Treatment of Lupus

Abstract

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

Description

[Background technology]

[0001] 1. Background 1.1. Systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE) is a chronic, multisystem, disabling autoimmune rheumatic disease of unknown etiology. There is a substantial unmet medical need in the treatment of SLE, especially in subjects with moderate or severe disease. In many subjects, the long-term prognosis remains poor.

[0002] A significant challenge associated with the treatment of SLE is the heterogeneous clinical manifestations of the disease. 1 In SLE, any organ may be affected, most frequently the skin, joints, and kidneys. 2~4 Inadequate disease control leads to progressive organ damage, poor quality of life, and increased mortality; approximately half of all patients with SLE develop organ damage within 10 years of diagnosis. 5、6 There remains a need for medical interventions that improve SLE disease activity across multiple organ systems.

[0003] Clinical manifestations of SLE include, but are not limited to, constitutional symptoms, alopecia, rash, serositis, arthritis, nephritis, vasculitis, lymphadenopathy, splenomegaly, hemolytic anemia, cognitive impairment, and other nervous system disorders. Increased hospitalizations and side effects of medications including chronic oral corticosteroids (OCS) and other immunosuppressive therapies increase the disease burden in SLE. 7~9 .

[0004] All of the currently used therapies for the treatment of SLE have well-known adverse effect profiles, and there is a medical need to identify new targeted therapies, especially agents that may reduce the need for corticosteroids and cytotoxic agents. Within about 50 years of hydroxychloroquine being approved for use in discoid lupus and SLE, only one new treatment for SLE (belimumab) has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). However, belimumab is not approved everywhere and uptake is limited. Many of the drugs currently used to treat SLE, such as azathioprine, cyclophosphamide, and mycophenolate mofetil / mycophenolic acid, are not approved for the disease. Furthermore, all of these drugs have well-documented safety issues and are not effective in all patients for all manifestations of lupus. Antimalarials (e.g., hydroxychloroquine) and corticosteroids may be used to control joint pain, arthritis, and rashes. Other treatments include nonsteroidal anti-inflammatory drugs (NSAIDs); analgesics for fever, joint pain, and arthritis; and topical sunscreens to minimize photosensitivity. It is often difficult to reduce subjects with moderate or severe disease from corticosteroids completely, which can cause long-term morbidity and contribute to premature cardiovascular mortality. 8、10 Long-term use of even small daily doses of 5 to 10 mg of prednisone carries an increased risk of side effects such as cataracts, osteoporosis, and coronary artery disease. 8 .

[0005] The clinical development of new drugs is a lengthy, costly process with a low chance of success. Of the molecules that make it into clinical development, fewer than 10% are ultimately approved by health regulators. 11 Moreover, early clinical development of biological therapeutics takes much longer than that of small molecules.

[0006] Phase II trials are performed in a small number of volunteers with the disease of interest. They are designed to test safety, pharmacokinetics, and pharmacodynamics. Phase II trials may provide preliminary evidence of drug efficacy. However, the small number of participants and major safety concerns in Phase II trials usually limit its ability to establish efficacy. Phase III trials are required to demonstrate efficacy and safety of the clinical candidate. Crucially, many clinical candidates fail in Phase III even if they show promise in Phase II. More than 90% of new therapeutics that enter Phase I trials fail during clinical development, mainly due to failures in efficacy or safety. Following Phase II success, the probability of success in Phase III is less than 50%. 12 .

[0007] The process of drug development is particularly challenging for SLE because it is a particularly complex and poorly understood disease. Not only is our understanding of the genetics of SLE underdeveloped, but compared with other diseases, our insight into the pathogenesis of most clinical symptoms is still relatively limited.

[0008] The complexity of SLE presents a challenge for the development of new therapeutics, with a large heterogeneity in the patient population. 13 This makes protocol design for clinical trials in SLE, e.g., regarding inclusion criteria and selection of primary and secondary endpoints, even more difficult. It is even more difficult to predict the disease course in each patient. This inevitably increases the background noise that reduces the statistical power of the clinical trial. The high placebo response rate limits the extent to which a tested new drug can show an efficacy signal, making the conduct and interpretation of clinical trials even more difficult.

[0009] Due to the difficulties in developing effective therapeutics for SLE, the failure rate of therapeutics is even higher within this area in clinical trials compared to therapeutics for other indications. Thus, the development of new therapeutics for the treatment of SLE has proven extremely difficult. There are many examples of clinical candidates that showed promise in Phase II but failed to demonstrate efficacy and / or safety in subsequent Phase or Phase III trials.

[0010] There remains an unmet clinical need in SLE, especially in patients who are resistant to conventional immunosuppressive therapy and immunomodulatory agents. There is also a subset of SLE patients whose disease remains refractory to existing treatments (refractory disease, RD). Morbidity and mortality from active SLE remain high in such patients, and the search for safe and effective therapies to treat them is ongoing.

[0011] 1.2. Steroids Glucocorticoids remain the primary treatment for SLE, with doses varying depending on the severity of disease manifestations. There is no "safe" dose of oral glucocorticoids with respect to the risk of developing glucocorticoid-induced disorders such as cataracts, osteoporosis, and coronary artery disease, and while exposure to large amounts of glucocorticoids has been shown to be associated with increased overall incidence of disorders, much lower to moderate doses may also be associated with increased disorders.

[0012] Glucocorticoids are the most commonly used therapy for patients with SLE based on their immunosuppressant and anti-inflammatory properties, reducing disease activity and preventing flares. Up to 80% of patients with SLE are exposed to glucocorticoids, and the majority are treated long-term. Although it may provide short-term efficacy, frequent or sustained use of oral glucocorticoid therapy carries a significant burden of toxicity that may independently contribute to morbidity and mortality and negatively impact health-related quality of life. Therefore, novel effective long-term treatments for SLE are needed to reduce both overall disease activity and glucocorticoid use.

[0013] Type I IFN and Anifrolumab Anifrolumab (MEDI-546) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) against subunit 1 of the type I interferon receptor (IFNAR1). It is composed of two identical light chains and two identical heavy chains with a total molecular weight of approximately 148 kDa. Anifrolumab inhibits the binding of type I IFNs to the type I interferon receptor (IFNAR) and inhibits the biological activity of all type I IFNs.

[0014] Type I interferons (IFNs) are cytokines that have been implicated in the pathogenesis of SLE based on the finding that IFN-stimulated gene expression is increased in most patients with SLE. In the phase 3 TULIP-2 trial of anifrolumab in patients with moderate-to-severe SLE, treatment response (assessed using the British Isles Lupus Assessment Group [BILAG]-based Combined Lupus Assessment [BICLA]) was achieved by significantly more patients receiving anifrolumab compared with placebo at week 52. 14 Results similar to this composite endpoint were seen in the phase 2 MUSE and phase 3 TULIP-1 trials. 15、16 .

[0015] 1.4. Conclusion There is a large unmet need for SLE therapies with better efficacy and safety profiles than currently available therapies 17、18 As mentioned above, a large number and a wide range of different biologics have been proposed and undergoing clinical trials, but these trials have failed to meet meaningful clinical endpoints in pivotal trials. Early promise in phase II of many proposed therapeutics did not translate into significant and meaningful clinical benefit in later pivotal phase III clinical trials. Furthermore, there is a need for SLE therapies that are effective across multiple organ domains. Moreover, even the treatments approved for SLE do not tolerate steroid tapering in many patients. Furthermore, there is a subset of patients with refractory disease, i.e., with moderate-to-severe SLE despite treatment with standard therapies. Thus, there remains a need for safe and effective treatments for SLE that have proven clinical benefit, for example, in phase III double-blind randomized placebo-controlled trials. 19 .

[0016] The present invention solves one or more of the problems set forth above. Summary of the Invention [Means for solving the problem]

[0017] 2. Overview The present invention relates to a method of treating systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject a type I IFN receptor (IFNAR1) inhibitor, wherein the method reduces SLE activity in the subject compared to the SLE activity in the subject prior to treatment with the IFNAR1 inhibitor, and the subject has been pre-treated with one or more immunomodulatory agents prior to administration of the IFNAR1 inhibitor.

[0018] The present invention also relates to a method for identifying a subject suitable for treatment with an IFNAR1 inhibitor, the method comprising identifying a subject who has been pretreated with one or more immunomodulatory agents prior to administration of the IFNAR1 inhibitor, and administering the IFNAR1 inhibitor to the subject.

[0019] The present invention also relates to a method of treating SLE in a subject in need thereof, comprising administering an IFNAR1 inhibitor to the subject, wherein the method reduces SLE activity in the subject compared to the SLE activity in the subject prior to treatment with the IFNAR1 inhibitor, and the subject has severe SLE, established SLE and / or refractory SLE.

[0020] The present invention is supported by data presented herein for the first time from two Phase III multicenter, multinational, randomized, double-blind, placebo-controlled clinical trials (NCT02446899 and NCT02962960) demonstrating, inter alia, that an IFNAR1 inhibitor (anifrolumab) treats SLE in patients previously treated with one or more immunomodulatory biologics (the SLE disease in the subject is not controlled). Treatment with anifrolumab is more effective in these patients than in biologic-naive patients. The present invention is also supported by data presented herein for the first time demonstrating that an IFNAR1 inhibitor treats SLE in subjects with moderate to severe SLE (i.e., refractory disease) despite standard therapy. [Brief description of the drawings]

[0021] [Figure 1] IFN score distribution [Diagram 2]Prior use of biologic immunomodulators. Figure 2A: Antineoplastic and immunomodulators. Figure 2A: Musculoskeletal. Percentages are based on all patients in the full analysis set within each study and treatment group. All medications are coded using WHO-DD version 2019SEP01 B3. Prior use: last day is prior to administration of investigational drug dose (anifrolumab) on Day 1. Biologic immunomodulators are identified using (ATC Level 4 and Preferred Terms: L04AA = selective immunosuppressants excluding preferred terms mycophenolate mofetil, mycophenolate mofetil hydrochloride, mycophenolate sodium, mycophenolic acid, apremilast, baricitinib, iguratimod and leflunomide) or (ATC Level 3: L01X = other antitumor agents) or (Preferred Terms: adalimumab, blissibimod, etanercept, infliximab, rontalizumab, sifalimumab, tabalumab and ustekinumab). The Phase III pool includes Study 04 (D3461C00004) and Study 05 (D3461C00005) (excluding the 150 mg group from Study 05). ATC: Anatomical Therapeutic Chemistry; N: Number of patients in treatment group; WHO-DD World Health Organization Drug Dictionary. [Diagram 3] Baseline demographics, disease characteristics, and SLE treatments in biologic-experienced and biologic-naive patients with SLE pooled from the TULIP-1 and TULIP-2 studies. Baseline demographics, disease characteristics, and non-biologic SLE treatments were generally similar between groups. [Figure 4] Forest plot of efficacy endpoints in biologic-experienced and biologic-naive patients with SLE in pooled data from the TULIP-1 and TULIP-2 trials. Anifrolumab was associated with greater treatment differences than placebo (Δ) in biologic-experienced versus biologic-naive patients across endpoints including BICLA response (Δ=19.4 vs. Δ=16.6), SRI(4) response (Δ=25.3 vs. Δ=9.1), and oral GC taper (Δ=24.7 vs. Δ=17.5). [Diagram 5] BICLA response rate at week 52 by prior use of abatacept, stratified Cochran-Mantel-Haenszel method. Figure 5A: Prior use of abatacept. Figure 5B: No prior use of abatacept. Baseline is defined as the last measurement prior to randomization and study drug dose administration on Day 1. The Phase III pool includes Study 04 (D3461C00004) and Study 05 (D3461C00005) (excluding the 150 mg group from Study 05). BICLA response is defined as a reduction in all baseline BILAG-2004 A and B scores and no deterioration in other organ systems, no deterioration from baseline in the SLEDAI-2K, and no increase of >=0.030 points on a 3-point PGA VAS from baseline. Subjects treated with restricted medications above the protocol-allowed threshold and subjects who discontinued study drug (anifrolumab) are considered non-responders. Responder / non-responder rates (percentages), differences in estimates and associated 95% CIs are calculated using the CMH method stratified by the stratification factors SLEDAI-2K score at screening, OCS dose at day 1 and type I IFN gene signature test result at screening. In pooled analyses, an additional stratification factor is added for study (Study 04 vs. Study 05). Nominal p-values ​​presented are based on this CMH model. Prior use: last day of therapy is prior to study drug dose administration on day 1. [Figure 6]BICLA response rate at week 52 by prior use of belimumab, stratified Cochran-Mantel-Haenszel method. Figure 6A: Prior use of belimumab. Figure 6B: No prior use of belimumab. Baseline is defined as the last measurement prior to randomization and study drug dose administration on Day 1. The Phase III pool includes Study 04 (D3461C00004) and Study 05 (D3461C00005) (excluding the 150 mg group from Study 05). BICLA response is defined as a reduction in all baseline BILAG-2004 A and B scores and no deterioration in other organ systems, no deterioration from baseline in SLEDAI-2K, and no increase >= 0.030 points on a 3-point PGA VAS from baseline. Subjects treated with restricted medications above the protocol-allowed threshold and subjects who discontinued study drug (anifrolumab) are considered non-responders. Responder / non-responder rates (percentages), differences in estimates and associated 95% CIs are calculated using the CMH method stratified by the stratification factors SLEDAI-2K score at screening, OCS dose at day 1 and type I IFN gene signature test result at screening. In pooled analyses, an additional stratification factor is added for study (Study 04 vs. Study 05). Nominal p-values ​​presented are based on this CMH model. Prior use: last day of therapy is prior to study drug dose administration on day 1. [Figure 7]BICLA response rate at week 52 by prior use of epratuzumab, stratified Cochran-Mantel-Haenszel method. Figure 7A: Prior use of epratuzumab. Figure 7B: No prior use of epratuzumab. Baseline is defined as the last measurement prior to randomization and study drug dose administration on Day 1. The Phase III pool includes Study 04 (D3461C00004) and Study 05 (D3461C00005) (excluding the 150 mg group from Study 05). BICLA response is defined as a reduction in all baseline BILAG-2004 A and B scores and no deterioration in other organ systems, no deterioration from baseline in the SLEDAI-2K, and no increase from baseline in the PGA VAS of >=0.030 points. Subjects treated with restricted medications above the protocol-allowed threshold and subjects who discontinued study drug (anifrolumab) are considered non-responders. Responder / non-responder rates (percentages), differences in estimates and associated 95% CIs are calculated using the CMH method stratified by the stratification factors SLEDAI-2K score at screening, OCS dose at day 1 and type I IFN gene signature test result at screening. In pooled analyses, an additional stratification factor is added for study (study 04 vs. study 05). Nominal p-values ​​presented are based on this CMH model. Prior use: last day of therapy is prior to study drug dose administration on day 1. [Figure 8]BICLA response rate at week 52 by prior use of rituximab, stratified Cochran-Mantel-Haenszel method. Figure 8A: Prior use of rituximab. Figure 8B: No prior use of rituximab. Baseline is defined as the last measurement prior to randomization and study drug dose administration on Day 1. The Phase III pool includes Study 04 (D3461C00004) and Study 05 (D3461C00005) (excluding the 150 mg group from Study 05). BICLA response is defined as a reduction in all baseline BILAG-2004 A and B scores and no deterioration in other organ systems, no deterioration from baseline in SLEDAI-2K, and no increase >= 0.030 points on a 3-point PGA VAS from baseline. Subjects treated with restricted medications above the protocol-allowed threshold and subjects who discontinued study drug (anifrolumab) are considered non-responders. Responder / non-responder rates (percentages), differences in estimates and associated 95% CIs are calculated using the CMH method stratified by the stratification factors SLEDAI-2K score at screening, OCS dose at day 1 and type I IFN gene signature test result at screening. In pooled analyses, an additional stratification factor is added for study (Study 04 vs. Study 05). Nominal p-values ​​presented are based on this CMH model. Prior use: last day of therapy is prior to study drug dose administration on day 1. [Figure 9]BICLA response rate at week 52 by prior use of sifalimumab, stratified Cochran-Mantel-Haenszel method. Figure 9A: Prior use of sifalimumab. Figure 9B: No prior use of sifalimumab. Baseline is defined as the last measurement prior to randomization and study drug dose administration on Day 1. The Phase III pool includes Study 04 (D3461C00004) and Study 05 (D3461C00005) (excluding the 150 mg group from Study 05). BICLA response is defined as a reduction in all baseline BILAG-2004 A and B scores and no deterioration in other organ systems, no deterioration from baseline in SLEDAI-2K, and no increase from baseline in the 3-point PGA VAS >= 0.030 points. Subjects treated with restricted medications above the protocol-allowed threshold and subjects who discontinued study drug (anifrolumab) are considered non-responders. Responder / non-responder rates (percentages), differences in estimates and associated 95% CIs are calculated using the CMH method stratified by the stratification factors SLEDAI-2K score at screening, OCS dose at day 1 and type I IFN gene signature test result at screening. In pooled analyses, an additional stratification factor is added for study (study 04 vs. study 05). Nominal p-values ​​presented are based on this CMH model. Prior use: last day of therapy is prior to study drug dose administration on day 1. [Figure 10]BICLA response rate at week 52 by prior use of tabalumab, stratified Cochran-Mantel-Haenszel method. Figure 10A: Prior use of tabalumab. Figure 10B: No prior use of tabalumab. Baseline is defined as the last measurement prior to randomization and study drug dose administration on Day 1. The Phase III pool includes Study 04 (D3461C00004) and Study 05 (D3461C00005) (excluding the 150 mg group from Study 05). BICLA response is defined as a reduction in all baseline BILAG-2004 A and B scores and no deterioration in other organ systems, no deterioration from baseline in SLEDAI-2K, and no increase >= 0.030 points on a 3-point PGA VAS from baseline. Subjects treated with restricted medications above the protocol-allowed threshold and subjects who discontinued study drug (anifrolumab) are considered non-responders. Responder / non-responder rates (percentages), differences in estimates and associated 95% CIs are calculated using the CMH method stratified by the stratification factors SLEDAI-2K score at screening, OCS dose at day 1 and type I IFN gene signature test result at screening. In pooled analyses, an additional stratification factor is added for study (Study 04 vs. Study 05). Nominal p-values ​​presented are based on this CMH model. Prior use: last day of therapy is prior to study drug dose administration on day 1. [Figure 11]BICLA response rate at week 52 by prior use of TNF inhibitors, stratified Cochran-Mantel-Haenszel method. Figure 11A: Prior use of TNF inhibitors. Figure 11B: No prior use of TNF inhibitors. Baseline is defined as the last measurement prior to randomization and study drug dose administration on Day 1. The Phase III pool includes Study 04 (D3461C00004) and Study 05 (D3461C00005) (excluding the 150 mg group from Study 05). BICLA response is defined as a reduction in all baseline BILAG-2004 A and B scores and no deterioration in other organ systems, no deterioration from baseline in SLEDAI-2K, and no increase >= 0.030 points on a 3-point PGA VAS from baseline. Subjects treated with restricted medications above the protocol-allowed threshold and subjects who discontinued study drug (anifrolumab) are considered non-responders. Responder / non-responder rates (percentages), differences in estimates and associated 95% CIs are calculated using the CMH method stratified by the stratification factors SLEDAI-2K score at screening, OCS dose at day 1 and type I IFN gene signature test result at screening. In the pooled analysis, an additional stratification factor is added for study (study 04 vs. study 05). Nominal p-values ​​presented are based on this CMH model. Prior use: last day of therapy is prior to study drug dose administration on day 1. TNF inhibitors are identified using the preferred terms: adalimumab, etanercept, infliximab. [Figure 12] Safety in biologic-experienced and biologic-naive patients with SLE in pooled data from the TULIP-1 and TULIP-2 trials. The incidence of serious adverse events was higher in biologic-experienced versus biologic-naive patients with anifrolumab and placebo. [Figure 13]Mean anifrolumab serum concentration-time profile. Figure 13A: Study MI-CP180 in SSc-mean anifrolumab serum concentration-time profile after single IV administration. Data represent + / -SD. Mean data below the LLOQ are not plotted. IV, intravenous; LLOQ, lower limit of quantification; MEDI 546, anifrolumab; n, number of patients in subgroup; SSc, systemic sclerosis. Figure 13B: Study 06 in healthy volunteers-mean anifrolumab serum concentration-time profile after single SC and IV administration. Samples with actual collection times deviating from the nominal collection times by more than 10% were excluded from the average. IV, intravenous; N, number of subjects; SC, subcutaneous. [Figure 14] Study design and results of Study 08. Figure 14A: Phase II study design of SC anifrolumab in patients with SLE. Study 08 (NCT02962960) evaluated the effect of two biweekly anifrolumab doses. Figure 14B: Mean serum concentrations of anifrolumab over time. Figure 14C: Anifrolumab neutralization of type I IFN gene signature. [Figure 15] Calculated median AUC ratios (SC / IV). Figure 15A: Median calculated AUC ratios (SC / IV) from 0 to 52 weeks at various SC doses. Median calculated AUC ratios (SC / IV) based on estimated bioavailability from Study 06 from 0 to 52 weeks (where the SC doses are 75 mg (+ symbol), 90 mg (open squares), 105 mg (circles), 120 mg (triangles) or 135 mg (closed squares). The SC doses here are administered once every 7 days (QW); the IV doses are administered once every 4 weeks (Q4W) at a dose of 300 mg. Based on AUC, both 90 and 105 mg SC QW appear to be equivalent to 300 mg IV. Figure 15B: Calculated median AUC ratios (SC / IV) for 90 mg and 105 mg SC QW. Calculated median AUC ratios (SC / IV) based on estimated bioavailabilities that were approximately 7% lower than the bioavailabilities calculated from Study 06 from Weeks 0 to 52 (subcutaneous doses were either 90 mg SC QW or 105 mg SC). [Figure 16]Anifrolumab concentrations over time at different doses. Figure 16A: Plots showing the (calculated) trough plasma concentrations of anifrolumab in patients receiving either (i) 105 mg anifrolumab subcutaneously every 7 days (straight line), (ii) 300 mg anifrolumab intravenously every 4 weeks (lower dotted line), or (ii) 1000 mg anifrolumab intravenously every 4 weeks (upper dotted line). The shaded region represents the 5th to 95th percentiles of the 300 mg IV Q4W dose. Figure 16B: Anifrolumab trough concentrations in SLE subjects with high IFNGS. Calculated trough concentrations of anifrolumab in plasma of IFNGS high patients after dosing are as follows: (i) 300 mg IV Q4W; (ii) 90 mg SC QW; (iii) 105 mg SC QW; (iv) 135 mg SC QW; (v) 1000 mg IV Q4W. SC = subcutaneous. Based on trough, both 90 mg and 105 mg SC QW were predicted to have greater PD suppression than 300 mg IV. [Figure 17] Positive exposure-BICLA correlation observed in TULIP 1 and TULIP 2 in IFNGS-high patients. Figure 17A: TULIP I for placebo, anifrolumab 150 mg and anifrolumab 300 mg. Figure 17B: TULIP II for placebo and 300 mg. [Figure 18] BICLA dose response. Figure 18A: Dose response curve (probability of meeting BICLA response criteria (in IFNGS high patients) for Anifrolumab Cave over 52 weeks) shows predicted mean (grey line) and 95% confidence interval (CI) (dashed area). Patients are grouped by dose (150 mg, n=62; 300 mg, n=242; and 1000 mg). Figure 18B: Predicted PK and efficacy at different SC doses. Probability of meeting BICLA (in IFNGS high patients) for weekly subcutaneous doses starting at 105 mg up to 150 mg. Assumptions for generating the data include no dose delays / interruptions. [Figure 19] Ctrough after thigh injection compared to abdominal injection. Figure 19A: 150mg SC Q2W. Figure 19B: 300mg SC Q2W. [Figure 20] Predicted exposure based on 81-87% bioavailability and preliminary PK modeling. Median anifrolumab Cave ratios of 90-150 mg SC QW to 300 mg Q4W predicted based on preliminary PK modeling and bioavailability assumptions. [Figure 21] Anifrolumab Cave in IFNGS high patients over 52 weeks at different SC and IV doses. Figure 21A: 105mg SC QW. Figure 21B: 120mg SC QW. Figure 21C: Overlap with 1000mg IV Q4W. [Figure 22] Cave median ratios for SC QW vs. 300 mg IV Q4W. Figure 22A: Assumes 81% bioavailability. Figure 22B: Assumes 70% bioavailability. [Figure 23] Mean Anifrolumab Concentration vs. Herpes Zoster Incidence. Herpes Zoster Incidence (%) in Study 1013 patients receiving placebo, 300 mg IV anifrolumab, or 1000 mg IV anifrolumab. [Figure 24]Baseline demographics, SLE disease characteristics, and treatments in pooled data from the TULI P-1 and TULIP-2 studies. Figure 24A: Baseline demographics in pooled data from TULIP-1 and TULIP-2. Figure 24B: Baseline disease characteristics in pooled data from TULIP-1 and TULIP-2. Figure 24C: Baseline SLE treatments in pooled data from TULIP-1 and TULIP-2. Patients with established disease versus patients with early stage disease were more likely to have a high IFN gene signature (IFNGS) (83.5% vs. 78.8%), anti-dsDNA antibody-positive (45.6% vs. 38.6%), low complement 4 (C4) (24.7% vs. 16.7%), ≧1 BILAG-2004A item (49.7% vs. 43.9%), and a higher mean global SDI score (0.7 vs. 0.1). Patients with established disease versus those with emerging disease were more likely to have received oral glucocorticoids (GCs) (83.2% vs. 76.5%) and / or immunosuppressants (49.8% vs. 40.9%) but not antimalarials (69.5% vs. 78.0%). C, complement; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; PGA, physician's global assessment; SD, standard deviation; SDI, SLICC / ACR Damage Index. IST, immunosuppressants. aImmunosuppressants: azathioprine, methotrexate, mycophenolate mofetil, mycophenolic acid, and mizoribine. [Diagram 25] Anifrolumab treatment of established disease. Figure 25A: Proportion of patients with BICLA response at week 52 in TULIP-1 and TULIP-2 studies. Figure 25B: BILAG-2004 organ comorbidity scores at baseline by disease duration: Patients are based on all patients in each disease duration group treated with either anifrolumab 300 mg or placebo. Organ domains (gastrointestinal, ophthalmic, hematological) were not included on the graphs because 1% of patients in either disease duration group had a BILAG-2004 A or B score. The phase 3 pool includes TULIP-1 and TULIP-2 (excluding the anifrolumab 150 mg group from TULIP-1). [Figure 26] Forest plot of BICLA response according to baseline standard therapy in patients with SLE in TULIP-1 and TULIP-2. BICLA, BILAG-based composite lupus assessment; CI, confidence interval; GC, glucocorticoids; IFNGS, interferon gene signature; n, number of responders; N, number of patients in group; PGA, physician's global assessment. Required BICLA response: reduction in all baseline BILAG-2004 A or new BILAG-2004 B0 of ≧2; no increase from baseline in SLEDAI-2K score; no increase from baseline in PGA score of ≧0.3 points; no use of restricted medications above protocol-allowed thresholds, and no interruption of study drug. Response rates, response rate differences, and associated 95% Cis were calculated using the Cochran-Mantel-Haenszel method stratified by the following stratification factors: SLEDAI-2K score at screening (<10 vs. ≥10), baseline oral GC dose (<10 vs. ≥10 mg / day prednisone or equivalent), IFNGS status (high vs. low), and study. aPrednisone or equivalent. bImmunosuppressants were ≥1 or were: azathioprine, methotrexate, mycophenolate, or mycophenolate. [Figure 27] Delivery Devices. Anifrolumab is administered by injection devices [1][9] such as a prefilled syringe (PFS) (Figure 27A) or an autoinjector (AI) (Figure 27B). [Figure 28] Autoinjector. An autoinjector for administering anifrolumab or a functional variant thereof in exploded (FIG. 28A), assembled (FIG. 28B) and bulk filled (FIG. 28C) views. [Figure 29] Pre-filled syringe with accessories. Pre-filled syringe with accessories (APFS) for anifrolumab or its functional variants. The basic tube is shown in assembled form (FIG. 29A) and exploded view (FIG. 29B). The APFS with its additional parts is shown in assembled form (FIG. 29C) and exploded view (FIG. 29D). [Diagram 30] Packaging for the delivery device. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] 4. Detailed Description 4.1. Methods for Treating Systemic Lupus Erythematosus (SLE) The present invention relates to a method of treating systemic lupus erythematosus (SLE) in a subject in need thereof, comprising administering to the subject a type I IFN receptor (IFNAR1) inhibitor, wherein the method reduces SLE activity in the subject compared to the SLE activity in the subject prior to treatment with the IFNAR1 inhibitor, and the subject has been pretreated with one or more immunomodulatory agents prior to administration of the IFNAR1 inhibitor. SLE disease activity can be measured, for example, using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) or a combination of the SLE and IFNAR1 inhibitors. 20 , Systemic Lupus International Joint Clinical Committee / American College of Rheumatology Damage Index 20 , Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) 21 , British Isles Lupus Assessment Group-2004 Index 22、23 , or SLE (ACR 1997 24 and / or EULAR / ACR 2019 25 (ACR classification criteria for SLE). The reduction in SLE disease activity in a subject may include a BILAG-based Composite Lupus Assessment (BICLA) response in the subject. The reduction in SLE disease activity in a subject may include an SRI(4) response in the subject. The reduction in SLE disease activity in a subject may include a reduction in the annualized relapse rate in the subject.

[0023] The ability of an IFNAR1 inhibitor to reduce SLE disease activity in subjects refractory to treatment with another immunomodulatory agent or in subjects who have relapsed during or after treatment with one or more immunomodulatory agents may be demonstrated in a Phase III clinical trial, optionally a multicenter, multinational, randomized, double-blind, placebo-controlled trial.

[0024] 4.2. Methods for identifying subjects The present invention also relates to a method for identifying a subject suitable for treatment with an IFNAR1 inhibitor, comprising identifying a subject who has been pretreated with one or more immunomodulators prior to administration of an IFNAR1 inhibitor, and administering an IFNAR1 inhibitor to the subject. The method may comprise identifying a subject as having severe SLE, refractory SLE and / or established SLE disease activity prior to treatment with an IFNAR1 inhibitor. Severe SLE may be identified as a SLEDAI-2K score of ≧10. Severe SLE may be identified as an A BLIAG-2004 organ score of ≧1. Severe SLE may be identified as a CLASI activity score of ≧10. Severe SLE may be identified as swollen joints of ≧6 and tender joints of ≧6. Severe SLE may be identified as a SDI (SLICC / ACR Damage Index) global score of ≧1. Severe SLE may be defined as an A BLIAG-2004 organ score of ≧1, a CLASI activity score of ≧10, swollen and tender joints of ≧6, and / or an SDI global score of ≧1. Refractory SLE may be identified as severe SLE despite standard treatment with oral glucocorticoids, antimalarials, NSAIDs, and / or one or more immunosuppressants. The one or more immunosuppressants may include azathioprine, methotrexate, mycophenolate.

[0025] The method may include identifying subjects who have been diagnosed with SLE at least 2 years prior to treatment with an IFNAR1 inhibitor. The method may include identifying subjects with high IFN gene signature, subjects who are anti-dsDNA antibody positive, subjects with low complement 4 (C4), subjects with a BILAG-2004 A item of ≧1, and / or subjects with a high average global SDI score. Low complement may be defined as less than about 0.1 g / L of C4 in blood and / or less than about 0.9 g / L of C3 in blood.

[0026] Immunomodulators The one or more immunomodulatory agents may include a biologic. The one or more immunomodulatory agents may include abatacept, atacicept, belimumab, epratuzumab, rituximab, tabalumab, sifalimumab, adalimumab, and / or infliximab. The one or more immunomodulatory agents may include a CTLA-4 fusion protein. The CTLA-4 fusion protein may be abatacept or a functional equivalent thereof. The CTLA-4 fusion protein may be abatacept or a functional equivalent thereof. The one or more immunomodulatory agents may include an anti-BAFF antibody. The anti-BAFF antibody may be belimumab or a functional equivalent thereof. The one or more immunomodulatory agents may include an anti-CD20 antibody. The anti-CD20 antibody may be rituximab or a functional equivalent thereof. The one or more immunomodulatory agents may include an anti-type I IFN antibody. The anti-type I IFN antibody may be sifalimumab or a functional equivalent thereof. The one or more immunomodulatory agents include belimumab and rituximab. The one or more immunomodulatory agents may not include an IFNAR1 inhibitor.

[0027] The subject may have been pretreated with an immunomodulatory agent at least 3 months prior to treatment with an IFNAR1 inhibitor. The subject may have been pretreated with an immunomodulatory agent at least 2 months prior to treatment with an IFNAR1 inhibitor. The subject may have been pretreated with an immunomodulatory agent 1 month prior to treatment with an IFNAR1 inhibitor.

[0028] IFNAR1 inhibitors "Type I interferon receptor inhibitor" refers to a molecule that is antagonistic to the receptor of type I interferon ligands, such as interferon-α and interferon-β. Such inhibitors, after administration to a patient, provide a reduction in the expression of at least one (preferably at least four) pharmacodynamic (PD) marker gene, preferably selected from the group consisting of IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPST1, IFIT3, LY6E, OAS2, PLSCR1, SIGLECl, USP18, RTP4, and DNAPTP6. The at least four genes may suitably be IFI27, IFI44, IFI44L, and RSAD2. The "type I interferon receptor" is preferably the interferon α / β receptor (IFNAR).

[0029] For example, a type I interferon receptor inhibitor can be an antibody or antigen-binding fragment thereof that inhibits type I IFN activity (by inhibiting the receptor). An example of a suitable antibody or antigen-binding fragment thereof (that inhibits type I IFN activity) is an interferon-α / β receptor (IFNAR) antagonist. A type I interferon receptor inhibitor can be an antibody or antigen-binding fragment thereof that inhibits type I IFN activity. Additionally or alternatively, a type I interferon receptor inhibitor can be a small molecule inhibitor of the type I interferon receptor (e.g., that pharmacologically inhibits type I interferon receptor activity).

[0030] The IFNAR1 inhibitor can be a human monoclonal antibody specific for IFNAR1. The IFNAR1 inhibitor can be a modified IgG1 class human monoclonal antibody specific for IFNAR1.

[0031] The antibody may comprise a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:3. The antibody may comprise a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:4. The antibody may comprise a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:5. The antibody may comprise a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence SEQ ID NO:6. The antibody may comprise a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence SEQ ID NO:7. The antibody may comprise a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence SEQ ID NO:8.

[0032] The antibody may comprise a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1. The antibody may comprise a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. The antibody may comprise a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 9. The antibody may comprise a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 10. The antibody may comprise an amino acid substitution of L234F in the Fc region as numbered according to the EU index as set forth in Kabat, said antibody exhibiting reduced affinity for at least one Fc ligand compared to the unmodified antibody. The antibody may comprise a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11. The antibody may comprise a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0033] The antibody may comprise: (a) heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:3; (b) heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:4; (c) heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:5; (d) light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO:6; (b) light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:7; and c) light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:8.

[0034] The antibody may comprise: (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO:11; and (b) a human light chain comprising the amino acid sequence of SEQ ID NO:12.

[0035] The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0036] 4.5. Dosage and Administration The method may include administering an intravenous dose of anifrolumab or a functional variant thereof to a subject. The intravenous dose may be ≧300 mg of anifrolumab or a functional variant thereof. The intravenous dose may be ≦1000 mg. The intravenous dose may be about 300 mg, about 900 mg, or about 1000 mg. The intravenous dose may be administered every four weeks (Q4W).

[0037] The method may include administering a subcutaneous dose of anifrolumab or a functional variant thereof. The subcutaneous dose may be >105 mg and <150 mg of anifrolumab or a functional variant thereof. The subcutaneous dose may be ≦135 mg of anifrolumab or a functional variant thereof. The subcutaneous dose may be about 120 mg. The subcutaneous dose may be administered in a single administration step. The subcutaneous dose may be administered at intervals of 6 to 8 days. The subcutaneous dose may be administered once a week. The subcutaneous dose may have a volume of about 0.5 to about 1 ml. The subcutaneous dose may have a volume of about 0.8 ml.

[0038] The subject can be a patient with a high type I interferon stimulated gene signature (IFNGS) test prior to treatment. The method can include identifying the subject as a patient with a high IFNGS test prior to treatment.

[0039] Many patients with SLE receive corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Anifrolumab allows for tapering (steroid sparing) of corticosteroids (glucocorticoids) in SLE patients. The treatment method or method may include administering a corticosteroid to a subject, optionally the corticosteroid is an oral corticosteroid. The method may include tapering (steroid sparing) a dose of corticosteroid administered to the subject. The method may include administering a first dose of corticosteroid and then administering a second dose of corticosteroid, where the second dose of corticosteroid is less than the first dose of corticosteroid. The second dose of corticosteroid may be equal to or less than about 7.5 mg of prednisone equivalent dose. The second dose of corticosteroid may be equal to or less than 5 mg of prednisone equivalent dose. The method or treatment method may include administering a second dose of the corticosteroid once a day. The first dose of the corticosteroid may be a prednisone equivalent dose of about 10 mg. The method may include tapering the dose of the corticosteroid administered to the patient from 10 mg or more per day to less than 10 mg per day. The method or treatment method may include administering a second dose of the corticosteroid once a day. The method may allow for administration of a reduced dose of the corticosteroid that is maintained for several weeks. The second dose of the corticosteroid may be administered for at least 24 weeks. The second dose of the corticosteroid may be administered for at least 28 weeks.

[0040] 4.6. Steroid Sparing The method may include steroid sparing in the subject, where the dose of steroid administered to the subject is tapered from a pre-sparing dose at baseline to a post-sparing dose. The post-sparing dose may be a prednisone or prednisone equivalent dose of ≦7.5 mg / day. The pre-sparing dose may be a prednisone or prednisone equivalent dose of 20 mg / day. The steroid may include a glucocorticoid. The steroid may include an oral glucocorticoid. Steroids include hydrocortisone, mometasone, fluticasone, fluocinolone acetonide, fluocinolone, flurandrenolone acetonide, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, clocortolone, dihydroxycortisone, alclometasone, amcinonide, diflucortolone valerate, and flucortolone. , fluprednidene, fluandrenolone, fluorometholone, halcinonide, halobetasol, desonide, diflorasone, flurandrenolide, fluocinonide, prednicarbate, desoximetasone, fluprednisolone, prednisone, azelastine, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, halopredone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, prednisolone, prednisolone 21-phosphate, clobetasol propionate, triamcinolone acetonide, or mixtures thereof. The steroid may be prednisone.

[0041] 4.7. Unit Dose The present invention also relates to unit doses for use in the methods of the present invention, the unit dose comprising >105 mg and ≦150 mg of anifrolumab or a functional variant thereof.

[0042] A unit dose may contain ≦135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. A unit dose may contain about 120 mg of anifrolumab or a functional variant thereof. A unit dose may contain 120 mg of anifrolumab or a functional variant thereof. A unit dose may consist essentially of >105 mg and <150 mg of anifrolumab or a functional variant thereof. A unit dose may consist essentially of ≦135 mg of anifrolumab or a functional variant thereof. A unit dose may consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in a unit dose may be about 150 mg / ml. The volume of the unit dose may be less than 1 ml. The volume of the dose or unit dose may be about 0.5 to about 1 ml. The concentration of the unit dose may be about 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose may comprise a formulation of about 150-200 mg / ml anifrolumab or functional variants thereof, about 25-150 mM lysine salt, and uncharged excipients. The unit dose may comprise a formulation of 150-200 mg / ml anifrolumab or functional variants thereof, 25-150 mM lysine salt, and uncharged excipients. The unit dose may comprise a formulation of 25 mM histidine-HCL, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation may have a pH of about 5.9.

[0043] In another aspect, the present invention relates to a method of treating SLE in a subject, comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, wherein weekly administration of the dose provides a subject plasma concentration at least equivalent to that provided by intravenous administration of 300 mg of anifrolumab or a functional variant thereof every 4 weeks. Weekly administration of the dose can provide a subject plasma concentration higher than that provided by intravenous administration of 300 mg of anifrolumab or a functional variant thereof every 4 weeks. Weekly administration of the dose can provide a subject plasma concentration at least equivalent to that provided by intravenous administration of 400 mg of anifrolumab or a functional variant thereof every 4 weeks. The dose can be administered in a single administration step. The dose administered to the subject can be <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject can be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject can be ≦135 mg (i.e., equal to or less than 135 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject can be about 120 mg of anifrolumab or a functional variant thereof.

[0044] Administration of a dose or unit dose may provide a plasma concentration of anifrolumab or functional variants thereof in a subject of ≧10 μg of anifrolumab or functional variants thereof per ml of plasma (i.e., ≧10 μg / ml). Administration of a dose or unit dose may provide a plasma concentration of anifrolumab or functional variants thereof in a subject of about 10-100 μg / ml. Administration of a dose or unit dose may provide a plasma concentration of anifrolumab or functional variants thereof in a subject of about 20-80 μg / ml. Administration of a dose or unit dose may provide a plasma concentration of anifrolumab or functional variants thereof in a subject of about 30-70 μg / ml. Administration of a dose or unit dose may provide a trough concentration of anifrolumab or functional variants thereof in a subject of ≧20 μg / ml (i.e., ≧20 μg / ml). Administration of a dose or unit dose may provide a trough concentration of anifrolumab or functional variants thereof in a subject of ≧30 μg / ml (i.e., 30 μg / ml or more). Administration of a dose or unit dose may provide a trough concentration of anifrolumab or functional variants thereof in a subject of ≧40 μg / ml (i.e., 40 μg / ml or more). Administration of a dose or unit dose may provide a trough concentration of anifrolumab or functional variants thereof in a subject of about 20-100 μg / ml. Administration of a dose or unit dose may provide a trough concentration of anifrolumab or functional variants thereof in a subject of about 30-80 μg / ml. Administration of a dose or unit dose may provide a trough concentration of anifrolumab or functional variants thereof in a subject of about 40-70 μg / ml.

[0045] The dose or unit dose may provide a therapeutic effect in a subject at least equivalent to that provided by administration of an intravenous dose of 300 mg of anifrolumab or a functional variant thereof administered once every four weeks (Q4W). The dose or unit dose may provide a trough concentration of anifrolumab or a functional variant thereof in a subject that is greater than the trough concentration of anifrolumab or a functional variant thereof provided by administration of an intravenous dose of 300 mg of anifrolumab or a functional variant thereof administered once every four weeks (Q4W). The anifrolumab or a functional variant thereof may be included in a pharmaceutical composition. The pharmaceutical composition may include about 150-200 mg / ml of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may include 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may include 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0046] The method of the invention may include administering a dose or unit dose at intervals of 6 to 8 days. The dose or unit dose may be administered once a week (QW). The dose or unit dose may be 120 mg of anifrolumab or a functional variant thereof, and the method includes administering the dose in a single administration step once a week (QW). In other words, the method includes administering 120 mg QW of anifrolumab or a functional variant thereof. The dose or unit dose may be administered once a week for at least about 4 weeks. The dose or unit dose may be administered once a week for at least about 8 weeks. The dose or unit dose may be administered once a week for at least about 12 weeks. The dose or unit dose may be administered once a week for at least about 16 weeks. The dose or unit dose may be administered once a week for at least about 20 weeks. The dose or unit dose may be administered once a week for at least about 24 weeks. The dose or unit dose may be administered once a week for at least about 28 weeks. The dose or unit dose may be administered once a week for at least about 32 weeks. The dose or unit dose may be administered once a week for about 8 weeks. The dose or unit dose may have a volume suitable for delivery in a single subcutaneous administration step. The dose or unit dose may have a volume of about 0.5 to about 1 ml. The dose or unit dose may have a volume of less than 1 ml. The dose or unit dose may have a volume of about 0.8 ml.

[0047] 4.8. Target The subject may be a human subject. The subject may be an adult. The subject may be a patient with an elevated type I IFN gene signature. The subject may be a patient with an elevated type I interferon stimulated gene signature (IFNGS) test prior to administration of the dose or unit dose. The subject may have elevated whole blood genes IFI27, IFI44, IFI44L and RSAD2. The method may include identifying the subject as a patient with an elevated IFNGS test prior to treatment with the dose or unit dose. The method may include measuring the expression of genes IFI27, IFI44, IFI44L and RSAD2 in the whole blood of the subject. The method may include measuring the expression of genes IFI27, IFI44, IFI44L and RSAD2 in the whole blood of the subject by RT-PCR.

[0048] The subject may have moderate to severe SLE prior to treatment with an IFNAR1 inhibitor. Prior to treatment with an IFNAR1 inhibitor, the subject may be refractory to treatment with another immunomodulatory agent or have relapsed during or after treatment with one or more immunomodulatory agents. Prior to treatment with an IFNAR1 inhibitor, the subject may have a SLEDAI-2K score of ≧10 (at least). Prior to treatment with an IFNAR1 inhibitor, the subject may have a CLASI activity score of ≧10 (at least 10). Prior to treatment with an IFNAR1 inhibitor, the subject may have a swollen and tender joint count of ≧6.

[0049] The subjects were those who met the ACR classification criteria for SLE (ACR 1997 24 and / or EULAR / ACR 2019 25 The patient may have moderate to severe SLE as defined by the pulmonary circulation disorder (PWD) or pulmonary edema (PWD).

[0050] Pharmaceutical Compositions The present invention also relates to a pharmaceutical composition for use in a method of treating CLE in a subject, the method comprising subcutaneously administering a pharmaceutical composition to a subject, the pharmaceutical composition comprising a dose of anifrolumab or a functional variant thereof, the dose being >105mg and <150mg. The dose of anifrolumab or a functional variant thereof can be a unit dose (unit dose form, pharmaceutical unit dose form, pharmaceutical unit dose). Functional anifrolumab variants include antigen-binding fragments of anifrolumab and antibodies and immunoglobulin derivatives of anifrolumab.

[0051] In another aspect, the invention relates to a pharmaceutical composition for use in a method of treating SLE in a subject, the method comprising subcutaneously administering a pharmaceutical composition to a subject, the pharmaceutical composition comprising a dose of anifrolumab or a functional variant thereof, wherein weekly administration of the pharmaceutical composition provides a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by intravenous administration of 300 mg of anifrolumab or a functional variant thereof every four weeks. Weekly administration of the dose can provide a plasma concentration in the subject that is approximately equivalent to the plasma concentration provided by intravenous administration of 400 mg of anifrolumab or a functional variant thereof once every four weeks. The dose can be <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The dose can be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose can be ≦135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. The dose can be about 120 mg of anifrolumab or a functional variant thereof.The dose can be about 120 mg of anifrolumab or a functional variant thereof.

[0052] The pharmaceutical composition may be administered at intervals of 6 to 8 days. The pharmaceutical composition may be administered once a week (QW). The pharmaceutical composition may be administered in a single administration step. The dose may be 120 mg of anifrolumab or a functional variant thereof, and the method of treatment may comprise administering the QW dose in a single administration step. The pharmaceutical composition may be administered once a week for at least about 4 weeks. The pharmaceutical composition may be administered once a week for at least about 8 weeks. The dose or unit dose may be administered once a week for at least about 12 weeks. The pharmaceutical composition may be administered once a week for at least about 16 weeks. The pharmaceutical composition may be administered once a week for at least about 20 weeks. The pharmaceutical composition may be administered once a week for at least about 24 weeks. The pharmaceutical composition may be administered once a week for at least about 28 weeks. The pharmaceutical composition may be administered once a week for at least about 32 weeks. The pharmaceutical composition may be administered once a week for about 8 weeks. The pharmaceutical composition may have a volume that allows suitable delivery in a single subcutaneous administration step. The pharmaceutical composition may have a volume of about 0.5 to about 1 ml. The pharmaceutical composition may have a volume of less than 1 ml. The pharmaceutical composition may have a volume of about 0.8 ml.

[0053] Administration of the pharmaceutical composition may provide a plasma concentration of anifrolumab or a functional variant thereof in a subject of ≧10 μg anifrolumab or a functional variant thereof per ml of plasma (i.e., a plasma concentration of ≧10 μg / ml). Administration of the pharmaceutical composition may provide a plasma concentration of anifrolumab or a functional variant thereof in a subject of about 10-100 μg / ml. Administration of the pharmaceutical composition may provide a plasma concentration of anifrolumab or a functional variant thereof in a subject of about 20-80 μg / ml. Administration of the pharmaceutical composition may provide a plasma concentration of anifrolumab or a functional variant thereof in a subject of about 30-70 μg / ml. Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof in a subject of ≧20 μg / ml (i.e., ≧20 μg / ml). Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof in the subject of ≧30 μg / ml (i.e., 30 μg / ml or more). Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof in the subject of ≧40 μg / ml (i.e., 40 μg / ml or more). Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof in the subject of about 20-100 μg / ml. Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof in the subject of about 30-80 μg / ml. Administration of the pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof in the subject of about 40-70 μg / ml.

[0054] The pharmaceutical composition may provide a therapeutic effect in a subject at least equivalent to that provided by administration of an intravenous dose of 300 mg of anifrolumab or a functional variant thereof administered once every four weeks (Q4W). The pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof in a subject that is greater than the trough concentration of anifrolumab or a functional variant thereof provided by administration of an intravenous dose of 300 mg of anifrolumab or a functional variant thereof once every four weeks (Q4W). Anifrolumab or a functional variant thereof may be included within a pharmaceutical composition. The pharmaceutical composition may include about 150-200 mg / ml of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may include 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may include 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0055] The pharmaceutical composition may comprise about 150-200 mg / mL anifrolumab or a functional variant thereof, about 25-150 mM lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise about 150-200 mg / mL anifrolumab or a functional variant thereof, about 25-150 mM lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0056] 4.10.Devices The present invention also relates to an injection device comprising a unit dose of the invention, or a pharmaceutical composition for any use of the invention.

[0057] The medicament in the injection device may comprise >105mg (i.e., greater than 105mg) and <150mg (i.e., less than 150mg) of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise about 120mg of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise 120mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the pharmaceutical composition in the injection device may be 150mg / ml. The volume of the pharmaceutical composition in the injection device may be at least about 0.8ml. The volume of the pharmaceutical composition may be about 0.8ml.

[0058] The pharmaceutical composition in the injection device may comprise about 150-200 mg / ml of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition in the injection device may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise 50 mM of lysine HCl. The pharmaceutical composition may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition in the injection device may comprise about 150-200 mg / ml of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition in the injection device may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM of lysine HCl. The pharmaceutical composition in the injection device may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition in the injection device may comprise 0.05% polysorbate 80. The pharmaceutical composition in the injection device may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition in the injection device may comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80 and 25 mM histidine / histidine HCl.

[0059] In another aspect, the invention relates to an injection device comprising a unit dose. The unit dose may comprise >105 mg (i.e. at least 105 mg) and <150 mg (i.e. less than 150 mg) of anifrolumab or a functional variant thereof. The unit dose may comprise ≦135 mg (i.e. equal to or less than 135 mg) of anifrolumab or a functional variant thereof. The unit dose may comprise about 120 mg of anifrolumab or a functional variant thereof. The unit dose of the injection device may comprise 120 mg of anifrolumab or a functional variant thereof. The unit dose of the injection device may consist essentially of >105 mg and <150 mg of anifrolumab or a functional variant thereof. The unit dose of the injection device may consist essentially of ≦135 mg of anifrolumab or a functional variant thereof. The unit dose of the injection device may consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or functional variants thereof in a unit dose in the injection device may be about 150 mg / ml. The volume of the unit dose in the injection device may be less than 1 ml. The unit dose in the injection device may have a volume of about 0.5 to about 1 ml. The concentration of the unit dose may be about 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose in the injection device may comprise a formulation of about 150-200 mg / ml anifrolumab or functional variants thereof, about 25-150 mM lysine salt, and uncharged excipients. The unit dose in the injection device may comprise a formulation of 150-200 mg / ml anifrolumab or functional variants thereof, about 25-150 mM lysine salt, and uncharged excipients. The unit dose comprises a formulation of 25 mM histidine-HCL, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation may have a pH of about 5.9.

[0060] The injection device may be a pre-filled syringe (PFS). The injection device may be a pre-filled syringe with accessory (AFPS). The injection device may be an automatic injection device (AI).

[0061] 4.11.Kit In another aspect, the invention relates to a kit comprising a unit dose of the invention and instructions for use, wherein the instructions for use comprise instructions for subcutaneous administration of the unit dose to a subject.

[0062] In another aspect, the invention relates to a kit comprising a pharmaceutical composition for use according to the invention, wherein the instructions for use comprise instructions for subcutaneous administration of the pharmaceutical composition to a subject.

[0063] In another aspect, the invention relates to a kit comprising any of the injection devices of the invention and instructions for use, the instructions for use comprising instructions for using the injection device to subcutaneously administer a unit dose or pharmaceutical composition to a subject.

[0064] The kit of the invention may include a package, the package adapted to hold the injection device and instructions for use. The instructions for use may be attached to the injection device. The instructions for use may include instructions for administration of >105 mg and <150 mg of anifrolumab or a functional variant thereof. The instructions for use may include instructions for administration of ≦135 mg of anifrolumab or a functional variant thereof. The instructions for use may include instructions for administration of 120 mg of anifrolumab or a functional variant thereof. The instructions for use may include instructions for administration of 120 mg of anifrolumab or a functional variant thereof every 4 weeks. The instructions for use may define the subject as having a type I IFN-mediated disease. The instructions may define the subject as having SLE. The instructions may define the subject as having moderate to severe SLE. The instructions for use may be written instructions.

[0065] The instructions for use may specify that the injection device, unit dose and / or pharmaceutical composition is for use in the treatment of SLE. The instructions for use include instructions for administration of 120 mg of anifrolumab or a functional variant thereof weekly. The instructions for use may specify that the unit dose or pharmaceutical composition of the invention is for use in the treatment of a subject who is refractory or non-responsive to treatment with one or more immunomodulatory agents. The instructions for use may specify that the unit dose or pharmaceutical composition of the invention is for use in the treatment of a subject who is refractory or non-responsive to treatment with one or more immunomodulatory agents. The instructions for use may specify that the unit dose or pharmaceutical composition of the invention is for use in any of the methods of the invention. The instructions for use may specify that the methods of the invention have been validated in Phase III clinical trials.

[0066] Preparations Anifrolumab or a functional variant thereof may be included in a pharmaceutical composition. The pharmaceutical composition may comprise about 150-200 mg / ml of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80 and 25 mM histidine / histidine HCl.

[0067] Stable formulations suitable for administration to a subject and containing anifrolumab are detailed in U.S. Pat. No. 10,125,195 B1, which is incorporated herein in its entirety.

[0068] 5.Definition IFNAR inhibitors Anifrolumab (MEDI-546, anifro, ANI) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) against subunit 1 of the type I interferon receptor (IFNAR1). Anifrolumab downregulates IFNAR signaling and suppresses the expression of IFN-inducible genes. Disclosures regarding anifrolumab can be found in U.S. Pat. Nos. 7,662,381 and 9,988,459, which are incorporated by reference in their entireties. Sequence information regarding anifrolumab is provided in Table 5-1: Anifrolumab Sequences.

[0069] [Table 1]

[0070] Anifrolumab is an immunoglobulin comprising HCDR1, HCDR2 and HCDR3 (or functional variants thereof) of SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, respectively; and LCDR1, LCDR2 and LCDR3 (or functional variants thereof) of SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, respectively. Anifrolumab is an immunoglobulin comprising VH of SEQ ID NO:1 and VL of SEQ ID NO:2.

[0071] The constant region of anifrolumab is modified such that anifrolumab exhibits reduced affinity for at least one Fc ligand compared to the unmodified antibody. Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 that contains an amino acid substitution L234F in the Fc region as numbered by the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 that contains an amino acid substitution L234F, L235E and / or P331S in the Fc region as numbered by the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is an antibody that contains a light chain constant region of SEQ ID NO:9. Anifrolumab is an antibody that comprises a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody that comprises a light chain constant region of SEQ ID NO: 9 and a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody that comprises a heavy chain of SEQ ID NO: 11. Anifrolumab is an antibody that comprises a light chain of SEQ ID NO: 12. Anifrolumab is an antibody that comprises a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0072] A functional variant of anifrolumab is a sequence variant that performs the same function as anifrolumab. A functional variant of anifrolumab is a variant that binds to the same target as anifrolumab and has the same effector function as anifrolumab. Functional anifrolumab variants include antigen-binding fragments of anifrolumab and antibodies and immunoglobulin derivatives of anifrolumab. Functional variants include biosimilars and interchangeable products. The terms biosimilar and interchangeable products are defined by the FDA and EMA. The term biosimilar refers to a biological product that is highly similar in structure to an approved (e.g., FDA-approved) biological product (reference product, e.g., anifrolumab) and has no clinically significant differences from the reference product in terms of pharmacokinetics, safety, and efficacy. The presence of clinically significant differences of a biosimilar can be evaluated in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and clinical immunogenicity evaluation. An interchangeable product is a biosimilar that is expected to produce the same clinical outcome as the reference product in any given patient.

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

[0074] A variant of a reference (anifrolumab) antibody may comprise a heavy chain CDR1 with at most one amino acid difference compared to SEQ ID NO:3; a heavy chain CDR2 with at most one amino acid difference compared to SEQ ID NO:4; a heavy chain CDR3 with at most one amino acid difference compared to SEQ ID NO:5; a light chain CDR1 with at most one amino acid difference compared to SEQ ID NO:6; a light chain CDR2 with at most one amino acid difference compared to SEQ ID NO:7; and a light chain CDR3 with at most one amino acid difference compared to SEQ ID NO:8, wherein the variant antibody optionally binds to the target (e.g., IFNAR) of anifrolumab with the same affinity.

[0075] A variant antibody may have up to 5, 4 or 3 amino acid differences overall within its CDRs, provided that there are up to 2 (optionally up to 1) amino acid differences per CDR when compared to the corresponding reference (anifrolumab) antibody. A variant antibody may have up to 2 (optionally up to 1) amino acid differences overall within its CDRs, provided that there are up to 2 amino acid differences per CDR when compared to the corresponding reference (anifrolumab) antibody. A variant antibody may have up to 2 (optionally up to 1) amino acid differences overall within its CDRs, provided that there is up to 1 amino acid difference per CDR when compared to the corresponding reference (anifrolumab) antibody.

[0076] A variant antibody may have up to 5, 4 or 3 amino acid differences overall in its framework regions, provided that there are up to 2 (optionally up to 1) amino acid differences per framework region when compared to a corresponding reference (anifrolumab) antibody. Optionally, a variant antibody has up to 2 (optionally up to 1) amino acid differences overall in its framework regions, provided that there are up to 2 amino acid differences per framework region when compared to a corresponding reference (anifrolumab) antibody. Optionally, a variant antibody has up to 2 (optionally up to 1) amino acid differences overall in its framework regions, provided that there is up to 1 amino acid difference per framework region when compared to a corresponding reference (anifrolumab) antibody.

[0077] The variant antibody may comprise a variable heavy chain and a variable light chain as described herein: the heavy chain has up to 14 amino acid differences (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region) compared to the heavy chain sequences herein; the light chain has up to 14 amino acid differences (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region) compared to the light chain sequences herein; the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody, preferably with the same affinity.

[0078] A variant heavy or light chain may be referred to as a "functional equivalent" of a reference heavy or light chain. A variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein the heavy chain has up to seven amino acid differences (up to one amino acid difference in each CDR and up to one amino acid difference in each framework region) compared to the heavy chain sequence herein; the light chain has up to seven amino acid differences (up to one amino acid difference in each CDR and up to one amino acid difference in each framework region) compared to the light chain sequence herein; the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody, preferably with the same affinity.

[0079] Functional variants of anifrolumab include the antibodies described in WO 2018 / 023976A1, which is incorporated by reference herein (Table 5-2).

[0080] [Table 2]

[0081] Functional variants include antibodies comprising the VH amino acid sequence SEQ ID NO: 13. Functional variants include antibodies comprising the VH amino acid sequence SEQ ID NO: 16. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 14. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 15. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15.

[0082] The IFNAR inhibitor may be a monoclonal antibody comprising the VH amino acid sequence SEQ ID NO: 13. The anti-IFNAR antibody may comprise the VH amino acid sequence SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VL amino acid sequence SEQ ID NO: 14. The anti-IFNAR antibody may comprise the VL amino acid sequence SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VL amino acid sequence SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VH sequence SEQ ID NO: 13 and the VL amino acid sequence SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VH sequence SEQ ID NO: 13 and the VL amino acid sequence SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VH sequence SEQ ID NO: 16 and the VL amino acid sequence SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VH sequence SEQ ID NO: 16 and the VL amino acid sequence SEQ ID NO: 14.

[0083] 5.1.1. Anifrolumab in clinical practice Eight blinded or open-label intravenous (IV) and subcutaneous (SC) studies have evaluated the safety of anifrolumab: six studies in patients with SLE (Study 05, Study 04, Study 1013, Study 1145, and Study 08), one study in patients with systemic sclerosis (SSc) (Study MI-CP180), and one study in healthy volunteers (Study 06) (Table 5-3). Two of these studies (Studies 08 and 06) used SC anifrolumab administration. Two studies are ongoing: one study in patients with SLE (Study 09) and one study in patients with lupus nephritis (LN) (Study 07).

[0084] [Table 3]

[0085] Study 1013 was published by Furie et al. 15 (incorporated herein by reference in its entirety). Study 04 was performed in Furie et al. 16(incorporated herein by reference in its entirety). The results of Study 05 are described in Morand et al. 2020 14 (incorporated herein by reference in its entirety). A complete summary of the evidence for the clinical efficacy of intravenous anifrolumab in SLE is provided in Tanaka et al., 2020. 27 (herein incorporated by reference in its entirety).

[0086] Immunomodulators 5.2.1.Abatacept Abatacept (Orencia) is a CTLA-4 fusion protein (CTLA4-Ig) that binds to CD80 / 86 on the surface of antigen-presenting cells and blocks signaling through CD-28 that is required for T cell activation. In preclinical studies, abatacept has been demonstrated to have immunomodulatory activity in the NZB / NZW mouse model of lupus. 28 Abatacept for the treatment of nonrenal SLE was evaluated in a phase IIb randomized, double-blind, placebo-controlled trial. 29 The primary outcome was the proportion of patients with a new (declared) Lupus flare according to the British Isles Lupus Assessment Group (BILAG) index A / B score after initiation of steroid tapering. The primary and secondary outcomes were not met.

[0087] [Table 4]

[0088] 5.2.2. Atacicept Atacicept (TACI-Ig) is a fully human recombinant fusion protein that neutralizes both BAFF and APRIL. Atacicept (SEQ ID NO: 13) is described in U.S. Patent No. 5,851,795, which is incorporated herein by reference. Atacicept is in clinical development for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, and psoriatic arthritis. In a Phase 2 / 3 clinical trial (NCT00624338), atacicept was administered to SLE patients at a subcutaneous dose of 75 mg or 150 mg.

[0089] A phase Ib study investigated the safety and tolerability of atacicept given intravenously at various doses ranging from 1 x 3 mg / kg to 2 x 9 mg / kg over a 3-week period compared with placebo. Intravenously administered atacicept was found to be generally well tolerated, both systemically and locally, in patients with mild-to-moderate SLE. 30 .

[0090] In the ADDRESS II study (NCT01972568), a Phase IIb placebo-controlled trial, atacicept was given weekly at either 75 or 150 mg doses. The proportion of patients with SRI(4) at week 24 was assessed as the primary endpoint. More patients reached the primary endpoint in the 75 mg atacicept group than in the 150 mg atacicept group (p=0.045). AEs were reported slightly more frequently in patients receiving atacicept, while a higher percentage of SAEs was observed in the placebo group. 31 Dosage information for atacicept is summarized in Table 5-5.

[0091] [Table 5]

[0092] 5.2.3. Belimumab (Benlysta) Belimumab (Benlysta) is an anti-BAFF (BLyS) antibody. Belimumab is described in U.S. Patent No. 7,138,501, which is incorporated herein by reference. Dosage information for belimumab is provided in Tables 5-6. Belimumab is approved for the treatment of SLE administered by intravenous infusion at a dose of 10 mg / kg, every 2 weeks for the first three doses, and then every 4 weeks. Belimumab is also approved for the treatment of SLE administered by subcutaneous injection at a dose of 200 mg once weekly. Belimumab formulations are described in U.S. Patent Application No. 20180289804A1, which is incorporated herein by reference in its entirety.

[0093] [Table 6]

[0094] Epratuzumab Epratuzumab is a monoclonal antibody that regulates B cell activity by binding to CD22 on the surface of mature B cells. Epratuzumab is described in U.S. Patent No. 5,789,554 and U.S. Patent No. 6,187,287, which are incorporated herein by reference. Epratuzumab is in development for the treatment of leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma, and follicular lymphoma).

[0095] ALLEVIATE-1 and ALLEVIATE-2 were two Phase IIb, multicenter, multinational, double-blind, placebo-controlled, randomized controlled trials investigating the efficacy and safety of epratuzumab in SLE. 32 The trials were stopped early due to drug shortages and data were pooled for analysis. ALLEVIATE-1 and ALLEVIATE-2 studied patients with at least one BILAG A organ system and at least two BILAG B organ systems, respectively, at baseline. In ALLEVIATE-1, patients received either their individual standard of care (SOC) or epratuzumab 360 mg / m 2or epratuzumab 720 mg / m 2 Patients were randomized to either rituximab or placebo. The trial failed to meet its primary endpoint, with no significant difference in BILAG response at week 12.

[0096] EMBODY 1 (NCT01262365) and EMBODY 2 (NCT01261793), multicenter Phase III trials of epratuzumab in patients with moderate-to-severe SLE, did not meet the primary efficacy endpoint of BICLA response at week 48. 33 Epratuzumab in EMBODY 1 and EMBODY 2 was administered as a 600 mg infusion delivered weekly for 4 weeks for a total of four 12-week treatment cycles (cumulative dose of 2400 mg) or as a 1200 mg infusion delivered every other week for 4 weeks for a total of four 12-week treatment cycles (cumulative dose of 2400 mg). 34 .

[0097] [Table 7]

[0098] Rituximab (Rituxan) Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody. Rituximab is an effective treatment for several autoimmune diseases, including rheumatoid arthritis and ANCA vasculitis. Rituximab is described in U.S. Patent No. 7,422,739, which is incorporated herein by reference.

[0099] Rituximab is approved for the treatment of adult patients with non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and rheumatoid arthritis (RA) in combination with glucocorticoids and moderate to severe pemphigus vulgaris (PV) in adult patients, in combination with methotrexate in adult and pediatric patients 2 years of age and older with moderate to severe active RA, granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis), and microscopic polyangiitis (MPA).

[0100] The efficacy and safety of rituximab in patients with moderate to severe SLE was evaluated in a multicenter, placebo-randomized, controlled phase II / III study (EXPLORER). 36 In the study, patients with baseline active SLE (defined as a new BILAG A score of ≥1 or a BILAG B score of ≥2) were randomized to rituximab or placebo. Patients were randomized in a 2:1 ratio to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. The primary endpoint was the proportion of rituximab- vs. placebo-treated patients achieving a complete clinical response (CCR), partial clinical response (PCR), or no response at week 52. The primary endpoint was not met, with similar complete and partial response rates in the rituximab and placebo arms at week 52. Differences in time to first moderate or severe flare and changes in HRQOL were also not significant. 36 Rituximab was also administered at 375 mg / m 2 or 1000 mg / m for two doses. 2 Used off-label in patients with SLE at a dose of 37 Rituximab is also being investigated for the treatment of SLE in combination with belimumab (NCT03312907).

[0101] Rituximab is administered intravenously. Dosing information is provided in Tables 5-8.

[0102] [Table 8]

[0103] Tabalumab Tabalumab (LY2127399) is a human IgG4 monoclonal antibody that binds to both soluble and membrane-bound B-cell activating factor (BAFF). The efficacy and safety of tabalumab were evaluated in two 52-week, phase III, multicenter, randomized, double-blind, placebo-controlled studies (ILLUMINATE-1 and ILLUMINATE-2) in patients with moderate-to-severe SLE. The primary endpoint was the proportion of patients achieving an SLE Responder Index 5 (SRI-5) response at week 52. In ILLUMINATE-1 (NCT01196091), the primary endpoint was not met. Key secondary efficacy endpoints (OCS sparing, time to severe flare, most severe fatigue in the last 24 hours) did not achieve statistical significance despite pharmacodynamic evidence of tabalumab bioactivity (significant reductions in anti-dsDNA, total B cells, and immunoglobulins). 38 In the higher dose arm (tavalumab 120 mg every 2 weeks) of ILLUMINATE-2 (NCT01205438), the primary endpoint was met; however, secondary endpoints, including OCS sparing, were not met. 39 Per ILLUMINATE-1 and ILLUMINATE-2, tabalumab development was put on hold given the small effect size and failure to meet other important clinical endpoints. Dosing information is provided in Tables 5-9.

[0104] [Table 9]

[0105] Sifalimumab Sifalimumab (MEDI-545) is a fully human immunoglobulin G1κ monoclonal antibody that binds to and neutralizes most IFN-α subtypes. 40Sifalimumab is described in U.S. Patent No. 7,741,449, which is incorporated herein by reference in its entirety. The efficacy and safety of sifalimumab were evaluated in a Phase IIb randomized, double-blind, placebo-controlled study (NCT01283139) in adults with moderately to severely active systemic lupus erythematosus (SLE). 431 patients were randomized to receive monthly intravenous sifalimumab (200 mg, 600 mg, or 1200 mg) or placebo in addition to standard of care. The primary efficacy outcome was the proportion of patients who achieved an SLE Responder Index response at week 52. Compared with placebo, a greater proportion of patients receiving sifalimumab (all doses) met the primary endpoint (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%).

[0106] TNF inhibitors Tumor necrosis factor (TNF)-alpha inhibitors, including etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab, are biologics that are FDA-approved to treat several inflammatory conditions, including ankylosing spondylitis, Crohn's disease, hidradenitis suppurativa (A), juvenile rheumatoid arthritis, plaque psoriasis, polyarticular juvenile rheumatoid arthritis, psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, and uveitis. 41 .

[0107] Adalimumab Adalimumab is a recombinant human IgG1 monoclonal antibody. Adalimumab is described in U.S. Patent No. 8,197,813 and U.S. Patent No. 8,372,401, which are incorporated herein by reference. Adalimumab is approved for the treatment of rheumatoid arthritis (RA), hidradenitis suppurativa; ankylosing spondylitis; inflammatory bowel disease (IBD) (Crohn's disease, ulcerative colitis), psoriasis vulgaris, and juvenile rheumatoid arthritis.

[0108] Etanercept Etanercept (Enbrel, Elrelzi, Eticovo, YLB113) is described in U.S. Patent No. 8,063,182, which is incorporated herein by reference. Etanercept is administered by subcutaneous injection. Dosage information is provided in Tables 5-10. Etanercept is approved for the treatment of rheumatoid arthritis (RA), ankylosing spondylitis, plaque psoriasis, juvenile rheumatoid arthritis, and plaque psoriasis.

[0109] [Table 10]

[0110] Infliximab Infliximab (Remicade, Avsola, Ixifi, Renflexis) is a TNF-alpha inhibitor. Infliximab is approved for the treatment of IBD (Crohn's disease, RA, AS, ulcerative colitis, and psoriasis vulgaris. Dosing information is shown in Tables 5-11.

[0111] [Table 11]

[0112] Functional variants A functional variant of a biologic is a sequence variant that performs the same function as anifrolumab. Functional variants include biosimilars and interchangeable products. The terms biosimilar and interchangeable products are defined by the FDA and EMA. The term biosimilar refers to a biological product that is highly similar in structure to an approved (e.g., FDA-approved) biological product (reference product, e.g., anifrolumab) and has no clinically significant differences from the reference product in terms of pharmacokinetics, safety, and efficacy. The presence of clinically significant differences of a biosimilar can be evaluated in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and clinical immunogenicity evaluation. An interchangeable product is a biosimilar that is expected to produce the same clinical outcome as the reference product in any given patient.

[0113] 5.3. Clinical Trials 5.3.1. Phase 2 / Phase II / Pivotal Trials Phase II trials gather preliminary data on efficacy. In Phase 2 trials, researchers administer the drug to a group of patients who have the disease or condition for which the drug is being developed. The trials, which typically involve several hundred patients, are not large enough to show whether the drug is beneficial. Instead, Phase 2 trials provide researchers with additional safety data. Researchers use these data to refine their research questions, develop study methods, and design new Phase 3 study protocols.

[0114] 5.3.2. Phase 3 / Phase III / Pivotal Studies or Clinical Trials Researchers design Phase 3 trials to demonstrate whether a product provides a therapeutic benefit to a particular population. These trials, sometimes known as pivotal trials, include 300 to 3,000 participants. Phase 3 trials provide the majority of safety data. It is possible that less common side effects may have gone unnoticed in earlier trials. Because these trials are larger and longer in duration, the results are more likely to show long-lasting or rare side effects. Regulatory agencies such as the EMA and FDA usually require Phase III clinical trials to demonstrate that a drug product is safe and at least as effective (if not better) than available drug therapies before new drug approval. Phase III clinical trials usually fail, even after successful Phase II clinical trials.

[0115] 5.4. Preparations Stable formulations containing anifrolumab suitable for administration to a subject are described in detail in U.S. Pat. No. 10,125,195 B1, which is incorporated herein in its entirety.

[0116] The following examples illustrate specific embodiments of the present disclosure and various uses thereof, they are provided for illustrative purposes only and should not be construed as limiting the scope of the disclosure in any way.

[0117] Steroids Oral corticosteroids (OCS, glucocorticoids) include prednisone, cortisone, hydrocortisone, methylprednisolone, prednisolone, and triamcinolone. Examples of equivalent doses of oral prednisone are shown in Table 5-12.

[0118] [Table 12]

[0119] 5.6. Delivery Device In addition to providing subcutaneous administration of antibodies, the ability to self-administer (e.g., for home use) can be further enhanced by subcutaneous administration with an accessory prefilled syringe (APFS), an autoinjector (AI), or a combination thereof. Such devices have been found to be well tolerated and reliable for administering subcutaneous doses of antibodies, providing an additional option for optimizing patient care. Indeed, such devices may reduce the burden of frequent office visits for patients. An example of a suitable APFS device is described in Ferguson et.al. 42 (which is incorporated herein by reference in its entirety).

[0120] The doses solved by the inventors provide further advantages in the context of APFS administration, since APFS devices typically administer a maximum volume of 1 ml. Doses in the range of >105 mg to <155 mg can be easily accommodated in a volume of about 0.8 ml, making the doses of the present invention very suitable for APFS and AI administration. For comparison, due to the viscosity of anifrolumab, larger doses (specifically doses >150 mg) need to be administered in a volume of >1 ml, which requires at least two SC injections, which is inconvenient for patients and requires multiple prefilled devices.

[0121] The delivery device may be a single-use, disposable system designed to allow manual SC administration of the dose.

[0122] 5.7. Dosage Form A unit dose (also called a unit dose form, pharmaceutical unit dose or pharmaceutical unit dose form) is a dose formed from a single unit. A unit dose (unit dose form) is suitable for administration to a subject in a single administration step. A unit dose (unit dose form) can be packaged in a single unit container, such as a single-use pre-filled syringe or an automatic injection device. Unit doses offer the advantage that they can be ordered, packaged, handled and administered as a single dose unit containing a predetermined drug amount. Unit doses reduce administration errors and reduce waste.

[0123] 5.8. Evaluation items 5.8.1. Patient-reported outcomes Physician's Global Assessment of Disease Activity (PGA and MDGA) refers to assessments where a physician assesses a subject's psoriatic arthritis (PsA) status using a visual analog scale (VAS). Subjects are rated according to their current arthritis status. The VAS is based on verbal descriptors ranging from "very good" to "very bad."

[0124] 5.8.2.BILAG-2004(British Isles Lupus Assessment Group-2004) BILAG-2004 is a translational index with nine organ systems (systemic, mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, ophthalmic, renal, and hematological) that can capture changes in the severity of clinical symptoms. It has an ordinal scale by design and does not have a global score; rather, it records disease activity through different organ systems at a glance by comparing the previous four weeks with the four weeks preceding them. It classifies disease activity into five different levels, A to E, based on the physician's intent to treat principle: Grade A represents very active disease requiring immunosuppressants and / or prednisone or its equivalent in doses >20 mg / day Grade B represents moderate disease activity requiring lower doses of corticosteroids, topical steroids, topical immunosuppressants, antimalarials, or NSAIDs. Grade C indicates mild, stable disease Grade D means there is no disease activity, but the system has been previously affected Grade E indicates no current or past disease activity

[0125] BILAG-2004 was developed based on the intention to treat principle, but treatment is not related to the scoring index: only the presence of active symptoms influences the scoring.

[0126] BILAG-defined improvements in the mucocutaneous or musculoskeletal organ systems represented rash or arthritis, respectively.

[0127] 5.8.3.BICLA (BILAG-Based Composite Lupus Assessment) BICLA is a composite index originally derived by expert consensus on disease activity index. BICLA response is defined as (1) at least one gradation of improvement in baseline BILAG score in all body systems with moderate or severe disease activity at entry (e.g., reduction of all A (severe disease) scores to B (moderate), C (mild) or D (no activity) and reduction of all B scores to C or D); (2) absence of new BILAG A or two or more new BILAG B scores; (3) no worsening from baseline in total SLEDAI score; (4) no significant worsening (≦10%) in physician's global assessment; and (5) no treatment failure (initiation of non-protocol treatment).

[0128] In particular, a subject is a BICLA responder if the following criteria are met: a) decline in all baseline BILAG-2004 A to B / C / D and decline in baseline BILAG-2004 B to C / D as defined by one new BILAG-2004 A or two or more new BILAG-2004 B entries and no deterioration in BILAG-2004 in other organ systems; b) no worsening from baseline on the SLEDAI-2K, as defined as an increase from baseline of >0 points on the SLEDAI-2K; c) no worsening from baseline in the subject's lupus disease activity, defined by an increase of ≥ 0.30 points on a 3-point PGA VAS; d) No discontinuation of investigational drug or use of restrictive medications above the thresholds allowed in the protocol prior to evaluation.

[0129] CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index Inflammatory Disease Activity) The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) was developed in 2005 as a means to specifically track skin activity and damage in patients with CLE. 21 The CLASI is a simple, single-page tool that quantifies skin disease activity and damage separately in each body part. 43 The CLASI features a summary score of skin activity (CLASI-A) and a summary score of damage (CLASI-D). The index has high inter- and intra-rater reliability and is responsive to change when used in adults with CLE and SLE. The CLASI activity score correlates with disease severity: mild, moderate, and severe disease corresponded to CLASI activity score ranges of 0-9 (sensitivity 93%, specificity 78%), 10-20, and 21-70 (sensitivity 80%, specificity 95%), respectively (Table 5-13).

[0130] [Table 13]

[0131] The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) quantifies disease activity and damage in cutaneous lupus erythematosus. It can distinguish between different levels of response to treatment, for example, it can detect a certain percentage decrease from baseline in activity score, or it can be reported by a mean / median score. In particular, the CLASI is a validated index used to evaluate the skin lesions of lupus, and consists of two separate scores: the first score summarizes the inflammatory activity of the disease; the second score is a measure of the damage caused by the disease. The activity score takes into account erythema, scaling / hypertrophy, mucosal lesions, recent hair loss, and non-scarring alopecia. The damage score represents pigmentation abnormalities, scarring / atrophy / panniculitis, and scarring of the scalp. The subject is asked if the subject's pigmentation abnormalities have lasted for more than 12 months, in which case the pigmentation abnormality score is doubled. Each of the above parameters is measured at 13 different anatomical locations and is specifically included because they are most often involved in cutaneous lupus erythematosus (CLE). The most severe lesions within each area are measured.

[0132] The revised CLASI (mCLASI) is defined as the activity portion of the CLASI, which describes skin erythema, scaling / swelling, and scalp inflammation. Activity of oral ulcers and alopecia without scalp inflammation is excluded from the mCLASI analysis, as are all measures of damage. A clinically meaningful improvement in rash is defined by a ≥ 50% reduction in baseline activity score, as assessed using the mCLASI.

[0133] 5.8.5. Systemic Lupus Erythematosus Responder Index (SRI) ≥ 4 A subject achieves SRI(4) if all of the following criteria are met: A reduction from baseline of ≥4 points on the SLEDAI-2K; No new affected organ systems as defined by ≥1 BILAG-2004 A or ≥2 ·BILAG-2004 B items will be compared to baseline using BILAG-2004; ·No worsening from baseline in the subject's lupus disease activity, defined as an increase of ≥ 0.30 points on a 3-point PGA VAS.

[0134] SRI(X) (X=5, 6, 7, or 8) is defined by the proportion of subjects meeting the following criteria: A decrease from baseline of ≥X points on SLEDAI-2K; No new affected organ systems as defined by 1 or more BILAG-2004 A or 2, or · More BILAG-2004 B items will be compared to baseline with BILAG-2004; No worsening from baseline in the subject's lupus disease activity as defined by: ≥ 0.30 point increase in 3-point PGA VAS

[0135] 5.8.6.SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) The SLEDAI-2K Disease Activity Index consists of a list of organ symptoms, each of which is defined. A qualified investigator or designated physician will complete the SLEDAI-2K assessment and determine whether each symptom is "present" or "absent" within the last 4 weeks. The assessment will also include blood and urine collection for evaluation of the SLEDAI-2K laboratory categories.

[0136] The SLEDAI-2K assessment consists of 24 lupus-related items. It is a weighting device, where the descriptors are multiplied by the "weight" of a particular organ. For example, the renal descriptor is multiplied by 4, the central nervous system descriptor by 8, and these weighted organ manifestations are summed into a final score. The SLEDAI-2K score ranges from 0 to 105 points, with 0 indicating inactive disease. The SLEDAI-2K score is a valid, reliable, and sensitive clinical assessment of lupus disease activity. The SLEDAI-2K calculated using a 30-day time frame prior to the clinic visit for clinical and laboratory values ​​has been shown to be similar to the SLEDAI-2K calculated using a 10-day time frame. 44 .

[0137] Resolution of rash as defined by SLEDAI-2K is defined as a score of 0 at Week 52 for those with a score of ≧2 for rash at baseline.

[0138] 5.8.7. Tender and swollen joints Swollen and tender joint counts may be based on the left and right shoulders, elbows, wrists, metacarpophalangeal (MCP)1, MCP2, MCP3, MCP4, MCP5, proximal interphalangeal (PIP)1, PIP2, PIP3, PIP4, PIP5 joints of the upper extremities, and the left and right knees of the lower extremities. Active joints for joint count assessment may be defined as those joints that are tender and swollen.

[0139] 5.8.8. Systemic Lupus International Joint Clinical Committee / American College of Rheumatology Damage Index (SDI) The SDI is used to measure organ damage in SLE patients. In particular, the SDI was developed to assess irreversible damage in SLE subjects occurring after disease onset, independent of its cause (SLE activity, therapy, comorbidities). Damage, i.e. irreversible damage since SLE onset, is usually defined as a clinical feature that must be present continuously for at least 6 months to be scored. In addition, some irreversible events, such as MI or cerebrovascular accident, are scored as damage at the time of their occurrence. Briefly, damage is defined for 12 organ systems; peripheral vascular, ocular, neuropsychiatric, renal, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, skin, endocrine (diabetes), gonads, and malignant tumors. Damage over time may be stable or may increase up to 47 points, but there should be no decrease in points. 45 .

[0140] 5.9.PK / PD The plasma levels obtainable by SC and IV administration can be compared based on the plasma drug concentration-time curve (AUC), which reflects the body's exposure to the antibody after administration of a dose of drug. For example, during a clinical trial, a patient's plasma drug concentration-time profile can be plotted by measuring the plasma concentration at several time points. When using an in silico modeling approach, the plasma drug concentration-time for any given dose can be predicted. The AUC (area under the curve) can then be calculated by integration of the plasma drug concentration-time curve. A suitable method is described in Tummala et.al., incorporated herein by reference in its entirety. 26 In the examples described herein, PK parameters were calculated by non-compartmental analysis using Phoenix WinNonlin V / 6.2 (Certara, Inc., Princeton, New Jersey, USA) and included the area under the serum concentration-time curve (AUC), clearance (CL, CL / F), maximum serum concentration (C max ) and the time to reach maximum serum concentration (t maxAll data were analyzed with SAS System V.9.2 (SAS Institute, Inc., Cary, NC, USA).

[0141] Advantageously, the ratio of the AUC obtained by SC administration to the AUC obtained by IV administration (AUC SC / AUC IV ) may be calculated to provide a numerical comparison of the bioavailability provided by the routes of administration. References herein to "AUC ratio" refer to the AUC SC / AUC IV AUC ratio means a ratio. In order to provide statistical robustness, AUC ratio is preferably the mean, median or mode value (e.g., the mean value) calculated from multiple repeated experiments (or computational simulations). This approach is illustrated with reference to the examples. The mean, median or mode value (preferably the mean value) can be derived by pooling data obtained from multiple patients (or multiple computational simulations). Thus, AUC ratio can reflect the mean, median or mode value (preferably the mean value) of AUC in multiple patients.

[0142] 5.10. Pharmacokinetic Glossary Area Under the Curve (AUC): The area under the plasma drug concentration versus time curve, which serves as a measure of drug exposure. C ave : Mean steady state concentration. C max : The maximum (or peak) concentration of a drug in plasma. C min :Minimum plasma drug concentration. C trough : Plasma drug concentration at steady state immediately before the administration of the next dose. Trough plasma concentration (measured concentration at the end of the dosing interval at steady state [just before the next dose]). LLOQ: Lower Limit of Quantitation, the smallest amount of analyte in a sample that can be quantified with adequate precision and accuracy. Linear pharmacokinetics: Drugs are said to exhibit linear pharmacokinetics if their concentration in blood or plasma increases proportionally with increasing dose and their rate of elimination is proportional to the concentration. The clearance and volume of distribution of these drugs are independent of dose. Nonlinear pharmacokinetics: In contrast to linear pharmacokinetics, the drug concentration in blood or plasma does not increase proportionally with increasing dose. Their clearance and distribution volume may vary depending on the dose administered. The nonlinearity may be associated with any component of the absorption, distribution and / or excretion process.

[0143] 5.11. Type I IFN Gene Signature (IFNGS) Type I IFN is believed to play a central role in the pathogenesis of SLE, and inhibition of this pathway is targeted by anifrolumab. To understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know whether the subject's disease is driven by type I IFN activation. However, direct measurement of type I IFN remains challenging. As such, transcript-based markers have been developed to assess the effect of overexpression of target proteins on a set of specific mRNA markers. Expression of these markers is easily detected in whole blood and shows a correlation with expression in affected tissues such as skin in SLE. The bimodal distribution of transcript scores for SLE subjects helps define subpopulations with high and low IFN test scores (Figure 1). Type I IFN testing is described in WO2011028933A1, which is incorporated herein by reference in its entirety. The type I IFN gene signature can be used to identify subjects as having high type I IFN gene signature (IFNGS) test patients or low IFNGS test patients. The IFNGS test measures the expression of genes IFI27, IFI44, IFI44L and RSAD2 in the whole blood of a subject, compared to three reference genes; 18S, ACTB and GAPDH. The result of the test is a score that is compared to pre-established cutoffs that classify patients into two groups with low or high levels of IFN-inducible gene expression (Figure 1).

[0144] Expression of the genes can be measured by RT-PCR. Suitable primers and probes for detection of the genes can be found in WO2011028933. A suitable kit for measuring gene expression for the IFNGS test is described in Brohawn et al. 46 (which is incorporated herein by reference in its entirety) is the QIAGEN therascreen® IFIGx RGQ RT-PCR kit (IFIGx kit).

[0145] 5.12. Standard of Care (SOC) The standard treatment is A dose of oral prednisone (≤40 mg / day) or a prednisone equivalent dose Azathioprine ≦200 mg / day Antimalarials: Chloroquine, hydroxychloroquine (200-400 mg per day), quinacrine (50-100 mg per day) Mycophenolate mofetil ≤ 2 g / day or mycophenolate ≤ 1.44 g / day Oral, subcutaneous (SC), or intramuscular methotrexate ≤ 25 mg / week Cyclosporine (75-100mg per day) Leflunomide (10-20mg per day) Mizoribine ≦150mg / day NSIADs, e.g. naproxen sodium (Aleve), ibuprofen Includes 47 . EXAMPLES

[0146] 6. Example 1: MUSE, ClinicalTrial.gov Identifier: NCT01438489 MUSE was a phase 2, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of two intravenous (IV) treatment regimens in adult participants with chronic, moderately to severely active SLE with inadequate response to standard of care (SOC) SLE. The study drug (anifrolumab or placebo) was administered as a fixed dose every 4 weeks (28 days) for a total of 13 doses.

[0147] MUSE is a methodology developed by Furie et al. 2017, which is incorporated herein by reference in its entirety. 15 (which is incorporated herein by reference in its entirety).

[0148] 7. Example 2: TULIP I and II, ClinicalTrial.gov Identifiers: NCT02446912 and NCT02446899 TULIP I and TULIP II were phase 3 multicenter, multinational, randomized, double-blind, placebo-controlled studies to evaluate the efficacy and safety of two doses of intravenous (IV) treatment regimens of anifrolumab compared with placebo in subjects with moderately to severely active autoantibody-positive systemic lupus erythematosus (SLE) receiving standard of care (SOC) treatment.

[0149] 7.1.1. Restricted medication Subjects were considered non-responders if they received one of the following: sulfasalazine; danazol; dapsone; azathioprine at >200 mg / day or a daily dose greater than week 0 (day 1); mycophenolate mofetil >2.0 g / day or mycophenolic acid >1.44 g / day or a daily dose greater than week 0 (day 1); oral, SC, or intramuscular methotrexate >25 mg / week or a daily dose greater than week 0 (day 1); mizoribine >150 mg / day or a daily dose greater than week 0 (day 1); any change in the route of administration of oral, SC, or intramuscular methotrexate; intravenous corticosteroids >40 mg. / day but ≦1 gm / day methylprednisolone or equivalent; intramuscular corticosteroids >80 mg / day methylprednisolone or equivalent; subcutaneous or intramuscular corticosteroid precursors; treatment with OCS >40 mg / day prednisone or equivalent; treatment with OCS above the first daily dose for a dosing period of >14 days; corticosteroids with long biological half-lives (e.g., dexamethasone, betamethasone); calcineurin inhibitors (e.g., cyclosporine, tacrolimus [including topical]) or other immunosuppressants including but not limited to leflunomide. Cyclosporine eye drops were permitted for use in the study.

[0150] TULIP I is a novel method for the synthesis of 1,2,3,4-trimethylsiloxyphenylalanine (1,2,3,4-trimethylsilyl) 1,2,3,4-trimethylsilyl 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,19,20,21,19,22,23,24,2 16 The results of TULIP II are described in more detail in Morand et al. 2020, which is incorporated by reference in its entirety. 14 is described in more detail in.

[0151] 8. Example 3: Efficacy of Anifrolumab in Patients with SLE Previously Treated with Biologics: A Post-Hoc Analysis of Data from Two Phase 3 Trials Background Anifrolumab, a monoclonal antibody that binds to the type I IFN receptor, was effective and well tolerated in adult patients with moderate to severe SLE despite standard therapy in the phase 3 TULIP-1 and TULIP-2 trials. Patients with SLE previously treated with biologics represent an important patient population with limited treatment options. We investigated whether prior exposure to immunomodulatory biologics influenced the efficacy and safety of anifrolumab in the pooled data from TULIP-1 and TULIP-2.

[0152] 8.2. Method This analysis included patients who received intravenous anifrolumab 300 mg or placebo every 4 weeks for 48 weeks in the 52-week TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) ​​trials. Eligible patients met ACR SLE criteria, had moderate-to-severe SLE, and were allowed prior biologic use with a 3- to 6-month drug holiday regardless of reason for discontinuation. Patients were divided into biologic-experienced or biologic-naive subgroups (≥ 1 or 0 prior biologic immunomodulators, respectively). Baseline SLE disease characteristics, efficacy, and safety were compared across subgroups. Efficacy measures included BILAG-Based Composite Lupus Assessment (BICLA) response at week 52 (W); SLE Responder Index of ≥ 4 (SRI[4]) response at W52; continued oral glucocorticoid (GC) tapering (≤ 7.5 mg / day prednisone equivalents from W40-52 if ≥ 10 mg / day at baseline); and annualized relapse rate through W52. Binary endpoints and safety were analyzed with Cochran-Mantel-Haenszel methods controlling for randomization stratification factors and study. Annualized relapse rate was analyzed with negative binomial regression models with treatment, randomization stratification factors, and study as covariates.

[0153] 8.3.Results There were 145 biologic-experienced patients (anifrolumab [n=75]; placebo [n=70]) and 581 biologic-naive patients (anifrolumab [n=285]; placebo [n=296]). Most prior biologic use was with belimumab (n=70), epratuzumab (n=49), tabalumab (n=18), or rituximab (n=14) (Figure 2A, Figure 2B). Baseline demographics, disease characteristics, and non-biologic SLE treatments were generally similar between groups. However, compared with biologic-naive patients, biologic-experienced patients had a longer time since SLE diagnosis, were more likely to be of North American origin, have a SLICC / ACR Damage Index organ damage score of ≥1, anti-dsDNA antibodies, and a higher IFN gene signature (Figure 3). There was a lower placebo response (potentially more refractory disease) in biologic-experienced versus biologic-naive patients (Figure 4). Anifrolumab was associated with greater treatment differences than placebo (Δ) in biologic-experienced versus biologic-naive patients across multiple endpoints, including BICLA response (Δ=19.4 vs. Δ=16.6), SRI(4) response (Δ=25.3 vs. Δ=9.1), and oral GC taper (Δ=24.7 vs. Δ=17.5) (Figure 4).

[0154] Anifrolumab was associated with a treatment difference (BICLA response) greater than placebo (Δ) in patients with prior use of abatacept (Figure 5A) versus patients without prior use of abatacept (Δ=66.7 vs. Δ=16.1) (Figure 5B). Anifrolumab was associated with a treatment difference (BICLA response) greater than placebo (Δ) in patients with prior use of belimumab (Figure 6A) versus patients without prior use of belimumab (Δ=19.3 vs. Δ=16.6) (Figure 6B). Anifrolumab was not associated with a treatment difference (BICLA response) greater than placebo (Δ) in patients with prior use of epratuzumab (Figure 7A) versus patients without prior use of epratuzumab (Δ=10.5 vs. Δ=17.3) (Figure 7B). Anifrolumab was associated with a treatment difference (BICLA response) greater than placebo (Δ) in patients with prior use of rituximab (Figure 8A) versus patients without prior use of rituximab (Δ=39.6 vs. Δ=16.2) (Figure 8B). Anifrolumab was associated with a treatment difference (BICLA response) greater than placebo (Δ) in patients with prior use of sifalimumab (Figure 9A) versus patients without prior use of sifalimumab (Δ=33.3 vs. Δ=16.2) (Figure 9B). Anifrolumab was not associated with a treatment difference (BICLA response) greater than placebo (Δ) in patients with prior use of tabalumab or TNF inhibitors (FIGS. 10A and 11A) versus patients without prior use of tabalumab or TNF inhibitors (Δ=39.6 vs. 16.2; (Δ=16.7 vs. Δ=16.6) (FIGS. 10B and 11B).

[0155] The incidence of severe adverse events was higher in biologic-experienced versus biologic-naive patients with anifrolumab and placebo (Figure 12). In biologic-experienced and biologic-naive patients, the incidence of herpes zoster was higher with anifrolumab versus placebo.

[0156] 8.4. Conclusion Patients with SLE who have previously received a biologic have high unmet need and limited treatment options. Anifrolumab was associated with a treatment difference greater than placebo in biologic-experienced patients versus biologic-naive patients across multiple endpoints. Anifrolumab was associated with a treatment difference greater than placebo in patients with prior use of abatacept, belimumab, rituximab, or sifalimumab. Anifrolumab was particularly effective in patients with prior use of belimumab. These data support the use of anifrolumab to treat SLE in patients with prior biologic use, particularly prior use of abatacept, belimumab, rituximab, or sifalimumab, most particularly prior use of belimumab.

[0157] 9. Example 3: Subcutaneous administration of anifrolumab 9.1. MI-CP180: A Phase I Study of IV Anifrolumab in Patients with SSc Mean anifrolumab serum concentrations after a single dose based on body weight are shown in Figure 13A. After a single dose, anifrolumab showed non-linear PK at low dose levels (<10.0 mg / kg) in both IFNGS-high and IFNGS-low patients. max A dose-proportional increase in AUC was observed, but the increase in AUC was greater than dose-proportional from 0.1 to 10.0 mg / kg. In the higher dose cohorts, anifrolumab t1 / 2 was longer. At the highest dose level examined (20.0 mg / kg), the elimination t1 / 2 was approximately 12 days.

[0158] 9.2. Phase I of IV and SC Anifrolumab in Healthy Volunteers (Study 06) In this phase I, randomized, placebo-controlled study, 30 healthy adults were assigned to three treatment cohorts (anifrolumab 300 mg SC (n=6), anifrolumab 300 mg IV (n=6), anifrolumab 600 mg SC (n=6)) and placebo (n=4 / cohort). After SC administration, exposure to anifrolumab increased dose-proportionally from 300 mg to 600 mg based on the area under the serum concentration curve. Arithmetic mean serum anifrolumab concentration-time profiles after single IV and SC administration are shown in Figure 13B. Tummala et al. 2018, incorporated herein by reference in its entirety. 26 As reported in, this study estimated that the bioavailability of anifrolumab in healthy volunteers was 87% of intravenous exposure.

[0159] 9.3. Phase II Study of SC Anifrolumab in Patients with SLE (Study 08) This study was designed to characterize the pharmacokinetics and pharmacodynamics of subcutaneously administered anifrolumab (Figure 14A).

[0160] This study explored the clinical pharmacology, safety, and exploratory efficacy of subcutaneous anifrolumab. The pharmacokinetics in Study 08 were consistent with the high bioavailability (healthy volunteers) and high CL in SLE patients with high IFNGS in Study 06. Anifrolumab administered subcutaneously every 2 weeks to patients with SLE and moderate to severe skin symptoms had nonlinear pharmacokinetics that exceeded dose proportionality and neutralized the type I interferon gene signature in a dose-dependent manner (Figures 14B and 14C). Notably, subcutaneous administration of 150 mg or 300 mg anifrolumab every 2 weeks for 50 weeks showed nonlinear pharmacokinetics and C trough Concentrations were more than dose-proportional. The number of adverse events with subcutaneous administration of anifrolumab was similar to that observed after intravenous administration in a large study of patients with SLE.

[0161] The results of Study 08 are reported in Bruce et al., which is incorporated herein by reference in its entirety. 48is described in detail in.

[0162] Study 08 was limited by a small sample size, which prevented conclusions from being drawn about the biological effects of the study drug (e.g., on complement C3 or C4 concentrations) or its clinical efficacy. The inclusion of only patients with a high type I interferon gene signature and active skin disease also limited the generalizability of the study to patients with similar disease characteristics. The study was further limited by an increasing frequency of missing data over time.

[0163] 9.4. Conclusion The PK of anifrolumab consistently demonstrated target-mediated drug elimination, with concentrations or exposure decreasing more than dose proportionally at low dose levels.High bioavailability of anifrolumab administered via SC injection was observed in Study 06 (healthy volunteers); the ratio of AUC of anifrolumab SC to anifrolumab IV below 300 mg was approximately 87%.

[0164] 10. Example 4: Determination of Optimal Subcutaneous Unit Dose 10.1. Purpose To find the optimal dosing regimen for subcutaneous administration of anifrolumab, we developed population PK and PK / PD models designed to utilize existing human clinical trials. PK data from Phase III studies 04 and 05 and Phase II study 1013 were used to aid in the development of the population PK model.

[0165] Our initial goal was to find a subcutaneous dose that would provide equivalent exposure to a standard 300 mg IV (Q4W) dose while allowing for more regular dosing that could be delivered in a smaller volume. This has been demonstrated, for example, by Furie et al. 2017, which is incorporated herein by reference in its entirety. 15 As reported in, summarized in Examples 3 and 4, based on the understanding that 300 mg IV Q4W provides an optimal clinical PK profile and clinical efficacy (e.g., with respect to achieving a BICLA response).

[0166] 10.2.Results 10.2.1 Initial Selection of Subcutaneous Anifrolumab Dose In initial analyses, we determined specific dosing regimens predicted to provide exposure equivalent to that achievable with 300 mg Q4W IV. Initially, a dosing regimen of 105 mg subcutaneously weekly (QW) was chosen based on the projected bioavailability, as Tummala et.al. 2018 found that the planned bioavailability accounts for interindividual variability in bioavailability. 26 (incorporated herein by reference in its entirety) (FIG. 15A). 105 mg SC QW appeared to provide comparable or improved median trough concentrations and IFNGS suppression as the comparable 300 mg Q4W mg IV dose (FIGS. 16A and 16B). From these initial analyses, it appeared that the SC 105 mg QW dose of anifrolumab was equivalent to 300 mg Q4W and therefore should be selected as having the optimal efficacy / risk profile for the treatment of SLE patients. Importantly, from these analyses, it was assumed that the 300 mg IV dose was close to the plateau of the dose-response curve for anifrolumab.

[0167] 10.2.2. Modification of Subcutaneous Anifrolumab Dose Selection Therefore, we initially considered 105 mg QW to be the optimal anifrolumab SC dose for the treatment of type I IFN-mediated diseases based on the available data from the MUSE study, Study 06, and Study 08. However, to confirm the selection of the 105 mg SC dose, we performed further analysis of data from the TULIP I (Study 04) and TULIP II (Study 05) clinical trials.

[0168] Additional data was used to demonstrate a positivity-exposure-BICLA association in IFNGS-high patients. Surprisingly, this association was observed even within the 300 mg IV Q4W group (Figures 17A and 17B). Thus, BICLA response was variable within the 300 mg IV Q4W patient group. Logistic regression of Week 52 BILCA response in patients confirmed that PK exposure was a significant covariate in both TULIP I and TULIP II. In both analyses of IFNGS-high patients who completed treatment individually in all participants and in both TULIP I and TULIP II, and in the pooled TULIP I and TULIP II analyses, C ave was found to be statistically significant. In the pooled data of the TULIP I and TULIP II trials, a higher C ave Exposure-response correlated with higher BICLA and SRI (4). In other words, there was exposure-dependent variability in response to anifrolumab among SLE patients receiving 300 mg Q4W IV (Figures 17A and 17B).

[0169] Thus, it was surprising to find that the suboptimal 150 mg IV dose was in the step region of the exposure-response curve, while the 300 mg IV Q4W dose was in the beginning of the exposure-response plateau ( FIG. 18A ). As a result of these analyses, the inventors determined that the 105 mg QW subcutaneous dose (previously considered equivalent to the 300 mg IV Q4W dose) did not provide an optimal balance of efficacy and safety in SLE patients. Thus, the inventors decided to select a different dose for SC administration that would mitigate the impact of variability in the response of the SLE patient population.

[0170] In summary, from early analysis, it seemed that administering a subcutaneous dose of 105mg QW anifrolumab would achieve at least similar efficacy as 300mg IV Q4W.However, surprisingly, after further analysis by the inventors of newly available data from further studies, it was found that the concentration of this once-weekly (QW) dose could be increased without reaching a maximum threshold for bioavailability and efficacy.In other words, the QW dose could be increased beyond 105mg to provide even higher plasma concentrations and IFNGS suppression, reducing the response variability observed in SLE patients.Therefore, the dose of 105mg would be suboptimal.

[0171] Surprising additional dose-response curve data were further validated by revealing that the probability of meeting an adequate BICLA response (in IFNGS-high patients) increased for weekly subcutaneous dosing at concentrations higher than the 105 mg dose (Table 10-1: SC efficacy predictions assuming no dose delays / interruptions). These data showed an unexpected location of the dose-response plateau (e.g., subcutaneous), which shifted to the right for doses increasing above 105 mg (Figure 18B), indicating that the maximum BICLA response is indeed achievable at doses higher than 105 mg, and that higher doses are preferred (Table 10-1).

[0172] [Table 14]

[0173] 10.2.3. Bioavailability of Anifrolumab is Highly Variable The inventors further investigated the bioavailability of anifrolumab and found that a surprisingly high level of variability in the bioavailability of anifrolumab following subcutaneous administration may exist among different patients. This high level of variability in the bioavailability of anifrolumab was not observed in previous studies that reported a bioavailability of >80% following subcutaneous administration. 26The bioavailability (F1) of anifrolumab in Study 08 (SLE patients, SC) was found to be 81% in healthy volunteers using a population PK model (Table 10-2).

[0174] [Table 15]

[0175] Typical bioavailability of monoclonal antibodies via subcutaneous injection ranges from 52 to 80%. 49 We performed external validation of Study 08, Ph2 SC in SLE using the PPK model developed with healthy volunteers and SLE patients from the IV study to determine bioavailability in the SLE population.

[0176] Detailed analysis of the data from Study 08 revealed that bioavailability was affected by the site of SC administration. In particular, when the bioavailability of 300 mg in the abdomen was extrapolated to IV, the bioavailability (F1) was estimated to be 85.4% compared to 81% when the injection site was not considered. Therefore, the C trough The C-value tended to be lower compared to abdominal injection (Figures 19A and 19B). It was therefore concluded that, surprisingly, bioavailability could indeed be as low as 70%, considering the variability due to injection site and the higher variability of bioavailability in SLE patients compared to healthy volunteers. Importantly, assuming a bioavailability (F1) of 81-87%, 105 mg initially had a C-value comparable to that of 300 mg IV. ave (Figure 20). In contrast, when the estimated bioavailability decreased to approximately 70% or less, the median C ave fell to less than 1 (Figures 21A, 21B and Table 10-3).

[0177] [Table 16]

[0178] Furthermore, there was no significant difference between the 105 mg SC QW and the suboptimal IV dose, 150 mg Q4W. ave There was an undesirable 30% overlap when the SC dose was used, compared to only 16% overlap when a bioavailability of 81% was assumed (Figure 21A). However, when the SC 120 mg dose was used, there was a significant difference in C with the 150 mg IV dose. ave The overlap was less than that with the optimal IV dose of 300 mg IV, even when a low bioavailability of 70% was assumed (Figure 21B). Furthermore, the 120 mg SC QW dose had minimal overlap with the undesirable 1000 mg IV dose (Figure 21C), which increases the risk of shingles infection (Figure 23). The 150 mg SC QW dose had undesirable overlap with the 1000 mg IV Q4W dose. Even more surprisingly, SC doses of 120 mg and above were predicted to have better PD suppression (Table 10-4) than the estimated optimal 300 mg IV dose (Table 10-5).

[0179] Therefore, selection of a dose higher than 105 mg, preferably 120 mg or higher, optimizes exposure-response by minimizing the impact of variability in response onset and bioavailability in SLE patients (Table 10-4, Figures 22A and 22B). A SC dose of less than 150 mg QW is also desirable to reduce the risk of herpes zoster infection.

[0180] [Table 17]

[0181] [Table 18]

[0182] The doses of 120 mg and 135 mg QW in particular offer a reasonable benefit-risk profile. At doses of 150 mg QW and above, assuming that a SC dose of 150 mg QW is equivalent to 1000 mg IV Q4W, there is an increased safety risk, e.g., increased risk of shingles in patients (Figure 21C, Figure 23). Thus, subcutaneous doses of less than 150 mg QW and greater than 105 mg QW were determined to be preferred doses. Subcutaneous doses of less than 150 mg QW and less than or equal to 135 mg were determined to be more preferred doses. The subcutaneous dose of 120 mg was determined to be the optimal dose.

[0183] In summary, the inventors surprisingly found that the optimal subcutaneous dose of anifrolumab may initially appear to be 105 mg QW, given the previously available preliminary data (Figure 12). However, further data and analysis surprisingly revealed that doses below 105 mg QW were under-compliant in a significant proportion of patients (Figure 18B, Table 10-3). Thus, the particularly advantageous dosing regimen identified by the inventors was a dose higher than 105 mg QW. In particular, the optimal dose was determined to be 120 mg subcutaneous QW, which is equivalent to approximately 400 mg IV Q4W, depending on the estimated bioavailability. Thus, the optimal SC dose is surprisingly >30% higher than that considered optimal based solely on a comparison with 300 mg IV Q4W and the previously understood bioavailability of anifrolumab.

[0184] Thus, the inventors have surprisingly shown that a dose of more than 105mg SC QW and less than 150mg SC QW, particularly a dose of 120mg QW, (a) maximizes efficacy while maintaining an acceptable safety profile, (b) mitigates the impact of bioavailability variability, and (c) mitigates the impact of response onset variability.Thus, dosing more than 105mg QW advantageously accounts for bioavailability variability and results in improved treatment outcomes.Dosages less than 150mg QW reduce the risk of herpes zoster infection.

[0185] Pharmacokinetic data from healthy volunteers (Study 06 [IV arm only]) and SLE patients (Studies 1013, 02, 04, and 05) were also pooled to evaluate the impact of covariates such as demographics and renal / liver function tests on PK exposure. Patients with high body weight and high type I IFN tests were found to have very high clearance (CL) and very low concentrations. However, surprisingly, there was no clinically relevant impact of these covariates on efficacy and safety. Surprisingly, other covariates related to specific populations evaluated in the population PK modeling were found to be insignificant, including race / ethnicity / region, age, sex, renal / liver function tests, standard of care therapies (e.g., OCS, antimalarials, azathioprine, methotrexate, mycophenolate mofetil, mycophenolic acid, mizoribine, and NSAIDs), and medications commonly used in SLE patients (ACE inhibitors and HMG-CoA reductase inhibitors).

[0186] 10.3. Conclusion We demonstrate that anifrolumab doses <150 mg Q and >105 mg QW have at least equivalent or higher C than 300 mg IV Q4W. ave It has been shown that the 120 mg SC QW dose provides efficacy at least similar to that shown for the 300 mg IV Q4W dose over a 52 week period. The 120 mg SC QW dose, in particular, provides efficacy at least similar to that shown for the 300 mg IV Q4W dose. Moreover, the 120 mg SC QW dose has been reasonably demonstrated to provide efficacy that exceeds that demonstrated for the 300 mg IV Q4W dose.

[0187] Based on the data demonstrated herein, a subcutaneous dose of anifrolumab was selected for a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study evaluating the efficacy and safety of subcutaneous anifrolumab in adult patients with SLE. The study design is shown in Figure 27A. In summary, two doses of SC anifrolumab (150 mg and 300 mg once every 2 weeks [Q2W]) were evaluated in a completed Phase 2 SC study (Study 06) in SLE patients with high type I IFN test results and active skin disease. The primary pharmacokinetic (PK) / pharmacodynamic (PD) endpoints of the Phase 2 SC study were analyzed at Week 12, and the safety and tolerability of SC administration of anifrolumab was evaluated through Week 52. Based on the PK / PD data from the Phase 2 SC study, and data from the anifrolumab IV study, mean concentrations (C ) of anifrolumab were comparable and non-inferior to a single injection of 300 mg IV. ave The 120 mg QW dose was selected for this current Phase 3 SC study to provide efficacy comparable to that of 300 mg IV Q4W, and thus 120 mg SC QW is expected to provide at least similar efficacy as 300 mg IV Q4W.

[0188] Considering the change in dosing interval from Q4W to QW, and at least a similar C ave By providing 120 mg SC QW, trough concentrations are predicted to be higher than those of 300 mg IV Q4W, and therefore are expected to provide comparable PD suppression to that of 300 mg IV. In addition, the C ave C1000 mg IV has been shown to be safe and tolerable (evaluated in Phase 2b study 1013). ave has minimal overlap with 1000 mg IV Q4W and therefore any dose equivalent to less than 1000 mg IV Q4W is considered safe.

[0189] The development of an SC administration route using the APFS of an AI for anifrolumab is expected to improve convenience and dosing flexibility, reduce patient and / or caregiver exposure to infection risks (including but not limited to influenza or COVID-19) associated with visiting a clinic for medication administration, and improve access to and compliance with treatment.

[0190] 11. Example 5: Classification of Patients with Systemic Lupus Erythematosus Enrolled in Two Phase 3 Trials Using EULAR / ACR 2019 Criteria 11.1. Background / Objectives The TULIP-1 and TULIP-2 trials of the anti-type I IFN receptor antibody anifrolumab enrolled patients with autoantibody positivity (ANA, anti-dsDNA, or anti-Smith [anti-Sm]) who met the ACR 1997 classification criteria for SLE. 14、16、24 The aim of this analysis was to assess the number of patients enrolled in the TULIP trial who also met the revised EULAR / ACR 2019 criteria. 25 .

[0191] 11.2. Method TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) ​​were randomized, placebo-controlled, 52-week trials of intravenously administered anifrolumab in patients with moderate-to-severe SLE despite standard therapy. Inclusion criteria included meeting at least four of the ACR 1997 criteria for SLE, positive ANA and / or anti-dsDNA and anti-Sm antibodies, and moderate-to-severe SLE. Data to explore classification using the EULAR / ACR 2019 criteria were pooled from ACR criteria, BILAG-specific SLE history, and documented medical history.

[0192] 11.3.Results The TULIP-1 and TULIP-2 data pools included 726 patients with SLE. Of these, all but two (99.7%) met the ACR 1997 SLE criteria (Table). The EULAR / ACR 2019 classification criteria for SLE were met by 712 / 726 patients (98.1%). Thus, the majority of patients (97.9% [711 / 726]) were concordant in meeting both the ACR 1997 and EULAR / ACR 2019 SLE classification criteria. Among patients classified as having SLE using the ACR 1997 criteria, 1.8% (13 / 726) did not meet the EULAR / ACR 2019 criteria. Of these 13 discordant patients, 8 were ANA negative but anti-dsDNA or anti-Sm antibody positive. Two patients did not meet the ACR 1997 criteria at baseline; one patient was not classified as having SLE using either the ACR 1997 or EULAR / ACR 2019 criteria, and the other patient was classified as having SLE using the EULAR / ACR 2019 criteria. This latter discordant patient did not meet the ACR 1997 criteria and had non-erosive arthritis and positive ANA, but met the EULAR / ACR 2019 criteria and had positive ANA, fever, non-scarring alopecia, and joint complications. At study baseline, positive ANA (97.2%) and non-erosive arthritis (97.5%) were the two most frequent ACR 1997 criteria among all patients.

[0193] [Table 19]

[0194] 11.4. Conclusion Nearly all patients enrolled in the TULIP-1 and TULIP-2 trials were classifiable as having SLE using both the ACR 1997 classification criteria and the EULAR / ACR 2019 criteria. Among patients not fulfilling the new criteria, the majority were ANA negative but had detectable autoantibodies to dsDNA and / or Sm.

[0195] 12. Example 6: Treatment of refractory SLE Background In two phase 3 trials, TULIP-1 and TULIP-2, the type I IFN receptor monoclonal antibody anifrolumab improved disease activity in patients with SLE. Here, we used pooled data from the TULIP trials to compare the efficacy of anifrolumab in patients with recent onset (defined by time since diagnosis) versus established SLE disease.

[0196] 12.2. Method TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) ​​were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab 300 mg every 4 weeks for 48 weeks in patients with moderate-to-severe SLE despite standard therapy. 1,2 All patients were aged 18–70 years and met ACR criteria for SLE. Baseline characteristics and BILAG-based Composite Lupus Assessment (BICLA) response rates at week 524 for anifrolumab 300 mg versus placebo were compared between patients who were within 2 years (recent) of SLE diagnosis at the baseline study visit and those who were diagnosed more than 2 years (established). Efficacy was analyzed with a stratified Cochran-Mantel-Haenszel method to control for randomization stratification factors and trials.

[0197] 12.3.Results Among 726 patients included from TULIP-1 and TULIP-2 (anifrolumab, n=360; placebo, n=366), 594 had established disease (anifrolumab, n=301; placebo, n=293) and 132 had recent disease (anifrolumab, n=59; placebo, n=73) at baseline. In contrast to patients with recent onset disease, patients with established disease were more likely to have a higher median age (43 vs. 37 years), be female (94.1% vs. 87.1%), have a high IFN gene signature (83.5% vs. 78.8%), be anti-dsDNA positive (45.6% vs. 38.6%), have a BILAG-2004 A entry of >1 (49.7% vs. 43.9%), and be receiving oral glucocorticoids (83.2% vs. 76.5%) or immunosuppressants (49.8% vs. 40.9%) at baseline (Figure 24). Patients with established versus recent disease were more likely to have a high IFN gene signature (IFNGS) (83.5% vs. 78.8%), anti-dsDNA antibody-positive (45.6% vs. 38.6%), low complement 4 (C4) (24.7% vs. 16.7%), ≥1 BILAG-2004 A item (49.7% vs. 43.9%), and a higher mean global SDI score (0.7 vs. 0.1). Patients with established versus recent disease were more likely to be receiving oral glucocorticoids (GCs) (83.2% vs. 76.5%) and / or immunosuppressants (49.8% vs. 40.9%) but not antimalarials (69.5% vs. 78.0%).

[0198] The number of BILAG-2004 A or B items across organ domains was similar in patients with established or recent disease, except for the kidney domain, where a higher proportion of patients with established disease had more severe scores (A or B items; 8.9% vs. 3.0%) (Figure 25).

[0199] A treatment benefit of anifrolumab versus placebo, as assessed by BICLA response at week 52, was present in patients with established disease (difference [95% CI] 17.1% [9.3, 24.8], nominal P < 0.001) and recent disease (difference [95% confidence interval (CI)] 14.4% [-2.2, 31.1], nominal P = 0.090).

[0200] 12.4. Conclusion Data from the TULIP trial provide evidence of the efficacy of anifrolumab in patients with SLE, either established or recent disease. Patients with established SLE disease were more likely to have high IFNGS, receive immunosuppressants at baseline, be anti-dsDNA antibody-positive, and have lower C4 levels, renal complications, and higher overall organ damage scores compared to patients with recent disease, likely indicating more severe and / or refractory disease. Despite differences in baseline characteristics between patients with established and recent disease, BICLA response rates with anifrolumab were similar in patients with established versus recent disease. Data from the TULIP trial support the efficacy of anifrolumab in patients with severe, refractory, and / or established SLE.

[0201] 13. Example 7: SLE Treatment History and Efficacy of Anifrolumab with Baseline Standard Therapy in Patients with Systemic Lupus Erythematosus from Two Phase 3 Studies Background In the phase 3 TULIP-1 and TULIP-2 trials, anifrolumab, a type I IFN receptor monoclonal antibody, improved disease activity versus placebo in patients with moderate-to-severe SLE despite standard therapy with oral glucocorticoids (GCs), antimalarials, and / or immunosuppressants (refractory disease).We investigated whether prior use of standard therapy, as well as baseline standard therapy, influenced the efficacy of anifrolumab in pooled data from TULIP-1 and TULIP-2.

[0202] 13.2. Method TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) ​​were 52-week trials of intravenous anifrolumab 300 mg or placebo every 4 weeks for 48 weeks, and eligible patients met ACR criteria for SLE. At screening, all patients were required to have moderate-to-severe SLE (SLEDAI-2K ≥ 6, BILAG-2004 organ domain scores of ≥ 1 A or ≥ 2 B, physician global assessment ≥ 1) and to be receiving one or more of the following: oral GCs, antimalarials, immunosuppressants (azathioprine, mizoribine, mycophenolate mofetil, mycophenolate, and / or methotrexate). Patients were divided into subgroups by baseline SLE treatment. British Isles Lupus Assessment Group Composite Lupus Assessment (BICLA) responses at week 52 were compared across baseline SLE treatment subgroups using stratified Cochran-Mantel-Haenszel methods.

[0203] 13.3.Results Overall, 726 patients received anifrolumab 300 mg (n=360) or placebo (n=366) in TULIP-1 and TULIP-2. Demographics and baseline disease characteristics were generally balanced between treatment groups. The median time from SLE diagnosis to randomization (pre-baseline) was 84.5 months, during which 89.5% of patients received GCs, 84.3% received antimalarials, and 68.0% received immunosuppressants. Prior to baseline, all patients received ≥1 SLE-related therapy, 34.3% received 2 SLE-related therapies, and 57.3% received ≥3 SLE-related therapies. At baseline, patients received GCs (82.0%), antimalarials (70.2%), and / or immunosuppressants (48.2%), with the majority receiving a combination of the three (Table 13-1). Anifrolumab 300 mg was associated with higher BICLA response rates versus placebo across all assessed baseline SLE standard therapy subgroups, with positive treatment differences ranging from 6.9% (antimalarials + immunosuppressants) to 50.8% (immunosuppressants only) (Figure 26); however, some groups had small sample sizes and the effect of dose on efficacy was not examined. Additionally, a positive treatment difference favoring anifrolumab 300 mg versus placebo was observed in patients receiving GCs + antimalarials + immunosuppressants at baseline, who were more likely to have treatment-refractory disease (53.6% vs. 32.2%; Δ=21.4%; 95% CI: 7.4 to 35.4).

[0204] [Table 20]

[0205] 13.4. Conclusion In two phase 3 studies, patients with potentially more treatment-refractory SLE, who required treatment with, for example, GCs, immunosuppressants, and antimalarials, consistently showed higher BICLA response rates with anifrolumab 300 mg than with placebo, regardless of the use of SLE standard therapy. Pooled data from the two phase 3 studies showed that the treatment effect of anifrolumab 300 mg on BICLA response was consistent regardless of baseline standard therapy use. In particular, the consistent treatment response for the subgroup of patients with the highest use of standard therapy at baseline plausibly demonstrates that anifrolumab treatment benefits patients with refractory disease.

[0206] 14. Example 8: Injection Device Anifrolumab is administered via an injection device [1][9] such as a prefilled syringe (PFS) (Figure 27A) or an autoinjector (AI) (Figure 27B).

[0207] 14.1. Automatic injection device Anifrolumab may be administered by an autoinjector [1]. The autoinjector is shown in exploded view (FIG. 28A) and assembled form (FIG. 28B). A label [4] is wrapped around or affixed to the autoinjector [1] (FIG. 28C). The autoinjector has an autoinjector housing [3], a cap and cap remover [2], and a drive unit [5]. A unit dose [6] of a liquid anifrolumab formulation is contained within the autoinjector housing [3]. The unit dose [6] is visible through a viewing window [7].

[0208] 14.2. Prefilled Syringes with Accessories Anifrolumab may be administered by an accessory prefilled syringe (APFS) [8]. The APFS [8] contains a unit dose of anifrolumab [6] contained in a primary container [9] shown in assembled form in FIG. 29A and in an exploded view in FIG. 29B. The primary container [9] has a plunger stopper

[16] . The primary container has a nominal fill volume

[17] of 0.8 ml, but may contain slightly more than 0.8 ml. The remainder of the space in the primary container [9] is occupied by an air bubble

[18] . The air bubble

[18] may have a size of 3-5 mm, optionally 4 mm. The primary container [9] has a defined stopper position

[19] .

[0209] The primary container [9] of the accessory prefilled syringe (APFS) is provided in a PFS assembly [8], including a needle guard

[12] , a finger flange

[11] , and a plunger rod

[13] . A label

[14] is provided with the primary container [9] in the PFS assembly [8]. The label

[14] is wrapped around the syringe [9] at a label placement location

[15] .

[0210] 14.3. Packaging An injection device [1] [8] is provided in a kit

[20] (FIG. 30). A label [4]

[14] is provided with the APFS or autoinjector in the package. The label includes instructions for use of the injection device [1], [8]. The package includes a tamper seal.

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Claims

1. A pharmaceutical composition comprising anifrolumab for use in a method for treating severe systemic lupus erythematosus (SLE) in a subject in need thereof, said method comprising administering anifrolumab to said subject.

2. 2. The pharmaceutical composition of claim 1, wherein the subject has a SLEDAI-2K score of ≧10 prior to treatment with anifrolumab.

3. The pharmaceutical composition of claim 1, wherein the method comprises administering an intravenous dose of anifrolumab to the subject.

4. 4. The pharmaceutical composition of claim 3, wherein the intravenous dose is ≧300 mg of anifrolumab.

5. 4. The pharmaceutical composition of claim 3, wherein the intravenous dose is ≦1000 mg.

6. 4. The pharmaceutical composition of claim 3, wherein the intravenous dose is about 300 mg, about 900 mg, or about 1000 mg.

7. 4. The pharmaceutical composition of claim 3, wherein the intravenous dose is administered every four weeks (Q4W).

8. The pharmaceutical composition of claim 1, wherein the method comprises administering a subcutaneous dose of anifrolumab.

9. 9. The pharmaceutical composition of claim 8, wherein the subcutaneous dose is >105 mg and <150 mg of anifrolumab.

10. 9. The pharmaceutical composition of claim 8, wherein the subcutaneous dose is ≦135 mg of anifrolumab.

11. 9. The pharmaceutical composition of claim 8, wherein the subcutaneous dose is about 120 mg.

12. 9. The pharmaceutical composition of claim 8, wherein the subcutaneous dose is administered once a week.

13. 2. The pharmaceutical composition of claim 1, wherein the subject has a CLASI activity score of ≧10 prior to treatment with anifrolumab.

14. 10. The pharmaceutical composition of claim 1, wherein the subject has a swollen and tender joint count of ≧6 prior to treatment with anifrolumab.

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