Treatment of lupus nephritis with Anti-type i inf receptor antibody anifrolumab

Abstract

To provide a new method for treating lupus nephritis (LN), which improves renal response, reduces recurrence, prevents eventual end-stage renal disease (ESRD), and reduces the need for glucocorticoids.SOLUTION: WHAT IS CLAIMED IS: 1. A method of reducing lupus nephritis (LN) disease activity in a subject in need thereof, comprising administering to the subject a type I IFN receptor (IFNAR1) inhibiting agent. Preferably, the IFNAR1 inhibitors are human monoclonal antibodies specific for IFNAR1, such as anifrolumab.SELECTED DRAWING: None

Description

[Background technology]

[0001] Lupus nephritis (LN) is one of the most common and severe manifestations of lupus, occurring in approximately 40% of SLE patients [1]. LN is more common in African-American, Hispanic, and Asian patients compared with patients of European descent [2]. The accumulation of immune complexes in renal tissue and the subsequent inflammatory response can lead to irreversible glomerular and tubulointerstitial damage [1]. LN is strongly associated with increased morbidity and premature mortality in SLE, with the standardized mortality ratio (SMR) being approximately three times higher in patients with LN compared with patients with extrarenal SLE and six to nine times higher compared with the general population. According to the World Health Organization (WHO) histological classification, proliferative LN includes patients with focal class III and diffuse class IV proliferative glomerulonephritis [3] and represents a subset of patients with a poor prognosis, with up to 45% progressing to end-stage renal disease within 15 years of diagnosis [4].

[0002] The ultimate treatment goal for patients with active proliferative LN is to prevent end-stage renal disease and death.[5] Persistent proteinuria and / or acute renal dysfunction indicate renal inflammation and are risk factors for progressive renal damage and poor long-term outcomes.[1] Therefore, short-term treatment goals include attenuation of proteinuria, measured using the urinary protein-to-creatinine ratio (UPCR), and stabilization / improvement of estimated glomerular filtration rate (eGFR).[5]

[0003] Histopathological class III and IV lesions generally represent proliferative LNs requiring intensive immunosuppressive therapy to achieve the therapeutic goals of renal remission, preservation of renal function, and eventual prevention of end-stage renal disease (ESRD). While immunosuppressive therapy using mycophenolate mofetil (MMF) or cyclophosphamide (CYC) in combination with glucocorticoids is currently the recommended off-label standard of care for proliferative LNs in international guidelines, there remains a clear unmet therapeutic need. Treatment typically consists of an initial period of intensive immunosuppression lasting 3–6 months, followed by several years of less intensive treatment to maintain remission. [5] However, not all patients respond to this treatment; only 10%–40% achieve remission after one year. [6] Disease recurrence is common. [7] Furthermore, current treatments have significant side effects, including the risk of early menopause induced by CYC and organ damage due to long-term glucocorticoid use.

[0004] The Food and Drug Administration (FDA) approved belimumab in 2020 and voclosporin in 2021 for the treatment of patients with LN based on positive efficacy results over standard therapies. However, in phase 3 trials, fewer than 50% of patients achieved a complete renal response (CRR) after treatment with belimumab (CRR; requiring a urinary protein-creatinine ratio (UPCR) <0.5 mg / mg) [8-10]. Therefore, additional treatment options that further increase response rates while reducing glucocorticoid exposure remain needed.

[0005] LN diagnosis is made by renal biopsy and histopathological classification according to the 2003 ISN / RPS classification criteria [3], which also guides treatment. Active class III and class IV LN generally require intensive immunosuppressive therapy initially combined with high-dose glucocorticoids, followed by several years of continuous immunosuppressive therapy to achieve the clinically important treatment goals of renal remission, preservation of renal function, and ultimately prevention of ESKD. The currently recommended immunosuppressive therapy for class III and IV LN (used off-label in most areas) consists of MMF or cyclophosphamide in combination with glucocorticoids [5].

[0006] Even when renal outcomes improve after the introduction of immunosuppressive therapy, only 10%–40% of patients achieve remission after one year [6], and disease recurrence is common. Importantly, despite treatment and therapy, up to 20% of LN patients develop ESKD within 10 years of initial diagnosis, with significant side effects, including organ damage from long-term glucocorticoid use. Despite the recent approval of belimumab in the US and EU and voclosporin in the US for the treatment of active adult patients, there remains a significant unmet need, as more than half of patients do not respond to these therapies. Therefore, novel, effective, and safe therapies targeting novel pathways for the treatment of active LN remain to achieve clinical therapeutic goals: improving renal remission rates, reducing recurrence, and preventing ESKD while reducing the need for glucocorticoids.

[0007] Therefore, there remains a substantial unmet need for novel targeted therapies to improve renal response, reduce recurrence, and prevent ESRD, as well as reduce the need for glucocorticoids. LN remission rates remain suboptimal [8], and patients are at high risk of developing end-stage renal disease [4] and drug-related toxicities, particularly those associated with the long-term use of high-dose glucocorticoids [5].

[0008] Anifrolumab is a human monoclonal antibody targeting the type I interferon (IFN) receptor subunit 1

[11] . Two phase 3 randomized controlled trials, TULIP-1 and TULIP-2 (NCT02446899 and NCT02962960, respectively), demonstrated that anifrolumab 300 mg administered intravenously every 4 weeks (Q4W) provided therapeutic benefit across multiple clinical endpoints and was well tolerated in patients with moderate to severe SLE. Patients with LN were excluded from TULIP-1 and TULIP-2. The safety and efficacy of type I IFN receptor inhibitors in patients with LN have not been demonstrated, and anifrolumab is not approved for the treatment of LN. Summary of the Invention [Means for solving the problem]

[0009] The present invention solves one or more of the problems set forth above.

[0010] The present invention relates to the treatment of lupus nephritis (LN). In particular, the present invention relates to the use of a type I IFN receptor (IFNAR1) inhibitor for use in a method of treating LN. The present invention is supported by, inter alia, efficacy and safety data from a Phase 2, multicenter, multinational, randomized, double-blind, placebo-controlled clinical trial (NCT02547922), which are presented herein for the first time.

[0011] In another aspect, the present invention also relates to safe and effective dosing regimens of type I IFNAR (also referred to herein as IFNAR1 and IFNR) inhibitors for use in the treatment of LN. Surprisingly, higher doses of IFNAR1 inhibitors than those previously described for SLE patients (as described in WO 2013 / 188494, which is incorporated herein by reference) are confirmed to be safe and effective in LN patients. The present invention is supported, inter alia, by efficacy and safety data from NCT02547922, and these data and dosage information are presented herein for the first time.

[0012] The present invention also relates to subcutaneous doses of IFNAR1 inhibitors and their use in the treatment of LN. The present invention is supported by efficacy, safety, and PK data from, inter alia, a Phase 3, multicenter, multinational, randomized, double-blind, placebo-controlled clinical trial in patients with SLE (NCT02446899 and NCT02962960), a Phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial in patients with SLE (NCT02962960), a Phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial in patients with LN (NCT02547922), and a Phase 1, randomized, placebo-controlled, double-blind, placebo-controlled clinical trial in healthy subjects (NCT02601625), as well as PK / PD modeling data presented for the first time herein. [Brief explanation of the drawings]

[0013] [Figure 1] IFN score distribution. Figure 1A: 4-gene IFN score distribution. Figure 1B: Distribution of the 21-gene IFNGS in patients with SLE, LN, and Sjögren's syndrome. LN: lupus nephritis; SLE: systemic lupus erythematosus (SLE). HD = healthy donors. [Figure 2-1] Study 7 TULIP-LN study design and patient disposition. Figure 2A: Flow chart of the TULIP-LN study design. [Figure 2-2]Figure 2B: Breakdown of patients who completed the 52-week double-blind treatment period. All percentages are based on 145 patients in the full analysis population. a Of the patients not randomized, 179 did not meet screening criteria, 7 withdrew consent, 2 experienced an AE, 1 was lost to follow-up, and 1 patient was not included due to investigator decision; b One patient was assigned to each of the anifrolumab regimens but did not receive at least one dose and was therefore not included in the analysis; c Reasons for not entering the 2-year extension period included AEs, occurrence of specific study intervention discontinuation criteria, patient decision, and lack of treatment response. [Figure 3] Time to discontinuation of study drug, Kaplan-Meier plot (mITT population). More patients (42.9%) in the placebo group discontinued the study intervention prematurely than in either anifrolumab group. BR, basic regimen; IR, intensive regimen; mITT, modified intention-to-treat. At the time of the primary analysis (week 52), the second-year study period was still ongoing, and data for patients who continued into the second-year study period were censored. [Figure 4-1] Progression of the primary efficacy endpoint. Figure 4A. Geometric mean (GM) change from baseline in 24-hour UPCR over time. GMR for the relative improvement in 24-hour UPCR for the anifrolumab group vs. placebo group (where a GMR <1 favors anifrolumab). A P value of ≤0.05 for the total anifrolumab group vs. placebo group was considered significant. All other P values ​​shown are nominal. Numerically greater improvements in 24-hour UPCR were observed in the total anifrolumab group and the anifrolumab IR group compared with the placebo group from Weeks 12 to 36, and in the anifrolumab IR group compared with the anifrolumab BR group at all time points. Figure 4B. Proportion of patients with CRR over time. Responses of anifrolumab BR for all CRR definitions were similar to or lower than those of the placebo group at all time points except Week 12. [Figure 4-2]Figure 4C: Progression of the primary efficacy endpoint. Time to sustained CRR0.5 was numerically shorter with anifrolumab IR compared with placebo. Time to CRR0.5 was sustained through week 52. BR, basic regimen; CI, confidence interval; CRR, complete renal response; CRR0.5, CRR with UPCR ≤ 0.5 mg / mg; GM, geometric mean; GMR, geometric mean ratio; HR, hazard ratio; IR, intensive regimen; UPCR, urinary protein-creatinine ratio. Error bars represent 95% CI. a GM of the ratio of 24-hour UPCR values ​​at each time point to baseline values ​​for each treatment group (a value of <1 indicates improvement); c Patients from Italy and France were excluded from the analysis; d Time to sustained CRR0.5 was analyzed post hoc. [Figure 5-1] 24-hour UPCR, CRR, and sustained steroid reduction. Figure 5A: Subgroup forest plot of 24-hour UPCR change from baseline at week 52. There were no significant differences in 24-hour UPCR between predefined subgroups. [Figure 5-2] Figure 5B: CRR and sustained steroid sparing. Anifrolumab IR was associated with CRR with sustained glucocorticoid sparing. [Figure 6] Changes in mean cumulative proteinuria (UPCR) over time. Both anifrolumab groups demonstrated numerically lower cumulative proteinuria than the placebo group throughout the treatment period. Mean cumulative proteinuria (area under the curve of UPCR normalized by the expected follow-up period) for anifrolumab IR, anifrolumab BR, and placebo was assessed using covariance-controlled analysis of baseline UPCR and stratification factors. All data after discontinuation were excluded from the analysis. Error bars represent standard error. [Figure 7] Changes in the proportion of patients with CRRa and CRR 0.5 over time. Figure 7A: Changes in the proportion of patients with CRRa over time. Figure 7B: Changes in the proportion of patients with CRR 0.5 over time. CRRa, complete renal response requiring an inactive urinary sediment; CRR 0.5, complete renal response requiring a urinary protein-creatinine ratio ≦0.5 mg / mg; IR, intensive regimen. Error bars indicate 95% confidence intervals. [Figure 8]Measurement of IFNGS neutralization and disease activity over time. Median 21-gene type I IFN PD neutralization rates in patients with elevated IFNGS test results. With anifrolumab IR, a median PD neutralization rate of >80% was observed at all visits (weeks 12, 24, 36, and 52). With anifrolumab BR, a median PD neutralization rate of >80% was observed only at visits 12 and 24, with subsequent rebound in IFNGS. BR, basic regimen; IFNGS, interferon gene signature; IR, intensive regimen; LS, least squares; MAD, median absolute deviation; PD, pharmacodynamics; PGA, physician global assessment; PtGA, patient global assessment; SE, standard error; SLEDAI-2K, systemic lupus erythematosus disease activity index 2000. The number of patients with nonmissing values ​​at visits is shown. [Figure 9] Plots of anti-dsDNA antibody and C3 complement levels. Figure 9A: Compared to the placebo group, patients who were anti-dsDNA antibody positive at baseline had a numerically greater decrease in anti-dsDNA antibody levels with anifrolumab IR than with placebo. Data points are median change from baseline, and error bars indicate median absolute deviation. Figure 9B: Patients with low C3 at baseline had increases in C3 across groups (IR and BR). Data points are median change from baseline, and error bars indicate median absolute deviation. [Figure 10] Plot of C4 complement levels. There was no apparent difference in C4 increase between groups. Data points are median change from baseline, and error bars indicate median absolute deviation. [Figure 11-1] SLEDAI-2K, PGA, and PtGA. Compared with placebo, anifrolumab IR induced numerically greater improvements from baseline in measures of disease activity (SLEDAI-2K, PGA, PtGA). Figure 11A: Change from baseline in non-renal SLEDAI-2K. Figure 11B: Change from baseline in PGA. [Figure 11-2] FIG. 11C: PtGa from baseline. [Figure 12]Logarithmic anifrolumab serum concentration-time profile (pharmacokinetic population). BR, basic regimen; IR, intensive regimen; LLOQ, lower limit of quantification. [Figure 13] PK modeling of anifrolumab concentrations over time for the anifrolumab basic and intensive regimens in IFNGS-high patients with LN and SLE. Figure 13A: In IFNGS-high patients (94.5%), the median steady-state concentration of anifrolumab at week 12 was 63.4 μg / mL with anifrolumab BR. Figure 13B: The median steady-state concentration of anifrolumab at week 12 was 63.4 μg / mL with anifrolumab IR (approximately 50% lower than non-renal SLE). The dashed black line indicates the median steady-state PK concentration at week 12 for patients with LN and non-renal SLE. PK modeling was performed using a nonlinear mixed-effects model using NONMEM 7.3 software (ICON Development Solutions, Ellicott City, MD, USA; 2006). Predicted anifrolumab concentrations for patients with SLE are based on pooled data from four clinical trials (n=664) of anifrolumab in patients with SLE: a phase 2 multicenter, open-label study in Japanese patients (NCT01559090), a phase 2b global multicenter MUSE RCT (NCT01438489), and a phase 3 global multicenter TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) ​​RCTs. [Figure 14] Overlay of concentration profiles measured for the baseline and intensive treatment regimens in Study 07 and the Model Project based on a population PK model of SLE patients. [Figure 15]Estimated anifrolumab clearance (L / day) in patients according to baseline 24-h UPCR values ​​(≤3 mg / mg vs. >3 mg / mg). Patients with baseline UPCR >3 mg / mg had higher anifrolumab clearance than patients with UPCR ≤3 mg / mg. BR, basic regimen; IR, intensive regimen; PK, pharmacokinetics; UPCR, urinary protein-creatinine ratio. Bars represent median ± interquartile range of anifrolumab clearance. Using a population-PK model developed for non-renal SLE, individual clearance estimates for baseline 24-h UPCR subgroups (≤3 mg / mg vs. >3 mg / mg) in the total anifrolumab group were estimated with a nonlinear mixed-effects model using NONMEM 7.3 software and fitted to the anifrolumab BR and anifrolumab IR datasets. PK data collected from the anifrolumab IR group after tapering to 300 mg were excluded due to the potential effect of tapering on changes in time-dependent clearance. [Figure 16] Mean anifrolumab serum concentration-time profiles. Figure 16A: MI-CP180 study in scleroderma (SSc) - Mean anifrolumab serum concentration-time profiles after a single IV dose. Data represent + / - SD. Mean data below the LLOQ are not plotted. IV, intravenous; LLOQ, lower limit of quantitation; MEDI546, anifrolumab; n, number of patients in subgroup; SSc, systemic sclerosis. Figure 16B: Study 06 in healthy volunteers - Mean anifrolumab serum concentration-time profiles after a single SC and IV dose. Samples where the actual collection time deviated from the nominal collection time by more than 10% were excluded from the average. IV, intravenous; N, number of subjects; SC, subcutaneous. [Figure 17-1] Study design and results of Study 08. Figure 17A: Phase II study design of SC anifrolumab in patients with SLE. Study 08 (NCT02962960) evaluated the effect of anifrolumab administered twice every other week. [Figure 17-2] Figure 17B: Mean serum concentrations of anifrolumab over time. Figure 17C: Neutralization of type I IFN gene signature by anifrolumab. [Figure 18]Neutralization of the type I IFN21 gene signature in patients with high type I IFN test levels in studies 04, 05, and 1013. [Figure 19] Median calculated AUC ratios (SC / IV). Figure 19A: Median calculated AUC ratios (SC / IV) from weeks 0 to 52 for various SC doses. Median AUC ratios (SC / IV) calculated based on estimated bioavailability from Study 06 from weeks 0 to 52 (where the subcutaneous dose is 75 mg (+ symbol), 90 mg (open squares), 105 mg (circles), 120 mg (triangles), or 135 mg (filled squares)). Here, the subcutaneous dose is administered once every seven days (QW) and the IV dose is administered once every four weeks (Q4W) at a dose of 300 mg. Based on AUC, both 90 mg SC QW and 105 mg SC QW appear similar to 300 mg IV. Figure 19B: Median calculated AUC ratios (SC / IV) for 90 mg and 105 mg SC QW. Between weeks 0 and 52, the median AUC ratio (SC / IV) calculated based on estimated bioavailability was approximately 7% lower than the bioavailability calculated from Study 06 (where the subcutaneous dose was 90 mg SC QW or 105 mg SC). [Figure 20] Figure 20A: Plot 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 area represents the 5th to 95th percentiles of the 300 mg IV Q4W dose. Figure 20B: Anifrolumab trough concentrations in IFNGS-high SLE subjects. Calculated trough concentrations of anifrolumab in plasma of patients with high IFNGS after dosing 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 administration. Based on trough, both 90 SC QW and 105 mg SC QW were predicted to have greater PD suppression than 300 mg IV. [Figure 21] Positive exposure-BICLA relationship observed in TULIP 1 and TULIP 2 in patients with elevated IFNGS. Figure 21A: TULIP I, placebo, anifrolumab 150 mg, and anifrolumab 300 mg. Figure 21B: TULIP II, placebo, and anifrolumab 300 mg. [Figure 22] BICLA dose response. Figure 22A: Dose-response curve (probability of meeting BICLA response criteria (in patients with high IFNGS) for anifrolumab Cave over 52 weeks) shows the predicted mean (gray 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 22B: Predicted PK and efficacy at different SC doses. Probability of meeting BICLA (in patients with high IFNGS) when administered subcutaneously once weekly starting at 105 mg up to 150 mg. Assumptions for generating the data did not include dose delays / interruptions. [Figure 23] Ctrough after thigh injection compared to abdominal injection. Figure 23A: 150 mg SC Q2W. Figure 23B: 300 mg SC Q2W. [Figure 24] Exposure prediction 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 25-1] Anifrolumab Cave in patients with elevated IFNGS over 52 weeks at different SC and IV doses. Figure 25A: 105 mg SC QW. Figure 25B: 120 mg SC QW. [Figure 25-2] Figure 25C: Overlap with 1000 mg IV Q4W. [Figure 26] Median Cave ratios for SC QW vs. 300 mg IV Q4W. Figure 26A: Assuming 81% bioavailability. Figure 26B: Assuming 70% bioavailability. [Figure 27]Mean anifrolumab concentration on incidence of herpes zoster. Incidence of herpes zoster (%) in Study 1013 patients receiving placebo, 300 mg IV anifrolumab, or 1000 mg IV anifrolumab. [Figure 28] Change in median UPCR over time and magnitude of change in clearance in patients with baseline 24-hour UPCR ≦3 mg / mg. Figure 28A: UPCR ≦3. Figure 28B: UPCR >3. CL, clearance; hr, time; n, number of patients; UPCR, urine protein-creatinine ratio; yr, years. [Figure 29] Type I IFN 21-GS in patients with LN. Figure 29A: Time course of PD suppression by treatment regimen in Study 07 for patients with a baseline 24-hour UPCR >3 mg / mg. Figure 29B: 24-hour UPCR values ​​stratified by steady-state PD suppression in Study 07 for patients with a baseline 24-hour UPCR >3 mg / mg. [Figure 30] Visual prediction check of the UPCR model. The plot shows the 95% confidence interval (dark gray) and 10th and 90th percentiles (light gray) of the model prediction of UPCR, along with the observed individual data (circles) and their median (solid line) and 10th and 90th percentiles (dashed lines). Model predictions are corrected for dropouts. Binning is indicated by vertical lines at the top. BR, basal regimen; IR, intensive regimen; UPCR, urine protein-creatinine ratio. [Figure 31] Visual prediction check of the PK model. The plot shows the 95% confidence interval (dark gray) and 10th and 90th percentiles (light gray) of the model-predicted median anifrolumab trough concentration, along with the measured individual data (circles) and their median (solid line) and 10th and 90th percentiles (dashed lines). Model predictions are corrected for dropouts. The lower line indicates the LLOQ of 0.02 μg / m. The 10th percentile of concentrations at week 12 in BR was below the LLOQ. Binning is indicated by the upper vertical line. BR, basic regimen; IR, intensive regimen; LLOQ, lower limit of quantitation; PK, pharmacokinetics. [Figure 32]Visual predictive check of the dropout model. The plot shows the 95% confidence interval of the model-predicted dropout (dark gray) along with the observed dropout (black line). BR, basic regimen; IR, intensive regimen. [Figure 33] Model-predicted impact of duration of intensification treatment on UPCR response. BR, basal regimen; IR, intensified regimen; IV, intravenous; Q4W, once every 4 weeks; QW, once weekly; SC, subcutaneous; UPCR, urine protein-creatinine ratio. [Figure 34] Model predictions of PK, UPCR, PD, and clearance for the proposed regimen. Simulations include only patients who did not drop out, showing the population median (bold line) and 10th-90th percentile interval (shaded area). The upper left panel shows anifrolumab concentrations. The baseline shows the median trough concentration at week 24 of 300 mg IV Q4W as predicted by a previously developed SLE PK model and the estimated IC80 and IC90 of the PD signature from the SLE PD model. The upper right panel shows UPCR. Percentage numbers indicate the proportion of patients with a dose <0.5 mg / mg (taking into account dropouts). The lower left panel shows PD suppression. 80% and 90% suppression values ​​are shown as references. The lower right panel shows anifrolumab clearance. CL, clearance; IC80, 80% inhibitory concentration; IC90, 90% inhibitory concentration; IV, intravenous; PD, pharmacodynamics; PK, pharmacokinetics; SLE, systemic lupus erythematosus; UPCR, urine protein-creatinine ratio. [Figure 35] 1150 mg SC provides a similar AUC to 900 mg IV in healthy volunteers. [Figure 36] 1150 mg SC provides a similar AUC to 900 mg IV in LN patients. Figure 36A: The AUC ratio is close to 1.0 throughout the entire 6 months of intensive treatment. Figure 36B: Median Ctrough (72 μg / mL) at week 24 is lower with SC compared to SLE patients on 1000 mg Q4W. Figure 36C: Trough PD suppression remains high throughout intensive treatment. [Figure 37]Urinary proteins in LN. Figure 37A: Urinary proteins associated with high NIH-AI and NIH-CI scores. Protein associations (FDR<0.1) are color-coded according to whether their concentration correlates positively (orange, +) or negatively (blue, -) with the respective outcome. Figure 37B: Urinary proteins associated with 4 or more clinical features. Protein associations (FDR<0.1) are color-coded according to whether their concentration correlates positively (+) or negatively (-) with the respective outcome. [Figure 38] Urinary proteins and IFNGS. Figure 38A: Correlation of urinary proteins associated with high IFNGS with other measures. Protein associations (FDR<0.1) are color-coded according to whether their concentrations correlate positively (+) or negatively (-) with the respective outcome. Figure 38B: Venn diagram of overlap in significant protein associations across the three kidney measures. Only proteins with statistically significant associations (FDR<0.1) are listed. [Figure 39] Ingenuity pathway analysis. Figure 39A: Ingenuity pathway analysis of 11 proteins commonly associated with eGFR, SLEDAI-R, and NIH-AI. The top four disease and molecular function categories scored by Fisher's exact test are shown. Highly redundant categories were removed. Significance threshold (dashed line). Figure 39B: Urinary proteins specific to all clinical features. [Figure 40] Delivery Devices. Anifrolumab is administered by injection devices [1][9] such as prefilled syringes (PFS) (Figure 40A) or autoinjectors (AI) (Figure 40B). [Figure 41] 41A, 41B, and 41C show exploded and assembled views of an autoinjector for administering anifrolumab or a functional variant thereof when filled with bulk drug. [Figure 42] Pre-filled syringe with accessories. Pre-filled syringe with accessories (APFS) for anifrolumab or its functional variants. The main tubing is shown in assembled form (FIG. 42A) and exploded view (FIG. 42B). The APFS and its additional components are shown in assembled form (FIG. 42D). [Figure 43] Packaging for the delivery device. [Figure 44] Anifrolumab heavy chain alignment. [Figure 45] Anifrolumab light chain alignment. DETAILED DESCRIPTION OF THE INVENTION

[0014] 4.1. Treatment of lupus nephritis (LN) In a first aspect, the present invention relates to a method for treating lupus nephritis (LN) in a subject in need thereof, comprising administering a type I IFN receptor (IFNAR) inhibitor to the subject to reduce lupus nephritis disease activity in the subject. The method may reduce the severity of LN disease in the subject. The method may prevent the progression of LN disease in the subject. LN diagnosis in a subject can be made by renal biopsy and histopathological classification according to the 2003 ISN / RPS classification criteria [3]. The LN may be proliferative LN. The LN may be class III or IV (either class V or not) LN. The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0015] The present invention also relates to a dosage regimen of an IFNAR inhibitor for treating LN in a subject. The data provided herein demonstrate that the dosage regimen of IFNAR previously identified as suitable for the treatment of SLE is insufficient for the treatment of LN. Treatment of LN requires an intensive dosage regimen (e.g., 900 mg Q4W IV or equivalent subcutaneous dose for at least 3 weeks), followed by a basic dosage regimen (e.g., 300 mg Q4W or equivalent subcutaneous dose).

[0016] Reducing LN disease activity in a subject can include treating the subject's LN. Reducing LN disease activity can include a complete renal response (CRR) in the subject after treatment compared to before treatment. CRR can be achieved by week 36 of treatment. Reducing LN disease activity in a subject can include a CRR and a UPCR of ≦0.5 mg / mg after treatment. Reducing LN disease activity in a subject can include a reduction in proteinuria in the subject after treatment compared to proteinuria in the subject before treatment. Proteinuria can be measured by UPCR. Proteinuria can be measured by 24-hour UPCR (see Section 5.5.7). Reducing lupus nephritis disease activity in a subject can include a surrogate CRR (aCRR) in the subject after treatment (see Section 5.5.5). The method can include administering mycophenolate mofetil (MMF) and / or steroids to the subject. The method may include steroid sparing in the subject, wherein the dose of steroid administered to the subject is tapered from a pre-sparing dose to a post-sparing dose. The post-sparing dose may be ≦7.5 mg / day of prednisone or prednisone equivalent (see Section 5.4). The pre-sparing dose may be 20 mg / day or prednisone equivalent. The steroid may include a glucocorticoid. The steroid may include an oral glucocorticoid.The method may include the use of hydrocortisone, mometasone, fluticasone, fluocinolone acetonide, fluocinolone, flurandrenolone acetonide, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, clocortolone, dihydroxycortisone, alclometasone, amcinonide, diflucortolone 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 include prednisone.

[0017] 4.2. Subject The subject may be a human subject. The subject may be an adult. The subject may be a patient with an increased 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 increased expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood. The subject may have increased expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood compared to a healthy subject. 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 expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subject's whole blood. The method may include measuring expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subject's whole blood by RT-PCR. The method can include measuring expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in a whole blood sample from the subject by RT-PCR. The subject can be a patient with a high type I IFN 21 gene signature. The subject can be a patient with a high type I IFN 4 gene signature.

[0018] The present invention also relates to a method of treating lupus nephritis, comprising analyzing the level of one or more proteins in a subject's urine before and / or after treatment, optionally in an isolated urine sample from the subject. The one or more proteins may be identified as elevated in the subject's urine before treatment compared to the level of the protein in a healthy subject. After treatment, the level of the one or more proteins in the subject's urine may be reduced compared to the pre-treatment level of the one or more proteins in the subject's urine.

[0019] The present invention also relates to a method for identifying a subject as suitable for treatment with an IFNAR1 inhibitor, the method comprising identifying or detecting elevated expression of one or more proteins in a urine sample isolated from the subject, compared to the expression of the respective one or more proteins in a healthy subject. The IFNAR1 inhibitor can be an IFNAR1 inhibitor according to the method of the present invention. The treatment method can be a treatment method of the present invention.

[0020] The subject may have proliferative LNs. The subject may have aggressive LNs. The subject may have class III or class IV LNs with or without coexisting class V LNs.

[0021] The one or more proteins may include adiponectin, alpha-2-macroglobulin (A2Macro), antithrombin-III (AT-III), apolipoprotein AI (Apo AI), apolipoprotein B (Apo B), apolipoprotein CI (Apo CI), apolipoprotein C-III (Apo C-III), fatty acid binding protein, heart (FABP, heart), lactoferrin (LTF), neuropilin-1, omentin, serum amyloid P component (SAP), and / or von Willebrand factor (vWF).

[0022] The one or more proteins may include Apo A-11, Apo B, Apo CI, cathepsin D, EN-RAGE, fibrinogen, LTF, MCP-1, RANTES, and / or IL-1β. The one or more proteins may include Apo B, Apo CI, and / or LTF.

[0023] Pharmaceutical Compositions In another aspect, the present invention relates to a pharmaceutical composition for use in treating LN in a subject, the method comprising subcutaneously administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising a unit dose of the present invention.

[0024] In another aspect, the present invention relates to a pharmaceutical composition for use in treating LN in a subject, the method comprising administering the pharmaceutical composition intravenously or subcutaneously to the subject.

[0025] In another aspect, the present invention relates to a pharmaceutical composition for use in a method for treating LN in a subject, the method comprising subcutaneously administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising a dose of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof), the dose being greater than 105 mg (>) and less than 150 mg (<). The dose of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) can be a unit dose (unit dosage form, pharmaceutical unit dosage form, pharmaceutical unit dose). Functional anifrolumab variants include antigen-binding fragments of anifrolumab and antibodies and immunoglobulin derivatives of anifrolumab.

[0026] In another aspect, the present invention relates to a pharmaceutical composition for use in a method of treating lupus nephritis in a subject, the method comprising subcutaneously administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising a dose of an IFNAR1 inhibitor (e.g., 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 an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) every four weeks. Weekly administration of the dose may provide a plasma concentration in the subject that is approximately equivalent to the plasma concentration provided by intravenous administration of 400 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) every four weeks. The dose may be <150 mg (i.e., less than 150 mg) of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The dose can be >105 mg (i.e., greater than 105 mg) of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The dose can be ≦135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The dose can be about 120 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The dose can be 120 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof).

[0027] The pharmaceutical compositions may comprise at least about 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 305, 310, 800, 805, 810, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 900, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 970, 975, 980, 985, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1101, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 12 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 1000, 1050, 1010, 1020, 1025, 1030, 1035, 1040, 1045, 1050, 1055, 1060, or 1065 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof).

[0028] The pharmaceutical composition may be administered to a subject in a single dose step or in multiple dose steps.

[0029] The pharmaceutical composition may be administered at intervals of 6 to 8 days. The pharmaceutical composition may be administered once weekly (QW). The pharmaceutical composition may be administered in a single administration step. The dose may be 120 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof), and the treatment method may include administering the dose in a single administration step once weekly (QW). The pharmaceutical composition may be administered once weekly for at least about 4 weeks. The pharmaceutical composition may be administered once weekly for at least about 8 weeks. The dose or unit dose may be administered once weekly for at least about 12 weeks. The pharmaceutical composition may be administered once weekly for at least about 16 weeks. The pharmaceutical composition may be administered once weekly for at least about 20 weeks. The pharmaceutical composition may be administered once weekly for at least about 24 weeks. The pharmaceutical composition may be administered once weekly for at least about 28 weeks. The pharmaceutical composition may be administered once weekly for at least about 32 weeks. The pharmaceutical composition may be administered once a week for approximately 8 weeks. The pharmaceutical composition may have a volume that allows delivery to a subject in a single subcutaneous administration step. The pharmaceutical composition may have a volume of 0.5 to 1 ml. The pharmaceutical composition may have a volume of less than 1 ml. The pharmaceutical composition may have a volume of approximately 0.8 ml.

[0030] Many patients with LN receive corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Anifrolumab allows for the gradual tapering of corticosteroids (glucocorticoids) in patients with LN (steroid sparing). A treatment method or method can include administering a corticosteroid to a subject, optionally an oral corticosteroid. The method can include tapering the dose of corticosteroid administered to the subject (steroid sparing). The method can include administering a first dose of corticosteroid followed by a second dose of corticosteroid, the second dose of corticosteroid being lower than the first dose of corticosteroid. The second dose of corticosteroid can be equal to or less than approximately 7.5 mg of prednisone equivalent (see Table 5). The second dose of corticosteroid can be equal to or less than 5 mg of prednisone equivalent. The method or treatment method may include administering a second dose of corticosteroid once daily. The first dose of corticosteroid may be approximately 10 mg of prednisone equivalent. The method may include gradually reducing the dose of corticosteroid administered to the patient from 10 mg or more per day to less than 10 mg per day. The method or treatment method may include administering a second dose of corticosteroid once daily. The method may allow for the administration of the reduced dose of corticosteroid to be maintained for several weeks. The second dose of corticosteroid may be administered for at least 24 weeks. The second dose of corticosteroid may be administered for at least 28 weeks.

[0031] Administration of the pharmaceutical composition may provide a plasma concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject of ≥ 10 μg (i.e., 10 μg or more). Administration of the pharmaceutical composition may provide a plasma concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject of 10-100 μg / ml. Administration of the pharmaceutical composition may provide a plasma concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject of 20-80 μg / ml. Administration of the pharmaceutical composition may provide a plasma concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject of 30-70 μg / ml. Administration of the pharmaceutical composition may provide a trough concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject of ≥ 20 μg / ml (i.e., 20 μg / ml or more). Administration of the pharmaceutical composition may provide a trough concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject of ≥ 30 μg / ml (i.e., 30 μg / ml or more). Administration of the pharmaceutical composition may provide a trough concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject of ≥ 40 μg / ml (i.e., 40 μg / ml or more). Administration of the pharmaceutical composition may provide a trough concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject of 20-100 μg / ml. Administration of the pharmaceutical composition may provide a trough concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject of 30-80 μg / ml. Administration of the pharmaceutical composition may provide a trough concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject of 40-70 μg / ml.

[0032] The subject may be a human subject. The subject may be an adult. The subject may have LN. The subject may be a patient with an increased 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 increased expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood. 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 expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subject's whole blood. The method may include measuring expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subject's whole blood by RT-PCR.

[0033] The pharmaceutical composition may provide a therapeutic effect in a subject that is at least equivalent to the therapeutic effect provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof administered once (Q4W). The pharmaceutical composition may provide a trough concentration of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in a subject that is higher than the trough concentration of anifrolumab or a functional variant thereof provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof once every four weeks (Q4W). The IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) may be included in the pharmaceutical composition. The pharmaceutical composition may comprise 150-200 mg / ml of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof), 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise about 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 or polysorbate 20. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0034] In another aspect, the invention relates to an injection device comprising a unit dose of the invention or a pharmaceutical composition for use according to the invention.

[0035] In another aspect, the present invention relates to an injection device comprising a pharmaceutical composition. The drug in the injection device may contain >105 mg (i.e., more than 105 mg) and <150 mg (i.e., less than 150 mg) of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The pharmaceutical composition in the injection device may contain about 120 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The pharmaceutical composition in the injection device may contain 120 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The pharmaceutical composition in the injection device may contain about 1150 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The pharmaceutical composition in the injection device may contain 1150 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The injection device may contain 0.8 ml of the pharmaceutical composition. The injection device may contain 7.7 ml of the pharmaceutical composition. The concentration of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) in the pharmaceutical composition in the injection device can be 150 mg / ml. The volume of the pharmaceutical composition in the injection device can be at least about 0.8 ml. The volume of the pharmaceutical composition can be about 0.8 ml.

[0036] The pharmaceutical composition in the injection device may comprise 150-200 mg / mL of anifrolumab or a functional variant thereof, 25-150 mM 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 lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition in the injection device may comprise 150-200 mg / mL of anifrolumab or a functional variant thereof, 25-150 mM 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 lysine HCl. The pharmaceutical composition in the injection device may comprise 130 mM trehalose dihydrate. The pharmaceutical composition in the injection device may comprise 0.05% polysorbate 80 or polysorbate 20. 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.

[0037] Devices In addition to providing subcutaneous administration of antibodies, the ability to self-administer (e.g., at home) can be further enhanced by subcutaneous administration using 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 additional options for optimizing patient care. Indeed, such devices may reduce the burden of frequent doctor visits for patients. An example of a suitable APFS device is described in Ferguson et al.

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

[0038] The doses discovered by the inventors offer further advantages in the context of APFS administration, as APFS devices typically administer a maximum dose of 1 ml. Doses in the range of >105 mg to <155 mg can be easily accommodated in a volume of approximately 0.8 ml, making the doses of the present invention highly suitable for APFS and AI administration. In comparison, larger doses (especially doses >150 mg) must be administered in a volume >1 ml due to the viscosity of anifrolumab, requiring at least two SC injections. This is inconvenient for patients and would require multiple prefilled devices.

[0039] The delivery device can be a single-use disposable system designed to allow manual SC administration of the dose.

[0040] In another aspect, the present 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 an IFNAR1 inhibitor, optionally wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof. The unit dose may comprise ≦135 mg (i.e., 135 mg or less) of an IFNAR1 inhibitor, optionally wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof. The unit dose may comprise approximately 120 mg of an IFNAR1 inhibitor, optionally wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof. The unit dose in the injection device may comprise 120 mg of an IFNAR1 inhibitor, optionally wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof. The unit dose in the injection device can consist essentially of >105 mg and <150 mg of the IFNAR1 inhibitor, optionally wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof. The unit dose in the injection device can consist essentially of ≦135 mg of the IFNAR1 inhibitor, optionally wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof. The unit dose in the injection device can consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the unit dose in the injection device can be about 150 mg / ml. The volume of the unit dose in the injection device can be less than 1 ml. The unit dose in the injection device can have a volume of 0.5 to 1 ml. The concentration of the unit dose can be about 0.8 ml. The volume of the unit dose can be 0.8 ml. A unit dose in the injection device may comprise a formulation of 150-200 mg / ml anifrolumab or functional variants thereof, 25-150 mM lysine salt, and uncharged excipients. A unit dose in the injection device may comprise a formulation of 150-200 mg / ml anifrolumab or functional variants thereof, 25-150 mM lysine salt, and uncharged excipients. A 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.

[0041] In another aspect, the present invention relates to an injection device comprising a unit dose. This unit dose may contain 1150 mg of an IFNAR inhibitor, and optionally, the IFNAR1 inhibitor is anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the unit dose in the injection device may be 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 0.5 to 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 volume of the unit dose in the injection device may be about 1 ml. The volume of the unit dose in the injection device may be 7.7 ml. The unit dose in the injection device may comprise a formulation of 150 to 200 mg / ml of anifrolumab or a functional variant thereof, 25 to 150 mM of a lysine salt, and an uncharged excipient. A unit dose in the injection device may contain a formulation of 150-200 mg / ml anifrolumab or a functional variant thereof, 25-150 mM lysine salt, and an uncharged excipient. The unit dose may contain 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.

[0042] 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 injector (AI).

[0043] 4.5.Kit In another aspect, the invention relates to a kit comprising a unit dose of the invention and instructions for use, wherein the instructions include directions for subcutaneous administration of the unit dose to a subject.

[0044] In another aspect, the invention relates to a kit comprising a pharmaceutical composition for use according to the invention, wherein the instructions for use include directions for subcutaneous administration of a unit dose to a subject.

[0045] In another aspect, the invention relates to a kit comprising any of the injection devices of the invention and instructions for use, wherein the instructions include directions for using the injection device to subcutaneously administer a unit dose or pharmaceutical composition to a subject.

[0046] The instructions may identify the injection device, unit dose, and / or pharmaceutical composition for use in treating lupus nephritis. The kits of the invention may include packaging, wherein the packaging is adapted to hold the injection device and the instructions. The instructions may accompany the injection device. The instructions may include instructions for administering >105 mg and <150 mg of anifrolumab or a functional variant thereof. The instructions may include instructions for administering ≦135 mg of anifrolumab or a functional variant thereof. The instructions may include instructions for administering 120 mg of anifrolumab or a functional variant thereof. The instructions may include instructions for administering 120 mg of anifrolumab or a functional variant thereof every four weeks. The instructions may define the subject as having a type I IFN-mediated disease. The instructions may define the subject as having LN. The instructions may be written instructions. The instructions may identify a unit dose of the pharmaceutical composition for use according to the methods of the invention. The instructions may include instructions for subcutaneous administration of anifrolumab or a functional variant thereof. The instructions may include instructions for administering 1150 mg of anifrolumab or a functional variant thereof. The instructions may define the subject as having a type I IFN-mediated disease. The instructions may define the subject as having LN. The instructions may be written instructions. The instructions may include instructions for intravenous administration of anifrolumab or a functional variant thereof. The instructions may include instructions for administering 900-1000 mg of anifrolumab or a functional variant thereof. The instructions may include instructions for administering 900 mg of anifrolumab or a functional variant thereof. The instructions may define the subject as having a type I IFN-mediated disease.

[0047] 4.6. Usage In another aspect, the present invention relates to an IFNAR1 inhibitor dosing regimen for the treatment of LN. The dosing regimen may include a first intensification regimen (IR) comprising three intravenous 900 mg doses Q4W, followed by a basic regimen (BR) of a) a weekly subcutaneous 120 mg dose, or b) an intravenous 300 mg dose Q4W (or a combination of a) and b). The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0048] In another aspect, the present invention relates to an IFNAR1 inhibitor dosing regimen for the treatment of LN. The dosing regimen may include a first intensification regimen (IR) comprising six intravenous 900 mg doses Q4W, followed by a basic regimen (BR) of a) a weekly subcutaneous 120 mg dose, or b) an intravenous 300 mg dose Q4W (or a combination of a) and b). The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0049] In another aspect, the present invention relates to an IFNAR1 inhibitor dosing regimen for the treatment of LN. The dosing regimen may include a first intensification regimen (IR) comprising six subcutaneous 1150 mg doses Q4W, followed by a basic regimen (BR) of a) a weekly subcutaneous 120 mg dose, or b) an intravenous 300 mg dose Q4W (or a combination of a) and b). The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0050] The method may include intravenously administering an intravenous dose of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be ≧300 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be ≦1000 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be 900 mg to 1000 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be >300 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose may be about 300 mg, about 900 mg, or 1000 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose can be 300 mg, 900 mg, or 1000 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The intravenous dose can be administered approximately every four weeks (Q4W). The intravenous dose can be administered approximately monthly. The 300 mg IV dose can be administered over a minimum of 30 minutes using an infusion pump. The 900 mg IV dose can be administered over a minimum of 60 minutes using an infusion pump. The anifrolumab 300 mg IV dose can be supplied as a 2 ml vial at a concentration of 150 mg / ml.

[0051] The method may include subcutaneously administering a subcutaneous dose of anifrolumab or a functional variant thereof. The subcutaneous dose may be administered after, before, or during the intravenous administration of the intravenous dose. The subcutaneous dose may be >105 mg and <150 mg of anifrolumab or a functional variant thereof. The subcutaneous dose may be ≦135 mg of anifrolumab or a functional variant thereof. The subcutaneous dose may be about 120 mg of anifrolumab or a functional variant thereof. The subcutaneous dose may be administered in a single administration step. The subcutaneous dose may be administered at intervals of 6 to 8 days. The subcutaneous dose may be administered once weekly. The subcutaneous dose may have a volume of 0.5 to 1 ml. The subcutaneous dose may have a volume of 0.5 to 1.0 ml. The subcutaneous dose may have a volume of about 0.8 ml. The subcutaneous dose may have a volume of 0.8 ml. A subcutaneous dose can be about 1150 mg (e.g., 1155 or 1150 mg) of anifrolumab or a functional variant thereof. A subcutaneous dose can have a volume of about 8 ml. A subcutaneous dose can have a volume of about 7.7 ml.

[0052] The method may include administering a first dose of an IFNAR1 inhibitor to a subject, followed by a second dose of the IFNAR1 inhibitor, wherein the first dose is higher than the second dose. The first dose may be administered intravenously. The first dose may be >300 mg. The first dose may be ≦1000 mg. The first dose may be about 900 mg. The first dose may be administered Q4W. The first dose may be administered to a subject three times before the second dose is administered to the subject. The first dose may be administered to a subject six times before the second dose is administered to the subject. The first dose may be administered every four weeks for 12 weeks before the second dose is administered. The first dose may be administered every four weeks for 24 weeks before the second dose is administered. The first dose may be administered subcutaneously. The first dose may be about 1150 mg or 1150 mg. The first dose may be administered Q4W. The first dose may be administered to the subject three times before the second dose is administered to the subject. The first dose may be administered to the subject six times before the second dose is administered to the subject. The first dose may be administered every four weeks for 12 weeks before the second dose is administered. The first dose may be administered every four weeks for 24 weeks before the second dose is administered. The intravenous dose may be administered as part of an intensive dosing regimen (IR), where the total dose of the IFNAR1 inhibitor administered during IR is 2.7 to 81 g, optionally 72.9 g, over 12 to 24 weeks. IR may include administration of an SC dose of the IFNAR1 inhibitor equivalent to a 900 to 1000 mg Q4W IV dose.

[0053] The second dose may be administered subcutaneously. The second dose may be >105 mg and <135 mg and may be administered subcutaneously. The second dose may be about 120 mg and may be administered subcutaneously. The second dose may be administered once a week.

[0054] The second dose may be administered intravenously. The second dose may be administered monthly. The second dose may be administered Q4W. The second dose may be ≧300 mg. The second dose may be ≦1000 mg and may be administered intravenously. The second dose may be about 300 mg and may be administered intravenously. The dose may be about 900 mg and may be administered intravenously Q4W, the second dose may be about 120 mg and may be administered subcutaneously Q4W. The dose may be about 900 mg and may be administered intravenously Q4W, the second dose may be about 300 mg and may be administered intravenously Q4W, and optionally, the first dose is administered to the subject at least three times before the second dose is administered to the patient, and optionally, the first dose is administered to the subject at least six times before the second dose is administered to the patient. The second dose may be administered for at least one year.

[0055] The method is about 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 305, 310, 800, 805, 810, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 11 The method may include administering a unit dose or pharmaceutical composition comprising 5, 880, 885, 890, 895, 890, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 1000, 1050, 1010, 1020, 1025, 1030, 1035, 1040, 1045, 1050, 1055, 1060, or 1065 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof).

[0056] 4.7. Unit Dose 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 auto-injector. A unit dose offers the advantage of being able to be ordered, packaged, handled, and administered as a single dose unit containing a predetermined amount of drug. A unit dose reduces administration errors and reduces waste.

[0057] In another aspect, the invention relates to unit doses (pharmaceutical unit doses, unit dosage forms, or pharmaceutical unit dosage forms) for subcutaneous administration containing >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg) of an IFNAR inhibitor (e.g., anifrolumab or a functional variant thereof). The unit dose may contain between 105 mg and 149 mg of the IFNAR inhibitor.

[0058] A unit dose may contain ≦135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor. A unit dose may contain 105 mg to 135 mg of the IFNAR inhibitor. A unit dose may contain about 120 mg of the IFNAR1 inhibitor. A unit dose may contain 120 mg of the IFNAR1 inhibitor. A unit dose may consist essentially of >105 mg and <150 mg of the IFNAR1 inhibitor. A unit dose may consist essentially of ≦135 mg of the IFNAR1 inhibitor. A unit dose may consist essentially of about the IFNAR1 inhibitor. The concentration of the IFNAR1 inhibitor in the unit dose may be about 150 mg / ml. The volume of the unit dose may be less than 1 ml. A dose or unit dose may have a volume of 0.5 to 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. A unit dose may comprise a formulation of 150-200 mg / ml of an IFNAR1 inhibitor, 25-150 mM of a lysine salt, and an uncharged excipient. A unit dose may comprise a formulation of 150-200 mg / ml of anifrolumab or a functional variant thereof, 25-150 mM of a lysine salt, and an uncharged excipient. A 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.

[0059] A unit dose may contain ≦135 mg (i.e., 135 mg or less) of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). A unit dose may contain about 120 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). A unit dose may contain 120 mg of an IFNAR1 inhibitor (e.g., 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 an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). A unit dose may consist essentially of about 120 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The concentration of the IFNAR1 inhibitor (e.g., 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 dose or unit dose may have a volume of 0.5 to 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 150 to 200 mg / ml anifrolumab or a functional variant thereof, 25 to 150 mM lysine salt, and an uncharged excipient. The unit dose may comprise a formulation of 150 to 200 mg / ml anifrolumab or a functional variant thereof, 25 to 150 mM lysine salt, and an uncharged excipient. 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. A unit dose may contain 1150 or 1155 mg of anifrolumab or a functional variant thereof.

[0060] The dosage or unit dosage is 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg or 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, or 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 167 mg 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 300 mg, 305 mg, 310 mg, 800 mg, 805 mg, 810 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 890 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 1000 mg, 1050 mg, 1010 mg, 1020 mg, 1025 mg,The dose may be 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1051 mg, 1052 mg, 1053 mg, 1054 mg, 1055 mg, 1056 mg, 1057 mg, 1058 mg, 1059 mg, 1060 mg, 1061 mg, 1062 mg, 1063 mg, 1064 mg, or 1065 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof).

[0061] In another aspect, the invention relates to a method of treating LN in a subject, the method comprising subcutaneously administering a unit dose of the invention to a subject having LN. In another aspect, the invention relates to a method of treating LN in a subject, the method comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, wherein the dose is >105 mg and <150 mg.

[0062] In another aspect, the present invention relates to a method for treating LN in a subject, comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, wherein weekly administration of the dose provides a plasma concentration in the subject that is at least equivalent to that provided by intravenous administration of 300 mg of anifrolumab or a functional variant thereof every four weeks. Weekly administration of the dose may provide a plasma concentration in the subject that is higher than that provided by intravenous administration of 300 mg of anifrolumab or a functional variant thereof every four weeks. Weekly administration of the dose may provide a plasma concentration in the subject that is at least equivalent to that provided by intravenous administration of 400 mg of anifrolumab or a functional variant thereof every four weeks. The dose may be administered in a single administration step. The dose administered to the subject may be <150 mg (i.e., less than 150 mg) of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The dose administered to the subject can be >105 mg (i.e., greater than 105 mg) of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The dose administered to the subject can be ≦135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof). The dose administered to the subject can be about 120 mg of the IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof).

[0063] The methods of the present 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 weekly (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 QW administration step. 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 weekly for at least about 4 weeks. The dose or unit dose may be administered once weekly for at least about 8 weeks. The dose or unit dose may be administered once weekly for at least about 12 weeks. The dose or unit dose may be administered once weekly for at least about 16 weeks. The dose or unit dose may be administered once weekly for at least about 20 weeks. The dose or unit dose may be administered once weekly 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 at least 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 0.5 to 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.

[0064] Administration of a dose or unit dose may provide a plasma concentration of anifrolumab or its functional variant in a subject of ≥ 10 μg per ml of plasma (i.e., 10 μg or more) (i.e., a plasma concentration of ≥ 10 μg / ml). Administration of a dose or unit dose may provide a plasma concentration of anifrolumab or its functional variant in a subject of about 10-100 μg / ml. Administration of a dose or unit dose may provide a plasma concentration of anifrolumab or its functional variant in a subject of 20-80 μg / ml. Administration of a dose or unit dose may provide a plasma concentration of anifrolumab or its functional variant in a subject of 30-70 μg / ml. Administration of a dose or unit dose may provide a trough concentration of anifrolumab or its functional variant 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 the IFNAR1 inhibitor (e.g., anifrolumab or functional variant thereof) in the subject of ≧30 μg / ml (i.e., 30 μg / ml or greater). Administration of a dose or unit dose may provide a trough concentration of the IFNAR1 inhibitor (e.g., anifrolumab or functional variant thereof) in the subject of ≧40 μg / ml (i.e., 40 μg / ml or greater). Administration of a dose or unit dose may provide a trough concentration of anifrolumab or functional variant thereof in the subject of 20-100 μg / ml. Administration of a dose or unit dose may provide a trough concentration of anifrolumab or functional variant thereof in the subject of about 30-80 μg / ml. Administration of a dose or unit dose may provide a trough concentration of anifrolumab or functional variant thereof in the subject of 40-70 μg / ml.

[0065] The dose or unit dose may provide a therapeutic effect in a subject that is at least equivalent to the therapeutic effect provided by administration of an intravenous dose of 300 mg of an IFNAR1 inhibitor (e.g., anifrolumab or a functional variant thereof) administered once (Q4W). The dose or unit dose may provide a trough concentration of anifrolumab or a functional variant thereof in a subject that is higher than the trough concentration of anifrolumab or a functional variant thereof provided by administration of an intravenous dose of 300 mg of anifrolumab or a functional variant thereof once every four weeks (Q4W).

[0066] IFNAR1 inhibitors "Type I interferon receptor inhibitor" refers to a molecule that is antagonistic to the receptors (IFNAR, IFNAR1) of type I interferon ligands, such as interferon α and interferon β. Following administration to a patient, such inhibitors 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).

[0067] 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 alpha / beta 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).

[0068] The IFNAR1 inhibitor may be a human monoclonal antibody specific to IFNAR1. The IFNAR1 inhibitor may be a modified IgG1 class human monoclonal antibody specific to IFNAR1.

[0069] The antibody may comprise a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:3. The antibody may comprise a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:4. The antibody may comprise a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:5. The antibody may comprise a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO:6. The antibody may comprise a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:7. The antibody may comprise a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:8.

[0070] 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, as numbered according to the EU index as set forth in Kabat, in the Fc region, wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to an 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.

[0071] The antibody may comprise: (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:3; (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:4; c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:5; (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO:6; (e) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:7; and (f) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:8.

[0072] 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.

[0073] The IFNAR1 inhibitor can be anifrolumab or a functional variant thereof.

[0074] 4.9. Formulations Anifrolumab or a functional variant thereof may be included in a pharmaceutical composition. The pharmaceutical composition may comprise 150 to 200 mg / ml of anifrolumab or a functional variant thereof, 25 to 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 or polysorbate 20. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition can include 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0075] 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.

[0076] 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, IFN-αR1, IFNAR). Anifrolumab downregulates IFNAR signaling and suppresses IFN-inducible gene expression. Disclosures regarding anifrolumab can be found in U.S. Patent Nos. 7,662,381 and 9,988,459, which are incorporated herein by reference. The sequence information for anifrolumab is listed in the WHO recommended INN:List71 (WHO Drug Information, Vol. 28, No. 1, 2014) and Peng et al.

[13] . The sequence information for anifrolumab is also provided in Table 1 and Figures 44 and 45.

[0077] [Table 1]

[0078] Anifrolumab is an immunoglobulin comprising HCDR1, HCDR2 and HCDR3 (or functional variants thereof) of SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, respectively; and LCDR1, LCDR2 and LCDR3 (or functional variants thereof) of SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, respectively. Anifrolumab is an immunoglobulin comprising a VH of SEQ ID NO:1 and a VL of SEQ ID NO:2.

[0079] The constant region of anifrolumab has been modified so that anifrolumab exhibits lower affinity for at least one Fc ligand compared to the unmodified antibody. Anifrolumab is an engineered IgG class monoclonal antibody specific for IFNAR1, containing an amino acid substitution of L234F in the Fc region, as numbered according to the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is an engineered IgG class monoclonal antibody specific for IFNAR1, containing an amino acid substitution of L234F, L235E, and / or P331S in the Fc region, as numbered according to the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO:9. Anifrolumab is an antibody comprising a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO: 9 and a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 11. Anifrolumab is an antibody comprising a light chain of SEQ ID NO: 12. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0080] 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. A functional variant of anifrolumab is a variant that binds to the same target as anifrolumab with the same or greater affinity 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 does not have clinically significant differences from the reference product in terms of pharmacokinetics, safety, and efficacy. The existence of clinically significant differences for biosimilars can be assessed in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and in clinical immunogenicity assessments. An interchangeable product is a biosimilar that is expected to produce the same clinical outcome as the reference product in any given patient.

[0081] For example, a variant of a reference (anifrolumab) antibody may comprise a heavy chain CDR1 that differs by up to two amino acids compared to SEQ ID NO:3; a heavy chain CDR2 that differs by up to two amino acids compared to SEQ ID NO:4; a heavy chain CDR3 that differs by up to two amino acids compared to SEQ ID NO:5; a light chain CDR1 that differs by up to two amino acids compared to SEQ ID NO:6; a light chain CDR2 that differs by up to two amino acids compared to SEQ ID NO:7; and a light chain CDR3 that differs by up to two amino acids compared to SEQ ID NO:8, wherein the variant antibody preferably binds to the target of anifrolumab (e.g., IFNAR) with the same affinity.

[0082] A variant of a reference (anifrolumab) antibody may comprise a heavy chain CDR1 that differs by at most one amino acid compared to SEQ ID NO:3; a heavy chain CDR2 that differs by at most one amino acid compared to SEQ ID NO:4; a heavy chain CDR3 that differs by at most one amino acid compared to SEQ ID NO:5; a light chain CDR1 that differs by at most one amino acid compared to SEQ ID NO:6; a light chain CDR2 that differs by at most one amino acid compared to SEQ ID NO:7; and a light chain CDR3 that differs by at most one amino acid compared to SEQ ID NO:8, wherein the variant antibody optionally binds to the target of anifrolumab (e.g., IFNAR) with the same affinity.

[0083] A variant antibody may differ by up to 5, 4, or 3 amino acids across its CDRs, provided that there are at most two amino acid differences (optionally at most one) per CDR, when compared to the corresponding reference (anifrolumab) antibody. A variant antibody may differ by up to two amino acid differences (optionally at most one) across its CDRs, provided that there are at most two amino acid differences per CDR, when compared to the corresponding reference (anifrolumab) antibody. A variant antibody may differ by up to two amino acid differences (optionally at most one) across its CDRs, provided that there are at most one amino acid differences per CDR, when compared to the corresponding reference (anifrolumab) antibody.

[0084] A variant antibody may differ by up to 5, 4, or 3 amino acids across its framework regions, provided that there are at most two (optionally, at most one) amino acid differences per framework region, when compared to the corresponding reference (anifrolumab) antibody. Optionally, a variant antibody differs by up to two (optionally, at most one) amino acid differences across its framework regions, provided that there are at most two amino acid differences per framework region, when compared to the corresponding reference (anifrolumab) antibody. Optionally, a variant antibody differs by up to two (optionally, at most one) amino acid differences across its framework regions, provided that there are at most one amino acid differences per framework region, when compared to the corresponding reference (anifrolumab) antibody.

[0085] The variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein the heavy chain has up to 14 amino acid differences compared to the heavy chain sequences herein (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region); and the light chain has up to 14 amino acid differences compared to the light chain sequences herein (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region); and the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody, preferably with the same affinity.

[0086] 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 compared to the heavy chain sequences herein (up to one amino acid difference in each CDR and up to one amino acid difference in each framework region); the light chain has up to seven amino acid differences compared to the light chain sequences herein (up to one amino acid difference in each CDR and up to one amino acid difference in each framework region); and the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody, preferably with the same affinity.

[0087] Functional variants of anifrolumab include the antibodies described in WO 2018 / 023976 A1, which is incorporated herein by reference (Table 2).

[0088] [Table 2]

[0089] Functional variants include antibodies comprising the VH amino acid sequence of SEQ ID NO: 13. Functional variants include antibodies comprising the VH amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VL amino acid sequence of SEQ ID NO: 14. Functional variants include antibodies comprising the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising 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: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0090] The IFNAR inhibitor may be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 13. The anti-IFNAR antibody may comprise the VH amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 14. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0091] Functional variants of anifrolumab and anti-IFNAR antibodies include the QX006N antibody described in CN11327807, which is incorporated herein by reference.

[0092] [Table 3]

[0093] The IFNAR inhibitor can be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 17. The anti-IFNAR antibody can comprise the VL amino acid sequence of SEQ ID NO: 18.

[0094] QX006N is an immunoglobulin comprising the HCDR1, HCDR2, and HCDR3 (or functional variants thereof) of SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively; and the LCDR1, LCDR2, and LCDR3 (or functional variants thereof) of SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 23, respectively. QX006N is an immunoglobulin comprising the VH amino acid sequence SEQ ID NO: 17 and the VL amino acid sequence SEQ ID NO: 18.

[0095] 5.2. Clinical trials of anifrolumab

[0096] [Table 4]

[0097] [Table 5]

[0098] 5.3. Lupus Nephritis (LN) Proteinuria, hematuria, or the presence of urinary granular casts, or unexplained decline in renal function, are all clinical manifestations of renal impairment in patients with SLE. The diagnosis of LN is made by renal biopsy and histopathological classification according to the 2003 ISN / RPS classification criteria, which are the gold standard for renal evaluation in LN [3].

[0099] LNs are histologically classified into one of classes I–V [3,14] (Table 4).

[0100] [Table 6]

[0101] Until very recently, there were no approved treatments for lupus nephritis (LN). Two newly approved treatments (Benlysta TM and Lupkynis TMBoth of these drugs (approved in the United States, with an MAA under review by the European Medicines Agency) are approved for use as add-on therapy to background standard of care (SoC) with mycophenolate mofetil (MMF) (which itself is not approved for LN in most regions, but is widely used as SoC according to international guidelines). Standard treatment for proliferative LN consists of 6–12 months of intensive immunosuppressive therapy (usually cyclophosphamide or mycophenolate mofetil [MMF] and high-dose corticosteroids), followed by prolonged, low-intensity maintenance therapy with MMF or azathioprine and low-dose steroids. The 2019 updated joint recommendation of the American College of Rheumatology (ACR) and the European League Against Rheumatism and the European Association for Renal Dialysis and Transplantation (EULAR / ERA-EDTA) for the treatment of lupus nephritis recommends oral administration of MMF at a total daily dose of 2–3 g, one-quarter of which is given for 6 months, followed by long-term administration at a dose of 1–2 g / day. Anifrolumab may be administered in combination with standard treatment for lupus nephritis.

[0102] The ultimate treatment goal for patients with active proliferative LN is to achieve rapid control of renal inflammation and preserve renal function to prevent the development of ESKD. End-stage renal disease occurs late and relatively infrequently, making its use as an endpoint in clinical trials impractical. Instead, the use of a composite renal endpoint, including measures of renal function and renal inflammation, to assess renal response to treatment has been endorsed by expert societies (ACR, EULAR, and KDIGO) and is consistent with current European Medicines Agency guidance for clinical trials in LN.

[0103] 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.

[0104] [Table 7]

[0105] Endpoints 5.5.1.eGFR (Estimated Glomerular Filtration Rate) The most widely used formulas for estimating glomerular filtration rate (GFR) from serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula

[15] and the isotope dilution mass spectrometry (IDMS) traceable MDRD study formula

[16] .

[0106] The CKD-EPI equation uses a 2-slope "spline" to model the relationship between GFR and serum creatinine, age, sex, and race. The table below shows the equation for creatinine (mg / dL). This equation can be expressed as a single equation: formula 1 GFR = 141 × min(Scr / κ,1)α × max(Scr / κ,1) - 1.209 × 0.993 years × 1.018 [for women] × 1.159 [for blacks] where Scr is serum creatinine (mg / dL); κ was 0.7 for women and 0.9 for men; α is -0.329 for women and -0.411 for men, min indicates the minimum value of Scr / κ or 1, max indicates the maximum value of Scr / κ or 1.

[0107] Below is the IDMS traceable MDRD research formula (for creatinine method calibrated against the IDMS reference method): formula 2 GFR (mL / min / 1.73m2) = 175 × (Scr) - 1.154 × (age) - 0.203 × (0.742 for women) × (1.212 for African Americans) where Scr is serum creatinine (mg / dL).

[0108] 5.5.2.CRR (Complete Renal Response) CRR is defined herein as follows: Estimated glomerular filtration rate (eGFR) ≥ 60 mL / min / 1.73 m 2 or no decline in eGFR of ≥ 20% from baseline ·24 hour UPCR≦0.7mg / mg

[0109] CRR is a recognized endpoint for demonstrating the efficacy of pharmaceutical interventions for the treatment and remission of LN [9, 17]. CRR was the primary endpoint in the phase III voclosporin trial for LN, and was the basis for the approval of voclosporin for the treatment of LN

[17] .

[0110] 5.5.3 PRR (partial renal response) A subject achieves a PRR if all of the following criteria are met: eGFR: ≥ 60 mL / min / 1.73 m2 or no decline in eGFR of ≥ 20% from baseline Improved 24-hour UPCR: For subjects with baseline UPCR ≤ 3mg / mg: < 1.0mg / mg - For subjects with baseline UPCR > 3mg / mg: improvement from baseline > 50% and ≤ 3.0mg / mg

[0111] 5.5.4. Graded CRR (Graded Complete Renal Response) A subject achieves graded CRR if all of the following criteria are met: Decrease in 24-hour UPCR: For subjects with baseline UPCR >3mg / mg: UPCR ≤ 1mg / mg For subjects with baseline UPCR ≤ 3mg / mg: UPCR ≤ 0.7mg / mg eGFR: ≥ 60 mL / min / 1.73 m2 or no decline in eGFR of ≥ 20% from baseline

[0112] 5.5.5. aCRR (Alternative Complete Renal Response) A subject achieves aCRR if all of the following criteria are met: eGFR: ≥ 60 mL / min / 1.73 m2 or no decline in eGFR of ≥ 20% from baseline ·24 hour UPCR≦0.7mg / mg Inactive urine sediment (defined as <10 RBC / hpf)

[0113] 5.5.6. Graded aCRR (Graded Alternative Complete Renal Response) A subject achieves graded aCRR if all of the following criteria are met: Decrease in 24-hour UPCR: For subjects with baseline UPCR >3mg / mg: UPCR ≤1mg / mg For subjects with baseline UPCR ≤ 3mg / mg: UPCR ≤ 0.7mg / mg eGFR: ≥ 60 mL / min / 1.73 m 2 or no decline in eGFR of ≥ 20% from baseline Inactive urine sediment (defined as <10 RBC / hpf)

[0114] Proteinuria The urinary protein / creatinine ratio (UPCR) provides a reading of the amount of blood protein excreted in the urine. UPCR can be measured in urine samples collected over a 24-hour period (24-hour UPCR). UPCR can also be spot UPCR, which provides a protein / creatinine ratio measured in randomly collected urine samples to estimate 24-hour protein excretion.

[0115] 5.5.8.SRI (Systemic Lupus Erythematosus Responder Index ≥ 4) A subject achieves SRI(4) if all of the following criteria are met: · ≥ 4-point reduction from baseline in SLEDAI-2K; No new affected organ systems as defined by ≥1 or ≥2 BILAG-2004 A · BILAG-2004 B items will be compared with baseline using BILAG-2004; · No worsening from baseline in the subject's lupus disease activity, defined by a ≥ 0.30 point increase on a 3-point PGA VAS.

[0116] 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 in SLEDAI-2K; one or more BILAG-2004 A scores compared to baseline using BILAG-2004; or ·No new affected organ systems as defined by two or more BILAG-2004 B items; No worsening from baseline in the subject's lupus disease activity as defined by: ≥ 0.30 point increase in 3-point PGA VAS

[0117] 5.5.9. SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) The SLEDAI-2K Disease Activity Index consists of a list of organ symptoms, each with its own definition. A certified 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.

[0118] The SLEDAI-2K assessment consists of 24 lupus-related items. It is a weighting system, in which descriptors are multiplied by the "weight" of a specific organ. For example, the renal descriptor is multiplied by 4, the central nervous system descriptor is multiplied by 8, and these weighted organ symptoms are summed to form 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.

[0119] 5.5.10. SLE Disease Activity Index-Renal Domain (SLEDAI-R) The SLEDAI-R score (range 0–16; 0 = inactive LN) represents the sum of the SLEDAI-2K renal components. If present, the following four SLEDAI-R components each receive a score of 4: proteinuria >0.5 g / day, hematuria and pyuria (all >5 cells / high-power field), and cellular casts

[18] .

[0120] 5.5.11. Time to renal flare Renal flare is defined as an increase in spot UPCR and / or a decline in renal function in subjects who have achieved at least a PRR (PRR or CRR) and then maintained it for at least one subsequent visit. Renal flare can be characterized as nephritic or proteinuric.

[0121] 5.5.12.PAG (Physician's Global Assessment) The PGA represents a physician's global assessment of mean disease severity on a visual assessment scale (VAS) ranging from 0 (none) to 3 (severe) of disease activity over a 30-day period.

[0122] 5.5.13.BILAG-2004(British Isles Lupus Assessment Group-2004) The BILAG-2004 is a nine-organ system (systemic, mucocutaneous, neuropsychiatric, musculoskeletal, cardiopulmonary, gastrointestinal, ophthalmic, renal, and hematological) conversion index that can capture changes in the severity of clinical symptoms in SLE patients. It has an ordinal scale by design and does not have a global score; rather, it records disease activity across different organ systems at a glance by comparing the previous four weeks with the four weeks preceding them. It categorizes disease activity into five different levels, A through 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 previous disease activity

[0123] Although the BILAG-2004 was developed based on the intention-to-treat principle, treatment is not related to the scoring index; only the presence of active symptoms influences the scoring.

[0124] 5.5.14.BICLA (BILAG-Based Composite Lupus Assessment) The BICLA is the first composite index derived from an expert consensus on disease activity. A BICLA response is defined as (1) at least one gradation of improvement in baseline BILAG scores in all body systems with moderate or severe disease activity at entry (e.g., a reduction in all A (severe disease) scores to B (moderate), C (mild), or D (no activity) and a reduction in all B scores to C or D); (2) the absence of new BILAG A or two or more new BILAG B scores; (3) no worsening from baseline in all SLEDAI scores; (4) no significant worsening (≤10%) in the physician's global assessment; and (5) no treatment failure (initiation of non-protocol treatment).

[0125] In particular, a subject is a BICLA responder if the following criteria are met: · Reduction of all baseline BILAG-2004 A to B / C / D, reduction of all baseline BILAG-2004 B to C / D, and no worsening of BILAG-2004 in other organ systems, as defined by one new BILAG-2004 A or two or more new BILAG-2004 B items; ·No worsening from baseline on the SLEDAI-2K, defined as an increase from baseline of >0 points on the SLEDAI-2K; ·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; No discontinuation of investigational drug or use of restricted medications above the threshold allowed by the protocol prior to evaluation

[0126] BICLA response is a composite endpoint requiring improvement in all baseline BILAG-2004 A and B scores, no worsening as assessed by SLEDAI-2K and PGA, and no discontinuation of IP or restricted medication use above protocol-accepted thresholds. BILAG captures relative improvement in organ systems (as opposed to SLEDAI-2K, which is used to indicate improvement in SRI and requires complete resolution of an organ system), and BILAG-2004, used to measure improvement in BICLA, can detect clinically meaningful relative improvements in organ systems.

[0127] 5.5.15.CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) The CLASI is a proven index used to evaluate skin lesions in SLE. It consists of two separate scores: the first summarizes the inflammatory activity of the disease, and the second is a measure of the damage caused by the disease. The activity score takes into account erythema, scaling / thickening, mucosal lesions, recent hair loss, and non-scarring alopecia. The damage score represents pigmentation abnormalities, scarring / atrophy / panniculitis, and scalp scarring. Subjects are asked whether their pigmentation abnormalities have persisted for more than 12 months; if so, a pigmentation abnormality score is suspected. Each of the above parameters is measured at 13 different anatomical locations, specifically included because they are most commonly involved in cutaneous lupus erythematosus (CLE). The most severe lesion within each area is measured.

[0128] 5.6. Pharmacokinetic Glossary Area Under the Curve (AUC): The area under the plasma drug concentration versus time curve (serves as a measure of drug exposure).

[0129] C ave : steady-state average concentration.

[0130] C max : The maximum (or peak) concentration of a drug in plasma.

[0131] C min :Minimum plasma drug concentration.

[0132] 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 [immediately before the next dose]).

[0133] LLOQ: Lower Limit of Quantitation, the smallest amount of analyte in a sample that can be quantified with adequate precision and accuracy.

[0134] 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 concentration. The clearance and volume of distribution of these drugs are independent of dose.

[0135] Nonlinear pharmacokinetics: In contrast to linear pharmacokinetics, the drug concentration in blood or plasma does not increase proportionally with increasing dose. Their clearance and volume of distribution may vary depending on the administered dose. The nonlinearity may be associated with any component of the absorption, distribution, and / or excretion processes.

[0136] 5.7.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 plasma concentrations at several time points. Using in silico modeling techniques, the plasma drug concentration-time for any given dose can be predicted. The AUC (area under the curve) can then be calculated by integrating the plasma drug concentration-time curve. A suitable method is described in Tummala et al.

[19] , which is incorporated herein by reference in its entirety. 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), and maximum serum concentration (C). max ) and the time to reach maximum serum concentration (t max All data were analyzed with SAS System V.9.2 (SAS Institute, Inc., Cary, NC, USA).

[0137] Advantageously, the ratio of the AUC obtained by SC administration to the AUC obtained by IV administration (AUC SC / AUC IV ) can 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 IVIt means a ratio. In order to provide statistical robustness, the 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, the AUC ratio can reflect the mean, median or mode value (preferably the mean value) of AUC in multiple patients.

[0138] 5.8. Type I IFN Gene Signature (IFNGS) Type I IFN is thought to play a central role in the pathogenesis of SLE disease, and anifrolumab targets inhibition of this pathway. Understanding the relationship between type I IFN expression and response to anti-IFN therapy requires knowing whether a subject's disease is driven by type I IFN activation. However, direct measurement of type I IFN remains challenging. Therefore, transcript-based markers were developed to assess the effect of target protein overexpression on a specific set of mRNA markers. Expression of these markers is easily detected in whole blood and correlates with expression in affected tissues, such as skin, in SLE. The bimodal distribution of transcript scores in SLE subjects helps define high and low IFN test subpopulations (Figure 1). Type I IFN testing is described in International Publication No. WO 2011028933A1, which is incorporated herein by reference in its entirety. The type I IFN gene signature can be used to identify subjects as having a high type I IFN gene signature (IFNGS) test or a low type I IFN gene signature (IFNGS) test. The IFNGS test measures the expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in a subject's whole blood, relative to three reference genes 18S, ACTB, and GAPDH. The result of the test is a score that is compared to pre-established cutoffs that classify patients into two groups: those with low or high levels of IFN-inducible gene expression (Figure 1).

[0139] Gene expression can be measured by RT-PCR. Suitable primers and probes for detecting genes can be found in WO2011028933. A suitable kit for measuring gene expression in the IFNGS test is the QIAGEN therascreen® IFIGx RGQ RT-PCR kit (IFIGx kit), as described by Brohawn et al.

[20] (which is incorporated herein by reference in its entirety).

[0140] Gene expression can be measured by detecting mRNA in the whole blood or tissue of a subject. IFNGS (4 genes, 5 genes, or 21 genes) score can be detected in a subject by measuring IFNGS gene expression (e.g., mRNA) in the blood or tissue of a subject, and comparing the gene expression level with the expression of housekeeping or control genes, such as ACTB, GAPDH, and 18S rRNA, in the blood or tissue.

[0141] The IFN 21-gene signature (IFNGS) is a validated pharmacodynamic marker of type I IFN signaling

[21] (Table 6) and is elevated in patients with lupus nephritis.

[0142] [Table 8] [Example]

[0143] The evidence provided in the examples below is summarized in Table 7.

[0144] [Table 9]

[0145] 7. Example 1: Anifrolumab in the Clinic The safety and efficacy of anifrolumab have been evaluated in eight blinded or open-label intravenous (IV) and subcutaneous (SC) studies: five in patients with SLE (Study 05, Study 04, Study 1013, Study 08), one in patients with systemic sclerosis (SSc) (MI-CP180), and one in healthy volunteers (Study 06) (Table 8). Two of these studies (Studies 08 and 06) used SC anifrolumab administration. Two studies are ongoing: one in patients with SLE (Study 09) and one in patients with lupus nephritis (LN) (Study 07).

[0146] [Table 10]

[0147] [Table 11]

[0148] Study 1013 is described in more detail in Furie et al. 2017

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

[22] (which is incorporated herein by reference in its entirety). The results of Study 05 are described in more detail in Morand et al. 2020

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

[24] (which is incorporated herein by reference in its entirety).

[0149] A two-compartment PK model with parallel primary and IFNAR-mediated elimination pathways was developed to describe the observed serum concentration profile of anifrolumab, as described by Wang et al.

[25] .

[0150] 8. Example 2: Phase 2 Randomized Study of the Type I Interferon Inhibitor Anifrolumab in Patients with Actively Proliferative LN (NCT02547922, Study 07) Overview 8.1.1. Purpose To evaluate the efficacy and safety of the type I interferon receptor antibody anifrolumab in patients with active, biopsy-proven proliferative LN. We evaluated whether treatment with anifrolumab neutralizes type I IFN signaling through human IFNAR1, which drives disease activity, thereby reducing disease severity in patients with proliferative LN.

[0151] 8.1.2. Method In this phase 2, double-blind, multicenter study (Study 7, NCT02547922), patients were randomized (1:1:1) to receive a monthly basic intravenous regimen of anifrolumab (BR, 300 mg IV), an intensive regimen (IR, 900 mg IV x 3, followed by 300 mg), or placebo in combination with standard therapy (oral glucocorticoid, mycophenolate mofetil). The rationale for selecting the 300 mg dose level for evaluation in LN subjects in this study was to replicate the dose identified in a phase 2b study (Study 1013) in extrarenal SLE subjects. The primary endpoint was improvement in baseline 24-hour urinary protein-to-creatinine ratio (UPCR) at week 52 in the total anifrolumab and placebo groups. A secondary endpoint was complete renal response (CRR) at week 52. Exploratory endpoints included a stricter definition of CRR and sustained glucocorticoid reduction (≤7.5 mg / day, weeks 24 to 52). Safety was analyzed descriptively.

[0152] 8.1.3.Results Patients received anifrolumab BR (n=45), IR (n=51), or placebo (n=49). At week 52, 24-hour UPCR improved by 69% and 70% in the total anifrolumab and placebo groups, respectively (geometric mean ratio = 1.03; 95% confidence interval: 0.62-1.71; P=0.905). Anifrolumab IR induced higher serum concentrations than anifrolumab BR, providing suboptimal exposure. Numerously more patients treated with anifrolumab IR achieved CRR (45.5% vs. 31.1%), CRR with UPCR ≤ 0.5 mg / mg (40.9% vs. 26.7%), CRR with inactive urinary sediment (40.9% vs. 13.3%), and sustained glucocorticoid reduction (55.6% vs. 33.3%) compared with placebo. Herpes zoster was more frequent in the anifrolumab group than in the placebo group (16.7% vs. 8.2%), but the incidence of serious adverse events was similar between groups (19.8% vs. 16.3%).

[0153] 8.1.4. Conclusion Although the primary endpoint was not met, anifrolumab IR induced numerical improvements over placebo across clinically meaningful endpoints.

[0154] 8.2. Patients and Methods 8.2.1.Patient Eligible patients were aged 18–70 years with a biopsy-proven diagnosis of class III or IV (both ±V) LN within 3 months of screening according to the WHO or International Society of Nephrology and Renal Pathology Society (ISN / RPS) 2003 criteria [3] (see Section 5.3). Eligible patients had a 24-h UPCR >1 mg / mg (113.17 mg / mmol) and eGFR ≥ 35 mL / min / 1.73 m 2Patients had ≥4 of 11 American College of Rheumatology (ACR) SLE classification criteria

[26] , including seropositivity for ≥1 of antinuclear antibodies, anti-double-stranded DNA (anti-dsDNA) antibodies, and / or anti-Smith antibodies at screening

[27] . eGFR was based on the MDRD formula. Patients were excluded if they received any of the following immunosuppressive induction therapy after a qualifying biopsy: prednisone equivalent >0.5 mg / kg / day or >40 mg / day for >8 weeks, mean MMF >2.5 g / day for >8 weeks, or cumulative methylprednisolone pulse >3000 mg.

[0155] 8.2.2. Dose Selection The study evaluated the safety and efficacy of anifrolumab across two dosing regimens: a basic regimen (BR), which remained at 300 mg throughout the treatment period, and an intensive regimen, which tested a higher dose of 900 mg for the first three doses followed by 300 mg for the remainder of the treatment period.

[0156] The selection of the 300 mg and 900 mg Q4W anifrolumab doses was based on safety and efficacy results from an interim analysis of a phase 2b study in extrarenal SLE that evaluated two doses of anifrolumab (300 mg and 1000 mg) compared with placebo (Study 1013). The 900 mg dose was chosen over the 1000 mg dose for ease of administration (anifrolumab is supplied in 150 mg vials). In the interim analysis of the phase 2b study, a clinically meaningful benefit was observed with the 300 mg dose, with no incremental benefit observed with the 1000 mg dose. Furthermore, the proportion of subjects reporting reactivation of herpes zoster was higher with the 1000 mg dose compared with the 300 mg dose. Based on these data, the 300 mg dose was identified as the optimal dose to be tested in phase 3 studies (TULIP I and TULIP II) for extrarenal SLE. Based on PK, efficacy, and safety considerations, anifrolumab 300 mg every 4 weeks was subsequently recommended as the optimal dose for a pivotal phase 3 trial in SLE patients.

[28] In TULIP-LN, the rationale for selecting the 300 mg dose level for evaluation in LN subjects was to replicate the dose identified in a phase 2b trial in extrarenal SLE subjects.

[0157] Study Design During the 52-week double-blind treatment period, patients were randomized (1:1:1) on day 1 to receive either anifrolumab basic regimen (BR; 300 mg, SLE-matched

[23] ), anifrolumab intensive regimen (IR; 900 mg for the first three doses, then 300 mg thereafter), or placebo intravenously every 4 weeks for 48 weeks, in parallel with prespecified standard therapy of oral glucocorticoids and MMF (Figure 2A). Randomization was stratified according to 24-h UPCR at screening (≤3.0 vs. >3.0 mg / mg) and type I IFNGS status (high vs. low, determined as previously described

[29] ).

[0158] The primary endpoint was assessed at week 52. Eligible patients had a GFR ≥ 60 mL / min / 1.73 m 2 Patients were eligible to enter the ongoing, double-blind, second-year treatment period if they achieved at least a partial renal response (PRR), defined as: no decline of ≥20% from baseline in eGFR; an improvement in 24-hour UPCR from baseline to week 52 (<1.0 mg / mg for patients with baseline ≤3 mg / mg; >50% improvement and ≤3 mg / mg for patients with baseline >3 mg / mg); and no discontinuation of study intervention. For patients who did not continue into the second year, a safety follow-up period continued for 12 weeks after the last dose of anifrolumab or placebo. Results from the 52-week treatment period are reported here.

[0159] Patients received a 500 mg intravenous methylprednisolone pulse at randomization unless they had already received it within <10 days prior to randomization. Tapering of oral glucocorticoid doses was mandatory, with goals of ≤10 mg / day (prednisolone or equivalent) by week 12 and ≤7.5 mg / day by week 24. MMF was titrated to a target dose of 2 g / day by week 8. Dose adjustments of MMF were permitted for suboptimal response, toxicity, or intolerance. Stable oral glucocorticoid and MMF doses were required from week 40 through week 52. Stable doses of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were required from week 4 onward.

[0160] Protocol-specified discontinuation criteria for the study intervention included failure to adhere to background standard of care (including glucocorticoid tapering requirements to <15 mg / day of prednisolone or equivalent by week 12 and ≤15 mg / day by week 24); use of prohibited rescue therapy (including >1 methylprednisolone pulse before week 8 or any methylprednisolone pulse after week 8, cyclophosphamide, or rituximab at any time); use of restricted or excluded medications, or worsening of predefined LN or SLE (confirmed LN-related eGFR decline of >30% from baseline at any time and eGFR <60 mL / min / 1.73 m). 2 , <75% decline from baseline in eGFR and <60 mL / min / 1.73 m at 12 or 24 weeks 2 or nephrotic-range UPCR at 12 or 24 weeks (defined as >50% of patients with baseline <3 mg / mg increasing to >3.5 mg / mg; <60% of patients with baseline >3 mg / mg improving or >3.5 mg / mg).

[0161] 8.2.4 Outcomes 8.2.4.1. Primary Endpoint The primary objective at study initiation was to evaluate the efficacy of anifrolumab plus SOC compared with placebo plus SOC in subjects with active proliferative LN, as measured by the relative difference in change from baseline to week 52 in 24-hour UPCR (Table 9).

[0162] [Table 12]

[0163] The goal of treatment for LN is the preservation of renal function. In the current SOC, the late onset and relatively low incidence of end-stage renal disease make its use as an endpoint in clinical trials impractical. Previous trials have used various composite endpoints for renal response. The core elements of all these criteria are stabilization or improvement of renal function and reduction or normalization of proteinuria. Improvement in proteinuria reflects control of inflammation and subsequent renal repair.

[0164] Therefore, the primary endpoint was the relative difference in the mean change from baseline to week 52 in 24-hour UPCR between the total anifrolumab group (IR+BR) and the placebo group. The mean change from baseline was calculated as the geometric mean (GM) of the relative difference in 24-hour UPCR at week 52 compared to baseline for each treatment group (a value of <1 indicates an improvement from baseline). Comparison with the placebo group was measured by the GM ratio (GMR) of the relative change from baseline for the total anifrolumab group vs. the placebo group (a GMR <1 favors anifrolumab) (Equation 3).

number

[0165] 8.2.4.2. Secondary Endpoints Secondary endpoints were aCRR (24-hour UPCR ≤ 0.7 mg / mg, eGFR ≥ 60 mL / min / 1.73 m) at 52 weeks. 2The differences between the total anifrolumab and placebo groups in the proportion of patients with a mean score of 0.001 or 0.025 or no decline of ≥20% from baseline (defined as no decline of ≥20% from baseline) as well as adherence to standard treatment protocols, no discontinuation of interventions, and no restricted medication use (Table 10).

[0166] 8.2.4.3. Exploratory Endpoints Exploratory endpoints included baseline oral glucocorticoid dose ≥ 20 mg / day, sustained dose reduction (≤ 7.5 mg / day, weeks 24-52); proportion of patients with CRR including requirement for inactive urinary sediment (CRR a <10 red blood cells in a high-power field; proportion of patients demonstrating aCRR at week 52 combined with achievement of sustained oral glucocorticoid dose reduction; mean change from baseline in the Extrarenal SLE Disease Activity Index 2000 (SLEDAI-2K)

[30] and Physician Global Assessment (PGA) 16 and Patient Global Assessment (PtGA)

[31] scores; mean change from baseline in lupus serology (anti-dsDNA antibodies, C3 / C4), and the immunogenicity, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of anifrolumab. PD neutralization was measured as the median percent change from baseline in the 21-gene type I IFNGS (Tables 11-16), as previously described [11,29,32].

[0167] [Table 13]

[0168] [Table 14]

[0169] [Table 15]

[0170] [Table 16]

[0171] [Table 17]

[0172] [Table 18]

[0173] [Table 19]

[0174] Post-hoc analyses included time course of mean UPCR, cumulative proteinuria (UPCR area under the curve normalized to the expected follow-up period), and aCRR of UPCR ≤ 0.5 mg / mg (CRR 0.5 ) and CRR sustained up to 52 weeks 0.5 The time to reaction was included.

[0175] Safety assessments were assessed by an independent Data Safety Monitoring Committee and included adverse events (AEs), laboratory assessments, and vital signs. Adverse events of special interest (AESIs) included non-opportunistic serious infections, opportunistic infections, malignancies, herpes zoster (HZ), influenza, tuberculosis, hypersensitivity reactions (including anaphylaxis or infusion reactions), and major adverse cardiovascular events (MACEs).

[0176] 8.2.4.4. Restricted medications Subjects were considered non-responders for the purposes of assessments such as CRR if they received any of the following after randomization: Azathioprine methotrexate Leflunomide Tacrolimus Mizoribine Cyclosporine Cholestyramine Increased corticosteroid dose or duration beyond that permitted by the protocol Corticosteroids with long biological half-lives (e.g., dexamethasone, betamethasone)

[0177] 8.2.4.5.Statistical analysis The primary endpoint was analyzed using a repeated measures mixed model fitted to log-transformed 24-hour UPCR values, controlling for stratification factors, and based only on observed data until discontinuation of the study intervention. The same analysis was used to assess changes from baseline in SLEDAI-2K, PGA, and PtGA, except that the data were not log-transformed.

[0178] For secondary / exploratory binary endpoints, estimated responder rates and 95% confidence intervals (CIs) were calculated using a stratified Cochran-Mantel-Haenszel approach controlling for stratification factors. Patients who discontinued the intervention, including those who withdrew from the study, were defined as non-responders from that point onward. Patients with missing data at one visit were imputed using the previous observation. If data were missing at two or more consecutive visits, the patient was considered a non-responder because of missing data at the second or subsequent visit. Time to sustained response was analyzed post hoc using a Cox regression model controlling for stratification factors. Cumulative proteinuria was assessed using baseline UPCR and analysis controlling for covariance of stratification factors. Serological tests (anti-dsDNA antibodies, C3 / C4), immunogenicity, PK, and PD were analyzed using summary statistics. Safety was also analyzed descriptively.

[0179] Efficacy and safety analyses included patients who received ≥1 dose of anifrolumab or placebo (modified intention-to-treat [mITT] population). After patient recruitment began, there was a protocol amendment that changed the eGFR and 24-hour UPCR cutoff values ​​for CRR criteria. This was not accepted by the Italian Medicines Agency or the Committee for Personal Protection (France), and these patients were therefore excluded from all CRR analyses.

[0180] A 1:1:1 randomization of 50 patients per treatment group was designed to provide approximately 87% power with a two-sided alpha of 0.0499 to detect a relative difference in 24-hour UPCR (GMR) improvement from baseline to week 52 in the total anifrolumab group relative to placebo of 0.76 or less, assuming 1) a 65% and 46% reduction in 24-hour UPCR from baseline to week 52 in the total anifrolumab and placebo groups, respectively, and 2) a normal distribution (SD) of log-transformed data with a standard deviation (SD) of 0.8. Analyses of individual anifrolumab regimens versus placebo for efficacy endpoints were performed using a hierarchical testing strategy to control for family-wise error. All analyses were performed using Statistical Analysis System® (SAS®; SAS Institute Inc, Cary, NC), version 9.3 or higher.

[0181] 8.3.Results 8.3.1. Study population A total of 338 patients were screened, of whom 147 were randomized to receive treatment (Figure 2B). The mITT population consisted of 145 patients (45 received anifrolumab BR, 51 received anifrolumab IR, and 49 received placebo).

[0182] Overall, 101 of 145 patients (69.7%) completed the 52-week treatment period (Figure 2B). More patients in the placebo group (42.9%) discontinued the study intervention early than in both anifrolumab groups (BR: 28.9%; IR: 19.6%; Figure 3), primarily due to patient decision, AEs, meeting of discontinuation criteria, or lack of treatment response. Overall, 75 patients entered the second-year extension period. Here, we report only the results of the initial 52-week treatment period.

[0183] Validity Surprisingly, in patients with proliferative LN, it was observed that anifrolumab BR induced suboptimal PK exposure and PD neutralization due to increased proteinuria.

[0184] At week 52, mean 24-hour UPCR improved by 69% and 70% from baseline to 0.92 mg / mg and 1.05 mg / mg in the total anifrolumab and placebo groups, respectively, resulting in a between-treatment GMR of 1.03 (95% CI: 0.62, 1.71, P = 0.905; a GMR < 1 favors anifrolumab; Figure 4A, Table 17).

[0185] [Table 20]

[0186] In the anifrolumab IR group, mean 24-h UPCR improved 71% from baseline to 0.96 mg / mg at week 52, compared with 0.963 for GMR vs. placebo (95% CI: 0.548, 1.693). Mean UPCR improved over time in all treatment groups (Table 18). From weeks 12 to 36, 24-h UPCR improved numerically more in the total anifrolumab and anifrolumab IR groups than in the placebo group, and at all time points, the anifrolumab IR group improved numerically more than the anifrolumab BR group (Figure 4A). There were no significant differences in 24-h UPCR between predefined subgroups (Figure 5A). Sensitivity of post-hoc analyses controlling for time from LN diagnosis and baseline 24-h UPCR did not reveal a major impact of these imbalances on the primary outcome. Both anifrolumab groups had numerically lower cumulative proteinuria than the placebo group throughout the treatment period (Figure 6).

[0187] [Table 21]

[0188] 8.3.3 Secondary and Exploratory Endpoints The proportion of patients experiencing aCRR at week 52 was similar in the total anifrolumab and placebo groups (31.0% vs. 31.1%, difference -0.1% [95% CI: -16.9, 16.8]) (Table 19). However, anifrolumab IR significantly increased the incidence of CRR (45.5% vs. 31.1%, difference 14.3% [95% CI: -5.8, 34.5]) and CRR (45.5% vs. 31.1%, difference 14.3% [95% CI: -5.8, 34.5]) compared with placebo at week 52. 0.5 (40.9% vs. 26.7%, difference 14.2% [95% CI: -5.4, 33.9]) and CRR a Anifrolumab IR induced a numerically higher proportion of patients with CRR (40.9% vs. 13.3%, difference 27.6% [95% CI: 9.4, 45.7]) (Table 19). Responses to all CRR definitions for anifrolumab IR were observed as early as week 12 and persisted through week 52 (Figures 4B and 4C; Figures 7A and 7B). Sustained CRR 0.5 The time to CRR was numerically shorter with anifrolumab than with placebo. 0.5 Hazard ratio 1.46; 95% CI: 0.71, 3.14) (Figure 4C). In contrast, the response of anifrolumab BR to all CRR definitions was similar to or lower than that of the placebo group at all time points except for week 12 (Figure 4B; Figure 4C, Figure 7A, and Figure 7B).

[0189] [Table 22]

[0190] Anifrolumab IR was associated with a higher proportion of patients with sustained glucocorticoid dose reduction to ≤7.5 mg / day compared with placebo (55.6% vs. 33.3%, difference 22.2% [95% CI: -0.8, 45.2]) and CRR with sustained glucocorticoid dose reduction (34.1% vs. 24.4%, difference 9.7% [95% CI: -9.5, 28.8]; Figure 5B).

[0191] Compared with placebo, anifrolumab IR induced numerically greater improvements from baseline in measures of disease activity (SLEDAI-2K, PGA, PtGA) (Figure 11) and lupus serology (Figure 9). Compared with the placebo group, patients who were anti-dsDNA antibody positive at baseline experienced numerically greater decreases in anti-dsDNA antibody levels with anifrolumab IR than with placebo (Figure 9A). Patients with low baseline C3 levels experienced increases in C3 levels in all groups (Figure 9B). There were no clear differences in C4 increases between groups (Figure 10). Compared with the placebo group, C3 increased numerically from week 36 with anifrolumab IR and from week 44 with anifrolumab BR (Figure 9B). Overall, the rate of antidrug antibody positivity at any time point during the study was low and comparable between groups (anifrolumab BR, 6.7%; anifrolumab IR, 3.9%; placebo, 4.1%).

[0192] Pharmacokinetics PK analysis included 95 patients who received anifrolumab and had at least one quantifiable serum PK observation after the first dose. Anifrolumab demonstrated nonlinear PK between the BR and IR groups (Figure 12). In patients with high IFNGS (94.5%), the median anifrolumab steady-state concentration at Week 12 was 63.4 μg / mL for anifrolumab IR (Figure 13B) and 8.2 μg / mL for anifrolumab BR (approximately 50% lower than in extrarenal SLE patients) (Figure 13A). When anifrolumab IR was tapered to 300 mg at Week 16, the median trough concentrations at Weeks 24 and 36 were lower than in extrarenal SLE patients. Patients with baseline UPCR >3 mg / mg had higher anifrolumab clearance than patients with UPCR ≤3 mg / mg (Figure 15).

[0193] Pharmacodynamics The PD analysis included 137 patients with elevated IFNGS. Median PD reversal rates of >80% were observed at all visits (weeks 12, 24, 36, and 52) with anifrolumab IR, and median PD reversal rates of >80% were observed only at week 12 and 24 with anifrolumab BR, with subsequent rebound in IFNGS (Figure 8). Minimal PD reversal was observed in the placebo group.

[0194] 8.3.6. Safety and tolerability Safety was assessed in the mITT population (Table 20).

[0195] The incidence of all AEs was similar between groups. AEs that were more common (≥5% difference) in the anifrolumab group compared with the placebo group included herpes zoster (16.7% vs. 8.2%), urinary tract infection (16.7% vs. 10.2%), and influenza (8.3% vs. 2.0%). Serious AEs occurred in 22.2%, 17.6%, and 16.3% of the anifrolumab BR, anifrolumab IR, and placebo groups, respectively. Herpes zoster was the only serious AE reported by more than one patient per treatment group. There were no deaths during the treatment period, but one fatal vascular neurological AE occurred during follow-up in the anifrolumab BR group. AEs leading to discontinuation of the study intervention occurred in 11% to 12% of patients across groups.

[0196] Slightly more patients in the anifrolumab group experienced infections or infestations (72.9% vs. 63.3%) compared with the placebo group, and slightly more patients experienced serious infections or infestations (10.4% vs. 8.2%). However, with the exception of HZ, the incidence of protocol-defined AESI infections was low and comparable to that of the placebo group (e.g., non-opportunistic serious infections (1.0% vs. 6.1%), opportunistic infections (1.0% vs. 2.0%), influenza (5.2% vs. 2.0%), and tuberculosis (none). HZ occurred in 20.0% and 13.7% of patients in the anifrolumab BR and anifrolumab IR groups, respectively. Of these 16 cases, 6 were serious, 5 were severe, and 11 were mild. The HZ events were of moderate to severe intensity, all occurring in the skin (13 localized and 3 disseminated). Most HZ events tended to occur early in the study and resolved with treatment. Other AESIs, including malignancies and MACE, occurred in <1% of patients across all anifrolumab groups. No anaphylaxis was reported, and one serious infusion reaction occurred in the anifrolumab BR group. No clinically significant deterioration was noted in hematology or chemistry panels, urinalysis, vital signs, or electrocardiograms.

[0197] [Table 23]

[0198] [Table 24]

[0199] 8.4. Discussion These data describe the results of the phase 2 TULIP-LN trial, which explored the safety and efficacy of adding two different doses of anifrolumab to standard treatment for patients with actively proliferating LN. Although the primary endpoint (UPCR improvement in the total anifrolumab group compared with the placebo group) was not met, anifrolumab IR was associated with numerical efficacy across a range of clinically meaningful renal endpoints, including proteinuria, multiple stringent CRR definitions (requiring UPCR improvement and an inactive urinary sediment), and sustained glucocorticoid dose reduction.

[0200] Surprisingly, in contrast to previous observations in SLE from Studies 1013, 05, and 04, intensified anifrolumab administration was necessary to induce clinical efficacy in patients with LN, as anifrolumab IR likely resulted in serum exposure and PD neutralization similar to that seen with anifrolumab BR (SLE administration) in extrarenal SLE. In contrast, because proteinuria in LN results in increased clearance, anifrolumab BR induced suboptimal serum exposure in patients with LN, approximately 50% lower than in non-renal SLE patients. Indeed, anifrolumab BR induced limited PD neutralization and clinical responses.

[0201] Reductions in proteinuria are significantly associated with a reduced risk of end-stage renal disease

[33] . Therefore, reductions in proteinuria are an appropriate objective surrogate endpoint in a phase 2 pooled-of-concept trial. Here, 24-hour UPCR improved by approximately 70% from baseline in all groups. Furthermore, anifrolumab IR numerically improved cumulative proteinuria by 30% compared with placebo at week 52, a unique endpoint in LN trials that adds clinical value because it represents an improvement in overall proteinuria over time and is less susceptible to short-term confounding factors such as sampling error, diet, and exercise.

[0202] Anifrolumab IR was also associated with superior efficacy compared with placebo across all CRR definitions as early as week 12. Anifrolumab IR did not require hematuria (a marker of glomerular inflammation and acute kidney injury

[34] ), a very stringent criterion for CRR. a In addition, more patients with a high baseline glucocorticoid dose achieved a sustained glucocorticoid dose reduction or a CRR with sustained dose reduction in the anifrolumab IR group compared with the placebo group.

[0203] Overall, the safety profile observed with anifrolumab in patients with LN was consistent with that observed in patients with extrarenal SLE, including a numerically higher incidence of influenza and cutaneous hereditary thrombosis with anifrolumab compared with placebo.

[11] Most AEs were mild or moderate, not serious, and did not lead to discontinuation of the study intervention. Notably, anifrolumab intravenous injection (IR) was not associated with a higher incidence of AEs or AESIs, including hereditary thrombosis, compared with anifrolumab BR.

[0204] LN patients are nearly twice as likely to develop serious infections as extrarenal SLE patients, putting them at higher risk of HZ infection than non-renal SLE patients.

[35] Consistent with this, the incidence of cutaneous HZ is higher in LN patients than in extrarenal SLE patients, likely due to the severity of LN disease, which requires more intensive background immunosuppressive treatment. [5] This theory is supported by the observation that cutaneous HZ tends to occur earlier in trials receiving higher doses of glucocorticoids.

[0205] Overall, the results of TULIP-LN support the efficacy and safety of IR anifrolumab in LN. IR anifrolumab was superior to placebo on several clinically relevant endpoints and was generally well tolerated over 52 weeks.

[0206] Overview The Phase II LN Study 07 was a 2-year, international, multicenter, exploratory, double-blind, placebo-controlled trial investigating the efficacy and safety of anifrolumab in patients with active Class III or IV (either Class V or not) LN. The study evaluated two anifrolumab dosing regimens versus placebo: a base regimen (300 mg IV Q4W) using the doses proposed for SLE patients and an intensive regimen (900 mg IV Q4W for the first three doses, followed by 300 mg IV Q4W for the remainder of the study). All patients received MMF plus glucocorticoids as background SOC therapy. One hundred and forty-seven patients were randomized in a 1:1:1 ratio to receive the anifrolumab intensive group, the anifrolumab base group, or placebo. Although the study did not meet its primary objective of determining the relative difference in change in UPCR from baseline to week 52 between the total anifrolumab and placebo groups, preliminary and post-hoc efficacy analyses suggested a beneficial effect of the anifrolumab-intensive regimen versus placebo on a range of clinically meaningful endpoints at week 52. The proportion of patients achieving a CRR with a UPCR threshold of ≤0.7 mg / mg was numerically greater in the anifrolumab group compared with the placebo group (treatment difference 14.3%; 95% CI: -5.8, 34.5). Additionally, more anifrolumab-treated patients achieved a CRR using a more stringent UPCR threshold (≤0.5 mg / mg) compared with placebo (treatment difference 14.2%; 95% CI: -5.4, 33.9).

[0207] One important treatment goal in LN is to achieve rapid and sustained control of kidney disease; in this study, the time to achieve sustained CRR (a UPCR threshold of ≤0.5 mg / mg) over time through week 52 was numerically shorter with intensive anifrolumab than with placebo (hazard ratio, 1.46; 95% CI: 0.71, 3.14). Furthermore, numerically more patients in the anifrolumab group achieved sustained reductions in oral glucocorticoids, i.e., reductions to a dose of ≤7.5 mg / day prednisolone or its equivalent by week 24 and maintenance of this dose through week 52 (treatment difference, 22.2%; 95% CI: -0.8, 45.2).

[0208] Anifrolumab exposure was likely suboptimal with the basal dosing regimen due to high clearance associated with proteinuria in LN, but exposure with the intensive regimen was more equivalent to that of 300 mg IV Q4W in extrarenal SLE.

[0209] 9. Example 3: Subcutaneous administration of anifrolumab 9.1. MI-CP180, a Phase I Study of IV Anifrolumab in Patients with SSc The mean anifrolumab serum concentrations after a single dose based on body weight are shown in Figure 16A. After a single dose, anifrolumab exhibited nonlinear 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 between 0.1 and 10.0 mg / kg. In the higher-dose cohorts, anifrolumab t1 / 2 was longer. At the highest dose level tested (20.0 mg / kg), the elimination t1 / 2 was approximately 12 days.

[0210] 9.2. Phase I Study 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), and anifrolumab 600 mg SC (n = 6)), and placebo (n = 4 / cohort). After SC administration, exposure to anifrolumab increased proportionally from 300 mg to 600 mg based on the area under the serum concentration-time curve. Arithmetic mean serum anifrolumab concentration-time profiles after single IV and SC administration are shown in Figure 16B. As reported in Tummala et al. 2018

[19] (which is incorporated herein by reference in its entirety), this study estimated the bioavailability of anifrolumab in healthy volunteers to be 87% of the intravenous exposure.

[0211] 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 17A).

[0212] This study explored the clinical pharmacology, safety, and exploratory efficacy of subcutaneous anifrolumab. The pharmacokinetics in Study 08 were consistent with the high bioavailability and high CL in SLE patients with high SIFNGS scores in Study 06 (healthy volunteers). 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 17B and 17C). In particular, subcutaneous administration of 150 mg or 300 mg anifrolumab every 2 weeks for 50 weeks showed nonlinear pharmacokinetics and C trough Concentrations were greater 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 in patients with SLE.

[0213] The results of Study 08 are described in detail in Bruce et al.

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

[0214] In Study 08, the small sample size prevented conclusions from being drawn about the biological effects of the study drug (e.g., 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.

[0215] 9.4. Conclusion The PK of anifrolumab consistently demonstrated target-mediated pharmacokinetics, with concentrations or exposure decreasing more than dose-proportionally at low dose levels. In Study 06 (healthy volunteers), high bioavailability of anifrolumab administered by SC injection was observed, with the AUC ratio of anifrolumab SC to anifrolumab IV at doses less than 300 mg being approximately 87%.

[0216] 10. Example 4: Determination of Optimal Subcutaneous Unit Dose 10.1. Purpose To identify the optimal dosing regimen for subcutaneous administration of anifrolumab, we developed a population PK and PK / PD model designed to utilize existing human clinical trials. PK data from Phase III studies 04 and 05 and Phase II study 1013 were used to support the development of the population PK model.

[0217] In studies 1013, 04, and 05 in patients with SLE, anifrolumab administered at doses of ≥300 mg Q4W rapidly and sustained >80% neutralization of the type I IFN 21 gene signature (Figure 18). Patients receiving 150 mg of anifrolumab demonstrated suboptimal neutralization of the type I IFN gene signature, whereas patients receiving placebo demonstrated no neutralization. Patients with higher PD suppression were associated with higher BICLA and SRI(4) responses at week 52.

[0218] Our initial goal was to find a subcutaneous dose that would provide equivalent exposure to the standard 300 mg IV (Q4W) dose while allowing for more regular administration that could be delivered in a smaller volume. This was 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 in SLE patients), as reported, for example, in Furie et al. 2017

[11] (which is incorporated herein by reference in its entirety).

[0219] 10.2.5.3: Results 10.2.1 Initial Selection of Subcutaneous Anifrolumab Dose In initial analyses, we determined specific dosing regimens predicted to provide exposures equivalent to those achievable with 300 mg Q4W IV. A 105 mg subcutaneous weekly (QW) dosing regimen was initially found to have an AUC ratio close to (or slightly greater than) 1 (Figure 19A), even when the predicted bioavailability, accounting for interindividual variability in bioavailability, was reduced by approximately 7% compared to that reported by Tummal et al. 2018

[19] (Figure 19B). The 105 mg subcutaneous QW dose appeared to provide comparable or improved median trough concentrations and IFNGS suppression compared to the comparative 300 mg Q4W IV dose (Figures 20A and 20B). 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, these analyses assumed that the 300 mg IV dose approximates the plateau of the anifrolumab dose-response curve, i.e., increasing the dose beyond 300 mg IV Q4W would not provide any significant benefit to patients, especially given the increased risk of herpes zoster infection at higher doses.

[0220] 10.2.2. Modification of Subcutaneous Anifrolumab Dose Selection Therefore, we initially considered 105 mg QW to be the optimal SC dose of anifrolumab for the treatment of type I IFN-mediated disease 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 further analyzed data from the TULIP I (Study 04) and TULIP II (Study 05) clinical trials.

[0221] Additional data were used to demonstrate the positivity-exposure-BICLA relationship in patients with high IFNGS. Surprisingly, this relationship was also observed in the 300 mg IV Q4W group (Figures 21A and 21B). Thus, BICLA response within the 300 mg IV Q4W patient group was variable. Logistic regression of BICLA response at Week 52 in patients confirmed that PK exposure was a significant covariate in both TULIP I and TULIP II. In both analyses of all participants and those with high IFNGS who completed treatment individually 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 The exposure-response correlated with higher BICLA and SRI(4). In other words, in lupus patients receiving 300 mg Q4W IV, there was exposure-dependent variability in response to anifrolumab (Figures 21A and 21B).

[0222] Surprisingly, the 300 mg IV Q4W dose was therefore found to be at the onset of the exposure-response plateau, while the suboptimal 150 mg IV dose was in the step region of the exposure-response curve ( FIG. 22A ). 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 lupus patients. Therefore, the inventors chose to select an alternative dose for SC administration that would mitigate the impact of response variability in the lupus patient population.

[0223] In summary, from the initial analysis, it seemed that the administration of a subcutaneous dose of 105 mg QW of anifrolumab would achieve at least the same efficacy as that of 300 mg 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 can be increased without reaching the maximum threshold for bioavailability and efficacy.In other words, the QW dose can be increased beyond 105 mg to provide even higher plasma concentration and IFNGS suppression, thereby reducing the response variability observed in SLE patients.Therefore, the dose of 105 mg would be suboptimal.

[0224] The surprising additional dose-response curve data were further validated by demonstrating that the probability of achieving a relevant BICLA response (in IFNGS-high patients) increased with weekly subcutaneous administration at concentrations higher than the 105 mg dose (Table 21). These data showed an unexpected location of the dose-response plateau (e.g., under subcutaneous administration), which shifted to the right at doses above 105 mg (Figure 22B), indicating that the maximum BICLA response is indeed achievable at doses above 105 mg and that higher doses would be preferred (Table 21).

[0225] [Table 25]

[0226] 10.2.3. Anifrolumab bioavailability 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 after 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% after subcutaneous administration (see Example 3)

[19] . The bioavailability (F1) of anifrolumab in Study 08 (SLE patients, SC) was found to be 81% in healthy volunteers using a population PK model (Table 22).

[0227] Typical bioavailability of monoclonal antibodies via subcutaneous injection ranges from 52 to 80%.

[37] We performed external validation of Study 08 (Ph2 SC) in SLE using a PPK model developed with healthy volunteers and SLE patients from the IV study to determine bioavailability in the lupus population.

[0228] [Table 26]

[0229] Detailed analysis of the data from Study 08 revealed that bioavailability was affected by the site of SC administration. Specifically, 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 after thigh injection trough The C tended to decrease compared to abdominal injection (Figures 23A and 23B). Therefore, it was surprisingly concluded that bioavailability could actually be as low as 70% considering the variability due to injection site and the higher variability in bioavailability in lupus (SLE) patients compared to healthy volunteers. Importantly, assuming a bioavailability (F1) of 81-87%, 105 mg initially had a C comparable to 300 mg IV.ave (Figure 24). In contrast, the C of 105 mg QW subcutaneous administration was predicted to be approximately 70% or less when the estimated bioavailability fell below 70%. ave The median value fell to less than 1 (Figures 26A, 26B and Table 23).

[0230] [Table 27]

[0231] 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 the bioavailability was assumed to be 81% (Figure 25A). 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 25B). Furthermore, the 120 mg SC QW dose had minimal overlap with the undesirable 1000 mg IV dose, which increases the risk of herpes zoster infection (Figure 25C) (Figure 27). 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 than the assumed optimal 300 mg IV dose (Table 24) (Table 25).

[0232] Therefore, choosing 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 patients with SLE and LN (Table 24, Figures 26A and 26B). SC doses of less than 150 mg QW are also desirable to reduce the risk of herpes zoster infection.

[0233] [Table 28]

[0234] [Table 29]

[0235] Doses of 120 mg and 135 mg QW offer particularly reasonable benefit-risk profiles. At doses of 150 mg QW or higher, there are increased safety risks, such as increased risk of shingles in patients, given that a 150 mg QW SC dose is equivalent to 1000 mg IV Q4W (Figures 25C and 27). Therefore, subcutaneous doses less than 150 mg QW and greater than 105 mg QW were determined as preferred doses. Subcutaneous doses less than 150 mg QW and 135 mg or less were determined as more preferred doses. A subcutaneous dose of 120 mg was determined as the optimal dose.

[0236] In summary, the inventors surprisingly found that the optimal subcutaneous dose of anifrolumab might initially appear to be 105 mg QW, given previously available preliminary data ( FIG. 12 ). However, further data and analysis surprisingly revealed that doses below 105 mg QW underdosed a significant proportion of patients ( FIG. 22B , Table 22). Thus, the particularly advantageous dosing regimens demonstrated by the inventors were doses higher than 105 mg QW. In particular, the optimal dose was determined to be 120 mg QW subcutaneously, which, based on estimated bioavailability, corresponds to approximately 400 mg IV Q4W. Thus, the optimal SC dose is surprisingly >30% higher than the dose considered optimal based solely on comparison with 300 mg IV Q4W and the previously understood bioavailability of anifrolumab.

[0237] Therefore, the inventors have surprisingly shown that a dose of more than 105 mg SC QW and less than 150 mg SC QW, particularly a dose of 120 mg 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.Therefore, administration of more than 105 mg QW advantageously accounts for bioavailability variability and leads to improved treatment results.A dose of less than 150 mg QW reduces the risk of shingles infection.

[0238] Pharmacokinetic data from healthy volunteers (Study 06 [IV group only]) and SLE patients (Studies 1013, 02, 04, and 05) were also pooled to assess 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 levels were found to have significantly higher clearance (CL) and lower concentrations. Surprisingly, however, these covariates had no clinically relevant impact on efficacy and safety. Surprisingly, other covariates relevant 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 therapy (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).

[0239] 10.3. Conclusion We demonstrate that anifrolumab doses <150 mg QW and >105 mg QW have at least equivalent or higher C than 300 mg IV Q4W. ave Over 52 weeks, the 120 mg SC QW dose has been shown to provide efficacy at least comparable to that demonstrated by the 300 mg IV Q4W dose, particularly in patients with LN and SLE. It is further plausible that the 120 mg SC QW dose provides greater efficacy than that demonstrated by the 300 mg IV Q4W dose.

[0240] Therefore, based on a combination of PK / PD data and modeling of data from the Phase II LN study (Study 07, see Section 8 and Table 8) and the clinical program of anifrolumab IV and SC in SLE described in Section 10.2, a dosing regimen of 900 mg anifrolumab IV Q4W for six doses followed by 120 mg anifrolumab SC QW was selected.

[0241] Study 07 evaluated two dosing regimens: a basic regimen (300 mg IV Q4W) using the proposed dose for patients with SLE, and an intensive regimen (900 mg IV Q4W for the first three doses, followed by 300 mg IV Q4W for the remainder of the study). The intensive regimen showed results suggesting a greater therapeutic benefit than the basic regimen.

[0242] However, exposure of the 300 mg IV Q4W dose in the initial phase of both regimens was suboptimal when compared with the 300 mg IV Q4W dose in SLE without active renal disease. Therefore, a more intensive dosing regimen was selected, with an initial dose of 900 mg IV Q4W for six doses, followed by 120 mg SC QW or 300 mg IV Q4W. This regimen provides sustained anifrolumab exposure / PD suppression and improved UPCR outcomes compared with the dosing regimen previously evaluated in Study 07. The 120 mg SC QW dose provides exposure and PD suppression that are at least equivalent to or noninferior to the 300 mg IV Q4W dose in patients with LN.

[0243] In summary, the primary objective of Study 07 was to evaluate the efficacy of anifrolumab, assessed with two different dosing regimens in addition to standard therapy, as measured by the relative difference between the total anifrolumab and placebo groups in the change in 24-hour UPCR from baseline to week 52. Although the study did not meet this primary endpoint, results demonstrated the efficacy of the intensive anifrolumab dosing regimen compared with placebo on a range of clinically meaningful endpoints, including CRR and sustained OCS tapering at week 52. In contrast, anifrolumab exposure was suboptimal with the basic dosing regimen due to higher clearance associated with proteinuria in the LNs.

[0244] The IV administration route has been primarily used in the anifrolumab clinical program in SLE without active renal disease, although a more convenient SC administration route is also being developed. In the anifrolumab clinical development program in patients with SLE (IV and SC) and LN (IV), both IV and SC routes of administration were shown to be safe and well tolerated. The SC administration route using aPFS for anifrolumab offers patients and / or caregivers increased convenience and dosing flexibility and reduced exposure to infection risks associated with visits for medication (including, but not limited to, influenza or COVID-19), and is expected to improve accessibility and compliance to treatment compared to IV administration.

[0245] 11. Example 5: Selection of Dosage Regimen for Lupus Nephritis Introduction In Study 07, the primary and secondary endpoints of all anifrolumab dosing regimens compared with placebo were not met, but efficacy results for the intensive dosing regimen suggested clinical benefit with an acceptable safety profile. In contrast, the basic dosing regimen provided therapeutic benefit but resulted in suboptimal anifrolumab exposure in patients with active proliferative LN compared with SLE without active renal disease.

[0246] The objective of Study 07 was to achieve the same exposure to anifrolumab as the proposed dose of 300 mg IV Q4W for SLE patients without active renal disease. Study 07 (NCT02547922, Section 8) evaluated two anifrolumab dosing regimens: a basic regimen (300 mg IV Q4W) using the proposed dose for SLE patients, and an intensive regimen (900 mg IV Q4W for the first three doses, followed by 300 mg IV Q4W for the remainder of the study). As described in Section 8, the intensive regimen demonstrated results suggesting a greater treatment benefit than the basic regimen. However, exposure with both regimens was suboptimal when compared with the 300 mg IV Q4W dose in SLE patients without active renal disease (Figures 13 and 14).

[0247] Pharmacokinetics Anifrolumab binds to IFN-αR1 with high specificity and affinity, preventing the formation of a complex with IFN-αR2, resulting in blockade of downstream signaling activity. The antibody-receptor complex is then rapidly internalized. Therefore, the PK of anifrolumab indicates target receptor-mediated clearance, with more rapid clearance observed at lower concentration levels.

[0248] In Study 07, consistent with earlier findings, nonlinear PK was observed between patients on the basic regimen (300 mg IV Q4W) and the intensive regimen (900 mg IV Q4W for the first three doses, followed by 300 mg IV Q4W), all of whom had mobile proliferative LNs. However, lower concentrations were observed during the maintenance phase of 300 mg IV Q4W in both the basic and intensive regimens compared to the SLE regimen (Figures 13 and 14).

[0249] An initial population PK analysis of data from LN patients in Study 07 revealed a higher typical clearance of anifrolumab in LN patients than in SLE patients: 0.245 L / day vs. 0.193 L / day. In addition to previously identified covariates, patients with lower baseline albumin and higher 24-hour UPCR measurements had higher clearance. Prior to the subsequent addition of time-dependent UPCR covariates, the initial model indicated that patients with a greater decrease in clearance over time showed a greater improvement in UPCR (Figures 28A and 28B).

[0250] Changes in clearance were estimated by a sigmoidal time-dependent function multiplied by the linear clearance of the final model presented in Section 3.5. formula 4

number

[0251] Pharmacodynamics Anifrolumab targets the IFN pathway. To track the biological effect of anifrolumab on its target, we measured type I IFN-inducible gene expression in whole blood in both SLE and LN studies using a 21-gene assay. Type I IFN gene signature test-low patients do not have elevated gene signatures, so neutralization of the type I IFN PD signature is only relevant in test-high patients. In SLE studies 1013, 04, and 05, anifrolumab administered at doses ≥300 mg Q4W rapidly and sustained neutralization of the type I IFN 21-gene signature by >80% (Figure 18).

[0252] In LN patients, both BR and IR showed rapid and significant neutralization of the type I IFN PD signature after the first dose of anifrolumab, a finding shared with SLE patients receiving doses of ≥300 mg. Similar to SLE patients, patients on the intensive regimen maintained a median neutralization of the type I IFN PD signature of ≥80% at all study visits through week 52, whereas lower PD suppression was observed in patients on the basic regimen (Figure 8). LN patients with high proteinuria had higher anifrolumab clearance. Accordingly, numerically lower PD suppression was observed in patients with high proteinuria and baseline UPCR >3 mg / mg receiving the basic regimen (300 mg IV Q4W) compared with patients on the intensive regimen (300 mg IV Q4W after the first three doses of 900 mg IV Q4W) (Figure 29A). Furthermore, much greater UPCR improvement was observed in patients with high proteinuria who were able to achieve greater than 90% PD suppression (Figure 29B), suggesting that greater PD suppression as a result of higher doses may improve the likelihood of UPCR outcomes.

[0253] 11.1.3. Pharmacokinetic / Pharmacodynamic Relationships A longitudinal population model was developed to characterize the relationship between anifrolumab PK and UPCR in patients with LN. Anifrolumab was found to improve proteinuria in an exposure-dependent manner, and improvement in proteinuria was subsequently found to reduce anifrolumab clearance. After the PK-UPCR model was completed, a dropout model was sequentially developed and integrated with the PK-UPCR model. The resulting PK-UPCR dropout model was used in simulations to evaluate various doses and dosing regimens. UPCR and treatment discontinuation are particularly interesting variables because they are two major drivers of the CRR endpoint.

[0254] 11.1.3.1.PK-UPCR Model The UPCR kinetic model was described by a modified turnover model defined by a differential equation. formula 5

number

[0255] The shape parameter x introduces flexibility, allowing the UPCR kinetics to deviate from perfect exponential behavior. The time-dependent effect of anifrolumab on UPCR kinetics was further defined as: Formula 6 E α (t)=1+a×c(t) During the ceremony, α is a parameter that determines the strength of the time-dependent effect of anifrolumab on UPCR kinetics; c(t) is the anifrolumab serum concentration measured in nM.

[0256] To avoid small values ​​of the parameter α, a scaling factor for the parameter was introduced in Equation 6. At x=1, anifrolumab is absent, so E α When (t) = 1, the parameter k is the half-life of the equilibration process of U(t). Therefore, according to this model, the effect of anifrolumab can be interpreted as a decrease in the UPCR equilibration half-life or, if x ≠ 1, a more general decrease in the characteristic time for onset of effect. The additional effect of anifrolumab on the UPCR steady state, i.e., ((1-E s )×U b ) x Adjusting the terms was considered, but did not significantly improve the model.

[0257] Parameters k and U bLog-normal inter-individual variability was defined for the standard deviation of residual error. s The inter-individual variability of E s =1-(1-E STV )e η (In the formula, E STV is E s is the standard value of , and η is a random effect parameter). This operation is defined by (1-E s ) parameter E, which effectively normalizes the logarithm but interprets the reduction in standard of care from the UPCR baseline s is intended to be included in the model.

[0258] The PK portion of the PK-UPCR model was based on a population PK model in SLE patients, with the following changes: parameters Q and K ss Because PK data from LN patients are relatively limited and sparse compared to the pooled PK data from SLE patients, we fixed the previous estimates. Furthermore, we omitted interindividual variability for parameter V2. Finally, and most importantly, we redefined the linear clearance of anifrolumab to include dependence on a time-dependent model state variable U(t) describing UPCR according to the following: Equation 7 CL=CL TV ×F IFN ×F WT ×F UPCR ×e η

[0259] Here, CL TV is the standard value of clearance, and η is the random effect parameter. The coefficient F IFN captures the effect of IFN testing on clearance, and in patients with high IFN levels, F IFN = 1, and in patients with low IFN levels, F IFN =F IFNLOW (where F IFNLOW are the estimated parameters). The coefficient F WT captures the effect of body weight on clearance according to: formula 8

number

[0260] F UPCR captures the time-dependent changes in clearance due to UPCR kinetics according to: Formula 9 F UPCR =1+CL UPCR ×(U(t)-2.53) During the ceremony, CL UPCR are the estimated parameters, The reference value of 2.53 is the median measured UPCR baseline value.

[0261] Parameter CL UPCR The interpretation is the relative change in anifrolumab clearance per mg / mg change in UPCR.

[0262] A large effect of anifrolumab on the onset of UPCR improvement was estimated (α = 1.11, CI 0.251-2.50). Furthermore, a 1 mg / mg decrease in UPCR was estimated to result in a 21.0% (CI 18.9-23.0) decrease in linear anifrolumab clearance, using the median measured UPCR baseline as the reference. The PK-UPCR model adequately described the UPCR and PK data, as assessed by the dropout-corrected visual prediction check plots (Figures 30 and 31).

[0263] 11.2. Dropout Model After developing the PK-UPCR model, its population parameters were fixed and the model was extended to account for dropout based on a time-to-event analysis. The purpose of this analysis was to determine whether anifrolumab exposure itself or its effect on UPCR might be associated with the risk of discontinuation. The following proportional hazards model was developed: Formula 10

number

[0264] The scaling coefficients of the parameters λ0 and β PK was introduced to avoid small values ​​of

[0265] Parameter estimates for the dropout model are shown in Table 26. The model described the dropout data well (Figure 32). The dropout model suggested that patients with high UPCR levels and low mean anifrolumab concentrations were more likely to discontinue treatment.

[0266] [Table 30]

[0267] 11.2.1. Simulation with the PK-UPCR-Dropout Model A PK-UPCR-dropout model was used to simulate different dosing regimens. For each simulated scenario, the placebo-adjusted proportion of UPCR responders was calculated as a function of time. UPCR responders were defined as patients with a UPCR 24-hour ≤0.5 mg / mg who did not discontinue treatment.

[0268] First, the impact of extending the intensification treatment period beyond three 900 mg doses was simulated. The PK-UPCR-dropout model revealed that extending the intensification period for the 900 mg dose from 12 weeks (3 doses) used in Study 07 to 24 weeks (6 doses) promoted an earlier onset of response compared to placebo and maintained that response through 52 weeks (Figure 33). However, further extension of the intensification period to 36 or 52 weeks (9 or 13 doses) was predicted to result in only an incremental effect per additional dose.

[0269] Second, we performed a more detailed simulation of the proposed regimen of six doses of 900 mg IV Q4W, followed by 120 mg SC QW (Figure 34). In addition to the PK-UPCR-dropout model described above, we incorporated a previously developed model for gene signature PD markers in SLE into the model. The simulation shows that the 900 mg initial dose drives a decrease in UPCR, thereby driving a decrease in anifrolumab clearance. The largest portion of the change in clearance occurs in the first half of the year, reflected in the PK profile, which shows a gradual increase in concentration during this period. Weekly dosing after the switch from IV to SC administration at week 24 provides sustained exposure, resulting in sustained PD suppression. Median PD suppression is predicted to exceed 90%, with more than 9 out of 10 patients predicted to have PD suppression greater than 80%.

[0270] 11.3. Subcutaneous Loading Dose for Lupus Nephritis As described above, an anifrolumab dosing regimen of 300 mg IV Q4 followed by a 900 mg IV Q4 loading dose (x3) demonstrated efficacy in patients with lupus nephritis. PK / PD modeling suggests that a 900 mg (x6) consolidation period followed by 300 mg IV Q4 is expected to provide additional benefit. Based on the analysis described above (see Section 10), the 300 mg IV dose for lupus nephritis may be substituted with a subcutaneous dose of >105 mg but <150 mg QW, and optionally a subcutaneous dose of 120 mg QW. A 120 mg SC QW dose after a consolidation period in LN is expected to provide at least equivalent efficacy to the 300 mg IV dose in patients with lupus nephritis, particularly considering that 120 mg SC provides similar exposure and is expected to be effective in SLE.

[0271] It would also be advantageous to provide a loading dose of LN to patients via subcutaneous delivery. The inventors used modeling techniques to determine the subcutaneous dose corresponding to a 900 mg IV dose of anifrolumab in patients with lupus nephritis. Based on the above-described modeling of the PK / PD of anifrolumab in patients with LN from Study 07, a dose of approximately 1150 mg was found to provide an AUC equivalent to 900 mg IV in healthy volunteers (Figure 35). Predicted subcutaneous vs. IV AUC 0-inf and C trough is shown in Figure 36.

[0272] [Table 31]

[0273] 1150 mg SC was also found to provide an AUC equivalent to 900 mg IV in patients with LN (Figure 36). To account for the volume limitations of the 150 mg / ml anifrolumab formulation (e.g., the need for a volume approximately 1 / 10 of 1 ml), a dose of 1155 mg SC anifrolumab may be used for practical reasons, which may be considered equivalent to a dose of 1150 mg.

[0274] 11.4. Conclusion A population model was developed based on Study 07 data on long-term anifrolumab exposure, proteinuria (UPCR) levels, and IP discontinuation (dropout). Simulations using this model suggested that increasing the number of initial 900 mg IV Q4W doses from 3 to 6 doses would result in a more rapid onset of renal response, as assessed by a decrease in UPCR. Furthermore, the model predicted a slightly lower discontinuation rate for the proposed regimen of six initial IV Q4W doses of anifrolumab compared with the intensified and basal dosing regimens examined in Study 07. The predicted lower likelihood of treatment discontinuation may be due to better improvement in UPCR and renal inflammation.

[0275] Therefore, we proposed a more intensive dosing regimen than Study 07 in patients with active proliferative LN: six loading doses of 900 mg IV Q4W (or approximately 1150 mg SC), followed by 300 mg IV Q4W (or 120 mg SC QW). This regimen is expected to provide sustained anifrolumab exposure / PD suppression and improve UPCR outcomes compared to the dosing regimen previously evaluated in Study 07 in patients with active proliferative LN. The proposed 1150 mg SC and 120 mg SC QW doses in LN patients will provide at least equivalent or non-inferior exposure and PD suppression compared to 900 mg IV Q4W and 300 mg IV Q4W, respectively. The doses of this invention are summarized in Tables 28 and 29.

[0276] [Table 32]

[0277] [Table 33]

[0278] The subcutaneous and intravenous administration regimens of anifrolumab for the treatment of LN are interchangeable. A SC IR regimen can be followed by an IV BR regimen. Similarly, IV IR can be followed by SC BR.

[0279] 12. Example 6: LN urine proteomics reveals common biological pathways identified by different disease measures Background LN is a serious consequence of SLE, and there remains a significant unmet need to discover urinary protein biomarkers that provide noninvasive surrogates of disease activity and response to treatment. The objective of this study was to measure protein biomarkers in urine samples from a diverse cohort of LN patients and evaluate their correlation with patient demographics and clinical characteristics, including estimated glomerular filtration rate (eGFR), SLEDAI-Kidney (SLEDAI-R), and renal measures of the National Institutes of Health Activity Index (NIH-AI) and Chronic Index (NIH-CI).

[0280] 12.2. Purpose To measure protein biomarkers in urine samples from a diverse cohort of LN patients and evaluate correlations between biomarkers and patient demographic and clinical characteristics.

[0281] 12.3. Method Demographics and characteristics of the 112 patient cohort are listed in Table 30. All patients fulfilled the 1997 ACR criteria for SLE, and all patients had biopsy-proven LN. Urine samples from patients and 16 healthy donors (HD) were analyzed by Luminex for 192 proteins and Simoa. TM Five proteins were analyzed by MRI. Protein concentrations were normalized to urinary creatinine levels. The logarithmic concentration of each protein was evaluated for correlation with clinical characteristics using linear regression adjusted for age, sex, ethnicity, disease duration, and treatment, and eGFR was assessed using a cutoff of >60. False discovery rates were calculated using the Benjamini-Hochberg method, and significance was determined using a cutoff of 0.1. Statistical significance of protein list intersections was assessed by permutation. Pathway evaluation was performed using the Ingenuity core analysis.

[0282] 12.4.Results 12.4.1 Overview Pre-filtering of proteins with LN-normalized mean concentrations greater than the HD mean + 1.5 SD yielded 97 differentially upregulated proteins. Most protein-outcome associations were confounded by age (but not disease duration), sex, and MMF dose. After removing the effects of all confounding factors, many proteins showed statistically significant differential expression with respect to eGFR, SLEDAI-2K, SLEDAI-R, serum C3 and C4, NIH-AI, and NIH-CI. Conversely, no proteins were significantly correlated with LN class, race, or SDI (SLICC / ACR disease index). The largest number of significant proteins was found in eGFR (55 proteins), followed by SLEDAI-R (36) and NIH-AI (20). The intersection of these three lists (intersection p = 4.1 × 10) -5 ) (Table 31), indicating that these clinical kidney measurements share common biological processes. Pathway analysis of the 11 common proteins showed enrichment for functions known to be related to fatty acid / lipid metabolism, cardiovascular disease, cell trafficking, and immune cell infiltration.

[0283] 12.4.2. Proteomic urinary biomarkers upregulated in LN Of the 197 proteins evaluated, 97 were significantly upregulated in LN patients compared with healthy donors. Of the five proteins analyzed by Simoa, three (BLC, IL-1β, and IL-6) were detectable in >70% of patients and dysregulated in LN.

[0284] 12.4.3. Association with demographic and clinical characteristics The strongest confounders of the protein-outcome associations were age (but not disease duration), sex, and MMF administration. Adjustment for oral corticosteroid dose, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers made no substantial difference to any of the proposed associations. Proteins were not significantly correlated with LN class, race, or SDI. After controlling for the effects of all confounders, many proteins showed statistically significant differential expression with respect to eGFR, SLEDAI-2K, SLEDAI-R, serum C3 and C4, NIH-AI, NIH-CI, and IFNGS.

[0285] 12.4.3.1C3 and C4 More proteins were associated with serum C4 than with serum C3. Of the four proteins associated with serum C3, C3, EN-RAGE, and IL-1β were also associated with serum C4. Myeloperoxidase was specifically associated with serum C3, whereas 15 proteins, including hemopexin (a lupus renal activity index [RAIL] biomarker), apolipoproteins, IL-6, APRIL, and CRP, were specifically associated with serum C4.

[0286] NIH-AI and NIH-CI: Proteins associated with high scores on the NIH-AI or NIH-CI were largely distinct (Figure 37A). Four proteins associated with both the NIH-AI and NIH-CI were associated with cellular senescence (cathepsin D, MCP-1) and atherosclerosis risk (OPG, TIMP-1). Unique proteins (NIH-AI and NIH-CI) were present in RAIL (adiponectin and KIM-1) or associated with T cell cytokines and apolipoproteins.

[0287] 12.4.3.3. ≥4 Clinical features Several proteins were associated with ≥4 of the clinical features (Figure 37B).

[0288] 12.4.3.4.IFNGS IFNGS was significantly associated with inflammatory immune-activating proteins (EN-RAGE, ICAM-1, VCAM-1); B cell activation markers and cytokine activators (PEACAM-1, BAFF); T cell, chemokine, and cytokine (RANTES, IP-10, IL-18); and innate cell activators (CD163, M-CSF) (Figure 38A). While most associations were specific, IFNGS most commonly overlapped with SLEDAI-R.

[0289] 12.4.3.5.eGFR, SLEDAI-R, NIH-AI The most significant protein association was found with eGFR (55 proteins), followed by SLEDAI-R (36) and NIH-AI (20).

[0290] 12.4.4. Proteins overlapping with high scores for eGFR, SLEDAI-R, and NIH-AI The 11 proteins associated with eGFR, SLEDAI-R, and NIH-AI significantly overlapped (intersection P = 4.1 × 10), indicating that these clinical renal measurements share common biological processes (Figure 38B). Of the 11 proteins common to high eGFR, SLEDAI-R, and NIH-AI scores, three were associated with clinical features of ≥4: Apo B, Apo CI, and LTF (Figure 37B). Pathway analysis of the 11 common proteins showed enrichment for functions known to be related to fatty acid / lipid metabolism, cardiovascular disease, cell trafficking, and immune cell infiltration (Figure 39A). Many of the disease and molecular function categories and subcategories are related to vascular disease in SLE, including lipid metabolism and cardiovascular disease, immune cell adhesion, leukocyte accumulation, and cell degranulation.

[0291] 12.4.5. Proteins specific to all clinical features Serum C3, C4, NIH-CI, and SLEDAI-2K were not associated with any unique proteins, while eGFR had the most unique proteins, followed by IFNGS (Figure 39B). SLEDAI-R and NIH-AI were associated with two unique proteins.

[0292] 12.5. Conclusion By analyzing LN urinary proteomics, we revealed that three clinical renal measurements: eGFR, SLEDAI-R, and NIH-AI, were commonly associated with various proteins and pathways, most of which supported the emerging importance of renal vascular pathology in LN.

[0293] Luminex (192 proteins) and Simoa (5 proteins) can be successfully used to measure dysregulated urinary proteins in LN. This approach provides quantitative protein outcomes for over 100 proteins without requiring special sample preparation or minimal sample volume. These results indicate that multiple inflammatory mediators and pathways contribute to LN pathophysiology. Three clinical renal measurements: eGFR, SLEDAI-R, and NIH-AI, are commonly associated with various LN proteins and pathways and may share common biological processes. Eleven proteins common to eGFR, SLEDAI-R, and NIH-AI are associated with lupus vascular pathology, suggesting that changes to the renal vasculature may be important in LN renal injury. IFNGS was significantly associated with immune-inflammatory pathways, including B cell activation, and most commonly overlapped with SLEDAI-R-associated proteins. Low serum C4 was associated with more dysregulated urinary proteins than C3, despite the small number of patients with low serum C4. This suggests that in patients with low serum C4 levels, serum C4 accumulates in the kidney.

[0294] [Table 34]

[0295] [Table 35]

[0296] [Table 36]

[0297] 13. Example 7: Delivery Device Anifrolumab is administered by injection devices such as prefilled syringes (PFS) (Figure 40A) or autoinjectors (AI) (Figure 40B).[1][9] Higher doses of anifrolumab can be administered by on-board delivery systems.

[0298] 13.1.Autoinjector Anifrolumab can be administered by an auto-injector [1]. The auto-injector is shown in exploded view (FIG. 41A) and assembled form (FIG. 41B). A label [4] is wrapped around or attached to the auto-injector [1] (FIG. 41C). The auto-injector has an auto-injector 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 auto-injector housing [3]. The unit dose [6] is visible through a viewing window [7].

[0299] 13.2. Prefilled syringes with accessories Anifrolumab can be administered via an accessory prefilled syringe (APFS) [8]. The APFS [8] contains a unit dose of anifrolumab [6] contained within a primary container [9], shown in assembled form in FIG. 42A and exploded view in FIG. 42B. 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 within 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] .

[0300] The primary container [9] of the accessory prefilled syringe (APFS) is provided within a PFS assembly [8], which includes a needle guard

[12] , a finger flange

[11] , and a plunger rod

[13] (FIGS. 42C, 42D). A label

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

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

[15] .

[0301] Packaging An injection device [1] [8] is provided in the kit

[20] (Figure 43). A label [4]

[14] is provided with the APFS or auto-injector in packaging. The label contains instructions for use of the injection device [1], [8]. The packaging contains a tamper seal.

[0302] References All publications mentioned herein are incorporated herein by reference. [1]JGHanly et al.,Rheumatol.Oxf.Engl.55,252(2016). [2] EC Baechler et al., Proc. Natl. Acad. Sci. USA100, 2610 (2003). [3]JJWeening et al., Kidney Int.65,521(2004). [4] N. Maroz and MS Segal, Am. J. Med. Sci. 346, 319 (2013). [5] A.Fanouriakis et al.,Ann.Rheum.Dis.79,713(2020). [6] EMGinzler, AJ Bollet, and EAFriedman, Annu. Rev. Med. 31, 463 (1980). [7] H.-J.Anders et al., Nat.Rev.Dis.Primer 6,7(2020). [8] R. Furie et al., N. Engl. J. Med. (2020). [9]C.Arriens et al.,Ann.Rheum.Dis.79,172(2020).

[10] BHRovin et al.,Kidney Int.95,219(2019).

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

[12] GTFerguson et al.,J.Asthma Allergy 11,63(2018).

[13] L.Peng et al.,mAbs 7,428(2015).

[14] IBajema et al.,Kidney Int.93,789(2018).

[15] ASLevey et al.,Ann.Intern.Med.150,604(2009).

[16] ASLevey et al.,Ann.Intern.Med.145,247(2006).

[17] BHRovin et al.,Lancet Lond.Engl.397,2070(2021).

[18] M.Petri et al.,Arthritis Rheum.58,1784(2008).

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

[20] ACR Meeting Abstracts(nd).

[21] BWHiggs et al.,Ann.Rheum.Dis.73,256(2014).

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

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

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

[25] B.Wang et al.,Clin.Pharmacol.Ther.93,483(2013).

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

[27] MCHochberg,Arthritis Rheum.40,1725(1997).

[28] Y.Lin Chia et al.,Rheumatol.Oxf.Engl.(2021).

[29] Y.Yao et al.,Arthritis Res.Ther.12,S6(2010).

[30] DDGladman,D.Ibanez,and MBUrowitz,J.Rheumatol.29,288 (2002).

[31] M.Petri et al.,Arthritis Rheum.34,937(1991).

[32] Y.Yao et al.,Hum.Genomics Proteomics HGP 2009,(2009).

[33] JLGorriz and A.Martinez-Castelao,Transplant.Rev.Orlando Fla 26,3(2012).

[34] JAMoreno et al.,Int.J.Mol.Sci.20,(2019).

[35] J.-Y.Jung et al.,Sci.Rep.9,9704(2019).

[36] INBruce et al.,Lancet Rheumatol.0,(2020).

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Claims

1. A method for treating lupus nephritis (LN) in a subject in need thereof, comprising administering a type I IFN receptor (IFNAR1) inhibitor to the subject, thereby reducing lupus nephritis (LN) disease activity in the subject.

2. The method of claim 1, wherein the IFNAR1 inhibitor is a human monoclonal antibody specific for IFNAR1, optionally a modified IgG1 class human monoclonal antibody.

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

4. The antibody a. a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 19; b. a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 20; c. A heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 21; d. a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence SEQ ID NO:22; e. a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence SEQ ID NO:23; and f. Light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence SEQ ID NO:24 The method of claim 2 , comprising:

5. The method of claim 2 or 3, wherein the antibody comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO:

2.

6. The method of claim 2 or 4, wherein the antibody comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO:

18.

7. 7. The method of any one of claims 2 to 6, wherein the antibody comprises an amino acid substitution in the Fc region of L234F, as numbered according to the EU index as set forth in Kabat, and wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody, and optionally the antibody comprises an amino acid substitution in the Fc region of L235E and / or P331S, as numbered according to the EU index as set forth in Kabat.

8. 6. The method of claim 2, 3, or 5, wherein the antibody comprises: (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11; and (b) a human light chain comprising the amino acid sequence of SEQ ID NO:

12.

9. 3. The method of claim 2, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof.

10. The method of claim 2, wherein the IFNAR1 inhibitor is QX006N or a functional variant thereof.

11. 11. The method of any one of claims 1 to 10, comprising administering an intravenous dose of said IFNAR1 inhibitor to said subject intravenously.

12. 12. The method of claim 11, wherein the intravenous dose is (≧) 300 mg or greater.

13. 13. The method of claim 11 or 12, wherein the intravenous dose is less than or equal to (≦) 1000 mg.

14. 14. The method of any one of claims 11 to 13, wherein the intravenous dose is greater than (>) 300 mg.

15. 15. The method of any one of claims 11, 12, or 14, wherein the intravenous dose is about 900 mg or about 1000 mg.

16. 16. The method of any one of claims 11-15, wherein the intravenous dose is administered every four weeks (Q4W), optionally wherein the intravenous dose is administered at least three times, and optionally wherein the intravenous dose is administered at least six times.

17. The method of any one of claims 1 to 10, comprising administering a subcutaneous dose of the IFNAR1 inhibitor subcutaneously.

18. 18. The method of claim 17, wherein the subcutaneous dose is greater than (>) 105 mg and less than (<) 150 mg.

19. 18. The method of claim 17, wherein the subcutaneous dose is ≦135 mg.

20. 18. The method of claim 17, wherein the subcutaneous dose is about 120 mg.

21. The method of any one of claims 17 to 20, wherein the subcutaneous dose is administered in a single administration step.

22. 22. The method of any one of claims 17 to 21, wherein the subcutaneous doses are administered at intervals of 6 to 8 days.

23. 23. The method of any one of claims 17 to 22, wherein the subcutaneous dose is administered once a week.

24. 24. The method of any one of claims 17 to 23, wherein the subcutaneous dose has a volume of about 0.5 to about 1 ml.

25. 25. The method of claim 24, wherein the subcutaneous dose has a volume of about 0.8 ml.

26. 18. The method of claim 17, wherein the subcutaneous dose is >1000 mg, optionally the subcutaneous dose is 1050-1200 mg, optionally the subcutaneous dose is 1100-1190 mg, optionally the subcutaneous dose is 1150-1160 mg, optionally the subcutaneous dose is about 1150 mg or 1155 mg.

27. 18. The method of claim 17, wherein the subcutaneous dose is administered in a volume of about 8 ml, optionally about 7.7 ml.

28. 11. The method of any one of claims 1 to 10, comprising administering to the subject a first dose of the IFNAR1 inhibitor, followed by a second dose of the IFNAR1 inhibitor, wherein the first dose is higher than the second dose.

29. 29. The method of claim 28, wherein the first dose is administered intravenously.

30. 30. The method of claim 29, wherein the first dose is >300 mg.

31. 31. The method of claim 29 or 30, wherein the first dose is ≦1000 mg.

32. 32. The method of any one of claims 29-31, wherein the first dose is about 900 mg.

33. 29. The method of claim 28, wherein the first dose is administered subcutaneously, optionally the first dose is >1000 mg, optionally the first dose is 1050-1200 mg, optionally the first dose is 1100-1190 mg, optionally the first dose is 1150-1160 mg, optionally the first dose is about 1150 mg or 1155 mg.

34. 34. The method of any one of claims 28-33, wherein the first dose is administered Q4W.

35. 35. The method of any one of claims 28-34, wherein the first dose is administered to the subject at least three times before the second dose is administered to the subject, and optionally the first dose is administered 3, 4, 5, or 6 times before the second dose is administered to the subject.

36. 36. The method of claim 35, wherein the first dose is administered to the subject at least six times before the second dose is administered to the subject.

37. 37. The method of any one of claims 28 to 36, wherein the second dose is administered subcutaneously.

38. 38. The method of claim 37, wherein the second dose is >105 mg and <135 mg.

39. 39. The method of claim 38, wherein the second dose is about 120 mg.

40. 40. The method of any one of claims 37 to 39, wherein the second dose is administered once a week.

41. 37. The method of any one of claims 28 to 36, wherein the second dose is administered intravenously.

42. 42. The method of claim 41, wherein the second dose is administered Q4W.

43. 43. The method of claim 41 or 42, wherein the second dose is > 300 mg.

44. 44. The method of any one of claims 41 to 43, wherein the second dose is ≦1000 mg.

45. 45. The method of any one of claims 41-44, wherein the second dose is about 300 mg.

46. 46. ​​The method of any one of claims 41-45, wherein the second dose is administered Q4W.

47. a. the first dose is about 900 mg and is administered intravenously Q4W and the second dose is about 120 mg and is administered subcutaneously QW; or b. the first dose is about 900 mg and is administered intravenously Q4W, and the second dose is about 300 mg and is administered intravenously Q4W; or c. the first dose is about 1150 or 1155 mg and is administered subcutaneously Q4W, and the second dose is about 300 mg and is administered intravenously Q4W; or d. the first dose is about 1150 mg or 1155 mg and is administered subcutaneously, and the second dose is about 120 mg and is administered subcutaneously QW; e. The method of claim 28, wherein optionally, the first dose is administered at least 3 months before administration of the second dose, and optionally, the first dose is administered at least 6 months before administration of the second dose.

48. 48. The method of any one of claims 1-47, wherein reducing lupus nephritis disease activity in the subject comprises complete renal response (CRR) in the subject after treatment compared to before treatment.

49. 49. The method of claim 48, wherein CRR is achieved by week 36 of treatment.

50. 51. The method of claim 49 or 50, wherein reducing LN disease activity in the subject comprises a post-treatment CRR and a UPCR of ≦0.5 mg / mg.

51. 51. The method of any one of claims 1-50, wherein reducing LN disease activity in the subject comprises a decrease in proteinuria in the subject after treatment compared to proteinuria in the subject before treatment.

52. 52. The method of claim 51, wherein proteinuria is measured by UPCR.

53. 53. The method of claim 52, wherein proteinuria is measured by 24-hour UPCR.

54. 54. The method of any one of claims 1 to 53, wherein reducing LN disease activity in the subject comprises surrogate CRR (aCRR) in the subject after treatment compared to baseline.

55. 55. The method of any one of claims 1-54, wherein reducing LN disease activity in the subject comprises treating LN in the subject, and optionally, the subject is in LN remission after treatment.

56. 56. The method of any one of claims 1 to 55, comprising administering mycophenolate mofetil (MMF) and / or a steroid to the subject.

57. 57. The method of any one of claims 1 to 56, comprising steroid sparing in the subject, wherein the dose of steroid administered to the subject is tapered from a pre-sparing dose to a post-sparing dose.

58. 58. The method of claim 57, wherein the post-sparing dose is ≦7.5 mg / day of prednisone or prednisone equivalent.

59. 59. The method of claim 57 or 58, wherein the pre-sparing dose is 20 mg / day of prednisone or prednisone equivalent.

60. 60. The method of any one of claims 57 to 59, wherein the steroid comprises a glucocorticoid.

61. 61. The method of claim 60, wherein the steroid comprises an oral glucocorticoid.

62. The steroids include hydrocortisone, mometasone, fluticasone, fluocinolone acetonide, fluocinolone, flurandrenolone acetonide, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, clocortolone, dihydroxycortisone, alclometasone, amcinonide, diflucortolone valerate, flucortolone, and fluprednide.

62. The method of any one of claims 57 to 61, wherein the active ingredient is fluandrenolone, fluorometholone, halcinonide, halobetasol, desonide, diflorasone, flurandrenolide, fluocinonide, prednicarbate, desoximetasone, fluprednisolone, prednisone, azelastine, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, halopredone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, prednisolone, prednisolone 21-phosphate, clobetasol propionate, triamcinolone acetonide, or a mixture thereof.

63. 63. The method of any one of claims 57 to 62, wherein the steroid comprises prednisone.

64. 64. The method of any one of claims 1 to 63, comprising analysing the level of one or more proteins in the subject's urine before and / or after treatment, optionally in an isolated urine sample from said subject.

65. 65. The method of any one of claims 1-64, wherein the level of the one or more proteins is identified as elevated in the subject's urine prior to treatment compared to the level of the protein in a healthy subject.

66. 66. The method of any one of claims 1-65, wherein after treatment, the level of the one or more proteins in the subject's urine is reduced compared to the pre-treatment level of the one or more proteins in the subject's urine.

67. A method for identifying a subject as suitable for treatment with an IFNAR1 inhibitor, comprising identifying elevated expression of one or more proteins in isolated urine of the subject compared to the expression of each of the one or more proteins in a healthy subject, wherein the subject is a lupus nephritis patient.

68. 68. The method of claim 67, wherein the one or more proteins comprise adiponectin, alpha-2-macroglobulin (A2Macro), antithrombin-III (AT-III), apolipoprotein A-I (Apo A-I), apolipoprotein B (Apo B), apolipoprotein C-I (Apo C-I), apolipoprotein C-III (Apo C-III), fatty acid binding protein, cardiac (FABP, cardiac), lactoferrin (LTF), neuropilin-1, omentin, serum amyloid P component (SAP), and / or von Willebrand factor (vWF).

69. 69. The method of claim 67 or 68, wherein the one or more proteins comprise Apo A-11, Apo B, Apo C-I, cathepsin D, EN-RAGE, fibrinogen, LTF, MCP-1, RANTES and / or IL-1β.

70. 70. The method of claim 69, wherein the one or more proteins comprise Apo B, Apo C-I and / or LTF.

71. 71. The method of any one of claims 1 to 70, wherein the lupus nephritis is proliferative lupus nephritis, and optionally the lupus nephritis is class III or class IV with or without coexisting class V.

72. Unit doses containing >105 mg and <= 150 mg of anifrolumab or a functional variant thereof.

73. 73. The unit dose of claim 72, comprising ≦135 mg of anifrolumab or said functional variant thereof.

74. 74. The unit dose of claim 72 or 73, comprising about 120 mg of anifrolumab or said functional variant thereof.

75. 73. The unit dose of claim 72, consisting essentially of >105 mg and <150 mg anifrolumab or a functional variant thereof.

76. 76. The unit dose of claim 75, consisting essentially of ≦135 mg of anifrolumab or said functional variant thereof.

77. 77. The unit dose of claim 76, consisting essentially of about 120 mg of anifrolumab or said functional variant thereof.

78. 78. The unit dose of any one of claims 72 to 77, wherein the concentration of anifrolumab or the functional variant thereof in the unit dose is about 150 mg / ml.

79. 79. The unit dose of any one of claims 72 to 78, wherein the volume of the unit dose is about 0.8 ml.

80. A unit dose containing >1000 mg of anifrolumab or a functional variant thereof.

81. 81. The unit dose of claim 80 comprising 1050-1200 mg of anifrolumab or said functional variant thereof, optionally 1100-1190 mg of anifrolumab or said functional variant thereof, optionally 1150-1160 mg of anifrolumab or said functional variant thereof, optionally about 1150 mg or 1155 mg of anifrolumab or said functional variant thereof.

82. 82. The unit dose of claim 81, comprising about 1150 mg or 1155 mg of anifrolumab in a volume of 7.7 ml, wherein the concentration of anifrolumab is 150 mg / ml.

83. 81. The unit dose of claim 80, consisting essentially of >1000 mg of anifrolumab or said functional variant thereof.

84. 82. The unit dose of claim 81, consisting essentially of 1050-1200 mg of anifrolumab or a functional variant thereof, 1100-1190 mg of anifrolumab or a functional variant thereof, 1150-1160 mg of anifrolumab or a functional variant thereof, about 1150 mg or 1155 mg of anifrolumab or a functional variant thereof.

85. 85. The unit dose of any one of claims 72-84, comprising a formulation of about 150-200 mg / ml anifrolumab or said functional variant thereof, 25-150 mM lysine salt and an uncharged excipient.

86. 86. The unit dose of claim 85, comprising a formulation of about 25 mM histidine-HCl, about 130 mM trehalose, and about 0.05% w / v polysorbate 80 or polysorbate 20.

87. 87. The unit dose of claim 85 or 86, wherein the formulation has a pH of about 5.

9.

88. A unit dose according to any one of claims 72 to 87 for use in a method according to any one of claims 1 to 71.

89. 73. The unit dose of claim 72, wherein the volume of the unit dose is about 7.7 ml.

90. 74. The unit dose of claim 72 or 73, comprising a formulation of 150-200 mg / ml anifrolumab or a functional variant thereof, 25-150 mM lysine salt and an uncharged excipient.

91. 91. The unit dose of claim 90, comprising a formulation of about 25 mM histidine-HCl, about 130 mM trehalose, and about 0.05% w / v polysorbate 80 or polysorbate 20.

92. 92. The unit dose of claim 90 or 91, wherein the formulation has a pH of about 5.

9.

93. 93. The unit dose of any one of claims 72 to 92, suitable for subcutaneous administration to a subject.

94. A unit dose according to any one of claims 72 to 93 for use in a method according to any one of claims 1 to 71.

95. 95. A pharmaceutical composition for use in the method of any one of claims 1 to 71, comprising anifrolumab or a functional variant thereof or a unit dose of any one of claims 72 to 94.

96. An injection device comprising a unit dose according to any one of claims 72 to 94 or a pharmaceutical composition according to claim 95.

97. 97. The injection device of claim 96, which is a pre-filled syringe (PFS).

98. 98. The injection device of claim 97, which is an accessory pre-filled syringe (AFPS).

99. 97. The injection device of claim 96, which is an automatic injector.

100. A kit comprising an injection device according to any one of claims 96 to 99 and instructions for use.

101. 101. The kit of claim 100, wherein the instructions include directions for subcutaneous administration of the pharmaceutical composition or unit dose to a subject.

102. 102. The kit of claim 100 or 101, wherein the instructions for use specify that the injection device, unit dose and / or pharmaceutical composition is for use in the treatment of LN.

103. 102. The kit of claim 100 or 101, comprising packaging adapted to hold the injection device and the instructions for use.

104. The kit of any one of claims 100 to 103, wherein the instructions for use are attached to the injection device.

105. 105. The kit of any one of claims 100 to 104, wherein the instructions for use comprise instructions for subcutaneous administration of anifrolumab or the functional variant thereof.

106. 106. The kit of claim 105, wherein the instructions for use comprise instructions for subcutaneous administration of >105 mg of anifrolumab or the functional variant thereof.

107. 107. The kit of claim 106, wherein the instructions include instructions for administering ≦135 mg of anifrolumab or the functional variant thereof.

108. 11. The kit of claim 10, wherein the instructions include instructions for administering 120 mg of anifrolumab or the functional variant thereof.

109. 106. The kit of claim 105, wherein the instructions include instructions for administering about 1150 mg or 1155 mg of anifrolumab or the functional variant thereof.

110. 110. The kit of claim 109, wherein the instructions for use comprise instructions for monthly administration of about 1150 mg or 1155 mg of anifrolumab or the functional variant thereof.

111. 111. The kit of any one of claims 100-110, wherein the instructions for use comprise instructions for intravenous administration of a 900 mg dose of anifrolumab or instructions for subcutaneous administration of anifrolumab at about a 1150 mg or 1155 mg dose, optionally with instructions that the intravenous or subcutaneous dose is administered Q4W in at least 3 doses, optionally at least 6 doses Q4W.

112. The kit of any one of claims 100 to 111, wherein the instructions for use include instructions for use in accordance with the method of any one of claims 1 to 71.

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