Methods of treating systemic lupus erythematosus

Abstract

The present disclosure relates to methods for treating systemic lupus erythematosus (SLE) using the selective JAK1 inhibitor upatinib.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 393,158, filed on July 28, 2022, and claims the benefit of U.S. Provisional Application No. 63 / 411,785, filed on September 30, 2022, each of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to methods of treating systemic lupus erythematosus (SLE) with the selective JAK1 inhibitor upadacitinib. Background Art

[0004] Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by antibodies to nuclear and cytoplasmic antigens, multisystem inflammation, variable clinical manifestations, and a relapsing and remitting course. SLE causes widespread inflammation and tissue damage in affected organs, which may include joints, skin, brain, lungs, kidneys, and blood vessels. Symptoms of SLE vary depending on the affected organ, but may include fatigue, rash, fever, and joint pain or swelling.

[0005] At present, there is no method for curing SLE, and existing therapies focus on improving quality of life by controlling symptoms and minimizing erythema outbreaks, mainly by using immunosuppressive drugs such as hydroxychloroquine and corticosteroids, and immunomodulators such as belimumab and aniluomab. Despite these treatments, there is still a significant unmet treatment need for SLE patients. This article provides a method for treating SLE. Summary of the invention

[0006] The present disclosure provides methods for treating systemic lupus erythematosus (SLE) with upadacitinib, a selective JAK1 inhibitor. The treatment methods generally include administering a therapeutically effective amount of upadacitinib to a patient in need thereof.

[0007] In one aspect, a method of treating a human patient having moderately to severely active systemic lupus erythematosus is provided, the method comprising orally administering 30 mg of upadacitinib to the patient once daily.

[0008] In another aspect, a method of treating a human patient having moderately to severely active systemic lupus erythematosus is provided, the method comprising orally administering 15 mg of upadacitinib to the patient once daily.

[0009] In yet another aspect, a method of treating a human patient with moderate to severe active systemic lupus erythematosus is provided, the method comprising orally administering 45 mg of upadacitinib to the patient once daily. In some embodiments, 45 mg of upadacitinib is an induction dose, followed by oral administration of a maintenance dose to the patient once daily. In some embodiments, the maintenance dose is 30 mg. In some embodiments, the maintenance dose is 15 mg.

[0010] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 52 weeks after the first daily administration.

[0011] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 52 weeks after the first daily administration.

[0012] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 52 weeks after the first daily administration.

[0013] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 52 weeks after the first daily administration.

[0014] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 52.

[0015] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 52, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0016] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 48 weeks after the first daily administration.

[0017] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 48 weeks after the first daily administration.

[0018] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 48 weeks after the first daily administration.

[0019] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 48 weeks after the first daily administration.

[0020] In some embodiments, the method results in a reduction in steroid burden as assessed by the change from baseline in prednisone equivalent steroid dose at week 48.

[0021] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 48, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0022] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 24 weeks after the first daily administration.

[0023] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 24 weeks after the first daily administration.

[0024] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 24 weeks after the first daily administration.

[0025] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 24 weeks after the first daily administration.

[0026] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 24.

[0027] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 24, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0028] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 20 weeks after the first daily administration.

[0029] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 20 weeks after the first daily administration.

[0030] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 20 weeks after the first daily administration.

[0031] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 20 weeks after the first daily administration.

[0032] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 20.

[0033] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 20, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0034] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 16 weeks after the first daily administration.

[0035] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 16 weeks after the first daily administration.

[0036] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 16 weeks after the first daily administration.

[0037] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 16 weeks after the first daily administration.

[0038] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 16.

[0039] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 16, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0040] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 12 weeks after the first daily administration.

[0041] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 12 weeks after the first daily administration.

[0042] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 12 weeks after the first daily administration.

[0043] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 12 weeks after the first daily administration.

[0044] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 12.

[0045] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 12, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0046] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 8 weeks after the first daily administration.

[0047] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 8 weeks after the first daily administration.

[0048] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 8 weeks after the first daily administration.

[0049] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 8 weeks after the first daily administration.

[0050] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 8.

[0051] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 8, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0052] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 4 weeks after the first daily administration.

[0053] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 4 weeks after the first daily administration.

[0054] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 4 weeks after the first daily administration.

[0055] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 4 weeks after the first daily administration.

[0056] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 4.

[0057] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 4, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0058] In some embodiments, the method results in a significant reduction in the levels of anti-dsDNA autoantibodies and complement C3 and C4.

[0059] In some embodiments, the method results in a significant increase in the number of circulating memory B cells, naive B cells, and total B cells.

[0060] In some embodiments, the patient has an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.

[0061] In some embodiments, the patient has had an inadequate response or is intolerant to methotrexate.

[0062] In some embodiments, the patient has an inadequate response to or is intolerant to antimalarial drugs.

[0063] In some embodiments, the patient has an inadequate response or is intolerant to an immunomodulatory agent.

[0064] In some embodiments, the patient has an inadequate response or is intolerant to corticosteroids.

[0065] In some embodiments, the patient has had an inadequate response or is intolerant to prednisone (or a prednisone equivalent), antimalarials, azathioprine, mycophenolic acid, leflunomide, cyclosporine, tacrolimus, or methotrexate.

[0066] In some embodiments, the patient has an inadequate response or is intolerant to belimumab.

[0067] In some embodiments, the patient has had an inadequate response or is intolerant to rituximab.

[0068] In some embodiments, the patient has an inadequate response or is intolerant to anirumab.

[0069] In some embodiments, the patient is concomitantly treated with an antimalarial drug.

[0070] In some embodiments, the patient is concomitantly treated with an immunomodulatory agent.

[0071] In some embodiments, the patient is concomitantly treated with corticosteroids.

[0072] In some embodiments, the patient is concomitantly treated with prednisone (or a prednisone equivalent), an antimalarial, azathioprine, mycophenolic acid, leflunomide, cyclosporine, tacrolimus, or methotrexate. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 is a schematic diagram of a clinical study according to an embodiment of the present disclosure.

[0074] Figure 2 is a graphical representation of the response rate over time for the primary endpoint (achievement of SRI-4 and steroid dose ≤ 10 mg prednisone equivalents QD) for subjects treated with placebo and upadacitinib 30 mg QD.

[0075] Figure 3 is a graphical representation of the rate of achieving SRI-4 responses over time for subjects treated with placebo and upadacitinib 30 mg QD.

[0076] Figure 4 is a graphical representation of the response rate to achieve BICLA over time for subjects treated with placebo and upadacitinib 30 mg QD.

[0077] Figure 5A Exposure-response quartiles of upadacitinib efficacy at Week 24 for the efficacy endpoints of SLE Responder Index-4 (SRI-4) and steroid dose ≤10 mg prednisone equivalents QD.

[0078] Figure 5B is a plot of exposure-response quartiles of upadacitinib efficacy at week 24 based on the BILAG-based Combined Lupus Assessment (BICLA) efficacy endpoint.

[0079] Figure 5C Figure 3 Exposure-response quartiles of upadacitinib efficacy at week 24, an efficacy endpoint of the SLE Responder Index (SRI-4).

[0080] Figure 6is a graphical representation of the response rate over 48 weeks for the primary endpoint (achievement of SRI-4 and steroid dose ≤ 10 mg prednisone equivalents QD) for subjects treated with placebo and upadacitinib 30 mg QD.

[0081] Figure 7 is a graphical representation of the rates of achieving SRI-4 responses over 48 weeks for subjects treated with placebo and upadacitinib 30 mg QD.

[0082] Figure 8 is a graphical representation of the rate of BICLA responses achieved over 48 weeks for subjects treated with placebo and upadacitinib 30 mg QD.

[0083] Fig. 9 Figure 2 is a graphical representation of the time to first onset of erythema over 48 weeks in subjects treated with placebo and upadacitinib 30 mg QD.

[0084] Fig. 10A Exposure-response quartiles of upadacitinib efficacy at week 48 for the efficacy endpoints of SLE Responder Index-4 (SRI-4) and steroid dose ≤10 mg prednisone equivalents QD.

[0085] Fig. 10B is a plot of exposure-response quartiles of upadacitinib efficacy at week 48 based on the BILAG-based Combined Lupus Assessment (BICLA) efficacy endpoint.

[0086] Fig. 10C Figure 3 Exposure-response quartiles of upadacitinib efficacy at week 48, an efficacy endpoint of the SLE Responder Index (SRI-4). DETAILED DESCRIPTION

[0087] This written description uses examples to disclose the invention and also enables any person skilled in the art to practice the invention, including making and using any of the disclosed compositions and performing any of the disclosed methods or processes. The patentable scope of the invention is defined by the claims and may include other examples that occur to one skilled in the art. Such other examples are intended to be within the scope of the claims if they have elements that are not different from the literal language of the claims or if they include equivalent elements.

[0088] I. Definitions

[0089] The section headings used in this section and throughout the disclosure are not intended to be limiting.

[0090] Where numerical ranges are stated, it is expressly contemplated that each intervening number within the stated range has the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated. In the same manner, all stated ratios also encompass all sub-ratios falling within the broader ratio.

[0091] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0092] The term "about" generally refers to a range of numbers that one of skill in the art considers equivalent to the stated value (ie, having the same function or result). In many cases, the term "about" may include numbers that are rounded to the nearest significant figure.

[0093] As used herein, the term "patient" refers to an adult. The terms "patient" and "subject" are used interchangeably herein.

[0094] "Pharmaceutically acceptable salts" refer to those that retain the biological effectiveness and properties of the free bases and are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, monomalic acid, monooxalic acid, tartaric acid such as monotartaric acid (e.g., (+)-tartaric acid or (-)-tartaric acid or mixtures thereof), amino acids (e.g., (+)-amino acids or (-)-amino acids or mixtures thereof), etc. These salts can be prepared by methods known to those skilled in the art.

[0095] abbreviation

[0096] Ab: Antibody

[0097] ACR: American College of Rheumatology

[0098] ADL: Activities of Daily Living

[0099] AE: adverse event

[0100] AESI: Adverse events of special interest

[0101] Ag: Antigen

[0102] ALT: Alanine transaminase

[0103] ANA: Antinuclear antibodies

[0104] ANC: Absolute neutrophil count

[0105] Anti-dsDNA: Anti-double-stranded DNA

[0106] AO: As observed

[0107] AST: Aspartate aminotransferase

[0108] AUC: Area under the plasma / serum concentration-time curve

[0109] AUC / D: dose-normalized AUC

[0110] AUC 0-24 : Area under the plasma / serum concentration-time curve from time 0 hours to 24 hours

[0111] AUC 24 : Area under the plasma / serum concentration-time curve at 24 hours

[0112] AUC inf : Area under the plasma / serum concentration-time curve from time 0 to extrapolated to infinity

[0113] AUC ss : Area under the steady-state plasma / serum concentration-time curve during the dosing interval

[0114] AUC t : Area under the plasma / serum concentration-time curve from time 0 to the time of the last measurable concentration

[0115] axSpA: axial spondyloarthritis

[0116] BCG: Bacillus Calmette-Guérin

[0117] BCR: B cell receptor

[0118] BCRP: Breast Cancer Resistance Protein

[0119] bDMARD: biologic disease-modifying antirheumatic drug

[0120] BL: Baseline

[0121] BMBT: Buccal bleeding time

[0122] B / P: whole blood-plasma distribution ratio

[0123] BP: Blood pressure

[0124] CAC: Cardiovascular Adjudication Committee

[0125] Cardiac: cardiovascular

[0126] CD: Crohn's disease

[0127] CIA: collagen-induced arthritis

[0128] CIS: Carcinoma in situ

[0129] CL / F: apparent clearance rate

[0130] CLL: Chronic lymphocytic leukemia

[0131] CLASI: Cutaneous lupus erythematosus disease area and severity index

[0132] CLp: total plasma clearance

[0133] CLr: renal clearance

[0134] Cmax: maximum observed serum or plasma concentration

[0135] Cmax / D: dose-normalized Cmax

[0136] CMH: Cochran-Mantel-Haenszel

[0137] CNS: Central nervous system

[0138] COVID-19: Coronavirus Disease 2019

[0139] CPK: Creatine phosphokinase

[0140] CRF: Case Report Form

[0141] csDMARD: conventional synthetic disease-modifying antirheumatic drugs

[0142] CT: Computed tomography

[0143] CTCAE: Common Terminology Criteria for Adverse Events

[0144] CVA: cerebrovascular accident

[0145] CXR: Chest X-ray

[0146] CYP3A: Cytochrome P4503A isoform subfamily

[0147] CYP1A2: Cytochrome P4501A2 isoform subfamily

[0148] CYP2B6: Cytochrome P4502B6 isoform subfamily

[0149] CYP2C19: Cytochrome P4502C19 isoform subfamily

[0150] DAP12L DNAX activating protein

[0151] DMC: Data Monitoring Committee

[0152] DNA: deoxyribonucleic acid

[0153] dsDNA: double-stranded deoxyribonucleic acid

[0154] EC 50 : Half maximum effective concentration

[0155] ECG: electrocardiogram

[0156] eCRF: Electronic Case Report Form

[0157] Emax: maximum induction effect determined in vitro

[0158] EU: European Union

[0159] EudraCT: European Clinical Trials Database

[0160] FACIT: Functional Assessment of Chronic Illness Therapy

[0161] FAS: Full Analysis Set

[0162] FcR: Fc receptor

[0163] FMO: flavin-containing monooxygenase

[0164] FSH: Follicle Stimulating Hormone

[0165] Fu: unbound fraction

[0166] GCA: giant cell arteritis

[0167] GCP: Good Clinical Practice

[0168] GCSF: Granulocyte colony stimulating factor

[0169] GFR: Glomerular filtration rate

[0170] GI: Gastrointestinal

[0171] GM-CSF: Granulocyte-macrophage colony-stimulating factor

[0172] GPVI: glycoprotein VI

[0173] GSH: Glutathione

[0174] GVHD: Graft versus host disease

[0175] HB: Hepatitis B

[0176] HBc Ab: Hepatitis B core antibody

[0177] HBs Ag: Hepatitis B surface antigen

[0178] HBV: Hepatitis B virus

[0179] HCV: Hepatitis C virus

[0180] HCV Ab: Hepatitis C virus antibody

[0181] hERG: human ether-a-go-go related gene

[0182] HIV: Human immunodeficiency virus

[0183] HIV Ab: HIV antibody

[0184] IC50: Inhibitory concentration that produces 50% inhibition

[0185] ICH: International Conference on Harmonization

[0186] IEC: Independent Ethics Committee

[0187] IEC / IRB: Independent Ethics Committee / Institutional Review Board

[0188] IERC: Internal Execution Review Committee

[0189] IFN: interferon

[0190] IgE: Immunoglobulin E

[0191] IgG: Immunoglobulin G

[0192] IgM: Immunoglobulin M

[0193] IM: intramuscular injection

[0194] IMP: Investigational Medicinal Product

[0195] IRB: Institutional Review Board

[0196] IRT: Interactive Response Technology

[0197] IU: International Unit

[0198] IUD: intrauterine device

[0199] IUS: intrauterine hormone-releasing system

[0200] ITAM: Immunoreceptor tyrosine-based activation motif IV: intravenous

[0201] IVIG: intravenous immunoglobulin

[0202] JAK: Janus kinase

[0203] JAK1: Janus kinase 1

[0204] JAK2: Janus kinase 2

[0205] JAK3: Janus kinase 3

[0206] JIA: Juvenile Idiopathic Arthritis

[0207] Km: The concentration at which the rate reaches half of the maximum value

[0208] LLDAS: Lupus Low Disease Activity State

[0209] LTE: Long Term Extension

[0210] LupusQoL: Lupus Quality of Life Questionnaire

[0211] MACE: major adverse cardiovascular events

[0212] MDCK-MDR1: Madin-Darby canine kidney cells transfected with human MDR1 gene

[0213] MDRD: Dietary changes in kidney disease

[0214] MedDRA: The Medical Dictionary for Regulatory Activities

[0215] MI: Myocardial infarction

[0216] MMRM: Mixed Effects Model for Repeated Measures

[0217] MPV: mean platelet volume

[0218] MTX: methotrexate

[0219] N / A: Not applicable

[0220] NCI: National Cancer Institute

[0221] NMSC: Non-melanoma skin cancer

[0222] NRI-C: Combining multiple inference processes

[0223] Imputation of non-responders when data are missing due to COVID-19

[0224] NRS: Numerical Rating Scale

[0225] NSAID: nonsteroidal anti-inflammatory drug

[0226] OC: Observation case

[0227] Papp: Apparent permeability coefficient

[0228] PBMC: peripheral blood mononuclear cells

[0229] PCR: polymerase chain reaction

[0230] PD: Premature Discontinuation

[0231] P-gp: P-glycoprotein

[0232] PhGA: Physician Comprehensive Assessment

[0233] PI: Principal Investigator

[0234] PK: Pharmacokinetics

[0235] PO: Oral (by mouth)

[0236] PPD: Purified protein derivative (tuberculin)

[0237] PRN: As needed

[0238] PRO: Patient-reported outcomes

[0239] PtGA: Patient Global Assessment

[0240] QD: Once daily

[0241] QTc: QT interval corrected for heart rate

[0242] QTcF: QT interval corrected for heart rate using Fridericia's formula

[0243] QTcV: QT interval corrected by Van de Water's formula

[0244] RA: Rheumatoid arthritis

[0245] Rac: Accumulation ratio

[0246] RANK: receptor activator of nuclear factor kappa B

[0247] RBC: Red blood cells

[0248] RCT: Randomized clinical trial

[0249] REML: Restricted Maximum Likelihood

[0250] RNA: ribonucleic acid

[0251] ROA: route of administration

[0252] SAE: Serious adverse event

[0253] SAP: Statistical Analysis Program

[0254] SAR: severe adverse reaction

[0255] SELENA: a national evaluation of the safety of estrogens in lupus erythematosus

[0256] SF-36: 36-item Short Form Health Survey

[0257] SFI: SLEDAI Erythema Index

[0258] SLE: Systemic lupus erythematosus

[0259] SLEDAI: Systemic Lupus Erythematosus Disease Activity Index

[0260] SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000

[0261] SJC: Swollen Joint Count

[0262] SLICC: Systemic Lupus Erythematosus International Collaboration Clinic

[0263] Sm / RNP: Smith / ribonucleoprotein

[0264] SRI: SLE Responder Index

[0265] SSc: Systemic Sclerosis

[0266] SUSAR: suspected unexpected serious adverse reaction

[0267] Syk: spleen tyrosine kinase

[0268] TAMD: Treatment Area MD

[0269] TB: Tuberculosis

[0270] TBNK: T lymphocytes, B lymphocytes and natural killer lymphocytes

[0271] TEAE: treatment-emergent adverse event

[0272] TJC: Tender Joint Count

[0273] TNF: Tumor necrosis factor

[0274] trFRET: time-resolved fluorescence resonance energy transfer

[0275] UC: ulcerative colitis

[0276] UK: United Kingdom

[0277] ULN: Upper limit of normal

[0278] UPCR: urine protein to creatinine ratio

[0279] US: United States

[0280] vs: yes

[0281] Vss / F: Apparent volume of distribution at steady state

[0282] WBC: White blood cells

[0283] WOCBP: Women of childbearing potential

[0284] End point definition :

[0285] The SLE Responder Index (SRI)-4 was defined as follows, with all criteria compared to baseline:

[0286] The Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score decreased by ≥ 4 points.

[0287] No worsening of PhGA, defined as an increase of <0.3 points from baseline on the 3-point Physician Global Assessment (PGA) visual analogue scale (VAS).

[0288] No new British Isles Lupus Assessment Group (BILAG) A or more than 1 new BILAGB disease activity score (i.e., no organ system changed from baseline B / C / D / E to A, and no more than 1 organ system changed from baseline C / D / E to B).

[0289] The BILAG-based combined lupus assessment (BICLA) is defined as follows:

[0290] Improvement of organ systems:

[0291] ■ Improvement in all initial (baseline) A and B scores, ie, all BILAG A scores at baseline improve to B or C or D, and all BILAG B scores at baseline improve to C or D.

[0292] ■No new BILAG A or more than one new BILAG B score compared to baseline (i.e., no organ system change from baseline B / C / D / E to A, and no more than 1 organ system change from baseline C / D / E to B).

[0293] No deterioration in overall condition, i.e., an increase of <0.3 points on the PhGA from baseline.

[0294] Improvement in disease activity: There was no increase in SLEDAI-2K total score from baseline.

[0295] Low lupus disease activity state (LLDAS) is defined as follows:

[0296] SLEDAI-2K score ≤4.

[0297] No activity in major organ systems: defined as no category A or B in any BILAG system other than mucocutaneous and musculoskeletal.

[0298] No new lupus disease activity compared with the previous assessment: In any of the BILAG systems, new lupus disease activity compared with the previous assessment is defined as Category A or B, where

[0299] Item ratings of "new" or "worse" result in an A or B category.

[0300] PhGA ≤ 1 (level 0-3).

[0301] Steroid dose ≤ 7.5 mg per day.

[0302] Well-tolerated standard maintenance doses of immunosuppressive drugs and approved biologics, excluding investigational drugs. Defined as no increase in concomitant immunosuppressive and antimalarial drug doses above baseline.

[0303] II. JAK1 Inhibition

[0304] Upadacitinib ((3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide) or a pharmaceutically acceptable salt or solid form thereof is an oral Janus kinase (JAK) inhibitor that exhibits unique selectivity for the JAK1 receptor. Upadacitinib has the structure shown below:

[0305]

[0306] The dosage strengths of upadacitinib described herein are based on the weight of the anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, "15 mg upadacitinib" or "UPA 15MG" refers to the neutral upadacitinib free base present in the active ingredient in an amount of 15 mg, excluding any coformers (e.g., solvents or water molecules) of solvates or hydrates (including hemihydrates) or counteranions of pharmaceutically acceptable salts that may also be present in the active ingredient. Thus, for example, administration of "15 mg upadacitinib" includes administration of 15.4 mg of crystalline upadacitinib free base hemihydrate (containing 1 / 2 a water coformer molecule per upadacitinib free base molecule), delivering 15 mg of anhydrous free base upadacitinib to the patient.

[0307] The dosage strengths of upadacitinib described herein are based on the weight of the anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, "30 mg upadacitinib" or "UPA 30MG" refers to the neutral upadacitinib free base present in the active ingredient in an amount of 30 mg, excluding any coformers (e.g., solvents or water molecules) of solvates or hydrates (including hemihydrates) or counteranions of pharmaceutically acceptable salts that may also be present in the active ingredient. Thus, for example, administration of "30 mg upadacitinib" includes administration of 30.7 mg of crystalline upadacitinib free base hemihydrate (containing 1 / 2 a water coformer molecule per upadacitinib free base molecule), delivering 30 mg of anhydrous free base upadacitinib to the patient.

[0308] The dosage strengths of upadacitinib described herein are based on the weight of the anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, "45 mg upadacitinib" or "UPA 45MG" refers to the neutral upadacitinib free base present in the active ingredient in an amount of 45 mg, excluding any coformers (e.g., solvents or water molecules) of solvates or hydrates (including hemihydrates) or counteranions of pharmaceutically acceptable salts that may also be present in the active ingredient. Thus, for example, administration of "45 mg upadacitinib" includes administration of 46.1 mg of crystalline upadacitinib free base hemihydrate (containing 1 / 2 a water coformer molecule per upadacitinib free base molecule), delivering 45 mg of anhydrous free base upadacitinib to the patient.

[0309] III. Treatment of systemic lupus erythematosus with upadacitinib

[0310] As described above, upadacitinib has anti-inflammatory properties, and therefore according to the present disclosure, it is predicted to be effective in reducing the signs and symptoms associated with active SLE in patients. In particular, it is expected that the inhibition of Janus kinase 1 (JAK1) via upadacitinib will disrupt T cell activation and type I interferon (IFN) signaling. Without being bound by theory, it is believed that the inhibition of JAK1 will lead to an improvement in lupus disease activity, and compared with the current SLE standard of care, treatment with upadacitinib has the potential to provide greater clinical effectiveness while maintaining an acceptable safety profile. In order to explore the safety, tolerance and effectiveness of upadacitinib in SLE, several Phase I and Phase II clinical studies have been conducted.

[0311] Therefore, on the one hand, a method for treating a human patient with systemic lupus erythematosus is provided. In some embodiments, a method for treating a human patient with systemic lupus erythematosus who is receiving standard therapy is provided. In some embodiments, a method for treating a human patient with moderate to severe active systemic lupus erythematosus is provided. In some embodiments, a method for treating a human patient with moderate to severe active systemic lupus erythematosus who is receiving standard therapy is provided. In some embodiments, a method for treating a human patient with moderate to severe systemic lupus erythematosus is provided. In some embodiments, a method for treating a human patient with moderate to severe systemic lupus erythematosus who is receiving standard therapy is provided. In some embodiments, a method for treating a human patient with active autoantibody-positive systemic lupus erythematosus is provided. In some embodiments, a method for treating a human patient with active autoantibody-positive systemic lupus erythematosus who is receiving standard therapy is provided.

[0312] In some embodiments, the standard therapy that the patient is receiving includes corticosteroids, antimalarials, or a combination thereof. In some embodiments, the standard therapy includes prednisone (or prednisone equivalents) and antimalarials. In some embodiments, the standard therapy includes antimalarials such as hydroxychloroquine. In some embodiments, the standard therapy also includes azathioprine, mycophenolic acid, leflunomide, cyclosporine, tacrolimus, methotrexate, or a combination thereof.

[0313] In another aspect, a method of treating a human patient having moderately to severely active systemic lupus erythematosus is provided, the method comprising orally administering 30 mg of upadacitinib to the patient once daily.

[0314] In another aspect, a method of treating a human patient having moderately to severely active systemic lupus erythematosus is provided, the method comprising orally administering 15 mg of upadacitinib to the patient once daily.

[0315] In another aspect, a method of treating a human patient having moderately to severely active systemic lupus erythematosus is provided, the method comprising orally administering 45 mg of upadacitinib to the patient once daily.

[0316] In yet another aspect, a method of treating a human patient with moderately to severely active systemic lupus erythematosus is provided, the method comprising orally administering to the patient an induction dose of upadacitinib once daily for a period of time. In some embodiments, the induction dose is 45 mg, administered once daily.

[0317] In some embodiments, the induction dose is followed by a maintenance dose. In some embodiments, the maintenance dose is 30 mg. In some embodiments, the maintenance dose is 15 mg.

[0318] Thus, in some embodiments, the method comprises orally administering to the patient a 45 mg induction dose of upadacitinib once daily for a period of time, followed by orally administering to the patient a 30 mg or 15 mg maintenance dose once daily.

[0319] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 52 weeks after the first daily administration.

[0320] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 52 weeks after the first daily administration.

[0321] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 52 weeks after the first daily administration.

[0322] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 52 weeks after the first daily administration.

[0323] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 52.

[0324] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 52, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0325] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 48 weeks after the first daily administration.

[0326] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 48 weeks after the first daily administration.

[0327] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 48 weeks after the first daily administration.

[0328] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 48 weeks after the first daily administration.

[0329] In some embodiments, the method results in a reduction in steroid burden as assessed by the change from baseline in prednisone equivalent steroid dose at week 48.

[0330] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 48, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0331] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 24 weeks after the first daily administration.

[0332] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 24 weeks after the first daily administration.

[0333] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 24 weeks after the first daily administration.

[0334] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 24 weeks after the first daily administration.

[0335] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 24.

[0336] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 24, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0337] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 20 weeks after the first daily administration.

[0338] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 20 weeks after the first daily administration.

[0339] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 20 weeks after the first daily administration.

[0340] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 20 weeks after the first daily administration.

[0341] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 20.

[0342] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 20, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0343] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 16 weeks after the first daily administration.

[0344] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 16 weeks after the first daily administration.

[0345] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 16 weeks after the first daily administration.

[0346] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 16 weeks after the first daily administration.

[0347] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 16.

[0348] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 16, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0349] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 12 weeks after the first daily administration.

[0350] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 12 weeks after the first daily administration.

[0351] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 12 weeks after the first daily administration.

[0352] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 12 weeks after the first daily administration.

[0353] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 12.

[0354] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 12, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0355] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 8 weeks after the first daily administration.

[0356] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 8 weeks after the first daily administration.

[0357] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 8 weeks after the first daily administration.

[0358] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 8 weeks after the first daily administration.

[0359] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 8.

[0360] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 8, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0361] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 4 weeks after the first daily administration.

[0362] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response 4 weeks after the first daily administration.

[0363] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 4 weeks after the first daily administration.

[0364] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 4 weeks after the first daily administration.

[0365] In some embodiments, the method results in a reduction in steroid load as assessed by the change from baseline in prednisone equivalent steroid dose at week 4.

[0366] In some embodiments, the method reduces the number of mild, moderate, or severe erythema per patient-year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe, and any) for each subject as of Week 4, as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

[0367] In some embodiments, the method results in a significant reduction in the levels of anti-dsDNA autoantibodies and complement C3 and C4. In some embodiments, the method results in a significant increase in the number of circulating memory B cells, naive B cells, and total B cells.

[0368] In some embodiments, the patient has an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. In some embodiments, the patient has an inadequate response or intolerance to methotrexate. In some embodiments, the patient has an inadequate response or intolerance to anti-TNF biologics. In some embodiments, the patient has an inadequate response or intolerance to antimalarial drugs.

[0369] In some embodiments, the patient has an inadequate response or is intolerant to an immunomodulatory agent.

[0370] In some embodiments, the patient has an inadequate response or is intolerant to corticosteroids.

[0371] In some embodiments, the patient has had an inadequate response or is intolerant to prednisone (or a prednisone equivalent), antimalarials, azathioprine, mycophenolic acid, leflunomide, cyclosporine, tacrolimus, or methotrexate.

[0372] In some embodiments, the patient is concomitantly treated with an antimalarial drug.

[0373] In some embodiments, the patient is concomitantly treated with an immunomodulatory agent.

[0374] In some embodiments, the patient is concomitantly treated with corticosteroids.

[0375] In some embodiments, the patient is concomitantly treated with methotrexate.In some embodiments, the patient is concomitantly treated with ≤ 20 mg / week methotrexate and concomitantly treated with ≤ 5 mg / week folic acid.

[0376] In some embodiments, the patient is concomitantly treated with azathioprine. In some embodiments, the patient is concomitantly treated with ≤ 150 mg / day of azathioprine.

[0377] In some embodiments, the patient is concomitantly treated with mycophenolate mofetil. In some embodiments, the patient is concomitantly treated with ≤ 2,000 mg / day mycophenolate mofetil.

[0378] In some embodiments, the patient is concomitantly treated with mycophenolate sodium. In some embodiments, the patient is concomitantly treated with ≤ 1,440 mg / day of mycophenolate sodium.

[0379] In some embodiments, the patient is concomitantly treated with hydroxychloroquine. In some embodiments, the patient is concomitantly treated with ≤ 400 mg / day hydroxychloroquine.

[0380] In some embodiments, the patient is concomitantly treated with chloroquine. In some embodiments, the patient is concomitantly treated with ≤ 500 mg / day chloroquine.

[0381] In some embodiments, the patient is concomitantly treated with quinacrine. In some embodiments, the patient is concomitantly treated with ≤ 100 mg / day quinacrine.

[0382] In some embodiments, the patient is concomitantly treated with leflunomide. In some embodiments, the patient is concomitantly treated with ≤ 20 mg / day leflunomide.

[0383] In some embodiments, the patient is concomitantly treated with cyclosporine. In some embodiments, the patient is concomitantly treated with cyclosporine administered at serum levels.

[0384] In some embodiments, the patient is concomitantly treated with tacrolimus. In some embodiments, the patient is concomitantly treated with tacrolimus administered at serum levels.

[0385] In some embodiments, the patient is concomitantly treated with corticosteroids (prednisone equivalent drugs). In some embodiments, the patient is concomitantly treated with ≤20mg / day corticosteroids, and the reduction is no faster than 5mg QD per week. In some embodiments, no matter how the baseline dose is, the corticosteroid is increased by no more than 5mg QD to the maximum dose of 25mg per week, by the 8th week of treatment.

[0386] IV. Pharmaceutical Compositions and Routes of Administration

[0387] Upadacitinib can be administered to a human patient by itself or in the form of a pharmaceutical composition, wherein upadacitinib is mixed with a biologically suitable carrier or excipient at a dose to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to a patient as a simple mixture or in the form of a suitably formulated pharmaceutical composition.

[0388] The pharmaceutical compositions of the present disclosure may be manufactured in a manner that is itself known, eg, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0389] Pharmaceutical compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Appropriate formulation depends upon the route of administration chosen.

[0390] example

[0391] Example 1: Safety and efficacy of upadacitinib in systemic lupus erythematosus (SLE)

[0392] This is a Phase 2 study (M19-130) to investigate the safety and efficacy of upadacitinib in subjects with moderately to severely active systemic lupus erythematosus.

[0393] Study population and number of subjects to be enrolled

[0394] Approximately 130 adult male or female subjects aged 18 to 65 years (inclusive) and with a clinical diagnosis of SLE at least 24 weeks prior to screening, meeting at least 4 of the 11 revised SLE classification criteria updated in 1997 according to the 1982 American College of Rheumatology (ACR), or meeting at least 4 of the 2012 Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) classification criteria, including at least 1 clinical criterion and 1 immunological criterion. Subjects must have active SLE, SLEDAI-2K ≥ 6, as reported and independently adjudicated at screening and baseline (clinical score ≥ 4, excluding lupus headache and / or organic brain syndrome). If the required entry score of 4 points is for arthritis, there must also be a minimum of 3 tender and 3 swollen joints.

[0395] Efficacy endpoints

[0396] Primary End Point

[0397] The primary efficacy endpoint was achievement of SLE Responder Index (SRI)-4 and steroid dose ≤10 mg prednisone equivalents once daily (QD) at Week 24. SLE Responder Index (SRI)-4 was defined as a ≥4-point decrease in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score without worsening of overall condition (no worsening in Physician's Global Assessment [PhGA], increase <0.3 points) or development of significant disease activity in a new organ system (no new British Isles Lupus Assessment Group ([BILAG]) A or >1 new BILAG B).

[0398] Secondary End Points

[0399] The following secondary efficacy endpoints were evaluated:

[0400] 1. Achieve SRI-4 at Week 24

[0401] 2. Achieve BILAG-Based Combined Lupus Assessment (BICLA) response at week 24

[0402] 3. Achieve lupus low disease activity state (LLDAS) at week 24

[0403] 4. Steroid load, as assessed by change from baseline at Week 24 5. Number and type of erythema for each subject as assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI) as of Week 24, and number of mild, moderate, or severe erythema per patient-year (individually and overall)

[0404] Another end point

[0405] The following additional efficacy endpoints were assessed at all visits unless otherwise specified:

[0406] 1. Implementing SRI-4

[0407] 2. Achieve SRI-5, SRI-6, SRI-7, SRI-8 and steroid dose ≤ 10 mg prednisone equivalent QD at weeks 24 and 48

[0408] 3. Achieve SRI-5, SRI-6, SRI-7, SRI-8

[0409] 4. Implement BICLA response

[0410] 5. Implementing LLDAS

[0411] 6. Achieve a reduction of ≥ 4 points in SLEDAI-2K from baseline

[0412] 7. Steroid load, as assessed by change from baseline 8. Number and type of erythema per subject, as assessed by SELENA SFI, and number of mild, moderate, or severe erythema per patient-year (individually and overall) up to Week 24 and Week 48

[0413] 9. Time to first onset of erythema after first study drug administration until Week 24 and Week 48 according to SELENA SFI

[0414] 10. Achieve 50% reduction in tender or swollen lupus joints defined as ≥50% reduction in tender or swollen joints (starting from a total of ≥6 affected joints)

[0415] 11. Achieve a 50% reduction in the cutaneous lupus erythematosus disease area and severity index (CLASI) activity score (starting from CLASI ≥ 10)

[0416] 12. Change from baseline in SLEDAI-2K

[0417] 13. Change from baseline in BILAG

[0418] 14. Change in PhGA from Baseline

[0419] 15. Change from baseline in patient global assessment (PtGA)

[0420] 16. Change from baseline in the Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue at Weeks 2, 12, 24, and 48

[0421] 17. Change from baseline in the 36-item Short Form Health Survey (SF-36) at weeks 2, 12, 24, and 48

[0422] 18. Change from baseline in the Lupus Quality of Life Questionnaire (LupusQoL) at weeks 2, 12, 24, and 48

[0423] 19. Change from baseline in Numerical Rating Scale (NRS) pain at weeks 2, 12, 24, and 48

[0424] Safety Endpoints

[0425] Routine safety assessments included adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiograms (ECGs), and clinical laboratory testing (hematology, chemistry, and urinalysis as measures of safety and tolerability throughout the study). SAEs were assessed at any dose resulting in death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability / incapacity, or congenital anomalies.

[0426] The following safety areas were routinely assessed to identify any major safety findings related to immunosuppression or potential risks associated with each class of therapy: serious and / or opportunistic infections, herpes zoster, active TB, malignancies (all types), adjudicated gastrointestinal (GI) perforations, adjudicated cardiovascular events (e.g., major adverse cardiovascular events [MACE]), anemia, neutropenia, lymphopenia, renal dysfunction, liver disorders, and adjudicated embolic and thromboembolic events (non-cardiac, non-central nervous system [CNS]), including venous thrombotic events defined as pulmonary embolism and deep vein thrombosis. Specific toxicity management measures were used for serious infections, serious GI events, cardiovascular events (MACE), malignancies, ECG abnormalities, and selected laboratory abnormalities. In addition, a 30-day follow-up telephone call was conducted from the last dose of study drug to determine the status of any ongoing AE / SAE or the occurrence of any new AE / SAE. An open-label internal DMC was established to ensure the overall integrity and conduct of the study. DMC reviews were performed at regular intervals. A routine systematic review of emerging safety data from all clinical studies of upadacitinib was performed by AbbVie. An independent external cardiovascular adjudication committee (CAC) adjudicated all blinded cardiovascular and cerebrovascular events, embolic / thrombotic events, and deaths, as defined in the CAC charts.

[0427] Pharmacokinetic endpoints

[0428] Descriptive statistics were used to summarize upadacitinib plasma concentrations at each sampling time point. A mixed effects modeling approach was used to estimate population central values ​​as well as empirical Bayesian estimates of individual values ​​of upadacitinib oral clearance (CL / F) and volume of distribution (Vss / F). Additional parameters and pharmacokinetic (PK) / pharmacodynamic relationships were estimated if useful in interpreting the data.

[0429] Biomarker research

[0430] Biological samples (whole blood, peripheral blood mononuclear cells [PBMC], plasma, and serum) are collected at specific time points throughout the study to evaluate known and / or novel disease-related or drug-related biomarkers. Types of biomarkers may include nucleic acids, proteins, lipids, RNA, DNA, and / or metabolites. The goal of this study is to analyze the samples for biomarkers that are helpful in understanding SLE, related conditions, and responses to treatment with upadacitinib or similar compounds.

[0431] Type I IFNs are key drivers of lupus disease pathogenesis, and a high IFN signature is associated with active SLE. Approximately 60% of lupus patients express an elevated type I IFN gene signature in the blood, indicating higher type I IFN activity in these individuals. JAK1 inhibition is expected to disrupt type I IFN signaling; therefore, lupus patients expressing a type I gene signature are more likely to benefit from upadacitinib treatment. A type I IFN RNA signature consisting of 4 genes (IFI6, IFI27, IFIT1, and MX1) was evaluated using a validated assay, and the cutoff point for IFN high was set at ≥-0.25 and the cutoff point for IFN low was set at <-0.25 (-0.25 was the upper limit of the cutoff point) using the type I IFN gene expression assay score.

[0432] In the event that the IFN score cannot be collected or analyzed at Screening due to COVID-19 laboratory visits, the subject remains enrolled in the study and the score is specified not to be applicable at the Screening visit. If collected, samples drawn at the Week 4 and Week 24 visits may be used for analysis.

[0433] These results are powerfully dichotomized high and low populations of IFN. Unless prohibited by local regulations or restrictions, determination is performed in screening samples and subsequent time points (IFN signature samples are not collected at various locations in China). Screening values ​​are used as the standard for subject enrichment, with the goal of recruiting 80% of the research subjects with a high composite core. Research stratification is allowed to increase confidence in the subject population to include approximately 80% of the high IFN score population.

[0434] The study may also include analyzing genes, epigenetics, gene expression and proteomic biomarkers that may be associated with SLE, related conditions or subjects to treatment responses. The study is exploratory in nature and the results may not be included in the clinical study report. The required biomarker samples are collected and analyzed from all subjects, unless local regulations or restrictions provide otherwise (in this case, the selection of collection / analysis is provided by appropriate informed consent).

[0435] Pilot Program

[0436] The study was designed to investigate the safety and efficacy of upadacitinib in subjects with moderately to severely active SLE despite standard of care therapy. Study duration included a 42-day maximum screening period, a 48-week randomized, placebo-controlled, double-blind, parallel-group treatment period, and 30-day follow-up calls. A Week 24 primary analysis was conducted when all subjects completed the Week 24 visit or discontinued the study. Sites and subjects remained blinded throughout the study. The study team remained blinded until the Week 24 primary analysis. Study visits were conducted at screening, baseline, and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 / early discontinuation (PD). A 30-day follow-up telephone call was conducted from the last dose of study drug to determine the status of any ongoing adverse event (AE) / serious adverse event (SAE) or the occurrence of any new AE / SAE.

[0437] The long-term extension (LTE) study was conducted under a separate protocol (LTE study M20-186) at sites approved by local authorities and ethics committees. At week 48, subjects entered the extension portion from the initial randomized portion of the study. A planned non-blinded interim analysis was conducted when 50% of the planned subjects completed their week 24 assessment. The purpose of this analysis was to re-evaluate the benefits / risks of the treatment regimen in study M19-130 and the expansion into LTE study M20-186. The interim analysis was conducted by an independent team at AbbVie that was separate and distinct from the blinded study team. The study M19-130 team remained blinded until the initial analysis at week 24.

[0438] Key inclusion criteria

[0439] The following are the key inclusion criteria for this study:

[0440] Adult male or female, aged 18 to 65 years (inclusive) at the time of screening.

[0441] Clinical diagnosis of SLE at least 24 weeks before screening and meeting at least 4 of the 11 revised SLE classification criteria updated in 1997 based on the 1982 ACR or at least 4 of the 2012 SLICC classification criteria, including at least 1 clinical criterion and 1 immunologic criterion.

[0442] At the time of screening, at least one of the following must be present:

[0443] ■ Antinuclear antibody test (ANA) + (titer ≥ 1:80)

[0444] ■Anti-double-stranded DNA (anti-dsDNA)+

[0445] ■Smith+

[0446] ■ SLEDAI-2K ≥ 6, despite background therapy reported and independently adjudicated at screening (clinical score ≥ 4, excluding lupus headache and / or organic brain syndrome). If the required entry score of 4 is for arthritis, there must also be a minimum of 3 tender and 3 swollen joints. If the subject has a rash and the principal investigator (PI) believes it is attributable to SLE, the subject consents to the collection of skin photographs for adjudication (reconfirmed at the baseline visit).

[0447] ■During the screening period, PhGA ≥ 1.

[0448] Patients must be on background therapy with prednisone (or prednisone equivalents) (≤20 mg), antimalarials, azathioprine (≤150 mg), mycophenolic acid (≤2 g), leflunomide (≤20 mg), cyclosporine, tacrolimus, and / or methotrexate (MTX) (≤20 mg) at baseline and throughout the study and must be stable for 30 days.

[0449] The above are not allowed to be combined with immunomodulators other than prednisone (or equivalent drugs) and antimalarial drugs. Intravenous (IV) or intramuscular (IM) corticosteroids greater than or equal to 40 mg prednisone equivalents are not allowed.

[0450] Study Drug and Duration of Treatment

[0451] Study medication was administered orally as 1 film-coated tablet containing 30 mg upadacitinib and / or matching placebo once daily with or without food for 24 weeks.

[0452] Overall study design and planning

[0453] This is a multicenter, randomized, double-blind, placebo-controlled Phase 2 study to investigate the safety and efficacy of upadacitinib in subjects with moderately to severely active SLE with a primary endpoint of Week 24. The study continued through Week 48 to further evaluate the maintenance of efficacy and safety of each treatment beyond Week 24.

[0454] Approximately 130 male and female subjects (18 to 65 years, inclusive) diagnosed with moderately to severely active SLE (clinical diagnosis of SLE at least 24 weeks before screening, meeting at least 4 of the 11 revised SLE classification criteria from the 1982 American College of Rheumatology [ACR] updated in 1997 or meeting at least 4 of the 2012 Systemic Lupus Erythematosus International Collaborating Clinics [SLICC] classification criteria, including at least 1 clinical criterion and 1 immunologic criterion), despite standard of care therapy, were randomized as follows:

[0455] Group 1: Upadacitinib 30 mg QD (n=65)

[0456] Group 2: Upadacitinib placebo QD (n=65)

[0457] Randomization was stratified based on the following factors:

[0458] Baseline corticosteroid dose higher than 10 mg prednisone equivalents (≤10 mg or >10 mg)

[0459] Screening SLEDAI-2K (<10 or ≥10)

[0460] High vs. low vs. not applicable IFN score (approximately 80% high) (this stratification factor was not applicable to subjects in China)

[0461] Baseline immunosuppressants (azathioprine, tacrolimus, cyclosporine, methotrexate

[0462] [MTX], mycophenolic acid, or leflunomide) (yes / no)

[0463] Study duration included a 42-day maximum screening period and a 48-week randomized, placebo-controlled, double-blind, parallel-group treatment period with a 30-day follow-up call. Sites and subjects remained blinded throughout the study. The Week 24 primary analysis was conducted when all subjects completed the Week 24 visit or discontinued the study. The study team remained blinded until the Week 24 primary analysis. A 30-day follow-up call was conducted from the last dose of study drug to determine the status of any ongoing AE / SAE or the occurrence of any new AE / SAE.

[0464] A schematic diagram of the study is shown in Figure 1 The long-term extension (LTE) study was conducted under a separate protocol (LTE study M20-186) at sites approved by local authorities and ethics committees. At week 48, subjects entered the extension portion from the initial randomized portion of the study. An unblinded interim analysis was performed by an independent team from AbbVie when 50% of the planned subjects completed the week 24 assessment.

[0465] Selection of control group

[0466] This is a parallel-group study consisting of treatment groups receiving upadacitinib or matching placebo to evaluate the safety and efficacy of upadacitinib once daily for 24 weeks in subjects with moderately or severely active SLE. Placebo served as the reference for the efficacy assessment.

[0467] Appropriateness of measurement

[0468] All efficacy and safety measurements in this study were standard for assessing disease activity in subjects with SLE treated with immunosuppressant therapy. The first safety assessment was performed at Week 2, and safety assessments were also performed at follow-up visits. All clinical and laboratory procedures in this study were standard and generally accepted.

[0469] Suitability of the subject population

[0470] Eligible for the study were adult male or female subjects aged 18 to 65 years (inclusive) who had a clinical diagnosis of SLE at least 24 weeks before screening and met at least 4 of the 11 revised SLE classification criteria updated in 1997 based on the 1982 ACR or at least 4 of the 2012 SLICC classification criteria, including at least 1 clinical criterion and 1 immunologic criterion, and at least one of the following at screening: positive antinuclear antibodies (ANA) (titer ≥1:80), anti-double-stranded DNA (dsDNA), or anti-Smith antibodies. Based on current knowledge of the drug, these selection criteria identify the intended target population for upadacitinib treatment in individuals with active SLE.

[0471] Entry criteria

[0472] Subjects must meet all of the following criteria to be included in this study. Any answers other than affirmative answers to the following questions will result in exclusion from the study.

[0473] Demographics and Laboratory Evaluations

[0474] 1. Adult male or female, aged 18 to 65 years (inclusive) at the time of screening.

[0475] 2. During the screening period, laboratory values ​​must not meet the following criteria

[0476] Before the first dose of study drug:

[0477] Serum aspartate aminotransferase (AST) > 2.0 × upper limit of normal (ULN);

[0478] Serum alanine aminotransferase (ALT) >2.0×ULN;

[0479] Glomerular filtration rate (GFR) estimated by the simplified 4-variable modification of diet in renal disease (MDRD) formula <40 mL / min / 1.73 m 2 ;

[0480] Absolute neutrophil count (ANC) <1,000 / μL;

[0481] Platelet count <50,000 / μL;

[0482] Hemoglobin < 9 g / dL.

[0483] 3. At screening, all 3 antiphospholipid antibodies known to be associated with venous thrombotic events must not have positive titers: lupus anticoagulant, anti-β2-glycoprotein 1, and anticardiolipin antibodies.

[0484] Disease activity

[0485] 1. Clinical diagnosis of SLE at least 24 weeks before screening, meeting at least 4 of the 11 revised SLE classification criteria updated in 1997 based on the 1982 ACR, or meeting at least 4 of the 2012 SLICC classification criteria, including at least 1 clinical criterion and 1 immunological criterion.

[0486] 2. At least one of the following must be present during the screening:

[0487] ANA+ (titer ≥1:80)

[0488] Anti-dsDNA+

[0489] Anti-Smith+

[0490] 3. SLEDAI-2K ≥ 6, despite background therapy reported and independently adjudicated at screening (clinical score ≥ 4, excluding lupus headache and / or organic brain syndrome):

[0491] If 4 of the required entry points are for arthritis, there must also be a minimum of three tender and three swollen joints.

[0492] If the required clinical score of 4 is for proteinuria attributable to active lupus nephritis, it must be 0.5 g / day equivalent (0.5 mg / mg).

[0493] If a subject has a rash and the principal investigator (PI) believes it is attributable to SLE, the subject must consent to the collection of skin photographs for adjudication.

[0494] Scores must be reconfirmed at the baseline visit.

[0495] 4. During the screening period, PhGA ≥ 1.

[0496] 5. Subjects must receive background therapy throughout the study. The following background therapy must be stable for 30 days before baseline and throughout the study

[0497] Antimalarials, prednisone (or prednisone equivalents) (≤ 20 mg), azathioprine (≤ 150 mg), mycophenolic acid (≤ 2 g), leflunomide (≤ 20 mg), cyclosporine, tacrolimus, and / or MTX (≤ 20 mg).

[0498] Background therapy was allowed in combination with antimalarials and / or prednisone (or equivalent), and in combination with one other immunosuppressant from the above list (not multiple).

[0499] Subject medical history

[0500] 1. Must not have active lupus nephritis (progressive class IV or >1 g / day equivalent [1 mg / mg] proteinuria) or have undergone induction therapy within the last 6 months.

[0501] 2. Must not receive hemodialysis (or other forms of renal replacement therapy).

[0502] 3. Must not have active neuropsychiatric SLE as defined by the CNS portion of SLEDAI-2K or BILAG (excluding lupus headache).

[0503] 4. Must not have any active, chronic or recurrent viral or bacterial infection that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study, including hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated (even single episode) herpes zoster, disseminated (even single episode) herpes simplex, or HIV. Active HBV, HCV, and HIV are defined as:

[0504] HBV: Sensitivity detected on a qualitative HBV DNA polymerase chain reaction (PCR) test in subjects who are positive (+) for hepatitis B surface antigen (HBs Ag) or positive (+) for hepatitis B core antibody (HBc Ab); (and in subjects who are positive (+) for hepatitis B surface antibody [HBs Ab] in China and Japan only).

[0505] 5. Must not have active TB or latent TB and have not completed the entire course of latent TB prevention.

[0506] 6. No history of any malignancy except successfully treated non-melanoma skin cancer (NMSC) or cervical carcinoma in situ (CIS).

[0507] 7. No history of clinically significant drug or alcohol abuse in the last 6 months (based on the investigator's judgment).

[0508] 8. No history of GI perforation (except appendicitis or penetrating injury), diverticulitis, or a significantly increased risk of GI perforation, as determined by the investigator.

[0509] 9. Subjects must not have any condition that may interfere with drug absorption, including but not limited to short bowel syndrome (e.g., subjects with a history of gastric bypass surgery are excluded). Subjects with a history of gastric banding / gastric segmentation are not excluded.

[0510] 10. Must not be a recipient of an organ transplant.

[0511] 11. The subject shall not have a history of clinically significant medical symptoms or any other reasons that the investigator believes will interfere with the subject's participation in this study or make the subject unsuitable for receiving the study drug.

[0512] 12. No active infection requiring treatment with parenteral anti-infective drugs within 30 days before the first dose of study drug or oral anti-infective drugs within 14 days.

[0513] 13. Must not have a confirmed diagnosis of COVID-19. Baseline visit must be at least 14 days from onset of signs / symptoms or positive SARS-CoV-2 test; symptomatic subjects must have recovered, defined as resolution of fever and improvement of symptoms without the use of antipyretics.

[0514] 14. No suspicion of COVID-19 infection. Subjects with signs / symptoms suggestive of COVID-19, known exposure, or high-risk behavior should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from potential exposure.

[0515] 15. No history of allergic reaction or significant sensitivity to the components of the study drug (and its excipients) and / or other products of the same type.

[0516] 16. No history of any of the following cardiovascular diseases:

[0517] Recent medical history (within the past 6 months) of cerebrovascular accident (CVA), myocardial infarction

[0518] (MI), coronary stenting, coronary artery bypass grafting.

[0519] Uncontrolled hypertension, defined as sustained systolic blood pressure (BP) >160 mm Hg or diastolic BP >100 mm Hg. For subjects with known hypertension, the subject's BP must be stable on current stable antihypertensive medication for at least 30 days.

[0520] Any other circumstances in which, in the opinion of the investigator, participation in the protocol would place the subject at risk.

[0521] 17. No clinically relevant or significant ECG abnormalities at screening, including an electrocardiogram with a QT interval >480 milliseconds corrected for heart rate (QTc) using the Fridericia correction formula (QTcF). For subjects with ventricular conduction delay (QRS>120 milliseconds), a cardiologist needs to be consulted.

[0522] 18. For Japanese subjects only: must not have a positive result for β-D-glucan or 2 consecutive indeterminate results for β-D-glucan (screening for Pneumocystis jiroveci infection).

[0523] Prior / concomitant medications

[0524] 1. No intravenous (IV) or intramuscular (IM) corticosteroids greater than or equal to 40 mg prednisone equivalent bolus were used within 30 days of planned randomization. No intra-articular, trigger or tender point, intrabursal, or intratenon sheath corticosteroid treatment was used in the first 8 weeks before the first dose of study drug.

[0525] 2. Subjects must be treatment naive or, if not currently benefiting from it, have discontinued the following treatments for each applicable washout period prior to the first dose of study drug, or for at least 5 times the mean terminal elimination half-life of the drug:

[0526] Plasmapheresis ≥ 6 months

[0527] For belimumab ≥ 3 months

[0528] Rituximab for ≥ 1 year, or ≥ 6 months if B cells have recovered to ≥ 50 B cells / μL

[0529] Cyclophosphamide ≥ 3 months

[0530] Abatacept, any anti-tumor necrosis factor (TNF) therapy, and all other biologics for ≥ 4 weeks

[0531] 3. Subjects must not receive intravenous immunoglobulin (IVIG) within 30 days prior to the first dose of study drug.

[0532] 4. No prior exposure to JAK inhibitors (including but not limited to upadacitinib, tofacitinib, baricitinib, filgotinib) or BTK inhibitors for 14 days or longer, or any intolerance to them. Before the first dose of study drug, the washout period of JAK and BTK inhibitors is ≥ 30 days or 5 times the half-life, whichever is longer.

[0533] 5. To avoid combinations of immunosuppressive drugs that are not permitted during the study (see criterion 10 above), subjects previously exposed to the following drugs may need to complete a washout period as described below prior to enrollment, or should be at least five times the mean terminal elimination half-life of the drug:

[0534] ≥ 4 weeks before the first study drug dose of MTX, azathioprine, tacrolimus, cyclosporine, or mycophenolic acid.

[0535] · If the washout schedule was not followed, or the washout schedule was not adhered to (i.e., use of cholestyramine for 11 days, or use of activated charcoal or washout according to local labeling for 30 days), ≥8 weeks prior to the first study drug dose of leflunomide.

[0536] 6. No exposure to IFN kinoid vaccination prior to vaccination.

[0537] 7. No prior exposure to anti-IFN therapy, including anti-IFN and anti-IFN receptor, within 3 months of study baseline.

[0538] 8. Patients must not have received any investigational drug treatment within 30 days or 5 half-lives of the drug (whichever is longer) before the first administration of the investigational drug, or are currently participating in another clinical study.

[0539] 9. Subjects must have discontinued all high-potency opioid preparations for at least 1 week and conventional Chinese medicine for at least 30 days prior to the first administration of study drug.

[0540] 10. Subjects must not have received any live vaccines within 30 days (56 days for Japan) prior to the first dose of study drug.

[0541] Illegal drugs and therapies

[0542] Medications and therapies with washout periods are prohibited while subjects are receiving study medication. In addition to the medications listed in the inclusion criteria, the following medications are prohibited while subjects are taking study medication:

[0543] Cyclophosphamide

[0544] Belimumab

[0545] ·Rituximab

[0546] Granulocyte colony stimulating factor (GCSF)

[0547] IVIG

[0548] Strong cytochrome P450 3A isoform subfamily (CYP3A) or cytochrome P450 1A2 isoform subfamily (CYP1A2) inhibitors and inducers (see Table 1 for examples)

[0549] ·traditional Chinese medicine

[0550] Elective surgery within the first 24 weeks.

[0551] High-potency anesthetics (unless given during hospitalization), including (but not limited to):

[0552] ○Oxycodone

[0553] ○Oxymorphone

[0554] ○Fentanyl

[0555] ○Oxymethyllevomorphan

[0556] Buprenorphine

[0557] ○Methadone

[0558] ○Hydromorphone

[0559] Morphine

[0560] ○Meperidine

[0561] ○ Of note, low-potency anesthetics were allowed to optimize SLE medications.

[0562] Table 1. Examples of commonly used strong CYP3A or CYP1A2 inhibitors and inducers

[0563]

[0564]

[0565] Concomitant medications / therapies

[0566] Investigators were encouraged to taper steroids in subjects who were stable or improving. The investigator may have decided not to initiate a taper or to postpone a taper at any time. By Week 16, the target steroid dose was ≤10 mg QD. The steroid dose could be increased by no more than 5 mg QD per week to a maximum of 25 mg, as needed for rescue up to Week 8. A taper of the steroid target to ≤10 mg was permitted until Week 16. No changes in steroid dose were permitted between Weeks 16 and 24. Beginning at Week 24, steroid tapers were again permitted per PI judgment, with a target of ≤10 mg QD. Subjects who did not achieve a steroid target of ≤10 mg QD at Week 24 were considered non-responders for the primary endpoint. Subjects who required rescue therapy between Weeks 8 and 48 were considered non-responders from the visit at which the subject underwent rescue therapy. For safety purposes, the steroid dose could be increased or decreased as needed. Subjects who required an increase of more than 5 mg QD per week were considered non-responders. Subjects who required intra-articular injections during the study were considered non-responders. Subjects considered non-responders were allowed to continue taking study medication at the investigator's discretion if they were not taking prohibited medications.

[0567] Subjects must maintain their background therapy throughout the study. The only allowed change in background therapy is steroid reduction. If applicable, subjects continue to give them stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen and low-potency anesthetics. For NSAIDs, acetaminophen / acetaminophen, tramadol, codeine, hydrocodone and propoxyphene as part of background therapy, no dose changes are allowed, including starting doses, except for rescue therapy defined in the protocol. Allow the following medications (PRN) to be taken as needed, but not within 24 hours before any study visit: NSAIDs, acetaminophen / acetaminophen, tramadol, codeine, hydrocodone and propoxyphene. In the case of tolerance (or other safety) issues, the dose of NSAID and / or acetaminophen may have been reduced or discontinued by substitution of another NSAID.

[0568] Any medications or vaccines (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) received by the subject at enrollment or during the study must have been documented by the post-treatment visit (30-day follow-up call). Subjects must be able to safely discontinue any contraceptive medications 30 days prior to initial study drug administration. To be eligible for the study, subjects must consent to the study before discontinuing the use of any contraceptive medications. See Table 2 for a list of permitted concomitant medications.

[0569] Table 2. Permitted concomitant medications

[0570]

[0571] Withdrawal of subjects and discontinuation of the study

[0572] Subjects may request to discontinue participation in the study at any time for any reason, including, but not limited to, disease progression or lack of response to treatment. The investigator may discontinue study treatment for any subject at any time for any reason, including, but not limited to, disease progression, lack of response to treatment, safety issues, or failure to comply with the protocol.

[0573] At Week 24, the investigator assessed and recorded whether continuing the study was in the best interest of the subject. The subject discontinued study medication immediately if any of the following occurred:

[0574] The development or worsening of lupus symptoms requires the introduction of certain prohibited drugs or doses, and continued use of the study drug puts the subject at risk. The following situations require immediate discontinuation of the study drug:

[0575] ○Cyclophosphamide

[0576] ○Belimumab

[0577] ○Rituximab

[0578] ○ Combination of more than one of the following: azathioprine, mycophenolic acid, leflunomide, MTX, cyclosporine, or tacrolimus

[0579] ○ Plasmapheresis

[0580] ○ High-dose corticosteroids (≥60 mg prednisone equivalents oral or parenteral)

[0581] IVIG

[0582] Clinically significant abnormal laboratory results or AEs that preclude continuation of study drug, as determined by the investigator Serious infections (e.g., pneumonia, sepsis) that are not adequately controlled by anti-infective therapy or that place the subject at risk for continued participation in the trial.

[0583] The investigator believes that this is in the best interests of the subject.

[0584] The subject requests to withdraw the study drug or study, or the sponsor decides to discontinue one or more treatment groups after an interim analysis.

[0585] The subject develops ECG changes that are considered clinically significant and have a reasonable likelihood of being related to the study drug, or a confirmed absolute QTcF value >500 msec, or a confirmed increase from baseline of ≥60 msec.

[0586] If a subject's QTcF increases by ≥60 milliseconds from baseline, the investigator will evaluate, confirm the value, and discontinue treatment.

[0587] The subject develops active or latent TB at any time during the study.

[0588] The subject becomes pregnant while taking the study drug.

[0589] Malignancy, except localized NMSC or CIS of the cervix.

[0590] The subject is clearly noncompliant with study procedures, including inconsistent study drug dosing, which places the subject at risk of continued participation in the trial.

[0591] The subject developed a GI perforation.

[0592] If deep vein thrombosis, pulmonary embolism or non-cardiac, non-neural arterial thrombosis is diagnosed.

[0593] - Subjects developed active neuropsychiatric SLE as defined by SLEDAI-2K or the CNS portion of BILAG (excluding lupus headache).

[0594] The subject develops Class IV lupus nephritis (confirmed by biopsy).

[0595] Study Drug

[0596] Upadacitinib or matching placebo (Table 3) manufactured by AbbVie was administered on day 1 (baseline) and taken at approximately the same time each day. Subjects were instructed to take study medication orally and take only 1 tablet of upadacitinib or placebo from the distribution bottle each day, with or without food. Subjects were instructed to take only 1 capsule or tablet from each distribution bottle each day. If subjects forget to take their upadacitinib or matching placebo at their regularly scheduled dosing time, they should take the forgotten dose as soon as they remember, as long as it is at least 10 hours before their next scheduled dosing. Otherwise, they will take the next dose at the next scheduled dosing time. Subject doses were recorded on the subject dose diary. Subjects were instructed to return all medication containers (even if empty) to the study site personnel at each study visit. Compliance was recorded by the study site personnel. Upadacitinib and matching placebo were packaged in bottles in amounts sufficient to accommodate the study design. Each kit was labeled according to local requirements, and the label remained fixed on the kit. Upon receipt, the study drugs were stored on the labels as specified and kept in a safe location. Each kit contains a unique kit number. The kit number is assigned to the subject via interactive response technology (IRT) and encodes the appropriate study drug to be assigned at the subject's corresponding study visit. Field staff filled in all blanks on the label before assignment to the subject. The study drug was used only to conduct the study.

[0597] Table 3. Study drugs

[0598]

[0599] N / A = Not Applicable

[0600] Randomization / drug allocation

[0601] All subjects were assigned a unique identification number by the IRT at the screening visit. For rescreened subjects, the screening number assigned by the IRT at the initial screening visit was used. The IRT assigned a randomization number that coded the subject's treatment group assignment according to the randomization schedule generated by the statistics department at AbbVie. Randomization was stratified based on the following factors:

[0602] Baseline corticosteroid dose higher than 10 mg prednisone equivalents (≤10 mg or >10 mg)

[0603] Screening SLEDAI-2K (<10 or ≥10).

[0604] High vs. low vs. not applicable IFN score (approximately 80% high)

[0605] This stratification factor was not applicable to Chinese subjects.

[0606] Baseline immunosuppressants (azathioprine, tacrolimus, cyclosporine, MTX, mycophenolic acid, or leflunomide) (yes / no)

[0607] Once approximately 20% of the total subjects with a low IFN signature have been randomized, further enrollment of such subjects may be suspended. Investigators, study site personnel, and subjects remained blinded to each subject's treatment throughout the study. To maintain blinding, upadacitinib tablets and matching placebo tablets provided for study use were identical in appearance.

[0608] Results from the Week 24 Interim Analysis

[0609] Demographics

[0610] A table summarizing the demographics of subjects in the placebo and upadacitinib 30 mg QD treatment groups of the clinical studies is provided in Table 4.

[0611] Table 4. Demographic characteristics of the study groups .

[0612]

[0613]

[0614] The baseline disease characteristics of the subjects in the placebo group and the upadacitinib 30 mg QD treatment group of the clinical study are provided in Table 5.

[0615] Table 5. Baseline disease characteristics of the study groups .

[0616]

[0617]

[0618] A summary of the subject disposition in the placebo and upadacitinib 30 mg QD treatment groups of the clinical studies is provided in Table 6.

[0619] Table 6. Subject disposition

[0620]

[0621]

[0622] Effectiveness

[0623] like Figure 2 A graphical representation of the response rate over time for the primary endpoint (achieving SRI-4 and steroid use ≤10 mg prednisone equivalents QD) for subjects treated with placebo and upadacitinib 30 mg QD over 24 weeks is provided. Upadacitinib 30 mg showed greater efficacy than placebo (51.6% vs. 36.0%; stratum-adjusted treatment difference: 14.0%; p=0.067).

[0624] like Figure 3 A graphical representation of the response rates over time in subjects treated with placebo and upadacitinib 30 mg QD over 24 weeks achieving SRI-4 is provided. Upadacitinib 30 mg showed greater efficacy than placebo in SRI-4 at week 24 (53.6% vs. 37.3%, p=0.046).

[0625] like Figure 4 A graphical representation of the response rates over time in subjects treated with placebo and upadacitinib 30 mg QD achieving BICLA over 24 weeks is provided. Upadacitinib 30 mg showed greater efficacy than placebo in BICLA at week 24 (58.1% vs. 40.0%, p=0.056).

[0626] A tabular summary of the primary and secondary endpoints and relevant statistics for the full analysis set is provided in Table 7, which further shows that upadacitinib 30 mg achieved greater efficacy than placebo in LLDAS at Week 24 (p<0.001), as well as lower erythema rate by Week 24 (p=0.075).

[0627] Table 7. Summary of results for primary and secondary endpoints in the full analysis set

[0628]

[0629] CI: confidence interval.

[0630] P values ​​for treatment differences were based on the CMH test for categorical end points and the MMRM for continuous end points, controlling for stratification factors and on the normal approximation of erythema rates through week 24.

[0631] Pharmacokinetics

[0632] Model-estimated median (90% prediction interval) steady-state (SS) C in subjects with SLE for upadacitinib 30 mg QD 平均 It is 28.4 (19.1-46.6) ng / mL.

[0633] Exposure-Response for Efficacy Endpoints

[0634] FIG. 5A to FIG. 5C Upadacitinib steady-state (SS) C 平均 quartile plot of the relationship between efficacy response at week 1 and week 24. Specifically, Figure 5A The exposure-response quartiles of upadacitinib efficacy at week 24 were plotted for the efficacy endpoints of the SLE Responder Index (SRI-4) and steroid dose ≤10 mg prednisone equivalents QD. Figure 5B is an exposure-response quartile plot of upadacitinib efficacy at week 24 based on the BILAG-based Lupus Assessment (BICLA) efficacy endpoint, and Figure 5C The exposure-response quartiles of upadacitinib efficacy, the efficacy endpoint of SLE Responder Index (SRI-4), at week 24 were plotted. Based on logistic regression analysis, upadacitinib plasma exposure had statistically significant relationships with SRI-4 and steroid use ≤10 mg prednisone equivalents, SRI-4, and BICLA at week 24 (p<0.05).

[0635] No plateau of efficacy was achieved at the upadacitinib plasma exposures evaluated in the study (associated with 30 mg QD).

[0636] Maximum upadacitinib steady-state (SS) C 平均The quartile (which would equate to 45 mg QD exposure) was consistently associated with the highest responses observed across the three endpoints and was the primary driver of upadacitinib exposure-response trends. The exposure-response model-predicted median (90% prediction interval) percentages of subjects achieving SRI-4 and steroid doses ≤ 10 mg prednisone equivalents QD, BICLA, and SRI-4 at Week 24 were 50% (42% to 58%), 57% (50% to 65%), and 55% (47% to 62%) for placebo, compared to 38% (31% to 46%), 39% (32% to 46%), and 40% (32% to 47%) for upadacitinib 30 mg UPA QD, respectively. Upadacitinib 45 mg QD dosing is expected to provide a 6% to 8% greater response than 30 mg QD.

[0637] Biomarker analysis

[0638] Compared with baseline, the upadacitinib 30 mg treatment group showed significant reductions in the levels of C3, C4 complement and IgM, as well as anti-dsDNA autoantibodies and IgG. Increased circulating memory B cells, naive B cells and total B cells were also observed.

[0639] Example 2: Safety and efficacy of upadacitinib in systemic lupus erythematosus (SLE)

[0640] This is an extension of the Phase 2 study of Example 1. Specifically, the study of Example 1 was further extended by 24 weeks to a total of 48 weeks to further evaluate the maintenance of efficacy and safety of upadacitinib 30 mg treatment beyond 24 weeks. A schematic diagram of the study is shown in Figure 1 Overall, the study included 62 subjects in the upadacitinib 30 mg group and 75 subjects in the placebo group.

[0641] result

[0642] Effectiveness

[0643] In Table 8 and Figures 6 to 9 The 24-week and 48-week results for selected efficacy endpoints from the continuous groups are presented in Table 8. It is worth noting that the 24-week results in Table 8 are based on the final database; therefore, they are slightly different from the 24-week values ​​in the corresponding Table 7 of Example 1.

[0644] After week 24, in both upadacitinib 30 mg groups, response rates in BICLA and SRI-4 were generally maintained, while placebo rates remained stable (SRI-4) or decreased (BICLA). Upadacitinib 30 mg showed a higher response rate than placebo in achieving BICLA at week 48 (53.2% vs. 25.3%; stratum-adjusted treatment difference: 30.8%; p<0.001). Upadacitinib 30 mg showed a higher response rate than placebo in achieving SRI-4 at week 48 (45.2% vs. 32.0%; stratum-adjusted treatment difference: 13.4%; p=0.075). Upadacitinib 30 mg also showed a reduction in erythema and a delay in the time to first erythema compared to placebo. In summary, these data suggest that upadacitinib 30 mg QD provides additional benefits over background medication alone in subjects with moderate to severe SLE.

[0645] Table 8. Efficacy Results at Week 24 and Week 48 (Full Analysis Set; Continuous Group)

[0646]

[0647]

[0648] CI: confidence interval.

[0649] 1 Adj.Diff: stratum-adjusted treatment differences excluding erythema, summarized as observed.

[0650] P values ​​for treatment differences were based on the CMH test for categorical end points and the MMRM for continuous end points, controlling for stratification factors and on the normal approximation of the erythema rate up to week 24 or up to week 48.

[0651] Exposure-Response for Efficacy Endpoints

[0652] At week 48, there was a significant exposure-response relationship between upadacitinib and SRI-4 and steroid use ≤10 mg prednisone equivalents, SRI-4, and BICLA (p<0.05). FIG. 10A to FIG. 10C Upadacitinib C 平均 Based on logistic regression analysis, there was an exposure-response relationship for upadacitinib with each of the week 48 efficacy endpoints (SRI-4 and steroid dose ≤10 mg prednisone equivalents QD, BICLA, and SRI-4) (p<0.05).

[0653] The exposure-response model-predicted median (90% prediction interval) percentages of subjects achieving SRI-4 and steroid doses ≤10 mg prednisone equivalents QD, BICLA, and SRI-4 at Week 48 were 50% (41% to 58%), 56% (47% to 64%), and 54% (45% to 61%) for placebo, compared with 34% (25% to 44%), 25% (18% to 34%), and 32% (24% to 42%) for upadacitinib 30 mg UPA QD, respectively. Upadacitinib 30 mg QD dosing is expected to provide an 8% to 16% greater efficacy response than 15 mg QD.

[0654] Biomarkers

[0655] Prespecified biomarker analyses at week 48 confirmed the trends observed at week 24. That is, treatment with upadacitinib 30 mg QD resulted in a significant and early reduction in anti-dsDNA autoantibodies (a known effect of JAK inhibitors), followed by a gradual normalization of complement C3 and C4 levels.

Claims

1. A method of treating a human patient with moderately to severely active systemic lupus erythematosus, the method comprising orally administering 30 mg of upadacitinib to the patient once daily.

2. A method of treating a human patient with moderately to severely active systemic lupus erythematosus, the method comprising orally administering 15 mg of upadacitinib to the patient once daily.

3. A method of treating a human patient with moderately to severely active systemic lupus erythematosus, the method comprising orally administering 45 mg of upadacitinib to the patient once daily.

4. The method of claim 3, wherein the 45 mg upadacitinib is an induction dose, followed by a maintenance dose administered orally once daily to the patient.

5. The method of claim 4, wherein the maintenance dose is 30 mg.

6. The method of claim 4, wherein the maintenance dose is 15 mg.

7. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 52 weeks after the first daily administration.

8. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response 52 weeks after the first daily administration.

9. The method of any one of claims 1 to 6, wherein the method results in a BILAG-based Combined Lupus Assessment (BICLA) response 52 weeks after the first daily administration.

10. The method of any one of claims 1 to 6, wherein the method results in a lupus low disease activity state (LLDAS) response 52 weeks after the first daily administration.

11. The method of any one of claims 1 to 6, wherein the method results in a reduction in steroid burden as assessed by the change from baseline in prednisone equivalent steroid dose at week 52.

12. The method according to any one of claims 1 to 6, wherein the method reduces the number of mild, moderate or severe erythema per patient year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe and any) for each subject as of week 52 according to the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

13. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 48 weeks after the first daily administration.

14. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response 48 weeks after the first daily administration.

15. The method of any one of claims 1 to 6, wherein the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 48 weeks after the first daily administration.

16. The method of any one of claims 1 to 6, wherein the method results in a lupus low disease activity state (LLDAS) response 48 weeks after the first daily administration.

17. The method of any one of claims 1 to 6, wherein the method results in a reduction in steroid burden as assessed by the change from baseline in prednisone equivalent steroid dose at week 48.

18. The method according to any one of claims 1 to 6, wherein the method reduces the number of mild, moderate or severe erythema per patient year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe and any) per subject as of week 48 according to the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

19. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 24 weeks after the first daily administration.

20. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response 24 weeks after the first daily administration.

21. The method of any one of claims 1 to 6, wherein the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 24 weeks after the first daily administration.

22. The method of any one of claims 1 to 6, wherein the method results in a lupus low disease activity state (LLDAS) response 24 weeks after the first daily administration.

23. The method of any one of claims 1 to 6, wherein the method results in a reduction in steroid burden as assessed by the change from baseline in prednisone equivalent steroid dose at week 24.

24. The method according to any one of claims 1 to 6, wherein the method reduces the number of mild, moderate or severe erythema per patient year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe and any) for each subject as of week 24 according to the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

25. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 20 weeks after the first daily administration.

26. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response 20 weeks after the first daily administration.

27. The method of any one of claims 1 to 6, wherein the method results in a BILAG-based Combined Lupus Assessment (BICLA) response 20 weeks after the first daily administration.

28. The method of any one of claims 1 to 6, wherein the method results in a lupus low disease activity state (LLDAS) response 20 weeks after the first daily administration.

29. The method of any one of claims 1 to 6, wherein the method results in a reduction in steroid burden as assessed by the change from baseline in prednisone equivalent steroid dose at week 20.

30. The method of any one of claims 1 to 6, wherein the method reduces the number of mild, moderate or severe erythema per patient year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe and any) for each subject as of week 20 according to the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

31. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 16 weeks after the first daily administration.

32. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response 16 weeks after the first daily administration.

33. The method of any one of claims 1 to 6, wherein the method results in a BILAG-based Combined Lupus Assessment (BICLA) response 16 weeks after the first daily administration.

34. The method of any one of claims 1 to 6, wherein the method results in a lupus low disease activity state (LLDAS) response 16 weeks after the first daily administration.

35. The method of any one of claims 1 to 6, wherein the method results in a reduction in steroid burden as assessed by change from baseline in prednisone equivalent steroid dose at week 16.

36. The method of any one of claims 1 to 6, wherein the method reduces the number of mild, moderate or severe erythema per patient year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe and any) for each subject as of Week 16 according to the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

37. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 12 weeks after the first daily administration.

38. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response 12 weeks after the first daily administration.

39. The method of any one of claims 1 to 6, wherein the method results in a BILAG-based Combined Lupus Assessment (BICLA) response 12 weeks after the first daily administration.

40. The method of any one of claims 1 to 6, wherein the method results in a lupus low disease activity state (LLDAS) response 12 weeks after the first daily administration.

41. The method of any one of claims 1 to 6, wherein the method results in a reduction in steroid burden as assessed by change from baseline in prednisone equivalent steroid dose at week 12.

42. The method of any one of claims 1 to 6, wherein the method reduces the number of mild, moderate or severe erythema per patient year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe and any) for each subject as of Week 12 according to the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

43. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 8 weeks after the first daily administration.

44. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response 8 weeks after the first daily administration.

45. The method of any one of claims 1 to 6, wherein the method results in a BILAG-based Combined Lupus Assessment (BICLA) response 8 weeks after the first daily administration.

46. ​​The method of any one of claims 1 to 6, wherein the method results in a lupus low disease activity state (LLDAS) response 8 weeks after the first daily administration.

47. The method of any one of claims 1 to 6, wherein the method results in a reduction in steroid burden as assessed by change from baseline in prednisone equivalent steroid dose at week 8.

48. The method of any one of claims 1 to 6, wherein the method reduces the number of mild, moderate or severe erythema per patient year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe and any) for each subject as of Week 8 according to the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

49. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response and a prednisone equivalent steroid dose ≤ 10 mg 4 weeks after the first daily administration.

50. The method of any one of claims 1 to 6, wherein the method results in a SLE Responder Index (SRI)-4 response 4 weeks after the first daily administration.

51. The method of any one of claims 1 to 6, wherein the method results in a BILAG-based Combined Lupus Assessment (BICLA) response 4 weeks after the first daily administration.

52. The method of any one of claims 1 to 6, wherein the method results in a lupus low disease activity state (LLDAS) response 4 weeks after the first daily administration.

53. The method of any one of claims 1 to 6, wherein the method results in a reduction in steroid burden as assessed by change from baseline in prednisone equivalent steroid dose at week 4.

54. The method of any one of claims 1 to 6, wherein the method reduces the number of mild, moderate or severe erythema per patient year (individually and overall) by assessing the number and type of erythema (mild / moderate, severe and any) per subject as of Week 4 according to the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Erythema Index (SFI).

55. The method of any one of claims 1 to 54, wherein the method results in a significant reduction in the levels of anti-dsDNA autoantibodies and complement C3 and C4.

56. The method of any one of claims 1 to 55, wherein the method results in a significant increase in the number of circulating memory B cells, naive B cells, and total B cells.

57. The method of any one of claims 1 to 56, wherein the patient has an inadequate response or intolerance to one or more disease-modifying anti-rheumatic drugs.

58. The method according to one of claims 1 to 57, wherein the patient has an inadequate response or is intolerant to methotrexate.

59. The method of any one of claims 1 to 58, wherein the patient has an inadequate response to or is intolerant to antimalarial drugs.

60. The method of any one of claims 1 to 59, wherein the patient has an inadequate response or is intolerant to an immunomodulator.

61. The method of any one of claims 1 to 60, wherein the patient has an inadequate response to or is intolerant to corticosteroids.

62. The method of any one of claims 1 to 61, wherein the patient has an inadequate response or is intolerant to prednisone (or prednisone equivalents), antimalarials, azathioprine, mycophenolic acid, leflunomide, cyclosporine, tacrolimus, or methotrexate.

63. The method of any one of claims 1 to 62, wherein the patient has an inadequate response or is intolerant to belimumab.

64. The method of any one of claims 1 to 63, wherein the patient has an inadequate response or is intolerant to rituximab.

65. The method of any one of claims 1 to 64, wherein the patient has an inadequate response or is intolerant to anirumab.

66. The method of any one of claims 1 to 65, wherein the patient is concomitantly treated with an antimalarial drug.

67. The method of one of claims 1 to 66, wherein the patient is concomitantly treated with an immunomodulator.

68. The method of any one of claims 1 to 67, wherein the patient is concomitantly treated with corticosteroids.

69. The method of any one of claims 1 to 68, wherein the patient is concomitantly treated with prednisone (or a prednisone equivalent), an antimalarial, azathioprine, mycophenolic acid, leflunomide, cyclosporine, tacrolimus, or methotrexate.

70. The method of any one of claims 1 to 69, wherein the patient is concomitantly treated with methotrexate.

71. The method of any one of claims 1 to 70, wherein the patient is concomitantly treated with azathioprine.

72. The method of any one of claims 1 to 71, wherein the patient is concomitantly treated with mycophenolate mofetil.

73. The method of any one of claims 1 to 72, wherein the patient is concomitantly treated with mycophenolate sodium.

74. The method of any one of claims 1 to 73, wherein the patient is concomitantly treated with hydroxychloroquine.

75. The method of any one of claims 1 to 74, wherein the patient is concomitantly treated with chloroquine.

76. The method of any one of claims 1 to 75, wherein the patient is concomitantly treated with quinacrine.

77. The method of any one of claims 1 to 76, wherein the patient is concomitantly treated with leflunomide.

78. The method of any one of claims 1 to 77, wherein the patient is concomitantly treated with cyclosporine.

79. The method of any one of claims 1 to 78, wherein the patient is concomitantly treated with tacrolimus.

80. The method of any one of claims 1 to 79, wherein the patient is concomitantly treated with prednisone or a prednisone equivalent medication.

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