Treatment of lupus

Abstract

The present disclosure relates to methods and compositions for the treatment of systemic lupus erythematosus (SLE). Specifically, the present disclosure relates to methods comprising administering a type I IFN receptor inhibitor to a subject.

Description

[Technical Field]

[0001] Anifrolumab (MEDI-546) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1). It is composed of two identical light chains and two identical heavy chains, with an overall molecular weight of approximately 148 kDa. Anifrolumab inhibits the binding of type I IFNs to the type I interferon receptor (IFNAR) and inhibits the biological activity of all type I IFNs.

[0002] Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem involvement that can range from mild to life-threatening. Given the need for long-term treatment, it is important to evaluate the safety and efficacy of novel therapies for SLE over the long term. However, long-term open-label studies of biologic agents leave some questions unanswered due to the lack of appropriate control groups [1, 2].

[0003] SLE disproportionately impacts the populations most severely affected by COVID-19. Individuals with SLE are often severely immunosuppressed and have a high comorbidity burden with multiple risk factors for more severe COVID-19. The causative agent of COVID-19 is SARS-CoV-2. Previous analyses have evaluated the outcomes of SARS-CoV-2 infection in rheumatic diseases as a group, but data on individuals with SLE are limited, and it remains unclear which risk factors are associated with worse COVID-19 outcomes in this population.

[0004] The effect of anifrolumab on SARS-CoV-2 infection or the efficacy of SARS-CoV-2 vaccination has not been evaluated. Vaccination efficacy depends on the stimulation of an immune response to the vaccine in vaccinated individuals. Therefore, inhibitors of type I IFN may be expected to reduce the efficacy of SARS-CoV-2 vaccination. SARS-CoV-2 vaccination has been shown to be less effective in immunocompromised populations [3]. It has also been suggested that treatment with anifrolumab may increase the risk of adverse events related to COVID-19, and that SLE patients should be vaccinated against viral infection before receiving anifrolumab treatment [4]. Treatment of patients with the biologic drug rituximab impairs antibody responses to immunity in patients with rheumatic diseases for at least 6–9 months after biologic infusion [5].

[0005] The present invention solves one or more of the problems set forth above. Summary of the Invention

[0006] The present invention relates to a method for treating systemic lupus erythematosus (SLE) and simultaneously preventing or reducing the risk of SARS-CoV-2 infection in a subject in need thereof, comprising administering to the subject a type I IFN receptor (IFNAR1) inhibitor and administering to the subject a therapeutically effective amount of a SARS-CoV-2 vaccine, thereby preventing or reducing the risk of SARS-CoV-2 infection in the subject after the subject has been exposed to SARS-CoV-2 and treating SLE in the subject.

[0007] The present invention also relates to a method for preventing or reducing the risk of SARS-CoV-2 infection in a subject in need thereof, wherein the subject has an autoimmune disease and is being treated with an IFNAR1 inhibitor. The method comprises administering a therapeutically effective amount of a SARS-CoV-2 vaccine to the subject, wherein the method prevents or reduces the risk of SARS-CoV-2 infection in the subject after the subject has been exposed to SARS-CoV-2.

[0008] The present invention also relates to a method for treating SLE in a subject in need thereof, wherein the subject has been vaccinated against COVID-19 with a SARS-CoV-2 vaccine. The method comprises administering to the subject a therapeutically effective amount of an IFNAR1 inhibitor, thereby treating SLE in the subject.

[0009] The invention also relates to pharmaceutical compositions and injection devices for use in such methods.

[0010] The present invention is particularly supported by data presented herein for the first time from a randomized, placebo-controlled, Phase 3 extension study of the long-term safety and tolerability of anifrolumab in SLE (NCT02794285). The data describe the first long-term, placebo-controlled study of SLE or a biologic during the global COVID-19 pandemic. The data surprisingly show that patients treated with IFNAR1 respond to vaccination with a SARS-CoV-2 vaccine. Vaccination of patients receiving long-term treatment with IFNAR1 has been shown to be effective in preventing COVID-19 infection, COVID-19 pneumonia, and COVID-19-related death in patients. The data further surprisingly show that COVID-19 vaccination does not affect the efficacy of treatment with an IFNAR1 inhibitor in patients with SLE. [Brief explanation of the drawings]

[0011] [Figure 1] Patients included in the TULIP-1 or TULIP-2 trials and the LTE study: Treatment randomization and treatment group definitions LTE, long-term extension. a There was an 8-week safety follow-up period. b All patients randomized to anifrolumab 150 mg were in TULIP-1. c Patients were re-randomized to anifrolumab 300 mg or placebo for the LTE study. [Figure 2]COVID-19 AE during the pandemic. AE, adverse event; BBC, British Broadcasting Corporation; COVID-19, coronavirus disease 2019; LTE, extended duration administration; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WHO, World Health Organization. Vaccine introduction dates: Argentina December 29, 2020; Australia February 21, 2021; Bulgaria December 30, 2020; Canada December 14, 2020; Chile December 21, 2020; Colombia February 17, 2021; France December 30, 2020; Germany December 23, 2020; Hungary December 23, 2020; Israel December 16, 2020; Japan February 17, 2021; Lithuania 2 December 23, 2020; Mexico December 24, 2020; Peru February 9, 2021; Poland December 23, 2020; Republic of Korea February 26, 2021; Romania January 27, 2021; Russia December 5, 2020; South Africa February 17, 2021; Spain December 30, 2020; Taiwan March 22, 2021; Ukraine February 24, 2021; United Kingdom December 21, 2020; United States December 14, 2020. Sources for vaccine introduction dates: Russia (BBC News), Taiwan (Ministry of Foreign Affairs, Republic of China (Taiwan)), other countries (WHO). Patients with multiple events are represented only once and report the most severe event (death, SAE, and AE; COVID-19 pneumonia, COVID-19, SARS-CoV-2 test positive). One AE, COVID-19 pneumonia, was not considered an SAE and did not require hospitalization. Circled dots indicate the event occurred after vaccination. One patient in the anifrolumab group received a single dose of COVID-19 vaccine before the reported event. [Figure 3] Change in mean SLEDAI-2K score from baseline to week 216. FU, follow-up; LS, least squares; LTE, long-term continuous treatment; SE, standard error; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000. [Figure 4]Cumulative glucocorticoid dose-normalized AUC over the 4-year study period for patients in the combination anifrolumab 300 mg or combination placebo groups, excluding 3 patients from the combination anifrolumab 300 mg group who had a glucocorticoid dose >40 mg / day at TULIP study baseline. AUC, area under the curve; GC, glucocorticoid; LTE, long-term extension; SE, standard error. [Figure 5] Mean SLEDAI-2K scores and mean GC dose-normalized AUC for patients receiving combination anifrolumab 300 mg or placebo, by study year. AUC, area under the curve; GC, glucocorticoid; SE, standard error; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000. Note: Analyses excluded patients with a glucocorticoid dose >40 mg / day at baseline. The number of participants at risk for aSLEDAI-2K was n = 358 (combination anifrolumab 300 mg) and n = 178 (combination placebo) for all time points. [Figure 6] Percentage of patients by glucocorticoid dose group in each year during the TULIP trial and the extension study. A, anifrolumab; P, placebo; GC, glucocorticoid; LTE, long-term extension. Proportion of patients by GC dose over time, excluding patients with a GC dose >40 mg / day at baseline. Combination anifrolumab 300 mg includes patients randomized to anifrolumab 300 mg at the start of the TULIP study and continued on anifrolumab 300 mg in the extension study. Combination placebo includes patients randomized to placebo in either the TULIP study or the extension study. [Figure 7]Mean ± SE change from baseline in SDI global score among patients with SDI ≥ 1 at Week 52 (LOCF). LOCF, last operation carried forward; LTE, Long-Term Continued Care; SDI, SDI Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index; SE, standard error. DETAILED DESCRIPTION OF THE INVENTION

[0012] Treatment method The present invention relates to a method for treating systemic lupus erythematosus (SLE) and preventing or reducing the risk of SARS-CoV-2 infection in a subject in need thereof, comprising: a) administering to the subject a type I IFN receptor (IFNAR1) inhibitor; and b) administering to the subject a therapeutically effective amount of a SARS-CoV-2 vaccine, wherein the method prevents or reduces the risk of SARS-CoV-2 infection in the subject after the subject has been exposed to SARS-CoV-2 and treats SLE in the subject.

[0013] The present invention also relates to a method for preventing or reducing the risk of SARS-CoV-2 infection in a subject in need thereof, wherein the subject has an autoimmune disease and is being treated with an IFNAR1 inhibitor, and the method comprises administering a therapeutically effective amount of a SARS-CoV-2 vaccine to the subject, wherein the method prevents or reduces the risk of SARS-CoV-2 infection in the subject after the subject has been exposed to SARS-CoV-2.

[0014] The present invention also relates to a method for treating SLE in a subject in need thereof, wherein the subject has been vaccinated against COVID-19 with a SARS-CoV-2 vaccine, and the method comprises administering to the subject a therapeutically effective amount of an IFNAR1 inhibitor, wherein the method treats SLE in the subject.

[0015] The present invention also relates to pharmaceutical compositions and injection devices for use in the methods of the present invention. The present invention relates to a pharmaceutical composition for use in a method for preventing or reducing the risk of SARS-CoV-2 infection in a subject, wherein the subject has an autoimmune disease and is being treated with an IFNAR1 inhibitor, the pharmaceutical composition comprising a SARS-CoV-2 vaccine, and the method comprising administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition prevents or reduces the risk of SARS-CoV-2 infection in the subject after the subject has been exposed to SARS-CoV-2. The present invention also relates to a pharmaceutical composition for use in a method for treating SLE in a subject in need thereof, wherein the subject has been vaccinated against COVID-19 with a SARS-CoV-2 vaccine, the pharmaceutical composition comprising an IFNAR1 inhibitor, and the method comprises administering the pharmaceutical composition to the subject, wherein the method treats SLE in the subject. The autoimmune disease may be lupus nephritis, cutaneous lupus erythematosus, myositis, or scleroderma.

[0016] COVID-19 and SARS-CoV-2 Vaccines Administration of a SARS-CoV-2 vaccine may prevent or reduce the risk of COVID-19 pneumonia in a subject. Administration of a SARS-CoV-2 vaccine may prevent or reduce the risk of COVID-19-related death in a subject. Administration of a SARS-CoV-2 vaccine may prevent or reduce adverse events associated with COVID-19 in a subject.

[0017] The IFNAR1 inhibitor may be administered to the subject less than one month before the SARS-CoV-2 vaccine. The IFNAR1 inhibitor may be administered on the same day as the SARS-CoV-2 vaccine.

[0018] The SARS-CoV-2 vaccine may be administered to the subject within about one month after administration of the IFNAR1 inhibitor to the subject. The SARS-CoV-2 vaccine may be administered to the subject one month after administration of the IFNAR1 inhibitor to the subject. The SARS-CoV-2 vaccine may be administered to the subject about 6, 5, 4, 3, or 2 months after administration of the IFNAR1 inhibitor to the subject. The SARS-CoV-2 vaccine may be administered to the subject one month after administration of the IFNAR1 inhibitor to the subject. The SARS-CoV-2 vaccine may be administered to the subject about four weeks after administration of the IFNAR1 inhibitor to the subject. The SARS-CoV-2 vaccine may be administered to the subject about 3, 2, or 1 week after administration of the IFNAR1 inhibitor to the subject.

[0019] The method may include administering at least two doses of a SARS-CoV-2 vaccine to a subject. The two doses of the SARS-CoV-2 vaccine may be administered to the subject within a period of 21 to 28 days. The two doses of the SARS-CoV-2 vaccine may be administered to the subject within a period of 14 to 56 days.

[0020] The IFNAR1 inhibitor may be administered to the subject less than one month before the SARS-CoV-2 vaccine is administered to the subject.

[0021] The subject may be fully vaccinated against COVID-19. The subject may be administered at least two doses of a SARS-CoV-2 vaccine. The two doses of a SARS-CoV-2 vaccine may be administered to the subject within a 21-28 day period. The two doses of a SARS-CoV-2 vaccine may be administered to the subject within a 14-56 day period. The subject may be vaccinated against COVID-19 within six months of administering the IFNAR1 inhibitor.

[0022] The SARS-CoV-2 vaccine may be selected from the group consisting of AZD1222, mRNA-1273, or BNT162b2 Tozinameran, or a combination thereof. The SARS-CoV-2 vaccine may be selected from the group consisting of SARS-CoV-2 vaccines including: intranasal SARS-CoV-2 vaccine (Altimmune), INO-4800 (Inovio Pharma and Beijing Advaccine Biotechnology Company), APN01 (APEIRON Biologics), mRNA-1273 vaccine (Moderna and the Vaccine Research Center), nucleoside-modified mNRA BNT162b2 Tozinameran (INN) (Pfizer-BioNTech), adenovirus-based vaccine AZD1222 (recombinant ChAdOx1 adenoviral vector encoding SARS-CoV-2 spike protein antigen; Oxford-AstraZeneca), Covishield (ChAdOx1_nCoV19) recombinant ChAdOx1 adenoviral vector encoding SARS-CoV-2 spike protein antigen (Serum Institute of India), SARS-CoV-2 vaccine (Vero cells), inactivated (lnCoV) (Sinopharm / BIBP), SARS-CoV-2 vaccine (Vero cells), inactivated (Sinovac), Ad26.COV2 encoding the SARS-CoV-2 spike (S) protein.S recombinant replication-incompetent type 26 adenovirus (Ad26) vectored vaccine (Janssen Pharmaceuticals Companies of Johnson & Johnson), Sputnik V human adenovirus vector-based Covid-19 vaccine (The Gamaleya National Center), Ad5-nCoV recombinant novel coronavirus vaccine (type 5 adenovirus vector) (CanSinoBIO), EpiVacCorona peptide antigen vaccine (Vector State Research Centre of Viralogy and Biotechnology, Russia), recombinant novel coronavirus vaccine (CHO) (Zhifei Longcom, China), SARS-CoV-2 vaccine, inactivated (Vero cells) (IMBCAMS, China), inactivated SARS-CoV-2 vaccine (Vero cells) (Sinopharm / WIBP), avian coronavirus infectious bronchitis virus (IBV) vaccine (MIGDAL Research Institute), modified horsepox virus vaccine TNX-1800 (Tonix Pharmaceuticals), a recombinant subunit vaccine based on the trimeric S protein (S-trimer) of the SARS-CoV-2 coronavirus (Clover Pharmaceuticals), an oral recombinant coronavirus vaccine (Vaxart), a linear DNA vaccine based on (i) the entire coronavirus spike gene or (ii) a coronavirus protein antigenic portion (Applied DNA Sciences and Takis Biotech), the SARS-Cov-2 coronavirus vaccine NVX-CoV2373 (Novavax), the SARS-Cov-2 coronavirus vaccine NVX-CoV2373 (Novavax), the intramuscular vaccine INO-4700 (GLS-5300) (Inovio Pharma and GeneOne Life Science), and combinations thereof.

[0023] SARS-CoV-2 Vaccine IFNAR1 inhibitors "Type I interferon receptor inhibitor" refers to a molecule that is antagonistic to the receptors of type I interferon ligands, such as interferon-α and interferon-β. After administration to a patient, such an inhibitor preferably results in a reduction in the expression of at least one (preferably at least four) pharmacodynamic (PD) marker gene selected from the group consisting of IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPST1, IFIT3, LY6E, OAS2, PLSCR1, SIGLECl, USP18, RTP4, and DNAPTP6. The at least four genes may suitably be IFI27, IFI44, IFI44L, and RSAD2. The "type I interferon receptor" is preferably the interferon-α / β receptor (IFNAR).

[0024] For example, a type I interferon receptor inhibitor may be an antibody or antigen-binding fragment thereof that inhibits type I IFN activity (by inhibiting the receptor). An example of a suitable antibody or antigen-binding fragment thereof (that inhibits type I IFN activity) is an interferon-α / β receptor (IFNAR) antagonist. A type I interferon receptor inhibitor may also be an antibody or antigen-binding fragment thereof that inhibits type I IFN activity. Additionally, or alternatively, a type I interferon receptor inhibitor may be a small molecule inhibitor of the type I interferon receptor (e.g., for pharmacological inhibition of type I interferon receptor activity).

[0025] The IFNAR1 inhibitor may be a human monoclonal antibody specific to IFNAR1. The IFNAR1 inhibitor may be a modified IgG1 class human monoclonal antibody specific to IFNAR1.

[0026] The antibody may comprise a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3. The antibody may comprise a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4. The antibody may comprise a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5. The antibody may comprise a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6. The antibody may comprise a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7. The antibody may comprise a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0027] The antibody may comprise a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1. The antibody may comprise a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. The antibody may comprise a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 9. The antibody may comprise a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 10. The antibody may comprise an amino acid substitution of L234F in the Fc region, as numbered by the EU index as set forth in Kabat, wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to the unmodified antibody. The antibody may comprise a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11. The antibody may comprise a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0028] The antibody may comprise: (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3; (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4; c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5; (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6; (b) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; (c) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0029] The antibody may comprise (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO:11, and (b) a human light chain comprising the amino acid sequence of SEQ ID NO:12.

[0030] The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0031] Dosage and administration method of IFNAR1 inhibitor The IFNAR1 inhibitor may be administered intravenously or subcutaneously. The IFNAR1 inhibitor may be administered at a dose of 120 mg to 1000 mg. The IFNAR1 inhibitor may be administered intravenously to a subject every four weeks (Q4W) at a dose of about 300 mg. The IFNAR1 inhibitor may be administered intravenously to a subject every four weeks (Q4W) at a dose of about 900 mg. The IFNAR1 inhibitor may be administered subcutaneously to a subject every week at a dose of about 120 mg.

[0032] The IFNAR1 inhibitor may be administered to a subject intravenously or subcutaneously. The IFNAR1 inhibitor may be administered to a subject at a dose of 120 mg to 1000 mg.

[0033] The IFNAR1 inhibitor may be administered intravenously to a subject at a dose of about 300 mg every four weeks (Q4W).The IFNAR1 inhibitor may be administered intravenously to a subject at a dose of about 900 mg every four weeks (Q4W).The IFNAR inhibitor may be administered subcutaneously to a subject at a dose of about 120 mg every week.

[0034] The method can include administering to a subject an intravenous dose of anifrolumab or a functional variant thereof. The intravenous dose can be ≧300 mg of anifrolumab or a functional variant thereof. The intravenous dose can be ≦1000 mg. The intravenous dose can be about 300 mg, about 900 mg, or about 1000 mg. The intravenous dose can be administered every four weeks (Q4W).

[0035] The method may include administering a subcutaneous dose of anifrolumab or a functional variant thereof. The subcutaneous dose may be >105 mg and <150 mg of anifrolumab or a functional variant thereof. The subcutaneous dose may be ≦135 mg of anifrolumab or a functional variant thereof. The subcutaneous dose may be about 120 mg. The subcutaneous dose may be administered in a single administration step. The subcutaneous dose may be administered at intervals of 6 to 8 days. The subcutaneous dose may be administered once weekly. The subcutaneous dose may have a volume of about 0.5 to about 1 ml. The subcutaneous dose may have a volume of about 0.8 ml.

[0036] The dosing regimen of the IFNAR1 inhibitor may include a first intensive regimen (IR) comprising 3 x 900 mg intravenous doses Q4W, followed by a basic regimen (BR) of a) weekly subcutaneous 120 mg doses, or b) intravenous 300 mg doses Q4W (or a combination of a) and b)). The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof. The dosing regimen may include a first intensive regimen (IR) comprising 6 x 900 mg intravenous doses Q4W, followed by a basic regimen (BR) of a) weekly subcutaneous 120 mg doses, or b) intravenous 300 mg doses Q4W (or a combination of a) and b). The dosing regimen may include a first intensive regimen (IR) comprising 6 x 1150 mg subcutaneous doses Q4W, followed by a basic regimen (BR) of a) weekly subcutaneous 120 mg doses, or b) intravenous 300 mg doses Q4W (or a combination of a) and b). The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0037] The method may include intravenously administering an intravenous dose of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) to a subject. The intravenous dose may be ≧300 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be ≦1000 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be 900 mg to 1000 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be >300 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be about 300 mg, about 900 mg, or 1000 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be 300 mg, 900 mg, or 1000 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be administered about every four weeks (Q4W). The intravenous dose may be administered about monthly. The 300 mg IV dose may be administered over a minimum of 30 minutes using an infusion pump. The 900 mg IV dose may be administered over a minimum of 60 minutes using an infusion pump. The 300 mg IV dose of anifrolumab may be supplied as a 2 ml vial at a concentration of 150 mg / mL.

[0038] The method may include subcutaneously administering a subcutaneous dose of anifrolumab or a functional variant thereof. The subcutaneous dose may be administered after, before, or during the intravenous administration of the intravenous dose. The subcutaneous dose may be >105 mg and <150 mg of anifrolumab or a functional variant thereof. The subcutaneous dose may be ≦135 mg of anifrolumab or a functional variant thereof. The subcutaneous dose may be about 120 mg of anifrolumab or a functional variant thereof. The subcutaneous dose may be administered in a single administration step. The subcutaneous dose may be administered at intervals of 6 to 8 days. The subcutaneous dose may be administered once weekly. The subcutaneous dose may have a volume of 0.5 to 1 ml. The subcutaneous dose may have a volume of 0.5 to 1.0 ml. The subcutaneous dose may have a volume of about 0.8 ml. The subcutaneous dose may have a volume of 0.8 ml. The subcutaneous dose can be about 1150 mg (e.g., 1155 or 1150 mg) of anifrolumab or a functional variant thereof. The subcutaneous dose may have a volume of about 8 ml. The subcutaneous dose may have a volume of about 7.7 ml.

[0039] The method may include administering to a subject a first dose of an IFNAR1 inhibitor, followed by a second dose of an IFNAR1 inhibitor, wherein the first dose is higher than the second dose. The first dose may be administered intravenously. The first dose may be >300 mg. The first dose may be ≦1000 mg. The first dose may be about 900 mg. The first dose may be administered Q4W. The first dose may be administered to a subject three times before the second dose is administered to the subject. The first dose may be administered to a subject six times before the second dose is administered to the subject. The first dose may be administered every four weeks for 12 weeks before the second dose is administered. The first dose may be administered every four weeks for 24 weeks before the second dose is administered. The first dose may be administered subcutaneously. The first dose may be about 1150 mg or 1150 mg. The first dose may be administered Q4W. The first dose may be administered to the subject three times before the second dose is administered to the subject. The first dose may be administered to the subject six times before the second dose is administered to the subject. The first dose may be administered every four weeks for 12 weeks before the second dose is administered. The first dose may be administered every four weeks for 24 weeks before the second dose is administered. The intravenous dose may be administered as part of an intensive administration regimen (IR), where the total dose of the IFNAR1 inhibitor administered during the IR is 2.7 to 81 g, optionally 72.9 g, over 12 to 24 weeks. The IR may include administration of an SC dose of the IFNAR1 inhibitor equivalent to a 900 to 1000 mg Q4W IV dose.

[0040] The second dose may be administered subcutaneously. The second dose may be >105 mg and ≦135 mg and may be administered subcutaneously. The second dose may be about 120 mg and may be administered subcutaneously. The second dose may be administered once a week.

[0041] The second dose may be administered intravenously. The second dose may be administered monthly. The second dose may be administered Q4W. The second dose may be ≧300 mg. The second dose may be ≦1000 mg and may be administered intravenously. The second dose may be about 300 mg and may be administered intravenously. The dose may be about 900 mg and may be administered intravenously Q4W, and the second dose is about 120 mg administered subcutaneously Q4W. The dose may be about 900 mg and may be administered intravenously Q4W, and the second dose is about 300 mg administered intravenously Q4W, optionally, the first dose is administered to the subject at least three times before the second dose is administered to the patient, and optionally, the first dose is administered to the subject at least six times before the second dose is administered to the patient. The second dose may be administered for at least one year.

[0042] The method provides a method for treating a subject with a steroid hormone, the method comprising administering to a subject ... The method may include administering a unit dose or pharmaceutical composition comprising 875, 880, 885, 890, 895, 890, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 1000, 1050, 1010, 1020, 1025, 1030, 1035, 1040, 1045, 1050, 1055, 1060, or 1065 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof).

[0043] The subject can be a patient with a high pre-treatment type I interferon stimulated gene signature (IFNGS) test. The method can include identifying the subject as a patient with a high pre-treatment IFNGS test.

[0044] Many SLE patients are administered corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Anifrolumab allows for the gradual reduction of corticosteroids (glucocorticoids) in SLE patients (steroid-sparing). A treatment method or method may include administering a corticosteroid to a subject, and optionally, the corticosteroid is an oral corticosteroid. The method may include gradually reducing the dose of corticosteroid administered to the subject (steroid-sparing). The method may include administering a first dose of corticosteroid, followed by administering a second dose of corticosteroid, where the second dose of corticosteroid is lower than the first dose of corticosteroid. The second dose of corticosteroid may be equal to or less than about 7.5 mg prednisone equivalent. The second dose of corticosteroid may be equal to or less than 5 mg prednisone equivalent. The method or treatment method may include administering a second dose of corticosteroid once daily. The first dose of corticosteroid may be approximately 10 mg prednisone equivalent. The method may include gradually reducing the dose of 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 a second dose of corticosteroid once daily. The method may allow for administration of a reduced dose of corticosteroid that is sustained for several weeks. The second dose of corticosteroid may be administered for at least 24 weeks. The second dose of corticosteroid may be administered for at least 28 weeks.

[0045] Steroid sparing The method may include steroid sparing in a subject, wherein the steroid dose administered to the subject is tapered from a pre-sparing dose at baseline to a post-sparing dose. The post-sparing dose may be a prednisone or prednisone equivalent dose of ≦7.5 mg / day. The pre-sparing dose may be a prednisone or prednisone equivalent dose of 20 mg / day. The steroid may include a glucocorticoid. The steroid may include an oral glucocorticoid. Steroids include hydrocortisone, mometasone, fluticasone, fluocinolone acetonide, fluocinolone, flurandrenolone acetonide, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, clocortolone, dihydroxycortisone, alclometasone, amcinonide, diflucortolone valerate, flucortolone, and fluprednidene. The steroid may be selected from the group consisting of fluandrenolone, fluorometholone, halcinonide, halobetasol, desonide, diflorasone, flurandrenolide, fluocinonide, prednicarbate, desoximetasone, fluprednisolone, prednisone, azelastine, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, 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.

[0046] subject The subject may be a human subject. The subject may be an adult. The subject may be a patient with an elevated type I IFN gene signature. The subject may be a patient with a high type I interferon stimulated gene signature (IFNGS) test before administration of a dose or unit dose. The subject may have elevated whole blood genes IFI27, IFI44, IFI44L, and RSAD2. The method may include identifying the subject as a patient with a high IFNGS test before treatment with a dose or unit dose. The method may include measuring expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subject's whole blood. The method may include measuring expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subject's whole blood by RT-PCR.

[0047] The subject may have previously been treated with an IFNAR1 inhibitor for moderate to severe SLE. Prior to treatment with an IFNAR1 inhibitor, the subject may be refractory to treatment with one or more immunomodulatory agents, or may have relapsed during or after treatment with one or more immunomodulatory agents. Prior to treatment with an IFNAR1 inhibitor, the subject may have a SLEDAI-2K score of (at least) 10 or greater. Prior to treatment with an IFNAR1 inhibitor, the subject may have a CLASI activity score of ≥ 10 (at least 10). Prior to treatment with an IFNAR1 inhibitor, the subject may have a swollen and tender joint count of ≥ 6.

[0048] The subject may have moderate to severe SLE as defined by the ACR classification criteria for SLE (ACR 1997

[10] and / or EULAR / ACR 2019

[11] ).

[0049] Pharmaceutical Composition The present 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 the subject, wherein the pharmaceutical composition comprises a dose of anifrolumab or a functional variant thereof, the dose being greater than 105 mg and less than 150 mg. The dose of anifrolumab or a functional variant thereof can be a unit dose (unit dosage form, pharmaceutical unit dosage form, pharmaceutical unit dose). Functional anifrolumab variants include antigen-binding fragments of anifrolumab, as well as antibodies and immunoglobulin derivatives of anifrolumab.

[0050] In another aspect, the present invention relates to a pharmaceutical composition for use in a method for treating SLE 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, and wherein weekly administration of the pharmaceutical composition provides a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by intravenous administration of 300 mg of anifrolumab or a functional variant thereof every four weeks. Administering the weekly dose may provide a plasma concentration in the subject that is approximately equivalent to the plasma concentration provided by intravenous administration of 400 mg of anifrolumab or a functional variant thereof every four weeks. The dose may be <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The dose may be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose may be ≦135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. The dose may be about 120 mg of anifrolumab or a functional variant thereof.The dose may be about 120 mg of anifrolumab or a functional variant thereof.

[0051] The pharmaceutical composition may be administered at intervals of 6 to 8 days. The pharmaceutical composition may be administered once weekly (QW). The pharmaceutical composition may be administered in a single administration step. The dose may be 120 mg of anifrolumab or a functional variant thereof, and the treatment method may comprise administering the dose in a single administration step once weekly (QW). The pharmaceutical composition may be administered once weekly for at least about 4 weeks. The pharmaceutical composition may be administered once weekly for at least about 8 weeks. The dose or unit dose may be administered once weekly for at least about 12 weeks. The pharmaceutical composition may be administered once weekly for at least about 16 weeks. The pharmaceutical composition may be administered once weekly for at least about 20 weeks. The pharmaceutical composition may be administered once weekly for at least about 24 weeks. The pharmaceutical composition may be administered once weekly for at least about 28 weeks. The pharmaceutical composition may be administered once weekly for at least about 32 weeks. The pharmaceutical composition may be administered once weekly for about 8 weeks. The pharmaceutical composition may have a volume that allows for adequate 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.

[0052] Administration of the pharmaceutical composition may provide in a patient a plasma concentration of anifrolumab or a functional variant thereof of ≥ 10 μg per ml of plasma (i.e., 10 μg or more) (i.e., a plasma concentration of ≥ 10 μg / ml). Administration of the pharmaceutical composition may provide in a subject a plasma concentration of anifrolumab or a functional variant thereof of about 10-100 μg / ml. Administration of the pharmaceutical composition may provide in a subject a plasma concentration of anifrolumab or a functional variant thereof of about 20-80 μg / ml. Administration of the pharmaceutical composition may provide in a subject a plasma concentration of anifrolumab or a functional variant thereof of about 30-70 μg / ml. Administration of the pharmaceutical composition may provide in a subject a trough concentration of anifrolumab or a functional variant thereof of ≥ 20 μg / ml (i.e., 20 μg / ml or more). Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof of ≥ 30 μg / ml (i.e., 30 μg / ml or more) in a subject. Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof of ≥ 40 μg / ml (i.e., 40 μg / ml or more) in a subject. Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof of about 20-100 μg / ml in a subject. Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof of about 30-80 μg / ml in a subject. Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof of about 40-70 μg / ml in a subject.

[0053] The pharmaceutical composition may provide a therapeutic effect in a subject that is at least equivalent to that provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof administered once (Q4W). The pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof in a subject that is higher than the trough concentration of anifrolumab or a functional variant thereof provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof once every four weeks (Q4W). Anifrolumab or a functional variant thereof may be contained within a pharmaceutical composition. The pharmaceutical composition may comprise about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0054] The pharmaceutical composition may comprise about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged 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 about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged 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% polysorbate 80. The pharmaceutical composition may include 25 mM histidine / histidine HCl. The pharmaceutical composition may include 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0055] device The present invention also relates to an injection device containing a pharmaceutical composition for use in the method of the present invention.

[0056] The pharmaceutical product in the injection device may contain >105 mg (i.e., more than 105 mg) and <150 mg (i.e., less than 150 mg) of anifrolumab or functional variants thereof. The pharmaceutical composition in the injection device may contain about 120 mg of anifrolumab or functional variants thereof. The pharmaceutical composition in the injection device may contain 120 mg of anifrolumab or functional variants thereof. The concentration of anifrolumab or functional variants thereof in the pharmaceutical composition in the injection device may be 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.

[0057] The pharmaceutical composition in the injection device may comprise about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged 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 about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged 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% polysorbate 80. The pharmaceutical composition in the injection device may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition in the injection device may comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0058] In another aspect, the present invention relates to an injection device comprising a unit dose for use in the methods of the present invention. The unit dose may comprise >105 mg (i.e., at least 105 mg) and <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The unit dose may comprise ≦135 mg (i.e., ≦135 mg) of anifrolumab or a functional variant thereof. 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 >105 mg and <150 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device may consist essentially of ≦135 mg of anifrolumab or a functional variant thereof. 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 functional variants thereof in a 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 unit dose in the injection device may have a volume of about 0.5 to about 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 to 200 mg / ml anifrolumab or functional variants thereof, about 25 to 150 mM lysine salt, and an uncharged excipient. The unit dose in the injection device may comprise a formulation of 150 to 200 mg / ml anifrolumab or functional variants thereof, 25 to 150 mM lysine salt, and an uncharged excipient. The unit dose comprises a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation may have a pH of about 5.9.

[0059] The injection device may be a pre-filled syringe (PFS). The injection device may be an accessory pre-filled syringe (AFPS). The injection device may be an auto-injector (AI).

[0060] kit In another aspect, the invention relates to a kit comprising a unit dose of the invention and instructions for use, wherein the instructions include instructions for subcutaneous administration of an IFNAR1 inhibitor to a subject.

[0061] In another aspect, the invention relates to a kit comprising a pharmaceutical composition for use according to the invention, wherein the instructions for use comprise instructions for subcutaneous administration of the pharmaceutical composition to a subject.

[0062] In another aspect, the invention relates to a kit comprising any of the injection devices of the invention and instructions for use, wherein the instructions comprise instructions for use of the injection device for subcutaneously administering a unit dose or pharmaceutical composition to a subject. The kit may also include a pharmaceutical composition comprising a SARS-CoV-2 vaccine.

[0063] The kit of the present invention can include packaging adapted to hold an injection device and instructions for use. The instructions for use may be attached to the injection device. The instructions for use may include instructions for administering >105 mg and <150 mg of anifrolumab or a functional variant thereof. The instructions for use may include instructions for administering ≦135 mg of anifrolumab or a functional variant thereof. The instructions for use may include instructions for administering 120 mg of anifrolumab or a functional variant thereof. The instructions for use may include instructions for administering 120 mg of anifrolumab or a functional variant thereof every four weeks. The instructions for use may define the subject as having a type I IFN-mediated disease. The instructions for use may define the subject as having an autoimmune disease. The instructions for use may define the subject as having SLE. The instructions for use may define the subject as having moderate to severe SLE. The instructions for use may be written instructions.

[0064] The instructions for use may specify that the injection device, unit dose, and / or pharmaceutical composition is for use in treating SLE or for use in accordance with the methods of the invention. The instructions for use include instructions for weekly administration of 120 mg of anifrolumab or a functional variant thereof. The instructions for use may specify that the unit dose or pharmaceutical composition of the invention is for use in treating a subject who may have received a SARS-CoV-2 vaccine. The instructions for use may specify that the unit dose or pharmaceutical composition of the invention is for use in any of the methods of the invention. The instructions for use may specify that the methods of the invention have been validated in a Phase III clinical trial.

[0065] formulation Anifrolumab or a functional variant thereof may be contained within a pharmaceutical composition. The pharmaceutical composition may comprise about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0066] Stable formulations comprising anifrolumab suitable for administration to a subject are described in detail in U.S. Pat. No. 10,125,195 (B1), which is incorporated herein in its entirety.

[0067] definition IFNAR inhibitors Anifrolumab Anifrolumab (MEDI-546, anifro, ANI) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) against subunit 1 of the type I interferon receptor (IFNAR1). Anifrolumab downregulates IFNAR signaling and suppresses the expression of IFN-inducible genes. Disclosures regarding anifrolumab can be found in U.S. Patent Nos. 7,662,381 and 9,988,459, which are incorporated by reference in their entireties. Sequence information for anifrolumab is provided in Table 1.

[0068] [Table 1]

[0069] Anifrolumab is an immunoglobulin comprising HCDR1, HCDR2, and HCDR3 (or functional variants thereof) of SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, respectively; and LCDR1, LCDR2, and LCDR3 (or functional variants thereof) of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively. Anifrolumab is an immunoglobulin comprising a VH of SEQ ID NO:1 and a VL of SEQ ID NO:2.

[0070] The constant region of anifrolumab has been modified so that anifrolumab exhibits reduced affinity for at least one Fc ligand compared to the unmodified antibody. Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1, containing an amino acid substitution L234F in the Fc region, as numbered by the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, VA). Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1, containing an amino acid substitution L234F, L235E, and / or P331S in the Fc region, as numbered by the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, VA). Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO: 9. Anifrolumab is an antibody comprising a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO: 9 and a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 11. Anifrolumab is an antibody comprising a light chain of SEQ ID NO: 12. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0071] Functional variants of anifrolumab are sequence variants that perform the same function as anifrolumab. Functional variants of anifrolumab are variants that bind to the same target as anifrolumab and have the same effector function 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 structurally similar to an approved (e.g., FDA-approved) biological product (reference product, e.g., anifrolumab) and does not have clinically meaningful differences from the reference product in terms of pharmacokinetics, safety, and efficacy. The presence of clinically meaningful differences in biosimilars can be evaluated in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and clinical immunogenicity assessments. An interchangeable product is a biosimilar that is expected to produce the same clinical outcome as the reference product in any given patient.

[0072] For example, a variant of a reference (anifrolumab) antibody may comprise a heavy chain CDR1 with at most two amino acid differences when compared to SEQ ID NO:3; a heavy chain CDR2 with at most two amino acid differences when compared to SEQ ID NO:4; a heavy chain CDR3 with at most two amino acid differences when compared to SEQ ID NO:5; a light chain CDR1 with at most two amino acid differences when compared to SEQ ID NO:6; a light chain CDR2 with at most two amino acid differences when compared to SEQ ID NO:7; and a light chain CDR3 with at most two amino acid differences when compared to SEQ ID NO:8; wherein the variant antibody binds to the target of anifrolumab (e.g., IFNAR), preferably with the same affinity.

[0073] For example, a variant of a reference (anifrolumab) antibody may comprise a heavy chain CDR1 that has at most one amino acid difference when compared to SEQ ID NO:3; a heavy chain CDR2 that has at most one amino acid difference when compared to SEQ ID NO:4; a heavy chain CDR3 that has at most one amino acid difference when compared to SEQ ID NO:5; a light chain CDR1 that has at most one amino acid difference when compared to SEQ ID NO:6; a light chain CDR2 that has at most one amino acid difference when compared to SEQ ID NO:7; and a light chain CDR3 that has at most one amino acid difference when compared to SEQ ID NO:8; wherein the variant antibody binds to the target of anifrolumab (e.g., IFNAR), optionally with the same affinity.

[0074] A variant antibody may have a total of at most 5, 4, or 3 amino acid differences in its CDRs when compared to the corresponding reference (anifrolumab) antibody, provided that there is at most 2 (optionally at most 1) amino acid difference per CDR. A variant antibody may have a total of at most 2 (optionally at most 1) amino acid difference in its CDRs when compared to the corresponding reference (anifrolumab) antibody, provided that there is at most 2 amino acid difference per CDR. A variant antibody may have a total of at most 2 (optionally at most 1) amino acid difference in its CDRs when compared to the corresponding reference (anifrolumab) antibody, provided that there is at most 1 amino acid difference per CDR.

[0075] A variant antibody may have a total of at most 5, 4, or 3 amino acid differences in its framework regions when compared to a corresponding reference (anifrolumab) antibody, provided that there is at most 2 (optionally at most 1) amino acid difference per framework region. Optionally, a variant antibody has a total of at most 2 (optionally at most 1) amino acid difference in its framework regions when compared to a corresponding reference (anifrolumab) antibody, provided that there is at most 2 amino acid difference per framework region. Optionally, a variant antibody has a total of at most 2 (optionally at most 1) amino acid difference in its framework regions when compared to a corresponding reference (anifrolumab) antibody, provided that there is at most 1 amino acid difference per framework region.

[0076] The variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein the heavy chain has at most 14 amino acid differences (at most two amino acid differences in each CDR and at most two amino acid differences in each framework region) compared to the heavy chain sequences herein, and the light chain has at most 14 amino acid differences (at most two amino acid differences in each CDR and at most two amino acid differences in each framework region) compared to the light chain sequences herein; the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody, preferably with the same affinity.

[0077] A variant heavy or light chain may be referred to as a "functional equivalent" of a reference heavy or light chain. A variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein the heavy chain has at most seven amino acid differences (at most one amino acid difference in each CDR and at most one amino acid difference in each framework region) compared to the heavy chain sequences herein, and the light chain has at most seven amino acid differences (at most one amino acid difference in each CDR and at most one amino acid difference in each framework region) compared to the light chain sequences herein; the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody, optionally with the same affinity.

[0078] Functional variants of anifrolumab Functional variants of anifrolumab include antibodies described in WO 2018 / 023976(A1), which is incorporated herein by reference (Table 2).

[0079] [Table 2]

[0080] Functional variants include antibodies comprising the VH amino acid sequence SEQ ID NO: 13. Functional variants include antibodies comprising the VH amino acid sequence SEQ ID NO: 16. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 14. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 15. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0081] The IFNAR inhibitor may be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 13. The anti-IFNAR antibody may comprise the VH amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 14. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0082] QX006N Functional variants of anifrolumab and anti-IFNAR antibodies include the QX006N antibody described in CN11327807, which is incorporated herein by reference.

[0083] [Table 3]

[0084] The IFNAR inhibitor may be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 17. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 18.

[0085] 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 of SEQ ID NO: 17 and the VL amino acid sequence of SEQ ID NO: 18.

[0086] Anifrolumab in the clinic The safety of anifrolumab has been evaluated in eight blinded or open-label intravenous (IV) and subcutaneous (SC) studies: six studies in patients with SLE (Study 05, Study 04, Study 1013, Study 1145, and Study 08), one study in patients with systemic sclerosis (SSc) (Study MI-CP180), and one study in healthy volunteers (Study 06) (Table 4). Two of these studies (Studies 08 and 06) used SC anifrolumab administration. Two studies are ongoing: one in patients with SLE (Study 09) and one in patients with lupus nephritis (LN) (Study 07).

[0087] [Table 4]

[0088] Study 1013 is described in more detail in Furie et al., 2017

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

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

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

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

[0089] formulation Stable formulations comprising anifrolumab suitable for administration to a subject are described in detail in U.S. Pat. No. 10,125,195 (B1), which is incorporated herein in its entirety.

[0090] The following examples illustrate certain aspects of the present disclosure and various uses thereof. They are provided for illustrative purposes only and should not be construed as limiting the scope of the disclosure in any way.

[0091] Type I IFN gene signature (IFNGS) Type I IFN is thought to play a central role in the pathogenesis of SLE disease, and inhibition of this pathway is targeted by anifrolumab. To understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know whether a subject's disease is driven by type I IFN activation. However, direct measurement of type I IFN remains challenging. Therefore, transcript-based markers were developed to assess the effect of target protein overexpression on a specific set of mRNA markers. Expression of these markers is easily detected in whole blood and correlates with expression in affected tissues, such as skin, in SLE. The bimodal distribution of transcript scores for SLE subjects supports the definition of high and low IFN test subpopulations (Error! Reference source not found). Type I IFN testing is described in International Publication No. 2011028933(A1), the entire contents of which are incorporated herein by reference. The type I IFN gene signature can be used to identify subjects as having a type I IFN gene signature (IFNGS) test high or IFNGS test low. The IFNGS test measures the expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in a subject's whole blood relative to three reference genes: 18S, ACTB, and GAPDH. The result of the test is a score compared to pre-established cutoffs that classify patients into two groups: those with low or high levels of IFN-inducible gene expression (Error! Reference source not found).

[0092] Gene expression can be measured by RT-PCR. Suitable primers and probes for detecting genes can be found in WO2011028933. A suitable kit for measuring gene expression for the IFNGS test is the QIAGEN therascreen® IFIGx RGQ RT-PCR kit (IFIGx kit) as described in Brohawn et al.

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

[0093] COVID-19 Vaccine Examples of vaccines against COVID-19 are shown in Table 5 below.

[0094] [Table 5]

[0095] SARS-CoV-2 vaccines include: intranasal SARS-CoV-2 vaccine (Altimmune), INO-4800 (Inovio Pharma and Beijing Advaccine Biotechnology Company), APN01 (APEIRON Biologics), mRNA-1273 vaccine (Moderna and the Vaccine Research Center), nucleoside-modified mNRA BNT162b2 Tozinameran (INN) (Pfizer-BioNTech), adenovirus-based vaccine AZD1222 (recombinant ChAdOx1 adenoviral vector encoding the SARS-CoV-2 spike protein antigen; Oxford-AstraZeneca), Covishield (ChAdOx1_nCoV19) recombinant ChAdOx1 adenoviral vector encoding the SARS-CoV-2 spike protein antigen (Serum Institute of India), SARS-CoV-2 vaccine (Vero cells), inactivated (lnCoV) (Sinopharm / BIBP), SARS-CoV-2 vaccine (Vero cells), inactivated (Sinovac), Ad26.COV2 encoding the SARS-CoV-2 spike (S) protein.S recombinant replication-incompetent type 26 adenovirus (Ad26) vectored vaccine (Janssen Pharmaceuticals Companies of Johnson & Johnson), Sputnik V human adenovirus vector-based Covid-19 vaccine (The Gamaleya National Center), Ad5-nCoV recombinant novel coronavirus vaccine (type 5 adenovirus vector) (CanSinoBIO), EpiVacCorona peptide antigen vaccine (Vector State Research Centre of Viralogy and Biotechnology, Russia), recombinant novel coronavirus vaccine (CHO) (Zhifei Longcom, China), SARS-CoV-2 vaccine, inactivated (Vero cells) (IMBCAMS, China), inactivated SARS-CoV-2 vaccine (Vero cells) (Sinopharm / WIBP), avian coronavirus infectious bronchitis virus (IBV) vaccine (MIGDAL Research Institute), modified horsepox virus vaccine TNX-1800 (Tonix Pharmaceuticals), a recombinant subunit vaccine based on the trimeric S protein (S-trimer) of the SARS-CoV-2 coronavirus (Clover Pharmaceuticals), an oral recombinant coronavirus vaccine (Vaxart), a linear DNA vaccine based on (i) the entire coronavirus spike gene or (ii) a coronavirus protein antigenic portion (Applied DNA Sciences and Takis Biotech), the SARS-Cov-2 coronavirus vaccine NVX-CoV2373 (Novavax), the SARS-Cov-2 coronavirus vaccine NVX-CoV2373 (Novavax), the intramuscular vaccine INO-4700 (GLS-5300) (Inovio Pharma and GeneOne Life Science), and combinations thereof.

[0096] Example 1: A randomized, placebo-controlled, phase 3 extension study of the long-term safety and tolerability of anifrolumab in active systemic lupus erythematosus summary the purpose To investigate the long-term safety and tolerability of anifrolumab 300 mg versus placebo in patients who completed the TULIP trial and were enrolled in a placebo-controlled 3-year extension study (CT.gov reference number NCT02794285).

[0097] method Patients received anifrolumab 300 mg or placebo every 4 weeks in a blinded extension study. The primary comparison in the long-term extension (LTE) was between patients who received anifrolumab 300 mg or placebo throughout both the TULIP study and the LTE. For rare safety events, comparisons included patients who received any dose of anifrolumab during the TULIP study or the LTE. Rates were adjusted for exposure per 100 patient-years (EAIR) when exposures differed.

[0098] result During the LTE period, the rate of serious adverse events (SAEs) was numerically lower with anifrolumab compared with placebo (8.5 vs. 11.2), including AEs leading to discontinuation of study drug (2.5 vs. 3.2). The rate of non-opportunistic serious infections was similar between groups (3.7 vs. 3.6). The rate of COVID-related AEs, including asymptomatic infections, was higher with anifrolumab compared with placebo (10.2 vs. 6.3). Surprisingly, no COVID-related AEs, including SAEs, occurred in fully vaccinated individuals. Rates of malignancies and serious acute cardiovascular events were low and comparable between anifrolumab and placebo. Treatment with anifrolumab was associated with lower cumulative glucocorticoid use and greater mean improvement in SLEDAI-2K compared with placebo.

[0099] conclusion This LTE study represents the longest placebo-controlled clinical trial conducted in SLE to date. No new safety findings were identified in the LTE, supporting the favorable benefit-risk profile of anifrolumab for patients with moderate to severe SLE receiving standard therapy. No COVID-related AEs occurred in patients after they completed vaccination.

[0100] Introduction We report here the results of the first long-term, placebo-controlled study in SLE to characterize the safety and tolerability of intravenous anifrolumab versus placebo in patients with moderate-to-severe SLE despite standard therapy. To be eligible for this placebo-controlled long-term extension (LTE) study (NCT02794285), patients had to have completed the Phase 3 TULIP trial (NCT02446912 or NCT02446899) ​​throughout the 52-week double-blind treatment period. Given the context of the COVID-19 pandemic that occurred during the final year of this comprehensive, multicenter extension study, this is also the first report on the safety profile of an investigational biologic in SLE during the pre- and post-vaccination periods of the COVID-19 pandemic.

[0101] method research design This study reports on a 3-year, phase 3, randomized, double-blind, placebo-controlled LTE study (15) conducted across 176 study sites in 24 countries in patients who completed the 52-week double-blind treatment period of one of the phase 3 TULIP trials (TULIP-1: NCT02446899 or TULIP-2: NCT02446912) [19, 20]. Patients were required to have moderate to severe SLE at the time of randomization to TULIP-1 or TULIP-2 and were allowed to participate in the extension study upon re-consent. The initiation of the LTE was at the end of the double-blind treatment period of the TULIP trial (Figure 1). At the time of extension study enrollment, patients previously treated with anifrolumab 300 mg remained on blinded anifrolumab 300 mg. Patients previously treated with anifrolumab 150 mg during TULIP-1 were switched to blinded anifrolumab 300 mg; patients previously randomized to placebo were re-randomized 1:1 to blinded anifrolumab 300 mg or placebo by the Interactive Voice / Web Response System algorithm, yielding an approximate final anifrolumab 300 mg to placebo ratio of 4:1.

[0102] For primary safety, the primary comparison group was between patients in the 3-year LTE study who received anifrolumab 300 mg in both TULIP and LTE ("LTE anifrolumab 300 mg") and patients who received placebo during the same time frame ("LTE placebo") (Figure 1). For rare safety events (e.g., malignancies, serious acute cardiovascular events), data throughout the 4-year TULIP and LTE periods were used, and the primary comparison group was patients with any anifrolumab exposure ("all anifrolumab" group) versus patients with any placebo exposure ("all placebo" group) (Figure 1). Data from patients randomized to placebo in TULIP and then to anifrolumab 300 mg in LTE are included in the "all anifrolumab" group after the first dose of anifrolumab in LTE. Because 150 mg anifrolumab is not the recommended dose for SLE, patients who switched from the 150 mg anifrolumab dose in TULIP-1 to the 300 mg dose in LTE were included in the overall anifrolumab group and are described only in the context of this group for the purposes of this analysis.

[0103] For efficacy comparisons, including disease activity and steroid use, the primary comparison group during the 4-year TULIP and LTE periods was patients who received anifrolumab 300 mg or placebo in the TULIP study and continued the same treatment through LTE (the "combined anifrolumab 300 mg" vs. "combined placebo" groups, respectively). Note that an important difference between these groups and the LTE anifrolumab 300 mg and LTE placebo groups was the time frame analyzed (TULIP and LTE: 1-4 years vs. LTE only: 2-4 years).

[0104] Patients received intravenous anifrolumab 300 mg or placebo every 4 weeks after initiation of LTE (after the last visit in the TULIP study) for up to 39 doses. After the 156-week treatment period in LTE (the last dose of study drug given at week 152), patients continued in the study for an additional 8 weeks to complete a 12-week safety follow-up period after their last dose. The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Guidance for Good Clinical Practice. All patients provided informed consent, and the study was approved by an ethical committee or institutional review board.

[0105] patient Patients enrolled in the LTE must have completed 52 weeks of treatment in either TULIP-1 or TULIP-2. Full details of the inclusion and exclusion criteria for the TULIP trial have been previously described [19, 20] and are briefly described below. The extension study was designed to reflect real-world clinical practice and allowed investigators to add or modify background standard of care treatments, including immunosuppressants and glucocorticoids, based on clinical judgment. However, the use of cyclophosphamide, other biologics, intravenous immunoglobulin, or intravenous glucocorticoids was not permitted.

[0106] TULIP research Briefly, inclusion criteria for the TULIP study were patients aged 18–70 years, with a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥6; a clinical SLEDAI-2K score of ≥4; a revised British Isles Lupus Assessment Group 2004 (BILAG-2004) organ domain score of ≥1 for item A or ≥2 for item B; a Physician's Global Assessment (PGA) score of ≥1 (on a 0–3 scale); seropositivity for antinuclear antibodies, anti-double-stranded DNA (anti-dsDNA), or anti-Smith antibodies; and ongoing stable treatment with at least one of the following: prednisone or equivalent, antimalarial drugs, azathioprine, mizoribine, mycophenolate mofetil, mycophenolic acid, or methotrexate.

[0107] LTE research To be included in the LTE study, patients had to have received anifrolumab or placebo in one of the TULIP trials, completed a 52-week double-blind treatment period, and provided written informed consent before participating in any protocol-related procedures. Patients were excluded if they had any condition that, in the investigator's opinion, would interfere with the evaluation of the study drug or with the patient's safety or interpretation of study results. Patients were excluded if they were concurrently enrolled in another clinical study other than TULIP-1 or TULIP-2. Regarding the exclusion criteria for concomitant medications, patients were also excluded if they had received any of the following within the last 60 days: azathioprine >200 mg / day; mycophenolate mofetil >2.0 g / day; mycophenolate >1.44 g / day; oral, subcutaneous, or intramuscular methotrexate >25 mg / week; or mizoribine >150 mg / day.

[0108] Safety evaluation AE data were recorded throughout the entire study and were classified as on-treatment or on-study according to the start date based on the administration of the last dose in either the TULIP trial or the extension study. Treatment-emergent AEs were defined as AEs with onset from the first dose of study treatment through the date of the last dose of study treatment + 28 days or the end of the study (whichever came first). Study-emergent AEs were defined as AEs with onset from the first dose of study treatment through the end of the study.

[0109] Tuberculosis Screening and Monitoring During the LTE Study If a patient had a newly positive QFT-G test result for TB at the time of randomization in the LTE study, prophylaxis was initiated within 30 days of randomization but before the second dose of study drug in the LTE. Each patient was monitored at each visit in the LTE to ensure the absence of signs or symptoms of active TB, no recent contact with anyone with active TB, and no history of latent or active TB. Patients identified with latent TB were evaluated by a local TB specialist to confirm the local standard of care used for diagnosis and treatment. Treatment was initiated as soon as latent TB was confirmed, and study drug was not administered until latent TB treatment had begun. In addition, newly diagnosed patients with latent TB had to agree to complete the locally recommended course of treatment for latent TB to continue receiving study drug.

[0110] Efficacy assessment: SLEDAI-2K, PGA, glucocorticoids, redness, and SDI SLEDAI-2K scores were reported at weeks 0 (TULIP baseline), 24, 52, 64, 76, 88, 104, 128, 156, 180, and 208, and at weeks 212 and 216 after the last dose during follow-up. PGA was reported for weeks 0, 24, 52, 64, 76, 88, 104, 128, 156, 180, and 208. Glucocorticoid dosage in the study was collected at each visit and is reported here by year (baseline and through year 4) during the TULIP and continuation periods. Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index (SDI) global scores were collected at weeks 52, 104, 156, and 208. Glucocorticoid dosage in the study was collected at each visit and is reported here by year (baseline and up to year 4) during the TULIP and continuation periods.

[0111] Redness was assessed using a modified Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) redness index, including the SLEDAI-2K. Mild-to-moderate redness was defined as at least one of the following: an increase of ≥3 but <7 points on the SLEDAI-2K from the previous visit; at least one new or worse sign of discoid, photosensitive, profundus, cutaneous vasculitis, bullous lupus, nasopharyngeal ulcer, pleurisy, pericarditis, arthropathy, or SLE fever; or an increase of ≥1 point on the PGA from the previous visit but ≤2.5 points on the PGA. Severe flares were defined as at least one of the following: an increase in SLEDAI-2K score of ≥ 7 points from the previous visit; at least one new or worse sign of central nervous system SLE, vasculitis, nephritis, myositis, or hemolytic anemia; hospitalization due to SLE disease activity; or an increase in PGA score of > 2.5 points.

[0112] Missing data for patients who were discontinued or lost to follow-up were not imputed, except for missing SDI global scores. In this case, a score was calculated if only one of "proteinuria ≥ 3.5 g / day" or "end-stage renal disease (regardless of dialysis or transplant)" was missing. The SDI global score was set to missing if both listed items were absent or if any other item was missing. Missing SDI scores were imputed based on the worst observation, both for missing median and decrement scores. Because the SDI global score should never decrement, item-level decrements were replaced by the worst (best) observation carried forward (WOCF). WOCF applies to all items, including those with intermittent missing values ​​(before study drug discontinuation). Time to first SDI deterioration was defined as the date of first SDI deterioration minus the date of first administration of study drug. If a patient did not deteriorate, time to SDI deterioration was censored at the end of exposure time or week 208, whichever occurred first.

[0113] statistical analysis Baseline demographics and characteristics are presented as descriptive statistics by treatment group. AEs are summarized by descriptive statistics, including exposure-adjusted incidence rates (EAIRs) and adjusted cumulative proportions. Exposure was calculated until the date of the last dose of treatment + 84 days or the date of study discontinuation, death, or withdrawal of consent, whichever occurred first. COVID-related events are described by event rates based on time-at-risk during the pandemic.

[0114] Observed values ​​and changes from baseline in the SLEDAI-2K, SDI, and PGA are presented by visit with descriptive statistics. The mean change from baseline in the SLEDAI-2K was analyzed using analysis of covariance, including randomization stratification factors scaled to baseline value (continuous), treatment group, visit, and type I IFN gene signature test results at screening and baseline glucocorticoid dose. For glucocorticoid use, the standardized area under the curve (AUC) and proportion of patients by glucocorticoid dose are both presented by treatment group and year with summary statistics. A sensitivity analysis for glucocorticoid use was performed to exclude patients with a glucocorticoid dose >40 mg / day at TULIP study baseline because the end date was unknown. Four patients with missing end dates for glucocorticoids initiated before randomization were excluded because these higher doses were administered throughout the study, magnifying the results. Redness rates per patient year are presented for mild to moderate redness, severe redness, and overall.

[0115] Definition of EAIR and event rate EAIR per 100 patient-years is defined as the number of patients with a particular event divided by the total exposure (years) × 100. Exposure time is defined as from the date of first administration of treatment until death, end of treatment + 84 days, or end of study (whichever comes first). Event rate per 100 patient-years is defined as the number of patients with an event divided by the total time at risk (years) during the pandemic × 100. Time at risk is defined as from the start of the pandemic until death, end of treatment + 84 days, or end of study (whichever comes first). When reporting events occurring only during treatment, 28 days are considered instead of end of period + 84 days.

[0116] Study outcomes The primary outcomes were long-term safety and tolerability, as assessed by rates of adverse events (AEs), serious adverse events (SAEs), including those leading to death, adverse events leading to treatment discontinuation (DAEs), and adverse events of special interest (AESIs). Safety information was collected at each visit. Exploratory efficacy outcomes included the Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K), Physician's Global Assessment (PGA), glucocorticoid use, incidence and severity of flares, and the Systemic Lupus International Collaborating Clinics / American College Rheumatology Damage Index (SDI) global score. Further information on study outcomes is provided in the Supplementary Methods.

[0117] COVID-19 pandemic The LTE began on June 30, 2016, and continued during the COVID-19 pandemic, which was declared by the World Health Organization on March 11, 2020. Total exposure during the pandemic was calculated for each patient as follows: Total exposure = End of period - Start date of pandemic + 1

[0118] Patients were considered fully vaccinated against COVID-19 if they received at least two doses of any approved vaccine, similar to the standard COVID-19 vaccination schedule, during the relevant time period.

[0119] result patient Of the 639 patients who completed treatment in the TULIP study, 547 were enrolled in the LTE and randomized to receive at least one dose of treatment (Figure 1). 257 patients continued on anifrolumab 300 mg (LTE anifrolumab 300 mg), and 67 patients crossed over from 150 mg to 300 mg anifrolumab. 223 patients who received placebo in TULIP-1 or TULIP-2 were re-randomized 1:1 to anifrolumab 300 mg (n = 111) or placebo (n = 112, LTE placebo) in the LTE. Among patients who would comprise the primary safety comparison group for the LTE study period, previously described as LTE anifrolumab 300 mg (n=257) and LTE placebo (n=112) (Figure 1), demographics and baseline disease characteristics at the start of the TULIP study were generally well balanced between groups (Table 6), with similar proportions of patients receiving glucocorticoids or immunosuppressants. For patients who continued on LTE, the mean (SD) disease activity score at TULIP baseline, as measured by the SLEDAI-2K global score, was 11.2 (3.7) in the LTE anifrolumab 300 mg group and 11.3 (3.6) in the LTE placebo group, consistent with the overall TULIP population.

[0120] [Table 6] Anti-dsDNA, anti-double-stranded DNA; ANA, antinuclear antibody; BILAG-2004, British Isles Lupus Assessment Group 2004; C3, complement 3; C4, complement 4; IFNGS, interferon gene signature; LTE, long-term continuous therapy; NSAID, nonsteroidal anti-inflammatory drug; PGA, physician's global assessment; SD, standard deviation; SDI, Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000.

[0121] Of patients in the LTE anifrolumab 300 mg group, 69.3% (178 / 257) completed the 3-year extension study, compared with 48.2% (54 / 112) in the LTE placebo group. The most commonly reported reasons for discontinuation were patient withdrawal and lack of efficacy, with higher percentages observed in the LTE placebo group compared with the LTE anifrolumab 300 mg group. Eight patients discontinued treatment due to the COVID pandemic (LTE anifrolumab 300 mg group: n = 7 [2.7%]; LTE placebo group: n = 1 [0.9%]).

[0122] Total exposure to anifrolumab during the extension study in the LTE anifrolumab 300 mg group was 683.5 patient-years, compared with 250.3 patient-years of exposure to placebo in the LTE placebo group (Table 7). Total exposure to anifrolumab across all doses and all groups in the TULIP study and 3 years of the LTE was 1568 patient-years.

[0123] [Table 7] AE, adverse event; AESI, adverse event of special interest; CI, confidence interval; EAIR, exposure-adjusted incidence rate; IFN, interferon; LTE, long-term continuous administration; PY, patient-year; SAE, serious adverse event; SLE, systemic lupus erythematosus. a Exposure (in days) for each patient was calculated as the date of the last dose of treatment + 84 days, or the date of study discontinuation, whichever came first - the date of the first dose of treatment + 1 day. b EAIR per 100 patient-years is defined as the number of patients with a particular event divided by the total exposure (years) × 100. Exposure time is defined as the time from the first dose of treatment to death, end of treatment + 84 days, or end of study (whichever comes first). c Latent tuberculosis was defined as a positive IFN-γ release assay. No active cases of tuberculosis were reported. dBy the Cardiovascular Events Adjudication Committee.

[0124] Safety and Tolerability The safety profile of anifrolumab in SLE during the 1-year TULIP study has been published (5, 6). Focusing on the comparison of the LTE anifrolumab 300 mg group versus the LTE placebo group, the exposure-adjusted incidence rates (EAIRs) of any AE (33.1 vs. 37.6), any SAE, including events with a fatal outcome (8.5 vs. 11.2), and any DAE (2.5 vs. 3.2), were all lower in the LTE anifrolumab 300 mg group compared with the LTE placebo group (Table 7). The safety profile among patients receiving any dose of anifrolumab, whether in one of the TULIP studies or in the LTE (all anifrolumab groups; n = 560), was similar to that in the combined TULIP and LTE dataset (combined anifrolumab 300 mg group; n = 358) of patients receiving anifrolumab 300 mg (Table 8).

[0125] [Table 8] AE, adverse event; AESI, adverse event of special interest; COVID-19, coronavirus disease 2019; CV, cardiovascular; EAIR, exposure-adjusted incidence rate; IFN, interferon; MI, myocardial infarction; PY, patient-year; SAE, serious adverse event; SLE, systemic lupus erythematosus a The data presented are combined from the TULIP trial and the extension study. b Exposure (in days) for each patient was calculated as the date of the last dose of treatment + 84 days, or the date of study discontinuation, whichever came first - the date of the first dose of treatment + 1 day. c EAIR per 100 patient-years is defined as the number of patients with a particular event divided by the total exposure (years) × 100. Exposure time is defined as the time from the first dose of treatment to death, end of treatment + 84 days, or end of study (whichever comes first). d Latent tuberculosis was defined as a positive IFN-γ release assay. No active cases of tuberculosis were reported.

[0126] The most common AEs in the LTE by EAIR were nasopharyngitis (9.7 vs. 5.5), urinary tract infection (8.5 vs. 6.3), and upper respiratory tract infection (8.3 vs. 7.2) in the LTE anifrolumab 300 mg and LTE placebo groups, respectively (Table 9). In the same groups, the most frequently reported type of SAE by EAIR was in the system organ class of infection and infestation (4.3 and 4.7). The EAIR for any AE with a fatal outcome was 0.4 in both the LTE anifrolumab 300 mg and LTE placebo groups, including three deaths from infection (one COVID and two pneumonia) reported with anifrolumab and one death from a serious acute cardiovascular event (acute myocardial infarction) reported with placebo (Table 7). In the group switched from placebo to anifrolumab, two additional deaths from COVID occurred during the LTE study. Considering all anifrolumab and placebo exposure over 4 years, a total of 12 deaths occurred, including the 3 previously reported in the TULIP trial and the 6 cases described above that occurred during LTE. Ten of these deaths were reported in all anifrolumab groups and 2 deaths were reported in all placebo groups, resulting in an EAIR of 0.6 vs. 0.3, respectively (Table 8). Among patients in the LTE anifrolumab 300 mg and LTE placebo groups who discontinued treatment due to an AE, no DAEs were reported in more than two patients per group (Table 10).

[0127] In the extension study, the rate of AESIs was low in both the LTE anifrolumab 300 mg group and the LTE placebo group (Table 7). AESI rates for non-opportunistic serious infections (3.7 vs. 3.6) were similar between treatment groups. Rates of herpes zoster (HZ; 3.4 vs. 2.8), latent tuberculosis (2.3 vs. 0.8), and influenza (2.2 vs. 0.8) were numerically higher in the LTE anifrolumab 300 mg group than in the LTE placebo group (Table 7). Of note, latent tuberculosis was defined as a positive IFN-γ release assay. There were no cases of active tuberculosis in either treatment group, and no opportunistic infections were reported in the LTE anifrolumab 300 mg group. Considering both the TULIP and LTE periods, the overall AESI rate in HZ decreased over time in all anifrolumab groups and was lower during the LTE period than during the first year of treatment in the TULIP trial (exposure-adjusted incidence rates based on time at risk: 6.8 [1 year], 5.7 [2 years], 3.9 [3 years], and 2.9 [4 years]).

[0128] To be comprehensive and include maximum exposure, rare AEs were reported over the 4-year exposure period (all anifrolumab: n = 560, total exposure 1,568.0 patient-years; all placebo: n = 360, total exposure 587.1 patient-years). Numerically lower rates of opportunistic infections (0.2 vs. 0.7) were observed in all anifrolumab groups compared with all placebo groups (0.2 vs. 0.7) (Table 8). Relatively low rates of malignancies (0.8 vs. 0.7), anaphylaxis (0.1 vs. 0.0), and serious acute cardiovascular events (0.8 vs. 0.5) were observed in both treatment groups. Only nonmelanoma skin cancers were reported in more than one patient in this study: basal cell carcinoma and squamous cell carcinoma (n = 2 each). Considering both the TULIP and LTE periods, the rate of any SAE among patients treated with anifrolumab (all anifrolumab groups) decreased over time and was lower during the LTE than during the first year of treatment in the TULIP trial (5, 6) (n [%], exposure-adjusted incidence rate based on time at risk: year 1, 53 [11.8%], 13.1; year 2, 49 [11.3%], 12.5; year 3, 23 [5.9%], 6.4; and year 4, 19 [5.6%], 6.1).

[0129] Treatment-emergent anti-drug antibodies were detected in 2.6% (9 / 358) of patients receiving combination anifrolumab 300 mg throughout the 4-year treatment period, with no trend or pattern suggesting any association with AEs.

[0130] [Table 9] EAIR, exposure-adjusted incidence rate; LTE, long-term continuous administration; PY, patient-years. a Time of exposure is defined as the date of first administration of treatment until the first event, death, end of treatment + 84 days, or end of study (whichever comes first). b EAIR per 100 patient-years is defined as the number of patients with a particular event divided by the total exposure time in days during the LTE for all subjects in the analysis set, multiplied by 36525.

[0131] [Table 10] AE, adverse event; COVID-19, coronavirus disease 2019; DAE, adverse event leading to discontinuation of investigational drug; EAIR, exposure-adjusted incidence rate; LTE, long-term extension study; PY, patient-year. a Multiple occurrences of a preferred term AE in a patient will be counted only once. b Time of exposure is defined as the date of first administration of treatment until the first event, death, end of treatment + 84 days, or end of study (whichever comes first). c EAIR per 100 patient-years is defined as the number of patients with a particular event divided by the total exposure time in days during the LTE for all subjects in the analysis set, multiplied by 36525.

[0132] COVID-19 During the final year of the LTE study, which continued through vaccine introduction, the unprecedented global COVID-19 pandemic was declared. Among patients in the overall anifrolumab group (n = 325) and the LTE placebo group (n = 64) who were on the LTE at the onset of the COVID-19 pandemic, total treatment exposure was 227.7 patient-years and 42.7 patient-years, respectively (Table 11).

[0133] [Table 11] AE, adverse event; CI, confidence interval; COVID-19, coronavirus disease 2019; LTE, long-term extension; SAE, serious adverse event. a The start date of the COVID-19 pandemic, as declared by the World Health Organization, was March 11, 2020. b Exposure during the pandemic for each patient will be calculated as the end of the period - the start date of the COVID-19 pandemic + 1 (where the end of the period is the date of the last dose of treatment + 84 days, study discontinuation, death, or withdrawal of consent, whichever occurs first). c Total exposure for n (%) data. Time at risk is defined as the time (inclusive) from the start date of the COVID-19 pandemic to the date of the first event or the end of the period (whichever comes first). d The event rate per 100 patient-years is defined as the number of patients with an event divided by the total time at risk (in years) during the pandemic × 100. Time at risk is defined as the time from the start of the pandemic to death, end of treatment + 84 days, or end of study (whichever comes first). When reporting events occurring only during treatment, 28 days is considered instead of end of period + 84 days.

[0134] Event rates for COVID-related AEs and SAEs (based on time at risk during the pandemic) were higher in all anifrolumab groups compared with the LTE placebo group during the extension study (AEs: 15.5 vs. 9.8; SAEs: 7.2 vs. 2.4, respectively) (Table 11). Of 33 COVID-related AEs in all anifrolumab groups, 16 were serious (16 / 33; [48.5%]); one SAE was reported in the LTE placebo group (1 / 4; 25%). Focusing on overall COVID-AE severity, COVID AE rates were similar for mild, moderate, or severe cases in all anifrolumab groups, and rates were higher compared with those reported in the broader placebo group. Of note, asymptomatic positive COVID test results were considered COVID-related AEs. Three deaths in all anifrolumab groups occurred within the first 6 months of the pandemic (Figure 2). No COVID AEs occurred in patients after they were fully vaccinated. In the anifrolumab group, 21 patients were fully vaccinated against COVID, and in the placebo group, 9 patients were fully vaccinated.

[0135] Effectiveness Efficacy data (SLEDAI-2K, PGA, glucocorticoid use, flare rate, and SDI) were evaluated in the combination anifrolumab 300 mg group (n=358) versus the combination placebo group (n=178) throughout the TULIP and extension periods. For patients who continued on to LTE, the baseline (from the start of TULIP) mean (SD) SLEDAI-2K score was 11.4 (3.8) in the combination anifrolumab 300 mg group and 11.3 (3.9) in the combination placebo group. At the start of LTE (week 52), the mean (SD) scores were 5.1 (3.5) and 6.0 (4.1) in the two groups, respectively. During the LTE period, patients in the combination anifrolumab 300 mg group had a greater mean improvement in SLEDAI-2K compared with the combination placebo group, and the improvement persisted over time (Figure 3); mean SLEDAI-2K scores steadily decreased from baseline to week 52 during the TULIP period in the combination anifrolumab 300 mg group and continued to decrease during the LTE until week 208.

[0136] The mean PGA score decreased from 1.8 at week 0 (TULIP baseline) to 0.6 at week 208 in the combination anifrolumab 300 mg group and from 1.8 at TULIP baseline to 0.7 at week 208 in the combination placebo group (Table 12).

[0137] [Table 12] PGA, physician global assessment; SD, standard deviation. a Changes in PGA scores presented for patients randomized to receive anifrolumab 300 mg throughout TULIP-1, TULIP-2, and the extension studies (“combined anifrolumab 300 mg”) and for all patients randomized to placebo in TULIP-1, TULIP-2, and the extension studies (“combined placebo”). b Data are exact means (SD) for PGA scores at week 0 (TULIP baseline).

[0138] Excluding three patients in the anifrolumab group with missing data during each of the four years of the TULIP and LTE periods, cumulative glucocorticoid dose was lower among patients in the combination anifrolumab 300 mg group compared with the combination placebo group (Figure 4; normalized AUC). Reductions in SLEDAI-2K were achieved in parallel with reductions in mean glucocorticoid dose (Figure 5). The proportion of patients receiving a mean glucocorticoid dose >7.5 mg / day was lower in the combination anifrolumab 300 mg group compared with the combination placebo group over the four years of the TULIP and extension periods (Figure 6). At the end of the extension study (year 4), 9.9% of patients in the combination anifrolumab 300 mg group were taking glucocorticoids >7.5 mg / day compared with 29.3% in the combination placebo group (Figure 6).

[0139] The overall annualized flare rate was 0.1 in the combination anifrolumab 300 mg group and 0.2 in the combination placebo group. All flares in both groups were mild to moderate in severity.

[0140] The mean change from baseline in SDI global score was evaluated in patients with an SDI global score ≥ 1 at Week 52, including 132 patients from the combination anifrolumab 300 mg group and 75 patients from the combination placebo group (Figure 7). At TULIP baseline, the mean SDI global score was 1.6 in the combination anifrolumab 300 mg group and 1.4 in the combination placebo group. At Week 52 (start of the extension study), the mean SDI scores were 1.8 and 1.5, respectively. During the LTE (Weeks 52–208), there were no differences in impairment, as the mean SDI scores remained stable in both treatment groups (Figure 7). A longer time to first SDI deterioration (mean [SD]) was observed in the combination anifrolumab 300 mg group (925.0 [553.0] days) compared with the combination placebo group (754.2 [523.3] days).

[0141] Consideration Anifrolumab is a recently approved first-in-class therapy for the treatment of moderate to severe SLE despite standard therapy, and the long-term data reported herein are important for prescribing physicians treating patients with this chronic disease. Notably, these data describe the first long-term, placebo-controlled study in SLE and further capture the duration of the global COVID pandemic. This study builds on existing evidence from the MUSE open-label extension trial and demonstrates that treatment with anifrolumab is well tolerated and has an acceptable long-term safety profile while maintaining reductions in disease activity and glucocorticoid use.

[0142] The overall incidence of SAEs during the second year with anifrolumab treatment was consistent with observations during the TULIP study, with rates decreasing over time in the LTE. Rates of both non-opportunistic serious infections and opportunistic infections were low and comparable to placebo in this LTE. Of particular interest, the increased rate of HZ reactivation reported in the TULIP study in the context of type I interferon blockade was further evaluated here. Although the HZ rate was numerically higher in those treated with anifrolumab 300 mg compared with placebo during the 3-year extension period (3.4 vs. 2.8), the anifrolumab-associated rate observed in this study was lower than that observed in the pooled anifrolumab 300 mg results from the TULIP-1, TULIP-2, and MUSE studies (LTE: 3.4 vs. pooled phase 2 and phase 3 data: 6.9). This suggests that the risk of anifrolumab-associated HZ is highest during the first year of treatment. The majority of HZ cases in the LTE study were mild to moderate and responded to antiviral treatment, with all but one patient able to continue on study. Furthermore, the overall incidence of HZ with anifrolumab in the LTE was 8.9% (LTE anifrolumab 300 mg: 23 / 257), similar to that reported with long-term belimumab treatment in the extension phase 3 BLISS-52 and BLISS-76 clinical trials in SLE (8.6%, 63 / 735)

[21] .

[0143] Latent tuberculosis in this study was defined as a positive IFN-γ release assay, which may lead to indeterminate results in patients with active SLE due to the use of immunomodulatory therapy and / or the common occurrence of lymphopenia. A higher rate of latent tuberculosis was reported in the anifrolumab group compared with placebo, likely due to improved disease control in the anifrolumab group, but there were no cases of active tuberculosis. Our experience suggests that screening for and treating latent tuberculosis is effective in the setting of anifrolumab use.

[0144] This is the only placebo-controlled study in patients with SLE to report continuous data spanning the onset of the COVID-19 pandemic (March 11, 2020)

[22] and the pre- and post-vaccination periods. There were no COVID-related AEs in patients after they were fully vaccinated against COVID. Studies have found that patients with SLE have a higher risk of severe COVID infection and poorer outcomes compared with the general population, raising concerns that some treatments for SLE may increase the risk of more severe viral disease

[23] . Type I IFNs are elevated in most SLE patients and may be involved in the course of COVID disease

[24] . Furthermore, type I IFN responses are important in host viral defense, and their absence (i.e., autoantibody status) has been associated with a higher risk of severe COVID and death

[26] . In this study of long-term treatment with anifrolumab, the rates of COVID-related AEs and SAEs were higher in patients treated with anifrolumab compared with placebo. Approximately 50% of COVID-related AEs were severe in all anifrolumab groups, and 25% of cases were severe in the LTE placebo group. However, most COVID-related SAEs and all three deaths occurred during the first 6 months of the pandemic, before COVID vaccinations or treatments became available

[27] . After patients were fully vaccinated against COVID, there were no COVID-related AEs in patients, suggesting that treatment with IFNAR1 inhibitors surprisingly did not affect vaccine efficacy. Overall COVID mortality observed with anifrolumab treatment was comparable to that reported for SLE patients treated with biologics at the time of COVID diagnosis

[30] . These data demonstrate sustained efficacy of COVID vaccination in patients also treated with anifrolumab.

[0145] The malignancy rate in this study was low and comparable to placebo. Only non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) were reported in more than two patients in this study. The long-term risk of malignancies will be further evaluated in a planned post-approval safety study. Serious cardiovascular events, as adjudicated by an independent cardiovascular review committee, were rare and comparable between anifrolumab and placebo. No patients in the LTE study experienced anaphylaxis.

[0146] Although this study was primarily designed to evaluate the long-term safety of anifrolumab in SLE, disease activity was assessed with the SLEDAI-2K, and a greater mean improvement was observed in patients receiving the combination anifrolumab 300 mg group than in patients receiving the combination placebo group. Improvements were sustained over time, and mean disease activity levels remained low with anifrolumab throughout the study. Despite the absence of glucocorticoid tapering required by the continuation study protocol, treatment with anifrolumab 300 mg allowed for glucocorticoid dose reductions and lower cumulative glucocorticoid doses compared with placebo. At year 4, 36.4% of anifrolumab-treated patients were glucocorticoid-free (0 mg / day), and the figure increased to 74.4% in patients with a glucocorticoid dose of 0 or 0 to ≤5 mg / day, which may have resulted in a lower prevalence of adverse events. The importance of glucocorticoid tapering in SLE is highlighted by a recent large meta-analysis showing a clear association between glucocorticoid exposure and osteoporosis with osteonecrosis, cardiovascular events, and fractures.

[31] These results from the LTE study are consistent with findings from a post-hoc analysis of the TULIP phase 3 trial, which showed that anifrolumab facilitated sustained glucocorticoid tapering in patients with SLE and was associated with fewer serious adverse events (SAEs). No signal for increased damage, as measured by the SDI score, was observed in this study.

[0147] This study is unique in that it is the first phase 3, double-blind, placebo-controlled, long-term safety study in SLE and was conducted both before and during the COVID pandemic, which not only allowed for early observation of COVID infection in patients with SLE, both pre- and post-vaccination, but also resulted in widespread study discontinuation, with treatment discontinuation and dropouts during the early part of the pandemic.

[0148] References [1] F. Zhang et al., RMD Open 8,e001669(2022). [2] Y. Tanaka et al., RMD Open 7, e001629 (2021). [3] S. Galmiche et al., Clin. Microbiol. Infect. 28, 163 (2022). [4]KAKirou et al.,Front.Immunol.13(2022). [5] R. Spiera, S. Jinich, and D. Jannat-Khah, Ann. Rheum. Dis. 80, 1357 (2021). [6] D. Gladman et al., Arthritis Rheum. 39, 363 (1996). [7] J. Albrecht et al., J. Invest. Dermatol. 125, 889 (2005). [8] C.-S. Yee et al., Rheumatol. Oxf. Engl. 49, 1665 (2010). [9] C.-S. Yee et al., Arthritis Rheum.56, 4113(2007).

[10] MC Chochberg, Arthritis Rheum. 40, 1725 (1997).

[11] M. Aringer et al., Arthritis Rheumatol. Hoboken NJ 71,1400(2019).

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

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

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

[15] EFMorand et al.,N.Engl.J.Med.382,211(2020)。

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

[17] ACR Meeting Abstracts(nd)。

[18] A.Kuhn et al.,Dtsch.Aerztebl.Int.112,423(2015)。

[19] EFMorand et al.,N.Engl.J.Med.382,211(2020)。

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

[21] RFvan Vollenhoven et al.,Rheumatol.Oxf.Engl.59,281(2020)。

[22] (nd)。

[23] M.Aringer et al.,Ther.Adv.Musculoskelet.Dis.14,1759720X221086719(2022)。

[24] R.Fernandez-Ruiz,JLParedes,and TBNiewold,Transl.Res.J.Lab.Clin.Med.232,13(2021)。

[25] WHO Solidarity Trial Consortium et al.,N.Engl.J.Med.384,497(2021)。

[26] P.Bastard et al.,Science 370,eabd4585(2020)。

[27] RECOVERY Collaborative Group et al.,N.Engl.J.Med.384,693(2021)。

[28] B.Meng et al.,Nature 603,706(2022)。

[29] R.Suzuki et al.,Nature 603,700(2022)。

[30] M.F.Ugarte-Gil et al.,Ann.Rheum.Dis.81,970(2022)。

[31] M.F.Ugarte-Gil et al.,Lupus Sci.Med.8,e000590(2021)。

Claims

1. 1. A method for treating systemic lupus erythematosus (SLE) and preventing or reducing the risk of SARS-CoV-2 infection in a subject in need thereof, comprising: a) administering to said subject a type I IFN receptor (IFNAR1) inhibitor; b) administering to said subject a therapeutically effective amount of a SARS-CoV-2 vaccine; wherein the method prevents or reduces the risk of SARS-CoV-2 infection in the subject following exposure of the subject to SARS-CoV-2, and wherein the method treats SLE in the subject.

2. 10. The method of claim 1, wherein the IFNAR1 inhibitor is administered to the subject less than one month prior to the SARS-CoV-2 vaccine.

3. 3. The method of claim 1 or 2, wherein the IFNAR1 inhibitor is administered on the same day as the SARS-CoV-2 vaccine.

4. The method of any one of claims 1 to 3, wherein the IFNAR1 inhibitor is administered intravenously or subcutaneously.

5. The method of any one of claims 1 to 4, wherein the IFNAR1 inhibitor is administered to the subject at a dose of 120 mg to 1000 mg.

6. 10. The method of claim 1, wherein the IFNAR1 inhibitor is administered intravenously to the subject at a dose of about 300 mg every four weeks (Q4W).

7. 10. The method of claim 1, wherein the IFNAR1 inhibitor is administered intravenously to the subject at a dose of about 900 mg every four weeks (Q4W).

8. 10. The method of claim 1, wherein the IFNAR1 inhibitor is administered subcutaneously to the subject at a dose of about 120 mg weekly.

9. 1. A method for preventing or reducing the risk of SARS-CoV-2 infection in a subject in need thereof, wherein the subject has an autoimmune disease and is being treated with an IFNAR1 inhibitor, the method comprising administering to the subject a therapeutically effective amount of a SARS-CoV-2 vaccine, wherein the method prevents or reduces the risk of SARS-CoV-2 infection in the subject after the subject has been exposed to SARS-CoV-2.

10. 10. The method of claim 9, wherein administration of the SARS-CoV-2 vaccine prevents or reduces the risk of COVID-19 pneumonia in the subject.

11. 11. The method of claim 9 or 10, wherein administration of the SARS-CoV-2 vaccine prevents or reduces the risk of COVID-19-related death in the subject.

12. The method of any of claims 9 to 11, wherein the SARS-CoV-2 vaccine is administered to the subject within one month after administration of the IFNAR1 inhibitor to the subject.

13. The method of any of claims 9 to 12, wherein the IFNAR1 inhibitor is administered intravenously or subcutaneously.

14. The method of any of claims 9 to 13, wherein the IFNAR1 inhibitor is administered to the subject at a dose of 120 mg to 1000 mg.

15. 15. The method of any of claims 9-14, wherein the IFNAR1 inhibitor is administered intravenously to the subject at a dose of about 300 mg every four weeks (Q4W).

16. 15. The method of any of claims 9-14, wherein the IFNAR1 inhibitor is administered intravenously to the subject at a dose of about 900 mg every four weeks (Q4W).

17. The method of any of claims 9 to 14, wherein the IFNAR1 inhibitor is administered subcutaneously to the subject at a dose of about 120 mg weekly.

18. 18. The method of any of claims 9-17, comprising administering at least two doses of the SARS-CoV-2 vaccine to the subject.

19. 19. The method of claim 18, wherein the two doses of the SARS-CoV-2 vaccine are administered to the subject within a period of 21 to 28 days.

20. 19. The method of claim 18, wherein the two doses of the SARS-CoV-2 vaccine are administered to the subject within a period of 14 to 56 days.

21. 21. The method of claim 9 or 20, wherein the IFNAR1 inhibitor was administered to the subject less than one month before the SARS-CoV-2 vaccine was administered to the subject.

22. 1. A method for treating SLE in a subject in need thereof, wherein the subject has been vaccinated against COVID-19 with a SARS-CoV-2 vaccine, the method comprising administering to the subject a therapeutically effective amount of an IFNAR1 inhibitor, wherein the method treats SLE in the subject.

23. 23. The method of claim 22, wherein the subject has been fully vaccinated against COVID-19.

24. 24. The method of claim 22 or 23, wherein the subject has received at least two doses of the SARS-CoV-2 vaccine.

25. 25. The method of claim 24, wherein the two doses of the SARS-CoV-2 vaccine were administered to the subject within a period of 21 to 28 days.

26. 25. The method of claim 24, wherein the two doses of the SARS-CoV-2 vaccine were administered to the subject within a period of 14 to 56 days.

27. 27. The method of claims 22-26, wherein the subject was vaccinated against COVID-19 within 6 months prior to administration of the IFNAR1 inhibitor.

28. 28. The method of any one of claims 1 to 27, wherein the SARS-CoV-2 vaccine is selected from the group consisting of AZD1222, mRNA-1273, or BNT162b2 Tozinameran, or a combination thereof.

29. The method of any one of claims 1 to 29, wherein the IFNAR1 inhibitor is a human monoclonal antibody specific for IFNAR1, optionally a modified IgG1 class human monoclonal antibody.

30. 30. The method of claim 29, wherein the antibody comprises: (a) a heavy chain variable region complementarity-determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:3; (b) a heavy chain variable region complementarity-determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:4; c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:5; (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence SEQ ID NO:6; (e) a light chain variable region complementarity-determining region 2 (LCDR2) comprising the amino acid sequence SEQ ID NO:7; and / or (f) a light chain variable region complementarity-determining region 3 (LCDR3) comprising the amino acid sequence SEQ ID NO:8 A method comprising:

31. 31. The method of claim 29 or 30, 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.

32. 32. The method of any one of claims 29 to 31, wherein the antibody comprises an Fc region comprising the following amino acid substitutions: L234F, L235E and / or P331S, numbered according to the EU index as set forth in Kabat.

33. 33. The method of any one of claims 29 to 32, 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.

34. The method of any one of claims 1 to 33, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof.

35. 1. A pharmaceutical composition for use in a method for preventing or reducing the risk of SARS-CoV-2 infection in a subject, wherein the subject has an autoimmune disease and is being treated with an IFNAR1 inhibitor, the pharmaceutical composition comprising a SARS-CoV-2 vaccine, the method comprising administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition prevents or reduces the risk of SARS-CoV-2 infection in the subject after the subject has been exposed to SARS-CoV-2.

36. 1. A pharmaceutical composition for use in a method of treating SLE in a subject in need thereof, wherein the subject has been vaccinated against COVID-19 with a SARS-CoV-2 vaccine, the pharmaceutical composition comprising an IFNAR1 inhibitor, the method comprising administering the pharmaceutical composition to the subject, wherein the method treats SLE in the subject.

37. 37. An injection device comprising the pharmaceutical composition of claim 35 or 36.

38. 38. The injection device of claim 37, wherein the injection device is a pre-filled syringe (PFS), an optionally attached pre-filled syringe (AFPS), or an autoinjector.

39. A kit comprising an injection device according to claim 37 or 28 and instructions for use.

40. 40. The kit of claim 39, wherein the instructions comprise instructions for subcutaneous administration of the pharmaceutical composition to the subject.

41. The kit of claim 39 or 40, wherein the instructions specify that the pharmaceutical composition is for use in the method of any one of claims 1 to 34.

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