WO2023006700A1 - Treatment of lupus - Google Patents

Treatment of lupus Download PDF

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Publication number
WO2023006700A1
WO2023006700A1 PCT/EP2022/070860 EP2022070860W WO2023006700A1 WO 2023006700 A1 WO2023006700 A1 WO 2023006700A1 EP 2022070860 W EP2022070860 W EP 2022070860W WO 2023006700 A1 WO2023006700 A1 WO 2023006700A1
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WIPO (PCT)
Prior art keywords
subject
anifrolumab
dose
sle
ifnar1
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PCT/EP2022/070860
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English (en)
French (fr)
Inventor
Catharina LINDHOLM
Rajendra TUMMALA
Emmanuelle MAHO
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AstraZeneca AB
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AstraZeneca AB
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Priority to EP22758427.3A priority Critical patent/EP4377349A1/en
Priority to CN202280051374.9A priority patent/CN117677638A/zh
Priority to JP2024504491A priority patent/JP2024527001A/ja
Priority to CA3226744A priority patent/CA3226744A1/en
Priority to KR1020247006291A priority patent/KR20240038773A/ko
Priority to AU2022317215A priority patent/AU2022317215A1/en
Priority to US18/291,671 priority patent/US20250326850A1/en
Priority to IL310241A priority patent/IL310241A/en
Publication of WO2023006700A1 publication Critical patent/WO2023006700A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin

Definitions

  • SLE Systemic lupus erythematosus
  • a significant problem associated with the treatment of SLE is the heterogeneous clinical manifestations of SLE 1 . Any organ may be affected in SLE, with the skin, joints, and kidneys being the most commonly involved 2 - 4 . Incomplete disease control leads to progressive organ damage, poor quality of life, and increased mortality, with approximately half of all patients with SLE developing organ damage within 10 years of diagnosis 5 ⁇ 6 . There remains the need for a medical intervention that improves SLE disease activity across multiple systems.
  • Clinical manifestations of SLE include, but are not limited to, constitutional symptoms, alopecia, rashes, serositis, arthritis, nephritis, vasculitis, lymphadenopathy, splenomegaly, haemolytic anaemia, cognitive dysfunction and other nervous system involvement.
  • Increased hospitalisations and side effects of medications including chronic oral corticosteroids (OCS) and other immunosuppressive treatments add to disease burden in SLE 7 - 9 .
  • OCS chronic oral corticosteroids
  • Antimalarial agents e.g. hydroxychloroquine
  • corticosteroids may be used to control arthralgia, arthritis, and rashes.
  • Other treatments include nonsteroidal anti-inflammatory drugs (NSAIDs); analgesics for fever, arthralgia, and arthritis; and topical sunscreens to minimize photosensitivity. It is often difficult to taper subjects with moderate or severe disease completely off corticosteroids, which cause long-term morbidity and may contribute to early cardiovascular mortality 8 ⁇ 10 .
  • Phase II trials are conducted in a small number of volunteers who have the disease of interest. They are designed to test safety, pharmacokinetics, and pharmacodynamics. A phase II trial may offer preliminary evidence of drug efficacy. However, the small number of participants and primary safety concerns within a phase II trial usually limit its power to establish efficacy. A Phase III trial is required to demonstrate the efficacy and safety of a clinical candidate. Critically, many clinical candidates that have shown promise at Phase II fail at Phase III. More than 90% of novel therapeutics entering Phase I trials fail during clinical development, primarily because of failure in efficacy or safety. The probability of success at phase III, following successful Phase II, is less than 50% 12 .
  • Glucocorticoids are the most commonly used therapy for patients with SLE owing to their immunosuppressant and anti-inflammatory properties, which reduce disease activity and prevent flares. Up to 80% of patients with SLE are exposed to glucocorticoids, with the majority being treated long-term. Although it may provide short-term efficacy, the frequent or maintenance use of oral glucocorticoid therapy carries a significant burden of toxicity that can independently contribute to morbidity and mortality and can adversely affect health-related quality of life. Therefore, novel, effective, and long-term treatments for SLE are needed to both reduce overall disease activity and glucocorticoid use.
  • Anifrolumab (MEDI-546) is a human immunoglobulin G1 kappa (IgGlK) monoclonal antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1). It is composed of 2 identical light chains and 2 identical heavy chains, with an overall molecular weight of approximately 148 kDa. Anifrolumab inhibits binding of type I IFN to type I interferon receptor (IFNAR) and inhibits the biologic activity of all type I IFNs.
  • Type I interferons are cytokines that have been implicated in SLE pathogenesis based on the finding of increased IFN-stimulated gene expression in most patients with SLE.
  • treatment response assessed using British Isles Lupus Assessment Group [BILAGj-based Composite Lupus Assessment [BICLA]
  • BICLA British Isles Lupus Assessment
  • the present invention solves one or more of the above-mentioned problems.
  • the present invention relates to a method of treating systemic lupus erythematous (SLE) in a subject in need thereof, the method comprising administering a type I IFN receptor (IFNAR1) inhibitor to the subject, wherein the method reduces SLE activity in the subject compared to the SLE activity in the subject before treatment with the IFNAR1 inhibitor, and wherein the subject has received prior treatment with one or more immunomodulators before administration of the IFNAR1 inhibitor.
  • SLE systemic lupus erythematous
  • the invention also relates to a method of identifying a subject as suitable for treatment with an IFNAR1 inhibitor, the method comprising identifying the subject as having received prior treatment with one or more immunomodulators before administration of the IFNAR1 inhibitor, and administering the IFNAR1 inhibitor to the subject.
  • the invention also relates to a method of treating SLE in a subject in need thereof, the method comprising administering a IFNAR1 inhibitor to the subject, wherein the method reduces SLE activity in the subject compared to the SLE activity in the subject before treatment with the IFNAR1 inhibitor, and wherein the subject has severe, established and/or refractory SLE.
  • the invention is supported inter alia by data, presented herein forthe first time, from two phase III, multicenter, multinational, randomized, double-blind, placebo-controlled clinical trials (NCT02446899 and NCT02962960) demonstrating that an IFNAR1 inhibitor (anifrolumab) treats SLE in patients that have been previously treated with one or more immunomodulator biologies, wherein the SLE disease in the subject has not been controlled. Treatment with anifrolumab is more effective in these patients than in biologic naive patients.
  • the invention is also supported by data, presented herein forthe first time, demonstrating that an IFNAR1 inhibitor treats SLE in subjects who have moderate to severe SLE despite standard therapy (i.e. refractory disease).
  • FIG. 1 IFN scores distribution
  • FIG. 2 Previous use of biologic immunomodulators
  • FIG. 2A Antineoplastic and immunomodulating agents.
  • FIG. 2A Musculo-skeletal system. Percentages are based on all patients in the full analysis set within the respective study and treatment group. All medication is coded using WHO-DD version 2019SEP01 B3. Previous use: the end date is prior to investigational product dose (anifrolumab) administration on Day 1.
  • Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05).
  • FIG. 3 Baseline demongraphics, disease characteristics, and SLE treatments in biologic- experienced and biologic-naive patietns with SLE pooled from the TULIP-1 and TULIP-2 trials
  • FIG.4 Forest plot of efficacy endpoints in the biologic-experienced and biologic-naive patients with SLE in data pooled from the TULIP-1 and TULIP-2 trials
  • FIG. 5 BICLA response rate at Week 52 by previous use of abatacept, stratified Cochran-Mantel- Haenszel approach
  • FIG. 5A Previous use of abatacept.
  • FIG. 5B No previous use of abatacept.
  • Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1.
  • Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05).
  • Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders.
  • the responder/non-responder rates are calculated using a stratified CMH approach, with stratification factors SLEDAI-2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1.
  • FIG. 6 BICLA response rate at Week 52 by previous use of belimumab, stratified Cochran-Mantel- Haenszel approach
  • FIG. 6A Previous use of BELIMUMAB.
  • FIG. 6B No previous use of belimumab.
  • Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1.
  • Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05).
  • Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders.
  • the responder/non-responder rates are calculated using a stratified CMH approach, with stratification factors SLEDAI- 2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1.
  • FIG. 7 BICLA response rate at Week 52 by previous use of epratuzumab, stratified Cochran-Mantel- Haenszel approach
  • FIG. 7A Previous use of epratuzumab.
  • FIG. 7B No previous use of epratuzumab.
  • Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1.
  • Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05).
  • FIG. 8 BICLA response rate at Week 52 by previous use of rituximab, stratified Cochran-Mantel- Haenszel approach
  • FIG. 9A Previous use ofsifalimumab.
  • FIG.9B No previous use ofsifalimumab.
  • Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1.
  • Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05).
  • Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders.
  • FIG. 10 BICLA response rate at Week 52 by previous use of tabalumab, stratified Cochran-Mantel- Haenszel approach
  • FIG. 10A Previous use of tabalumab.
  • FIG. 10B No previous use of tabalumab.
  • Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1.
  • Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05).
  • Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders.
  • the responder/non-responder rates are calculated using a stratified CMH approach, with stratification factors SLEDAI-2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1.
  • FIG. 11 BICLA response rate at Week 52 by previous use of TNF inhibitors, stratified Cochran- Mantel-Haenszel approach
  • the responder/non-responder rates are calculated using a stratified CMH approach, with stratification factors SLEDAI- 2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1. TNF inhibitors are identified using preferred terms: adalimumab, etanercept, infliximab.
  • FIG. 12 Safety in biologic-experienced and biologic-naive patients with SLE in data pooled from the TULIP-1 and TULIP-2 trials
  • FIG. 13A Study MI-CP180 in SSc- Mean anifrolumab serum concentration-time profiles following a single IV dose. Data represent +/- SD. Mean data below LLOQ are not plotted. IV, intravenous; LLOQ, lower limit of quantification; MEDI 546, anifrolumab; n, number of patients in a subgroup; SSc, systemic sclerosis.
  • FIG. 13B Study 06 in healthy volunteers - Mean anifrolumab serum concentration-time profiles following a single SC and IV dose. Samples with actual collection time deviating from nominal collection time by >10% were excluded from the mean. IV, intravenous; N, number of subjects; SC, subcutaneous.
  • FIG. 14 Study 08 study design and results
  • FIG. 14A Study design for phase II of SC anifrolumab in SLE patients.
  • Study 08 (NCT02962960) evaluated the effect of two anifrolumab doses every other week.
  • FIG. 14B Mean serum concentration of anifrolumab overtime.
  • FIG. 14C Anifrolumab neutralization of the type I IFN gene signature
  • FIG. 15 Computed median AUC Ratios (SC/IV)
  • FIG. 15A Computed median AUC Ratio (SC/IV) between weeks 0-52 for various SC doses.
  • the computed median AUC Ratio (SC/IV) based on the estimated bioavailability from Study 06, between weeks 0-52, where the subcutaneous dose is either 75mg (+ sign), 90 mg (empty squares), 105 mg (circles), 120 mg (triangles), or 135 mg (filled squares).
  • the subcutaneous dose here is administered once every 7 days (QW); the IV dose is administered once every 4 weeks (Q4W) at a dose of 300 mg. Based on the AUC, both 90 and 105 mg SC QW appear similar to 300 mg IV.
  • FIG. 16 Anifrolumab concentration over time at different doses
  • FIG. 16A A plot showing (computed) trough concentrations of plasma anifrolumab in a patient administered either (i) 105 mg of anifrolumab subcutaneously, once every 7 days (straight line); (ii) 300 mg anifrolumab intravenously, once every 4 weeks (lower dotted line); (ii) 1000 mg anifrolumab intravenously, once every 4 weeks (upper dotted line). Shaded area represents the area between 5th and 95th percentiles of the 300 mg IV Q4W dose.
  • FIG. 16B Anifrolumab trough concentration in IFNGS high SLE subjects.
  • SC subcutaneous. Based on trough, both 90 and 105 mg SC QWwere projected to have higher PD suppressions than 300 mg IV.
  • FIG. 17 Positive Exposure-BICLA relationship observed in TULIP 1 & TULIP 2 in IFNGS high patients
  • FIG. 18 BICLA dose response
  • FIG. 18B Predicted PK and efficacy for different SC doses. The probability of meeting BICLA (in IFNGS high patients) for weekly subcutaneous doses starting from 105 mg, and up to 150 mg. Assumptions for generating the data include no dose delays/interruptions.
  • FIG. 19 Ctroug hs following injection at thigh compared to injection at abdomen [0038]
  • FIG. 19A 150 mg SC Q2W.
  • FIG. 19B 300 mg SC Q2W
  • FIG. 20 Exposure prediction based on 81-87% bioavailability and preliminary PK modelling
  • FIG.21 Anifrolumab Cave medium ratio predicted for 90-150 mg SC QW to 300 mg Q4W, based on PK preliminary modelling and bioavailability assumptions.
  • FIG.21 Anifrolumab C ave over 52 weeks in IFNGS high patients for different SC and IV doses [0040]
  • FIG. 21 A 105 mg SC QW.
  • FIG. 21 B 120 mg SC QW.
  • FIG. 21 C Overlap with 1000 mg IV Q4W.
  • FIG.22 Cave median ratio SC QWto 300 mg IV Q4W
  • FIG. 22A 81% bioavailability assumed.
  • FIG. 22B 70% bioavailability assumed.
  • FIG.23 Average anifrolumab concentration versus herpes zoster incidence
  • FIG. 24 Baseline demographics, SLE disease characteristics, and treatments in data pooled from TULI P-1 and TULIP-2 trials
  • BICLA BILAG-based Composite Lupus Assessment
  • Cl confidence interval
  • GC glucocorticoid
  • IFNGS interferon gene signature
  • n number of responders
  • N number of patients in the group
  • PGA Physicians’ Global Assessment.
  • FIG.28 Autoinjector
  • the accessorized pre-filled syringe (APFS) for anifrolumab of the functional variant thereof The primary tube is shown in assembled form (FIG. 29A) and in exploded view (FIG. 29B).
  • the APFS with its additional components is shown in assembled form (FIG. 29C) and in exploded view FIG. 29D).
  • the invention relates to a method of treating systemic lupus erythematous (SLE) in a subject in need thereof, the method comprising administering a type I IFN receptor (IFNAR1) inhibitor to the subject, wherein the method reduces SLE activity in the subject compared to the SLE activity in the subject before treatment with the IFNAR1 inhibitor, and wherein the subject has received prior treatment with one or more immunomodulators before administration of the IFNAR1 inhibitor.
  • SLE systemic lupus erythematous
  • the method may comprise identifying the subject as having been diagnosed with SLE at least 2 years before treatment with the IFNAR1 inhibitor.
  • the method may comprise identifying the subject as being IFN gene signature high subject, anti-dsDNA antibody positive, complement 4 (C4) low, having >1 BILAG-2004 A item and/or having a higher mean global SDI score.
  • Low complement may be defined as less than about 0.1 g/L C4 in the blood and/or less than about 0.9 g/L C3 in the blood.
  • the IFNAR1 inhibitor may be a human monoclonal antibody specific for IFNAR1.
  • the IFNAR1 inhibitor may be a modified lgG1 class human monoclonal antibody specific for IFNAR1.
  • the method may comprise steroid sparing in the 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.
  • the postsparing dose may be ⁇ 7.5 mg/day prednisone or prednisone equivalent dose.
  • the pre-sparing dose may be 20 mg/day prednisone or prednisone equivalent dose.
  • the steroid may comprise a glucocorticoid.
  • the steroid may comprise an oral glucocorticoid.
  • Administering the dose every week may provide a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by intravenous administration of 400 mg of anifrolumab or the functional variant thereof every 4 weeks.
  • the dose may be administered in a single-administration step.
  • the dose administered to the subject may be ⁇ 150 mg (i.e. less than 150 mg) anifrolumab or the functional variant thereof.
  • the dose administered to the subject may be >105 mg (i.e. more than 105 mg) anifrolumab orthe functional variant thereof.
  • the dose of administered to the subject may be ⁇ 135 mg (i.e. 135 mg or less) anifrolumab orthe functional variant thereof.
  • the dose administered to the subject may be about 120 mg anifrolumab orthe functional variant thereof.
  • Administration of the dose or unit dose may provide a trough concentration of anifrolumab or the functional variant thereof in the subject of about 20-100 pg/ml.
  • Administration of the dose or unit dose may provide a trough concentration of anifrolumab or the functional variant thereof in the subject of about 30-80 pg/ml.
  • Administration of the dose or unit dose may provide a trough concentration of anifrolumab or the functional variant thereof in the subject of about 40-70 pg/ml.
  • the dose or unit dose may provide a therapeutic effect in the subject that is at least equivalent to a therapeutic effect provided by administration of an intravenous dose of 300 mg anifrolumab or the functional variant thereof administered once every (Q4W).
  • the dose or unit dose may provide a trough concentration of anifrolumab or the functional variant thereof in the subject that is greater than a trough concentration of anifrolumab or the functional variant thereof provided by administration of an intravenous dose of 300 mg anifrolumab or the functional variant thereof once every 4 weeks (Q4W).
  • the anifrolumab or the functional variant thereof may be comprised within a pharmaceutical composition.
  • the pharmaceutical composition may comprise about 150 to 200 mg/ml anifrolumab or the functional variant thereof, about 25 to 150 mM of lysine sale and an uncharged excipient.
  • the pharmaceutical composition may comprise 150 mg/ml_ anifrolumab or the functional variant thereof.
  • the pharmaceutical composition may comprise 50 mM lysine HCI.
  • the pharmaceutical composition may comprise 130 mM trehalose dihydrate.
  • the pharmaceutical composition may comprise 0.05% polysorbate 80.
  • the pharmaceutical composition may comprise 25 mM histidine/histidine HCI.
  • the methods of the invention may comprise administering the dose or unit dose at intervals of 6-8 days.
  • the dose or unit dose may be administered once per week (QW).
  • the dose or unit dose may be 120 mg anifrolumab or the functional variant thereof, wherein the method comprises administering the dose in a single administration step once per week (QW). In other words, the method comprises administering 120 mg QW of anifrolumab of the functional variant thereof.
  • the dose or unit dose may be administered once per week for at least about 4 weeks.
  • the dose or unit dose may be administered once per week for at least about 8 weeks.
  • the dose or unit dose may be administered once per week for at least about 12 weeks.
  • the dose or unit dose may be administered once per week for at least about 16 weeks.
  • the dose or unit dose may be administered once per week for at least about 20 weeks.
  • the dose or unit dose may be administered once per week for at least about 24 weeks.
  • the dose or unit dose may be administered once per week for at least about 28 weeks.
  • the dose or unit dose may be administered once per week for at least about 32 weeks.
  • the dose or unit dose may be administered once per week for about 8 weeks.
  • the dose or unit dose may have a volume permitted it suitable delivery in a single subcutaneous administration step.
  • the dose or unit dose may have a volume of about 0.5 to about 1 ml.
  • the dose or unit dose may have a volume of less than 1 ml.
  • the dose or unit dose may have a volume of about 0.8 ml. 4.8.
  • the subject may have moderate to severe SLE pre-treatment with the IFNAR1 inhibitor.
  • Pretreatment with the IFNAR1 inhibitor the subject may be refractive to treatment with the one more immunomodulators or has relapsed during or following treatment with the one or more immunomodulators.
  • Pretreatment with the IFNAR1 inhibitor the subject may have a SLEDAI-2K score of >10 (at least).
  • Pretreatment with the IFNAR1 inhibitor the subject may have a CLASI activity score of >10 (at least 10).
  • Pretreatment with the IFNAR1 inhibitor the subject may have a swollen and tender joint count of >6.
  • the subject may have moderate to severe SLE as defined by the ACR Classification Criteria for SLE (ACR 1997 24 and/or EULAR/ACR 2019 25 ).
  • the invention also relates to a pharmaceutical composition for use in a method of treating CLE in a subject, the method comprising subcutaneously administering the pharmaceutical composition to a subject, wherein the pharmaceutical composition comprises a dose of anifrolumab or functional variant thereof, wherein the dose is >105 mg and ⁇ 150 mg.
  • the dose of anifrolumab of the functional variant thereof may 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.
  • anifrolumab or the functional variant thereof less than 150 mg anifrolumab or the functional variant thereof.
  • the dose may be >105 mg (i.e. more than 105 mg) anifrolumab or the functional variant thereof.
  • the dose may be ⁇ 135 mg (i.e. 135 mg or less) anifrolumab or the functional variant thereof.
  • the dose may be about 120 mg anifrolumab or the functional variant thereof.
  • the dose may be 120 mg anifrolumab or the functional variant thereof.
  • the pharmaceutical composition may be administered once per week for at least about 28 weeks.
  • the pharmaceutical composition may be administered once per week for at least about 32 weeks.
  • the pharmaceutical composition may be administered once per week for about 8 weeks.
  • the pharmaceutical composition may have a volume permitted it suitable delivery in a single subcutaneous administration step.
  • the pharmaceutical composition may have a volume of about 0.5 to about 1 ml.
  • the pharmaceutical composition may have a volume of less than 1 ml.
  • the pharmaceutical composition may have a volume of about 0.8 ml.
  • Administration of the pharmaceutical composition may provide a plasma concentration of anifrolumab or the functional variant thereof in the patient of > 10 pg (i.e. 10 pg or more) anifrolumab or the functional variant thereof per ml of plasma (i.e. a plasma concentration of > 10 pg/ml).
  • Administration of the pharmaceutical composition may provide a plasma concentration of anifrolumab or the functional variant thereof in the subject of about 10-100 pg/ml.
  • Administration of the pharmaceutical composition may provide a plasma concentration of anifrolumab or the functional variant thereof in the subject of about 20-80 pg/ml.
  • Administration of the pharmaceutical composition may provide a plasma concentration of anifrolumab or the functional variant thereof in the subject of about 30-70 pg/ml.
  • Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or the functional variant thereof in the subject of about 30-80 m9/itiI.
  • Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or the functional variant thereof in the subject of about 40-70 pg/ml.
  • the pharmaceutical composition may provide a therapeutic effect in the subject that is at least equivalent to a therapeutic effect provided by administration of an intravenous dose of 300 mg anifrolumab or the functional variant thereof administered once every (Q4W).
  • the pharmaceutical composition may provide a trough concentration of anifrolumab or the functional variant thereof in the subject that is greater than a trough concentration of anifrolumab or the functional variant thereof provided by administration of an intravenous dose of 300 mg anifrolumab or the functional variant thereof once every 4 weeks (Q4W).
  • the anifrolumab or the functional variant thereof may be comprised within a pharmaceutical composition.
  • the pharmaceutical composition may comprise about 150 to 200 mg/ml anifrolumab or the functional variant thereof, about 25 to 150 mM of lysine sale and an uncharged excipient.
  • the pharmaceutical composition may comprise 150 mg/ml_ anifrolumab or the functional variant thereof.
  • the pharmaceutical composition may comprise 50 mM lysine HCI.
  • the pharmaceutical composition may comprise 130 mM trehalose dihydrate.
  • the pharmaceutical composition may comprise 0.05% polysorbate 80.
  • the pharmaceutical composition may comprise 25 mM histidine/histidine HCI.
  • the pharmaceutical composition may comprise 150 mg/ml_ anifrolumab or the functional variant thereof, 50 mM lysine HCI, 130 mM trehalose dihydrate, 0.05% polysorbate 80 and 25 mM histidine/histidine HCI.
  • the pharmaceutical composition may comprise about 150 to 200 mg/ml anifrolumab or the functional variant thereof, about 25 to 150 mM of lysine sale and an uncharged excipient.
  • the pharmaceutical composition may comprise 150 mg/ml_ anifrolumab or the functional variant thereof.
  • the pharmaceutical composition may comprise 50 mM lysine HCI.
  • the pharmaceutical composition may comprise 130 mM trehalose dihydrate.
  • the pharmaceutical composition may comprise about 150 to 200 mg/ml anifrolumab or the functional variant thereof, about 25 to 150 mM of lysine sale and an uncharged excipient.
  • the pharmaceutical composition may comprise 150 mg/ml_ anifrolumab or the functional variant thereof.
  • the pharmaceutical composition may comprise 50 mM lysine HCI.
  • the invention also relates to an injection device comprising the unit dose of the invention, or the pharmaceutical composition for the use of any of the invention.
  • the pharmaceutical composition in the injection device may comprise about 150 to 200 mg/ml anifrolumab or the functional variant thereof, about 25 to 150 mM of lysine sale and an uncharged excipient.
  • the pharmaceutical composition in the injection device may comprise 150 mg/ml_ anifrolumab or the functional variant thereof.
  • the pharmaceutical composition in the injection device may comprise 50 mM lysine HCI.
  • the pharmaceutical composition may comprise 130 mM trehalose dihydrate.
  • the pharmaceutical composition in the injection device may comprise about 150 to 200 mg/ml anifrolumab or the functional variant thereof, about 25 to 150 mM of lysine sale and an uncharged excipient.
  • the pharmaceutical composition in the injection device may comprise 150 mg/ml_ anifrolumab or the functional variant thereof.
  • the pharmaceutical composition may comprise 50 mM lysine HCI.
  • the pharmaceutical composition in the injection device may comprise 130 mM trehalose dihydrate.
  • the pharmaceutical composition in the injection device may comprise 0.05% polysorbate 80.
  • the pharmaceutical composition in the injection device may comprise 25 mM histidine/histidine HCI.
  • the pharmaceutical composition in the injection device may comprise 150 mg/ml_ anifrolumab or the functional variant thereof, 50 mM lysine HCI, 130 mM trehalose dihydrate, 0.05% polysorbate 80 and 25 mM histidine/histidine HCI.
  • the invention in another aspect relates to an injection device comprising a unit dose.
  • the unit dose may comprise >105 mg (i.e. at least 105 mg) and ⁇ 150 mg (i.e. less than 150 mg) anifrolumab or a functional variant thereof.
  • the unit dose may comprise ⁇ 135 mg (i.e. 135 mg or less) anifrolumab or the functional variant thereof.
  • the unit dose may comprise about 120 mg anifrolumab or the functional variant thereof.
  • the unit dose in the injection device may comprise 120 mg anifrolumab or the functional variant thereof.
  • the unit dose in the injection device may consist essentially of >105 mg and ⁇ 150 mg anifrolumab or the functional variant thereof.
  • the kit of the invention may comprise packaging, wherein the packaging is adapted to hold the injection device and the instructions for use.
  • the instructions for use may be attached to the injection device.
  • the instruction for use may comprise instructions for administration of >105 mg and ⁇ 150 mg anifrolumab or functional variant thereof.
  • the instruction for use may comprise instructions for administration of ⁇ 135 mg anifrolumab or the functional variant thereof.
  • the instruction for use may comprise instructions for administration of 120 mg anifrolumab or the functional variant thereof.
  • the instruction for use may comprise instructions for administration of 120 mg anifrolumab or the functional variant thereof every 4 weeks.
  • the instructions for use may define the subject as having a type I IFN mediated disease.
  • the instructions may define the subject as having SLE.
  • the instructions may define the subject as having moderate to severe SLE.
  • the instructions for use may be written instructions.
  • the instructions for use may specify that the injection device, unit dose and/or pharmaceutical composition are for use in the treatment of SLE.
  • the instructions for use comprise instructions for administration of 120 mg anifrolumab or the functional variant thereof every week.
  • the instructions for use may specify that the unit dose or pharmaceutical composition of the invention are for use in the treatment of a subject that is refractory or unresponsive to treatment with the one or more immunomodulators.
  • the instructions for use may specify that the unit dose or pharmaceutical composition of the invention is for use in the treatment of a subject that is refractory or unresponsive to treatment with the one or more immunomodulators.
  • the instruction for use may specify that the unit dose or pharmaceutical composition of the invention is for use in any of the method of the invention.
  • the instructions for use may specify that the method of the invention has been demonstrated in a phase III clinical trial. 4.12. Formulations
  • the anifrolumab or the functional variant thereof may be comprised within a pharmaceutical composition.
  • the pharmaceutical composition may comprise about 150 to 200 mg/ml anifrolumab or the functional variant thereof, about 25 to 150 mM of lysine sale and an uncharged excipient.
  • the pharmaceutical composition may comprise 150 mg/ml_ anifrolumab or the functional variant thereof.
  • the pharmaceutical composition may comprise 50 mM lysine HCI.
  • the pharmaceutical composition may comprise 130 mM trehalose dihydrate.
  • the pharmaceutical composition may comprise 0.05% polysorbate 80.
  • the pharmaceutical composition may comprise 25 mM histidine/histidine HCI.
  • the pharmaceutical composition may comprise 150 mg/ml_ anifrolumab or the functional variant thereof, 50 mM lysine HCI, 130 mM trehalose dihydrate, 0.05% polysorbate 80 and 25 mM histidine/histidine HCI.
  • Anifrolumab (MEDI-546, anifro, ANI) is a human immunoglobulin G1 kappa (IgGlK) monoclonal antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1).
  • IFNAR1 type I interferon receptor
  • Anifrolumab downregulates IFNAR signaling and suppresses expression of IFN-inducible genes. Disclosures related to anifrolumab can be found in U.S. Patent No. 7662381 and U.S. Patent No. 9988459, which are incorporated herein by reference in their entirety. Sequence information for anifrolumab is provided in Table 5-1: Anifrolumab Sequences.
  • anifrolumab in terms of structure and has no clinically meaningful differences in terms of pharmacokinetics, safety and efficacy from the reference product.
  • the presence of clinically meaningful differences of a biosimilar may be assessed in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and an assessment of clinical immunogenicity.
  • An interchangeable product is a biosimilar that is expected to produce the same clinical result as the reference product in any given patient.
  • a variant of the reference (anifrolumab) antibody may comprise: 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 with the same affinity.
  • anifrolumab e.g. IFNAR
  • Sifalimumab (MEDI-545) is a fully human, immunoglobulin G1 k monoclonal antibody that binds to and neutralizes the majority of IFN-a subtypes 40 .
  • Sifalimumab is described US patent 7,741 ,449, which is incorporated herein by reference in its entirety.
  • the efficacy and safety of sifalimumab were assessed in a phase lib, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE).
  • SLEDAI-2K-defined resolution of rash is defined as a score of 0 at Week 52 for those with a score >2 for rash at baseline.
  • a dose of greater than 105 mg SC QW and less than 150 mg SC QW, and in particular a dose of 120 mg QW (a) maximizes efficacy whilst maintaining an acceptable safety profile, (b) mitigates the impact of variability in bioavailability and (c) mitigates the impact of variability in the onset of response.
  • dosing at greater than 105 mg QW advantageously accounts for the variance in bioavailability, leading to improved therapeutic outcome.
  • a dose of less than 150 mg QW mitigates the risk of herpes zoster infection.
  • TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) were randomized, placebo-controlled, 52- week trials of intravenously administered anifrolumab in patients with moderate to severe SLE despite standard therapy.
  • Inclusion criteria included fulfilling at least 4 of the ACR 1997 criteria for SLE, positive ANA and/or anti-dsDNA and anti-Sm antibodies, and moderate to severe SLE.
  • Data for investigating classification using EULAR/ACR 2019 criteria were combined from the ACR criteria, BILAG-specific SLE history, and documented medical history.

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See also references of EP4377349A1
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