Treatment of lupus

Abstract

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

Description

Background Art

[0001] Anifrolumab (MEDI-546) is a human immunoglobulin G1κ (IgG1κ) monoclonal antibody (mAb) against subunit 1 of the type I interferon receptor (IFNAR1). It consists of two identical light chains and two identical heavy chains, with a total molecular weight of approximately 148 kDa. Anifrolumab inhibits the binding of type I IFN 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 multi-system involvement, which can range from mild to life-threatening disease. Given the need for long-term treatment, it is important to evaluate the safety and efficacy of new therapies for SLE over an extended period. However, due to the lack of a suitable control comparison group, long-term open-label studies of biologic agents have left some questions [1,2].

[0003] SLE disproportionately affects the populations most severely affected by COVID-19. Individuals with SLE are typically severely immunosuppressed and have a high comorbidity burden, with multiple risk factors leading to more severe COVID-19. The pathogen of COVID-19 is SARS-Cov-2. Although previous analyses have evaluated the outcomes of SARS-Cov-2 infection in rheumatic diseases as a group, data on individuals with SLE are limited, and it remains unclear which risk factors in this population are associated with worse COVID-19 outcomes.

[0004] The effect of anifrolumab on SARS-CoV-2 infection or SARS-CoV-2 vaccination efficacy has not been evaluated. Vaccination efficacy depends on the stimulation of an immune response against the vaccine in vaccinated individuals. Therefore, inhibitors of type I IFN are expected to reduce SARS-CoV2 vaccination efficacy. SARS-CoV2 vaccination has been shown to be less effective in immunocompromised populations [3]. Further, treatment with anifrolumab may increase the risk of COVID-19-related adverse events, and SLE patients should be vaccinated against viral infections before receiving anifrolumab treatment [4]. Treatment of patients with the biologic drug rituximab attenuates the antibody response to immunization in patients with rheumatic diseases for at least 6-9 months after infusion of the biologic agent [5].

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

[0006] The present invention relates to a method for simultaneously treating systemic lupus erythematosus (SLE) and preventing or reducing the risk of SARS-CoV-2 infection in a subject in need thereof, the method comprising administering to the subject an inhibitor of the type I IFN receptor (IFNAR1), and 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 is exposed to SARS-CoV-2, and wherein the method treats the subject's SLE.

[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 has been treated with an IFNAR1 inhibitor. The method comprises 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 is 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 and treating the subject's SLE.

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

[0010] The present invention is in particular supported by data from a randomized, placebo-controlled, phase 3 extension trial of the long-term safety and tolerability of anifrolumab in SLE (NCT02794285), presented herein for the first time. The data describe the first long-term placebo-controlled study in SLE or in biologics during the global COVID-19 pandemic. The data surprisingly show that patients treated with IFNAR1 respond to vaccination with SARS-CoV-2. Vaccination of patients treated with IFNAR1 long-term was shown to be effective in preventing COVID-19 infection, COVID-19 pneumonia, and COVID-19-related death in patients. The data also surprisingly show that COVID-19 vaccination does not affect the efficacy of treatment with an IFNAR1 inhibitor in patients with SLE. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 : Patients included in the TULIP-1 or TULIP-2 trials and LTE studies: treatment randomization and treatment groups Definition

[0012] LTE, Long-Term Extension. a There is an 8-week safety follow-up period. b Patients randomized to anifrolumab 150 mg are all in TULIP-1. c Patients are re-randomized to anifrolumab 300 mg or placebo for the LTE study.

[0013] Figure 2 : COVID-19 AE During the Pandemic

[0014] AE, adverse event; BBC, British Broadcasting Corporation; COVID-19, Coronavirus Disease 2019; LTE, Long-Term Extension; SAE, serious adverse event; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; WHO, World Health Organization.

[0015] Date of vaccine introduction: 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, 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; Ukraine, February 24, 2021; United Kingdom, December 21, 2020; United States of America, December 14, 2020.

[0016] Source of date of vaccine introduction: Russia (BBC News), other countries (WHO).

[0017] Patients with multiple events are represented only once, reporting the event with the highest severity (death, SAE, and AE; COVID-19 pneumonia, COVID-19, SARS CoV 2 test positive). One of the AEs of COVID-19 pneumonia is not considered an SAE and does not require hospitalization.

[0018] The circled dots indicate that the event occurred after vaccination. One patient in the anifrolumab group received a single dose of the COVID-19 vaccine before reporting the event.

[0019] Figure 3 : Change in mean SLEDAI-2K score from baseline to week 216

[0020] FU, Follow - up; LS, Least Squares; LTE, Long - Term Extension; SE, Standard Error; SLEDAI - 2K, Systemic Lupus Erythematosus Disease Activity Index 2000.

[0021] Figure 4 : Patients in the group receiving 300 mg of anifrolumab in combination or in the placebo group had cumulative sugar during the 4-year study period Corticosteroid dose-normalized AUC, excluding combination from glucocorticoid dose > 40 mg / day at baseline in the TULIP study Three patients in the anifrolumab 300 mg group

[0022] AUC, Area Under the Curve; GC, Glucocorticoid; LTE, Long - Term Extension; SE, Standard Error.

[0023] Figure 5 : Mean SLEDAI-2K in patients receiving anifrolumab 300 mg or placebo according to study year Score and mean GC dose-normalized AUC

[0024] AUC, Area Under the Curve; GC, Glucocorticoid; SE, Standard Error; SLEDAI - 2K, Systemic Lupus Erythematosus Disease Activity Index 2000. Note: Analyses excluded patients with glucocorticoid dose > 40 mg / day at baseline. a For all time points, the number of participants at risk for SLEDAI - 2K was n = 358 (anifrolumab 300 mg combination) and n = 178 (placebo combination).

[0025] Figure 6 : Percentage of patients passing through each corticosteroid dose group annually during the TULIP trial and extension study

[0026] A, Anifrolumab; P, Placebo; GC, Glucocorticoid; LTE, Long - Term Extension. Proportion of patients with GC dose over time, excluding patients with GC dose > 40 mg / day at baseline. Anifrolumab 300 mg combination includes patients randomized to anifrolumab 300 mg at the start of the TULIP study and patients who continued anifrolumab 300 mg in the extension study. Placebo combination includes patients randomized to placebo in the TULIP study and the extension study.

[0027] Figure 7 : Mean ± SE change in SDI overall score from baseline (LOCF) in patients with SDI ≥ 1 at Week 52

[0028] LOCF, Last Observation Carried Forward; LTE, Long - Term Extension; SDI, SDI Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index; SE, Standard Error. Detailed implementation

[0029] Treatment method

[0030] 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, the method comprising a) administering to the subject an inhibitor of type I IFN receptor (IFNAR1), 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 is exposed to SARS-CoV-2, and wherein the method treats the subject's SLE.

[0031] 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 has been treated with an IFNAR1 inhibitor, the method comprising administering to the subject a therapeutically effective amount of a SARS-CoV-2 vaccine, and wherein the method prevents or reduces the risk of SARS-CoV-2 infection in the subject after the subject is exposed to SARS-CoV-2.

[0032] 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 comprising administering to the subject a therapeutically effective amount of an IFNAR1 inhibitor, wherein the method treats the subject's SLE.

[0033] 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 has been treated with an IFNAR1 inhibitor, wherein the pharmaceutical composition comprises 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 is 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, wherein the pharmaceutical composition comprises an IFNAR1 inhibitor, the method comprising administering the pharmaceutical composition to the subject, wherein the method treats the subject's SLE. The autoimmune disease can be lupus nephritis, cutaneous lupus erythematosus, myositis or scleroderma.

[0034] COVID-19 and SARS-CoV-2 vaccines

[0035] Administration of a SARS-CoV-2 vaccine can prevent or reduce the risk of COVID-19 pneumonia in a subject. Administration of a SARS-CoV-2 vaccine can prevent or reduce the risk of COVID-19-related death in a subject. Administration of a SARS-CoV-2 vaccine can prevent or reduce COVID-19-related adverse events in a subject.

[0036] An IFNAR1 inhibitor can be administered to a subject less than 1 month before a SARS-CoV-2 vaccine. An IFNAR1 inhibitor can be administered on the same day as a SARS-CoV-2 vaccine.

[0037] A SARS-CoV-2 vaccine can be administered to a subject about 1 month or less after administering an IFNAR1 inhibitor to the subject. A SARS-CoV-2 vaccine can be administered to a subject 1 month after administering an IFNAR1 inhibitor to the subject. A SARS-CoV-2 vaccine can be administered to a subject about 6 months, 5 months, 4 months, 3 months, or 2 months after administering an IFNAR1 inhibitor to the subject. A SARS-CoV-2 vaccine can be administered to a subject 1 month after administering an IFNAR1 inhibitor to the subject. A SARS-CoV-2 vaccine can be administered to a subject about 4 weeks after administering an IFNAR1 inhibitor to the subject. A SARS-CoV-2 vaccine can be administered to a subject about 3 weeks, 2 weeks, or 1 week after administering an IFNAR1 inhibitor to the subject.

[0038] The method can include administering at least 2 doses of a SARS-CoV-2 vaccine to a subject. The 2 doses of the SARS-CoV-2 vaccine can be administered to the subject over a period of 21 days to 28 days. The 2 doses of the SARS-CoV-2 vaccine can be administered to the subject over a period of 14 days to 56 days.

[0039] An IFNAR1 inhibitor can be administered to a subject less than 1 month before administering a SARS-CoV-2 vaccine to the subject.

[0040] The subject may have been fully vaccinated against COVID-19. The subject may have received at least 2 doses of a SARS-CoV-2 vaccine. The 2 doses of the SARS-CoV-2 vaccine may have been administered to the subject over a period of 21 days to 28 days. The 2 doses of the SARS-CoV-2 vaccine may have been administered to the subject over a period of 14 days to 56 days. The subject may have been vaccinated against COVID-19 6 months or less before administering an IFNAR1 inhibitor.

[0041] The SARS-CoV-2 vaccine can be selected from the group consisting of: AZD1222, mRNA-1273 or BNT162b2 Tozinameran, or a combination thereof. The SARS-CoV-2 vaccine can be selected from the group consisting of SARS-CoV-2 vaccines including the following: intranasal SARS-CoV-2 vaccine (Altimmune), INO-4800 (Inovio Pharma and Beijing Advaccine Biotechnology Company), APN01 (APEIRON Biologics), mRNA-1273 vaccine (Moderna and Vaccine Research Center), nucleoside-modified mNRA BNT162b2 Tozinameran (INN) (Pfizer-BioNTech), adenovirus-based vaccine AZD1222 (recombinant ChAdOx1 adenovirus vector encoding the SARS-CoV-2 spike protein; Oxford-AstraZeneca), Covishield (ChAdOx1_nCoV19) recombinant ChAdOx1 adenovirus vector encoding the SARS-CoV-2 spike protein antigen (Serum Institute of India), SARS-CoV-2 vaccine (Vero Cell), inactivated (lnCoV) (Sinopharm / BIBP), SARS-CoV-2 vaccine (Vero cell), inactivated (Sinovac), Ad26.COV2 encoding the SARS-CoV-2 spike (S) protein.S recombinant replication-incompetent adenovirus type 26 (Ad26) vector vaccine (Janssen Pharmaceuticals Companies of Johnson & Johnson), Covid-19 vaccine based on Sputnik V human adenovirus vector (The Gamaleya National Center), Ad5-nCoV recombinant novel coronavirus vaccine (adenovirus type 5 vector) (CanSinoBIO), EpiVacCorona peptide antigen vaccine (Vector State Research Centre of Virology 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), recombinant subunit vaccine based on the trimeric S protein (S-trimer) of the SARS-CoV-2 coronavirus (Clover Pharmaceuticals), oral recombinant coronavirus vaccine (Vaxart), linear DNA vaccine based on (i) the complete spike gene of the coronavirus or (ii) the antigenic part of the coronavirus protein (Applied DNA Sciences and Takis Biotech), SARS-Cov-2 coronavirus vaccine NVX-CoV2373 (Novavax), SARS-Cov-2 coronavirus vaccine NVX-CoV2373 (Novavax), intramuscular vaccine INO-4700 (GLS-5300) (Inovio Pharma and GeneOne Life Science), and combinations thereof.

[0042] SARS-CoV-2 vaccine

[0043] IFNAR1 inhibitor

[0044] "Type I interferon receptor inhibitor" refers to a molecule that antagonizes the receptor for type I interferon ligands (such as interferon-α and interferon-β). Such an inhibitor preferably provides, after administration to a patient, a reduction in the expression of at least 1 (preferably at least 4) pharmacodynamic (PD) marker genes 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 4 genes may suitably be IFI27, IFI44, IFI44L, and RSAD2. "Type I interferon receptor" is preferably the interferon-α / β receptor (IFNAR).

[0045] For example, a type I interferon receptor inhibitor can be an antibody or an antigen-binding fragment thereof that inhibits type I IFN activity (by inhibiting the receptor). Examples of suitable antibodies or antigen-binding fragments thereof that inhibit type I IFN activity are interferon-α / β receptor (IFNAR) antagonists. A type I interferon receptor inhibitor can be an antibody or an antigen-binding fragment thereof that inhibits type I IFN activity. Additionally or alternatively, a type I interferon receptor inhibitor can be a small molecule inhibitor of the type I interferon receptor (e.g., for pharmacological inhibition of type I interferon receptor activity).

[0046] An IFNAR1 inhibitor can be a human monoclonal antibody specific for IFNAR1. An IFNAR1 inhibitor can be a modified IgG1 class human monoclonal antibody specific for IFNAR1.

[0047] The antibody may comprise a heavy chain variable region complementarity determining region 1 (HCDR1) containing the amino acid sequence of SEQ ID NO:3. The antibody may comprise a heavy chain variable region complementarity determining region 2 (HCDR2) containing the amino acid sequence of SEQ ID NO:4. The antibody may comprise a heavy chain variable region complementarity determining region 3 (HCDR3) containing the amino acid sequence of SEQ ID NO:5. The antibody may comprise a light chain variable region complementarity determining region 1 (LCDR1) containing the amino acid sequence of SEQ ID NO:. The antibody may comprise a light chain variable region complementarity determining region 2 (LCDR2) containing the amino acid sequence of SEQ ID NO:7. The antibody may comprise a light chain variable region complementarity determining region 3 (LCDR3) containing the amino acid sequence of SEQ ID NO:8.

[0048] 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, numbered as per the EU index as described in Kabat, and wherein the antibody exhibits a reduced affinity for at least one Fc ligand as compared to the unmodified antibody. The antibody may comprise a human heavy chain 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.

[0049] The antibody may comprise: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:3; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:4; c) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:5; (d) a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence SEQ ID NO:6; (b) a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:7; c) a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:8.

[0050] 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.

[0051] The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0052] Administration dose and method of IFNAR1 inhibitor

[0053] 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 at a dose of approximately 300 mg every 4 weeks (Q4W). The IFNAR1 inhibitor may be administered intravenously to a subject at a dose of approximately 900 mg every 4 weeks (Q4W). The IFNAR1 inhibitor may be administered subcutaneously to a subject at a dose of approximately 120 mg per week.

[0054] The IFNAR1 inhibitor may have been administered intravenously or subcutaneously to a subject. The IFNAR1 inhibitor may have been administered to a subject at a dose of 120 mg to 1000 mg.

[0055] The IFNAR1 inhibitor may have been administered intravenously to the subject at a dose of approximately 300 mg every 4 weeks (Q4W). The IFNAR1 inhibitor may have been administered intravenously to the subject at a dose of approximately 900 mg every 4 weeks (Q4W). The IFN inhibitor may have been administered subcutaneously to the subject at a dose of approximately 120 mg per week.

[0056] The method may include administering an intravenous dose of anifrolumab or a functional variant thereof to the subject. The intravenous dose may be ≥300 mg of anifrolumab or a functional variant thereof. The intravenous dose may be ≤1000 mg. The intravenous dose may be approximately 300 mg, approximately 900 mg, or approximately 1000 mg. The intravenous dose may be administered once every four weeks (Q4W).

[0057] 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 approximately 120 mg. The subcutaneous dose may be administered in a single administration step. The subcutaneous dose may be administered at intervals of 6 - 8 days. The subcutaneous dose may be administered once a week. The subcutaneous dose may have a volume of approximately 0.5 ml to approximately 1 ml. The subcutaneous dose may have a volume of approximately 0.8 ml.

[0058] The dosing regimen of the IFNAR1 inhibitor may include a first induction regimen (IR) containing x3 intravenous 900 mg doses Q4W, followed by a basal regimen (BR) of a) a subcutaneous 120 mg dose per week, or b) an intravenous 300 mg dose Q4W (or a mixture of a) and b)). The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof. The dosing regimen may include a first induction regimen (IR) containing x6 intravenous 900 mg doses Q4W, followed by a basal regimen (BR) of a) a subcutaneous 120 mg dose per week or b) an intravenous 300 mg dose Q4W (or a mixture of a) and b)). The dosing regimen may include a first induction regimen (IR) containing x6 subcutaneous 1150 mg doses Q4W, followed by a basal regimen (BR) of a) a subcutaneous 120 mg dose per week or b) an intravenous 300 mg dose Q4W (or a mixture of a) and b)). The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0059] The method may include intravenously administering an intravenous dose of an IFNAR1 inhibitor (e.g., administering 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 the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be administered approximately once every four weeks (Q4W). The intravenous dose may be administered approximately monthly. A 300 mg IV dose may be administered using an infusion pump over a minimum of 30 minutes. A 900 mg IV dose may be administered using an infusion pump over a minimum of 60 minutes. Anifrolumab 300 mg IV may be provided in a 2 ml vial at a concentration of 150 mg / mL.

[0060] 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 between 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 - 8 days. The subcutaneous dose may be administered once a week. The subcutaneous dose may have a volume of 0.5 ml to 1 ml. The subcutaneous dose may have a volume of 0.5 ml to 1.0 ml. The subcutaneous dose may have a volume of approximately 0.8 ml. The subcutaneous dose may have a volume of 0.8 ml. The subcutaneous dose may be about 1150 mg (e.g., 1155 mg or 1150 mg) of anifrolumab or a functional variant thereof. The subcutaneous dose may have a volume of approximately 8 ml. The subcutaneous dose may have a volume of approximately 7.7 ml.

[0061] The method may include administering a first dose of an IFNAR1 inhibitor to a subject, followed by administering a second dose of the 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 the subject 3 times before administering the second dose to the subject. The first dose may be administered to the subject 6 times before administering the second dose to the subject. The first dose may be administered every 4 weeks before administering the second dose, for 12 weeks. The first dose may be administered every 4 weeks before administering the second dose, for 24 weeks. 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 3 times before administering the second dose to the subject. The first dose may be administered to the subject 6 times before administering the second dose to the subject. The first dose may be administered every 4 weeks before administering the second dose, for 12 weeks. The first dose may be administered every 4 weeks before administering the second dose, for 24 weeks. The intravenous dose may be administered as part of an intensified regimen (IR), wherein the total dose of IFNAR1 inhibitor administered during IR is 2.7 g to 81 g, optionally 72.9 g, for 12 to 24 weeks. The IR may include administering an SC dose of the IFNAR1 inhibitor equivalent to an IV dose of 900 mg to 1000 mg Q4W.

[0062] The second dose may be administered subcutaneously. The second dose may be >105 mg and ≤135 mg, and administered subcutaneously. The second dose may be about 120 mg, and administered subcutaneously. The second dose may be administered once a week.

[0063] 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 administered intravenously. The second dose may be about 300 mg, and administered intravenously. The dose may be about 900 mg, and administered Q4W intravenously, wherein the second dose is about 120 mg administered QW subcutaneously. The dose may be about 900 mg, and administered Q4W intravenously, wherein the second dose is about 300 mg administered Q4W intravenously, optionally wherein the first dose is administered to the subject at least 3 times before administering the second dose to the patient, optionally wherein the first dose is administered to the subject at least 6 times before administering the second dose to the patient. The second dose may be administered for at least one year.

[0064] The method can include administering a unit dose or pharmaceutical composition that comprises about 105, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 300 mg, 305 mg, 310 mg, 800 mg, 805 mg, 810 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 890 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 1000 mg, 1050 mg, 1010 mg, 1020 mg, 1025 mg, 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg or 1065 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof).

[0065] The subject can be a patient who tests high for type I interferon-stimulated gene signature (IFNGS) prior to treatment. The method can include identifying the subject as a patient who tests high for IFNGS prior to treatment.

[0066] Many patients with SLE receive corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Anifrolumab permits corticosteroid (glucocorticoid) taper (steroid taper) in patients with SLE. The treatment method or approach can include administering a corticosteroid to a subject, optionally wherein the corticosteroid is an oral corticosteroid. The method can include tapering the dose of corticosteroid administered to the subject (steroid taper). The method can include administering a first dose of corticosteroid and subsequently administering a second dose of corticosteroid, wherein the second dose of corticosteroid is lower than the first dose of corticosteroid. The second dose of corticosteroid can be a dose of about 7.5 mg prednisone equivalent or less. The second dose of corticosteroid can be a dose of 5 mg prednisone equivalent or less. The method or treatment approach can include administering the second dose of corticosteroid once daily. The first dose of corticosteroid can be a dose of about 10 mg prednisone equivalent. The method can include tapering 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 approach can include administering the second dose of corticosteroid once daily. The method can permit the administration of a reduced dose of corticosteroid for several weeks. The second dose of corticosteroid can be administered for at least 24 weeks. The second dose of corticosteroid can be administered for at least 28 weeks.

[0067] Steroid reduction

[0068] The method may include steroid tapering in a subject, wherein the dose of steroid administered to the subject is gradually reduced from a pre-tapering dose at baseline to a post-tapering dose. The post-tapering dose may be ≤ 7.5 mg / day of prednisone or prednisone equivalent dose. The pre-tapering dose may be 20 mg / day of prednisone or prednisone equivalent dose. The steroid may include glucocorticoids. The steroid may include oral glucocorticoids. The steroid may be selected from the group consisting of: 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 valeratevalerate), flucortolone, fluprednidene, 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 can be prednisone.

[0069] Subjects

[0070] The subject can be a human subject. The subject can be an adult. The subject can be a patient with an elevated type I IFN gene signature. The subject can be a patient who tests high for type I interferon-stimulated gene signature (IFNGS) prior to administration of the dose or unit dose. The subject may have elevated genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood. The method can include identifying the subject as a patient who tests high for IFNGS prior to treatment with the dose or unit dose. The method can include measuring the expression of genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood of the subject. The method can include measuring the expression of genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood of the subject by RT-PCR.

[0071] Subjects may have moderate to severe SLE prior to treatment with an IFNAR1 inhibitor. Prior to treatment with an IFNAR1 inhibitor, subjects may have responded to treatment with one or more immunomodulators or relapsed during or after treatment with one or more immunomodulators. Prior to treatment with an IFNAR1 inhibitor, subjects may have an SLEDAI-2K score of ≥10 (at least). Prior to treatment with an IFNAR1 inhibitor, subjects may have a CLASI activity score of ≥10 (at least 10). Prior to treatment with an IFNAR1 inhibitor, subjects may have a swollen and tender joint count of ≥6.

[0072] Subjects may have moderate to severe SLE as defined by the ACR classification criteria for SLE (ACR 1997

[10] and / or EULAR / ACR 2019

[11] ).

[0073] Drug composition

[0074] 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, wherein the dose is >105 mg and <150 mg. The dose of anifrolumab or a functional variant thereof may be a unit amount (unit dosage form, pharmaceutical unit dosage form, pharmaceutical unit dose). Functional anifrolumab variants include antigen-binding fragments of anifrolumab and antibody and immunoglobulin derivatives of anifrolumab.

[0075] In another aspect, the present invention relates to a pharmaceutical composition for use in a method of 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, wherein weekly administration of the pharmaceutical composition provides in the subject a plasma concentration that is at least equivalent to the plasma concentration provided by intravenous administration of 300 mg of anifrolumab or a functional variant thereof every 4 weeks. Weekly administration of the dose may provide in the subject a plasma concentration that is approximately equivalent to the plasma concentration provided by intravenous administration of 400 mg of anifrolumab or a functional variant thereof every 4 weeks. The dose 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 approximately 120 mg of anifrolumab or a functional variant thereof. The dose may be 120 mg of anifrolumab or a functional variant thereof.

[0076] The pharmaceutical composition can be administered at intervals of 6 - 8 days. The pharmaceutical composition can be administered once a week (QW). The pharmaceutical composition can be administered in a single administration step. The dose can be 120 mg of anifrolumab or a functional variant thereof, and the treatment method can include administering the dose once a week (QW) in a single administration step. The pharmaceutical composition can be administered once a week for at least about 4 weeks. The pharmaceutical composition can be administered once a week for at least about 8 weeks. The dose or unit dose can be administered once a week for at least about 12 weeks. The pharmaceutical composition can be administered once a week for at least about 16 weeks. The pharmaceutical composition can be administered once a week for at least about 20 weeks. The pharmaceutical composition can be administered once a week for at least about 24 weeks. The pharmaceutical composition can be administered once a week for at least about 28 weeks. The pharmaceutical composition can be administered once a week for at least about 32 weeks. The pharmaceutical composition can be administered once a week for about 8 weeks. The pharmaceutical composition can have a volume that allows for its proper delivery in a single subcutaneous administration step. The pharmaceutical composition can have a volume of about 0.5 ml to about 1 ml. The pharmaceutical composition can have a volume of less than 1 ml. The pharmaceutical composition can have a volume of about 0.8 ml.

[0077] Administration of the pharmaceutical composition can provide a plasma concentration of anifrolumab or a functional variant thereof of ≥ 10 μg per milliliter of plasma (i.e., 10 μg or higher), i.e., a plasma concentration of ≥ 10 μg / ml, in a patient. Administration of the pharmaceutical composition can provide a plasma concentration of anifrolumab or a functional variant thereof of about 10 μg / ml - 100 μg / ml in a subject. Administration of the pharmaceutical composition can provide a plasma concentration of anifrolumab or a functional variant thereof of about 20 μg / ml - 80 μg / ml in a subject. Administration of the pharmaceutical composition can provide a plasma concentration of anifrolumab or a functional variant thereof of about 30 μg / ml - 70 μg / ml in a subject. Administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof of ≥ 20 μg / ml (i.e., 20 μg / ml or higher) in a subject. Administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof of ≥ 30 μg / ml (i.e., 30 μg / ml or higher) in a subject. Administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof of ≥ 40 μg / ml (i.e., 40 μg / ml or higher) in a subject. Administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof of about 20 μg / ml - 100 μg / ml in a subject. Administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof of about 30 μg / ml - 80 μg / ml in a subject. Administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof of about 40 μg / ml - 70 μg / ml in a subject.

[0078] The therapeutic effect provided by the pharmaceutical composition in a subject can be at least equivalent to the therapeutic effect provided by administering an intravenous dose of 300 mg of anifrolumab or a functional variant thereof administered every four weeks (Q4W). The trough concentration of anifrolumab or a functional variant thereof provided by the pharmaceutical composition in a subject can be greater than the trough concentration of anifrolumab or a functional variant thereof provided by administering an intravenous dose of 300 mg of anifrolumab or a functional variant thereof administered once every four weeks (Q4W). Anifrolumab or a functional variant thereof can be included in the pharmaceutical composition. The pharmaceutical composition can include from about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, from about 25 mM to 150 mM of a lysine salt, and a charge-neutral excipient. The pharmaceutical composition can include 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition can include 50 mM of lysine HCl. The pharmaceutical composition can include 130 mM of trehalose dihydrate. The pharmaceutical composition can include 0.05% of polysorbate 80. The pharmaceutical composition can include 25 mM of histidine / histidine HCl. The pharmaceutical composition can include 150 mg / mL of anifrolumab or a functional variant thereof, 50 mM of lysine HCl, 130 mM of trehalose dihydrate, 0.05% of polysorbate 80, and 25 mM of histidine / histidine HCl.

[0079] The pharmaceutical composition can include from about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, from about 25 mM to 150 mM of a lysine salt, and a charge-neutral excipient. The pharmaceutical composition can include 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition can include 50 mM of lysine HCl. The pharmaceutical composition can include 130 mM of trehalose dihydrate. The pharmaceutical composition can include from about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, from about 25 mM to 150 mM of a lysine salt, and a charge-neutral excipient. The pharmaceutical composition can include 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition can include 50 mM of lysine HCl. The pharmaceutical composition can include 130 mM of trehalose dihydrate. The pharmaceutical composition can include 0.05% of polysorbate 80. The pharmaceutical composition can include 25 mM of histidine / histidine HCl. The pharmaceutical composition can include 150 mg / mL of anifrolumab or a functional variant thereof, 50 mM of lysine HCl, 130 mM of trehalose dihydrate, 0.05% of polysorbate 80, and 25 mM of histidine / histidine HCl.

[0080] Device

[0081] The present invention also relates to an injection device comprising the pharmaceutical composition for use in the method of the present invention.

[0082] The drug in the injection device may comprise anifrolumab or a functional variant thereof in an amount greater than 105 mg (i.e., more than 105 mg) and less than 150 mg (i.e., less than 150 mg). The pharmaceutical composition in the injection device may comprise approximately 120 mg of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the pharmaceutical composition in the injection device may be 150 mg / ml. The volume of the pharmaceutical composition in the injection device may be at least approximately 0.8 ml. The volume of the pharmaceutical composition may be approximately 0.8 ml.

[0083] The pharmaceutical composition in the injection device may comprise anifrolumab or a functional variant thereof at a concentration of about 150 mg / ml to 200 mg / ml, about 25 mM to 150 mM lysine, and a non-charged 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 lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition in the injection device may comprise anifrolumab or a functional variant thereof at a concentration of about 150 mg / ml to 200 mg / ml, about 25 mM to 150 mM lysine, and a non-charged 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 lysine HCl. The pharmaceutical composition in the injection device may comprise 130 mM trehalose dihydrate. The pharmaceutical composition in the injection device may comprise 0.05% polysorbate 80. The pharmaceutical composition in the injection device may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition in the injection device may comprise 150 mg / mL 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.

[0084] In another aspect, the present invention relates to an injection device comprising a unit dose for use in the method of the present invention. The unit dose may comprise anifrolumab or a functional variant thereof in an amount > 105 mg (i.e., at least 105 mg) and < 150 mg (i.e., less than 150 mg). The unit dose may comprise anifrolumab or a functional variant thereof in an amount ≤ 135 mg (i.e., 135 mg or less). The unit dose may comprise approximately 120 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device may comprise 120 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device may consist essentially of anifrolumab or a functional variant thereof in an amount > 105 mg and < 150 mg. The unit dose in the injection device may consist essentially of anifrolumab or a functional variant thereof in an amount ≤ 135 mg. The unit dose in the injection device may consist essentially of approximately 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the unit dose in the injection device may be approximately 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 from approximately 0.5 ml to approximately 1 ml. The concentration of the unit dose may be approximately 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose in the injection device may comprise a formulation of anifrolumab or a functional variant thereof at a concentration of from approximately 150 mg / ml to 200 mg / ml, from approximately 25 mM to 150 mM lysine, and a non-charged excipient. The unit dose in the injection device may comprise a formulation of anifrolumab or a functional variant thereof at a concentration of from 150 mg / ml to 200 mg / ml, from 25 mM to 150 mM lysine, and a non-charged 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 approximately 5.9.

[0085] The injection device may be a prefilled syringe (PFS). The injection device may be an attached prefilled syringe (AFPS). The injection device may be an autoinjector (AI).

[0086] Kit

[0087] In another aspect, the present invention relates to a kit comprising the unit dose of the present invention and instructions for use, wherein the instructions for use include instructions for subcutaneous administration of an IFNAR1 inhibitor to a subject.

[0088] In another aspect, the present invention relates to a kit comprising a pharmaceutical composition for use in the uses of the present invention, wherein the instructions for use include instructions for subcutaneous administration of the pharmaceutical composition to a subject.

[0089] In another aspect, the present invention relates to a kit comprising an injection device of any one of the present invention and instructions for use, wherein the instructions for use include instructions for using the injection device to subcutaneously administer a unit dose or a pharmaceutical composition to a subject. The kit may comprise a pharmaceutical composition containing a SARS-CoV-2 vaccine.

[0090] The kit of the present invention may comprise a package, wherein the package is adapted to accommodate the injection device and the 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 4 weeks. The instructions for use may define the subject as suffering from a type I IFN-mediated disease. The instructions for use may define the subject as suffering from an autoimmune disease. The instructions may define the subject as suffering from SLE. The instructions may define the subject as suffering from moderate to severe SLE. The instructions for use may be written instructions.

[0091] The instructions for use may specify the injection device, the unit dose, and / or the pharmaceutical composition for the treatment of SLE or for use in accordance with the methods of the present invention. The instructions for use include instructions for administering 120 mg of anifrolumab or a functional variant thereof weekly. The instructions for use may specify the unit dose or the pharmaceutical composition of the present invention for treating a subject who may have received a SARS-CoV-2 vaccine. The instructions for use may specify the unit dose or the pharmaceutical composition of the present invention for use in any one of the methods of the present invention. The instructions for use may specify that the methods of the present invention have been confirmed in phase III clinical trials.

[0092] Formulation

[0093] Anifrolumab or a functional variant thereof may be included in the pharmaceutical composition. The pharmaceutical composition may comprise from about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, from about 25 mM to 150 mM lysine salt, and a charge-neutral 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.

[0094] A stable formulation suitable for administration to a subject and containing anifrolumab is described in detail in U.S. Patent No. 10,125,195 B1, which is incorporated herein by reference in its entirety.

[0095] Definition

[0096] IFNAR inhibitor

[0097] Anifrolumab

[0098] Anifrolumab (MEDI-546, anifro, ANI) is a human immunoglobulin G1κ (IgG1κ) monoclonal antibody (mAb) against subunit 1 of the type I interferon receptor (IFNAR1). Anifrolumab downregulates IFNAR signaling and inhibits the expression of IFN-inducible genes. Disclosures related to anifrolumab can be found in U.S. Patent No. 7,662,381 and U.S. Patent No. 9,988,459, which are incorporated herein by reference in their entirety. The sequence information of anifrolumab is provided in Table 1.

[0099] Table 1: Anifrolumab sequence

[0100]

[0101]

[0102] 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. Anifrolumab is an immunoglobulin comprising VH of SEQ ID NO: 1 and VL of SEQ ID NO: 2.

[0103] The constant region of anifrolumab has been modified such that anifrolumab exhibits a reduced affinity for at least one Fc ligand compared to the unmodified antibody. Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 that contains the amino acid substitution L234F in the Fc region, numbered according to EU as described in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 that contains the amino acid substitutions L234F, L235E, and / or P331S in the Fc region, numbered according to EU as described in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is an antibody that contains the light chain constant region of SEQ ID NO:9. Anifrolumab is an antibody that contains the heavy chain constant region of SEQ ID NO:10. Anifrolumab is an antibody that contains the light chain constant region of SEQ ID NO:9 and the heavy chain constant region of SEQ ID NO:10. Anifrolumab is an antibody that contains the heavy chain of SEQ ID NO:11. Anifrolumab is an antibody that contains the light chain of SEQ ID NO:12. Anifrolumab is an antibody that contains the heavy chain of SEQ ID NO:11 and the light chain of SEQ ID NO:12.

[0104] Functional variants of anifrolumab are sequence variants that perform the same function as anifrolumab. Functional variants of anifrolumab are variants that bind the same target as anifrolumab and have the same effector function as anifrolumab. Functional anifrolumab variants include antigen-binding fragments of anifrolumab and antibody and immunoglobulin derivatives of anifrolumab. Functional variants include biosimilars and interchangeable products. The terms biosimilar and interchangeable product are defined by the FDA and EMA. The term biosimilar refers to a biological product that is highly similar in structure to an approved (e.g., FDA-approved) biological product (reference product, e.g., anifrolumab) and that has no clinically meaningful differences from the reference product in terms of pharmacokinetics, safety, and efficacy. The presence of clinically meaningful differences in a biosimilar can be evaluated in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and in the assessment of clinical immunogenicity. An interchangeable product is a biosimilar that is expected to produce the same clinical outcome as the reference product in any given patient.

[0105] For example, variants of the reference (anifrolumab) antibody can include: a heavy chain CDR1 having at most 2 amino acid differences when compared to SEQ ID NO:3; a heavy chain CDR2 having at most 2 amino acid differences when compared to SEQ ID NO:4; a heavy chain CDR3 having at most 2 amino acid differences when compared to SEQ ID NO:5; a light chain CDR1 having at most 2 amino acid differences when compared to SEQ ID NO:6; a light chain CDR2 having at most 2 amino acid differences when compared to SEQ ID NO:7; and a light chain CDR3 having at most 2 amino acid differences when compared to SEQ ID NO:8; wherein the variant antibody binds to the target of anifrolumab (e.g., IFNAR) and preferably binds with the same affinity.

[0106] Variants of the reference (anifrolumab) antibody can include: a heavy chain CDR1 having at most 1 amino acid difference when compared to SEQ ID NO:3; a heavy chain CDR2 having at most 1 amino acid difference when compared to SEQ ID NO:4; a heavy chain CDR3 having at most 1 amino acid difference when compared to SEQ ID NO:5; a light chain CDR1 having at most 1 amino acid difference when compared to SEQ ID NO:6; a light chain CDR2 having at most 1 amino acid difference when compared to SEQ ID NO:7; and a light chain CDR3 having at most 1 amino acid difference when compared to SEQ ID NO:8; wherein the variant antibody optionally binds to the target of anifrolumab (e.g., IFNAR) with the same affinity.

[0107] When compared to the corresponding reference (anifrolumab) antibody, the variant antibody can have a total of at most 5, 4, or 3 amino acid differences in its CDRs, provided that there are at most 2 (optionally at most 1) amino acid differences in each CDR. When compared to the corresponding reference (anifrolumab) antibody, the variant antibody can have a total of at most 2 (optionally at most 1) amino acid differences in its CDRs, provided that there are at most 2 amino acid differences in each CDR. When compared to the corresponding reference (anifrolumab) antibody, the variant antibody can have a total of at most 2 (optionally at most 1) amino acid differences in its CDRs, provided that there is at most 1 amino acid difference in each CDR.

[0108] When compared to the corresponding reference (anifrolumab) antibody, the variant antibody can have a total of at most 5, 4, or 3 amino acid differences in its framework regions, provided that there are at most 2 (optionally at most 1) amino acid differences in each framework region. Optionally, when compared to the corresponding reference (anifrolumab), the variant antibody has a total of at most 2 (optionally at most 1) amino acid differences in its framework regions, provided that there are at most 2 amino acid differences in each framework region. Optionally, when compared to the corresponding reference (anifrolumab), the variant antibody has a total of at most 2 (optionally at most 1) amino acid differences in its framework regions, provided that there is at most 1 amino acid difference in each framework region.

[0109] The variant antibody can comprise a variable heavy chain and a variable light chain as described herein, wherein: when compared to the heavy chain sequence herein, the heavy chain has at most 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region); when compared to the light chain sequence herein, the light chain has at most 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region); wherein the variant antibody binds to the same target antigen as the reference (anifrolumab) antibody (e.g., IFNAR), and preferably binds with the same affinity.

[0110] The variant heavy or light chain can be referred to as a "functional equivalent" of the reference heavy or light chain. The variant antibody can comprise a variable heavy chain and a variable light chain as described herein, wherein: when compared to the heavy chain sequence herein, the heavy chain has at most 7 amino acid differences (at most 1 amino acid difference in each CDR and at most 1 amino acid difference in each framework region); when compared to the light chain sequence herein, the light chain has at most 7 amino acid differences (at most 1 amino acid difference in each CDR and at most 1 amino acid difference in each framework region); wherein the variant antibody binds to the same target antigen as the reference (anifrolumab) antibody (e.g., IFNAR), and optionally binds with the same affinity.

[0111] Functional variants of anifrolumab

[0112] Functional variants of anifrolumab include the antibodies described in WO 2018 / 023976 A1, which is incorporated herein by reference (Table 2).

[0113] Table 2: Anti-IFNAR antibody sequences

[0114]

[0115]

[0116] 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 SEQ ID NO:13 and the VL amino acid sequence SEQ ID NO:16. Functional variants include antibodies comprising the VH sequence SEQ ID NO:13 and the VL amino acid sequence SEQ ID NO:15. Functional variants include antibodies comprising the VH sequence SEQ ID NO:16 and the VL amino acid sequence SEQ ID NO:15. Functional variants include antibodies comprising the VH sequence SEQ ID NO:16 and the VL amino acid sequence SEQ ID NO:14.

[0117] The IFNAR inhibitor can be a monoclonal antibody comprising the VH amino acid sequence SEQ ID NO:13. The anti-IFNAR antibody can comprise the VH amino acid sequence SEQ ID NO:16. The anti-IFNAR antibody can comprise the VL amino acid sequence SEQ ID NO:14. The anti-IFNAR antibody can comprise the VL amino acid sequence SEQ ID NO:15. The anti-IFNAR antibody can comprise the VL amino acid sequence SEQ ID NO:16. The anti-IFNAR antibody can comprise the VH sequence SEQ ID NO:13 and the VL amino acid sequence SEQ ID NO:16. The anti-IFNAR antibody can comprise the VH sequence SEQ ID NO:13 and the VL amino acid sequence SEQ ID NO:15. The anti-IFNAR antibody can comprise the VH sequence SEQ ID NO:16 and the VL amino acid sequence SEQ ID NO:15. The anti-IFNAR antibody can comprise the VH sequence SEQ ID NO:16 and the VL amino acid sequence SEQ ID NO:14.

[0118] QX006N

[0119] Functional variants of anifrolumab and anti-IFNAR antibodies include the QX006N antibody described in CN 11327807, which is incorporated herein by reference.

[0120] Table 3: QX006N antibody sequence

[0121]

[0122] The IFNAR inhibitor can be a monoclonal antibody comprising the VH amino acid sequence SEQ ID NO:17. The anti-IFNAR antibody can comprise the VL amino acid sequence SEQ ID NO:18.

[0123] QX006N is an immunoglobulin comprising, respectively, the HCDR1, HCDR2, and HCDR3 (or functional variants thereof) of SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21; and the LCDR1, LCDR2, and LCDR3 (or functional variants thereof) of SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:23. QX006N is an immunoglobulin comprising the VH amino acid sequence SEQ ID NO:17 and the VL amino acid sequence SEQ ID NO:18.

[0124] Anifrolumab in clinical practice

[0125] The safety of anifrolumab has been evaluated in 8 blinded or open-label intravenous (IV) and subcutaneous (SC) studies: 6 studies in patients with SLE (Study 05, Study 04, Study 1013, Study 1145, and Study 08), 1 study in patients with systemic sclerosis (SSc) (Study MI-CP180), and 1 study in healthy volunteers (Study 06) (Table 4). In these studies, two (Study 08 and Study 06) used SC anifrolumab administration. Two studies are ongoing: 1 study in SLE patients (Study 09) and 1 study in patients with lupus nephritis (LN) (Study 07).

[0126] Table 4: Anifrolumab clinical studies

[0127]

[0128] Study 1013 is described in more detail in Furie et al. 2017

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

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

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

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

[0129] Formulation

[0130] A stable formulation suitable for administration to a subject and containing anifrolumab is described in detail in U.S. Patent 10125195B1, which is incorporated herein by reference in its entirety.

[0131] The following examples are illustrative of specific embodiments of the present disclosure and its various uses. They are set forth for purposes of explanation only and should not be construed as limiting the scope of the present disclosure in any way.

[0132] Type I IFN gene signature (IFNGS)

[0133] Type I IFN is thought to play an important role in the pathogenesis of SLE, and anifrolumab targets the inhibition of this pathway. To understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know whether the subject's disease is driven by type I IFN activation. However, the direct measurement of type I IFN remains a challenge. Therefore, transcript-based markers have been developed to evaluate the effect of overexpression of the target protein on a specific group of mRNA markers. The expression of these markers is readily detectable in whole blood and has been shown to be correlated with expression in diseased tissues such as the skin in SLE. The bimodal distribution of the transcriptomic scores in SLE subjects supports the definition of IFN test high and low subsets (Error! Reference source not found). The type I IFN test is described in WO2011028933 A1, which is incorporated herein by reference in its entirety. The type I IFN gene signature can be used to identify whether a subject is a patient who is high for the type I IFN gene signature (IFNGS) test or low for the IFNGS test. The IFNGS test measures the expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subject's whole blood compared to three reference genes, 18S, ACTB, and GAPDH. The test result is a score compared to a pre-established cut-off value that divides patients into two groups with low or high levels of IFN-inducible gene expression (Error! Reference source not found).

[0134] The expression of the genes can be measured by RT-PCR. Suitable primers and probes for detecting the genes can be found in WO2011028933. A suitable kit for measuring the gene expression of the IFNGS test is the QIAGEN IFIGx RGQ RT-PCR Kit (IFIGx Kit), as described in Brohawn et al.

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

[0135] COVID-19 vaccine

[0136] Exemplary vaccines for COVID-19 are shown in Table 5 below.

[0137] Table 5: COVID-19 vaccines

[0138]

[0139]

[0140] SARS-CoV-2 includes the following: intranasal SARS-CoV-2 vaccine (Altimmune), INO-4800 (Inovio Pharma and Beijing Advaccine Biotechnology Company), APN01 (APEIRON Biologics), mRNA-1273 vaccine (Moderna and Vaccine Research Center), nucleoside-modified mNRABNT162b2 Tozinameran (INN) (Pfizer-BioNTech), adenovirus-based vaccine AZD1222 (recombinant ChAdOx1 adenovirus vector encoding the SARS-CoV-2 spike protein; Oxford-AstraZeneca), Covishield (ChAdOx1_nCoV19) recombinant ChAdOx1 adenovirus vector encoding the SARS-CoV-2 spike protein antigen (Serum Institute of India), SARS-CoV-2 vaccine (Vero Cell), inactivated (lnCoV) (Sinopharm / BIBP), SARS-CoV-2 vaccine (Vero cell), inactivated (Sinovac), Ad26.COV2 encoding the SARS-CoV-2 spike (S) protein.S recombinant replication-incompetent adenovirus type 26 (Ad26) vector vaccine (Janssen Pharmaceuticals Companies of Johnson & Johnson), Covid-19 vaccine based on Sputnik V human adenovirus vector (The Gamaleya National Center), Ad5-nCoV recombinant novel coronavirus vaccine (adenovirus type 5 vector) (CanSinoBIO), EpiVacCorona peptide antigen vaccine (Vector State Research Centre of Virology 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), recombinant subunit vaccine based on the trimeric S protein (S-trimer) of the SARS-CoV-2 coronavirus (Clover Pharmaceuticals), oral recombinant coronavirus vaccine (Vaxart), linear DNA vaccine based on (i) the complete spike gene of the coronavirus or (ii) the antigenic portion of the coronavirus protein (Applied DNA Sciences and Takis Biotech), SARS-Cov-2 coronavirus vaccine NVX-CoV2373 (Novavax), SARS-Cov-2 coronavirus vaccine NVX-CoV2373 (Novavax), intramuscular vaccine INO-4700 (GLS-5300) (Inovio Pharma and GeneOne Life Science), and combinations thereof.

[0141] Example 1: Randomized, placebo-controlled phase 3 extension trial of the long-term safety and tolerability of anifrolumab in active systemic lupus erythematosus Objective Summary of the Invention

[0143] Method

[0144] The long-term safety and tolerability of anifrolumab 300 mg compared to placebo were studied in patients who completed the TULIP trial and were enrolled in a placebo-controlled 3-year extension study (CT.gov reference NCT02794285).

[0145] Result

[0146] Patients received anifrolumab 300 mg or placebo every 4 weeks during the blinded extension. The primary comparison for the long-term extension (LTE) was between patients who received anifrolumab 300 mg or placebo in both the overall TULIP study and the LTE. For rare safety events, the comparison also included patients who received any dose of anifrolumab during the TULIP study or the LTE. When exposures were different, ratios were adjusted for exposure per 100 patient-years (EAIR).

[0147] Conclusion

[0148] During the LTE period, the rate of serious adverse events (SAEs) for anifrolumab was numerically lower than placebo (8.5 vs 11.2), including AEs leading to study product discontinuation (2.5 vs 3.2). The rate of non-opportunistic serious infections between groups was comparable (3.7 vs 3.6). The rate of COVID-related AEs (including asymptomatic infections) was higher for anifrolumab compared to placebo (10.2 vs 6.3). Surprisingly, no COVID-related AEs, including SAEs, occurred in fully vaccinated individuals. The rates of malignancies and major acute cardiovascular events were low and comparable between anifrolumab and placebo. Treatment with anifrolumab was associated with lower cumulative glucocorticoid use and a greater mean improvement in SLEDAI-2K compared to treatment with placebo.

[0149] Introduction

[0150] The LTE study represents the longest placebo-controlled clinical trial conducted to date in SLE. No new safety findings were identified in the LTE, which supports a favorable benefit-risk profile of anifrolumab for patients with moderate to severe SLE receiving standard therapy. No COVID AEs occurred in patients after full vaccination.

[0151] Method

[0152] This report presents the results of the first long-term placebo-controlled trial in SLE to characterize the safety and tolerability of intravenous anifrolumab compared to 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 complete a Phase 3 TULIP trial (NCT02446912 or NCT02446899) during a 52-week double-blind treatment period. Given the circumstances of the COVID-19 pandemic that emerged during the last year of this global multi-center extension study, this is also the first report on the safety profile of investigational biologics in SLE during the pre- and post-vaccination periods of the COVID-19 pandemic.

[0153] Study design

[0154] Figure 1

[0155] This study reports a 3-year, Phase 3, randomized, double-blind, placebo-controlled LTE study (15)[19, 20] conducted at 176 study sites in 24 countries in patients who completed a 52-week double-blind treatment period in one of the Phase 3 TULIP trials (TULIP-1: NCT02446912 or TULIP-2: NCT02446899). Patients were required to have moderate to severe SLE at the time of randomization in TULIP-1 or TULIP-2 and were permitted to participate in the extension study upon re-consent; the start of the LTE was 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 in TULIP-1 were switched to blinded anifrolumab 300 mg; and patients previously randomized to placebo were re-randomized 1:1 to blinded anifrolumab 300 mg or placebo via an interactive voice / web response system algorithm to give a final anifrolumab 300 mg:placebo ratio of approximately 4:1.

[0156] For primary safety, the main comparison group was between patients who received anifrolumab 300 mg in both TULIP and the LTE during the 3-year LTE study (“LTE anifrolumab 300 mg”) compared to 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 from the entire 4-year TULIP and LTE periods were used, and the primary comparison group was patients with any anifrolumab exposure (“full anifrolumab” group) versus patients with any placebo exposure (“full placebo” group; Figure 1 )。After the first dose of anifrolumab in LTE, data from patients who were randomized to placebo in TULIP and then to anifrolumab 300 mg in LTE were included in the “full anifrolumab” group. Since anifrolumab 150 mg is not a recommended dose for SLE, patients who switched from anifrolumab 150 mg in TULIP-1 to 300 mg in LTE were included in the full anifrolumab group and will be described only in the context of this group for the purposes of this analysis.

[0157] For efficacy comparisons (including disease activity and steroid use), the primary comparison groups during the 4-year TULIP and LTE periods were patients who received anifrolumab 300 mg or placebo in the TULIP study and continued their same treatment throughout LTE (the “combined anifrolumab 300 mg” group versus the “combined placebo” group, respectively). Note that the key difference between these groups and the LTE anifrolumab 300 mg and LTE placebo groups is the time frame analyzed (TULIP and LTE: 1 - 4 years versus LTE only: 2 - 4 years).

[0158] Patients received intravenous anifrolumab 300 mg or placebo every 4 weeks starting after the start of LTE (after the last visit in the TULIP study), for a total of up to 39 doses. After the 156-week treatment period in LTE (with the last dose of the study product 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 ethics committee or institutional review board.

[0159] Patients

[0160] Patients enrolled in 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 trials have been described previously [19, 20] and are briefly described below. The extension study was designed to reflect real-world clinical practice, allowing investigators to add or change background criteria for care treatment based on clinical judgment, including immunosuppressants and glucocorticoids. However, the use of cyclophosphamide, other biologics, intravenous immunoglobulins, or intravenous glucocorticoids was not permitted.

[0161] TULIP study

[0162] For the inclusion criteria in the TULIP study, briefly, patients were aged 18 - 70 years and were required to have a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥6; a clinical SLEDAI-2K score of ≥4; a British Isles Lupus Assessment Group 2004 (BILAG-2004) organ domain score of ≥1 in category A or ≥2 in category B; a Physician's Global Assessment (PGA) score of ≥1 (grade 0 - 3); seropositivity for antinuclear antibody, anti-double-stranded DNA (anti-dsDNA), or anti-Smith antibody; and stable treatment with at least one of prednisone or its equivalent, antimalarials, azathioprine, mizoribine, mycophenolate mofetil, mycophenolic acid, or methotrexate.

[0163] LTE study

[0164] To be included in the LTE study, patients must have received anifrolumab or placebo in one of the TULIP trials and completed a 52-week double-blind treatment period, and must have provided written informed consent prior to 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 product or the interpretation of the patient's safety or study results; patients were excluded if they were concurrently enrolled in another clinical study that was not TULIP-1 or TULIP-2. For exclusion criteria related to concomitant drug treatment, 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; mycophenolic acid > 1.44 g / day; oral, subcutaneous, or intramuscular methotrexate > 25 mg / week; mizoribine > 150 mg / day.

[0165] Safety assessment

[0166] AE data were recorded throughout the study and classified as during treatment or during the study based on the start date of the last dose administered, whether in the TULIP trial or the extension study. An AE that occurred during treatment was defined as an AE from the day of the first dose of study treatment until the day of the last dose of study treatment plus 28 days or the end of the study date, whichever was earliest. An AE that occurred during the study was defined as an AE from the day of the first dose of study treatment until the end of the study day.

[0167] Tuberculosis screening and monitoring during the LTE study

[0168] If patients had a new positive QFT-G test result for tuberculosis at randomization in the LTE study, they initiated prophylaxis within 30 days of randomization but before the second dose of the study product in the LTE. Each patient was monitored at each visit in the LTE to ensure the absence of signs or symptoms of active tuberculosis, no recent contact with anyone having active tuberculosis, and no history of latent or active tuberculosis. Patients identified as having latent tuberculosis were evaluated by local tuberculosis experts to confirm the diagnosis and the local standard of care used in treatment. Once latent tuberculosis was confirmed, treatment was initiated immediately and the study product was not administered until the start of treatment for latent tuberculosis. Additionally, patients with newly diagnosed latent tuberculosis had to agree to complete the locally recommended course of treatment for latent tuberculosis to continue receiving the study product.

[0169] Efficacy assessment: SLEDAI-2K, PGA, glucocorticoids, flares, and SDI

[0170] SLEDAI-2K was reported at Week 0 (TULIP baseline), Week 24, Week 52, Week 64, Week 76, Week 88, Week 104, Week 128, Week 156, Week 180, and Week 208, and at Week 212 and Week 216 after the last dose during the follow-up period. PGA was reported at Week 0, Week 24, Week 52, Week 64, Week 76, Week 88, Week 104, Week 128, Week 156, Week 180, and Week 208. The glucocorticoid dose in the study was collected at each visit and reported annually (baseline and up to Year 4) during TULIP and the extension period. The Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index (SDI) overall score was collected at Week 52, Week 104, Week 156, and Week 208. The glucocorticoid dose in the study was collected at each visit and reported annually (baseline and up to Year 4) during TULIP and the extension period.

[0171] Flare-ups were evaluated using the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - Flares Index, including the SLEDAI-2K. A mild to moderate flare-up was defined as an increase in the SLEDAI-2K of ≥3 points but <7 points from the previous visit in at least one of the following: at least one new or worsening manifestation among discoid, photosensitive, deep, cutaneous vasculitis, bullous lupus, nasopharyngeal ulcer, pleuritis, pericarditis, arthritis, or SLE fever; or an increase in the PGA of ≥1 point from the previous visit, provided that the PGA value was ≤2.5 points. A severe flare-up was defined as an increase in the SLEDAI-2K of ≥7 points from the previous visit in at least one of the following: at least one new or worsening manifestation among central nervous system SLE, vasculitis, nephritis, myositis, or hemolytic anemia; hospitalization due to SLE disease activity; or an increase in the PGA to >2.5 points.

[0172] No imputation of missing data was performed for discontinued or lost-to-follow-up patients, except for the missing SDI overall score. In such cases, the score was calculated if only one of "proteinuria ≥3.5 g / day" or "advanced kidney disease (whether dialysis or transplantation)" was missing. If neither of the two items described was present or any other item was missing, the SDI overall score was set to missing. For both missing intermediate values and decreasing scores, the missing SDI score was estimated based on the worst observation. Since the SDI overall score never decreases, a project-level decrease was replaced by carrying forward the worst (highest) observation result (WOCF). WOCF was applied to all items, including intermittent missing values (before the study product interruption). The time to the first SDI deterioration was defined as the date of the first SDI deterioration minus the date of the first administration of the study product. If the patient did not deteriorate, the time to SDI deterioration was censored at the end of the exposure period or week 208, whichever occurred earlier.

[0173] Statistical analysis

[0174] Baseline demographics and characteristics of the treatment groups were presented as descriptive statistics. AEs were summarized by descriptive statistics, including exposure-adjusted incidence rate (EAIR) and adjusted cumulative proportion. Exposure was calculated up to the date of the last dose of treatment +84 days or the date of study interruption, death, or consent withdrawal, whichever occurred earlier. COVID-related events were characterized by event rates based on the time at risk during the pandemic.

[0175] Values observed in the SLEDAI-2K, SDI, and PGA and changes from baseline were presented by visit descriptive statistics. Analysis of covariance was used to analyze the mean change from baseline in the SLEDAI-2K, which included baseline values (continuous), treatment group, visit, and a randomization stratification factor, which was simplified to the factor I IFN gene signature test result at screening and the glucocorticoid dose at baseline. For glucocorticoid use, both the standardized area under the curve (AUC) and the proportion of patients with glucocorticoid dose were presented by treatment group and summary statistics by year. A sensitivity analysis for glucocorticoid use was performed to exclude patients with glucocorticoid doses >40 mg / day at the baseline of the TULIP study due to unknown end dates. Four patients with missing glucocorticoid discontinuation dates starting before randomization were excluded because these high doses were throughout the study and thus inflated the results. Flare rates per patient-year were presented for mild to moderate flares, severe flares, and overall flares.

[0176] Definition of EAIR and event rate

[0177] The EAIR per 100 patient-years was defined as the number of patients with a specific event divided by the total exposure in years × 100. The exposure time was defined as the date from the first administration of treatment until death, end of treatment plus 84 days, or end of study, whichever occurred first. The event rate per 100 patient-years was defined as the number of patients with an event divided by the total time in years at risk during the pandemic × 100. The time at risk was defined as the date from the start of the pandemic until death, end of treatment plus 84 days, or end of study, whichever occurred first. When reporting events that occurred only during treatment, the end of the period plus 28 days was considered instead of 84 days.

[0178] Study results

[0179] The primary outcomes were long-term safety and tolerability evaluated by the 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 Global Assessment (PGA), glucocorticoid use, flare incidence and severity, and the overall score of the Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index (SDI). Further information on the study outcomes is described in the Supplementary Methods.

[0180] COVID-19 pandemic

[0181] LTE began on June 30, 2016 and continued during the COVID-19 pandemic declared by the World Health Organization on March 11, 2020. The total exposure of each patient during the pandemic was calculated as:

[0182] Total exposure = End of period - Start date of pandemic + 1

[0183] Patients were considered fully vaccinated against COVID-19 if they received at least 2 doses of any approved vaccine, which is the standard COVID-19 vaccination schedule during the relevant time period.

[0184] Result

[0185] Patients

[0186] Of the 639 patients who completed treatment in the TULIP study, 547 were enrolled in LTE and randomly assigned to receive at least one dose of treatment ( Figure 1 ). There were 257 patients who continued anifrolumab 300 mg (LTE anifrolumab 300 mg), and 67 patients who switched from anifrolumab 150 mg to 300 mg. The 223 patients who received placebo in TULIP-1 or TULIP-2 were re-randomized 1:1 in LTE to anifrolumab 300 mg (n = 111) or placebo (n = 112, LTE placebo). Among the patients who would continue to be included in the primary safety comparison group during the LTE study period previously described as LTE anifrolumab 300 mg (n = 257) and LTE placebo (n = 112) ( Figure 1 ), the demographics and baseline disease characteristics at the start of the TULIP study were generally well-balanced between groups (Table 6), and similar proportions of patients were receiving glucocorticoids or immunosuppressants. For patients continuing LTE, the disease activity score at TULIP baseline as measured by the mean (SD) SLEDAI-2K overall score was 11.2 (3.7) in the LTE anifrolumab 300 mg group and 11.3 (3.6) in the LTE placebo group. This was consistent with the overall TULIP population.

[0187] Table 6: Demographics and SLE disease characteristics at TULIP baseline in patients continuing treatment in the LTE study

[0188]

[0189]

[0190] 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 extension; NSAID, non-steroidal 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.

[0191] Among patients in the LTE anifrolumab 300 mg group, 69.3% (178 / 257) completed the 3-year extension study, compared with 48.2% (54 / 112) of patients in the LTE placebo group. The most frequently 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%]).

[0192] During the extension study, the total exposure to anifrolumab in the LTE anifrolumab 300 mg group was 683.5 patient-years, compared with an exposure to placebo of 250.3 patient-years in the LTE placebo group (Table 7). Across all doses and all groups in the TULIP study and the 3-year LTE, the total exposure to anifrolumab was 1,568 patient-years.

[0193] Table 7: Incidence of AE, death, and exposure-adjusted in any category during treatment and follow-up in the extension study

[0194]

[0195]

[0196] AE, adverse event; AESI, adverse event of special interest; CI, confidence interval; EAIR, exposure-adjusted incidence rate; IFN, interferon; LTE, long-term extension; PY, patient-year; SAE, serious adverse event; SLE, systemic lupus erythematosus.

[0197] a The exposure days per patient were calculated as the earlier of (date of treatment of the last dose + 84 days, or date of study discontinuation) - date of treatment of the first dose + 1 day.

[0198] b Define the exposure-adjusted incidence rate (EAIR) per 100 patient-years as the number of patients with a specific event divided by the total exposure in years × 100. Define the exposure period as from the date of the first administration of treatment until death, end of treatment plus 84 days, or end of the study, whichever occurs first.

[0199] c Define latent tuberculosis as a positive IFN-γ release assay. No cases of active tuberculosis were reported.

[0200] d According to the Cardiovascular Event Adjudication Committee.

[0201] Safety and tolerability

[0202] During the 1-year TULIP study, the safety profile of anifrolumab in SLE 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 (EAIR) of any adverse event (AE) (33.1 vs 37.6), any serious adverse event (SAE) (including events resulting in death) (8.5 vs 11.2), and any drug-related adverse event (DAE) (2.5 vs 3.2) in the LTE anifrolumab 300 mg group were lower compared with the LTE placebo group, respectively (Table 7). The safety profile of anifrolumab generated in those patients receiving any dose of anifrolumab (total anifrolumab group; n = 560) (either in one of the TULIP studies or in LTE) was similar to the profile generated in those patients receiving 300 mg of anifrolumab in the combined TULIP and LTE datasets (combined anifrolumab 300 mg group; n = 358) (Table 8).

[0203] Table 8: Incidence of AE, SAE, death, AESI, and exposure-adjusted in any category during treatment and follow-up from week 0 to week 216 a Table 9: Adverse events and event rates according to preferred terms during LTE treatment

[0204]

[0205] 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 pooled from the TULIP trial and the extension study.

[0206] b Calculate the exposure days per patient as the earlier of (date of the last dose of treatment + 84 days, or date of study discontinuation) - date of the first dose of treatment + 1 day.

[0207] c Define the EAIR per 100 patient - years as the number of patients with a specific event divided by the total exposure in years × 100. Define the exposure time as from the date of the first administration of treatment until death, end of treatment plus 84 days, or end of study, whichever occurs first.

[0208] d Define latent tuberculosis as a positive IFN - γ release assay. No cases of active tuberculosis were reported.

[0209] According to the EAIR, the most common AEs in the LTE 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 300mg group and the LTE placebo group, respectively (Table 9). In the same groups, the most frequently reported SAE type by EAIR was the system organ class of infections and infestations (4.3 and 4.7). In both the LTE anifrolumab 300mg group and the LTE placebo group, the EAIR for any AE resulting in death was 0.4, including three deaths due to infections reported with anifrolumab (one COVID and two pneumonias), and one death due to a major acute cardiovascular event (acute myocardial infarction) reported with the placebo (Table 7). During the LTE study, there were an additional 2 deaths due to COVID in the group switched from placebo to anifrolumab. When considering the four - year total anifrolumab and placebo exposure, there were a total of 12 deaths, including the 3 deaths previously reported in the TULIP trial and the six deaths described above that occurred during the LTE. There were ten deaths in the total anifrolumab group and 2 deaths reported in the total placebo group, giving EAIRs of 0.6 vs 0.3, respectively (Table 8). Among the patients in the LTE anifrolumab 300mg group and the LTE placebo group who discontinued treatment due to an AE, no DAE was reported in more than two patients in each group (Table 10).

[0210] In the extension study, the rates of AESIs were low in both the LTE anifrolumab 300 mg group and the LTE placebo group (Table 7). The AESI rates for non-opportunistic serious infections (3.7 vs 3.6) were similar between the treatment groups. The 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). Notably, 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. When considering the TULIP and LTE periods together, the overall AESI rate for HZ decreased over time in the overall anifrolumab group and was lower during the LTE period than during the first year of treatment in the TULIP trial (exposure-adjusted event rates based on time at risk: 6.8 [Year 1], 5.7 [Year 2], 3.9 [Year 3], and 2.9 [Year 4]).

[0211] To be comprehensive and include the maximum exposure, rare AEs were reported over a 4-year exposure period (overall anifrolumab: n = 560, total exposure 1,568.0 patient-years; overall placebo: n = 360, total exposure 587.1 patient-years). The rate of opportunistic infections was numerically lower in the overall anifrolumab group compared with the overall placebo group (0.2 vs 0.7) (Table 8). Relatively low rates of malignancies (0.8 vs 0.7), allergic reactions (0.1 vs 0.0), and major acute cardiovascular events (0.8 vs 0.5) were observed in both treatment groups. In this study, only non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma (n = 2 each), were reported in more than one patient. When considering the TULIP and LTE periods together, the rate of any SAE decreased over time in patients treated with anifrolumab (overall anifrolumab group) and was lower during the LTE period than during the first year of treatment in the TULIP trial (5, 6) (n [%], exposure-adjusted event rates 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).

[0212] Over the entire 4-year treatment period, treatment-emergent antidrug antibodies were detected in 2.6% (9 / 358) of patients receiving combination anifrolumab 300 mg, with no trend or pattern indicating any association with AEs.

[0213] Table 10: Adverse events leading to study product discontinuation during treatment and follow-up in LTE and event rates according to preferred terms a

[0214]

[0215]

[0216] EAIR, Exposure - Adjusted Incidence Rate; LTE, Long - Term Extension; PY, Patient - Year.

[0217] a Define the exposure period as the date from the first administration of the treatment to the date of the first event, death, end of treatment plus 84 days, or the end of the study, whichever occurs first.

[0218] b Define the EAIR per 100 patient - years as the number of patients with a specific event divided by the total exposure time in days of all subjects during the LTE period multiplied by 36,525.

[0219] Table 11: COVID-19-related AE and event rates during treatment and follow-up in the extension study Figure 2

[0220]

[0221] AE, Adverse Event; COVID - 19, Coronavirus Disease 2019; DAE, Adverse Event Leading to Discontinuation of the Investigational Product; EAIR, Exposure - Adjusted Incidence Rate; LTE, Long - Term Extension Study; PY, Patient - Year.

[0222] a Multiple occurrences of AEs of the preferred option in a patient are counted only once.

[0223] b Define the exposure period as the date from the first administration of the treatment to the date of the first event, death, end of treatment plus 84 days, or the end of the study, whichever occurs first.

[0224] c Define the EAIR per 100 patient - years as the number of patients with a specific event divided by the total exposure time in days of all subjects during the LTE period multiplied by 36,525.

[0225] Efficacy

[0226] The unprecedented global COVID - 19 pandemic was declared during the last year of the LTE study that continued through the introduction of the vaccine. Among the entire anifrolumab group (n = 325) and the LTE placebo group (n = 64), among the patients in the LTE at the start of the COVID - 19 pandemic, the total treatment exposures were 227.7 patient - years and 42.7 patient - years, respectively (Table 11).

[0227] Figure 3

[0228]

[0229] AE, adverse event; CI, confidence interval; COVID-19, coronavirus disease 2019; LTE, long-term extension; SAE, serious adverse event.

[0230] a The start date of the COVID-19 pandemic was March 11, 2020, as declared by the World Health Organization.

[0231] b Calculate each patient's exposure during the pandemic as the end of the period - the start date of the COVID-19 pandemic + 1 (where the end of the period is the earlier of the date of the last dose of treatment + 84 days, the date of study discontinuation, death, or consent withdrawal).

[0232] c n(%) total exposure of the data. Define the time at risk as the time from the start date of the COVID-19 pandemic to the date of the first event or the end of the period (including start and end dates), whichever occurs first.

[0233] d Define the event rate per 100 patient-years as the number of patients with an event divided by the total time at risk in years during the pandemic × 100. Define the time at risk as the date from the start of the pandemic to death, end of treatment plus 84 days, or end of the study, whichever occurs first. When reporting events that occur only during treatment, consider the end of the period plus 28 days instead of 84 days.

[0234] During the extension study period, compared with the LTE placebo group, the event rates of COVID-related AEs and SAEs in the anifrolumab full group (based on the time at risk during the pandemic) were higher (AE: 15.5 vs 9.8; SAE: 7.2 vs 2.4) (Table 11). Among the 33 COVID-related AEs in the anifrolumab full group, 16 were severe (16 / 33; [48.5%]); one SAE was reported in the LTE placebo group (1 / 4; 25%). Focusing on the overall COVID-AE severity, in the anifrolumab full group, the ratio of COVID AEs was the same frequency for mild, moderate, or severe cases, and the ratio was higher compared with those reported in the broader full placebo group. Notably, asymptomatic positive COVID tests were considered COVID-related AEs. Three deaths in the anifrolumab full group occurred within the first 6 months of the pandemic ( Table 12: Change in mean PGA score from baseline to week 208 a ). After full vaccination, no COVID AEs occurred in the patients. Twenty-one patients in the anifrolumab group were fully vaccinated against COVID, and nine patients in the placebo group were fully vaccinated.

[0235] Figure 4

[0236] Throughout the TULIP and extension periods, efficacy data (SLEDAI-2K, PGA, glucocorticoid use, flare rate, and SDI) were evaluated in the combination anifrolumab 300 mg group (n = 358) compared to the combination placebo group (n = 178). For patients continuing in the LTE, the baseline (starting from 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 the LTE (Week 52), the mean (SD) scores for the two groups were 5.1 (3.5) and 6.0 (4.1), respectively. During the LTE period, patients in the combination anifrolumab 300 mg group had a greater mean improvement in SLEDAI-2K, with continued improvement over time compared to the combination placebo group ( Figure 5 ); in the combination anifrolumab 300 mg group, the mean SLEDAI-2K score decreased steadily from baseline to Week 52 during the TULIP period and continued to decrease during the LTE to Week 208.

[0237] In the combination anifrolumab 300 mg group, the mean PGA score decreased from 1.8 at Week 0 (TULIP baseline) to 0.6 at Week 208, and in the combination placebo group, it decreased from 1.8 at TULIP baseline to 0.7 at Week 208 (Table 12).

[0238] Figure 6

[0239]

[0240]

[0241] PGA, Physician Global Assessment; SD, Standard Deviation.

[0242] a Change in PGA scores for patients randomized to receive anifrolumab 300 mg (“combination anifrolumab 300 mg”) in the overall TULIP-1, TULIP-2, and extension studies and all patients randomized to receive placebo (“combination placebo”) in the TULIP-1, TULIP-2, and extension studies.

[0243] b Data are the exact mean (SD) of PGA scores at Week 0 (TULIP baseline).

[0244] In each of the four years during the TULIP phase and the LTE phase, the cumulative glucocorticoid dose was lower in patients in the combination anifrolumab 300 mg group compared to the combination placebo group ( Figure 6 ; standardized AUC), which excluded 3 patients in the anifrolumab group due to missing data. The reduction in SLEDAI-2K was achieved in parallel with the reduction in the mean glucocorticoid dose ( Figure 7 ). Over the 4 years spanning TULIP and the extension period, the proportion of patients receiving a mean glucocorticoid dose > 7.5 mg / day was lower in the combination placebo group compared to the combination anifrolumab 300 mg group ( Figure 7 ). At the end of the extension study (Year 4), 9.9% of patients in the combination anifrolumab 300 mg group were taking glucocorticoids at > 7.5 mg / day, compared to 29.3% of patients in the combination placebo group taking glucocorticoids ( Discussion ).

[0245] The overall annual flare rate was 0.1 in the combination anifrolumab 300 mg group and 0.2 in the combination placebo group. The severity of all flares in both groups was mild to moderate.

[0246] The mean change in the SDI overall score from baseline was evaluated in patients with an SDI overall score ≥ 1 at Week 52, including 132 patients from the combination anifrolumab 300 mg group and 75 patients from the combination placebo group ( References ). At TULIP baseline, the mean SDI overall 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 LTE (Week 52 to Week 208), there was no difference in damage as the mean SDI scores remained stable in both treatment groups ( ​ ). A longer time to first SDI worsening (mean [SD]) was observed in the combination anifrolumab 300 mg group (925.0 [553.0] days) compared to the combination placebo group (754.2 [523.3] days).

[0247] ​

[0248] Despite the standard of care, anifrolumab is the first class of therapy recently approved for the treatment of moderate to severe SLE, and the long-term data reported herein are important for prescribers treating patients with this chronic disease. In particular, these data describe the first long-term placebo-controlled study in SLE and additionally capture the period of the global COVID pandemic. The study builds on existing evidence from the MUSE open-label extension study and shows that treatment with anifrolumab is well tolerated and has an acceptable long-term safety profile while maintaining reduced disease activity and glucocorticoid use.

[0249] The overall incidence of 2-year SAE with anifrolumab treatment was consistent with observations during the TULIP study and decreased over time in the LTE. In this LTE, the rates of both non-opportunistic serious infections and opportunistic infections were low and comparable to placebo. 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 herein. Although there was a numerically higher HZ rate (3.4 compared to 2.8) among those treated with anifrolumab 300 mg compared to patients treated with placebo during the 3-year extension period, the anifrolumab rate observed in this study was lower than that observed in the combined anifrolumab 300 mg results from the TULIP-1, TULIP-2, and MUSE studies (LTE: 3.4 compared to combined phase 2 and 3 data: 6.9). This suggests that the risk of HZ with anifrolumab is highest during the first year of treatment. Most HZ cases in the LTE study were mild to moderate, responded to treatment with antivirals, and all patients except one were able to continue the study. Additionally, the overall frequency of the HZ incidence with anifrolumab in the LTE was similar to that reported for long-term treatment with belimumab (8.6%, 63 / 735) in the extension of the phase 3 BLISS-52 and BLISS-76 clinical trials in SLE, at 8.9% (LTE anifrolumab 300 mg: 23 / 257)

[21] .

[0250] Latent tuberculosis in this study was defined as a positive IFN-γ release assay, which can result in indeterminate results in patients with active SLE due to the common occurrence of immunomodulatory therapy and / or lymphopenia. Although a higher rate of latent tuberculosis was reported in the anifrolumab group compared to placebo, likely due to improved disease control in the anifrolumab group, no cases of active tuberculosis occurred. Our experience suggests that screening and treating latent tuberculosis is effective in the context of anifrolumab use.

[0251] This is the only placebo-controlled study reporting consecutive data across the start of the COVID-19 pandemic (March 11, 2020)

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

[23] . Type I IFN is elevated in the majority of patients with SLE and may play a role in the course of COVID

[24] . In addition, type I IFN responses are important in host viral defense, and their absence (i.e., autoantibody status) is associated with a high 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 to those treated with placebo. Approximately 50% of COVID-related AEs were severe in the full anifrolumab group, and 25% of cases were severe in the LTE placebo group. However, most COVID-related SAEs and all 3 deaths occurred during the first 6 months of the pandemic before vaccination or treatment for COVID was effective

[27] . There were no COVID-related AEs in patients after full vaccination against COVID, indicating that therapy with an IFNAR1 inhibitor surprisingly does not affect vaccine efficacy. The overall COVID mortality rate observed with anifrolumab treatment was comparable to the mortality rate reported in SLE patients treated with biologics at the time of COVID diagnosis

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

[0252] The rate of malignancies in this study was low and comparable to placebo. In this study, only non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) were reported in more than one patient. The long-term malignancy risk will be further evaluated in a planned post-authorization safety study. Major cardiovascular events adjudicated by an independent cardiovascular adjudication committee were rare and comparable between anifrolumab and placebo. No patient experienced anaphylaxis in the LTE study.

[0253] Although the study was primarily designed to evaluate the long-term safety of anifrolumab in SLE, disease activity was assessed using the SLEDAI-2K, and greater mean improvements were observed in patients in the anifrolumab 300 mg combination group than in those in the placebo combination group. Improvements persisted over time, and mean disease activity levels remained low throughout the study in the presence of anifrolumab. Although the extended study protocol did not require glucocorticoid tapering, treatment with anifrolumab 300 mg resulted in lower glucocorticoid doses and lower cumulative glucocorticoid doses compared with placebo treatment. At year 4, 36.4% of patients treated with anifrolumab were not using glucocorticoids (0 mg / day), and this number increased to 74.4% of patients with glucocorticoid doses of 0 or 0–≤5 mg / day, which may have contributed to a lower incidence of AEs. Recent extensive meta-analyses have highlighted the importance of glucocorticoid reduction in SLE, which have shown clear associations of glucocorticoid exposure with osteonecrosis, cardiovascular events, and osteoporosis and fractures

[31] . These results in the LTE study were consistent with findings in 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 SAEs. No signal of increased damage was observed in the study, as measured by the SDI score.

[0254] The study was unique in that it was the first phase 3, double-blind, placebo-controlled long-term safety study in SLE and was conducted both before and during the COVID pandemic. This not only enabled initial observations of COVID infections in patients with SLE in both the pre-vaccination and post-vaccination periods but also led to extensive study interruptions, treatment discontinuation in the early part of the pandemic, and dropouts.

[0255] ​

[0256] [1]F.Zhang et al.,RMD Open 8,e001669(2022).

[0257] [2]Y.Tanaka et al.,RMD Open 7,e001629(2021).

[0258] [3]S.Galmiche et al.,Clin.Microbiol.Infect.28,163(2022).

[0259] [4]K.A.Kirou et al.,Front.Immunol.13,(2022).

[0260] [5] R. Spiera, S. Jinich, and D. Jannat-Khah, Ann. Rheum. Dis. 80, 1357 (2021).

[0262] [6] D. Gladman et al., Arthritis Rheum. 39, 363 (1996).

[0263] [7] J. Albrecht et al., J. Invest. Dermatol. 125, 889 (2005).

[0264] [8] C.-S. Yee et al., Rheumatol. Oxf. Engl. 49, 1665 (2010).

[0265] [9] C.-S. Yee et al., Arthritis Rheum. 56, 4113 (2007).

[0266]

[10] M. C. Hochberg, Arthritis Rheum. 40, 1725 (1997).

[0267]

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

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

[0268]

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

[0269]

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

[0270]

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

[0271]

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

[0272]

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

[0273]

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

[0274]

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

[0275]

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

[0276]

[21] R.F.van Vollenhoven et al.,Rheumatol.Oxf.Engl.59,281(2020).

[22] (n.d.).

[0277]

[23] M.Aringer et al.,Ther.Adv.Musculoskelet.Dis.14,

[0278] 1759720X221086719(2022).

[0279]

[24] R.Fernandez-Ruiz,J.L.Paredes,and T.B.Niewold,Transl.Res.J.

[0280] Lab.Clin.Med.232,13(2021).

[0281]

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

[0283]

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

[0284]

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

[0286]

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

[0287]

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

[0288]

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

[0289]

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

Claims

1. A method for treating systemic lupus erythematosus (SLE) in a subject in need thereof and preventing or reducing the risk of SARS-CoV-2 infection, the method comprising a) administering to the subject an inhibitor of type I IFN receptor (IFNAR1), 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 is exposed to SARS-CoV-2, and wherein the method treats SLE in the subject.

2. The method according to claim 1, wherein the IFNAR1 inhibitor is administered to the subject less than 1 month before the SARS-CoV-2 vaccine.

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

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

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

6. The method according to claim 1, wherein the IFNAR1 inhibitor is administered intravenously to the subject at a dose of approximately 300 mg every 4 weeks (Q4W).

7. The method according to claim 1, wherein the IFNAR1 inhibitor is administered intravenously to the subject at a dose of approximately 900 mg every 4 weeks (Q4W).

8. The method according to claim 1, wherein the IFNAR1 inhibitor is administered subcutaneously to the subject at a dose of approximately 120 mg per week.

9. 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 has been treated with an IFNAR1 inhibitor, the method comprising administering to the subject a therapeutically effective amount of a SARS-CoV-2 vaccine, and wherein the method prevents or reduces the risk of SARS-CoV-2 infection in the subject after the subject is exposed to SARS-CoV-2.

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

11. The method according to 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 according to any one of claims 9 to 11, wherein the SARS-CoV-2 vaccine is administered to the subject within 1 month or less after the IFNAR1 inhibitor is administered to the subject.

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

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

15. The method according to any one of claims 9 to 14, wherein the IFNAR1 inhibitor is administered intravenously to the subject at a dose of about 300 mg every 4 weeks (Q4W).

16. The method according to any one of claims 9 to 14, wherein the IFNAR1 inhibitor is administered intravenously to the subject at a dose of about 900 mg every 4 weeks (Q4W).

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

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

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

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

21. The method according to any one of claims 9 or 20, wherein the IFNAR1 inhibitor is administered to the subject less than 1 month before the SARS-CoV-2 vaccine is administered to the subject.

22. 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 the subject's SLE.

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

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

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

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

27. The method according to claims 22 to 26, wherein the subject was vaccinated against COVID-19 within 6 months or less before administering the IFNAR1 inhibitor.

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

30. The method according to 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 of SEQ ID NO: 6; (e) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; and / or (f) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:

8.

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

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

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

36. 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, wherein the pharmaceutical composition comprises an IFNAR1 inhibitor, the method comprising administering the pharmaceutical composition to the subject, wherein the method treats the subject's SLE.

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

38. The injection device according to claim 37, wherein the injection device is a prefilled syringe (PFS), optionally a prefilled syringe with attachment (AFPS) or an autoinjector.

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

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

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

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