Method for treating systemic lupus erythematosus

Abstract

The present disclosure is directed to methods for treating systemic lupus erythematosus (SLE) using upadacitinib, a selective JAK1 inhibitor.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 393,158, filed Jul. 28, 2022, and U.S. Provisional Application No. 63 / 411,785, filed Sep. 30, 2022, the entire disclosures of each provisional application being incorporated herein by reference.

[0002] This disclosure is directed to methods of treating systemic lupus erythematosus (SLE) with upadacitinib, a selective JAK1 inhibitor.

Background Art

[0003] Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by antibodies against nuclear and cytoplasmic antigens, multi-system inflammation, amorphous clinical signs, and a relapsing and remitting course. SLE causes widespread inflammation and tissue damage in affected organs, which can include joints, skin, brain, lungs, kidneys, and blood vessels. The symptoms of SLE vary depending on the affected organs but can include fatigue, rash, fever, and joint pain or swelling.

[0004] Currently, there is no cure for SLE, and existing therapies primarily focus on controlling symptoms and minimizing flares through the use of immunosuppressive drugs such as hydroxychloroquine and corticosteroids, as well as immunomodulatory agents such as belimumab and anifrolumab, to improve quality of life. Despite these treatments, significant unmet therapeutic needs remain for SLE patients. Methods of treating SLE are provided herein.

Summary of the Invention

Problems to be Solved by the Invention

[0005] (Summary of the Invention) The present disclosure provides methods for treating systemic lupus erythematosus (SLE) with upadacitinib, a selective JAK1 inhibitor. The treatment methods generally include administering to a patient in need thereof a therapeutically effective amount of upadacitinib. **Means for Solving the Problems**

[0006] In one aspect, there is provided a method of treating a human patient having moderate to severe active systemic lupus erythematosus, the method comprising orally administering 30 mg of upadacitinib to the patient once daily.

[0007] In another aspect, there is provided a method of treating a human patient having moderate to severe active systemic lupus erythematosus, the method comprising orally administering 15 mg of upadacitinib to the patient once daily.

[0008] In yet another aspect, there is provided a method of treating a human patient having moderate to severe active systemic lupus erythematosus, the method comprising orally administering 45 mg of upadacitinib to the patient once daily. In some embodiments, the 45 mg of upadacitinib is an induction dose, and thereafter, a maintenance dose is orally administered to the patient once daily. In some embodiments, the maintenance dose is 30 mg. In some embodiments, the maintenance dose is 15 mg.

[0009] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response and a Prednisone Equivalent Steroid Dose ≤ 10 mg after 52 weeks of the first daily administration.

[0010] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response after 52 weeks of the first daily administration.

[0011] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 52 weeks after the first day of administration.

[0012] In some embodiments, the method results in a low disease activity state (LLDAS) response 52 weeks after the first day of administration.

[0013] In some embodiments, the method results in a reduction in steroid burden, evaluated as the change from baseline in prednisone-equivalent steroid dose, at week 52.

[0014] In some embodiments, the method results in a decrease in the number and type (mild / moderate, severe, and either) of flares per subject up to week 52, as evaluated by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI flare index (SFI), of the number (each and overall) of mild, moderate, or severe flares per patient-year.

[0015] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response and prednisone-equivalent steroid dose ≤ 10 mg 48 weeks after the first day of administration.

[0016] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response 48 weeks after the first day of administration.

[0017] In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response 48 weeks after the first day of administration.

[0018] In some embodiments, the method results in a low disease activity state (LLDAS) response 48 weeks after the first day of administration.

[0019] In some embodiments, the method results in a reduction in steroid burden, as evaluated as the change from baseline in prednisone-equivalent steroid dose at week 48.

[0020] In some embodiments, the method results in a reduction in the number and type (mild / moderate, severe, and either) of flares per subject by week 48, as evaluated by the Safety of Estrogens in Lupus National Assessment (SELENA) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index (SFI), of mild, moderate, or severe flares (each and overall) per patient-year.

[0021] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤10 mg at 24 weeks after the first day of dosing.

[0022] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response at 24 weeks after the first day of dosing.

[0023] In some embodiments, the method results in a British Isles Lupus Assessment Group (BILAG)-based combined lupus assessment (BICLA) response at 24 weeks after the first day of dosing.

[0024] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response at 24 weeks after the first day of dosing.

[0025] In some embodiments, the method results in a reduction in steroid burden, as evaluated as the change from baseline in prednisone-equivalent steroid dose at week 24.

[0026] In some embodiments, the method results in a reduction in the number of mild, moderate, or severe relapses (each and overall) per patient-year, as measured by the Safety of Estrogens in Lupus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Relapse Index (SFI), which is evaluated by the number and type (mild / moderate, severe, and either) of relapses per subject up to week 24.

[0027] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤ 10 mg 20 weeks after the first day of dosing.

[0028] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response 20 weeks after the first day of dosing.

[0029] In some embodiments, the method results in a BILAG-based Lupus Combination Assessment (BICLA) response 20 weeks after the first day of dosing.

[0030] In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response 20 weeks after the first day of dosing.

[0031] In some embodiments, the method results in a reduction in steroid burden, evaluated as the change from baseline in prednisone-equivalent steroid dose, at week 20.

[0032] In some embodiments, the method results in a reduction in the number of mild, moderate, or severe relapses (each and overall) per patient-year, as measured by the Safety of Estrogens in Lupus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Relapse Index (SFI), which is evaluated by the number and type (mild / moderate, severe, and either) of relapses per subject up to week 24.

[0033] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤ 10 mg 16 weeks after the first day of dosing.

[0034] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response 16 weeks after the first day of administration.

[0035] In some embodiments, the method results in a BILAG-based Lupus Combination Assessment (BICLA) response 16 weeks after the first day of administration.

[0036] In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response 16 weeks after the first day of administration.

[0037] In some embodiments, the method results in a reduction in steroid burden, evaluated as the change from baseline in prednisone-equivalent steroid dose, at week 16.

[0038] In some embodiments, the method results in a decrease in the number and type (mild / moderate, severe, and either) of flares per subject up to week 16, in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index (SFI), evaluated as the number of mild, moderate, or severe flares per patient-year (each and overall).

[0039] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤10 mg 12 weeks after the first day of administration.

[0040] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response 12 weeks after the first day of administration.

[0041] In some embodiments, the method results in a BILAG-based Lupus Combination Assessment (BICLA) response 12 weeks after the first day of administration.

[0042] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 12 weeks after the first day of administration.

[0043] In some embodiments, the method results in a reduction in steroid burden, as evaluated as a change from baseline in prednisone-equivalent steroid dose, at week 12.

[0044] In some embodiments, the method results in a decrease in the number and type (mild / moderate, severe, and either) of flares per subject up to week 12, as evaluated by the Safety of Estrogens in Lupus National Assessment (SELENA) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) flare index (SFI), of mild, moderate, or severe flares (each and overall) per patient-year.

[0045] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤10 mg 8 weeks after the first day of administration.

[0046] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response 8 weeks after the first day of administration.

[0047] In some embodiments, the method results in a British Isles Lupus Assessment Group (BILAG)-based combined lupus assessment (BICLA) response 8 weeks after the first day of administration.

[0048] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 8 weeks after the first day of administration.

[0049] In some embodiments, the method results in a reduction in steroid burden, as evaluated as a change from baseline in prednisone-equivalent steroid dose, at week 8.

[0050] In some embodiments, the method results in a decrease in the number of mild, moderate or severe relapses (respectively and overall) per patient-year, as measured by the Estrogen Safety in Lupus National Assessment (SELENA) SLEDAI Relapse Index (SFI), which is evaluated by the number and type (mild / moderate, severe and either) of relapses per subject up to week 8.

[0051] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤ 10 mg four weeks after the first day of administration.

[0052] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response four weeks after the first day of administration.

[0053] In some embodiments, the method results in a BILAG-based Lupus Combination Assessment (BICLA) response four weeks after the first day of administration.

[0054] In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response four weeks after the first day of administration.

[0055] In some embodiments, the method results in a decrease in steroid burden, evaluated as the change from baseline in prednisone-equivalent steroid dose at week 4.

[0056] In some embodiments, the method results in a decrease in the number of mild, moderate or severe relapses (respectively and overall) per patient-year, as measured by the Estrogen Safety in Lupus National Assessment (SELENA) SLEDAI Relapse Index (SFI), which is evaluated by the number and type (mild / moderate, severe and either) of relapses per subject up to week 4.

[0057] In some embodiments, the method results in a significant decrease in the levels of anti-dsDNA autoantibodies and complement C3 and C4.

[0058] In some embodiments, the method results in a significant increase in the number of circulating memory, naive, and total B cells.

[0059] In some embodiments, the patient has an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.

[0060] In some embodiments, the patient has an inadequate response or intolerance to methotrexate.

[0061] In some embodiments, the patient has an inadequate response or intolerance to antimalarial agents.

[0062] In some embodiments, the patient has an inadequate response or intolerance to immunomodulatory substances.

[0063] In some embodiments, the patient has an inadequate response or intolerance to corticosteroids.

[0064] In some embodiments, the patient has an inadequate response or intolerance to prednisone (or prednisone equivalent), antimalarial agents, azathioprine, mycophenolate, leflunomide, cyclosporine, tacrolimus, or methotrexate.

[0065] In some embodiments, the patient has an inadequate response or intolerance to belimumab.

[0066] In some embodiments, the patient has an inadequate response or intolerance to rituximab.

[0067] In some embodiments, the patient has an inadequate response or intolerance to anifrolumab.

[0068] In some embodiments, the patient is treated concurrently with an antimalarial agent.

[0069] In some embodiments, the patient is treated concurrently with an immunomodulatory substance.

[0070] In some embodiments, the patient is treated concurrently with a corticosteroid.

[0071] In some embodiments, the patient is treated concurrently with prednisone (or a prednisone equivalent), an antimalarial agent, azathioprine, mycophenolate, leflunomide, cyclosporine, tacrolimus, or methotrexate. BRIEF DESCRIPTION OF THE DRAWINGS

[0072]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5A

Figure 5B

Figure 5C

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10A

Figure 10B

Figure 10C

Mode for Carrying Out the Invention

[0073] This specification uses examples to disclose the present invention and to enable any person skilled in the art to make and use any of the disclosed compositions and to perform any of the disclosed methods or processes so as to be able to practice the present invention. The scope of what can be patented for the present invention is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have elements that do not differ from the literal language of the claims or if they include equivalent elements.

[0074] I. Definitions The headings used in this section and throughout this disclosure are not intended to be limiting.

[0075] When numerical ranges are recited, each number between the recited ranges is considered to have the same degree of precision explicitly. For example, for the range of 6 - 9, in addition to 6 and 9, the numbers 7 and 8 are considered, and for the range of 6.0 - 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 explicitly considered. Similarly, all recited ratios also include all sub - ratios that fall within the broader ratio.

[0076] The singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0077] The term "about" generally refers to a range of numbers that a person skilled in the art would consider equivalent to the recited value (i.e., having the same function or result). In many cases, the term "about" may include numbers rounded to the nearest significant digit.

[0078] As used herein, the term "patient" refers to an adult human. The terms "patient" and "subject" are used interchangeably herein.

[0079] "Pharmaceutically acceptable salts" refer to salts obtained by reacting a free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or an organic acid such as a 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, monomaleic acid, monosuccinic acid, monotartaric acid (e.g., (+) or (-) tartaric acid or a mixture thereof), or an amino acid (e.g., (+) or (-) amino acid or a mixture thereof), etc., which retain the biological effects and properties of the free base. These salts can be prepared by methods known to those skilled in the art.

[0080] Abbreviations Ab: Antibody ACR: American College of Rheumatology ADL: Activities of Daily Living AE: Adverse Event AESI: Adverse Event of Special Interest Ag: Antigen ALT: Alanine Transaminase ANA: Antinuclear Antibody ANC: Absolute Neutrophil Count Anti-dsDNA: Anti-double-stranded DNA AO: Based on Observed Value AST: Aspartate Transaminase AUC: Area Under the Plasma / Serum Concentration-Time Curve AUC / D: AUC Normalized by Dose AUC 0~24 : Area Under the Plasma / Serum Concentration-Time Curve from 0 to 24 Hours AUC 24 : Area Under the Plasma / Serum Concentration-Time Curve at 24 Hours AUC inf : Area Under the Plasma / Serum Concentration-Time Curve Extrapolated from 0 Hours to Infinity AUC SS : Area Under the Plasma / Serum Concentration-Time Curve at the Dosing Interval in the Steady State AUC t : Area Under the Plasma / Serum Concentration-Time Curve from 0 Hours to the Final Measurable Time axSpA: Axial Spondyloarthritis BCG: Bacillus Calmette-Guérin BCR: B cell receptor BCRP: Breast cancer resistance protein bDMARD: Biological disease-modifying antirheumatic drug BL: Baseline BMBT: Buccal mucosal bleeding times B / P: Blood / plasma concentration ratio BP: Blood pressure CAC: Cardiovascular Event Assessment Committee Cardiac: Cardiovascular CD: Crohn's disease CIA: Collagen-induced arthritis CIS: Carcinoma in situ [[ID=2"]] CL / F: Apparent clearance CLL: Chronic lymphocytic leukemia CLASI: Cutaneous lupus erythematosus area and severity index CLp: Total plasma clearance CLr: Renal clearance Cmax: Maximum serum / plasma concentration (measured value) Cmax / D: Cmax normalized by dose CMH: Cochran-Mantel-Haenszel CNS: Central nervous system COVID-19: Coronavirus disease 2019 CPK: Creatine phosphokinase CRF: Case report form csDMARD: Conventional synthetic disease-modifying antirheumatic drug CT: Computed tomography CTCAE: Common Terminology Criteria for Adverse Events CVA: Cerebrovascular accident CXR: Chest X-ray CYP3A: Cytochrome P450 3A isoform subfamily CYP1A2: Cytochrome P450 1A2 isoform subfamily CYP2B6: Cytochrome P450 2B6 isoform subfamily CYP2C19: Cytochrome P450 2C19 isoform subfamily DAP12L: DNAX Activating Protein DMC: Data Monitoring Committee DNA: Deoxyribonucleic Acid dsDNA: Double-stranded Deoxyribonucleic Acid EC 50 : Concentration that brings about 50% maximum effect ECG: Electrocardiogram eCRF: Electronic Case Report Form Emax: Maximum induction effect measured in vitro EU: European Union EudraCT: European Clinical Trials Database FACIT: Functional Assessment of Chronic Illness Therapy FAS: Full Analysis Set FcR: Fc Receptor FMO: Flavin-containing Monooxygenase FSH: Follicle-stimulating Hormone Fu: Unbound Fraction GCA: Giant Cell Arteritis GCP: Good Clinical Practice GCSF: Granulocyte Colony-stimulating Factor GFR: Glomerular Filtration Rate GI: Gastrointestinal Tract GM-CSF: Granulocyte Macrophage Colony-stimulating Factor GPVI: Glycoprotein VI GSH: Glutathione GVHD: Graft-versus-host Disease HB: Hepatitis B HBc Ab: Hepatitis B Core Antibody HBs Ag: Hepatitis B Surface Antigen HBV: Hepatitis B Virus HCV: Hepatitis C Virus HCV Ab: Hepatitis C Virus Antibody hERG: Human Ether-a-go-go Related Gene HIV: Human Immunodeficiency Virus HIV Ab: HIV Antibody IC50: 50% Inhibitory Concentration ICH: International Conference on Harmonization IEC: Independent Ethics Committee IEC / IRB: Independent Ethics Committee / Institutional Review Board IERC: Internal Executive Review Committee IFN: Interferon IgE: Immunoglobulin E IgG: Immunoglobulin G IgM: Immunoglobulin M IM: Intramuscular IMP: Investigational Medicinal Product IRB: Institutional Review Board IRT: Interactive Response Technology IU: International Unit IUD: Intrauterine Device IUS: Intrauterine Hormone-Releasing System ITAM: Immunoreceptor Tyrosine-Based Activation Motif IV: Intravenous IVIG: Intravenous Immunoglobulin JAK: Janus Kinase JAK1: Janus Kinase 1 JAK2: Janus Kinase 2 JAK3: Janus Kinase 3 JIA: Juvenile Idiopathic Arthritis Km: Concentration at which the velocity is half of the maximum LLDAS: Lupus Low Disease Activity State LTE: Long-Term Exposure LupusQoL: Lupus Quality of Life Questionnaire MACE: Major Adverse Cardiovascular Event MDCK-MDR1: Madin-Darby Canine Kidney Cells Transfected with the Human MDR1 Gene MDRD: Modification of Diet in Renal Disease MedDRA: ICH International Medical Terminology MI: Myocardial Infarction MMRM: Mixed Effects Model Repeated Measures MPV: Mean Platelet Volume MTX: Methotrexate N / A: Not Applicable NCI: National Cancer Institute NMSC: Non-Melanoma Skin Cancer NRI-C: Nonresponder Imputation Incorporating Multiple Imputation Method for Handling Missing Data Due to COVID-19 NRS: Numerical Rating Scale NSAID: Non-Steroidal Anti-Inflammatory Drug OC: Observed Cases Papp: Apparent Permeability Coefficient PBMC: Peripheral Blood Mononuclear Cell PCR: Polymerase Chain Reaction PD: Premature Discontinuation P-gp: P-Glycoprotein PhGA: Physician's Global Assessment PI: Principal Investigator PK: Pharmacokinetics PO: Oral PPD: Purified Protein Derivative (Tuberculin) PRN: As Needed PRO: Patient-Reported Outcome PtGA: Patient Global Assessment QD: Once Daily QTc: QT Interval Corrected for Heart Rate QTcF: QT Interval Corrected for Heart Rate Using Fridericia's Correction Formula QEcV: QT Interval Corrected Using Van de Water's Correction Formula RA: Rheumatoid Arthritis Rac: Accumulation Ratio RANK: Receptor Activator of Nuclear Factor κB RBC: Red Blood Cell RCT: Randomized Clinical Trial REML: Restricted Maximum Likelihood RNA: Ribonucleic Acid ROA: Route of Administration SAE: Serious Adverse Event SAP: Statistical Analysis Plan SAR: Serious Adverse Reaction SELENA: Safety of Estrogens in the National Evaluation of Systemic Lupus Erythematosus SF-36: 36-Item Short-Form Health Survey SFI: SLEDAI Flare Index SLE: Systemic Lupus Erythematosus SLEDAI: Systemic Lupus Erythematosus Disease Activity Index SLEDAI-2K: 2000 Systemic Lupus Erythematosus Disease Activity Index SJC: Number of Swollen Joints SLICC: Systemic Lupus Erythematosus International Collaborating Clinics Sm / RNP: Smith / Ribonucleoprotein SRI: SLE Responder Index SSc: Systemic Sclerosis SUSAR: Suspected Unexpected Serious Adverse Reaction Syk: Spleen Tyrosine Kinase TA MD: Treatment Area MD TB: Tuberculosis TBNK: T lymphocytes, B lymphocytes and natural killer lymphocytes TEAE: Treatment Emergent Adverse Event TJC: Number of Tender Joints TNF: Tumor Necrosis Factor trFRET: Time-Resolved Fluorescence Resonance Energy Transfer UC: Ulcerative Colitis UK: United Kingdom ULN: Upper Limit of Normal UPCR: Urine Protein Creatinine Ratio US: United States vs: Versus Vss / F: Apparent Volume of Distribution at Steady State WBC: White Blood Cells WOCBP: Women of Childbearing Potential

[0081] Definition of Evaluation Items: The SLE Responder Index (SRI)-4 is defined as follows for all criteria compared to baseline: · A decrease of ≥ 4 points in the 2000 Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) score. ·No worsening of PhGA, i.e., an increase of < 0.3 points compared to the baseline of the 3-point physician global assessment (PGA) visual analog scale (VAS). ·No new British Isles Lupus Assessment Group (BILAG) A, or no more than one new BILAG B disease activity score (i.e., no change in organ system from baseline B / C / D / E to A, and no more than one change in organ system from baseline C / D / E to B).

[0082] BILAG-based lupus combined assessment (BICLA) is defined as follows: ·Improvement in organ system: ·Improvement in all initial (baseline) A and B scores, i.e., improvement of all BILAG A scores at baseline to B or C or D, and improvement of all BILAG B scores at baseline to C or D. ·No new BILAG A, or no more than one new BILAG B score compared to baseline (i.e., no change in organ system from baseline B / C / D / E to A, and no more than one change in organ system from baseline C / D / E to B). ·No worsening of general condition, i.e., an increase of < 0.3 points in PhGA compared to baseline. ·Improvement in disease activity: no increase in the total SLEDAI-2K score from baseline.

[0083] Lupus low disease activity state (LLDAS) is defined as follows: ·SLEDAI-2K score ≤ 4. ·No activity in major organ systems: defined as no category A or B in any BILAG system excluding skin mucosa and musculoskeletal. ·No new lupus disease activity compared to previous assessment: New lupus disease activity compared to previous assessment is defined as category A or B in any BILAG system where the score of the "new" or "worsened" item leads to category A or B. ·PhGA ≤ 1 (0 - 3 scale). · Steroid dosage ≤ 7.5 mg per day. · Immunosuppressive drugs and approved biological agents at standard maintenance dosages with good tolerability, excluding investigational drugs. Defined as no increase in concomitant immunosuppressive drugs and antimalarial drugs higher than the baseline dosage.

[0084] II. JAK1 Inhibition 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:

[0085]

Chemical formula

[0086] The dosage strengths of upadacitinib listed herein are based on the weight of anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, a dosage of "15 mg of upadacitinib" or "UPA 15 MG" refers to an amount of 15 mg of neutral upadacitinib free base present in the active ingredient, excluding any conformational isomers (e.g., solvent or water molecules of a solvate or hydrate (including hemihydrate)) or counter anions of pharmaceutically acceptable salts that may also be present in the active ingredient. Thus, for example, administration of "15 mg of upadacitinib" includes administration of 15.4 mg of crystalline upadacitinib free base hemihydrate (including 1 / 2 water conformational isomer molecule per molecule of upadacitinib free base) that delivers 15 mg of anhydrous free base upadacitinib to the patient.

[0087] The dosing strength of upadacitinib listed in this specification is based on the weight of anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, a dose of "30 mg of upadacitinib" or "UPA 30 MG" refers to an amount of 30 mg of neutral upadacitinib free base present in the active ingredient, without including any conformational isomers (such as the solvent or water molecules of a solvate or hydrate (including hemihydrate)) or counter anions of pharmaceutically acceptable salts that may similarly be present in the active ingredient. Thus, for example, administration of "30 mg of upadacitinib" includes administration of 30 mg of anhydrous free base upadacitinib to the patient and includes administration of 30.7 mg of crystalline upadacitinib free base hemihydrate (including 1 / 2 water conformational isomer molecule per molecule of upadacitinib free base).

[0088] The dosing strength of upadacitinib listed in this specification is based on the weight of anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, a dose of "45 mg of upadacitinib" or "UPA 45 MG" refers to an amount of 45 mg of neutral upadacitinib free base present in the active ingredient, without including any conformational isomers (such as the solvent or water molecules of a solvate or hydrate (including hemihydrate)) or counter anions of pharmaceutically acceptable salts that may similarly be present in the active ingredient. Thus, for example, administration of "45 mg of upadacitinib" includes administration of 45 mg of anhydrous free base upadacitinib to the patient and includes administration of 46.1 mg of crystalline upadacitinib free base hemihydrate (including 1 / 2 water conformational isomer molecule per molecule of upadacitinib free base).

[0089] III. Treatment of Systemic Erythematosus with Upadacitinib As described above in this specification, upadacitinib has anti-inflammatory properties and thus, according to the present disclosure, is predicted to be effective in reducing the signs and symptoms associated with active SLE in patients. In particular, Janus kinase 1 (JAK1) inhibition via upadacitinib is expected to disrupt T cell activation and type I interferon (IFN) signaling. Without wishing to be bound by theory, inhibition of JAK1 is thought to result in improvement of lupus disease activity, and treatment with upadacitinib has the potential to provide higher clinical efficacy compared to current standard treatments for SLE while maintaining an acceptable safety profile. To explore the safety, tolerability, and efficacy of upadacitinib in SLE, several Phase I and Phase II clinical trials have been conducted.

[0090] Accordingly, in one aspect, a method of treating a human patient having systemic lupus erythematosus is provided. In some embodiments, a method of treating a human patient having systemic lupus erythematosus who is receiving standard treatment is provided. In some embodiments, a method of treating a human patient having moderate to severe active systemic lupus erythematosus is provided. In some embodiments, a method of treating a human patient having moderate to severe active systemic lupus erythematosus who is receiving standard treatment is provided. In some embodiments, a method of treating a human patient having moderate to severe systemic lupus erythematosus is provided. In some embodiments, a method of treating a human patient having moderate to severe systemic lupus erythematosus who is receiving standard treatment is provided. In some embodiments, a method of treating a human patient having active autoantibody-positive systemic lupus erythematosus is provided. In some embodiments, a method of treating a human patient having active autoantibody-positive systemic lupus erythematosus who is receiving standard treatment is provided.

[0091] In some embodiments, the standard treatment the patient is receiving includes corticosteroids, antimalarials, or a combination thereof. In some embodiments, the standard treatment includes prednisone (or prednisone equivalent) and an antimalarial. In some embodiments, the standard treatment includes an antimalarial such as hydroxychloroquine. In some embodiments, the standard treatment further includes azathioprine, mycophenolate, leflunomide, cyclosporine, tacrolimus, methotrexate, or a combination thereof.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] In yet another aspect, a method of treating a human patient having moderately to severely active systemic lupus erythematosus is provided, the method comprising orally administering an induction dose of upadacitinib to the patient once daily for a period of time. In some embodiments, the induction dose is 45 mg and is administered once daily.

[0096] In some embodiments, a maintenance dose is administered after the induction dose. In some embodiments, the maintenance dose is 30 mg. In some embodiments, the maintenance dose is 15 mg.

[0097] Thus, in some embodiments, the method comprises orally administering to a patient an initial dose of 45 mg of upadacitinib once daily for a period of time, followed by orally administering to the patient a maintenance dose of 30 mg or 15 mg once daily.

[0098] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤ 10 mg after 52 weeks of the first daily dose.

[0099] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response after 52 weeks of the first daily dose.

[0100] In some embodiments, the method results in a BILAG-based Lupus Combined Assessment (BICLA) response after 52 weeks of the first daily dose.

[0101] In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response after 52 weeks of the first daily dose.

[0102] In some embodiments, the method results in a reduction in steroid burden, evaluated as the change from baseline in prednisone-equivalent steroid dose, at week 52.

[0103] In some embodiments, the method results in a decrease in the number and type (mild / moderate, severe, and either) of flares per subject up to week 52, as evaluated by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index (SFI), in the number of mild, moderate, or severe flares per patient-year (each and overall).

[0104] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤ 10 mg after 48 weeks of the first daily dose.

[0105] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response 48 weeks after the first day of administration.

[0106] In some embodiments, the method results in a BILAG-based combined lupus assessment (BICLA) response 48 weeks after the first day of administration.

[0107] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 48 weeks after the first day of administration.

[0108] In some embodiments, the method results in a reduction in steroid burden, evaluated as the change from baseline in prednisone-equivalent steroid dose, at week 48.

[0109] In some embodiments, the method results in a decrease in the number and type (mild / moderate, severe, and either) of flares per subject up to week 48, as evaluated by the Safety of Estrogens in Lupus National Assessment (SELENA) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index (SFI), of the number of mild, moderate, or severe flares per patient-year (each and overall).

[0110] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤10 mg 24 weeks after the first day of administration.

[0111] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response after 24 weeks of the first day of administration.

[0112] In some embodiments, the method results in a BILAG-based combined lupus assessment (BICLA) response after 24 weeks of the first day of administration.

[0113] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response after 24 weeks of the first day of administration.

[0114] In some embodiments, the method results in a reduction in steroid burden, as evaluated as the change from baseline in prednisone-equivalent steroid dose at week 24.

[0115] In some embodiments, the method results in a decrease in the number of mild, moderate or severe relapses per patient-year (each and overall), as evaluated by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Relapse Index (SFI), based on the number and type (mild / moderate, severe, and either) of relapses per subject up to week 24.

[0116] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤ 10 mg at 20 weeks after the first day of dosing.

[0117] In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 20 weeks after the first day of dosing.

[0118] In some embodiments, the method results in a BILAG-based Lupus Combination Assessment (BICLA) response at 20 weeks after the first day of dosing.

[0119] In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 20 weeks after the first day of dosing.

[0120] In some embodiments, the method results in a reduction in steroid burden, as evaluated as the change from baseline in prednisone-equivalent steroid dose at week 20.

[0121] In some embodiments, the method results in a reduction in the number of mild, moderate or severe relapses (each and overall) per patient-year as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Relapse Index (SFI), which is evaluated by the number and type (mild / moderate, severe, and either) of relapses per subject up to week 20.

[0122] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤ 10 mg at 16 weeks after the first day of dosing.

[0123] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response at 16 weeks after the first day of dosing.

[0124] In some embodiments, the method results in a BILAG-based Lupus Combination Assessment (BICLA) response at 16 weeks after the first day of dosing.

[0125] In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 16 weeks after the first day of dosing.

[0126] In some embodiments, the method results in a reduction in steroid burden, evaluated as the change from baseline in prednisone-equivalent steroid dose, at week 16.

[0127] In some embodiments, the method results in a reduction in the number of mild, moderate or severe relapses (each and overall) per patient-year as measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Relapse Index (SFI), which is evaluated by the number and type (mild / moderate, severe, and either) of relapses per subject up to week 16.

[0128] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤ 10 mg at 12 weeks after the first day of dosing.

[0129] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response 12 weeks after the first day of administration.

[0130] In some embodiments, the method results in a BILAG-based combined lupus assessment (BICLA) response 12 weeks after the first day of administration.

[0131] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 12 weeks after the first day of administration.

[0132] In some embodiments, the method results in a reduction in steroid burden, evaluated as the change from baseline in prednisone-equivalent steroid dose, at week 12.

[0133] In some embodiments, the method results in a decrease in the number and type (mild / moderate, severe, and either) of flares per subject up to week 12, as evaluated by the Safety of Estrogens in Lupus National Assessment (SELENA) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) flare index (SFI), of mild, moderate, or severe flares per patient-year (each and overall).

[0134] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response and prednisone-equivalent steroid dose ≤ 10 mg 8 weeks after the first day of administration.

[0135] In some embodiments, the method results in a Systemic Lupus Erythematosus Responder Index (SRI)-4 response 8 weeks after the first day of administration.

[0136] In some embodiments, the method results in a BILAG-based combined lupus assessment (BICLA) response 8 weeks after the first day of administration.

[0137] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 8 weeks after the first day of administration.

[0138] In some embodiments, the method results in a reduction in steroid burden, evaluated as a change from baseline in prednisone-equivalent steroid dose, at week 8.

[0139] In some embodiments, the method results in a decrease in the number of mild, moderate, or severe flares per patient-year (each and overall), as evaluated by the Safety of Estrogens in Lupus National Assessment (SELENA) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index (SFI), based on the number and type (mild / moderate, severe, and either) of flares per subject up to week 8.

[0140] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response and a prednisone-equivalent steroid dose ≤ 10 mg 4 weeks after the first day of administration.

[0141] In some embodiments, the method results in an SLE Responder Index (SRI)-4 response 4 weeks after the first day of administration.

[0142] In some embodiments, the method results in a British Isles Lupus Assessment Group (BILAG)-based combined lupus assessment (BICLA) response 4 weeks after the first day of administration.

[0143] In some embodiments, the method results in a lupus low disease activity state (LLDAS) response 4 weeks after the first day of administration.

[0144] In some embodiments, the method results in a reduction in steroid burden, evaluated as a change from baseline in prednisone-equivalent steroid dose, at week 4.

[0145] In some embodiments, the method results in a decrease in the number of mild, moderate or severe relapses (each and overall) per patient-year, as evaluated by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) flare index (SFI) in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA), which is evaluated by the number and type (mild / moderate, severe, and either) of flares per patient up to week 4.

[0146] In some embodiments, the method results in a significant decrease in the levels of anti-dsDNA autoantibodies and of complement C3 and C4. In some embodiments, the method results in a significant increase in the number of circulating memory, naive and total B cells.

[0147] In some embodiments, the patient has an insufficient response or intolerance to one or more disease-modifying antirheumatic drugs. In some embodiments, the patient has an insufficient response or intolerance to methotrexate. In some embodiments, the patient has an insufficient response or intolerance to anti-TNF biological agents. In some embodiments, the patient has an insufficient response or intolerance to antimalarial agents.

[0148] In some embodiments, the patient has an insufficient response or intolerance to immunomodulatory substances.

[0149] In some embodiments, the patient has an insufficient response or intolerance to corticosteroids.

[0150] In some embodiments, the patient has an insufficient response or intolerance to prednisone (or prednisone equivalent), antimalarial agents, azathioprine, mycophenolate, leflunomide, cyclosporine, tacrolimus or methotrexate.

[0151] In some embodiments, the patient is being treated concurrently with an antimalarial agent.

[0152] In some embodiments, the patient is being treated concurrently with an immunomodulatory substance.

[0153] In some embodiments, the patient is concurrently treated with an adrenal corticosteroid.

[0154] In some embodiments, the patient is concurrently treated with methotrexate. In some embodiments, the patient is concurrently treated with methotrexate at ≤20 mg / week together with concomitant folic acid ≤5 mg / week.

[0155] In some embodiments, the patient is concurrently treated with azathioprine. In some embodiments, the patient is concurrently treated with azathioprine at ≤150 mg / day.

[0156] In some embodiments, the patient is concurrently treated with mycophenolate mofetil. In some embodiments, the patient is concurrently treated with mycophenolate mofetil at ≤2,000 mg / day.

[0157] In some embodiments, the patient is concurrently treated with mycophenolate sodium. In some embodiments, the patient is concurrently treated with mycophenolate sodium at ≤1,440 mg / day.

[0158] In some embodiments, the patient is concurrently treated with hydroxychloroquine. In some embodiments, the patient is concurrently treated with hydroxychloroquine at ≤400 mg / day.

[0159] In some embodiments, the patient is concurrently treated with chloroquine. In some embodiments, the patient is concurrently treated with chloroquine at ≤500 mg / day.

[0160] In some embodiments, the patient is concurrently treated with quinacrine. In some embodiments, the patient is concurrently treated with quinacrine at ≤100 mg / day.

[0161] In some embodiments, the patient is treated concomitantly with leflunomide. In some embodiments, the patient is treated concomitantly with leflunomide at ≤20 mg / day.

[0162] In some embodiments, the patient is treated concomitantly with cyclosporine. In some embodiments, the patient is treated concomitantly with cyclosporine administered according to serum levels.

[0163] In some embodiments, the patient is treated concomitantly with tacrolimus. In some embodiments, the patient is treated concomitantly with tacrolimus administered according to serum levels.

[0164] In some embodiments, the patient is treated concomitantly with corticosteroids (prednisone equivalents). In some embodiments, the patient is treated concomitantly with corticosteroids at ≤20 mg / day, decreasing at a rate of 5 mg QD or less per week. In some embodiments, the corticosteroids increase up to a maximum of 25 mg by week 8 of treatment, at a rate of 5 mg QD or less per week, regardless of the baseline dose. IV. Pharmaceutical Compositions and Routes of Administration Upadacitinib can be administered to human patients at a dose that treats or ameliorates the diseases or conditions described herein, either alone or in a pharmaceutical composition mixed with a biologically suitable carrier or excipient. Mixtures of these compounds can also be administered to patients, either as a simple mixture or in a suitably formulated pharmaceutical composition.

[0165] The pharmaceutical compositions of the present disclosure can be manufactured in a manner known per se, for example using conventional mixing, dissolving, granulating, sugar coating, wet milling, emulsifying, encapsulating, entrapping or lyophilization processes.

[0166] Thus, pharmaceutical compositions for use in accordance with the present disclosure can be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries that facilitate processing the active compound into a pharmaceutically usable preparation. Appropriate formulation depends on the chosen route of administration.

Example

[0167] [Example 1: Safety and Efficacy of Upadacitinib in Systemic Lupus Erythematosus (SLE)] This was a Phase 2 trial (M19-130) to investigate the safety and efficacy of upadacitinib in subjects with moderate to severe active systemic lupus erythematosus.

[0168] Study Population and Number of Enrolled Subjects Approximately 130 adult male or female subjects, 18 to 65 years of age (including 18 and 65 years), who had received a clinical diagnosis of SLE at least 24 weeks prior to screening and met at least 4 of 11 revised 1982 American College of Rheumatology (ACR) 1997 revised classification criteria for SLE, including at least 1 clinical criterion and 1 immunologic criterion, or met at least 4 of the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. Subjects had to have active SLE as defined by SLEDAI-2K ≥ 6, as reported and independently determined at screening and baseline (excluding clinical score ≥ 4, lupus headache, and / or organic brain syndrome). If 4 of the required entry points were for arthritis, there had to be minimal tenderness in at least 3 joints and swelling in at least 3 joints.

[0169] Efficacy Evaluation Items Primary Evaluation Items The primary efficacy evaluation items were achievement of the Systemic Lupus Erythematosus Responder Index (SRI)-4 at week 24 and achievement of a once-daily (QD) steroid dose ≤ 10 mg prednisone equivalent. The Systemic Lupus Erythematosus Responder Index (SRI)-4 was defined as a ≥ 4-point decrease in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score without worsening of the overall condition (no worsening of the Physician's Global Assessment [PhGA], increase of < 0.3 points) or occurrence of significant disease activity in a new organ system (no new British Isles Lupus Assessment Group [BILAG] A or new BILAG B > 1).

[0170] Secondary evaluation items The following secondary efficacy evaluation items were evaluated: 1. Achievement of SRI-4 at week 24 2. Achievement of the BILAG-based Lupus Combined Assessment (BICLA) response at week 24 3. Achievement of the lupus low disease activity state (LLDAS) at week 24 4. Steroid burden, evaluated as change from baseline at week 24 5. Safety of estrogen in the Systemic Lupus Erythematosus National Assessment (SELENA) SLEDAI flare index (SFI), evaluated by the number and type of flares per subject up to week 24, with the number of mild, moderate, or severe flares per patient-year (each and overall)

[0171] Additional evaluation items Unless otherwise specifically mentioned, at all visits, the following additional efficacy evaluation items were evaluated: 1. Achievement of SRI-4 2. Achievement of SRI-5, -6, -7, -8 and QD steroid dose ≤ 10 mg prednisone equivalent at weeks 24 and 48 3. Achievement of SRI-5, -6, -7, -8 4. Achievement of the BICLA response 5. Achievement of LLDAS 6. Achievement of a ≥ 4-point decrease in SLEDAI-2K from baseline 7. Steroid load, evaluated as change from baseline 8. Number and type of flares per subject up to week 24 and week 48, mild, moderate or severe flare rate per patient-year according to SELENA SFI (each and overall) 9. Period to first flare according to SELENA SFI after first administration of the investigational drug up to week 24 and week 48 10. Achievement of 50% reduction in joint tenderness or swelling, defined as ≥50% reduction in either joint tenderness or swelling (starting in joints affected at ≥6 locations in total) 11. Achievement of 50% reduction in cutaneous lupus erythematosus area severity index (CLASI) activity score (starting with CLASI ≥10) 12. Change in SLEDAI-2K from baseline 13. Change in BILAG from baseline 14. Change in PhGA from baseline 15. Change in patient global assessment (PtGA) from baseline 16. Change in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT - Fatigue) from baseline at week 2, week 12, week 24 and week 48 17. Change in 36-Item Short-Form Health Survey (SF-36) from baseline at week 2, week 12, week 24 and week 48 18. Change in Lupus Quality of Life Questionnaire (LupusQoL) from baseline at week 2, week 12, week 24 and week 48 19. Change in Pain Numerical Rating Scale (NRS) from baseline at week 2, week 12, week 24 and week 48

[0172] Safety assessment items The safety assessment by conventional methods included, over the entire study period, as measures of safety and tolerability, adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiograms (ECGs), and clinical laboratory tests (including hematology, chemistry, and urinalysis). SAEs were evaluated at all doses that resulted in death, hospitalization of an inpatient or prolongation of an existing hospitalization, persistent or significant physical impairment / incapacity, or congenital anomaly.

[0173] The following areas of safety were evaluated by conventional methods to identify any major safety findings related to immunosuppression or potential risks associated with each type of therapy: severe and / or opportunistic infections, herpes zoster, active tuberculosis, malignancies (all types), determined gastrointestinal (GI) perforation, determined cardiovascular events (e.g., major adverse cardiovascular events [MACE]), anemia, neutropenia, lymphopenia, renal dysfunction, liver impairment, and determined embolism and thromboembolism (non-cardiac, non-central nervous system [CNS]), including venous thromboembolism defined as pulmonary embolism and deep vein thrombosis. Special toxicity management measures were utilized for severe infections, severe GI events, cardiovascular events (MACE), malignancies, ECG abnormalities, and selected laboratory test abnormalities. Also, follow-up calls were made on day 30 after the final dose of the investigational 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 overall integrity and conduct of the study. Periodic reviews were conducted by the DMC at regular intervals. A periodic organized review of all newly emerging safety data from all clinical trials using upadacitinib was conducted by AbbVie. An independent external Cardiovascular Event Adjudication Committee (CAC) adjudicated all blinded cardiovascular and cerebrovascular events, embolism / thromboembolism, and deaths, as defined in the CAC charter.

[0174] Pharmacokinetic evaluation items Descriptive statistics were used to summarize the plasma concentrations of upadacitinib at each sampling time point. Population central values and empirical Bayesian estimates of individual values for upadacitinib oral clearance (CL / F) and volume of distribution (Vss / F) were estimated using a mixed-effects modeling approach. Additional parameters and pharmacokinetic (PK) / pharmacodynamic relationships were estimated if data interpretation was useful.

[0175] Biomarker Research Throughout the study, biological samples (whole blood, peripheral blood mononuclear cells [PBMC], plasma, and serum) were collected at defined time points to evaluate known and / or novel disease- or drug-related biomarkers. Biomarker types could include nucleic acids, proteins, lipids, RNA, DNA, and / or metabolites. The purpose of this study was to analyze samples for biomarkers that would help understand SLE, related conditions, and the response to treatment with upadacitinib or similar compounds.

[0176] Type I IFN is an important driver of pathogenesis in lupus, and high IFN signatures are associated with active SLE. Approximately 60% of lupus patients express elevated type I IFN gene signatures in the blood, suggesting higher type I IFN activity in these individuals. JAK1 inhibition is expected to disrupt type I IFN signaling; thus, lupus patients expressing type I gene signatures may be more likely to benefit from treatment with upadacitinib. A validated assay using a type I IFN gene expression assay score with a cut-off point set at ≥ -0.25 for high IFN and < -0.25 for low IFN (-0.25 is the upper limit of the cut-off point) was used to evaluate the type I IFN RNA signature consisting of four genes (IFI6, IFI27, IFIT1, and MX1).

[0177] In the event that IFN scores could not be collected or analyzed during screening for access to the laboratory due to COVID-19, the subject was still registered in the study and a score corresponding to no screening visit was assigned. If collected, samples taken at the 4-week and 24-week visits could be used for analysis.

[0178] These results are strongly dichotomized into high IFN and low IFN groups. Assays were performed on screening samples, unless made impossible by local regulations or restrictions at a later time (IFN signature samples were not collected at sites in China). Screening values were used as a criterion to enrich the cohort for the purpose of enrolling 80% of the study subjects with a high composite core. Stratifying the study to include approximately 80% of the high IFN score cohort enabled an increase in the reliability of the subject population.

[0179] The study may also have included analysis of genetic, epigenetic, gene expression, and proteomic biomarkers that may be related to the subject's response to SLE, related conditions, or treatment. This study was essentially exploratory and the results may not have been included in the clinical trial report. Necessary biomarker samples were collected and analyzed from all subjects, unless made impossible by local regulations or restrictions (in which case, selectivity of collection / analysis was provided through appropriate consent documentation).

[0180] Trial Plan A study was designed to investigate the safety and efficacy of upadacitinib in subjects with moderate to severe active SLE despite standard therapy. The study period included a maximum screening period of 42 days, a randomized placebo-controlled double-blind parallel-group treatment period of 48 weeks, and a follow-up phone call on day 30. A primary analysis at week 24 was performed when all subjects completed their visit at week 24 or the study was terminated. Sites and subjects remained blinded throughout the study. The study team remained blinded until the primary analysis at week 24. Study visits were conducted at screening, baseline, and at weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 / early termination (PD). A follow-up phone call was made on day 30 after the final dose of investigational drug to determine the status of any ongoing adverse events (AEs) / serious adverse events (SAEs) or the occurrence of any new AEs / SAEs.

[0181] Long-term extension (LTE) studies were conducted at sites approved by local relevant authorities and ethics committees under separate protocols (LTE study M20-186). The rollover of subjects in the first randomized part of the study occurred at week 48. A planned unblinded interim analysis was conducted when 50% of the planned subjects completed their assessment at week 24. The purpose of this analysis was to re-evaluate the benefit / risk of the treatment regimen of study M19-130 and the rollover to LTE study M20-186. The interim analysis was conducted by a separate independent AbbVie team different from the blinded study team. The study M19-130 team remained blinded throughout the primary analysis at week 24.

[0182] Key eligibility criteria The following were the key eligibility criteria for the study: · Adult men or women, 18 to 65 years of age (including 18 and 65 years) at screening. · Clinical diagnosis of SLE at least 24 weeks prior to screening, meeting at least 4 out of 11 revised SLE classification criteria according to the 1997 revision of the 1982 ACR, including at least 1 clinical criterion and 1 immunological criterion, or meeting at least 4 of the 2012 SLICC classification criteria. · At screening, must have had at least 1 of the following: · Positive antinuclear antibody test (ANA) (antibody titer ≥ 1:80) · Positive anti-double-stranded DNA (anti-dsDNA) · Positive anti-Smith · SLEDAI-2K ≥ 6 at screening as reported and independently determined (excluding clinical score ≥ 4, lupus headache and / or organic brain syndrome), despite background therapy. If 4 of the required entry points are for arthritis, must have had minimal tenderness in 3 joints and swelling in 3 joints. If the subject had a rash and the principal investigator (PI) thought it could be attributed to SLE, the subject complied with skin photo collection for determination (reconfirmed at baseline visit). · PhGA ≥ 1 during the screening period. · At baseline and throughout the trial period, must have been on stable background therapy for 30 days with prednisone (or prednisone equivalent) (≤ 20 mg), antimalarial agents, azathioprine (≤ 150 mg), mycophenolate (≤ 2 g), leflunomide (≤ 20 mg), cyclosporine, tacrolimus, and / or methotrexate (MTX) (≤ 20 mg). · Combinations with immunomodulatory substances other than prednisone (or prednisone equivalent) and antimalarial agents as described above were not permitted. Must not have used intravenous (IV) or intramuscular (IM) corticosteroids equivalent to 40 mg or more of prednisone.

[0183] Investigational drug and treatment duration The investigational drug was orally administered once daily for 24 weeks as 1 film-coated tablet containing 30 mg of upadacitinib and / or matching placebo, with or without food.

[0184] Overall study design and plan This was the primary assessment item at week 24 for investigating the safety and efficacy of upadacitinib in subjects with moderate to severe active SLE. It was a multicenter, randomized, double-blind, placebo-controlled, phase 2 trial. The study continued until week 48 to further evaluate the maintenance of efficacy and safety of each treatment beyond 24 weeks.

[0185] Approximately 130 male and female subjects, aged 18 to 65 years (including 18 and 65 years), with moderate to severe active SLE (diagnosed at least 24 weeks before screening, meeting at least 4 out of 11 revised SLE classification criteria according to the 1997 revision of the 1982 American College of Rheumatology [ACR] criteria, including at least 1 clinical criterion and 1 immunological criterion, or meeting at least 4 of the 2012 Systemic Lupus Erythematosus International Collaborating Clinics [SLICC] classification criteria), despite standard treatment, were randomized as follows: Group 1: Upadacitinib 30 mg QD (n = 65) Group 2: Upadacitinib placebo QD (n = 65) Randomization was stratified based on the following factors: · Baseline corticosteroid dose higher than 10 mg prednisone equivalent (≤10 mg or 10 mg) · Screening SLEDAI-2K (<10 or ≥10) · High vs low vs no IFN score (approximately 80% higher) (This stratification factor was not applicable to Chinese subjects.) · Baseline immunosuppressive drugs (azathioprine, tacrolimus, cyclosporine, methotrexate [MTX], mycophenolate, or leflunomide) (yes / no)

[0186] The study period included a maximum screening period of 42 days and a randomized placebo-controlled double-blind parallel-group treatment period of 48 weeks, with a follow-up call on day 30. Sites and subjects remained blinded throughout the study. A primary analysis at week 24 was conducted when all subjects completed their week 24 visit or the study was terminated. The study team remained blinded until the primary analysis at week 24. A follow-up call was made on day 30 after the last dose of the investigational drug to determine the status of any ongoing AE / SAE or the occurrence of any new AE / SAE.

[0187] A schematic diagram of the study is shown in Figure 1. A long-term extension (LTE) study was conducted at sites approved by local relevant authorities and ethics committees under separate protocols (LTE study M20-186). The rollover of subjects in the first randomized part of the study occurred at week 48. When 50% of the planned subjects completed their week 24 assessment, an unblinded interim analysis was conducted by an independent team at AbbVie.

[0188] Selection of the Control Group This was a parallel-group study consisting of treatment groups receiving upadacitinib or matching placebo to evaluate the safety and efficacy of once-daily upadacitinib over 24 weeks in subjects with moderate to severe active SLE. The placebo served as a reference for efficacy assessment.

[0189] Appropriateness of Measurements All efficacy and safety measurements in this study were standard for the assessment of disease activity in subjects with SLE treated with immunosuppressive therapy. The first safety assessment was at week 2 and all subsequent visits. All clinical and laboratory procedures in this study were standard and generally approved.

[0190] Suitability of the Subject Population Subjects eligible for this study were adult men or women aged 18 to 65 years (inclusive of 18 and 65 years) who had received a clinical diagnosis of SLE at least 24 weeks prior to screening, met at least 4 out of 11 of the revised 1997 ACR SLE classification criteria according to the 1982 ACR, including at least 1 clinical criterion and 1 immunological criterion, or at least 4 of the 2012 SLICC classification criteria, and met at least 1 of the following at screening: positive antinuclear antibody (ANA) (antibody titer ≥ 1:80), anti-double-stranded DNA (dsDNA) or anti-Smith antibody. The selection criteria were based on current knowledge of the drug and were intended to identify individuals with active SLE in the target population for treatment with upadacitinib.

[0191] Eligibility Criteria Subjects had to meet all of the following criteria to be included in the study. Anything other than a positive response to the following questions resulted in exclusion from study participation.

[0192] Demographics and Laboratory Assessments 1. Adult men or women, 18 to 65 years (inclusive of 18 and 65 years) at screening. 2. During the screening period prior to the first dose of investigational drug, must not have had test values meeting the following criteria: · Serum aspartate aminotransferase (AST) > 2.0 × upper limit of normal (ULN); · Serum alanine aminotransferase (ALT) > 2.0 × ULN; · Estimated glomerular filtration rate (GFR) formula by Modification of Diet in Renal Disease (MDRD) for simple 4-variable renal disease < 40 mL / min / 1.73m 2 ; · Absolute neutrophil count (ANC) < 1,000 / μL; · Platelet count < 50,000 / μL; · Hemoglobin < 9 g / dL. 3. At screening, must not have had positive antibody titers for all 3 antiphospholipid antibodies known to be associated with venous thrombosis: lupus anticoagulant, anti-β2 glycoprotein 1, and anticardiolipin antibody.

[0193] Disease activity 1. Clinical diagnosis of SLE at least 24 weeks prior to screening, meeting at least 4 out of 11 revised SLE classification criteria according to the 1997 revision of the 1982 ACR, including at least 1 clinical criterion and 1 immunological criterion, or meeting at least 4 of the 2012 SLICC classification criteria. 2. At screening, must have at least 1 of the following: · ANA+(antibody titer ≥ 1:80) · Anti-dsDNA+ · Anti-Smith+ 3. Despite background therapy, SLEDAI-2K ≥ 6 at screening as reported and independently determined (excluding clinical score ≥ 4, lupus headache and / or organic brain syndrome): · If 4 of the required entry points are for arthritis, there must be no tenderness in at least 3 joints and swelling in 3 joints. · If 4 of the required clinical scores are for proteinuria attributable to active lupus nephritis, this must be > 0.5 g / day (0.5 mg / mg) in conversion. · If the subject has a rash and the principal investigator (PI) considers it attributable to SLE, the subject must comply with skin photo collection for determination. · The score must be reconfirmed at baseline visit. 4. PhGA ≥ 1 during the screening period. 5. The subject must receive background therapy throughout the study. Background therapy is stable for 30 days prior to baseline and throughout the study, · Must not have used antimalarials, prednisone (or prednisone equivalent) (≤ 20 mg), azathioprine (≤ 150 mg), mycophenolate (≤ 2 g), leflunomide (≤ 20 mg), cyclosporine, tacrolimus and / or MTX (≤ 20 mg). ·Combination of basic treatment with antimalarial agents and / or prednisone (or equivalent) is permitted, and from the above list, a single, rather than multiple, additional immunosuppressive agent is permitted.

[0194] Subject's medical history 1. Must not have active lupus nephritis (progressive class IV or >1 g / day equivalent [1 mg / mg] proteinuria), or must have received induction therapy within the last 6 months. 2. Must not be receiving hemodialysis (or other forms of renal replacement therapy). 3. Must not have active psychiatric symptoms due to SLE as defined by the CNS part of SLEDAI-2K or BILAG (except lupus headache). 4. Must not have any active, chronic, or recurrent viral or bacterial infections that, based on the investigator's clinical evaluation, make the subject inappropriate as a candidate for the study, including hepatitis B virus (HBV), hepatitis C virus (HCV), recurrent or disseminated (even if a single episode) herpes zoster, disseminated (even if a single episode) herpes simplex, or HIV. Active HBV, HCV, and HIV are: ·HBV: Subjects positive (+) for hepatitis B surface antigen (HBs Ag), or positive (+) for the detection sensitivity of the HBV DNA polymerase chain reaction (PCR) qualitative test for hepatitis B core antibody (HBc Ab); (and, only in China and Japan, subjects positive [+] for hepatitis B surface antibody [HBs Ab]) Are defined as. 5. Must not have active TB or latent TB and must not have completed the entire process of latent TB prevention. 6. Must not have a history of any malignant tumors except for successfully treated non-melanoma skin cancer (NMSC) or carcinoma in situ (CIS) of the cervix. 7. Must not have a history of clinically significant drug or alcohol abuse (at the investigator's discretion) within the last 6 months. 8. Must not have a history of GI perforation (other than appendicitis or penetrating injury), diverticulitis, or a significant increase in the risk of GI perforation at the investigator's discretion. 9. Must not have any condition that can interfere with drug absorption, including but not limited to short bowel syndrome (for example, subjects with a history of gastric bypass surgery are excluded). Subjects with a history of gastric banding / splitting are excluded. 10. Must not be an organ transplant recipient. 11. Must not have a history of clinically significant medical conditions or any other reason that, in the opinion of the investigator, would interfere with the subject's participation in this study or make the subject inappropriate as a candidate to receive the investigational drug. 12. Must not have an active infection that requires treatment with parenteral anti-infective drugs within 30 days or oral anti-infective drugs within 14 days prior to the first dose of the investigational drug. 13. Must not have confirmed COVID-19. Baseline visit must be at least 14 days from the onset of signs / symptoms or a positive SARS-CoV-2 test; symptomatic subjects must have recovered, defined as resolution of fever without the use of antipyretics and improvement of symptoms. 14. Must not have suspected COVID-19. Subjects with signs / symptoms suggestive of COVID-19, known exposure, or high-risk behavior should undergo a molecular (e.g., PCR) test to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days following a possible exposure. 15. Must not have a history of allergic reaction or significant sensitivity to the components of the investigational drug (and its excipients) and / or other products of the same class. 16. Must not have a history of any of the following cardiovascular conditions: · Cerebrovascular accident (CVA), recent history of myocardial infarction (within the past 6 months) · (MI), coronary artery stent placement, coronary artery bypass surgery. · Poorly controlled hypertension defined by persistent systolic blood pressure (BP) > 160 mmHg or diastolic BP > 100 mmHg. For subjects with known hypertension, the subject's BP must have been stable on current antihypertensive medication for at least 30 days. · Any other condition in which, in the opinion of the investigator, the subject would be at risk by participating in the protocol. 17. At screening, there should be no clinically relevant or significant ECG abnormalities, including an ECG with a corrected QT interval (QTc) corrected for heart rate (QTcF) > 480 msec using Fridericia's correction formula. Subjects with ventricular conduction delay (QRS > 120 msec) will need to be examined by a cardiologist. 18. Only for Japanese subjects: There should be no positive results for beta-D-glucan or two consecutive indeterminate results for beta-D-glucan (screening for Pneumocystis jiroveci infection).

[0195] Previous treatment drugs / concomitant drugs 1. During the planned 30-day randomization period, intravenous (IV) or intramuscular (IM) corticosteroids at a dose equivalent to 40 mg or more of prednisone as a bolus should not be used. Within 8 weeks before the first administration of the investigational drug, treatment with corticosteroids within joints, trigger points or tender points, bursae or tendon sheaths should not have been carried out. 2. Subjects must be naive to, or have discontinued and not received benefit from, or have had a washout period of at least 5 times the mean elimination half-life of the drug, prior to the first administration of the investigational drug, according to the following applicable washout periods: · For plasma exchange therapy: ≥ 6 months · For belimumab (Benlysta®): ≥ 3 months · For rituximab: ≥ 1 year, or ≥ 6 months if B cells have reached ≥ 50 cells per microliter · For cyclophosphamide: ≥ 3 months · For abatacept, any anti-tumor necrosis factor (TNF) therapy and all other biological agents: ≥ 4 weeks 3. Subjects should not have received intravenous immunoglobulin (IVIG) within 30 days before the first administration of the investigational drug. 4. There should be no prior exposure for more than 14 days or any prior intolerance to JAK inhibitors (including, but not limited to, upadacitinib, tofacitinib, baricitinib, and filgotinib) or BTK inhibitors. The washout period of JAK inhibitors and BTK inhibitors before the first dose of the investigational drug should be the longer of ≥ 30 days or 5 times the half-life. 5. To avoid unpermitted co-administration of immunosuppressive drugs during the study (see criterion 10 above), subjects who have been previously exposed to the following drug therapies may need to complete a washout period before enrollment or should have a washout period of at least 5 times the average elimination half-life of the drug, as defined below: · For MTX, azathioprine, tacrolimus, cyclosporine, and mycophenolate, ≥ 4 weeks before the first dose of the investigational drug. · For leflunomide, if there is no subsequent elimination procedure or if it is attached to an elimination procedure (i.e., a washout period of 11 days with cholestyramine or 30 days with activated charcoal, or depending on the regional classification label), ≥ 8 weeks before the first dose of the investigational drug. 6. There should be no prior exposure to IFN kinoid vaccines. 7. There should be no prior exposure to anti-IFN therapies, including anti-IFN and anti-IFN receptor, within 3 months of the study baseline. 8. No subject should be treated with any investigational drug or currently enrolled in another clinical trial within 30 days or 5 times the half-life of the drug (whichever is longer) before the first dose of the investigational drug. 9. Subjects must discontinue all potent sedatives at least one week before the first dose of the investigational drug and must discontinue all herbal medicines at least 30 days before. 10. Subjects should not have received any live vaccines within 30 days (56 days for Japan) before the first dose of the investigational drug.

[0196] Prohibited Drug Therapies and Treatments Drug therapies and treatments with washout periods were prohibited while the subject was receiving the investigational drug. While the subject was receiving the investigational drug, in addition to the drug therapies listed in the eligibility criteria, the following were prohibited: · Cyclophosphamide · Belimumab · Rituximab · Granulocyte colony-stimulating factor (GCSF) · IVIG · Potent cytochrome P450 3A isoform subfamily (CYP3A) or cytochrome P450 1A2 isoform subfamily (CYP1A2) inhibitors and inducers (examples found in Table 1) · Chinese herbal medicine · Elective surgery within the first 24 weeks · Potent narcotics including, but not limited to, the following (unless administered during hospitalization): · Oxycodone · Oxymorphone · Fentanyl · Levorphanol · Buprenorphine · Methadone · Hydromorphone · Morphine · Meperidine · Notably, weak narcotics are permitted to optimize SLE drug therapy.

[0197]

Table 1

[0198] Concomitant drug / treatment Investigators were encouraged to taper steroids in subjects who were stable or improving. Investigators could at any time decide not to initiate tapering or to delay tapering. The target steroid dose was ≤10 mg QD by week 16. The steroid dose could be increased, as needed for life-saving purposes, up to a maximum of 25 mg per week at ≤5 mg QD until week 8. Tapering to the steroid target of ≤10 mg was permitted until week 16. No change in the steroid dose was permitted from weeks 16 to 24. Starting at week 24, steroid tapering was again permitted at the discretion of the PI, with a target of ≤10 mg QD. Subjects who did not achieve the steroid target of ≤10 mg QD by week 24 were considered non-responders to the primary assessment. Subjects who required life-saving treatment from weeks 8 to 48 were considered non-responders starting from the visit at which the subject received life-saving treatment. The steroid dose could be increased or decreased as needed for safety purposes. Subjects who required an increase greater 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 continued on the investigational drug at the discretion of the investigator, provided they were not receiving prohibited drug therapy.

[0199] Subjects had to remain on their background therapy throughout the study. The only permitted change to background therapy was steroid tapering. Where applicable, subjects continued their stable dose of non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and weak opioids. For NSAIDs, changes in dose, including initiation, were not permitted for acetaminophen / paracetamol, tramadol, codeine, hydrocodone, and propoxyphene, which were part of the background therapy, except for life-saving therapy as defined by the protocol. The following drug therapies taken as needed (PRN) were permitted but not taken within 24 hours prior to any study visit: NSAIDs, acetaminophen / paracetamol, tramadol, codeine, hydrocodone, and propoxyphene. In the event of tolerance (or other safety) issues, the dose of NSAIDs and / or acetaminophen could be decreased or discontinued by substitution with another NSAID.

[0200] Any drug therapy or vaccine (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) that the subject was receiving at the time of enrollment or during the study had to be recorded through the post-treatment visit (30-day follow-up call). Subjects had to be able to safely discontinue any prohibited drug therapy 30 days prior to the first administration of investigational drug. Subjects had to consent to the study before discontinuing any prohibited drug therapy for the purpose of meeting eligibility for the study. See Table 2 for the list of permitted concomitant medications.

[0201]

Table 2

[0202] Subject Withdrawal and Study Termination The subject could withdraw from the study at any time for any reason, including but not limited to disease progression or lack of response to treatment. The investigator could discontinue the study treatment of any subject at any time for any reason, including but not limited to disease progression, lack of response to treatment, safety concerns, or failure to comply with the protocol.

[0203] At week 24, the investigator evaluated and documented in the source whether continuation of the study was in the best interest of the subject. The investigational medicinal product was discontinued immediately if any of the following occurred to the subject: · The occurrence or worsening of lupus symptoms requiring the introduction of a specific prohibited pharmacotherapy or dosing such that the subject would be at risk if the investigational medicinal product were continued. The following were those for which discontinuation of the investigational medicinal product was immediately required: · Cyclophosphamide · Belimumab · Rituximab · In combination, more than one of the following: azathioprine, mycophenolate, leflunomide, MTX, cyclosporine or tacrolimus · Plasma exchange therapy · High-dose corticosteroids (oral or parenteral ≥60 mg prednisone equivalent) · IVIG · Clinically significant abnormal laboratory results or AEs that made continuation of the investigational medicinal product impossible as determined by the investigator · Severe infections (e.g., pneumonia, sepsis) that could not be adequately controlled by anti-infective therapy or for which the subject could be at risk if participation in the trial were continued. · The investigator considered it to be in the best interest of the subject. · The subject requested discontinuation of the investigational medicinal product or the study, or the sponsor decided to discontinue one or more treatment groups after an interim analysis. · The subject had an ECG change that was considered clinically significant, had a reasonable possibility of being related to the investigational medicinal product, or had a confirmed absolute QTcF value >500 msec or a confirmed increase from baseline of ≥60 msec. · The subject's QTcF increased from the baseline by ≥ 60 msec, and the investigator determined to evaluate the value, confirm it, and discontinue treatment. · At any time during the study, the subject developed active or latent TB. · The subject became pregnant while receiving the investigational drug. · Malignant tumors, excluding localized NMSC or CIS of the cervix. · The subject was significantly non-compliant with the study procedures, including inconsistent administration of the investigational drug, such that the subject was at risk for continued participation in the study. · The subject developed a GI perforation. · When the diagnosis of deep vein thrombosis, pulmonary embolism, or non-cardiac, non-neurological arterial thrombosis was confirmed. · The subject developed active psychiatric symptoms (excluding lupus headache) due to SLE as defined by the CNS portion of SLEDAI-2K or BILAG. · The subject developed class IV lupus nephritis (confirmed by biopsy).

[0204] Investigational drug 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 the investigational drug orally, with or without food, only 1 tablet of upadacitinib or placebo from the bottles allocated to them daily. Subjects were instructed to take only 1 capsule or tablet from the bottles allocated to them daily. If a subject missed taking their upadacitinib or matching placebo dose at the normally scheduled dosing time, they were to take the missed dose as soon as they remembered, provided it was at least 10 hours before the next scheduled dose. Otherwise, the next dose was to be taken at the next scheduled dosing time. Subjects' dosing was recorded in the subjects' dosing diary. Subjects were instructed to return all drug containers (even if empty) to the study facility staff at each study visit. The study facility staff documented compliance. Upadacitinib and matching placebo were bottled in amounts sufficient to accommodate the study design. Depending on regional requirements, each kit was labeled and this label remained attached to the kit. Upon receipt, the investigational drug was to be stored as specified on the label and kept in a secure location. Each kit contained i a unique kit number. This kit number was assigned to subjects via two-way automated response technology (IRT) and encoded the appropriate investigational drug to be dispensed at the subjects' corresponding study visit. Prior to assignment to subjects, the site staff completed all margins of the label. The investigational drug was to be used only for the conduct of the study.

[0205]

Table 3

[0206] Randomization / Drug Allocation All subjects were assigned a unique identification number by IRT at the screening visit. For all subjects who were re-screened, the screening number assigned by IRT at the first screening visit was used. IRT assigned a randomization number that coded the assignment of subjects to treatment groups according to a randomization schedule created by AbbVie's Statistics department. Randomization was stratified based on the following factors: · Baseline corticosteroid dose higher than 10 mg prednisone equivalent (≤10 mg or >10 mg) · Screening SLEDAI-2K (<10 or ≥10) · High vs low vs not applicable IFN score (approximately 80% higher) · This stratification factor was not applied to subjects in China. · Baseline immunosuppressive drugs (azathioprine, tacrolimus, cyclosporine, MTX, mycophenolic acid or leflunomide) (yes / no) If approximately 20% of all subjects were randomized to the low IFN signature, further enrollment of such subjects could have been stopped. The investigators, study site staff, and subjects were blinded to the treatment of each subject throughout the study. To maintain blinding, the upadacitinib tablets and matching placebo tablets provided for the study were identical in appearance.

[0207] <� Results of the interim analysis at Week 24 Demographics Table 4 shows a summary of the demographics of subjects in the placebo and upadacitinib 30 mg QD treatment groups of the clinical trial.

[0208]

Table 4

[0209] Table 5 shows a table of the baseline disease characteristics of subjects in the placebo and upadacitinib 30 mg QD treatment groups of the clinical trial.

[0210]

Table 5

[0211] The breakdown of subjects in the placebo and upadacitinib 30 mg QD treatment groups in the clinical trial is outlined in Table 6.

[0212]

Table 6

[0213] Efficacy A graph showing the time-course response rates for the primary endpoints (achievement of SRI-4 and achievement of steroid dose ≤ 10 mg prednisone equivalent QD) in subjects treated with placebo and upadacitinib 30 mg QD over 24 weeks is shown in Figure 2. Upadacitinib 30 mg showed higher efficacy than placebo (51.6% vs 36.0%; stratum-adjusted treatment difference: 14.0%; p = 0.067).

[0214] A graph showing the time-course response rates for achievement of SRI-4 in subjects treated with placebo and upadacitinib 30 mg QD over 24 weeks is shown in Figure 3. Upadacitinib 30 mg showed higher efficacy than placebo at week 24 for SRI-4 (53.6% vs 37.3% at p = 0.046).

[0215] A graph showing the time-course response rates for achievement of BICLA in subjects treated with placebo and upadacitinib 30 mg QD over 24 weeks is shown in Figure 4. Upadacitinib 30 mg showed higher efficacy than placebo at week 24 for BICLA (58.1% vs 40.0% at p = 0.056).

[0216] The summary of the main and secondary evaluation items and the related statistics of the largest analysis population is presented in Table 7, which further shows that upadacitinib 30 mg achieved higher efficacy (p < 0.001) than placebo at week 24 in LLDAS and a lower relapse rate (p = 0.075) by week 24.

[0217]

Table 7

[0218] Pharmacokinetics Median (90% prediction interval) steady state (SS) C estimated from the model in SLE subjects avg was 28.4 (19.1 - 46.6) ng / mL for upadacitinib 30 mg QD.

[0219] Exposure - response for efficacy evaluation items The quartile plot of the relationship between upadacitinib steady state (SS) C at week 24 avg and the efficacy response is shown in Figures 5A - 5C. In particular, Figure 5A is the exposure - response quartile plot of upadacitinib efficacy at week 24 for the efficacy evaluation items of the SLE responder index (SRI - 4) and steroid dose ≤ 10 mg prednisone equivalent QD, Figure 5B is the exposure - response quartile plot of upadacitinib efficacy at week 24 for the efficacy evaluation items of BILAG - based lupus combined assessment (BICLA), and Figure 5C is the exposure - response quartile plot of upadacitinib efficacy at week 24 for the efficacy evaluation items of the SLE responder index (SRI - 4). Based on logistic regression analysis, upadacitinib plasma exposure had a statistically significant relationship (p < 0.05) with SRI - 4 and steroid dose ≤ 10 mg prednisone equivalent, SRI - 4, and BICLA at week 24.

[0220] In the upadacitinib plasma exposure (associated with 30 mg QD) evaluated in this study, a plateau of efficacy was not reached.

[0221] Highest upadacitinib steady state (SS) C avg The quartiles (corresponding to 45 mg QD exposure) were consistently associated with responses observed across the top three assessment items and were the major drivers of the trends in upadacitinib exposure-response. Median (90% prediction interval) percentages estimated from exposure-response models for subjects achieving SRI-4 and steroid dose ≤ 10 mg prednisone equivalent QD, BICLA, and SRI-4 at Week 24 were 50% (42% - 58%), 57% (50% - 65%), and 55% (47% - 62%) for upadacitinib 30 mg UPA QD, compared with 38% (31% - 46%), 39% (32% - 46%), and 40% (32% - 47%) for placebo, respectively. The upadacitinib 45 mg QD dose is predicted to result in a 6% - 8% higher response compared with 30 mg QD.

[0222] Biomarker analysis The upadacitinib 30 mg treatment group showed significant decreases in the levels of C3, C4 complement, and IgM, as well as significant decreases in the levels of anti-dsDNA autoantibodies and IgG, compared with baseline. Increases in circulating memory, naive, and total B cells were also observed.

[0223] [Example 2: Safety and Efficacy of Upadacitinib in Systemic Lupus Erythematosus (SLE)] This was an extension of the Phase 2 trial in Example 1. Specifically, the study in Example 1 was extended for an additional 24 weeks, up 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 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.

[0224] Results Efficacy Results at week 24 and week 48 for selected efficacy evaluation items for the continuous group are shown in Table 8 and Figures 6 - 9. Notably, the week 24 results in Table 8 are based on the final database; thus, this result is slightly different from the week 24 value in the corresponding Table 7 of Example 1.

[0225] After week 24, the response rates in both BICLA and SRI - 4 were generally maintained in the upadacitinib 30 mg group, while the placebo rate was either stable (SRI - 4) or decreasing (BICLA). Upadacitinib 30 mg showed a higher response rate than placebo for BICLA achievement at week 48 (53.2% vs 25.3%; treatment difference adjusted for strata: 30.8%; p < 0.001). Upadacitinib 30 mg showed a higher response rate than placebo for SRI - 4 achievement at week 48 (45.2% vs 32.0%; treatment difference adjusted for strata: 13.4%; p = 0.075). Upadacitinib 30 mg also showed a reduction in relapse and a delay in the time to first relapse compared to placebo. Overall, the data as a whole suggest that upadacitinib 30 mg QD provides additional benefits over basal drug therapy alone in subjects with moderate to severe SLE.

[0226]

Table 8

[0227] Exposure - response for efficacy evaluation items At week 48, there was a clear exposure - response relationship for upadacitinib with SRI - 4 and steroid dose ≤10 mg prednisone equivalent, SRI - 4, and BICLA (p < 0.05). Upadacitinib C at week 48 avgQuartile plots of the relationship between and the efficacy response are shown in Figures 10A - 10C (SRI - 4 and steroid dose ≤ 10 mg prednisone equivalent, SRI - 4, and BICLA, respectively). Based on logistic regression analysis, there is an exposure - response relationship between upadacitinib and each of the efficacy evaluation items at week 48 (p < 0.05) (SRI - 4 and steroid dose ≤ 10 mg prednisone equivalent QD, BICLA, and SRI - 4).

[0228] The median (90% prediction interval) percentages estimated from the exposure - response models of subjects who achieved SRI - 4 and steroid dose ≤ 10 mg prednisone equivalent QD, BICLA, and SRI - 4 at week 48 are 50% (41% - 58%), 56% (47% - 64%), and 54% (45% - 61%) for upadacitinib 30 mg UPA QD, compared with 34% (25% - 44%), 25% (18% - 34%), and 32% (24% - 42%) for placebo, respectively. The upadacitinib 30 mg QD dose is predicted to result in an 8% - 16% higher efficacy response compared with 15 mg QD.

[0229] Biomarker The trends observed at week 24 were confirmed by pre - defined biomarker analysis at week 48. That is, treatment with upadacitinib 30 mg QD resulted in a significant and early decrease in anti - dsDNA autoantibodies (a known effect of JAK inhibitors), followed by a progressive normalization of complement C3 and C4 levels.

Claims

1. A pharmaceutical composition comprising upadacitinib for use in a method of treating a human patient having moderate to severe active systemic lupus erythematosus, the method comprising orally administering 15 mg of upadacitinib to the patient once daily.

2. The pharmaceutical composition according to claim 1, wherein the method results in a BILAG-based lupus combination evaluation (BICLA) response 52 weeks after the first daily dose.

3. The pharmaceutical composition according to claim 1, wherein the method produces a BILAG-based lupus combination evaluation (BICLA) response 48 weeks after the first daily dose.

4. The pharmaceutical composition according to claim 1, wherein the method results in a BILAG-based lupus combination evaluation (BICLA) response 24 weeks after the first daily dose.

5. The pharmaceutical composition according to claim 1, wherein the method produces a BILAG-based lupus combination evaluation (BICLA) response 20 weeks after the first daily dose.

6. The pharmaceutical composition according to claim 1, wherein the method produces a BILAG-based lupus combination evaluation (BICLA) response 16 weeks after the first daily dose.

7. The pharmaceutical composition according to claim 1, wherein the method produces a BILAG-based lupus combination evaluation (BICLA) response 12 weeks after the first daily dose.

8. The pharmaceutical composition according to claim 1, wherein the method produces a BILAG-based lupus combination evaluation (BICLA) response eight weeks after the first daily dose.

9. The pharmaceutical composition according to claim 1, wherein the method produces a BILAG-based lupus combination evaluation (BICLA) response four weeks after the first daily dose.

Images