant antibody has up to a total of 2 (optionally at most 1) amino acid differences in its framework regions, provided that there is at most 1 amino acid difference in each framework region.

[0302] The variant antibody can 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 up to 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region); and when compared to the light chain sequence herein, the light chain has up to 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region); wherein the variant antibody binds the same target antigen (e.g., IFNAR) as the reference (anifrolumab) 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 can 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 up to 7 amino acid differences (at most 1 amino acid difference in each CDR and at most 1 amino acid difference in each framework region); and when compared to the light chain sequence herein, the light chain has up to 7 amino acid differences (at most 1 amino acid difference in each CDR and at most 1 amino acid difference in each framework region); wherein the variant antibody binds the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody and preferably binds with the same affinity.

[0304] Functional variants of anifrolumab 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 containing the VH amino acid sequence SEQ ID NO:13. Functional variants include antibodies containing the VH amino acid sequence SEQ ID NO:16. Functional variants include antibodies containing the VL amino acid sequence SEQ ID NO:14. Functional variants include antibodies containing the VL amino acid sequence SEQ ID NO:15. Functional variants include antibodies containing the VH amino acid sequence SEQ ID NO:16. Functional variants include antibodies containing the VH sequence SEQ ID NO:13 and the VL amino acid sequence SEQ ID NO:16. Functional variants include antibodies containing the VH sequence SEQ ID NO:13 and the VL amino acid sequence SEQ ID NO:15. Functional variants include antibodies containing the VH sequence SEQ ID NO:16 and the VL amino acid sequence SEQ ID NO:15. Functional variants include antibodies containing the VH sequence SEQ ID NO:16 and the VL amino acid sequence SEQ ID NO:14.

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

[0309] Functional variants of anifrolumab 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 can be a monoclonal antibody comprising the VH amino acid sequence SEQ ID NO:17. The anti-IFNAR antibody can comprise the VL amino acid sequence SEQ ID NO:18.

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

[0314] 5.1.2. Certolizumab

[0315] Certolizumab (MEDI-545) is a fully human immunoglobulin G1κ monoclonal antibody that binds and neutralizes most IFN-α subtypes [7]. Certolizumab is described in U.S. Patent 7,741,449, which is incorporated herein by reference in its entirety. In a Phase IIb, randomized, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE), the efficacy and safety of certolizumab were evaluated. 431 patients were randomly assigned and received intravenous certolizumab (200 mg, 600 mg, or 1200 mg) or placebo monthly in addition to standard-of-care medications. The primary efficacy endpoint was the percentage of patients who achieved a SLE Responder Index response at week 52. A greater percentage of patients who received certolizumab (all doses) reached 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(4) if all of the following criteria are met:

[0323] · The decrease in SLEDAI-2K relative to baseline is ≥ 4 points;

[0324] · Using BILAG-2004, there is no new organ system involvement compared to baseline, as defined by 1 or more BILAG-2004A or 2 or more

[0325] · BILAG-2004 B items;

[0326] · According to the 3-point PGA VAS, the subject's lupus disease activity does not worsen relative to baseline, as defined by an increase of ≥ 0.30 points.

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

[0328] · The decrease in SLEDAI-2K relative to baseline is ≥ X points;

[0329] · Using BILAG-2004, there is no new organ system involvement compared to baseline, as defined by 1 or more BILAG-2004A or 2 or

[0330] · More BILAG-2004 B items;

[0331] · According to the 3-point PGA VAS, the subject's lupus disease activity does not worsen relative to baseline, as

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

[0333] The SLEDAI-2K disease activity index consists of a series of organ manifestations each with a defined presence. A certified investigator or designated physician will complete the SLEDAI-2K assessment and determine whether each manifestation was "present" or "absent" in the past 4 weeks. This assessment also includes collecting blood and urine to evaluate the laboratory categories of SLEDAI-2K.

[0334] The SLEDAI-2K assessment consists of 24 lupus-related items. It is a weighted tool where descriptors are multiplied by the "weights" of specific organs. For example, the kidney descriptor is multiplied by 4, and the central nervous descriptor is multiplied by 8, and the weighted organ manifestations are totaled to a 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 transformation index for 9 organ systems (general condition, mucocutaneous, neuropsychiatric, musculoskeletal, heart and lungs, gastrointestinal, eyes, kidneys, and blood), which can capture the severity of changes in clinical manifestations in SLE patients. By design, it has ordinal levels and no global score; rather, it records the disease activity across different organ systems at a glance by comparing the most recent 4 weeks with the 4 weeks prior to it. It is based on the principle of intention-to-treat by doctors and classifies disease activity into 5 different levels from A to E:

[0337] · Grade A indicates very active disease, requiring immunosuppressive drugs and / or a prednisone dose of > 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 disease stability

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

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

[0342] Although BILAG-2004 was developed based on the principle of intention-to-treat, treatment is not related to the scoring index. Only the presence of active manifestations affects the score.

[0343] 5.3.4. BICLA (BILAG-Based Composite Lupus Assessment)

[0344] BICLA is a composite index initially derived by expert consensus of disease activity indices. The BICLA response is defined as (1) at least one grade improvement in the baseline BILAG score in all body systems with moderate or severe disease activity at entry (e.g., all A (severe disease) scores decrease to B (moderate), C (mild), or D (inactive) and all B scores decrease 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 deterioration (≤10%) in the physician global assessment; and (5) no treatment failure (initiation of off-protocol treatment).

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

[0346] · All baseline BILAG-2004 A's are reduced to B / C / D and all baseline BILAG-2004 B's are reduced to C / D, and there is no BILAG-2004 worsening in other organ systems, as defined by 1 new BILAG-2004 A or more than 1 new BILAG-2004 B item;

[0347] · The SLEDAI-2K does not worsen relative to baseline, as defined by an increase in SLEDAI-2K relative to baseline >0 points;

[0348] · The lupus disease activity of the subject does not worsen relative to baseline according to the 3-point PGA VAS, as defined by an increase ≥0.30 points;

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

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

[0351] CLASI is a validated index for assessing skin lesions in SLE and consists of 2 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, scale / hypertrophy, mucosal lesions, recent hair loss, and non-scarring alopecia. The damage score represents hyperpigmentation, scarring / atrophy / panniculitis, and scalp scarring. The subject is asked whether the hyperpigmentation has persisted for 12 months or longer, in which case the hyperpigmentation score is doubled. Each of the above parameters is measured at 13 different anatomical locations specifically included because these anatomical locations are most frequently involved 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 mean concentration.

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

[0358] C 最小 : Minimum plasma drug concentration.

[0359] C 谷 : Drug concentration in plasma at steady state immediately before administration of the next dose. Trough plasma concentration (concentration measured at the end of the dosing interval at steady state [obtained immediately before the next administration]).

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

[0361] Linear Pharmacokinetics: When the concentration of a drug in blood or plasma increases proportionally with increasing dose and the elimination rate is proportional to the concentration, the drug is considered to exhibit linear pharmacokinetics. The clearance and volume of distribution of these drugs are dose-independent.

[0362] Nonlinear pharmacokinetics: In contrast to linear pharmacokinetics, the concentration of a drug in blood or plasma does not increase proportionally with increasing dose. The clearance and volume of distribution may vary depending on 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 obtainable by SC administration and IV administration can be compared based on the plasma drug concentration-time curve (AUC), which reflects the exposure of the body to the antibody after administration of the drug dose. For example, during a clinical study, the plasma drug concentration-time curve of a patient can be plotted by measuring the plasma concentration at several time points. If a computer simulation modeling method is employed, 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. Suitable methods are 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 Inc., 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 the maximum serum concentration (t 最大 ). All data were analyzed using the SAS system V.9.2 (SAS Institute Inc., Cary, NC, USA).

[0365] Conveniently, the ratio of the AUC obtained by SC administration to the AUC obtained by IV administration (AUC SC / AUC IV ) can be calculated, providing a numerical comparison of the bioavailability provided by the dosing route. The "AUC ratio" as referred to herein means the AUC SC / AUC IV ratio. To provide statistical robustness, the AUC ratio is preferably the mean, median, or mode (e.g., mean) calculated from multiple replicate experiments (or computer simulations). The reference examples demonstrate this method. The mean, median, or mode (preferably the mean) can be derived by aggregating data obtained from multiple patients (or multiple computer simulations). Thus, the AUC ratio can reflect the mean, median, or mode (preferably the mean) AUC of multiple patients.

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

[0367] 5.6. Type I IFN-mediated diseases

[0368] Type I IFN-mediated diseases can be defined as a disease characterized by the 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). The type I IFN-mediated disease 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 with healthy subjects, the type I IFN-mediated diseases can be characterized by an association with a high 21-gene IFNGS. Compared with healthy subjects, the type I IFN-mediated diseases can be characterized by an association with a high 4-gene-IFNGS. Compared with healthy subjects, the type I IFN-mediated diseases can be characterized by an association with a high 5-gene-IFNGS.

[0370] 5.6.1. Myositis

[0371] Like SLE, myositis (also known as idiopathic inflammatory myopathy (IMM)) is also a connective tissue disease severely affected by type 1 IFN. Myositis is a rare, progressive, and debilitating disease. Myositis is a type I IFN-mediated disease. In particular, type I IFN-induced genes are overexpressed in the whole blood and muscle of myositis patients [10,11]. Type I IFN gene expression is associated with myositis disease activity [10,11]. In addition, plasmacytoid DCs (pDCs) secreting type I IFN are present in the target tissues of myositis patients [12,13]. In addition, myositis is de novo induced or exacerbated by IFN treatment [13,14]. Finally, in DM and PM, the anti-IFN-α monoclonal antibody siltuximab neutralizes IFN gene expression in muscle, which is associated with improved muscle function (see examples, section 11.4). Clinical manifestations such as fatigue, rash, photosensitivity, and joint pain are common in both lupus and myositis.

[0372] 5.6.2. Scleroderma

[0373] Like SLE, systemic sclerosis (scleroderma, SSc) is also a connective tissue disease with severe involvement of type 1 IFN. Systemic sclerosis is a multi-system autoimmune disease characterized by abnormal function and structure of small blood vessels and fibrosis of the skin and internal organs. The type 1 IFN pathway is a pathogenic driver of SSc. Evidence for the central role of type I IFN in the pathogenesis of SSc (inflammatory and fibrotic processes) includes multiple relevant genetic polymorphisms that are associated with the type 1 IFN pathway in SSc

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

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

[17] . In addition, digital ulcers resulting from SSc small-vessel vasculopathy are associated with high IFN signatures

[18] .

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

[0375] This interferon gene signature (IFNGS) is defined as a set of specific gene transcripts whose expression increases once the IFN receptor (IFNAR1) is activated by the 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 siltuximab trials to provide different readouts: the 4-gene interferon gene signature is a peripheral blood signature derived from genome-wide gene expression studies and further validated by quantitative PCT testing (developed to specifically measure IFN gene expression based on 4 genes). It was further used at baseline to understand whether the disease or the disease in a particular patient is driven by type I IFN. The 21-interferon gene signature is a peripheral blood signature derived from genome-wide gene expression studies. It was used to study the pharmacodynamic effects of Saphnelo by providing a measure of the inhibition of type 1 interferon signaling after treatment.

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

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

[0377] The 4-gene IFNGS score is calculated by measuring the expression of IFI27, IFI44, IFI44L, and RSAD2. The 5-gene IFNGS score is calculated by measuring the expression of IFI27, RSAD2, IFI44, IFI44L, and IFI6. By Figure 28The measurement of the genes shown in is used to calculate the 21-gene IFNGS score. Gene expression can be measured by detecting mRNA in the whole blood or tissues of a subject. The IFNGS (4-gene, 5-gene or 21-gene) score can be detected by measuring the IFNGS gene expression (e.g., mRNA) in the blood or tissues of a subject and comparing these gene expression levels with the expression of house-keeping genes or control genes (e.g., ACTB, GAPDH and 18S rRNA) in the blood or tissues.

[0378] 6. Example 1: Anifrolumab in the Clinic

[0379] The safety of anifrolumab has been evaluated in 8 blind or open-label intravenous (IV) and subcutaneous (SC) studies: 6 studies in patients with SLE (Study 05, Study 04, Study 1013, Study 1145 and Study 08), 1 study in patients with systemic sclerosis (SSc) (Study MI-CP180), and 1 study in healthy volunteers (Study 06) (Table 6-1). In these studies, two (Study 08 and Study 06) used SC anifrolumab administration. Two studies are in progress: 1 study in patients with SLE (Study 09) and 1 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 given in Morand et al. 2020

[21] , which is incorporated herein by reference in its entirety. Tanaka et al., 2020

[22] provides a complete overview of the evidence of the clinical efficacy of intravenous anifrolumab in SLE, which is incorporated herein by reference in its entirety.

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

[0385] 7.1. Efficacy

[0386] The primary evaluation of the efficacy of anifrolumab was based on data from 3 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 3 studies was to evaluate the effect of anifrolumab on overall disease activity compared with placebo. Secondary objectives were selected to further characterize the efficacy of anifrolumab compared with placebo, such as the ability to reduce glucocorticoid use, the effect on organ-specific endpoints (cutaneous SLE activity and joints), and the relapse rate.

[0387] In 3 double-blind, global Phase 2 / 3 studies (studies 04, 05, and 1013), the efficacy of anifrolumab 300 mg IV Q4W was observed in patients with moderate to severe SLE across a range of important clinical endpoints. Anifrolumab had an early and sustained effect on overall disease activity, was able to taper corticosteroid use to a clinically beneficial level (≤7.5 mg / day) and maintain that level through Week 52, which had an early and sustained benefit on cutaneous activity and resulted in a clinically meaningful reduction in the relapse rate.

[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 anifrolumab 300 mg and 1000 mg compared with placebo in adult patients with moderate to severe active SLE who were on standard of care (SOC) therapy. During the trial, tapering of OCS was encouraged but left to the discretion of the investigator. The primary efficacy endpoint was evaluated as a reduction in SLE disease activity measured by SRI(4), with continued reduction in OCS use after 24 weeks of treatment.

[0390] At Week 24, more patients receiving anifrolumab (34.3% and 28.8% for patients receiving 300 mg [n = 99] and 1000 mg [n = 104], respectively) achieved the primary endpoint of the composite of SRI(4) response with sustained OCS reduction compared to placebo (17.6% [n = 102]; p = .014 and p = .063 for 300 mg and 1000 mg, respectively, versus placebo). 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 anifrolumab 300 mg and 1000 mg, respectively, achieving the primary endpoint, compared to 13.2% of patients receiving placebo. Among patients with low IFNGS at baseline, the corresponding response rates of patients achieving the primary endpoint were 29.2%, 30.8%, and 30.8% for anifrolumab 300 mg, anifrolumab 1000 mg, and placebo, respectively.

[0391] Study 1013

[19] is described in more detail in Furie et al 2017, 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 (Treating Uncontrolled Lupus via the IFN Pathway) program included 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 anifrolumab or placebo IV Q4W from Week 0 to Week 48, for a total of 13 doses. The primary endpoint was evaluated at Week 52. In both studies, patients receiving baseline oral prednisone ≥10 mg / day or equivalent were required to undergo a gradual OCS taper trial from Week 8 to Week 40 until a dose ≤7.5 mg / day was achieved, which had to be maintained until Week 52. Both studies utilized 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 dose of 300 mg of anifrolumab selected every 4 weeks (Q4W) was based on the safety and efficacy results of the mid - analysis of Phase 2b Study 1013, in which two doses of anifrolumab (300 mg and 1000 mg) were evaluated relative to placebo and dose - response modeling and simulation (as described in U.S. Patent 9,493,570, corresponding to PCT Publication WO 2013 / 188494, which is incorporated herein by reference in its entirety). In the mid - analysis of the Phase 2b study, clinically meaningful benefits were observed with the 300 - mg dose, while no additional benefits were seen with the 1000 - mg dose. In addition, a higher proportion of subjects in the 1000 - mg group reported recurrence of herpes zoster compared to 300 mg. Considering the comparable efficacy between the 300 - mg and 1000 - mg anifrolumab 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 profile 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 anifrolumab 300 mg (TULIP - 1 and TULIP - 2), anifrolumab 150 mg (TULIP - 1 only), or placebo intravenously Q4W for 48 weeks, concomitant with standard therapy. Randomization was stratified according to the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI - 2K) score at screening (<10 vs. ≥10), 4 - gene IFNGS status (high vs. low), and oral glucocorticoid dose at baseline (<10 vs. ≥10 mg prednisone or equivalent per day). TULIP - 1 and TULIP - 2 trials had consistent efficacy variables, safety variables, assessment frequencies, and inclusion / exclusion criteria (Figure 1). -1 Prednisone or equivalent).

[0396] 7.1. The Study 04 (TULIP I, NCT02446912)

[0397] Study 04 compared anifrolumab 150 mg and 300 mg with placebo in adult patients with moderate to severe active SLE who were on SOC treatment. Efficacy was evaluated based on the reduction of SLE disease activity as measured by the SRI(4) response.

[0398] In Study 04, the proportion of patients achieving the primary outcome of an SRI(4) response at Week 52 was comparable between anifrolumab 300 - mg (84 / 180 [47%]) and the placebo group (79 / 184 [43%]; difference - 3.9; 95% CI - 6.3, 14.1; p =.45) 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] Anifrolumab also had significant benefits for sustained OCS reduction and reduction of skin disease severity (reduction of CLASI score) ( Figure 2 ). Among patients receiving prednisone ≥10 mg / day or equivalent at baseline, 51.7% (45 / 87) of patients treated with anifrolumab and 30.1% (25 / 83) of patients receiving placebo achieved 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 (CLASI score ≥10) at baseline, 49.0% (24 / 49) of patients receiving anifrolumab and 25.0% (10 / 40) of patients receiving placebo had 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 pre-specified analysis, the BICLA response definition requires improvement in all affected organ systems at baseline (reducing all baseline BILAG-2004A and B area scores to B / C / D and C / D, respectively), and no new relapses in the remaining BILAG-2004 organ systems. At baseline, the organ areas most affected in the enrolled patients were mucocutaneous and musculoskeletal (>80% affected by BILAG-2004A or B). Baseline BILAG-2004A or B scores were less frequent in the cardiorespiratory, constitutional, renal, neuropsychiatric, gastrointestinal, hematological, and ophthalmic regions. Thus, by definition, responses occurred in all of these affected BILAG-2004 organ systems in patients achieving a BICLA response. In the anifrolumab group, the annual recurrence rate based on BILAG-2004 was 0.43, compared with 0.64 in the placebo group (adjusted 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) in the anifrolumab group and 37.5% (34 / 90) in the placebo group had a ≥50% reduction in the swollen and tender joint count at week 52 (adjusted difference 4.7%; 95% CI -10.6, 20.0; adjusted p =.55).

[0405] The results of Study 05 were given in Morand et al 2020

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

[0406] 7.1.4. Efficacy Conclusions

[0407] Based on the pre-specified BICLA primary endpoint, Study 05 provided strong evidence for the efficacy of anifrolumab in patients with moderate to severe active SLE who were treated with SOC. The combined data from all three clinical trials further supported the efficacy of anifrolumab 300 in these patients across a range of clinically meaningful endpoints. Importantly, for the BICLA response rate at Week 52, anifrolumab 300 mg had a consistent benefit across all studies; a treatment difference >16% was observed compared to placebo in the BICLA response rate of all three studies. Additionally, in TULIP-2 and MUSE, anifrolumab demonstrated treatment benefit for SRI(4) response. Consistent, supportive efficacy evidence for anifrolumab 300 (e.g., reduced OCS, improved CLASI score, reduced flares) across many key secondary endpoints was related to the overall magnitude of the anifrolumab treatment effect, particularly given the heterogeneity of SLE manifestations.

[0408] Anifrolumab demonstrated efficacy in reducing flares, and the treatment effect of reducing disease activity began to emerge as early as 8 - 12 weeks after treatment initiation when a numerical separation in the BICLA response rate >10% (in favor of anifrolumab 300 mg) was observed and was maintained over the 52-week treatment course. Additionally, the steroid-sparing effect of anifrolumab reduced the cumulative risk of long-term organ damage associated with SLE. The improvement in anifrolumab treatment in skin manifestations (CLASI activity score) was also particularly important as they are common and often present as visible lesions on the face, head, and neck.

[0409] Tanaka et al., 2020

[22] provided a comprehensive overview of the evidence for the clinical efficacy of intravenous anifrolumab in SLE, and this literature is incorporated herein by reference in its entirety.

[0410] 7.2. Safety

[0411] In all three efficacy studies, the safety and tolerability of anifrolumab were consistent and generally similar. In all studies, the percentage of patients who had any adverse event (AE) in the anifrolumab treatment groups was 85% to 89%, and for the placebo groups it was 77% to 84%. The most common AEs included upper respiratory tract infection, nasopharyngitis, and infusion-related reactions. Anifrolumab infusions were generally well tolerated, and there was one report of anaphylaxis in a patient receiving 150 mg of anifrolumab in TULIP-1. A small number of patients had anaphylaxis, and most of the infusion-related AEs were not serious and were of mild or moderate intensity. In patients treated with anifrolumab, 8%–16% had serious AEs (SAEs), and in patients receiving placebo, 16–19% had SAEs. There was one death during the treatment period in each of TULIP-1 and TULIP-2, both in the anifrolumab treatment arms and both due to pneumonia. There was also one death in MUSE in a patient who received 1 dose of 1000 mg of anifrolumab and had acute colitis. In TULIP-2 and MUSE, the percentage of patients with AEs leading to discontinuation was smaller for patients receiving anifrolumab compared with placebo, but in TULIP-1, the percentage of patients with AEs leading to discontinuation was larger in patients treated with anifrolumab (6% compared with 3% for placebo).

[0412] The incidence of herpes zoster was increased in the anifrolumab treatment groups (5%–7%) compared with the placebo groups (1%–2%); most were cutaneous, not serious, and did not lead to discontinuation. All patients responded to SOC treatment and 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 evidence on the safety and tolerability of anifrolumab is provided in Tanaka et al., 2020

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

[0414] 7.3. Conclusions

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

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

[0417] In all three studies, a greater number of patients received anifrolumab compared to placebo, and consistently achieved BICLA responses, as did the sustained reduction in OCS and improvement in CLASI. In MUSE and TULIP-2, a higher percentage of patients achieved an SRI(4) response with anifrolumab compared to placebo. In the efficacy studies, the safety profiles of anifrolumab were similar, with 8%-16% of anifrolumab-treated patients and 16%-19% of placebo recipients experiencing SAEs. In all three studies, the incidence of herpes zoster was increased in the anifrolumab treatment group compared to the placebo group, but most occurred on the skin and responded to SOC treatment. The clinical trial evidence discussed above indicates that in patients with active SLE, anifrolumab 300mg administered IV Q4W is superior to placebo in achieving the composite endpoint of disease activity response, as well as reducing the OCS dose, skin disease severity, and recurrence rate. Therefore, from the clinical studies of IV anifrolumab administration, it was concluded that 300mg IV Q4W is the optimal dose compared to 150mg Q4W. Increasing the dose to 1000mg Q4W was found to only provide incremental benefits, and a dose-related increase in herpes zoster infection was observed ( Figure 4 ).

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

[0419] 8.1. Phase I study MI-CP180 of IV anifrolumab in SSc patients

[0420] After weight-based single-dose administration, the mean anifrolumab serum concentration was as Figure 5A shown. After single-dose administration, anifrolumab exhibited non-linear-linear PK at lower dose levels (<10.0mg / kg) in both high-dose and low-dose IFNGS patients. A dose-proportional increase in C 最大 was observed, but the increase in AUC exceeded dose proportionality between 0.1mg / kg and 10.0mg / kg. In the high-dose cohort, the anifrolumab t1 / 2 was prolonged more. At the highest dose level (20.0mg / kg) of the study, the terminal t1 / 2 was approximately 12 days.

[0421] 8.2. Phase I (Study 06) of IV and SC anifrolumab in healthy volunteers

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

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

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

[0425] This study explored the clinical pharmacology, safety, and exploratory efficacy of subcutaneous anifrolumab. The pharmacokinetics in Study 08 were consistent with the high bioavailability in Study 06 (healthy volunteers) and the high CL in high IFNGS SLE patients. Anifrolumab administered subcutaneously every 2 weeks to patients with SLE and moderate to severe cutaneous manifestations had supra-dose-proportional nonlinear pharmacokinetics and neutralized the type I interferon gene signature in a dose-dependent manner ( Figure 6B and Figure 6C ). In particular, subcutaneous administration of 150 mg or 300 mg anifrolumab every 2 weeks for 50 weeks had nonlinear pharmacokinetics, whereby C 谷 concentrations exceeded dose proportion. The number of adverse events with subcutaneous anifrolumab was similar to the number observed after intravenous administration in large studies in SLE patients.

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

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

[0427] Study 08 was limited by a small sample size and was unable to draw conclusions about the biological effects of the study drug (e.g., complement C3 or C4 concentrations) or its clinical efficacy. Inclusion of only patients with high type I interferon gene signatures and active skin disease also limited 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. Conclusions

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

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

[0431] 9.1. Objectives

[0432] To detect the optimal dosing regimen for subcutaneous administration of anifrolumab, the inventors developed population PK and PK / PD models, aiming to utilize existing human clinical trials. The 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 objective was to detect a subcutaneous dose that provides equivalent exposure to the standard 300 mg IV (Q4W) dose while allowing for more routine dosing at a lower dose. This was based on the understanding that 300 mg IV Q4W provides the optimal clinical PK profile and clinical efficacy (e.g., achieving a BICLA response), as reported in Furie et al. 2017

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

[0434] 9.2. Results

[0435] 9.2.1. Initial Selection of Anifrolumab Subcutaneous Doses

[0436] In the initial analysis, the inventors identified a specific dosing regimen that predicted to provide equivalent exposure achievable with 300 mg Q4W IV. Initially, it was found that a dosing regimen of 105 mg subcutaneously weekly (QW) could provide an AUC ratio of close to (or slightly greater than) 1 ( Figure 7A ), even with an expected approximately 7% reduction in bioavailability compared to that reported by Tummal et al. 2018 [8] (which is hereby incorporated by reference in its entirety) to account for the inter-individual variability in bioavailability ( Figure 7B ). 105 mg subcutaneously QW was shown to provide median trough concentrations and IFNGS inhibition equivalent to or improved compared to the comparator 300 Q4W mg IV dose ( Figure 8A and Figure 8B)。From these initial analyses, it appears that the anifrolumab dose of 105 mg QW should be selected, which is equivalent to 300 mg Q4W, thus having the best efficacy / risk curve for treating SLE patients. Importantly, these analyses assume that the 300 mg IV dose is at or near the plateau of the anifrolumab dose-response curve, i.e., increasing the dose beyond 300 mg IV Q4W will not bring any meaningful benefits to patients, especially considering the increased risk of herpes zoster infection at high doses.

[0437] 9.2.2. Revised Selection of Anifrolumab Subcutaneous Doses

[0438] Therefore, based on the data available from the MUSE study, Study 06, and Study 08, the inventors first considered that 105 mg QW was the optimal SC anifrolumab dose for treating type I IFN-mediated diseases. However, to confirm the selection of the 105 mg SC dose, the inventors further analyzed the data from the TULIP I (Study 04) and TULIP II (Study 05) clinical trials.

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

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

[0441] In summary, from the initial analysis, it appeared that the subcutaneous dose of 105 mg QW anifrolumab would achieve at least similar efficacy to 300 mg IV Q4W. However, surprisingly, after further analysis by the inventors of the newly available data from further studies, it was found that the concentration of this once-weekly (QW) dose could increase, but would not reach the maximum threshold in terms of bioavailability and efficacy. In other words, the QW dose could be increased above 105 mg to provide higher plasma concentrations and IFNGS inhibition, and mitigate the response variability observed in SLE patients. Accordingly, the 105 mg dose is suboptimal.

[0442] The surprising additional dose-response curve data (Table 9-1) were further verified by demonstrating that the concentration of doses above 105 mg administered subcutaneously once a week increases the probability of achieving the relevant BICLA response (in patients with high IFNGS). These data demonstrate the unexpected location of the dose-response platform (e.g., subcutaneous administration), which shifts to the right when the dose is increased above 105 mg ( Figure 10B ), indicating that the maximum BICLA response can actually be achieved when the dose exceeds 105 mg, and 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 anifrolumab is highly variable

[0446] After further investigation of the bioavailability of anifrolumab, the inventors elucidated that there can be a surprisingly high level of variability in the bioavailability of anifrolumab after subcutaneous administration in different patients. The high level of variability in the bioavailability of anifrolumab was not appreciated in previous studies reporting a bioavailability > 80% after subcutaneous administration (see Example 3) [8]. In Study 08 (SLE patients, SC), the bioavailability (F1) of anifrolumab in healthy volunteers was found to be 81% using a population PK model (Table 9-2).

[0447] Table 9-2: Anifrolumab bioavailability based on healthy volunteers

[0448]

[0449] The inventors externally validated Study 08 (Ph2 SC in SLE) using the PPK model, which was developed based on healthy volunteers and SLE patients in IV studies, to determine the bioavailability in the lupus population.

[0450] In-depth analysis of Study 08 data showed that the SC administration site affects bioavailability. In particular, when estimating the bioavailability of 300 mg in the abdomen relative to IV, the bioavailability (F1) was estimated to be 85.4%, compared to 81% when not considering the injection site. Thus, compared to abdominal injection, C after thigh injection 谷 showed a downward trend ( Figure 11A and Figure 11B ). Therefore, considering the variability attributed to the injection site and the higher variability of bioavailability in lupus (SLE) patients compared to healthy volunteers, the surprising conclusion was reached that the bioavailability could actually be as low as 70%. Importantly, if the bioavailability (F1) was assumed to be 81% - 87%, then 105 mg was initially expected to provide a C equivalent to 300 mg IV 平均 ( Figure 12 ). In contrast, when the estimated bioavailability was reduced to approximately 70% or lower, the median C of the 105 mg QW subcutaneous dose 平均 dropped below 1 ( Figure 13A , Figure 13B and Table 9 - 3).

[0451] Table 9 - 3: Anifrolumab Bioavailability

[0452]

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

[0454] In addition, between 105 mg SC QW and the suboptimal IV dose of 150 mg Q4W, there was an undesirable 30% overlap in C 平均 , while only a 16% overlap was observed when the bioavailability was assumed to be 81% ( Figure 13A ). However, when using the SC120 mg dose, the overlap with the C of the 150 mg IV dose 平均 was less than the overlap with the optimal IV dose of 300 mg IV, even assuming a low bioavailability of 70% ( Figure 13B ). In addition, the 120 mg SC QW dose had the least overlap with the undesirable 1000 mg IV dose (13C), at which the risk of herpes zoster infection increases ( Figure 15)。There is an undesirable overlap between the 150 mg SC QW dose and the 1000 mg IV Q4W dose. Even more surprisingly, SC doses of 120 mg or above are expected to have better PD inhibition (Table 9-4) than the hypothesized optimal 300 mg IV dose (Table 9-5).

[0455] Therefore, 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 patients with lupus (e.g., SLE) (Table 9-4, Figure 14A , Figure 14B )。SC doses below 150 mg QW also contribute to reducing the risk of herpes zoster infection ( Figure 15 )。

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

[0457]

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

[0459]

[0460] Doses of 120 mg and 135 mg QW particularly provide a reasonable benefit-risk profile. At doses of 150 mg QW or above, safety risks increase, e.g., the risk of herpes zoster in patients increases because the 150 mg QW SC dose is equivalent to 1000 mg IV Q4W ( Figure 13C , Figure 15 )。Therefore, subcutaneous doses less than 150 mg QW and greater than 105 mg QW are determined to be preferred doses. Subcutaneous doses less than 150 mg QW and less than or equal to 135 mg are determined to be more preferred doses. A subcutaneous dose of 120 mg is determined to be the optimal dose.

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

[0462] Thus, the inventors surprisingly demonstrated that doses greater than 105 mg SC QW and less than 150 mg SC QW, particularly a dose of 120 mg QW, (a) maximize efficacy while maintaining an acceptable safety profile, (b) mitigate the impact of bioavailability variability, and (c) mitigate the impact of variability at the onset of response. Thus, doses greater than 105 mg QW are beneficial in accounting for variability in bioavailability, thereby improving treatment outcomes. Doses less than 150 mg QW mitigate 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 impact 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 impact on efficacy and safety. Surprisingly, other covariates specific to the population evaluated in the population PK model were not significant, including race / ethnicity / region, age, sex, renal / liver function tests, standard of care therapies (e.g., OCS, antimalarials, azathioprine, methotrexate, mycophenolate mofetil, mycophenolic acid, mizoribine, and NSAIDs), and drugs commonly used in SLE patients (ACE inhibitors and HMG-CoA reductase inhibitors).

[0464] 9.3. Conclusions

[0465] The inventors have demonstrated that an anifrolumab dose of <150mg Q and >105mg QW will provide a C that is at least similar or even higher than 300mg IV Q4W over 52 weeks 平均 . In lupus patients, a dose of 120mg SC QW will specifically provide efficacy that is at least equivalent to a 300mg IV Q4W dose. It is further plausibly demonstrated that a 120mg SC QW dose will provide greater efficacy than that demonstrated by a 300mg IV Q4W dose.

[0466] Based on the data presented herein, a subcutaneous dose of anifrolumab has been selected for a multicenter, randomized, double-blind, placebo-controlled Phase 3 study to evaluate the efficacy and safety of subcutaneous anifrolumab in adult SLE patients. In summary, in a completed Phase 2 SC study of SLE patients with high Type I IFN test results and active skin disease, two doses of SC anifrolumab (150mg and 300mg [Q2W] every two weeks) were evaluated (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 anifrolumab SC administration was evaluated at Week 52. Based on the PK / PD data from the Phase 2 SC study and the data from anifrolumab IV studies, a dose of 120mg QW has been selected for the current Phase 3 SC study to provide an average concentration (C 平均 ) that is equivalent to and not inferior to 300mg IV in a single injection, and thus 120mg SC QW is expected to provide at least similar efficacy to 300mg IV Q4W.

[0467] Considering the change in dosing interval from Q4W to QW, and by providing at least a similar C 平均 , it is expected that the trough concentration of 120mg SCQW will be higher than that of 300mg IV Q4W, and thus it is expected to provide PD inhibition that is not inferior to 300mg IV. Additionally, over 52 weeks, the C 平均 of 120mg SC QW has minimal overlap with the C 平均 of 1000mg IV (evaluated in Phase 2b study 1013), which has been shown to be safe and tolerable, and thus any dose below 1000mg IV Q4W is considered safe.

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

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

[0470] 10.1. Abstract

[0471] This study aimed to clarify the pharmacokinetic / pharmacodynamic and pharmacodynamic / efficacy relationships of the type I interferon receptor antibody anifrolumab in patients with moderate to severe systemic lupus erythematosus (SLE). Pooled data from the randomized, 52-week, placebo-controlled TULIP-1 and TULIP-2 trials of intravenous anifrolumab (150 mg / 300 mg, every 4 weeks [Q4W] for 48 weeks) were used. In patients with high IFNGS, pharmacodynamic neutralization was measured using a 21-gene type I interferon gene signature (21-IFNGS). The pharmacokinetic / pharmacodynamic relationship was analyzed graphically and modeled using a non-linear mixed effects model. In the 21-IFNGS neutralization quartiles, the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rates were compared. Overall, 819 patients received ≥1 dose of anifrolumab or placebo, of whom 676 had high IFNGS. Over 52 weeks, higher mean anifrolumab serum concentrations were associated with increased median 21IFNGS neutralization, rapid and sustained with anifrolumab 300 mg (>80%, weeks 12 - 52), reduced and delayed with anifrolumab 150 mg (>50%, week 52), and minimal with placebo. The proportion of patients with anifrolumab trough concentration (C 80 ) above IC 谷 (3.88 μg / mL) at week 24 was greater in anifrolumab 300 mg compared with anifrolumab 150 mg (approx. 83% vs. approx. 27%) because the estimated median C 谷 was higher (15.6 μg / mL vs. 0.2 μg / mL). The BICLA response rate increased with 21IFNGS neutralization; at week 52, increasing numbers of patients had a BICLA response in the highest and lowest neutralization quartiles (58.1% vs. 37.6%). In summary, anifrolumab IV 300 mg Q4W rapidly, substantially and continuously neutralized 21IFNGS and was associated with clinical efficacy, supporting a 300 mg IV dosing regimen and corresponding 120 mg SC dose for SLE patients.

[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, heightened inflammatory signaling cascades, and immune deposits, 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 classes of type I IFN (α, β, ε, κ, ω) activate the type I IFN-α receptor (IFNAR), which mediates downstream signaling to stimulate the transcription of IFN-regulated genes, measured using the IFN gene signature (IFNGS). In 50%-80% of SLE patients, elevated type I IFNGS occurs in blood or tissues, and this is associated with increased disease activity. 10-13 Patients with high IFNGS have a more active SLE disease with higher levels of anti-double-stranded DNA (anti-dsDNA) antibodies compared to patients with low IFNGS.

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

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

[0476] In an analysis of ainulimab pharmacokinetics (PK) exposure across 5 clinical trials, the median ainulimab serum concentration of ainulimab 300 mg Q4W was consistent throughout the 52-week treatment period (across trials and within each trial), with few patients having trough concentrations (C 谷)Below the limit of quantification. High IFNGS expression was associated with lower systemic anifrolumab exposure, as the median time to elimination was shorter in patients with high IFNGS compared to those with low IFNGS (57 days vs. 67 days). Anifrolumab PK concentrations were also negatively correlated with body weight but were not affected by other covariates (race, age, gender, renal and liver function, immunogenicity, and use of common SLE medications).

[0477] Higher anifrolumab doses were associated with greater PD neutralization in patients with systemic sclerosis and SLE; however, the PK / PD relationship and the PD / efficacy relationship, and whether these are affected by disease characteristics, remain to be fully characterized. Here, our aim was to confirm that the intravenous 300 mg anifrolumab Q4W dosing regimen, the recommended recommended dose, provides adequate PK exposure and PD neutralization in patients with high IFNGS SLE. PD neutralization was quantified as the change in 21-IFNGS score from baseline; thus, patients with low IFNGS were not included in our analysis as their baseline 21-IFNGS expression was insufficient to observe meaningful PD neutralization. To study PK and PD in patients with high IFNGS, we used data pooled from the TULIP-1 and TULIP-2 trials to evaluate how different serum anifrolumab exposures affected PD neutralization of 21-IFNGS and how 21-IFNGS neutralization in turn related to clinical efficacy.

[0478] 10.3. Methods

[0479] 10.3.1. 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 (aged 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 antibody, anti-dsDNA antibody, and / or anti-Smith antibody and had received at least one stable standard therapy. At screening, the central laboratory used an analytically validated 4-gene (IFI27, IFI44, IFI44L, and RSAD2) quantitative polymerase chain reaction (qPCR) whole-blood test for patients to classify them as high or low 4-gene type I IFNGS.

[0483] 10.3.3. Efficacy Endpoints

[0484] Both the TULIP-1 and TULIP-2 trials evaluated the proportion of patients with a BICLA response at week 52 (primary endpoint of TULIP-2, secondary endpoint of TULIP-1) or an SLE responder index ≥4 (SRI[4]) at week 52 (primary endpoint of TULIP-1, secondary endpoint of TULIP-2) in the anifrolumab 300 mg group compared with the placebo group. Using the Cochran-Mantel-Haenszel method, the percentage of patients classified as BICLA or SRI(4) responders, the difference between the anifrolumab and placebo groups, and the associated 95% confidence interval (CI) were adjusted for stratifying factors.

[0485] The BICLA response was defined as all of the following: all baseline BILAG-2004 A and B region scores decreased to B / C / D and C / D, respectively, and no worsening in other BILAG-2004 organ systems; no increase in SLEDAI-2K score (from baseline); no increase in the physician global assessment (PGA) score (≥0.3 points from baseline); no study treatment discontinuation; and no use of restricted medications.

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

[0487] 10.3.4. PK Measures and Models

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

[0489] 10.3.5. PD metrics

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

[0491] 10.3.6. PK / PD analysis

[0492] Baseline 21-IFNGS scores in 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 PK / PD or PD / efficacy analyses.

[0493] 10.3.6.1. Graphical PK / PD analysis

[0494] The graphical PK / PD analysis included high IFNGS patients in all treatment groups who had at least one PD measurement before discontinuation and at least one quantifiable serum PK observation in the 150 mg and 300 mg anifrolumab groups. Patients treated with anifrolumab were classified according to the median or tertiles (depending on the sample size) of the predicted mean anifrolumab concentration (C 平均 ) over the duration of treatment with 150 mg or anifrolumab 300 mg. The median 21-IFNGS PD neutralization in the C 平均 subgroups was compared over the 52-week treatment period.

[0495] 10.3.6.2. PK / PD Model

[0496] The PK / PD model analysis population included high IFNGS patients in all groups who had baseline and at least one post-baseline PD measurement before discontinuation and at least one quantifiable serum PK observation in the anifrolumab groups. The relationship between anifrolumab exposure (PK) and PD neutralization of 21-IFNGS was described by an indirect response model in which anifrolumab inhibits the production of type I IFN-induced genes. The model is a non-linear mixed effects model originally developed to describe the PK / PD relationship of anifrolumab in patients with systemic sclerosis. A schematic of the model is shown as Figure 16 . The PK / PD model was implemented in the software NONMEM (version 7.3 or higher, ICON Development Solutions, Ellicott City, Maryland; 2006) to provide PK / PD parameter estimates. Visual predictive checks were performed to ensure that the observed data were adequately captured by 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 high IFNGS patients who had baseline and at least one post-baseline PD assessment before discontinuation. At weeks 12, 24, 36, and 52, the individual median 21-IFNGS neutralization from baseline to steady state was calculated based on the observed data pooled from the anifrolumab 150 mg and 300 mg treatment groups, excluding PD measurements collected after discontinuation. Patients in the pooled anifrolumab 150 mg and 300 mg treatment groups were divided into subgroups according to the median percentage 21-IFNGS neutralization quartiles. The BICLA and SRI(4) response rates were calculated for the week 52 quartile subgroups and the overall placebo treatment group.

[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 anifrolumab 300 mg, anifrolumab 150 mg, or placebo; 676 (82.5%) and 143 (17.5%) were 4-gene type I IFNGS high and IFNGS low, respectively. Since the 4 genes of the dichotomous 4-gene IFNGS test are a subset of the 21-IFNGS, 19,27 4-gene IFNGS status (high vs low) was strongly correlated with the median 21-IFNGS score, which was 15.1 in IFNGS-high patients and 1.1 in IFNGS-low patients (Table 10-1, Figure 17 ).

[0502] Table 10-1: Summary Characteristics of IFNGS-High and IFNGS-Low Patients at Baseline and Throughout the TULIP-1 and TULIP-2 Trials

[0503]

[0504]

[0505] anti-dsDNA, anti-double-stranded DNA; BILAG-2004, British Isles Lupus Assessment Group - 2004; C3, complement 3; C4, complement 4; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; IFNGS, interferon gene signature; IQR, interquartile range; SD, standard deviation; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000.

[0506] The table includes all patients who received at least one dose of anifrolumab 300 mg, anifrolumab 150 mg, or placebo in the TULIP-1 and TULIP-2 trials.

[0507] a The 21-IFNGS score was calculated as the 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.

[0508] b The percentages shown are the percentages of patients who are IFNGS high or low in each geographic region or ethnic group, including patients treated with anifrolumab 150 mg, anifrolumab 300 mg, or placebo in TULIP-1 and TULIP-2.

[0509] c Anti-dsDNA antibody levels were classified as positive (>15 U / mL -1) or negative (≤15 U / mL -1 ) and measured using automated fluorescence immunoassay in the central laboratory.

[0510] 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 the central laboratory.

[0511] The discontinuation rate was shown as the number of patients (n) who discontinued relative to the number of patients (N) in each treatment subgroup.

[0512] f The restricted medication use rate was shown as the number of patients (n) who used any medication exceeding the protocol - allowed limit relative to the number of patients (N) in each treatment subgroup.

[0513] 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). A negative association was observed between age and IFNGS expression for the dichotomous IFNGS test at screening and the median 21 - IFNGS score at baseline ( Figure 18 ). Compared with other geographical regions, North American patients were slightly older (median age 44 years vs. 40 - 41 years) and were possibly slightly lower for IFNGS - high (72.6% vs. 88.5% - 90.9%). The proportion of black / African American patients (86.1%) and Asian patients (95.2%) with high IFNGS was higher than that of white patients dominated in North America (78.3%).

[0514] IFNGS - high patients had more severe disease than IFNGS - low patients; at baseline, there were 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%), and more patients with SLEDAI - 2K score ≥ 10 (71.9% vs. 62.9%) (Table 10 - 1). The association between disease severity and IFNGS was also reflected in the placebo group, where the proportion of IFNGS - high patients using medications restricted by the TULIP - 1 and TULIP - 2 protocols 16,17 was higher than that of IFNGS - low patients (34.1% vs. 18.8%); in contrast, at week 52 (about 21%), the restricted medication use in IFNGS - high patients receiving 300 mg of anifrolumab was similar to that of IFNGS - low patients.

[0515] 10.4.2. PK / PD Analysis

[0516] The baseline 21-IFNGS scores in the low IFNGS subgroup were similar to those of healthy subjects and were insufficient to observe meaningful PD neutralization; therefore, in patients with low IFNGS, the median percentage of neutralization of 21-IFNGS over time was minimal ( Figure 19 ) when using anifrolumab 300 mg and placebo. Therefore, patients with low IFNGS were not included in the PK / PD or PD / efficacy analyses.

[0517] Table 10-2: Anifrolumab C for graphical PK / PD analysis 平均 Subgroup thresholds

[0518]

[0519] C 平均 , mean anifrolumab concentration during the treatment duration; M, median; PD, pharmacodynamics; PK, pharmacokinetics; T, tertile.

[0520] In contrast, in patients with high IFNGS treated with anifrolumab 300 mg, PD neutralization of 21-IFNGS occurred in all baseline 21-IFNGS groups. However, patients in the lowest baseline 21-IFNGS quartile (patients with the 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 ( Figure 20 ).

[0521] 10.4.2.1. PK / PD Graphical Analysis

[0522] PK / PD graphical analysis included 357 patients with high IFNGS from TULIP-1 who received placebo (n = 144), anifrolumab 150 mg (n = 72), or anifrolumab 300 mg (n = 141), and 297 patients with high IFNGS from TULIP-2 who received placebo (n = 149) or anifrolumab 300 mg (n = 148) (Figure 21).

[0523] Patients treated with anifrolumab 300 mg were classified by C 平均 tertiles, which were generally consistent across TULIP-1 and TULIP-2. Due to the small sample size, based on whether the C 平 mean was higher or lower than the median (11.5 μg mL -1) Patients treated with anifrolumab 150 mg were divided into subgroups. As previously reported, due to the non-linearity of PK exposure, patients treated with anifrolumab 300 mg generally had higher C 平均 values than patients treated with anifrolumab 150 mg, and the minimum overlap of C 平均 values was observed between groups (Table 10-2).

[0524] All three anifrolumab 300 mg C 平均 terciles reached ~80% median PD neutralization, which persisted from week 12 to week 52; however, in both trials, the variability in the lowest C 平均 tercile was greater than that of the two higher C 平均 terciles ( Figure 21A , Figure 21B ). The median PD neutralization of the two highest C 平均 terciles stabilized at approximately 90%. In baseline disease activity subgroups (including subgroups based on SLEDAI-2K score (<10 vs ≥10), oral glucocorticoid dose (<10 vs ≥10 mg per day -1 ) and lupus serology (anti-dsDNA antibody, C3, and C4)), substantial and sustained PD neutralization was consistently observed with anifrolumab 300 mg ( Figure 22 ). In contrast, in the subgroup of patients treated with anifrolumab 150 mg with C 平均 values below the median, PD neutralization varied widely (large MAD values), although it was numerically greater than the slight PD neutralization observed with placebo.

[0525] 10.4.2.2. PK / PD Model Analysis

[0526] This PK / PD model analysis included 646 high IFNGS patients from the pooled TULIP-1 and TULIP-2 trials who received placebo (n = 289), anifrolumab 150 mg (n = 70), or anifrolumab 300 mg (n = 287). As demonstrated by visual predictive checks, the PK / PD indirect response model adequately captured the observed data through the 95% prediction interval ( Figure 23 ). The NONMEM output diagnostic plots are shown in Figure 25A -D. The PK / PD model parameter estimates are shown in Table 10-3.

[0527] IC 80 was defined as the approximate anifrolumab concentration required to achieve 80% of the maximum inhibition of 21-IFNGS expression relative to baseline. The model gave an IC -1 estimate of 3.88 μg / mL 80 , which was based on an IC of 6.56 nM50 Estimated values and the molecular weight of anifrolumab at 148 kDa. Due to non-linearity, the estimated median Week 24 C for anifrolumab 300 mg 谷 was higher than that for anifrolumab 150 mg (15.6 μg mL -1 relative to 0.2 μg mL -1 )( Figure 24 ). Thus, a higher proportion of patients treated with anifrolumab 300 mg had Week 24 C 谷 above IC 80 (approx. 83% vs. approx. 27%) compared to those treated with 150 mg. For patients with high IFNGS, the baseline 21-IFNGS score estimated by the model was 13.1 (Table 10-3).

[0528] Table 10-3: Anifrolumab parameters estimated by the PK / PD model

[0529]

[0530]

[0531] GS0, baseline gene marker; IC 50 , potency, the approximate anifrolumab concentration required to produce 50% of the maximum inhibition of 21-IFNGS expression relative to baseline; IFN, interferon; I 最大 , the approximate anifrolumab concentration required to produce the maximum inhibition of 21-IFNGS expression relative to baseline; k out , elimination rate constant; PD, pharmacodynamics; PK, pharmacokinetics; Var(η IC50 ), between-subject variability of IC 50 ; Var(η GS0 ), between-subject variability of GS0; σ 2 , residual variability.

[0532] 10.4.3. PD neutralization in pooled anifrolumab 150 mg and 300 mg groups

[0533] 341 patients with high IFNGS who received anifrolumab 150 mg or 300 mg were classified according to PD neutralization quartiles (Q1 < 51.7%, Q2 ≥ 51.7% - 85.3%, Q3 ≥ 85.3% - 92.6%, Q4 ≥ 92.6%). Patients in the anifrolumab 300 mg group predominantly resided in the higher PD neutralization quartiles (Q2 - Q4); the median PD neutralization from Week 12 to Week 52 was > 86% for anifrolumab 300 mg vs. < 37% for anifrolumab 150 mg.

[0534] Among the 273 high IFNGS patients from the 300 mg anifrolumab group included in PD and the analysis, 41 (15.0%) were in the lowest quartile of PD neutralization (<51.7% neutralization). Among these 41 patients, 18 (43.9%) had a baseline 21-IFNGS score in the bottom quartile (Q1 < 3.8), which was associated with lower PD neutralization ( Figure 20 ). The remaining 23 patients tended to have low PK exposure; 19 were in the lowest anifrolumab 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 anifrolumab 300 mg PK C 平均 quartiles are shown in Table 10-4). Compared with the total high IFNGS population (n = 676), these 23 patients tended to have more active baseline disease, with a higher proportion of patients positive for 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 vs 10.2 mg / day -1 ).

[0535] Table 10-4: C 平均 PK quartiles of anifrolumab 300 mg in pooled TULIP-1 and TULIP-2 data

[0536]

[0537] C 平均 , mean anifrolumab concentration during the treatment duration; M, median; PK, pharmacokinetics; Q, quartile; Q4W, every 4 weeks.

[0538] Quartiles of mean PK concentration are based on patients from pooled data of TULIP-1 and TULIP-2 who were treated with 300 mg anifrolumab and completed the treatment.

[0539] 10.4.4. PD / Efficacy Analysis

[0540] The PD / efficacy analysis included 341 patients with high IFNGS who received 150 mg or 300 mg of anifrolumab and 280 patients who received placebo. The PD / efficacy analysis is as Figure 26A and Figure 26B shown. The proportion of patients with a BICLA response at Week 52 increased with higher PD neutralization in the anifrolumab groups (Q1 37.6%, Q2 49.4%, Q3 51.8%, Q4 58.1%); the response rates for all anifrolumab quartiles were numerically greater than placebo (30%). Similarly, in the anifrolumab groups, the proportion of patients with an SRI(4) response at Week 52 increased with the PD neutralization subgroup (Q1 48.2%, Q2 56.5%, Q3 58.8%, Q4 64.0%); the response rates for all anifrolumab quartiles were numerically greater than placebo (40%).

[0541] 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 anifrolumab 300 mg group, the BICLA response rate at Week 52 (Q4≥20.7) was numerically higher for patients with a higher baseline 21-IFNGS score compared to patients with a low 21-IFNGS score (Q1<3.8) (TULIP-1: 54% versus 40%; TULIP-2: 47% versus 43%). However, for all baseline 21-IFNGS score quartiles in TULIP-1 and TULIP-2, the BICLA response with anifrolumab 300 mg was higher relative to placebo ( Figure 27 ).

[0542] 10.5. Discussion

[0543] Relating drug concentration, pharmacodynamics, and efficacy can provide important insights into the relationship between the mechanism of action of a drug 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 anifrolumab. This study identified an association between anifrolumab serum concentration and PD neutralization of type I IFN-induced genes (21-IFNGS), which in turn was associated with improved efficacy at Week 52 in patients with high IFNGS at screening. These findings support the mechanism of action of anifrolumab; 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 were improved.

[0544] At screening, PD neutralization in patients with low IFNGS was not meaningful, so only patients with high IFNGS were included in this analysis. Additionally, it was important to specifically consider patients with high IFNGS because these patients had a higher clearance rate of anifrolumab compared to patients with low IFNGS. Elevated IFNGS expression was associated with more active and difficult-to-treat disease, increased 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 high IFNGS had higher baseline disease activity compared to patients with low IFNGS, with more patients being seropositive for anti-dsDNA antibodies or having abnormal C3 / C4 at baseline. In the placebo group, patients with high IFNGS were more likely to use restricted medications throughout the trial compared to patients with low IFNGS. However, treatment with 300 mg of anifrolumab in patients with high IFNGS was associated with a reduction in restricted medication use, similar to that observed in patients with low IFNGS. In both patients with high and low IFNGS, the treatment discontinuation rate with 300 mg of anifrolumab was lower than that with placebo.

[0545] The PK / PD model, IFNAR1 internalization kinetics, and information from the SLE study appeared to be robust as the estimates were consistent with the observed data. The parameters predicted by the model indicated a strong PK / PD relationship. In the 300 mg anifrolumab group, it was predicted that the trough concentration of anifrolumab in approximately 83% of patients would cause >80% inhibition of 21-IFNGS expression. In fact, rapid (at week 12), substantial (∼80%), and sustained (up to week 52) neutralization of 21-IFNGS was observed in all three anifrolumab 300 mg C 平均 tertiles. In contrast, in the 150 mg anifrolumab group, it was predicted that the trough concentration of anifrolumab in only approximately 27% of patients would cause >80% inhibition of 21-IFNGS. Therefore, lower, more variable, and delayed PD neutralization was observed with 150 mg of anifrolumab, especially in patients with C 平均 below the median, in whom PD neutralization was minimal and similar to that observed with placebo. In the trial and dosing regimen, lower anifrolumab serum exposure led to a more variable PD neutralization curve.

[0546] During the entire trial, a small subset (15%) of patients with high IFNGS in the anifrolumab 300 mg group did not experience high PD neutralization (median percent neutralization of baseline 21-IFNGS was less than 51.7%). Nearly half of these patients had baseline 21-IFNGS scores in the lower quartile (although assigned a high IFNGS status due to the dichotomous nature of the 4-gene IFNGS test), and thus did not require high PD neutralization to achieve 21-IFNGS scores similar to those of healthy controls. The other half of these patients had low PK exposure, supporting the PK / PD relationship, and tended to have numerically higher disease activity at baseline. However, in the overall pooled population, baseline disease activity measures did not appear to affect PD neutralization by anifrolumab 300 mg, further supporting the anifrolumab IV 300 mg dosing regimen and corresponding 120 mg subcutaneous dose in the patient subgroup, regardless of disease activity.

[0547] Therefore, it may be suggested that a subset of patients with low PD neutralization may benefit from anifrolumab at a dose higher than 300 mg; however, there is no evidence that the BICLA response rate is higher when the dose exceeds IV 300 mg. For example, in the Phase 2 MUSE study, the Week 52 BICLA response rate with anifrolumab 300 mg (53.3%) was higher than that with anifrolumab 1000 mg (41.2%). Additionally, in an analysis modeling the relationship between PK exposure and BICLA response rate in TULIP-1 and TULIP-2, due to non-linearity, anifrolumab 1000 mg was predicted to provide only incremental benefit compared to anifrolumab 300 mg. However, as shown in Example 4: When determining the optimal subcutaneous unit dose, this variability combined with variability in bioavailability justifies a surprisingly high subcutaneous dose greater than 105 mg.

[0548] PD neutralization of 21-IFNGS is associated with improved clinical efficacy. All anifrolumab

[0549] The proportion of BICLA and SRI(4) responders in the PD neutralization quartiles was numerically higher than that in the placebo group. However, the absolute BICLA and SRI(4) response rates in the highest anifrolumab PD neutralization quartile were approximately 21% and 16% higher, respectively, than those in the lowest anifrolumab PD neutralization quartile (composed mainly of patients in the anifrolumab 150 mg group). These results are consistent with the association analysis between PK and efficacy in the TULIP-1 and TULIP-2 trials, which identified the exposure-efficacy relationship and demonstrated that the BICLA / SRI(4) response rates in all anifrolumab PK subgroups were higher than those in the placebo group.

[0550] Early changes in PD markers associated with clinical efficacy at later time points have clinical value. This study shows that the degree of IFNGS neutralization can serve as a defined PD marker for the design of future anifrolumab trials in different populations (such as pediatric patients or other lupus populations such as lupus nephritis (LN) or cutaneous lupus erythematosus (CLE)) or different administration methods (such as subcutaneous injection).

[0551] In the phase 2 MUSE trial, anifrolumab IV 300 mg every 4 weeks was selected as the optimal dosing regimen for patients with moderate to severe SLE because it has a favorable benefit-risk profile. Across all studies, the C 平均 of anifrolumab 300 mg was consistent and higher than that elicited by anifrolumab 150 mg, with little overlap between subgroups, consistent with the non-linear PK curve of anifrolumab. The steady-state concentration of anifrolumab quantified by the trough concentration at week 24 was predicted to be approximately 80-fold higher with anifrolumab 300 mg compared to anifrolumab 150 mg.

[0552] 10.6. Conclusions

[0553] Here, the inventors have demonstrated a clear relationship between anifrolumab serum exposure and PD neutralization in patients with moderate to severe SLE receiving standard therapy, providing evidence to support the anifrolumab IV 300 mg Q4W and anifrolumab SC 120 mg QW dosing regimens. Indeed, anifrolumab 300 mg provides sufficient PK exposure for patients with high IFNGS, resulting in rapid, substantial, and sustained neutralization of 21-IFNGS, which in turn is associated with improved clinical efficacy. Therefore, for anifrolumab SC doses greater than 105 mg (e.g., 120 mg, QW), similar clinical efficacy is expected.

[0554] 11. Example 7: Treatment of type I IFN diseases

[0555] 11.1. Type I IFN markers

[0556] To understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know whether the disease in a subject is driven by type I IFN activation. However, direct measurement of type I IFN remains challenging. 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 can be easily detected in whole blood, for example using PCR (e.g., TaqMan) assays.

[0557] Gene expression can be measured by RT-PCR. Suitable primers and probes for detecting the gene can be found in WO2011028933. A suitable kit for measuring gene expression in the IFNGS test is the QIAGEN IFIGx RGQ RT-PCR Kit (IFIGx Kit), as described by Brohawn et al.

[26] , which is incorporated herein by reference in its entirety. As previously described [24,25], the 21-IFNGS assay consists of 21 type I IFN-α / β-inducible genes ( Figure 28 ), including 4 genes in the dichotomous IFNGS test.

[0558] The bimodal distribution of transcript scores in SLE subjects supports the definition of subsets with high and low IFN tests (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 high or low type I IFN gene signature (IFNGS) test ([[]]END]] 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 3 reference genes 18S, ACTB, and GAPDH. The test result is a score compared to a pre-determined cut-off value that divides the patients into 2 groups with low or high levels of IFN-inducible gene expression ( Figure 29B ).

[0559] The type I IFN gene score has been shown to be associated with expression in diseased tissues (such as skin) in SLE. In particular, the high type I IFN gene signature is associated with increased disease activity and OCS use in SLE ( Figure 29C ).

[0560] IFNGS can be used to identify other type I IFN-mediated diseases suitable for treatment with IFNAR1 inhibitors. Type I IFN-mediated diseases include lupus nephritis (LN) and Sjogren's syndrome, in which patients may be identified as having elevated IFNGS ( Figure 31A and Figure 31B ). In patients with SSc and myositis, a similar core type I IFN signature (5-gene score) is activated (Figure 32).

[0561] 11.2. Lupus

[0562] The IFNGS (21-gene) in lupus (SLE) is inhibited by type I IFN signaling inhibitors (such as the anti-IFNɑ antibody siltuximab ( Figure 30A) or the type I IFN receptor (IFNAR1) inhibitor anifrolumab ( Figure 30B )) neutralization. See also Section 10.

[0563] 11.3. Scleroderma

[0564] Systemic sclerosis (scleroderma, 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 anifrolumab in SSc subjects ( Figure 33 ). The IFNGS score in SSc patients was determined as the median fold change (FC) of 5 IFN-induced genes compared to healthy controls, which are among the most differentially regulated genes in scleroderma patients. These 5 genes are a subset of the 21-gene IFNGS.

[0565] As measured using the 5-gene signature (IFI27, RSAD2, IFI44, IFI44L, IFI6), the 5-gene IFNGS in whole blood (WB) of scleroderma patients is elevated ( Figure 31B ). The 5-gene IFNGS score in SSc patients is comparable to the 5-gene IFNGS score in SLE patients ( Figure 32A Figure 34A ). The baseline IFN signature is highly correlated between affected tissues and the periphery and is highly correlated with baseline disease activity ( Figure 34B ). There is also a positive correlation between the baseline 5-gene IFNGS score and SSc disease activity as measured by the modified Rodnan skin score (mRTSS) ( Figure 34C ).

[0566] As described in WO 2013 / 188494 (incorporated herein by reference in its entirety), the 5-gene IFNGS can be neutralized in patients with scleroderma (SSc) ( Figure 35 ). In particular, in the CP180 study (NCT0093082), approximately 2 / 3 of SSc patients were positive for the type I IFN signature at baseline. After treatment with anifrolumab, at a dose of 1 mg / kg (mpk) or higher (single dose and multiple doses) ( Figure 35 ), there was a rapid and near-complete inhibition of IFNGS (day 1), and there was a significant dose-dependent effect on the duration of inhibition of the pre-treatment signature ( Figure 35 ). The IFN score used in the CP180 study is similar to the scores used in other autoimmune indications and has been confirmed to be a sensitive PD biomarker, relevant to the treatment of type I IFN-mediated signaling inhibitors in SSc.

[0567] ​Treatment of SSc patients with anifrolumab also inhibits T cell activation (through decreased CXCL10 and CD40L) (Figure 36). Anifrolumab further inhibits collagen formation markers and upregulates collagen degradation markers (Figure 36), indicating a mechanism of action for regulating tissue through inhibition of type I IFN signaling in SSc patients. Skin scores were further improved (mRSS at the highest dose).

[0568] In summary, when treating SSc patients with anifrolumab, type I IFN scores in WB and skin were almost completely inhibited and were dose-dependent. The core IFNGS was elevated in SSc patients treated with anifrolumab neutralizing antibody gene markers. Anifrolumab has also been shown to have a therapeutic effect on SSc patients. Therefore, the therapeutic effect of anifrolumab in SSc patients is similar to that in SLE and LN patients, and the dose is similar or the same as the dose of anifrolumab that is safe and effective in SLE, namely 300 mg IV Q4W or greater than 105 mg and less than 150 mg QW, especially the equivalent SC dose of 120 mg SC QW.

[0569] 11.4. Myositis

[0570] Type I IFN was first observed in myositis muscle biopsies by immunohistochemical studies

[27] , and subsequently, an increase in PDC in muscle and skin biopsies of dermatomyositis (DM) has been reported [28, 29]. DM or polymyositis (PM) has been observed to occur after IFN-α or IFN-β therapy, indicating that type I IFN is a potential target for the treatment of these two indications [30, 31]. In PM and dermatomyositis / JDM7, IFN-β rather than IFN-α transcripts are overexpressed. IFNβ is elevated in the blood of DM patients and is associated with type I IFN-induced genes in the blood

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

[28] .

[0571] In patients with dermatomyositis (DM) or polymyositis (PM), type I IFN-induced genes (136 genes) in the blood are overexpressed compared to healthy volunteers (defined as values <4)

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

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

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

[0572] The type I IFN gene signaling inhibitor (sifalimumab) neutralized the 13-gene IFNGS score in the blood and muscle of DM and PM patients in a dose-dependent manner (study MI-CP151, Figure 39 ). In particular, in the 0.3 mg / kg cohort, the median maximum neutralization of the type I IFN gene signature was 91%, and the mean neutralizations in the sifalimumab treatment cohorts were 47%, 33%, and 65% at days 28, 56, and 98, respectively. At day 98, the four sifalimumab-treated cohorts showed a median neutralization range of 54% - 91% for the gene signature. When treating myositis patients with sifalimumab, neutralization of the type I IFN signature in the muscle showed up to 80% ( Figure 38 ). More dose-dependent IFNGS inhibition was observed in all 4 sifalimumab dose groups (0.3 mg / kg, 1.0 mg / kg, 3.0 mg / kg, and 10 mg / kg) compared to the placebo group. IFNα inhibition reduced infiltration of immune cells into myositis muscle (DM and PM) ( Figure 41 ). Sifalimumab inhibits the downstream pathway of type I IFN in the muscle of myositis patients and targets neutralization associated with improvement of muscle function (MMT8) in myositis patients [10,11] (Figure 42). Thus, importantly, targeted modulation of the type I IFN gene signature in the blood shows a relevant trend of disease activity in DM and PM patients ( Figure 40A ). In addition, targeted inhibition of the type I IFN gene signature is associated with inhibition of important disease-related signaling events in muscle tissue ( Figure 40B ).

[0573] In summary, the core IFNGS is elevated in patients with myositis, and treatment with siltuximab neutralizes this genetic marker. Thus, the IFNGS marker data reasonably suggest that the range of IFN pathway activation in myositis is similar to that in SLE. Similar IFN activation is observed in SLE, DM, and PM (Figure 32). In addition, due to the universality of the type I IFN receptor, the general availability of the receptor is a major driver for dose selection in myositis. Data show that the PF / PD is similar across different disease states (e.g., comparing SLE and SSc). In addition, the subcutaneous dose data provided by Studies 06 and 08 support the selection of a dose of approximately 120 mg SC QW in myositis. Anifrolumab completely inhibits type I IFN signaling through IFNAR, while siltuximab targets only most of the IFN-α( Figure 43 ). Thus, the neutralization of IFNGS by anifrolumab in patients with myositis is similar to that of siltuximab, and the dose is similar or equivalent to the dose of anifrolumab shown to be safe and effective in SLE, i.e., 300 mg IV Q4W or an SC dose equivalent of greater than 105 mg and less than 150 mg QW (specifically 120 mg SC QW).

[0574] 12. Example 8: Injection device

[0575] Anifrolumab is administered by an injection device [1][9] such as a prefilled syringe (PFS)( Figure 44A ) or an autoinjector (AI)( Figure 44B ).

[0576] 12.1. Autoinjector

[0577] Anifrolumab can be administered by an autoinjector [1]. The autoinjector is shown in exploded view( Figure 45A ) and assembled form( Figure 45B ). The label [4] is wrapped around and attached to the autoinjector [1]( Figure 45C ). The autoinjector has an autoinjector housing [3], a cap and cap remover [2], and a drive device [5]. The liquid anifrolumab formulation unit dose [6] is contained in the autoinjector housing [3]. The unit dose [6] can be observed through the observation window [7].

[0578] 12.1.1.1. Prefilled syringe with attachment

[0579] Anifrolumab can be administered by a prefilled syringe with attachment (APFS) [8]. The APFS [8] includes a unit dose [6] of anifrolumab contained in a main container [9], as shown in the assembled state in Figure 46A and Figure 46BAs shown in the exploded view. 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 air bubbles

[18] . The air bubbles

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

[19] .

[0580] The pre-filled syringe with attachment (APFS) main container [9] is disposed within the PFS assembly [8], which includes a needle guard

[12] , a finger flange

[11] , and a plunger rod

[13] . A label

[14] is provided with the main container [9] within the PFS assembly [8]. The label

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

[15] .

[0581] 12.1.1.2. Packaging

[0582] The injection device [1][8] is provided in a kit

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

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

[0583] References

[0584] All publications mentioned and / or cited below in this specification are hereby incorporated by reference.

[0585] [1] M.R. Turner and S.V. Balu-Iyer, J. Pharm. Sci. 107, 1247 (2018).

[0586] [2] B. Bittner, W. Richter, and J. Schmidt, Biodrugs 32, 425 (2018).

[0587] [3] J. Witcher et al., Br. J. Clin. Pharmacol. 81, 908 (2016).

[0588] [4] D.A. Isenberg et al., Ann. Rheum. Dis. 75, 323 (2016).

[0589] [5] J.T. Merrill et al., Ann. Rheum. Dis. 75, 332 (2016).

[0590] [6]G.T. Ferguson et al., J.Asthma Allergy 11, 63(2018).

[0591] [7]M. Khamashta et al., Ann.Rheum.Dis. 75, 1909(2016).

[0592] [8]R. Tummala et al., Lupus Sci.Med. 5, e000252(2018).

[0593] [9]A. Psarras, P. Emery, and E.M. Vital, Rheumatol.Oxf.Engl. 56, 1662(2017).

[0594]

[10] B.W. Higgs et al., Ann.Rheum.Dis. 73, 256(2014).

[0595]

[11] S.A. Greenberg et al., Genes Immun. 13, 207(2012).

[0596]

[12] J.C. Hall and A. Rosen, Nat.Rev.Rheumatol. 6, 40(2010).

[0597]

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

[0598]

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

[0599]

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

[0600]

[16] B.W. Higgs et al., Ann.Rheum.Dis. 70, 2029(2011).

[0601]

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

[0602]

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

[0603]

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

[0604]

[20] R.A.Furie et al.,Lancet Rheumatol.1,e208(2019).

[0605]

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

[0606]

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

[0607]

[23] I.N.Bruce et al.,Lancet Rheumatol.0,(2020).

[0608]

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

[0609]

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

[0610]

[26] ACR Meeting Abstracts(n.d.).

[0611]

[27] D.A.Isenberg et al.,Clin.Exp.Immunol.63,450(1986).

[0612]

[28] S.A.Greenberg et al.,Neurology 65,1782(2005).

[0613]

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

[0614]

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

[0615]

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

[0616]

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

Claims

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

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

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

4. The unit dose according to any one of claims 1 - 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, and wherein the disease is a type I interferon (IFN)-mediated disease.

5. The unit dose for use according to claim 4, wherein the disease is an autoimmune disease.

6. The unit dose for use according to claim 5, wherein the disease is lupus.

7. The unit dose for use according to claim 6, wherein the disease is SLE.

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

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

10. The unit dose 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 dose for use according to claim 5, wherein the disease is scleroderma.

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