Steroid-sparing type 1 interferon receptor inhibitors in patients with systemic lupus erythematosus

Abstract

The present disclosure relates to methods and compositions for treating systemic lupus erythematosus (SLE).

Description

[Background technology]

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

[0002] A key issue related to the treatment of SLE is the heterogeneous clinical manifestations of SLE. 1 Any organ can be affected in SLE, with the skin, joints, and kidneys being the most commonly affected. 2-4 Incomplete disease control leads to progressive organ damage, reduced quality of life, and increased mortality; approximately half of all SLE patients develop organ damage within 10 years of diagnosis. 5,6 There remains a need for medical interventions that improve SLE disease activity across multiple systems.

[0003] Clinical manifestations of SLE include, but are not limited to, constitutional symptoms, alopecia, skin rash, serositis, arthritis, nephritis, vasculitis, lymphadenopathy, splenomegaly, hemolytic anemia, cognitive impairment, and other neurological complications. The disease burden of SLE is increasing due to increased hospitalizations and side effects of medications, including chronic oral corticosteroids (OCS) and other immunosuppressive treatments. 7-9 .

[0004] All therapies currently used to treat SLE have well-known adverse effect profiles, and there is a medical need to identify new targeted therapies, particularly agents that may reduce the need for corticosteroids and cytotoxic drugs. In the nearly 50 years since hydroxychloroquine was approved for use in discoid lupus and SLE, only one new treatment for SLE (belimumab) has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). However, belimumab is not approved everywhere and is not widely available. Many drugs currently used to treat SLE, such as azathioprine, cyclophosphamide, and mycophenolate mofetil / mycophenolic acid, are not approved for this disease. In addition, all of these drugs have well-documented safety issues and are not effective in all patients for all symptoms of lupus. Antimalarials (e.g., hydroxychloroquine) and corticosteroids may be used to control joint pain, arthritis, and skin rashes. Other treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics for fever, joint pain, and arthritis, and topical sunscreens to minimize photosensitivity. Complete weaning of corticosteroids from patients with moderate or severe disease is often difficult and can cause long-term morbidity and contribute to premature death from cardiovascular disease. 8,10 Long-term use of even small doses of prednisone, such as 5 to 10 mg per day, has been linked to increased risk of side effects, including cataracts, osteoporosis, and coronary artery disease. 8 .

[0005] 1.2 Steroids Glucocorticoids remain the mainstay of treatment for SLE, with doses varying according to the severity of disease manifestations. There is no "safe" dose of oral glucocorticoids with respect to the risk of developing glucocorticoid-induced damage such as cataracts, osteoporosis, and coronary artery disease, but increasing exposure to glucocorticoids has been shown to be associated with a spontaneous increase in overall damage, and very low to moderate doses may also be associated with increased damage.

[0006] Glucocorticoids are the most commonly used treatment for SLE patients because they have immunosuppressive and anti-inflammatory properties, which reduce disease activity and prevent flares. Up to 80% of SLE patients are exposed to glucocorticoids, the majority of whom receive long-term treatment. Although this may provide short-term efficacy, frequent or maintenance use of oral glucocorticoid therapy is associated with a significant toxicity burden and may independently contribute to morbidity and mortality, negatively impacting health-related quality of life. Therefore, novel, effective, and long-term treatments for SLE are needed to reduce both overall disease activity and glucocorticoid use.

[0007] 1.3 The challenge of finding a cure for SLE The clinical development of new drugs is a lengthy, expensive process with a low probability of success: fewer than 10% of molecules that progress to clinical development are ultimately approved by health regulators. 11 Moreover, early clinical development of biopharmaceuticals takes much longer than that of small molecules.

[0008] Phase II trials are conducted on a small number of volunteers with the disease of interest. These trials are designed to test safety, pharmacokinetics, and pharmacodynamics. Phase II trials may provide preliminary evidence of efficacy. However, Phase II trials usually have limited ability to establish efficacy due to small participant numbers and major safety concerns. Phase III trials are necessary to demonstrate efficacy and safety of clinical candidates. Importantly, many clinical candidates that show promise in Phase II fail Phase III. Over 90% of novel therapeutics that enter Phase I trials fail during clinical development, mainly due to poor efficacy or safety. After passing Phase II, there is less than a 50% chance of passing Phase III. 12 .

[0009] The drug development process is particularly challenging for SLE because it is a particularly complex and poorly understood disease: not only is our understanding of the genetics of SLE rudimentary, but insight into the pathogenesis of most clinical symptoms remains relatively limited compared to other diseases.

[0010] The complexity of SLE presents a challenge to those hoping to develop new treatments, as the patient population is widely heterogeneous. 13 This makes the design of clinical trial protocols in SLE more difficult, for example with regard to inclusion criteria and the selection of primary and secondary endpoints. It is more difficult to predict the progression of the disease in each patient. This inevitably increases the background noise and reduces the statistical power of the trials. The high placebo response rate limits the extent to which a tested new drug can show an efficacy signal, making the conduct and interpretation of clinical trials more difficult.

[0011] The development of effective therapeutics for SLE is challenging, leading to a higher failure rate in clinical trials for therapeutics in this field compared to therapeutics for other indications. Thus, the development of novel therapeutics for the treatment of SLE has proven extremely challenging. There are numerous examples of clinical candidates that showed promise in Phase II trials but failed to demonstrate efficacy and / or safety in subsequent Phase or Phase III trials.

[0012] 1.4 Tabalumab Tabalumab (LY2127399) is a human IgG4 monoclonal antibody that binds to both soluble and membrane-bound B-cell activating factor (BAFF). The efficacy and safety of tabalumab were evaluated in two 52-week, multicenter, randomized, double-blind, placebo-controlled phase III studies (ILLUMINATE-1 and ILLUMINATE-2) in patients with moderate-to-severe SLE. The primary endpoint was the proportion of patients achieving an SLE Responder Index 5 (SRI-5) response at week 52. In ILLUMINATE-1 (NCT01196091), the primary endpoint was not met. Despite pharmacodynamic evidence of tabalumab's biological activity (significant reductions in anti-dsDNA, total B cells, and immunoglobulins), key secondary efficacy endpoints (OCS-sparing effect, time to severe flare, and most severe fatigue in the past 24 hours) also did not achieve statistical significance. 14 The primary endpoint was met in the higher dose arm (tavalumab 120 mg every 2 weeks) of ILLUMINATE-2 (NCT01205438); however, secondary endpoints, including OCS-sparing efficacy, were not met. 15 After ILLUMINATE-1 and ILLUMINATE-2, development of tabalumab was halted due to small effect sizes and failure to meet other important clinical endpoints.

[0013] 1.5 Brisibimod Brisibimod is a fusion protein consisting of four BAFF-binding domains fused to the N-terminal Fc fragment of human IgG1 Ig. Brisibimod for the treatment of SLE showed promising phase II results but failed phase III. In a phase 2 double-blind randomized placebo-controlled clinical trial (PEARL-SC), patients with serologically active SLE and a SELENA-SLEDAI score ≥ 6 were randomized to three different doses of brisibimod or placebo (NCT01162681). At week 24, the highest dose group (200 mg weekly) had a significantly higher SRI-5 response rate compared to the placebo group. 16However, in a subsequent placebo-controlled, randomized, double-blind phase III study (CHABLIS-SC1) conducted in seropositive SLE patients with persistently high disease activity (SELENA-SLEDAI score ≥ 10), the primary endpoint (SRI-6) was not met (NCT01395745), and the secondary endpoints (SRI-4 and SRI-8) were also not met. 17 .

[0014] 1.6 Atacicept Atacicept (TACI-Ig) is a fully human recombinant fusion protein that neutralizes both BAFF and APRIL. The efficacy of atacicept for the treatment of SLE was evaluated in two Phase II / III placebo-randomized controlled trials (APRIL-LN and APRIL-SLE). In the APRIL-LN trial, the renal response to atacicept was compared to placebo plus standard of care (newly started MMF and glucocorticoids) in patients with SLE nephritis. The trial was stopped after serious adverse events were reported. In APRIL-SLE, the primary endpoint, defined as a significant reduction in the proportion of patients who developed a new flare from the BILAG A or BILAG B domain scores, was not met in the lower dose (75 mg) arm (NCT00624338). Treatment of patients with the higher dose (150 mg) arm was discontinued due to serious AEs. 18 .

[0015] 1.7 Abechimus Abetimus (LJP394) consists of four synthetic oligodeoxynucleotides linked to a triethylene glycol backbone, and more than 97% of these oligonucleotides are derived from dsDNA. The drug was designed to neutralize anti-dsDNA antibodies. In a double-blind, placebo-controlled study in SLE patients, treatment of patients with high-affinity antibodies against DNA epitopes with LJP394 extended the time to renal flare and reduced the number of renal flares. 19However, a subsequent Phase III trial (NCT00089804) using a higher dose of avetimus with time to renal flare as the primary endpoint failed to demonstrate efficacy at an interim analysis, and the trial and further drug development were discontinued. 20 .

[0016] 1.8 Rituximab Rituximab is a chimeric anti-CD20 monoclonal antibody. It is an effective treatment for several autoimmune diseases, including rheumatoid arthritis and ANCA vasculitis. A few uncontrolled studies in lupus nephritis have suggested that rituximab may also be potentially effective in patients with lupus nephritis. The efficacy and safety of rituximab were evaluated in a randomized, double-blind, placebo-controlled phase III study in patients with lupus nephritis treated in combination with mycophenolate mofetil (MMF) and corticosteroids (LUNAR) (NCT00282347). Rituximab therapy did not improve clinical outcomes after 1 year of treatment. 21 The efficacy and safety of rituximab in patients with moderate-to-severe SLE was evaluated in a multicenter, placebo-randomized, controlled, phase II / III study (EXPLORER). In this study, patients with baseline active SLE (defined as a new BILAG A score ≥ 1, or a BILAG B score ≥ 2) were randomized to rituximab or placebo. The primary endpoint was the proportion of rituximab- vs. placebo-treated patients who achieved a complete clinical response (CCR), partial clinical response (PCR), or no response at week 52. The primary endpoint was not met, and complete and partial response rates in the rituximab and placebo groups were similar at week 52. Also, differences in time to first moderate or severe flare and change in HRQOL were not significant. 22 .

[0017] 1.9 Abatacept Abatacept is a CTLA-4 fusion protein that binds to CD80 / 86 on the surface of antigen-presenting cells and blocks CD-28-mediated signaling required for T cell activation. In preclinical studies, abatacept has been demonstrated to have immunomodulatory activity in the NZB / NZW mouse model of lupus. 23 Abatacept for treating nonrenal SLE was evaluated in a phase IIb randomized, double-blind, placebo-controlled trial. 24 (NCT00119678). The primary endpoint was the proportion of patients with a new (adjudicated) Lupus flare according to the British Isles Lupus Assessment Group (BILAG) index A / B score after initiation of steroid tapering. The primary and secondary endpoints were not met.

[0018] 1.10 Epratuzumab Epratuzumab is a monoclonal antibody that regulates B-cell activity by binding to CD22 on the surface of mature B cells. Epratuzumab first showed efficacy in the treatment of SLE in a Phase II study, but this was not confirmed in a second follow-up Phase IIb study or in a subsequent Phase III study. Two Phase IIb studies have evaluated the efficacy of epratuzumab in patients with moderate-to-severe SLE using a BILAG-based primary endpoint (ALLEVIATE 1 and 2). A trend toward clinical efficacy was observed, and the primary endpoint was met by more patients treated with epratuzumab than placebo. Epratuzumab treatment also improved health-related quality of life (HRQOL) and mean glucocorticoid dose. 25In another phase IIb study (EMBLEM), patients with moderate-to-severe SLE were randomized to one of five epratuzumab doses or placebo. The primary endpoint, BICLA response at week 12, was greater with all doses of pertuzumab than with placebo, but the effect was not statistically significant. In subsequent multicenter phase III studies, EMBODY 1 and EMBODY 2, patients with moderate-to-severe SLE did not meet the primary efficacy endpoint of BICLA response at week 48. No significant differences were observed in secondary endpoints such as total SLEDAI-2K scores, PGA, or mean glucocorticoid dose. 26 .

[0019] 1.11 PF-04236921 PF-04236921 is a monoclonal antibody that binds to soluble IL-6, a cytokine elevated in SLE patients. The efficacy of PF-0436921 was evaluated in a phase II RCT in patients with active SLE (BUTTERFLY) (NCT01405196). Patients were randomized to receive either subcutaneous PF-04236921 10 mg, 50 mg, or 200 mg, or placebo every 8 weeks. The 200 mg dose group was stopped early due to three deaths. The primary efficacy endpoint was SRI-4 response at week 24, and the secondary endpoint was BICLA. The primary efficacy endpoint was not met 27 .

[0020] 1.12 Belimumab Belimumab is an anti-BAFF antibody approved for the treatment of patients with SLE. Belimumab has been used for almost 60 years as the only novel treatment for SLE approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Belimumab is also the only biologic approved for the treatment of SLE. However, steroid sparing is not tolerated with belimumab, as evaluated in three phase 3, multicenter, double-blind, 52-week studies (BLISS-52, BLISS-76, and BLISS-SC) in adult patients with active SLE.28-30 In these trials, sustained steroid sparing in patients receiving belimumab (IV or SC) did not reach statistical significance. 28-30 For example, among patients receiving >7.5 mg / day prednisone at baseline, only 18-19% of 10 mg / kg belimumab recipients were able to reduce their prednisone dose by 25% or more to 7.5 mg / day or less over 12 weeks, compared with 12-13% of placebo recipients. 28 A post-hoc analysis of the BLISS-52 and BLISS-76 datasets showed that overall exposure to all corticosteroids was indeed increased on average in both the belimumab and placebo treatment groups. 31 .

[0021] 1.13 Type I IFN and Anifrolumab Anifrolumab (MEDI-546) is a human immunoglobulin G1 kappa (IgG1 kappa) monoclonal antibody (mAb) against subunit 1 of the type I interferon receptor (IFNAR1). It consists of two identical light chains and two identical heavy chains with an overall molecular weight of approximately 148 kDa. Anifrolumab inhibits the binding of type I IFNs to the type I interferon receptor (IFNAR) and inhibits the biological activity of all type I IFNs.

[0022] Type I interferons (IFNs) are cytokines implicated in the pathogenesis of SLE based on findings of increased IFN-stimulated gene expression in most SLE patients. In the phase 3 TULIP-2 trial of anifrolumab in patients with moderate-to-severe SLE, treatment response (as assessed using the British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA]) was achieved by significantly more patients receiving anifrolumab compared with placebo at week 52. 32 Similar results using this composite endpoint were observed in the phase 2 MUSE and phase 3 TULIP-1 trials.33,34 Importantly, composite endpoints used in SLE trials, such as BICLA and the SLE Responder Index (SRI), dichotomize changes in disease activity across different organ domains into binary responder and non-responder outcomes. Although this approach is useful for conclusive demonstration of efficacy, it is limited in its ability to interpret treatment efficacy across the many organ domains that may affect SLE patients.

[0023] 1.14 Conclusion There remains a significant unmet need for treatments for SLE with better efficacy and safety profiles than currently available therapies 35,36 As mentioned above, a large number and wide range of different biologics have been proposed and undergone clinical trials, but these clinical trials have failed to achieve clinically meaningful endpoints in pivotal trials. Many proposed therapies initially showed promise in phase II but failed to achieve significant and meaningful clinical benefits in subsequent pivotal phase III clinical trials. Furthermore, there is a need for SLE therapies that are effective across multiple organ domains. Moreover, even approved therapies for SLE do not allow for steroid tapering in many patients.

[0024] Thus, there remains a need for safe and effective treatments for SLE with demonstrated clinical benefit, for example, in Phase III double-blind, randomized, placebo-controlled trials. 37 SLE is a highly heterogeneous disease and there remains a need for treatments for SLE symptoms that are effective across multiple organ systems, including the musculoskeletal, mucocutaneous, and immune domains.

[0025] The present invention solves one or more of the problems set forth above. Summary of the Invention

[0026] The present invention relates to a method of steroid-sparing in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a type I IFN receptor (IFNAR1) inhibitor and a steroid, wherein the dose of the steroid administered to the subject is tapered from a baseline pre-sparing dose to a post-sparing dose, wherein the subject has systemic lupus erythematosus (SLE).

[0027] The present invention also relates to a method for treating SLE in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of an IFNAR1 inhibitor, whereby treatment reduces or prevents an increase in steroid administration to the subject.The present invention also relates to a method for treating SLE in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of an IFNAR1 inhibitor, whereby treatment reduces or prevents an increase in steroid administration to the subject.

[0028] The present invention also relates to a method of treating SLE in a subject in need of treatment comprising administering to the subject a therapeutically effective amount of a type I IFN receptor (IFNAR1) inhibitor, wherein the method does not comprise administering to the subject a steroid.

[0029] The present invention is supported by data presented herein for the first time, including, inter alia, post-hoc analyses of the Phase 2 MUSE study and the Phase 3 TULIP-1 and TULIP-2 studies (NCT01438489, NCT02446912, and NCT02446899, respectively). These data show that treatment with IFNAR1 inhibitors in SLE patients can spare the patient steroid doses while simultaneously treating SLE-related disease, compared to placebo. The data further show that treatment with IFNAR1 inhibitors prevents the SLE patient from increasing steroid doses, compared to placebo. Furthermore, IFNAR1 inhibitors have been shown to reduce steroid-associated organ damage and increase body weight in underweight SLE patients. [Brief description of the drawings]

[0030] [Figure 1]Distribution of IFN transcript scores. [Diagram 2] Glucocorticoid dose changes with sustained glucocorticoid tapering response in TULIP-1 and TULIP-2 (pooled data). Glucocorticoid AUC through week 52 for sustained glucocorticoid tapering responders and nonresponders. The mean cumulative glucocorticoid dose during 52 weeks of treatment was 44% lower among patients who were glucocorticoid tapering responders versus nonresponders. Error bars represent SE. Sustained glucocorticoid tapering responders are defined as those with a reduction in glucocorticoid dose ≦7.5 mg / day by week 40, with no dose increase from week 40 to week 52, in patients with a baseline glucocorticoid dose ≧10 mg / day. AUC, area under the curve; SE, standard error. [Diagram 3]PRO responses at week 52 with sustained glucocorticoid tapering response in TULIP-1 and TULIP-2 (pooled data). More patients in the sustained glucocorticoid tapering responder group had clinically meaningful improvements in FACIT-F, SF-36 PCS, and SF-36 MCS scores (all P<0.001) compared with nonresponders. Patients with responses in (A) FACIT-F defined as an improvement of >3 from baseline to week 52, (B) SF-36 PCS defined as an increase of >3.4 from baseline to week 52 in the PCS domain, and (C) SF-36 MCS defined as an increase of >4.6 from baseline to week 52 in the MCS domain. A-C, error bars represent 95% CI. Response rates, 95% CI, and nominal P values ​​were calculated using a stratified Cochran-Mantel-Haenszel approach. CI, confidence interval; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; MCS, mental health; PCS, physical health; PRO, patient-reported outcome; SF-36, Short Form 36 Health Survey. a Sustained glucocorticoid tapering responder was defined as a reduction in glucocorticoid dose to ≤7.5 mg / day by week 40 with no dose escalation from weeks 40 to 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day. [Figure 4]Changes in glucocorticoid response and dose in patients receiving ≥10 mg / day glucocorticoids at baseline in TULIP-1 and TULIP-2 (pooled data). Using a more stringent threshold of glucocorticoid reduction ≤5 mg / day, more patients in the anifrolumab group achieved sustained glucocorticoid reduction ≤5 mg / day from weeks 40 to 52 compared with placebo. Patients who achieved sustained oral glucocorticoid dose reduction to ≤7.5 mg / day (A) and ≤5 mg / day (B) at week 52. Error bars represent 95% CI. The mean cumulative dose of glucocorticoids during 52 weeks of treatment was 8% lower in the anifrolumab group compared with the placebo group and 44% lower among patients who were glucocorticoid responders compared with nonresponders. C: Oral glucocorticoid AUC through week 52 by treatment group. Error bars represent SE. D: Oral glucocorticoid AUC through week 52 for glucocorticoid responders and non-responders. Error bars represent SE. Glucocorticoid responders are defined as a reduction in glucocorticoid dose ≦7.5 mg / day by week 40 with no dose escalation from week 40 to week 52 in patients with a baseline glucocorticoid dose ≧10 mg / day. AUC, area under the curve; CI, confidence interval; LS, least squares; SE, standard error. [Diagram 5]Sustained glucocorticoid tapering response in patients classified by BICLA response at week 52 in patients receiving ≥10 mg / day glucocorticoids at baseline in TULIP-1 and TULIP-2 (pooled data). A total of 46.8% (89 / 190) of patients treated with anifrolumab and receiving baseline glucocorticoids ≥10 mg / day achieved a BICLA response at week 52 compared with 31.4% (58 / 185) of patients receiving placebo. BICLA, British Isles Lupus Assessment Group-based Composite Lupus Assessment; BILAG-2004, British Isles Lupus Assessment Group 2004; PtGA, Patient's Global Assessment; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; VAS, visual analog scale. a Sustained glucocorticoid tapering responder is defined as a reduction in glucocorticoid dose to ≤7.5 mg / day by Week 40 in patients with a baseline glucocorticoid dose ≥10 mg / day, with no dose escalation from Weeks 40-52. b BICLA response is defined as a reduction in all baseline BILAG-2004 A and B scores, no deterioration in other organ systems, no deterioration from baseline on SLEDAI-2K, and no increase from baseline on the 3-point PtGA VAS ≥0.3 points. [Figure 6]PRO response at week 52 in patients receiving ≥10 mg / day glucocorticoids at baseline in TULIP-1 and TULIP-2 (pooled data). Treatment with anifrolumab resulted in more patients with nominally significant improvement in SF-36 MCS score (P=0.03) compared with placebo, but not in SF-36 PCS or FACIT-F. The glucocorticoid responder group had more patients with nominally significant improvement in all PROs (all P<0.001) compared with nonresponders. Patients with response in FACIT-F defined as an improvement of >3 from baseline to week 52 (A,D); SF-36 PCS defined as an increase of >3.4 from baseline to week 52 in the PCS domain (B,E); and SF-36 MCS defined as an increase of >4.6 from baseline to week 52 in the MCS domain (C,F). A-F, error bars represent 95% CI. Response rates, CIs, and nominal P values ​​were calculated using a stratified Cochran-Mantel-Haenszel approach. CI, confidence interval; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; MCS, mental health; PCS, physical health; PRO, patient-reported outcomes; SF-36, Short Form 36 Health Survey. Glucocorticoid responders were defined as a reduction in glucocorticoid dose ≤7.5 mg / day by week 40 and no dose escalation from week 40 to week 52 in patients with a baseline glucocorticoid dose ≥10 mg / day. [Figure 7]Sustained glucocorticoid tapering response in patients classified by BICLA response at week 52 in patients receiving ≥10 mg / day glucocorticoids at baseline in TULIP-1 and TULIP-2 (pooled data). BICLA, British Isles Lupus Assessment Group-based Composite Lupus Assessment; BILAG-2004, British Isles Lupus Assessment Group 2004; PtGA, Patient's Global Assessment; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; VAS, visual analog scale. Glucocorticoid responders are defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 with no dose escalation from week 40 to week 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day. BICLA response was defined as a reduction in all baseline BILAG-2004 A and B scores, no deterioration in other organ systems, no deterioration from baseline on SLEDAI-2K, and no increase from baseline of ≥ 0.30 points on the 3-point PtGA VAS. [Figure 8]Combined BICLA and SIR(4) responses in SLE patients at week 52 in the MUSE, TULIP-1, and TULIP-2 studies, and definition of stringent BICLA response. Proportions, differences, 95% Ci, and nominal P values ​​were calculated using a stratified Cochran-Mantel-Haenszel approach (stratification factors, SLEDAI-2K score at screening, day 1 GC dose, and IFNGS test status at screening). Responses to all endpoints did not require interruption of study treatment or use of protocol-restricted medications. BICLA response, v baseline: improvement in all BILAG-2004 organ domains (A and B scores reaching B / C / D and C / D, respectively, no worsening of BILAG-2004 domains, worsening SRI(4) response, and no worsening of PGA (≥0.3 points). [Figure 9] crBICLA response in SLE patients (requiring complete resolution of all BILAG-2004 A / B scores). crBICLA response criteria are defined in Table 9-1. Error bars represent standard error of the mean. *nominal P<0.05; **nominal P<0.01; ***nominal P<0.001. [Figure 10] Delivery device. Anifrolumab is administered via an injection device [1][9], such as a prefilled syringe (PFS) (A) or an autoinjector (AI) (B). [Figure 11] Autoinjector. The autoinjector for administration of anifrolumab or its functional variants shown disassembled (A), assembled (B), and loaded with drug substance (C). [Figure 12] Pre-filled Syringe with Safety. Pre-filled Syringe with Safety (APFS) for Anifrolumab or its functional variants. The main tube is shown in assembled form (A) and exploded view (B). The APFS with additional components is shown in assembled form (C) and exploded view (D). [Figure 13] Packaging for a delivery device DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] 4.1 How to gradually reduce steroids The present invention relates to a method of steroid-sparing in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a type I IFN receptor (IFNAR1) inhibitor and a steroid, wherein the dose of the steroid administered to the subject is tapered from a baseline pre-sparing dose to a post-sparing dose, wherein the subject has systemic lupus erythematosus (SLE).

[0032] The method may not worsen SLE disease activity in the subject. The post-sparing dose may be ≦75% of the pre-sparing dose. The post-sparing dose may be ≦50% of the pre-sparing dose. The post-sparing dose may be ≦25% of the pre-sparing dose. The post-sparing dose may be ≦10% of the pre-sparing dose. The post-sparing dose may be about 60% of the pre-sparing dose.

[0033] The pre-sparing steroid dose and the post-sparing steroid dose may be daily doses. The pre-sparing steroid dose may be a prednisone or prednisone equivalent dose of about ≧10 mg / day. The pre-sparing steroid dose may be a prednisone or prednisone equivalent dose of about ≦7 mg / day. The pre-sparing steroid dose may be a prednisone or prednisone equivalent dose of about ≦5 mg / day. The post-sparing dose may be maintained for ≧12 weeks. The post-sparing dose may be maintained for ≧12 weeks, where the post-sparing dose is a prednisone or prednisone equivalent dose of ≦7.5 mg / day. The post-sparing dose may be maintained for ≧12 weeks, where the post-sparing dose is a prednisone or prednisone equivalent dose of ≦5 mg / day. The post-sparing dose may be sustained for at least one week.

[0034] The present invention also relates to a method of treating SLE in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of an IFNAR1 inhibitor, whereby treatment reduces or prevents the need for increased steroid administration to the subject.

[0035] This method may be validated in a Phase III clinical trial.

[0036] 4.2 Prevention of organ damage The method of the present invention may not worsen the activity of SLE disease in a subject. The method may reduce and / or prevent steroid-related side effects in a subject. The method may reduce the blood pressure of a subject. The method may reduce and / or prevent steroid-related organ damage. The method may reduce the diastolic blood pressure of a subject. The method may reduce the systolic blood pressure of a subject. The method may reduce the resting heart rate of a subject. The method may prevent the blood pressure of a subject from increasing. The method may prevent the diastolic blood pressure of a subject from increasing. The method may prevent the systolic blood pressure of a subject from increasing.

[0037] 4.3 Steroids The steroid may be a glucocorticoid (GC). The steroid may include oral glucocorticoids. The steroid may be 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, flu 13. The method of any of the preceding claims comprising prednisone, 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.

[0038] The steroid may include prednisone.

[0039] 4.4 Reduction in SLE disease activity The method may reduce SLE disease activity in the subject. The reduction in SLE disease activity may include an improvement in the subject's SF-36MCS score. The reduction in SLE disease activity may include a BICLA response. The reduction in SLE disease activity may include both a BICLA response and an SRI(4) response. The reduction in SLE disease activity may include a BICLA response, where the post-sparing dose is maintained for >12 weeks. The reduction in SLE disease activity may include a complete BICLA (crBICLA) response. A crBICLA response may be achieved by week 32 of treatment. The reduction in SLE disease activity may include a reduction in SLE flares. The method may increase the subject's body mass index (BMI). The method may increase the subject's weight. The subject may be underweight prior to treatment, where underweight is defined by BMI.

[0040] The ability of IFNAR1 inhibitors to reduce SLE disease activity in a subject may be demonstrated in Phase III clinical trials.

[0041] 2. The method of any preceding claim, wherein the subject has moderate to severe SLE.

[0042] 4.5 IFNAR1 inhibitors "Type I interferon receptor inhibitor" refers to a molecule that antagonizes the receptor of type I interferon ligands, such as interferon alpha and interferon beta. Such an inhibitor, after administration to a patient, preferably reduces the expression of at least one (preferably at least four) pharmacodynamic (PD) marker gene 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 alpha / beta receptor (IFNAR).

[0043] For example, the type I interferon receptor inhibitor may be an antibody or antigen-binding fragment thereof that inhibits type I IFN activity (by inhibiting the receptor). One example of a suitable antibody or antigen-binding fragment thereof (that inhibits type I IFN activity) is an interferon alpha / beta receptor (IFNAR) antagonist. The type I interferon receptor inhibitor may be an antibody or antigen-binding fragment thereof that inhibits type I IFN activity. Additionally or alternatively, the type I interferon receptor inhibitor may be a small molecule inhibitor of the type I interferon receptor (e.g., for pharmacological inhibition of type I interferon receptor activity).

[0044] The IFNAR1 inhibitor may be a human monoclonal antibody specific for IFNAR1.The IFNAR1 inhibitor may be a human monoclonal antibody of modified IgG1 class specific for IFNAR1.

[0045] 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.

[0046] 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 the unmodified antibody. The antibody may comprise a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11. The antibody may comprise a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0047] 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; (b) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:7; and (c) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:8.

[0048] 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.

[0049] The IFNAR1 inhibitor may be anifrolumab or a functional variant thereof.

[0050] 4.6 Dosage and Administration The method may include administering to the subject an intravenous dose of anifrolumab or a functional variant thereof. The intravenous dose may be ≧300 mg of anifrolumab or a functional variant thereof. The intravenous dose may be ≦1000 mg. The intravenous dose may be about 300 mg, about 900 mg, or about 1000 mg. The intravenous dose may be administered once every four weeks (Q4W).

[0051] The method may include administering a subcutaneous dose of anifrolumab or a functional variant thereof. The subcutaneous dose may be >105 mg and <150 mg anifrolumab or a functional variant thereof. The subcutaneous dose may be ≦135 mg anifrolumab or a functional variant thereof. The subcutaneous dose may be about 120 mg. The subcutaneous dose may be administered in a single administration step. The subcutaneous dose may be administered at intervals of 6 to 8 days. The subcutaneous dose may be administered once a week. The subcutaneous dose may have a volume of about 0.5 to about 1 ml. The subcutaneous dose may have a volume of about 0.8 ml.

[0052] The subject may have moderate to severe SLE prior to treatment. The subject may have mild SLE. Moderate to severe SLE may be defined as a CLASI score of ≧10.

[0053] The subject may be a pre-treatment high type I interferon stimulated gene signature (IFNGS) test patient. The method may include identifying the subject as a pre-treatment high IFNGS test patient.

[0054] Many SLE patients are administered corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Anifrolumab allows corticosteroids (glucocorticoids) to be tapered in SLE patients (steroid sparing). The treatment method or method may include administering a corticosteroid to a subject, optionally the corticosteroid is an oral corticosteroid. The method may include tapering a dose of the corticosteroid administered to the subject (steroid sparing). The method may include administering a first dose of the corticosteroid followed by a second dose of the corticosteroid, where the second dose of the corticosteroid is less than the first dose of the corticosteroid. The second dose of the corticosteroid may be about 7.5 mg prednisone equivalent or less. The second dose of the corticosteroid may be about 5 mg prednisone equivalent or less. The method or treatment method may include administering a second dose of the corticosteroid once a day. The first dose of the corticosteroid may be a prednisone equivalent dose of about 10 mg. The method may include tapering the dose of the corticosteroid administered to the patient from 10 mg or more per day to less than 10 mg per day. The method or treatment method may include administering a second dose of the corticosteroid once a day. This method may allow for administration of a reduced dose of the corticosteroid that is sustained for several weeks. The second dose of the corticosteroid may be administered for at least 24 weeks. The second dose of the corticosteroid may be administered for at least 28 weeks.

[0055] The method may include steroid sparing in the subject, where the subject is administered a steroid at a dose tapered from a pre-sparing dose at baseline to a post-sparing dose. The post-sparing dose may be a prednisone or prednisone equivalent dose of ≦7.5 mg / day. The pre-sparing dose may be a prednisone or prednisone equivalent dose of 20 mg / day. The steroid may include a glucocorticoid. The steroid may include an oral glucocorticoid. Steroids include hydrocortisone, mometasone, fluticasone, fluocinolone acetonide, fluocinolone, flurandrenolone acetonide, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, clocortolone, dihydroxycortisone, alclometasone, amcinonide, diflucortolone valerate, flucortolone, The steroid may be selected from the group consisting of fluprednidene, fluandrenolone, fluorometholone, halcinonide, halobetasol, desonide, diflorasone, flurandrenolide, fluocinonide, prednicarbate, desoximetasone, fluprednisolone, prednisone, azelastine, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, halopredone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, prednisolone, prednisolone 21-phosphate, clobetasol propionate, triamcinolone acetonide, or mixtures thereof. The steroid may be prednisone.

[0056] The present invention also relates to a unit dose for use in the methods of the present invention, the unit dose comprising >105 mg and ≦150 mg of anifrolumab or a functional variant thereof.

[0057] The unit dose may comprise ≦135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. The unit dose may comprise about 120 mg of anifrolumab or a functional variant thereof. The unit dose may comprise 120 mg of anifrolumab or a functional variant thereof. The unit dose may consist essentially of >105 mg and <150 mg of anifrolumab or a functional variant thereof. The unit dose may consist essentially of ≦135 mg of anifrolumab or a functional variant thereof. The unit dose may consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the 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 about 0.5 to about 1 ml. The concentration of the unit dose may be about 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose may comprise a formulation of about 150-200 mg / ml anifrolumab or functional variant thereof, about 25-150 mM lysine salt, and uncharged excipients. The unit dose may comprise a formulation of 150-200 mg / ml anifrolumab or functional variant thereof, 25-150 mM lysine salt, and uncharged excipients. The unit dose may comprise a formulation of 25 mM histidine-HCL, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation may have a pH of about 5.9.

[0058] In another aspect, the present invention relates to a method for treating SLE in a subject, the method comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, the weekly administration of the dose resulting in a plasma concentration in the subject at least equivalent to that obtained by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. The weekly administration of the dose can result in a plasma concentration in the subject that is greater than that obtained by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. The weekly administration of the dose can result in a plasma concentration in the subject that is at least equivalent to that obtained by intravenously administering 400 mg of anifrolumab or a functional variant thereof every 4 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 anifrolumab or a functional variant thereof. The dose administered to the subject may be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject may be ≦135 mg (i.e., equal to or less than 135 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject may be about 120 mg of anifrolumab or a functional variant thereof.

[0059] Administration of a dose or unit dose may result in a plasma concentration of anifrolumab or functional variant thereof in a subject of ≧10 μg (i.e., 10 μg or more) of anifrolumab or functional variant thereof per ml of plasma (i.e., a plasma concentration of ≧10 μg / ml). Administration of a dose or unit dose may result in a plasma concentration of anifrolumab or functional variant thereof in a subject of about 10-100 μg / ml. Administration of a dose or unit dose may result in a plasma concentration of anifrolumab or functional variant thereof in a subject of about 20-80 μg / ml. Administration of a dose or unit dose may result in a plasma concentration of anifrolumab or functional variant thereof in a subject of about 30-70 μg / ml. Administration of a dose or unit dose may result in a trough concentration of anifrolumab or functional variant thereof in a subject of ≧20 μg / ml (i.e., 20 μg / ml or more). Administration of a dose or unit dose may result in a trough concentration of anifrolumab or functional variant thereof in a subject of ≧30 μg / ml (i.e., 30 μg / ml or more). Administration of a dose or unit dose may result in a trough concentration of anifrolumab or functional variant thereof in a subject of ≧40 μg / ml (i.e., 40 μg / ml or more). Administration of a dose or unit dose may result in a trough concentration of anifrolumab or functional variant thereof in a subject of about 20-100 μg / ml. Administration of a dose or unit dose may result in a trough concentration of anifrolumab or functional variant thereof in a subject of about 30-80 μg / ml. Administration of a dose or unit dose may result in a trough concentration of anifrolumab or functional variant thereof in a subject of about 40-70 μg / ml.

[0060] 4.7 Target The subject may be a human subject. The subject may be an adult. The subject may be a patient with an elevated type I IFN gene signature. The subject may be a patient with a high type I interferon stimulated gene signature (IFNGS) test before administration of the dose or unit dose. The subject may have elevated genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood. The method may include identifying the subject as a patient with a high IFNGS test before treatment of the dose or unit dose. The method may include measuring the expression of genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood of the subject. The method may include measuring the expression of genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood of the subject by RT-PCR.

[0061] The subject may have moderate to severe SLE.

[0062] 4.8 Dosage and Administration The method may include administering to the subject an intravenous dose of anifrolumab or a functional variant thereof. The intravenous dose may be ≧300 mg of anifrolumab or a functional variant thereof. The intravenous dose may be ≦1000 mg. The intravenous dose may be about 300 mg, about 900 mg, or about 1000 mg. The intravenous dose may be administered once every four weeks (Q4W).

[0063] The method may include administering a subcutaneous dose of anifrolumab or a functional variant thereof. The subcutaneous dose may be >105 mg and <150 mg anifrolumab or a functional variant thereof. The subcutaneous dose may be ≦135 mg anifrolumab or a functional variant thereof. The subcutaneous dose may be about 120 mg. The subcutaneous dose may be administered in a single administration step. The subcutaneous dose may be administered at intervals of 6 to 8 days. The subcutaneous dose may be administered once a week. The subcutaneous dose may have a volume of about 0.5 to about 1 ml. The subcutaneous dose may have a volume of about 0.8 ml.

[0064] The subject may have moderate to severe SLE prior to treatment. The subject may have mild SLE.

[0065] The subject may be a pre-treatment high type I interferon stimulated gene signature (IFNGS) test patient. The method may include identifying the subject as a pre-treatment high IFNGS test patient.

[0066] Many SLE patients are administered corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Anifrolumab allows corticosteroids (glucocorticoids) to be tapered in SLE patients (steroid sparing). The treatment method or method may include administering a corticosteroid to a subject, optionally the corticosteroid is an oral corticosteroid. The method may include tapering a dose of the corticosteroid administered to the subject (steroid sparing). The method may include administering a first dose of the corticosteroid followed by a second dose of the corticosteroid, where the second dose of the corticosteroid is less than the first dose of the corticosteroid. The second dose of the corticosteroid may be about 7.5 mg prednisone equivalent or less. The second dose of the corticosteroid may be about 5 mg prednisone equivalent or less. The method or treatment method may include administering a second dose of the corticosteroid once a day. The first dose of the corticosteroid may be a prednisone equivalent dose of about 10 mg. The method may include tapering the dose of the corticosteroid administered to the patient from 10 mg or more per day to less than 10 mg per day. The method or treatment method may include administering a second dose of the corticosteroid once a day. This method may allow for administration of a reduced dose of the corticosteroid that is sustained for several weeks. The second dose of the corticosteroid may be administered for at least 24 weeks. The second dose of the corticosteroid may be administered for at least 28 weeks.

[0067] The method may include steroid sparing in the subject, where the subject is administered a steroid at a dose tapered from a pre-sparing dose at baseline to a post-sparing dose. The post-sparing dose may be a prednisone or prednisone equivalent dose of ≦7.5 mg / day. The pre-sparing dose may be a prednisone or prednisone equivalent dose of 20 mg / day. The steroid may include a glucocorticoid. The steroid may include an oral glucocorticoid. Steroids include hydrocortisone, mometasone, fluticasone, fluocinolone acetonide, fluocinolone, flurandrenolone acetonide, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, clocortolone, dihydroxycortisone, alclometasone, amcinonide, diflucortolone valerate, flucortolone, The steroid may be selected from the group consisting of fluprednidene, fluandrenolone, fluorometholone, halcinonide, halobetasol, desonide, diflorasone, flurandrenolide, fluocinonide, prednicarbate, desoximetasone, fluprednisolone, prednisone, azelastine, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, halopredone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, prednisolone, prednisolone 21-phosphate, clobetasol propionate, triamcinolone acetonide, or mixtures thereof. The steroid may be prednisone.

[0068] The present invention also relates to a unit dose for use in the methods of the present invention, the unit dose comprising >105 mg and ≦150 mg of anifrolumab or a functional variant thereof.

[0069] The unit dose may comprise ≦135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. The unit dose may comprise about 120 mg of anifrolumab or a functional variant thereof. The unit dose may comprise 120 mg of anifrolumab or a functional variant thereof. The unit dose may consist essentially of >105 mg and <150 mg of anifrolumab or a functional variant thereof. The unit dose may consist essentially of ≦135 mg of anifrolumab or a functional variant thereof. The unit dose may consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the 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 about 0.5 to about 1 ml. The concentration of the unit dose may be about 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose may comprise a formulation of about 150-200 mg / ml anifrolumab or functional variant thereof, about 25-150 mM lysine salt, and uncharged excipients. The unit dose may comprise a formulation of 150-200 mg / ml anifrolumab or functional variant thereof, 25-150 mM lysine salt, and uncharged excipients. The unit dose may comprise a formulation of 25 mM histidine-HCL, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation may have a pH of about 5.9.

[0070] In another aspect, the present invention relates to a method for sparing steroids in a subject suffering from SLE, comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, the dose being administered weekly to provide a plasma concentration in the subject at least equivalent to that obtained by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. The dose being administered weekly can provide a plasma concentration in the subject that is greater than that obtained by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. The dose being administered weekly can provide a plasma concentration in the subject at least equivalent to that obtained by intravenously administering 400 mg of anifrolumab or a functional variant thereof every 4 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 anifrolumab or a functional variant thereof. The dose administered to the subject may be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject may be ≦135 mg (i.e., equal to or less than 135 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject may be about 120 mg of anifrolumab or a functional variant thereof.

[0071] Administration of a dose or unit dose may result in a plasma concentration of anifrolumab or functional variant thereof in a subject of ≧10 μg (i.e., 10 μg or more) of anifrolumab or functional variant thereof per ml of plasma (i.e., a plasma concentration of ≧10 μg / ml). Administration of a dose or unit dose may result in a plasma concentration of anifrolumab or functional variant thereof in a subject of about 10-100 μg / ml. Administration of a dose or unit dose may result in a plasma concentration of anifrolumab or functional variant thereof in a subject of about 20-80 μg / ml. Administration of a dose or unit dose may result in a plasma concentration of anifrolumab or functional variant thereof in a subject of about 30-70 μg / ml. Administration of a dose or unit dose may result in a trough concentration of anifrolumab or functional variant thereof in a subject of ≧20 μg / ml (i.e., 20 μg / ml or more). Administration of a dose or unit dose may result in a trough concentration of anifrolumab or functional variant thereof in the subject of ≧30 μg / ml (i.e., 30 μg / ml or more). Administration of a dose or unit dose may result in a trough concentration of anifrolumab or functional variant thereof in the subject of ≧40 μg / ml (i.e., 40 μg / ml or more). Administration of a dose or unit dose may result in a trough concentration of anifrolumab or functional variant thereof in the subject of about 20-100 μg / ml. Administration of a dose or unit dose may result in 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 result in a trough concentration of anifrolumab or functional variant thereof in the subject of about 40-70 μg / ml.

[0072] The dose or unit dose may provide in a subject a therapeutic effect at least equivalent to that provided by administration of an intravenous dose of 300 mg of anifrolumab or functional variant thereof administered once every four weeks (Q4W). The dose or unit dose may provide in a subject a trough concentration of anifrolumab or functional variant thereof that is greater than the trough concentration of anifrolumab or functional variant thereof achieved by administration of an intravenous dose of 300 mg of anifrolumab or functional variant thereof administered once every four weeks (Q4W). The anifrolumab or functional variant thereof may be included within a pharmaceutical composition. The pharmaceutical composition may include about 150-200 mg / ml of anifrolumab or functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may include 150 mg / mL of anifrolumab or functional variant thereof. The pharmaceutical composition may include 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may contain 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0073] The method of the invention may include administering a dose or unit dose at intervals of 6 to 8 days. The dose or unit dose may be administered once a week (QW). The dose or unit dose may be 120 mg of anifrolumab or a functional variant thereof, and the method includes administering the dose in a single administration step once a week (QW). In other words, the method includes administering 120 mg of anifrolumab or a functional variant thereof QW. The dose or unit dose may be administered once a week for at least about 4 weeks. The dose or unit dose may be administered once a week for at least about 8 weeks. The dose or unit dose may be administered once a week for at least about 12 weeks. The dose or unit dose may be administered once a week for at least about 16 weeks. The dose or unit dose may be administered once a week for at least about 20 weeks. The dose or unit dose may be administered once a week for at least about 24 weeks. The dose or unit dose may be administered once a week for at least about 28 weeks. The dose or unit dose may be administered once a week for at least about 32 weeks. The dose or unit dose may be administered once a week for about 8 weeks. The dose or unit dose may have a volume that is suitable for delivery in a single subcutaneous administration step. The dose or unit dose may have a volume of about 0.5 to about 1 ml. The dose or unit dose may have a volume of less than 1 ml. The dose or unit dose may have a volume of about 0.8 ml.

[0074] 4.9 Pharmaceutical Compositions The present invention also relates to a pharmaceutical composition for use in a method for treating SLE in a subject, the method comprising subcutaneously administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising a dose of anifrolumab or a functional variant thereof, the dose being >105mg and <150mg. The dose of anifrolumab or a functional variant thereof may be a unit dose (unit dosage form, pharmaceutical unit dosage form, pharmaceutical unit dose). Functional variants of anifrolumab include antigen-binding fragments of anifrolumab, as well as antibodies and immunoglobulin derivatives of anifrolumab.

[0075] In another aspect, the invention relates to a pharmaceutical composition for use in a method of the invention, the method comprising subcutaneously administering a pharmaceutical composition to a subject, the pharmaceutical composition comprising a dose of anifrolumab or a functional variant thereof, wherein weekly administration of the pharmaceutical composition results in a plasma concentration in the subject at least equivalent to the plasma concentration obtained by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. Weekly administration of the dose can result in a plasma concentration in the subject approximately equivalent to the plasma concentration obtained by intravenously administering 400 mg of anifrolumab or a functional variant thereof every 4 weeks. The dose can be <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The dose can be >105 mg (i.e., more than 105 mg) of anifrolumab or a functional variant thereof. The dose can be ≦135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. The dose may be about 120 mg of anifrolumab or a functional variant thereof.The dose may be about 120 mg of anifrolumab or a functional variant thereof.

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

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

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

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

[0080] 4.10 Equipment The invention also relates to an injection device comprising a unit dose of the invention, or a pharmaceutical composition for any use according to the invention.

[0081] The pharmaceutical product in the injection device may comprise >105mg (i.e., greater than 105mg) and <150mg (i.e., less than 150mg) of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise about 120mg of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise 120mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the pharmaceutical composition in the injection device may be 150mg / ml. The volume of the pharmaceutical composition in the injection device may be at least about 0.8ml. The volume of the pharmaceutical composition may be about 0.8ml.

[0082] The pharmaceutical composition in the injection device may comprise about 150-200 mg / ml of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition in the injection device may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise 50 mM of lysine HCl. The pharmaceutical composition may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition in the injection device may comprise about 150-200 mg / ml of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition in the injection device may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM of lysine HCl. The pharmaceutical composition in the injection device may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition in the injection device may include 0.05% polysorbate 80. The pharmaceutical composition in the injection device may include 25 mM histidine / histidine HCl. The pharmaceutical composition in the injection device may 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.

[0083] In another aspect, the invention relates to an injection device comprising a unit dose. The unit dose may comprise >105 mg (i.e. at least 105 mg) and <150 mg (i.e. less than 150 mg) of anifrolumab or a functional variant thereof. The unit dose may comprise ≦135 mg (i.e. equal to or less than 135 mg) of anifrolumab or a functional variant thereof. The unit dose may comprise about 120 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device may comprise 120 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device may consist essentially of >105 mg and <150 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device may consist essentially of ≦135 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device may consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or 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 about 0.5 to about 1 ml. The concentration of the unit dose may be about 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose in the injection device may comprise a formulation of about 150-200 mg / ml anifrolumab or functional variant thereof, about 25-150 mM lysine salt, and an uncharged excipient. The unit dose in the injection device may comprise a formulation of 150-200 mg / ml anifrolumab or functional variant thereof, 25-150 mM lysine salt, and an uncharged excipient. The unit dose comprises a formulation of 25 mM histidine-HCL, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation may have a pH of about 5.9.

[0084] The injection device may be a pre-filled syringe (PFS). The injection device may be a pre-filled syringe with safety feature (AFPS). The injection device may be an auto-injector (AI).

[0085] 4.11 Kits In another aspect, the invention relates to a kit comprising a unit dose of the invention and instructions for use, the instructions for use comprising instructions for subcutaneously administering the unit dose to a subject. In another aspect, the invention relates to a kit comprising a pharmaceutical composition for use of the invention, the instructions for use comprising instructions for subcutaneously administering the pharmaceutical composition to a subject. In another aspect, the invention relates to a kit comprising any of the injection devices of the invention and instructions for use, the instructions for use comprising instructions for using the injection device to subcutaneously administer the unit dose or pharmaceutical composition to a subject.

[0086] The kit of the invention may include a package, the package adapted to hold an injection device and instructions for use. The instructions for use may be attached to the injection device. The instructions for use may include instructions for administering >105 mg and <150 mg of anifrolumab or a functional variant thereof. The instructions for use may include instructions for administering ≦135 mg of anifrolumab or a functional variant thereof. The instructions for use may include instructions for administering 120 mg of anifrolumab or a functional variant thereof. The instructions for use may include instructions for administering 120 mg of anifrolumab or a functional variant thereof every 4 weeks. The instructions for use may define the subject as having a type I IFN-mediated disease. The instructions may define the subject as having SLE. The instructions may define the subject as having moderate to severe SLE. The instructions for use may be written instructions.

[0087] The instructions for use may specify that the injection device, unit dose, and / or pharmaceutical composition is for use in treating SLE. The instructions for use include instructions for administering 120 mg of anifrolumab or a functional variant thereof weekly.

[0088] The instructions may specify that administering an IFNAR1 inhibitor to the subject allows for steroid tapering. The instructions may specify that the subject has moderate to severe SLE. The instructions may specify that the subject has active SLE. The instructions may specify that the subject has steroid-associated organ damage. The instructions may specify that the subject is tapering a steroid dose.

[0089] The instructions may specify that administration of an IFNAR1 inhibitor to a subject may allow for tapering of steroids from a baseline pre-sparing steroid dose to a post-sparing steroid dose, which may be ≦75%, ≦50%, ≦25%, or ≦10% of the pre-sparing dose. The instructions for use state that the steroids are: 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. The active ingredient may be specified to include benzodiazepine, benzoyl peroxide ...

[0090] The instructions may specify that administering an IFNAR1 inhibitor to the subject may reduce and / or prevent steroid-related side effects in the subject. The instructions may specify that administering an IFNAR1 inhibitor to the subject may reduce SLE disease activity in the subject. The reduction in SLE disease activity may include an improvement in the subject's SF-36MCS score. The instructions may specify that the reduction in SLE disease activity may include a BICLA response. The instructions may specify that the reduction in SLE disease activity may include both a BICLA response and an SRI(4) response. The instructions may specify that the reduction in SLE disease activity may include a BICLA response, in which case the instructions may specify that the post-sparing dose should be maintained for ≧12 weeks. The instructions may specify that the reduction in SLE disease activity includes a complete BICLA (crBICLA) response. The instructions may specify that a crBICLA response may be achieved by week 32 of treatment. The instructions may specify that reducing SLE disease activity may include reducing SLE flares.

[0091] The instructions may specify that administration of the IFNAR1 inhibitor may increase the subject's body mass index (BMI).The instructions may specify that administration of IFNAR1 may increase the subject's weight.

[0092] The instructions for use may specify that the ability of IFNAR1 inhibitors to reduce SLE disease activity in subjects has been demonstrated in Phase III clinical trials.

[0093] The instructions for use may specify that the IFNAR1 inhibitor is anifrolumab or a functional variant thereof.

[0094] The instructions may specify a method comprising administering to a subject a therapeutically effective amount of a type I IFN receptor (IFNAR1) inhibitor and a steroid, wherein the subject is tapered from a baseline pre-sparing dose to a post-sparing dose, and the subject has systemic lupus erythematosus (SLE). The instructions may specify that the method does not worsen SLE disease activity. The instructions may specify that the post-sparing dose is ≦75% of the pre-sparing dose. The instructions may specify that the post-sparing dose is ≦50% of the pre-sparing dose. The instructions may specify that the post-sparing dose is ≦25% of the pre-sparing dose. The instructions may specify that the post-sparing dose is ≦10% of the pre-sparing dose. The instructions may specify that the post-sparing dose is about 60% of the pre-sparing dose. The pre-sparing steroid dose and the post-sparing steroid dose are daily doses.

[0095] The instructions may be specified for carrying out any of the methods of the invention.

[0096] The instructions may specify that the pre-sparing steroid dose is about ≧10 mg / day of prednisone or prednisone equivalent dose. The instructions may specify that the post-sparing steroid dose is about ≦7 mg / day of prednisone or prednisone equivalent dose. The instructions may specify that the post-sparing steroid dose is about ≦5 mg / day of prednisone or prednisone equivalent dose. The instructions may specify that the post-sparing dose should be maintained for ≧12 weeks. The instructions may specify that the post-sparing dose should be maintained for ≧12 weeks and that the post-sparing dose should be ≦7.5 mg / day of prednisone or prednisone equivalent dose. The instructions may specify that the post-sparing dose should be maintained for ≧12 weeks and that the post-sparing dose should be ≦5 mg / day of prednisone or prednisone equivalent dose. The instructions may specify that the post-sparing dose may be about 0 mg / day of prednisone or prednisone equivalent. The instructions may specify that the post-sparing dose should be sustained for at least one week.

[0097] 4.12 Preparations The anifrolumab or functional variant thereof may be included within a pharmaceutical composition. The pharmaceutical composition may comprise about 150-200 mg / ml of anifrolumab or functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition 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.

[0098] Stable formulations containing anifrolumab suitable for administration to a subject are described in detail in U.S. Patent 10,125,195 B1, which is incorporated herein in its entirety.

[0099] 5 Definition 5.1 Type I IFN receptor inhibitors "Type I interferon receptor inhibitor" refers to a molecule that antagonizes the receptor of type I interferon ligands, such as interferon alpha and interferon beta. Such an inhibitor, after administration to a patient, preferably reduces the expression of at least one (preferably at least four) pharmacodynamic (PD) marker gene 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 alpha / beta receptor (IFNAR).

[0100] For example, a type I interferon receptor inhibitor may be an antibody or antigen-binding fragment thereof that inhibits type I IFN activity (by inhibiting the receptor). One example of a suitable antibody or antigen-binding fragment thereof (that inhibits type I IFN activity) is an interferon alpha / beta receptor (IFNAR) antagonist.

[0101] Additionally or alternatively, the type I interferon receptor inhibitor may be a small molecule inhibitor of the type I interferon receptor (eg, for pharmacological inhibition of type I interferon receptor activity).

[0102] The type I interferon receptor inhibitor may be an antibody or an antigen-binding fragment thereof that inhibits type I IFN activity. A particularly preferred type I interferon receptor inhibitor is the antibody anifrolumab or a functional variant thereof. Anifrolumab is a monoclonal antibody that targets IFNAR1 (the receptor for α, β, and ω interferon). Disclosures related to anifrolumab can be found in U.S. Patent No. 7,662,381 and U.S. Patent No. 9,988,459, which are incorporated herein by reference.

[0103] 5.1.1 Anifrolumab Anifrolumab (MEDI-546, Anifro, ANI) is a human immunoglobulin G1 kappa (IgG1 kappa) monoclonal antibody (mAb) against subunit 1 of type I interferon receptor (IFNAR1). Anifrolumab downregulates IFNAR signaling and suppresses the expression of IFN-inducible genes. Disclosures related to anifrolumab can be found in U.S. Patent No. 7,662,381 and U.S. Patent No. 9,988,459, which are incorporated herein by reference in their entirety. The sequence information of anifrolumab is listed in Table 5-1: Sequences. [Table 1]

[0104] Anifrolumab is an immunoglobulin comprising HCDR1, HCDR2, and HCDR3 (or functional variants thereof) of SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, respectively, and LCDR1, LCDR2, and LCDR3 (or functional variants thereof) of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively. Anifrolumab is an immunoglobulin comprising VH of SEQ ID NO:1 and VL of SEQ ID NO:2.

[0105] The constant region of anifrolumab is modified such that anifrolumab exhibits reduced affinity for at least one Fc ligand compared to the unmodified antibody. Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1, comprising an amino acid substitution of L234F in the Fc region, as numbered by the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1, comprising an amino acid substitution of L234F, L235E, and / or P331S in the Fc region, as numbered by the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO:9. Anifrolumab is an antibody that comprises a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody that comprises a light chain constant region of SEQ ID NO: 9 and a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody that comprises a heavy chain of SEQ ID NO: 11. Anifrolumab is an antibody that comprises a light chain of SEQ ID NO: 12. Anifrolumab is an antibody that comprises a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0106] 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 includes antigen-binding fragments of anifrolumab, as well as antibodies and immunoglobulin derivatives of anifrolumab. Functional variants include biosimilars and interchangeables. The terms biosimilar and interchangeable 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 meaningful differences from the reference product in terms of pharmacokinetics, safety, and efficacy. The presence of clinically meaningful differences of a biosimilar may be evaluated in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and clinical immunogenicity evaluation. An interchangeable product is a biosimilar that is expected to produce the same clinical outcome as the reference product in any given patient.

[0107] For example, a variant of a reference (anifrolumab) antibody may comprise a heavy chain CDR1 with up to 2 amino acid differences when compared to SEQ ID NO:3, a heavy chain CDR2 with up to 2 amino acid differences when compared to SEQ ID NO:4, a heavy chain CDR3 with up to 2 amino acid differences when compared to SEQ ID NO:5, a light chain CDR1 with up to 2 amino acid differences when compared to SEQ ID NO:6, a light chain CDR2 with up to 2 amino acid differences when compared to SEQ ID NO:7, and a light chain CDR3 with up to 2 amino acid differences when compared to SEQ ID NO:8, and the variant antibody binds to the target (e.g., IFNAR) of anifrolumab, preferably with the same affinity.

[0108] A variant of a reference (anifrolumab) antibody may comprise a heavy chain CDR1 with at most one amino acid difference when compared to SEQ ID NO:3, a heavy chain CDR2 with at most one amino acid difference when compared to SEQ ID NO:4, a heavy chain CDR3 with at most one amino acid difference when compared to SEQ ID NO:5, a light chain CDR1 with at most one amino acid difference when compared to SEQ ID NO:6, a light chain CDR2 with at most one amino acid difference when compared to SEQ ID NO:7, and a light chain CDR3 with at most one amino acid difference when compared to SEQ ID NO:8, and the variant antibody binds to the target (e.g., IFNAR) of anifrolumab, optionally with the same affinity.

[0109] A variant antibody may have a total of up to 5, 4, or 3 amino acid differences in its CDRs when compared to the corresponding reference (anifrolumab) antibody, with the proviso that there are a maximum of 2 (optionally a maximum of 1) amino acid differences per CDR. A variant antibody may have a total of up to 2 (optionally a maximum of 1) amino acid differences in its CDRs when compared to the corresponding reference (anifrolumab) antibody, with the proviso that there are a maximum of 2 amino acid differences per CDR. A variant antibody may have a total of up to 2 (optionally a maximum of 1) amino acid differences in its CDRs when compared to the corresponding reference (anifrolumab) antibody, with the proviso that there are a maximum of 1 amino acid difference per CDR.

[0110] A variant antibody may have a total of up to 5, 4, or 3 amino acid differences in its framework regions when compared to the corresponding reference (anifrolumab) antibody, with the proviso that there are a maximum of 2 (optionally a maximum of 1) amino acid differences per framework region. Optionally, a variant antibody has a total of up to 2 (optionally a maximum of 1) amino acid differences in its framework regions when compared to the corresponding reference (anifrolumab) antibody, with the proviso that there are a maximum of 2 amino acid differences per framework region. Optionally, a variant antibody has a total of up to 2 (optionally a maximum of 1) amino acid differences in its framework regions when compared to the corresponding reference (anifrolumab) antibody, with the proviso that there are a maximum of 1 amino acid difference per framework region.

[0111] 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 (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region) when compared to the heavy chain sequences herein, and the light chain has up to 14 amino acid differences (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region) when compared to the light chain sequences herein, and wherein the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody, preferably with the same affinity.

[0112] A variant heavy or light chain may be referred to as a "functional equivalent" of a reference heavy or light chain. A variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein the heavy chain has up to seven amino acid differences (up to one amino acid difference in each CDR and up to one amino acid difference in each framework region) compared to the heavy chain sequences herein, and the light chain has up to seven amino acid differences (up to one amino acid difference in each CDR and up to one amino acid difference in each framework region) compared to the light chain sequences herein, and the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody, preferably with the same affinity.

[0113] Functional variants of anifrolumab include the antibodies described in WO2018 / 023976A1, which is incorporated by reference herein (Table 5-2). [Table 2]

[0114] 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 VH 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: 15.

[0115] 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 ...4.

[0116] Functional variants of anifrolumab and anti-IFNAR antibodies include the QX006N antibody described in CN11327807, which is incorporated herein by reference. [Table 3]

[0117] The IFNAR inhibitor may be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 17. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO:18.

[0118] QX006N is an immunoglobulin comprising HCDR1, HCDR2, and HCDR3 (or functional variants thereof) of SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively, and 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 of SEQ ID NO: 17, and the VL amino acid sequence of SEQ ID NO: 18.

[0119] 5.2 Steroids Oral corticosteroids (OCS, glucocorticoids) include prednisone, cortisone, hydrocortisone, methylprednisolone, prednisolone, and triamcinolone. Examples of equivalent doses of oral prednisone are shown in Table 5-4. [Table 4]

[0120] 5.3 Clinical Trials 5.3.1 Phase 2 / Phase II / Pivotal Trials Phase II trials gather preliminary data on efficacy. In Phase 2 trials, researchers administer the drug to a group of patients suffering from the disease or condition for which the drug is being developed. Typically, these trials, which involve several hundred patients, are not large enough to show whether the drug is effective. Instead, Phase 2 trials provide researchers with additional safety data. Researchers use these data to refine research questions, develop research methods, and design novel Phase 3 research protocols.

[0121] 5.3.2 Phase 3 / Phase III / Pivotal Studies or Clinical Trials Researchers design Phase 3 trials to show whether a product provides a therapeutic benefit in a particular population. These trials, sometimes known as pivotal trials, involve 300 to 3,000 participants. Phase 3 trials provide the majority of safety data. Less common side effects may not have been detected in earlier trials. These trials are large and long-lasting, so the results are more likely to show long-term or rare side effects. Regulatory agencies such as the EMA and FDA usually require Phase III clinical trials to demonstrate that the product is safe and at least as effective (if not better) than available drugs before approving a new drug. Phase III clinical trials usually fail, even if they had passed Phase II clinical trials.

[0122] 5.4 Dosage Form A unit dose (also called a unit dosage form, pharmaceutical unit dose or pharmaceutical unit dosage form) is a dose formed from a single unit. A unit dose (unit dosage form) is suitable for administration to a subject in a single administration step. A unit dose (unit dosage form) may be packaged in a single unit container, such as a single-use pre-filled syringe or auto-injector. Unit doses offer the advantage that they can be ordered, packaged, handled, and administered as a single-dose unit containing a predetermined amount of drug. Unit doses reduce administration errors and waste.

[0123] 5.5 PK / PD The plasma levels obtained by SC and IV administration may be compared based on the plasma drug concentration-time curve (AUC), which reflects the body's exposure to the antibody after drug administration. For example, during a clinical trial, the plasma drug concentration-time profile of a patient can be plotted by measuring the plasma concentration at several time points. When using an in silico modeling approach, the plasma drug concentration-time for any given dose can be predicted. The AUC (area under the curve) can then be calculated by integration of the plasma drug concentration-time curve. A suitable method is described in Tummala et.al. 41 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 the area under the serum concentration-time curve (AUC), clearance (CL, CL / F), maximum serum concentration (C max ), and the time to reach maximum serum concentration (t max All data were analyzed using SAS System V.9.2 (SAS Institute, Inc., Cary, NC, USA).

[0124] Advantageously, the ratio of AUC obtainable by SC administration to AUC obtainable by IV administration (AUC SC / AUC IV) may be calculated to provide a numerical comparison of the bioavailability provided by the routes of administration. As used herein, "AUC ratio" refers to the AUC SC / AUC IV AUC ratio means ratio. To provide statistical robustness, AUC ratio is preferably the mean, median or mode (e.g., mean) calculated from multiple repeated experiments (or computational simulations). This approach is illustrated with reference to examples. Mean, median or mode (preferably mean) may be derived by pooling data obtained from multiple patients (or multiple computational simulations). Thus, AUC ratio may reflect the mean, median or mode (preferably mean) of AUC in multiple patients.

[0125] 5.6 Pharmacokinetic Terminology List Area Under the Curve (AUC): The area under the plasma drug concentration versus time curve that serves as a measure of drug exposure.

[0126] C ave : Mean steady state concentration.

[0127] C max : The maximum (or peak) concentration of a drug in plasma.

[0128] C min :Minimum plasma drug concentration.

[0129] C trough : The drug concentration in plasma at steady state just before the next dose. Trough plasma concentration (the concentration measured at the end of the dosing interval at steady state [obtained just before the next dose]).

[0130] LLOQ: Lower Limit of Quantitation, the smallest amount of analyte in a sample that can be quantitatively measured with adequate precision and accuracy.

[0131] Linear pharmacokinetics: If the concentration of a drug in blood or plasma increases in proportion to increasing dose, and the rate of elimination is proportional to the concentration, the drug is said to exhibit linear pharmacokinetics. The clearance and volume of distribution of these drugs are dose-independent.

[0132] Nonlinear pharmacokinetics: In contrast to linear pharmacokinetics, the drug concentration in blood or plasma does not increase proportionally with increasing dose. Their clearance and distribution volumes may vary depending on the dose administered. Nonlinearity may be associated with any component of the absorption, distribution, and / or elimination process.

[0133] 5.7 Delivery device In addition to providing subcutaneous administration of antibodies, the ability for self-administration (e.g., at home) may be further enhanced by subcutaneous administration via a prefilled syringe with safety feature (APFS), an autoinjector (AI), or a combination thereof. Such devices have proven to be well tolerated and reliable for administering subcutaneous doses of antibodies, providing further options for optimizing patient care. Indeed, such devices may reduce the burden of frequent office visits for patients. An example of a suitable APFS device is described by Ferguson et.al. 42 and is incorporated herein by reference in its entirety.

[0134] The doses elucidated by the inventors provide further advantages in the context of APFS administration, since APFS devices typically administer a maximum volume of 1 ml. Doses in the range of >105 mg to <155 mg can be easily accommodated by a volume of about 0.8 ml, making the dose(s) of the present invention uniquely suitable for APFS and AI administration. For comparison, the viscosity of anifrolumab would require administration of higher doses (especially doses >150 mg) in a volume of >1 ml, which would require at least two subcutaneous injections that are inconvenient for patients, and would require multiple pre-filled devices.

[0135] The delivery device may be a single-use, disposable system designed to allow for manual subcutaneous administration of the dose.

[0136] 5.8 Endpoints 5.8.1 BILAG-2004 (British Isles Lupus Assessment Group-2004) BILAG-2004 is a conversion index that includes nine organ systems (general, mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, ophthalmologic, renal, and hematological) that can capture changes in the severity of clinical symptoms. It has an ordinal scale by design and does not have a global score, but rather records disease activity across various organ systems at a glance by comparing the last 4 weeks with the previous 4 weeks. It is based on the physician's intention to treat principle and classifies disease activity into five different levels, A to E: Grade A represents very active disease requiring >20 mg / day of immunosuppressants and / or prednisone or equivalent Grade B represents moderate disease activity requiring lower doses of corticosteroids, topical steroids, topical immunosuppressants, antimalarials, or NSAIDs. Grade C indicates mild stability Grade D indicates no disease activity, but that an organ has previously been affected Grade E indicates no current or previous disease activity

[0137] The BILAG-2004 was developed based on the intention-to-treat principle, where treatment does not influence the score index: only the presence of active symptoms influences the score.

[0138] Improvements in the mucocutaneous or musculoskeletal systems according to the BILAG definition represented skin rash or arthritis, respectively.

[0139] 5.8.2 BICLA (BILAG-Based Composite Lupus Assessment) BICLA is a composite index initially derived by expert consensus of disease activity indices. BICLA response is defined as (1) at least one improvement in baseline BILAG scores in all body systems with moderate or severe disease activity at the start (e.g., reduction of all A (severe disease) scores to B (moderate), C (mild), or D (inactivity) and reduction of all B scores to C or D), (2) absence of one or more new BILAG A or two or more new BILAG B scores, (3) no worsening from baseline in total SLEDAI score, (4) no significant worsening (≦10%) in physicians global assessment, and (5) no treatment failure (initiation of non-protocol treatment).

[0140] In particular, a subject is a BICLA responder if he or she meets the following criteria: a) decline of all baseline BILAG-2004 A to B / C / D and decline of baseline BILAG-2004 B to C / D, and no deterioration of BILAG-2004 in other organ systems (defined by one new BILAG-2004 A or multiple new BILAG-2004 B items), b) no worsening from baseline on the SLEDAI-2K, defined as an increase from baseline on the SLEDAI-2K of >0 points; c) There has been no worsening of the subject's lupus disease activity from baseline, as defined by an increase of ≥ 0.30 points on the 3-point PGA VAS; d) There was no discontinuation of the investigational drug prior to evaluation, or no use of restricted medications beyond the threshold permitted by the clinical trial protocol.

[0141] Complete resolution (crBICLA, also called modified BICLA (mBICLA)) response requires complete resolution of all baseline BILAG-2004 activity (all baseline A / B scores to D; no worsening of C or D scores).

[0142] 5.8.3 CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index Inflammatory Disease Activity) The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) was developed in 2005 as a means to specifically track skin activity and damage in patients with CLE. 43 CLASI is a simple, single-page tool that quantifies skin disease activity and damage separately for each body part. 44 The CLASI is characterized by a Skin Activity Summary Score (CLASI-A) and a Damage Summary Score (CLASI-D).

[0143] The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) quantifies disease activity and damage in cutaneous lupus erythematosus. It can distinguish between different levels of response to treatment, for example, it can detect a certain percentage decrease in activity score from baseline, or it can be reported by a mean / median score. In particular, the CLASI is a validated index used to evaluate lupus skin lesions, and consists of two separate scores: the first score summarizes the inflammatory activity of the disease, and the second score is a measure of the damage caused by the disease. The activity score takes into account erythema, scaling / hypertrophy, mucosal lesions, recent hair loss, and non-scarring alopecia. The damage score represents pigmentation, scarring / atrophy / panniculitis, and scarring of the scalp. Subjects are asked if their pigmentation has persisted for more than 12 months, and if so, the pigmentation score is doubled. Each of the above parameters will be measured at 13 different anatomical locations specifically included because they are most commonly involved in cutaneous lupus erythematosus (CLE). The most severe lesions in each area will be measured.

[0144] The modified CLASI (mCLASI) is defined as the activity portion of the CLASI representing skin erythema, scaling / swelling, and scalp inflammation. Mouth ulcers and alopecia activity without scalp inflammation are excluded from the mCLASI analysis, as are damage rating scales. Clinically meaningful improvement in skin rash as measured using the mCLASI is defined by a ≥ 50% reduction in baseline activity score.

[0145] 5.8.4 SRI (Systemic Lupus Erythematosus Responder Index ≥ 4) A subject achieves SRI(4) if he or she meets all of the following criteria: A reduction from baseline of ≥ 4 points on the SLEDAI-2K scale, No new organ system effects as defined by one or more BILAG-2004 A or two or more BILAG-2004 B items compared to baseline using BILAG-2004; ·No worsening of the subject's lupus disease activity from baseline, as defined by an increase of ≥ 0.30 points on the 3-point PGA VAS.

[0146] SRI(X) (X=5, 6, 7, or 8) is defined by the proportion of subjects who meet the following criteria: A reduction from baseline of ≥X points on the SLEDAI-2K scale, No new organ system effects as defined by one or more BILAG-2004 A or two or more BILAG-2004 B items compared to baseline using BILAG-2004; ·No worsening of the subject's lupus disease activity from baseline, as defined by an increase of ≥ 0.30 points on the 3-point PGA VAS.

[0147] 5.8.5 SLEDAI-2K(Systemic Lupus Erythematosus Disease Activity Index 2000) The SLEDAI-2K Disease Activity Index consists of a list of organic symptoms, each with a definition. Qualified investigators or designated physicians complete the SLEDAI-2K assessment and determine whether each symptom is "present" or "absent" during the last 4 weeks. The assessment also includes blood and urine collection for evaluation of the SLEDAI-2K laboratory categories.

[0148] The SLEDAI-2K assessment consists of 24 lupus-related items. It is a weighted approach in which descriptors are multiplied by the "weight" of a particular organ. For example, renal descriptors are multiplied by 4, central nervous descriptors are multiplied by 8, and these weighted organ symptoms are summed into a final score. The SLEDAI-2K score ranges from 0 to 105 points, with 0 indicating inactive disease. The SLEDAI-2K score is a valid, reliable, and sensitive clinical assessment of lupus disease activity. The SLEDAI-2K calculated using a 30-day period prior to the visit for laboratory values ​​has been shown to be similar to the SLEDAI-2K with a 10-day window. 45 .

[0149] Resolution of rash as defined by SLEDAI-2K is defined as a score of 0 at Week 52 for patients with a baseline rash score of ≧2.

[0150] 5.9 Type I IFN gene signature (IFNGS) Type I IFN is thought to play a central role in SLE disease pathogenesis, and anifrolumab targets inhibition of this pathway. To understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know whether type I IFN activation leads to disease progression in subjects. However, direct measurement of type I IFN remains a challenge. Therefore, transcript-based markers have been developed to assess the effect of overexpression of target proteins on a specific set of mRNA markers. Expression of these markers is easily detected in whole blood and correlates with expression in diseased tissues such as skin in SLE. The bimodal distribution of transcript scores for SLE subjects supports the demarcation of subpopulations with high and low IFN tests (Figure 1). Type I IFN tests are described in WO2011028933A1, which is incorporated herein by reference in its entirety. Type I IFN gene signatures may be used to identify subjects with high type I IFN gene signature (IFNGS) test patients or low IFNGS test patients. The IFNGS test measures the expression of genes IFI27, IFI44, IFI44L, and RSAD2 relative to three reference genes, 18S, ACTB, and GAPDH, in a subject's whole blood. The result of the test is a score compared to pre-established cutoffs that classify patients into two groups: those with low or high levels of IFN-inducible gene expression (Figure 1).

[0151] Gene expression may be measured by RT-PCR. Suitable primers and probes for detecting genes are described in WO2011028933. A suitable kit for measuring gene expression for the IFNGS test is the QIAGEN therascreen® IFIGx RGQ RT-PCR kit (IFIGx kit), which is described in Brohawn et al. 46 and is incorporated herein by reference in its entirety.

[0152] 5.10 Type I IFN Gene Signature (IFNGS) The interferon gene signature (IFNGS) is defined as a set of transcripts of specific genes whose expression is increased upon activation of the IFN receptor (IFNAR1) by binding of type I IFN ligands (IFN-α, IFN-β, and IFN-ω). Two interferon gene signatures were used as part of the Saphnelo and sifalimumab trials, providing distinct readouts: the 4-gene interferon gene signature is a peripheral blood signature that was derived from a genome-wide gene expression study and further validated by a quantitative PCT test (developed to specifically measure IFN gene expression based on four genes). This is further used at baseline to understand if a disease or a particular patient's disease is caused by type I IFN. The 21-interferon gene signature is a peripheral blood signature that was derived from a genome-wide gene expression study. This is used to test the pharmacodynamic effects of Saphnelo by providing a measure of type 1 interferon signaling inhibition after treatment.

[0153] The IFN21 gene signature (IFNGS) is a validated pharmacodynamic marker of type I IFN signaling and is elevated in patients with type I IFN-mediated diseases including SLE, lupus nephritis, myositis, Sjogren's, and scleroderma.

[0154] A 4-gene IFNGS score is calculated by measuring IFI27, IFI44, IFI44L, and RSAD2 expression. A 5-gene IFNGS score is calculated by measuring IFI27, RSAD2, IFI44, IFI44L, and IFI6 expression. A 21-gene IFNGS score is calculated by measuring the genes shown in Table 5. Gene expression may be measured by detecting mRNA in whole blood or tissue of a subject. An IFNGS (4-gene, 5-gene, or 21-gene) score may 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. [Table 5] EXAMPLES

[0155] 6 Example 1: MUSE, ClinicalTrial.gov Identifier: NCT01438489 MUSE was a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2 study evaluating the efficacy and safety of two intravenous (IV) treatment regimens in adult participants with chronic, moderately to severely active SLE who had an inadequate response to standard of care (SOC). Study medications (anifrolumab or placebo) were administered in fixed doses every 4 weeks (28 days) for a total of 13 doses.

[0156] MUSE is a method for the detection and reporting of cancer using the method described by Furie et al. 2017, which is incorporated herein by reference in its entirety. 33 is described in more detail in.

[0157] 7 Example 2: TULIP I and II, ClinicalTrial.gov Identifiers: NCT02446912 and NCT02446899 TULIP I and TULIP II are phase 3, multicenter, multinational, randomized, double-blind, placebo-controlled trials to evaluate the efficacy and safety of a two-dose intravenous (IV) treatment regimen of anifrolumab versus placebo in subjects with moderately to severely active autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care (SOC) treatment.

[0158] 7.1.1 Restricted Drugs Subjects were considered non-responders if they received one of the following: sulfasalazine; danazol; dapsone; azathioprine >200 mg / day or a daily dose greater than week 0 (day 1); mycophenolate mofetil >2.0 g / day or mycophenolic acid >1.44 g / day or a daily dose greater than week 0 (day 1); oral, subcutaneous, or intramuscular methotrexate >25 mg / week or a daily dose greater than week 0 (day 1); mizoribine 150 mg / day or a daily dose greater than week 0 (day 1); a change in the route of administration of oral, subcutaneous, or intramuscular methotrexate; intravenous corticosteroids >40 mg / day, except methylprednisolone or equivalent ≦1 mg / day; intramuscular corticosteroids >80 mg / day methylprednisolone or equivalent; subcutaneous or intramuscular corticosteroid precursors; subcutaneous or intramuscular precursors of corticosteroids; treatment with OCS >40 mg / day prednisone or equivalent; treatment with OCS above the day 1 dose for an administration period of more than 14 days; corticosteroids with long biological half-lives (e.g., dexamethasone, betamethasone); other immunosuppressants including, but not limited to, calcineurin inhibitors (e.g., cyclosporine, tacrolimus [including topical]) or leflunomide. Cyclosporine eye drops were acceptable for use in this study.

[0159] TULIP I is a method for the preparation of a novel marker for pulmonary circulation (PHL) by Furie et al. 34 The results of TULIP II are described in more detail in Morand et al. 32and is incorporated herein by reference in its entirety.

[0160] 8 Example 3: Steroid Tapering 8.1 Overview 8.1.1 Background and Objectives Glucocorticoids remain the mainstay of systemic lupus erythematosus (SLE) treatment, despite being associated with significant toxicity. Thus, a priority goal of SLE treatment is to reduce glucocorticoid use. Glucocorticoid sparing is an important priority for the management of systemic lupus erythematosus (SLE). We analyzed pooled data from the TULIP-1 and TULIP-2 phase 3 trials in patients with moderate to severe SLE to evaluate the effect of anifrolumab on glucocorticoid tapering.

[0161] 8.1.2 Method TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week studies of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). We evaluated glucocorticoid dose changes, clinical laboratory assessments, patient-reported outcomes (PROs), and safety in patients receiving ≥10 mg / day glucocorticoids at baseline, by treatment group, and by glucocorticoid tapering response regardless of treatment group. In a pooled cohort of patients receiving ≥10 mg / day glucocorticoids at baseline, we evaluated glucocorticoid dose changes, patient-reported outcomes (PROs), and safety in patients who achieved a sustained glucocorticoid tapering response, defined as achieving ≤7.5 mg / day by week 40 and sustained through week 52.

[0162] 8.1.3 Results A total of 50.5% (96 / 190) of patients receiving ≥10 mg / day glucocorticoids at baseline who were treated with anifrolumab achieved sustained glucocorticoid reduction (≤7.5 mg / day, weeks 40–52; glucocorticoid responders) compared with 31.8% (59 / 185) on placebo (nominal P < 0.001). Mean cumulative glucocorticoid dose was reduced by 8% with anifrolumab compared with placebo and by 44% in glucocorticoid responders compared with nonresponders. Most patients classified as responders (by British Isles Lupus Assessment Group-based Composite Lupus Assessment) to anifrolumab treatment were glucocorticoid responders (80% [72 / 89]). Safety was similar between groups. However, more severe adverse events have been reported in non-responders to glucocorticoids.

[0163] 8.1.4 Conclusion Anifrolumab improved disease activity while reducing glucocorticoid doses. Glucocorticoid tapering is also associated with additional health benefits. In patients with moderate-to-severe SLE, sustained glucocorticoid tapering is associated with improved PROs, blood pressure, and fewer SAEs. In addition to higher rates of glucocorticoid tapering in patients treated with anifrolumab, these results demonstrate the ability of anifrolumab to reduce glucocorticoid-related adverse effects, an important goal in SLE management.

[0164] 8.2 Introduction Glucocorticoids are used in up to 80% of SLE patients, with the majority receiving long-term treatment. Despite their short-term benefits, glucocorticoids are associated with a significant amount of toxicity. Compared with patients not taking glucocorticoids, SLE patients with a mean prednisone dose >7.5 mg / day over 4 years had a nearly 10-fold increased risk of organ damage, including cataracts, osteoporotic fractures, diabetes, and cardiovascular disease. In contrast, daily doses ≤7.5 mg / day are associated with fewer adverse effects.

[0165] Compared with no glucocorticoid use in patients with SLE, a mean prednisone dose >7.5 mg / day over a 4-year period was associated with a nearly 10-fold increased risk of organ damage, including cataracts, osteoporotic fractures, diabetes, and cardiovascular disease. In contrast, a daily dose ≤7.5 mg was associated with fewer side effects, and this prednisone dose threshold is used to define a low lupus disease activity state with a lower risk of adverse outcomes, but patients with low lupus disease activity and treated with prednisone may still have poor emotional well-being, even at low doses. Thus, new, effective, and long-term treatments for SLE are needed to reduce both overall disease activity and glucocorticoid use.

[0166] In this analysis of pooled data from the TULIP-1 and TULIP-2 trials, we further investigated the impact of anifrolumab treatment on glucocorticoid dose reduction compared to placebo. In addition, we investigated whether there were changes associated with glucocorticoid reduction in patient-reported outcomes (PROs), laboratory values, serious adverse events (SAEs), and cardiovascular adverse events (AEs). Analyses were performed both by treatment group and by non-treatment group (patients who were able to taper glucocorticoids ≦7.5 mg / day, glucocorticoid responders) to better define the potential health benefits of glucocorticoid dose tapering.

[0167] 8.3 Method 8.3.1 Patients and Study Design This was a post-hoc analysis of pooled data from the 52-week TULIP-1 and TULIP-2 trials of anifrolumab, in which patients with moderate-to-severe SLE despite standard treatment with glucocorticoids, antimalarials, and / or immunosuppressants were randomized to receive anifrolumab 300 mg or placebo intravenously every 4 weeks for 48 weeks. The study design and methods have been described in detail previously. 32,34 Briefly, eligible patients were aged 18–70 years and met the American College of Rheumatology 1997 classification criteria for SLE. A protocol-defined attempt to taper to ≤7.5 mg / day was required in patients receiving oral glucocorticoids ≥10 mg / day (prednisone or equivalent) at baseline, and taper was permitted in patients receiving oral glucocorticoids <10 mg / day at baseline. A stable oral glucocorticoid dose was required in all patients at weeks 40–52.

[0168] 8.3.2 Study Endpoints and Evaluations In this analysis, we evaluated the prespecified secondary endpoint of sustained glucocorticoid dose reduction at week 52 in pooled data from TULIP-1 and TULIP-2 for patients receiving baseline glucocorticoids ≥ 10 mg / day. Analyses included only patients receiving baseline glucocorticoids ≥ 10 mg / day who were randomized to receive anifrolumab 300 mg or placebo; the anifrolumab 150 mg group in TULIP-1 was excluded from these analyses. Pooled patient data were evaluated by both treatment group and / or glucocorticoid tapering response, regardless of treatment group assignment. Glucocorticoid responders were defined as achieving an oral glucocorticoid dose ≤ 7.5 mg / day by week 40, with stable glucocorticoid dose from week 40 to week 52, and no permanent premature discontinuation of study drug or restricted medication use above protocol-permitted thresholds. Patients were defined as nonresponders if any of the conditions could not be assessed at week 52 (e.g., because of missing values).

[0169] 8.3.3 Evaluation of outcomes in the anifrolumab and placebo treatment groups Outcome measures, including the proportion of patients achieving sustained oral glucocorticoid dose reduction, least-squares (LS) mean change from baseline daily glucocorticoid dose, and cumulative dose of glucocorticoid measured by mean area under the curve (AUC), were compared between patients randomized to receive anifrolumab 300 mg and placebo.Changes in PROs, including response in the Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] (defined as a >3-point improvement), Short Form 36 Health Survey version 2 [SF-36-v2] physical health scale [PCS] and mental health scale [MCS] (defined as an improvement of >3.4 in PCS and >4.6 in MCS), were assessed from baseline to week 52. LS mean changes in weight, body mass index (BMI), fasting glucose, cholesterol, hematological values ​​(hematocrit, red blood cells, white blood cells, lymphocytes, neutrophils, and platelets), and cardiovascular measures (diastolic and systolic blood pressure, and heart rate) were assessed from baseline to weeks 24 and 52. Serious adverse events (SAEs) and cardiovascular adverse events (AEs) were also assessed.

[0170] 8.3.4 Outcomes assessed in the anifrolumab 300 mg and placebo treatment groups Outcome measures including the proportion of patients achieving a sustained glucocorticoid tapering response, LS mean change from baseline daily glucocorticoid dose, cumulative glucocorticoid dose, improvement in response on PROs, and safety were also compared between patients receiving baseline glucocorticoids ≥ 10 mg / day and randomized to receive anifrolumab 300 mg or placebo.Additional analyses of the proportion of sustained glucocorticoid tapering responders and British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) responders, as defined in the TULIP trial, were compared between treatment groups.

[0171] 8.3.5 Assessment of outcomes in glucocorticoid responders and non-responders Cumulative doses of glucocorticoids, PROs, laboratory parameters, and safety were compared between glucocorticoid responders and nonresponders at week 52, regardless of treatment group assignment. Additionally, the proportions of glucocorticoid responders and British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) responders were compared between treatment groups. BICLA response was defined as reductions in all baseline BILAG-2004 A and B scores, no deterioration in other organ systems, no deterioration from baseline on the SLEDAI-2K, and no increase from baseline of ≥ 0.30 points on the 3-point Patient's Global Assessment visual analogue scale.

[0172] 8.3.6 Statistical analysis The similar design of the TULIP-1 and TULIP-2 trials allowed for pooling of results. Sample sizes for TULIP-1 and TULIP-2 were selected based on power to detect the primary and key secondary endpoints, and to ensure an adequate safety database. For TULIP-1 and TULIP-2, 180 patients / group provided >99% and >88% power, respectively, to reject the hypothesis (no difference in the primary endpoint) using a two-sided alpha of 0.05. Changes from baseline were analyzed using mixed models for repeated measures (MMRM), proportions of responders vs. non-responders were calculated using a stratified Cochran-Mantel-Haenszel approach, and glucocorticoid AUC was analyzed by model analysis of covariance. Models included fixed effects and stratification factors for baseline values, including oral glucocorticoid dose (<10 mg / day or ≥10 mg / day), treatment group, visit (including studies in the pooled analysis), treatment-by-visit interactions, and stratification factors (SLEDAI-2K score at screening [<10 vs. ≥10] and type 1 IFN gene signature test result at screening [high vs. low]). All P values, 95% CIs, and standard errors are based on these models. All P values ​​are nominal, as these analyses were not part of a formal study strategy. Missing data were imputed using the last observation made for the first visit with missing data and were not imputed for subsequent visits with missing data.

[0173] 8.4 Results 8.4.1 Patient demographics and clinical characteristics Across the two TULIP trials, 726 patients were randomized to receive anifrolumab 300 mg (n=360 [180 patients in each trial]) or placebo (n=366 [184 and 182 patients in TULIP-1 and TULIP-2, respectively]). The majority of patients, 595 / 726 (82%), received oral glucocorticoids (prednisone or equivalent) at baseline, of which 375 received ≥10 mg / day (n=190, anifrolumab; n=185 placebo), with a mean daily dose of 15.2 mg for both treatment arms. Patient demographics and baseline clinical characteristics were comparable between treatment arms for patients receiving baseline glucocorticoids ≥10 mg / day from the pooled TULIP trials (Table 8-1). [Table 6-1] [Table 6-2] [Table 6-3] BILAG-2004, British Isles Lupus Assessment Group-2004;BMI, Body Mass Index;CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index;HDL, high density lipoprotein;IFNGS, interferon gene signature;LDL, low density lipoprotein;PGA, Physician's Global Assessment;SD, standard deviation;SDI, Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index;SLE, systemic lupus erythematosus;SLEDAI-2K, SLE Disease Activity Index 2000. aA sustained glucocorticoid tapering responder is defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 in patients with a baseline glucocorticoid dose of ≥10 mg / day, with no dose escalation from weeks 40 to 52. bOral glucocorticoids include prednisone or equivalent.

[0174] Regardless of treatment group assignment, among patients receiving baseline glucocorticoids ≥ 10 mg / day, 155 patients were classified as glucocorticoid responders and 220 as glucocorticoid nonresponders at week 52. Patient demographics and clinical characteristics were also similar between glucocorticoid responder and nonresponder groups, although a higher proportion of black / African American patients were glucocorticoid nonresponders, and glucocorticoid nonresponders had a higher baseline mean daily glucocorticoid dose compared with responders (Table 8-1).

[0175] 8.4.2 Outcomes of responders versus non-responders to sustained glucocorticoid tapering The mean cumulative glucocorticoid dose during 52 weeks of treatment was 44% lower among patients who were glucocorticoid tapering responders versus nonresponders (mean [SE] AUC at week 52: 2808.2 [76.0] mg vs. 5025.9 [231.7] mg) (Figure 2). More patients in the sustained glucocorticoid tapering responder group showed clinically meaningful improvements in FACIT-F, SF-36 PCS, and SF-36 MCS scores (all P < 0.001) compared with nonresponders (Figure 3A-C).

[0176] In the 52-week study, the proportion of patients with ≥1 AE was 90.3% (140 / 155) of sustained glucocorticoid tapering responders and 83.2% (183 / 220) of nonresponders. The incidence of severe AEs was 16.8% (26 / 155) of sustained glucocorticoid tapering responders and 28.2% (62 / 220) of nonresponders (Table 8-2). Of the severe AEs, severe infections, including pneumonia, were the most commonly reported, occurring in 5.8% (9 / 155) of glucocorticoid responders and 13.2% (29 / 220) of nonresponders, and exacerbations of SLE were reported in 2.6% (4 / 155) of glucocorticoid tapering responders and 5% (11 / 220) of nonresponders (Table 8-2). Cardiovascular AEs were reported in 12.3% (19 / 155) and 11.4% (25 / 220) of glucocorticoid tapering responders and nonresponders, respectively (Table 8-3). Hypertension was the most common cardiovascular AE reported in both responders and nonresponders. [Table 7-1] [Table 7-2] [Table 7-3] SAE, severe adverse event. a A sustained glucocorticoid tapering responder was defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 with no dose escalation from weeks 40 to 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day.

[0177] At week 40 (when glucocorticoid dosing was expected to remain stable from this point onward), sustained glucocorticoid tapering responders had lower systolic and diastolic sitting blood pressures compared with nonresponders (P = 0.023 and P < 0.001, respectively), with differences maintained at week 52 for diastolic (P = 0.010) but not systolic (P = 0.381) sitting blood pressure (Table 8-4). Fewer sustained glucocorticoid tapering responders than nonresponders initiated new blood pressure support therapy during the 52-week study (7.5% [11 / 155] vs. 15.9% [35 / 220]) (P = 0.029). [Table 8] AE, adverse event. a A sustained glucocorticoid tapering responder was defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 with no dose escalation from weeks 40 to 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day.

[0178] The mean changes in weight, BMI, fasting glucose, cholesterol, and blood counts are shown in Table 8-5. At week 52, the mean changes were generally similar between glucocorticoid responders and non-responders. Both groups showed a moderate increase in weight and BMI from baseline to week 52. Glucocorticoid responders also showed a modest decrease in triglycerides at week 52 compared with non-responders, who showed no change (Table 8-5). [Table 9] CI, confidence interval; LS, least squares; SD, standard deviation; SE, standard error. aA sustained glucocorticoid tapering responder was defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 with no dose escalation from weeks 40 to 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day. [Table 10-1] [Table 10-2] BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation. a Sustained glucocorticoid tapering responders were defined as a reduction in glucocorticoid dose to ≤7.5 mg / day by week 40 with no dose escalation from weeks 40 to 52 for patients receiving ≥10 mg / day at baseline.

[0179] 8.4.3 Glucocorticoid tapering Patient demographics and baseline clinical characteristics were comparable between treatment groups for patients receiving baseline glucocorticoids ≥ 10 mg / day from the pooled cohort (Table 8-6). [Table 11-1] [Table 11-2] BILAG-2004, British Isles Lupus Assessment Group-2004;BMI, Body Mass Index;CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index;HDL, high density lipoprotein;IFNGS, interferon gene signature;LDL, low density lipoprotein;PGA, Physician's Global Assessment;SD, standard deviation;SDI, Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index;SLE, systemic lupus erythematosus;SLEDAI-2K, SLE Disease Activity Index 2000. a Oral glucocorticoids include prednisone or equivalent.

[0180] In the prespecified TULIP-1 and TULIP-2 trials, secondary endpoints included sustained reductions in glucocorticoids to ≤7.5 mg / day in patients receiving ≥10 mg / day at baseline, and in the pooled data set, more patients receiving anifrolumab achieved a glucocorticoid response compared with placebo (50.5% [96 / 185] vs. 31.8% [59 / 185]) (P < 0.001). Using a more stringent threshold of glucocorticoid reduction ≤5 mg / day, more patients in the anifrolumab group achieved sustained glucocorticoid reduction ≤5 mg / day at weeks 40–52 compared with placebo (P = 0.003) (Figure 4A; Figure 4B).

[0181] 8.4.4 Changes in glucocorticoid dose during the study The LS mean (SD) percent reduction from baseline in daily glucocorticoid dose was -42.5% (4.5) for patients in the anifrolumab group compared with -27.7% (4.6) for patients in the placebo group (LS mean difference -14.8%, 95% CI -27.17% to -2.42%, nominal P < 0.019). Also, more patients in the anifrolumab group compared with the placebo group demonstrated more severe sustained glucocorticoid reductions from baseline at weeks 40 through 52, including sustained glucocorticoid reductions of ≥ 25% (P < 0.001), ≥ 50% (P = 0.001), ≥ 75% (P = 0.06), and ≥ 90% (P = 0.09) (Tables 8-7). Six patients in the anifrolumab group and five patients in the placebo group who reached an oral glucocorticoid dose ≦7.5 mg / day at week 40 increased their dose to >7.5 mg / day after week 40. [Table 12] CI, confidence interval; IFNGS, interferon gene signature; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000. A stratified Cochran-Mantel-Haenszel approach was used to calculate the difference in response rates, using the stratification factors SLEDAI-2K score at screening (<10 vs. ≥10) and type I IFNGS test result at screening (high vs. low). In the pooled analysis, we add an additional stratification factor for the test (TULIP-1 vs. TULIP-2).

[0182] The mean cumulative glucocorticoid dose during 52 weeks of treatment was 8% lower in the anifrolumab group compared with the placebo group (mean [SD] AUC at week 52: 3947.1 [3655.5] mg vs. 4275.8 [1859.0] mg) and 44% lower among patients who were glucocorticoid responders compared with nonresponders (mean [SD] AUC at week 52: 2808.2 [945.9] mg vs. 5025.9 [3436.6] mg) (Figure 4C, D).

[0183] The LS mean (SE) percent reduction from baseline in daily glucocorticoid dose at week 52 was -42.5% (4.5) for patients in the anifrolumab group compared with -27.7% (4.7) for patients in the placebo group (LS mean difference -14.8%, 95% CI -27.17%, -2.42%, P = .021). Also, more patients in the anifrolumab group had more severe sustained glucocorticoid reductions from baseline at weeks 40-52 compared with placebo, including sustained reductions in glucocorticoid dose of ≥ 25% (P < .001), ≥ 50% (P = .001), ≥ 75% (P = .057), and ≥ 90% (P = .086) (Table 8-8). [Table 13] CI, confidence interval; IFNGS, interferon gene signature; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000. Differences in response rates, 95% CIs, and nominal P values ​​were calculated using a stratified Cochran-Mantel-Haenszel approach.

[0184] 8.4.5 PRO FACIT-F, SF-36 PCS, and SF-36 MCS scores were similar across treatment groups and between glucocorticoid responders and nonresponders at baseline (Tables 8-9). Treatment with anifrolumab resulted in more patients with nominally significant improvement in SF-36 MCS scores (P=0.03) compared with placebo, but not in SF-36 PCS or FACIT-F (Figures 6A-C). The glucocorticoid responder group had more patients with nominally significant improvement in all PROs (all P<0.001) compared with nonresponders (Figures 6D-F). [Table 14] FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; MCS, mental health; PCS, physical health; PRO, patient-reported outcome; SD, standard deviation; SF-36, Short Form 36 Health Survey. a Glucocorticoid responders were defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 and no dose escalation from weeks 40 to 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day.

[0185] 8.4.6 Association between glucocorticoid responders and BICLA responders Of the anifrolumab-treated patients who achieved a BICLA response, 80.1% (72 / 89) had a sustained glucocorticoid-sparing response (glucocorticoid responders) compared with 74.1% (43 / 58) of the placebo-treated patients who achieved a BICLA response. Thus, with anifrolumab treatment, 37.8% (72 / 190) of patients achieved both a BICLA response and a glucocorticoid response at week 52 compared with 23.2% (43 / 185) of placebo-treated patients.

[0186] A total of 46.8% (89 / 190) of patients treated with anifrolumab and receiving baseline glucocorticoids ≥ 10 mg / day achieved a BICLA response at week 52 compared with 31.4% (58 / 185) of patients receiving placebo (Figures 5, 7). A high proportion of BICLA responders also achieved a sustained glucocorticoid tapering response (80.9% [72 / 89] of anifrolumab and 74.1% [43 / 58] of placebo). Thus, with anifrolumab treatment, 37.8% (72 / 190) of patients achieved a combined BICLA response and sustained glucocorticoid tapering response at week 52 compared with 23.3% (43 / 185) of patients receiving placebo (difference 14.6%, 95% CI 5.3%, 23.9%, P = 0.002) (Figure 5, Figure 7).

[0187] 8.4.7 Laboratory changes 8.4.7.1 Vital Signs Baseline mean systolic and diastolic sitting blood pressures and heart rate were lower in anifrolumab treatment compared with placebo at week 40, when glucocorticoid doses were expected to remain constant (all nominal P<0.05), and at week 52, treatment differences between groups were not significantly different (Tables 8-10). Similarly, glucocorticoid responders had lower systolic and diastolic sitting blood pressures compared with nonresponders at week 40 (P=0.02 and P<0.001, respectively), and at week 52, the differences in diastolic sitting blood pressure (P=0.01) but not in systolic sitting blood pressure (P=0.38) were maintained. Heart rate differences between glucocorticoid responders and nonresponders did not reach nominal significance at weeks 40 or 52 (Tables 8-10). The use of supplemental blood pressure medications initiated in the anifrolumab group during patient treatment was 6.3% (12 / 190) and 18.4% (34 / 185) in the placebo group, whereas 7.1% (11 / 155) of glucocorticoid responders and 15.9% (35 / 220) of nonresponders initiated new blood pressure medications during the study (Tables 8-11). [Table 15-1] [Table 15-2] LS, least squares; SD, standard deviation; SE, standard error. a Glucocorticoid responders were defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 and no dose escalation from weeks 40 to 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day. [Table 16-1] [Table 16-2] a Glucocorticoid responders were defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 and no dose escalation from weeks 40 to 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day.

[0188] 8.4.7.1.1 Laboratory Values The LS mean changes in weight, BMI, fasting glucose, cholesterol, and blood cell counts are shown in Tables 8-12. The LS mean changes at weeks 24 and 52 were generally similar between treatment groups and between glucocorticoid responders and non-responders. Of note, anifrolumab treatment and glucocorticoid response increased weight and BMI from baseline at weeks 24 and 52. Shift tables for BMI are shown in Tables 8-13. Additionally, anifrolumab treatment increased blood cell counts (red blood cells, white blood cells, lymphocytes, neutrophils, and platelets) compared to placebo, while placebo patients experienced mean decreases from baseline or stable values. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] BMI, body mass index; LS, least squares; SD, standard deviation; SE, standard error. a Glucocorticoid responders were defined as a reduction in glucocorticoid dose to ≦7.5 mg / day by week 40 and no dose escalation from weeks 40 to 52 for patients receiving ≧10 mg / day at baseline. [Table 18-1] [Table 18-2] [Table 18-3] BMI, Body Mass Index a Glucocorticoid responders were defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 and no dose escalation from weeks 40 to 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day.

[0189] 8.4.8 Safety The incidence of severe AEs was 21.1% (40 / 190) in the anifrolumab group and 25.9% (48 / 185) in the placebo group, with severe AEs reported in 16.8% (26 / 155) of glucocorticoid responders and 28.2% (62 / 220) of nonresponders (Table 8-14). Cardiovascular AEs were reported in 10.0% and 13.5% of patients in the anifrolumab and placebo groups, respectively, and in 11.4% and 12.3% of glucocorticoid responders and nonresponders, respectively (Table 8-15). Hypertension was the most common cardiovascular AE reported in all groups. [Table 19-1] [Table 19-2] [Table 19-3] SAE, severe adverse event a Glucocorticoid responders were defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 and no dose escalation from weeks 40 to 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day. [Table 20] AE, adverse event a Glucocorticoid responders were defined as a reduction in glucocorticoid dose of ≤7.5 mg / day by week 40 and no dose escalation from weeks 40 to 52 in patients with a baseline glucocorticoid dose of ≥10 mg / day.

[0190] 8.5 Discussion Control of disease activity and avoidance of drug toxicity due to glucocorticoid use are the two most important treatment goals emphasized in SLE disease management guidelines. In an analysis of pooled data from the TULIP-1 and TULIP-2 trials of anifrolumab in patients with moderate-to-severe SLE, we evaluated the downstream effects of sustained glucocorticoid tapering independent of treatment assignment. Sustained glucocorticoid tapering was associated with a 44% reduction in the mean cumulative glucocorticoid dose used over 52 weeks. Patients who sustained glucocorticoid tapering tended to show meaningful improvements in fatigue, physical and mental health, and blood pressure reduction compared with glucocorticoid non-responders. Sustained tapering was also associated with a reduction in SAEs, including infections.

[0191] Anifrolumab treatment promoted greater glucocorticoid tapering compared with placebo, and anifrolumab-treated patients were more likely to achieve a combination of sustained glucocorticoid tapering and reduced disease activity.

[0192] In this post-hoc analysis of pooled data from the TULIP-1 and TULIP-2 trials, among patients who received a glucocorticoid dose of ≥10 mg / day at baseline, those who received anifrolumab were more likely to have their glucocorticoid dose reduced than those who received placebo. While facilitating glucocorticoid tapering, anifrolumab treatment also had beneficial effects on disease activity, blood pressure, blood counts, and health-related quality of life. Regardless of treatment group, patients who were able to taper their glucocorticoids showed improvements similar to or greater than those observed with anifrolumab treatment.

[0193] In patients with SLE, persistent disease activity and prolonged glucocorticoid treatment are major predictors of organ damage. Therefore, reducing glucocorticoid use while improving disease activity is one of the most important therapeutic goals for managing SLE for both clinicians and patients. However, some patients, especially those receiving long-term glucocorticoid therapy, have difficulty achieving and maintaining complete and steroid-free clinical remission. 47 Nonetheless, it has been reported that reducing glucocorticoid exposure is beneficial and limits the adverse effects of glucocorticoids, regardless of whether patients achieve low doses (≤7.5 mg / day), as each 1 mg / day reduction in mean prednisone dose was estimated to lead to an estimated 3%-6% reduction in the risk of future organ damage. In our analysis, in addition to sustained dose reductions, anifrolumab-treated patients achieved reduced daily glucocorticoid doses, reduced cumulative doses over 52 weeks, greater threshold reductions, and fewer dose escalations than placebo-treated patients, all of which could provide long-term health benefits for SLE patients. Sustained glucocorticoid tapering was associated with improved PROs, including reduced fatigue and improved physical and mental health. The mechanisms behind these improvements may in part be directly related to reduced glucocorticoid doses, as sleep disturbances, mood disturbances, and catabolic effects on muscle are all recognized adverse effects of high doses of glucocorticoids.

[0194] Glucocorticoid use has been reported to be a risk factor for coronary heart disease in SLE patients, regardless of disease activity. Many reports have shown increases in serum total cholesterol, blood pressure, blood glucose, triglycerides, and body weight in relation to the dose of prednisone. 48We examined treatment differences in several areas of cardiovascular health, including systolic and diastolic blood pressure, heart rate, new blood pressure medications on treatment, and cardiovascular AEs. Patients treated with anifrolumab showed significant reductions in systolic and diastolic blood pressure at week 40. Use of supplemental blood pressure medications by patients randomized to receive anifrolumab was consistently greater than that of patients randomized to placebo, which may have confounded treatment differences at week 52. There was no difference in the rate at which glucocorticoid responders and nonresponders initiated new blood pressure medications during the study. Consistent with reports of hypertension in up to 74% of SLE patients, hypertension was the most common cardiovascular AE reported in 2% to 6% of patients across treatment and responder groups.

[0195] We found that glucocorticoid tapering was associated with measured reductions in systolic and diastolic blood pressure. Furthermore, a small number of glucocorticoid tapering patients started new antihypertensive drugs during the study. Reduction in blood pressure is a practical benefit of glucocorticoid tapering in this population, as this intervention tends to minimize the absolute difference in blood pressure observed. These changes in blood pressure may contribute to a reduction in the long-term risk of future cardiovascular disease in this population.

[0196] Unexpectedly, mean changes in weight and BMI showed mild weight gain for patients treated with anifrolumab and for patients classified as glucocorticoid responders, which may be due to weight gain in response to improved health status as disease activity improved in patients during the TULIP trial.

[0197] In conclusion, in pooled data from patients with moderate-to-severe SLE in the TULIP-1 and TULIP-2 trials, anifrolumab treatment improved overall SLE disease activity while allowing a reduction in oral glucocorticoid therapy. These results support the potential of anifrolumab to reduce the cumulative glucocorticoid dose and the resulting glucocorticoid-associated risk of side effects, which is a goal of long-term SLE treatment.

[0198] 9 Example 4: Novel stringent outcome assessment scales applied to phase 2 and 3 anifrolumab trials 9.1 Background technology Treatment of patients with systemic lupus erythematosus (SLE) should aim to reduce disease activity and prevent flares while maintaining glucocorticoids (GCs) at the lowest possible dose. The British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) is a comprehensive disease activity assessment frequently used in SLE clinical trials. BICLA response requires improvement in all domains affected at baseline as assessed by BILAG-2004, no deterioration in other BILAG-2004 domains, and no deterioration vs. baseline in both the SLE Disease Activity Index 2000 (SLEDAI-2K) and Physician's Global Assessment (PGA).

[0199] Patients with systemic lupus erythematosus (SLE) treated with the type I interferon receptor antibody anifrolumab had higher BILAG-based Composite Lupus Assessment (BICLA) response rates compared with placebo at week 52 in the phase 2 MUSE and phase 3 TULIP-1 and TULIP-2 trials. Patients treated with anifrolumab also had fewer flares and more patients were able to taper off glucocorticoids (GCs) compared with placebo.

[0200] 9.2 Purpose To evaluate anifrolumab treatment response versus placebo in SLE patients from TULIP-2, TULIP-1 and MUSE using the more stringent BICLA definition and to evaluate a novel endpoint requiring dual response in BICLA and the SLE Responder Index (SRI[4]).

[0201] 9.3 Method MUSE, TULIP-1, and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks) in patients with moderate-to-severe SLE despite standard treatment. In patients receiving ≥10 mg / day GCs at baseline, tapering was considered sustained if tapering to ≤7.5 mg / day was achieved by week 40 and maintained through week 52. In patients receiving <10 mg / day GCs at baseline, GC tapering was sustained if the dose at week 40 was equal to or less than the baseline dose and was not increased from week 40 to week 52. In this post-hoc analysis, response rates of five new endpoints were compared between anifrolumab 300 mg vs. placebo for patients who: 1) met both BICLA and SRI (4) response criteria, 2) achieved a BICLA response at week 52 with sustained GC taper, 3) achieved a BICLA response at week 52 and had no flare at week 12 or later (flare defined as a new BILAG-2004 A score of ≥ 1 or a new BILAG-2004 B score of ≥ 2 compared to the previous visit), 4) achieved a BICLA response at week 52 with sustained GC taper and had no flare at week 12 or later, and 5) achieved a modified BICLA (mBICLA, crBICLA) response requiring complete resolution of all baseline BILAG-2004 activity at week 52 (all baseline A / B scores to D; no worsening of C or D scores).

[0202] 9.3.1 Novel stringent outcome measures In this post-hoc analysis, response rates of five new endpoints were compared between anifrolumab 300 mg vs. placebo for patients who: 1) met both BICLA and SRI (4) response criteria, 2) achieved a BICLA response at week 52 with sustained GC taper, 3) achieved a BICLA response at week 52 and had no flare after week 12 (flare defined as a new BILAG-2004 A score of ≥ 1 or a new BILAG-2004 B score of ≥ 2 compared to the previous visit), 4) achieved a BICLA response at week 52 with sustained GC taper and had no flare after week 12, and 5) achieved a modified BICLA (crBICLA) response requiring complete resolution of all baseline BILAG-2004 activity (all baseline A / B scores to D; no worsening of C or D scores) at week 52 (Table 9-1). [Table 21]

[0203] 9.3.2 Statistical analysis Response rates, treatment differences, 95% confidence intervals (CIs), odds ratios, standard errors, and nominal P values ​​were calculated using a stratified Cochran-Mantel-Haenszel approach6 (stratification factors: SLEDAI-2K score at screening, day 1 GC dose, and interferon gene signature [IFNGS] status at screening).

[0204] 9.4 Results Evaluable patients received anifrolumab 300 mg (MUSE, n=99; TULIP-1 and TULIP-2, n=180) or placebo (MUSE, n=102; TULIP-1, n=184; TULIP-2, n=182). Demographic and baseline disease characteristics were generally well-balanced (Table 9-2).

[0205] Differences in response rates favoring anifrolumab 300 mg over placebo were observed for all five stringent BICLA end points across MUSE, TULIP-1, and TULIP-2 (Figure 8). More patients met response criteria for both BICLA and SRI (4) at week 52 in the presence of anifrolumab compared with placebo (treatment difference, 14.3% to 28.6%; nominal P value ≤ 0.004). A greater proportion of patients had a BICLA response at week 52 with sustained GC taper in the presence of anifrolumab compared with placebo. More patients had a BICLA response at week 52 without flare after week 12 in the presence of anifrolumab compared with placebo. More patients had a BICLA response at week 52 with sustained GC taper and no flare after week 12 in the presence of anifrolumab compared with placebo (treatment difference, 15.3% to 19.3%; nominal P value ≤ 0.006). More patients achieved a crBICLA response (requiring complete resolution of baseline disease activity) at week 52 in the presence of anifrolumab compared with placebo (treatment difference, 11.1% to 14.1%; nominal P value ≤ 0.017).

[0206] Odds ratios favoring anifrolumab 300 mg versus placebo were observed for all five endpoints at week 52 (Figure 8). - BICLA response + sustained GC tapering, range: 1.72-3.97 - BICLA response + no flare after week 12, range: 2.30-3.47 - BICLA response + no flare after week 12 + sustained GC taper, range: 2.65-4.16 - Complete Resolution BICLA (crBICLA) response (requiring complete resolution of BILAG-2004 A / B scores), range: 2.45 to 2.74 - BICLA+SRI(4) response, range: 1.89-3.76

[0207] A positive treatment difference favoring anifrolumab over placebo for crBICLA response was observed beginning at approximately week 32 (week 28 in TULIP-1) and persisted through week 52 in TULIP-2, TULIP-1, and MUSE (Figure 9) [Table 22]

[0208] 9.5 Conclusion In phase 2 and 3 studies in patients with SLE, anifrolumab treatment was consistently associated with improved disease control compared with placebo when using five novel stringent BICLA-based endpoint definitions, including BICLA response with sustained GC tapering and no flares, BICLA response requiring complete resolution of baseline disease activity, and dual response in BICLA and SRI (4). crBICLA response, requiring complete resolution of all baseline BILAG-2004 A / B scores, was sustained as early as week 28 and through week 52. These results support the ability of anifrolumab to reduce global disease activity, suppress flares, and minimize GC use, which are important treatment goals in patients with SLE.

[0209] 10 Example 5: Injection Device Anifrolumab is administered via an injection device [1][9] such as a prefilled syringe (PFS) (Figure 10A) or an autoinjector (AI) (Figure 10B).

[0210] 10.1 Autoinjector Anifrolumab may be administered by autoinjector [1]. The autoinjector is shown in exploded (FIG. 11A) and assembled form (FIG. 11B). A label [4] is wrapped and attached to the autoinjector [1] (FIG. 11C). The autoinjector has an autoinjector housing [3], a cap and cap remover [2], and an actuator [5]. A unit dose [6] of the liquid anifrolumab formulation is contained in the autoinjector housing [3]. The unit dose [6] is visible through a sight window [7].

[0211] 10.2 Prefilled Syringes with Safety Devices Anifrolumab may be administered by a prefilled syringe with safety feature (APFS) [8]. The APFS [8] contains a unit dose of anifrolumab [6] housed in a primary container [9] shown assembled in FIG. 12A and in an exploded view in FIG. 12B. 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 remaining space within the primary container [9] is entrapped with 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] .

[0212] A prefilled syringe with safety (APFS) primary container [9] is provided within a PFS assembly [8] that includes a needle guard

[12] , finger flange

[11] , and plunger rod

[13] (FIGS. 12C, 12D). A label

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

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

[15] .

[0213] 10.3 Packages An injection device [1][8] is provided in the kit

[20] (Figure 13). A label [4]

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

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The Role of Ultrasound in Assessing Musculoskeletal Symptoms of Systemic Lupus Erythematosus: A Systematic Literature Review.Rheumatology (Oxford) 2016, 55 (3), 485-494. https: / / doi.org / 10.1093 / rheumatology / kev343. (5) Sa, C.;E, A.;A, R.;D, I. Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years https: / / pubmed.ncbi.nlm.nih.gov / 19359343 / (accessed Feb 8, 2021). https: / / doi.org / 10.1093 / rheumatology / kep062. (6) Murimi-Worstell, I. B.;Lin, D. H.;Nab, H.;Kan, H. J.;Onasanya, O.;Tierce, J. C.;Wang, X.;Desta, B.;Alexander, G. C.;Hammond, E. R. Association between Organ Damage and Mortality in Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis.BMJ Open 2020, 10 (5), e031850. https: / / doi.org / 10.1136 / bmjopen-2019-031850. (7) Doria, A.;Briani, C. Lupus: Improving Long-Term Prognosis.Lupus 2008, 17 (3), 166-170. https: / / doi.org / 10.1177 / 0961203307087612. (8) Petri, M. 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Claims

1. A composition comprising anifrolumab for a method of treating systemic lupus erythematosus (SLE) in a subject in need of treatment therefor, the method comprising administering anifrolumab and a steroid to the subject, wherein a dose of the steroid administered to the subject is tapered from a pre-sparing dose at baseline to a post-sparing dose, the post-sparing dose being ≦50% of the pre-sparing dose.

2. The composition of claim 1 , wherein the method does not worsen SLE disease activity in the subject.

3. 3. The composition of claim 1 or 2, wherein the post-sparing dose is ≦25% of the pre-sparing dose.

4. 3. The composition of claim 1 or 2, wherein the post-sparing dose is ≦10% of the pre-sparing dose.

5. A composition comprising anifrolumab for a method of treating SLE in a subject in need of treatment therefor, the method comprising administering to the subject anifrolumab and a steroid, wherein a dose of the steroid administered to the subject is tapered from a pre-sparing dose at baseline to a post-sparing dose, the post-sparing dose being a prednisone or prednisone equivalent dose of ≦5 mg / day.

6. 10. The composition of claim 1 or 5, wherein the pre-sparing steroid dose is a prednisone or prednisone equivalent dose of about > 10 mg / day.

7. 10. The composition of claim 1 or 5, wherein the post-sparing dose is maintained for ≧12 weeks.

8. 10. The composition of claim 1 or 5, wherein the post-sparing dose is about 0 mg / day of prednisone or a prednisone equivalent dose.

9. 10. The composition of claim 1 or 5, wherein the post-sparing dose is sustained for at least one week.

10. 10. The composition of claim 1 or 5, wherein the steroid comprises a glucocorticoid, optionally wherein the steroid comprises an oral glucocorticoid.

11. The steroid may be 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, flu 6. The composition of claim 1 or 5 comprising prednidene, 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.

12. 10. The composition of claim 1 or 5, wherein the steroid comprises prednisone.

13. The composition of claim 1 or 5, wherein the method comprises administering to the subject anifrolumab at a dose of 300-1000 mg every four weeks (Q4W).

14. The composition of claim 1 or 5, wherein the method comprises intravenously administering anifrolumab to the subject.

15. The composition of claim 1 or 5, wherein the method comprises subcutaneously administering anifrolumab to the subject.

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