S1P1 receptor modulators for treatment of type 1 IFN-mediated diseases

Abstract

The present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a type 1 interferon-mediated disease in a subject having a high score of type 1 interferon (IFN-1) gene characteristics or an increased interferon-alpha (IFN-alpha) and / or interferon-gamma (IFN-gamma) content in the plasma of the subject.

Description

Technical Field

[0001] The present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for preventing or treating a type 1 interferon-mediated disease in a subject, wherein the subject has a high type 1 interferon (IFN-1) gene signature score or the interferon-α (IFN-α) and / or interferon-γ (IFN-γ) level in the subject's plasma is elevated. Background Art

[0002] Sphingosine 1-phosphate (S1P) is a lipid mediator formed by the metabolism of sphingomyelin. In vertebrates, S1P is secreted into the extracellular environment and transmits signals via G protein-coupled S1P receptors (including the S1P1 receptor, which plays an important role in lymphocyte trafficking) [Mendelson, K. et al., Development 2014, 141, 5-9, PMID: 24346695].

[0003] S1P1 receptor modulators are approved for the treatment of multiple sclerosis and inflammatory bowel disease and are being studied in other inflammatory diseases involving lymphocyte-driven inflammatory processes [Burg, N. et al., Nat Rev Rheumatol. 2022, 18(6), 335-351, PMID: 35508810].

[0004] (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol (hereinafter also referred to as "the compound" or "cenerimod") is a potent, selective, orally active S1P1 receptor modulator that prevents lymphocyte extravasation from secondary lymphoid organs into the vascular circulation via internalization of the S1P1 receptor. Therefore, its immunomodulatory effects in autoimmune diseases may be beneficial in the treatment of such diseases where lymphocytes play an important role in the spread of disease. The preparation of (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol and its medical use are described in PCT application WO 2011 / 007324, WO 2013 / 175397 and WO 2016 / 184939.

[0005] Both B and T lymphocytes play an important role in the pathogenesis of systemic lupus erythematosus (SLE), a complex, heterogeneous autoimmune disease of unknown etiology characterized by the production of high titers of pathogenic autoantibodies, infiltrating lymphocytes, and tissue damage across multiple organ systems [Rahman, A. et al., N Engl J Med 2008, 358, 929-939, PMID: 18305268].

[0006] In a Phase 2 clinical trial, siponimod reduced both circulating B lymphocytes and T lymphocytes, confirming the mode of action (Hermann V et al. Lupus Science & Medicine 2019; 6: e000354. DOI: 10.1136 / lupus-2019-000354). In addition, siponimod reduced interferon (IFN)-related proteins in plasma [Strasser, DS et al., RMD Open 2020, 6, e001261, PMID: 32917831].

[0007] IFNs are major effector molecules produced in large quantities during the immune response to infection, activating defense mechanisms and causing inhibition of microbial replication. Type 1 IFNs are the largest group and include several classes and subclasses. Almost all cells can produce IFN-α and IFN-β (members of type 1 IFNs), including dendritic T and B cells, monocytic T and B cells of the immune system. IFN-γ is the only type 2 IFN and is produced primarily by NK cells and T cells of the immune system [McNab, F. et al., Nat Rev Immunol 2015, 15, 87-103, PMID: 25614319; L. et al., Lupus Sci Med 2019, 6, e000270, PMID: 31497305; Colonna, M. et al., Current Opinion Immunol 2002, 14, 373-379, PMID: 11973137].

[0008] Type 1 IFN conducts signals via heterodimeric transmembrane receptors consisting of subunits IFNAR1 and IFNAR2, which are widely expressed in a variety of cell types. Similarly, type 2 IFN engages with heterodimers IFNGR1 and IFNGR2. Both IFNAR and IFNGR complexes recruit members of the JAK kinase family. IFNAR recruits TYK2 and JAK1, while IFNGR recruits JAK1 and JAK2. This causes subsequent STAT1 and STAT2 phosphorylation and subsequent translocation of signal transduction pathway transcription factors into the nucleus. These complexes then bind to the IFN response assembly on DNA, initiating transcription of the entire host gene [Platanias, LC., Nat Rev Immunol 2005, 5, 375-386, PMID: 15864272].

[0009] Importantly, activation of these pathways overlaps to some extent. Activation of gene transcription by IFNs can be described by IFN gene signatures, which can consist of hundreds of genes, depend on the kinetics and cell types involved, and can lead to a variety of outcomes and nuances. L. et al., Curr Opin Rheumatol 2013, 25(2), 248-253, PMID: 23249830].

[0010] In the late 1970s, it was observed that IFN increased in SLE, and studies of interferon disease showed that IFN can actually cause SLE-like symptoms. In these studies, it has been found that genetic mutations in genes within the type 1 and type 2 IFN induction pathways cause constitutive overproduction of type 1 IFN. These individuals have significant IFN characteristics, and some patients present SLE-like phenotypes [Lee-Kirsch, MA., Annu Rev Med 2017, 68, 297-315, PMID: 27813875]. The reason for the increase in IFN levels in SLE is unclear, and not all patients diagnosed with SLE have elevated type 1 IFN [Northcott, M. et al., Lupus Sci Med 2022, 9, e000625, PMID: 35197305]. There is a lot of evidence that genetic predisposition and environmental risk factors can lead to increased IFN levels. This mainly reflects the involvement of multiple pattern recognition receptors in the IFN activation mentioned above and their activation methods. An important mechanism is believed to be an immune complex composed of autoantibodies (such as anti-dsDNA and anti-nuclear antibodies), nucleic acids, and nucleic acid-binding proteins. This suggests that nucleic acids are a potential cause and that having autoantibodies against nucleic acids is a risk factor for developing SLE.

[0011] Plasmacytoid dendritic cells (pDCs) sense nucleic acids in other cells and are considered to be the key cell type for type 1 IFN production in SLE.

[0012] Increased IFN signaling has been demonstrated not only in SLE but also in other autoimmune diseases, but the frequency and distribution within the population is unique to each autoimmune disease.[ L. et al., Curr Opin Rheumatol 2013, 25(2), 248-253, PMID: 23249830].

[0013] Although pDCs produce large amounts of type 1 IFN [Cella, M. et al., Nature Med 1999, 5(8), 919-923, PMID: 10426316], other cell types may also be involved in IFN production in SLE, including keratinocytes, endothelial cells, fibroblasts and monocytes, NK cells, B cells and T cells. Finally, genetic risk factors associated with IFN production or response to IFN have been identified in SLE, further supporting the hypothesis that perturbations in IFN regulation can lead to SLE [Deng, Y. et al., Curr Rheumatol Rep 2017, 19, 68 PMID: 28983873; Catalina, MD. et al., Communications Biology 2019, 2(140), https: / / doi.org / 10.1038 / s42003-019-0382-x, PMID: 31044165].

[0014] Gene transcription analysis of IFN-induced genes was first performed in 2003 using peripheral blood from SLE patients, which confirmed that hundreds of genes associated with IFN activation were induced [Baechler, E.C. et al., PNAS 2003, 100(5), 2610-2615, PMID: 12604793], and provided evidence for an IFN gene signature in SLE patients. Thus, the IFN-1 signature reflects IFN-regulated genes, meaning that those genes are upregulated due to the biological activity of type 1 IFN. Subsequent studies have confirmed that between 50% and 80% of SLE patients always have an IFN-1 signature in their blood and that this signature remains stable over time [Northcott, M. et al., Lupus Sci Med 2022, 9, e000625, PMID: 35197305; Kirou, KA. et al., Arthritis Rheumatism, 2004, 50(12), 3958-3967, PMID: 15593221; Oke, V. et al., Arthritis Research Therapy 2019, 21, 107, PMID: 31036046; Psarras, A. et al., Rheumatology 2017, 56, 1662-1675, PMID: 28122959; L. et al., Lupus Sci Med 2019, 6, e000270, PMID: 31497305]. The commonality between all IFN-1 gene signatures lies in the fact that the IFN response components are present in genes induced by IFN signaling.

[0015] Increased IFN signaling has broad and widespread effects on the body, and increased IFN production may be associated with underlying disease manifestations in SLE patients, the major disease manifestations of which are outlined below.

[0016] There is a significant correlation between elevated IFN and SLE-related nephritis [Feng, X. et al., Arthritis Rheumatism 2006, 54 (9), 2951-2962, PMID: 16947629; Kirou, KA. et al., Arthritis Rheumatism, 2005, 52 (5), 1491-1503, PMID: 15880830]. In addition, IFN is also higher in kidney tissue, indicating a close connection between IFN and kidney damage [Castellano, G. et al., Arthritis Research Therapy 2015, 17, 72, PMID: 25889472].

[0017] This evidence clearly indicates that IFN is involved in SLE disease, however, the association of blood IFN signatures with clinical disease features is not limited to any one manifestation. In addition, IFN signatures cannot distinguish between high and low disease activity [Kennedy, WP. et al., Lupus Sci Med 2015, 2, e000080, PMID: 25861459], as defined by various criteria, but can predict subsequent disease severity over time [Mai, L. et al., Arthritis Research Therapy 2021, 23, 29, PMID: 33451338].

[0018] Data on the distribution of high type 1 IFN gene signatures versus low IFN signatures within the general SLE population are somewhat limited, but reports place it in the 60% to 80% range [Psarras, A. et al., Rheumatology 2017, 56, 1662-1675, PMID: 28122959]. An important property of the IFN-1 gene signature is the bimodal distribution in SLE patients, allowing for stratification into high or low IFN-1 gene signature strata [El-Sherbiny, YM. et al., Scientific Reports 2018, 8, 5793, DOI: 10.1038 / s41598-018-24198-1, PMID: 29643425] and was observed in a double-blind, randomized, placebo-controlled phase 2b clinical study in SLE patients (CARE study; Figure 1A). In the high IFN-1 group, reports showed an association with renal disease, low complement C3 and autoantibodies, which is consistent with the molecular function of IFN [Landolt-Marticorena, C. et al., Ann Rheum Dis 2009, 68, 1440-1446, PMID: 18772188; Feng, X. et al., Arthritis Rheumatism 2006, 54 (9), 2951-2962, PMID: 16947629; Kirou, KA. et al., Arthritis Rheumatism, 2005, 52 (5), 1491-1503, PMID: 15880830]. In a longitudinal study, patients with high type 1 interferon (IFN-1) gene signature scores ("high IFN-1 patients") were more likely to receive higher immunosuppressive agents and glucocorticoids than low IFN-1 patients (75% vs. 50%), were younger, and were of Asian descent [Northcott, M. et al., Lupus Sci Med 2022, 9, e000625, PMID: 35197305]. The effects of glucocorticoids on IFN gene expression were evaluated in a small cohort of SLE patients. The authors found no effect of glucocorticoid dose on the expression of genes regulated by type 1 interferon. Patients with a high type 1 interferon gene signature had reduced expression of the glucocorticoid gene signature compared to patients with a low type 1 interferon gene signature matched for glucocorticoid dose, suggesting that type 1 interferons inhibit glucocorticoid-stimulated gene expression [Northcott, M. et al., Lancet Rheumatology 2021, 3(5), e357-e370, DOI: 10.1016 / S2665-9913(21)00006-0].

[0019] The prominent role of IFN in SLE has prompted efforts to target this pathway as a means of treating SLE, and it has been investigated in clinical trials. A typical example is anifrolumab, an antibody that targets the IFN-1 receptor. In addition, other potential therapies have been investigated for their potential ability to modulate the IFN-1 gene signature score.

[0020] Phase 3 studies of aniluomab confirmed the suppression of the interferon signature observed in the phase 2 trial in patients with high baseline IFN-1, but the association of this effect with clinical efficacy was not confirmed. In TULIP 1, the efficacy of aniluomab (placebo adjusted) as measured by the (SLE) response index (SRI-4) [Furie, R. et al. Arthritis Rheumatism 2009, 61(9), 1143-1151, PMID: 19714615] was modest, i.e., 6 percentage points, in patients with high baseline IFN-1. In TULIP 2, the efficacy of aniluomab (placebo adjusted) as measured by the SRI-4 was numerically higher in patients with high baseline IFN-1 than in patients with low IFN-1, i.e., 17.3 and 11.2 percentage points, respectively. The authors of the TULIP 2 manuscript stated that due to the small number of patients with low IFN-1 (30 patients with low IFN-1 vs. 150 patients with high IFN-1, 17%), the effect of aniluomab in such patients requires further analysis. The pooled phase 3 studies TULIP 1 and 2 allowed for a larger sample size to be compared in the low IFN-1 group (i.e., 122 patients with low IFN-1 treated with 300 mg or placebo, vs. 60 and 62 patients, respectively) [Vital, EM. et al., Ann Rheum Dis 2022, 81, 951-961, PMID: 35338035]. There was no treatment effect of SRI-4 in the low IFN-1 group (45.2% and 45.3% for 300 mg anirumab and placebo, respectively), whereas a weak effect of 9 percentage points was observed for BICLA (46.8% and 37.5% for 300 mg anirumab and placebo, respectively).

[0021] The FDA analysis of the NDA for anirumab 150, 300, and 1000 mg concluded that "while neutralization of the IFN-1 gene signature reflects a direct pharmacological effect of anirumab and there was a clear dose-dependent PD response, its clinical relevance remains unclear because nonresponders in the 300 mg group had higher PD responses compared with responders in the 150 mg group" [FDASAPHNELO multi-discipline review, pages 44-47 (CENTER FOR DRUG EVALUATION AND RESEARCH, BLA 761123 Multi-disciplinary Review and Evaluation, Saphnelo (anifrolumab-fnia) for adults with SLE, version date: October 12, 2018)]. This was based on the FDA analysis of PD response (neutralization of the type 1 gene signature and responder / nonresponder analyses of SRI-4 and BICLA).

[0022] In summary, while the AZ indicates that further studies are needed to investigate the efficacy differences between the high IFN-1 population and the low IFN-1 population, the FDA gave a broader SLE population-specific indication. This suggests that it is not clear that by specifically targeting the type 1 IFN pathway, there is benefit only in high IFN patients and also in low IFN patients. Conversely, it is not clear that by targeting mechanisms not directly related to regulating the type 1 interferon pathway, one would expect to see a beneficial effect only in high IFN SLE patients and not in low IFN patients, which is exactly what was observed with siponimod ( Figure 1 c).

[0023] Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros and Aiolos. Aiolos is a B cell regulatory factor and is required for plasma cell maturation. Ikaros is required for the development of B cells and plasmacytoid pDCs, which are important producers of IFN-α [Lipsky, PE. et al., Ann Rheum Dis 2022, 81, 1136-1142, PMID: 35477518].

[0024] In the Phase 2 study, 179 of 288 patients (62%) had high baseline IFN-1 relative to placebo at doses of 0.15, 0.30, and 0.45 mg of ipomitamide. This trial was not stratified by genetic characteristics at baseline, with the highest proportion of high IFN-1 in the 0.45 mg group (70%) and the lowest in the placebo group (58%) [Merrill, JT. et al., NEngl J Med 2022, 386, 1034-1045, PMID: 35294813].

[0025] At week 24, 44 of 81 patients (54%) receiving the 0.45-mg dose of ipomitamide had a maximum SRI-4 response (primary endpoint), and 29 of 83 patients (35%) receiving placebo had a maximum SRI-4 response (adjusted difference, 19.4 percentage points). There were no significant differences between ipomitamide and placebo on most secondary endpoints. Among patients with high IFN-1 status, 34 of 57 patients (60%) in the 0.45-mg ipomitamide group had a response, compared with 16 of 48 patients (33%) in the placebo group. Even though exploratory analyses indicated that the highest cut point in the IFN-1 subgroup (representing 31% of the total study population) was associated with the greatest enhancement of response, with a treatment difference of 54 percentage points compared with placebo (5 of 27 patients (20.0%) vs. 17 of 23 patients (74%)) [Lipsky, PE. et al., Ann Rheum Dis 2022, 81, 1136-1142, PMID: 35477518], 10 of 24 patients (42%) in low IFN-1 status responded to 0.45 mg of ipomitamide. Analysis of biomarker changes showed that stage 2 SLE patients with high IFN-1 status at baseline showed a significant reduction in IFN signature due to active treatment, while patients with low baseline IFN signature did not [Lipsky, PE. et al., Ann Rheum Dis 2022, 81, 1136-1142, PMID: 35477518]. Ipomitamide treatment was associated with a significant, dose-dependent reduction in pDCs and mDCs, which are considered the main source of type 1 IFN.

[0026] Rontalizumab, although targeting the IFN-1 pathway, was found to be more effective in patients with low IFN-1 (Kalunian, K. et al., Ann Rheum Dis 2016, 75, 196-202, PMID: 26038091). This further highlights the complexity of identifying responding patient subgroups.

[0027] Sifalimumab is a fully human immunoglobulin G1κ monoclonal antibody that binds and neutralizes most IFN-α subtypes. Sifalimumab was developed by AstraZeneca, and its development was stopped by the emergence of aniluomab. Early clinical trials of sifalimumab have determined its inhibition of IFN-α-induced genes and have shown favorable effects on clinical outcome measures [Petri, M. et al., Arthritis Rheumatism 2013, 65(4), 1011-1021, PMID: 23400715].

[0028] Although the IFN pathway and its association with SLE have been extensively studied, the association of S1P1 receptor regulation with IFN signaling has not been fully explored to date. Early evidence of an association between IFNα and S1P1 was published in 2006 (Shiow, L. et al., Nature 2006, 440, 540-544, PMID: 16525420). It was reported here that mice treated with poly(I:C), a double-stranded RNA mimetic that induces IFN signaling, caused CD69 regulation and subsequently inhibited lymphocyte extravasation from lymph nodes via downregulation of the S1P1 signaling pathway. This suggests that IFN signaling can regulate S1P1-mediated lymphocyte migration. Teijaro (Teijaro, JR. et al., PNAS 2016, 113 (5), 1351-1356, PMID: 26787880) further reported that 1-phosphate sphingosine (S1P)-S1PR1 signaling in plasmacytoid dendritic cells (pDCs) directly inhibits IFN-α autoamplification by inducing degradation of the interferon α receptor 1 (IFNAR1) receptor, again indicating that S1P1 receptor modulators can cause a reduction in IFN-mediated signaling. However, it has been reported that in a mouse model of influenza, S1P1 receptor signaling on lung endothelial cells in vivo attenuates but does not eliminate IFN-α production [Teijaro, JR. et al., Cell 2011, 146 (6), 980-991, PMID: 21925319].

[0029] Strasser et al. recently investigated the potential role of S1P modulators in regulating IFN-related proteins in the context of SLE. In the MRL / lpr mouse model of SLE, peripheral lymphocyte reduction and improved survival confirmed the efficacy of S1P modulators. In addition, a small exploratory study was conducted involving 13 patients diagnosed with SLE who were treated with siponimod for 12 weeks. Large heterogeneity of IFN-related biomarkers was observed between patients in the study, and siponimod treatment resulted in a trend towards a decrease in IFN-related biomarkers [Strasser, DS et al., RMD Open 2020, 6, e001261, PMID: 32917831].

[0030] Together, these data suggest a complex and paradoxical interplay between IFN-1 and S1P1 signaling pathways in the context of disease. Previously, there was no evidence that S1P1 modulation could improve health outcomes in SLE patients, who in particular exhibited a high IFN-1 gene signature and elevated IFN-related proteins as measured by mSLEDAI-2K. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 exhibit: A) Histogram showing the distribution of type 1 IFN gene signature scores at baseline in the CARE study for the combined placebo and 4 mg siponimod groups. Clearly visible is a bimodal distribution. The gray line depicts the cutoff between low IFN-1 and high IFN-1 at -0.5. B) Box plots depicting individual (high IFN-1) patients (represented as dots) in the placebo and 4 mg siponimod treatment groups in the CARE study at baseline and at month 6 of treatment, showing the type 1 IFN gene signature score (IFN-1 score) for each individual measured by blood. In the box plots, the minimum and maximum ranges are indicated. A decrease in the mean IFN-1 score was observed in the 4 mg siponimod group after 6 months compared to baseline, while in the placebo group, minimal differences in the mean values ​​were observed within 6 months. C) shows a graph of the least square (LS) mean change of modified SLEDAI-2K (mSLEDAI-2K) from baseline to 6 months. The upper figure shows patients classified as high IFN-1 at baseline, and compares placebo with 4 mg siponimod for up to 6 months. The lower figure shows patients classified as low IFN-1 at baseline, and compares placebo with 4 mg siponimod. In the low IFN-1 group, no difference was observed between the mSLEDAI-2K of placebo and 4 mg siponimod at 6 months. In the high IFN-1 group, it was observed that there was a significant difference between 4 mg siponimod and placebo at 6 months compared to the decline observed at baseline. Figure 2 exhibit: Effect of placebo and 4 mg siponimod on blood lymphocyte counts during the 6-month treatment period. Mean changes in lymphocyte counts from baseline are shown. Placebo did not reduce blood lymphocyte counts, while rapid and sustained reductions were observed in both high IFN-1 and low IFN-1 patient subgroups treated with 4 mg siponimod. Figure 3 exhibit: A) Box plots depicting individual patients (represented as dots) in the placebo and 4 mg siponimod treatment groups in the CARE study at baseline and at month 6 of treatment, showing the amount of IFNα protein measured by plasma for each individual (in pg / ml). In the box plots, the minimum and maximum ranges are indicated. A decrease in the mean IFNα protein in the 4 mg siponimod group was observed after 6 months compared to baseline, while in the placebo group, a slight increase in the mean was observed within 6 months. B) IFNα protein in plasma (in pg / ml) of the healthy volunteer group (control) and the placebo and 4 mg siponimod groups in the CARE study at baseline, depicted in the form of a box plot. Individual patients are represented as dots. 95% of the healthy volunteers had values ​​below 0.1 pg / ml and are represented by the line shown. This marks the dividing point between high and low. The patient group had higher IFNα protein levels compared to the healthy volunteer group. C) The difference in mSLEDAI-2K values ​​at 6 months compared to baseline for the placebo and 4 mg siponimod groups in the CARE study is depicted in the form of a box plot. The placebo and 4 mg siponimod groups were divided into low IFNα and high IFNα groups based on their IFNα measurements at baseline. The reduction in mSLEDAI-2K scores (i.e., improvement in clinical readings) was similar for the placebo and 4 mg siponimod low IFNα protein groups. The mSLEDAI-2K reduction in the placebo high IFN group was less. However, when compared with the other 3 groups, the 4 mg siponimod high IFNα protein group showed a significant reduction in mSLEDAI-2K. Figure 4 exhibit: A) Box plots depicting individual patients (represented as dots) in the placebo and 4 mg siponimod treatment groups in the CARE study at baseline and at month 6 of treatment, showing the amount of IFNγ protein measured by plasma for each individual (in pg / ml). In the box plots, the minimum and maximum ranges are indicated. A decrease in the mean IFNγ protein in the 4 mg siponimod group was observed between baseline and after 6 months of treatment, while in the placebo group, a slight increase in the mean was observed within 6 months. B) IFNγ protein in plasma (in pg / ml) of the healthy volunteer group (control) and the placebo and 4 mg siponimod groups in the CARE study at baseline, depicted in the form of a box plot. Individual patients are represented as dots. 95% of the healthy volunteers had values ​​below 9.5 pg / ml and are represented by the line shown. This marks the dividing point between high and low. The patient group had higher IFNγ protein levels compared to the healthy volunteer group. C) The difference in mSLEDAI-2K values ​​at 6 months compared to baseline for the placebo and 4 mg siponimod groups in the CARE study is depicted in the form of a box plot. The placebo and 4 mg siponimod groups were divided into low IFNγ and high IFNγ groups based on their IFNγ measurements at baseline. The reduction in mSLEDAI-2K scores (i.e., improvement in clinical readings) was similar for the placebo and 4 mg siponimod low IFNγ protein groups. The mSLEDAI-2K reduction in the placebo high IFNγ group was less. However, when compared with the other 3 groups, the 4 mg siponimod high IFNγ group showed a significant reduction in mSLEDAI-2K. Figure 5 exhibit: A significant correlation was observed between plasma IFN-α levels and blood IFN-1 gene expression scores (A). Treatment with 4 mg siponimod for 6 months reduced IFN-1 gene expression scores in patients with high and low IFN-1 states. In contrast, treatment with placebo for 6 months actually increased IFN-1 gene expression scores in patients with high and low IFN-1 states (B). DETAILED DESCRIPTION

[0032] Various embodiments of the present invention are presented below:

[0033] 1) The first embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof, which is used for preventing or treating (especially treating) a type 1 interferon-mediated disease in a subject, wherein the subject has a high type 1 interferon (IFN-1) gene signature score.

[0034] In the context of "a subject having a high type 1 interferon (IFN-1) gene signature score", the term "having" refers to a subject having and / or identified as having and / or diagnosed as having a high type 1 interferon (IFN-1) gene signature score.

[0035] 2) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in embodiment 1), wherein the subject has a high type 1 interferon (IFN-1) gene signature score at the start of treatment.

[0036] 3) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof as used in any one of embodiments 1) or 2), wherein the type 1 interferon gene signature score is calculated based on any one of the following type 1 interferon-related gene groups: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) IFI6, RSAD2, IFI44, IFI44L and IFI27; or d) IFI6, RSAD2, IFI44 and IFI44L; or e) IFI6, RSAD2, IFI44L and IFI27; or f) IFI6, RSAD2, IFI44 and IFI27; or g) RSAD2, IFI44, IFI44L and IFI27; or h) IFI6, IFI44, IFI44L and IFI27; or i) IFI6, MX1, IFIT1 and HERC5; or j) EIF2AK2, MX1 and IFIT1; or k) EIF2AK2, IFI44 and IFIT1; or l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0037] Group a) is disclosed in WO 2020 / 084591; Group b) is disclosed in WO 2022 / 074123 and Yao Y et al. Human Genomics and Proteomics 2009; Article ID 374312, DOI: 10.4061 / 2009 / 374312; Groups c) to h) are disclosed in WO 2011 / 028933 and Furie R et al. Arthritis & Rheumatology 2017; 69(2)376-386; Group i) is disclosed in Westra HJ et al. Nature Genetics 2013; 45(10)1238-1243, DOI: 10.1038 / ng.2756; Group j) is disclosed in Niewold, T et al. Genes and Immunity 2007; 8 492-502, DOI: 10.1038 / sj.gene.6364408; Group k) is disclosed in Kirou, K. et al. Arthritis & Rheum. 2005; 52(5)1491-1503; and Groups l) and m) are disclosed in Northcott M et al. Lupus Science & Medicine 2022; 9:e000625; DOI: 10.1136 / lupus-2021-000625.

[0038] 4) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof as used in any one of embodiments 1) or 2), wherein the type 1 interferon gene signature score is calculated based on any one of the following type 1 interferon-related gene groups: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) RSAD2, IFI44, IFI44L and IFI27; or d) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or e) RSAD2, IFI27, IFIT1 and HERC5.

[0039] 5) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof as used in any one of embodiments 1) or 2), wherein the type 1 interferon gene signature score is calculated based on any one of the following type 1 interferon-related gene groups: a) RSAD2, IFI44, IFI44L and IFI27; or b) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or c) RSAD2, IFI27, IFIT1 and HERC5.

[0040] 6) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof as used in any one of embodiments 1) or 2), wherein the type 1 interferon gene signature score is calculated based on any one of the following type 1 interferon-related gene groups: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

[0041] 7) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof as used in any one of embodiments 1) or 2), wherein the type 1 interferon gene signature score is calculated based on the type 1 interferon-related genes EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15.

[0042] 8) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof as used in any one of embodiments 1) or 2), wherein the type 1 interferon gene signature score is calculated based on the type 1 interferon-related genes RSAD2, IFI27, IFIT1 and HERC5.

[0043] The subject's type 1 interferon gene signature score can be calculated according to any of the methods given in the following documents: WO2011 / 028933; WO 2020 / 084591; Furie R et al. Arthritis & Rheumatology 2017; 69(2)376-386; or Northcott M et al. Lupus Science & Medicine 2022; 9: e000625; DOI: 10.1136 / lupus-2021-000625. Northcott et al. particularly describe a method for calculating a subject's IFN-1 gene signature score based on four genes RSAD2, IFI27, IFIT1 and HERC5, and further disclose that the IFN-1 gene signature score cutoff value between subjects with low and high IFN-1 gene signature scores is -0.5. Northcott et al. further mention an IFN-1 test that can be purchased from DxTerity Diagnostics Inc. In particular, the type 1 interferon gene signature score of a subject can be calculated by a method originally developed by DxTerity Diagnostics Inc. by the following steps: (i) measuring the gene (RNA) expression levels of type 1 interferon-related genes RSAD2, IFI27, IFIT1 and HERC5 in a blood sample of the subject (e.g., by measuring the corresponding peak heights in a capillary electropherogram); (ii) measuring the gene expression levels of three housekeeping (normalization) genes ACTB, GAPDH and TFRC in a blood sample of the subject; (iii) calculating the binary logarithm (log2) of the expression level of each of the three housekeeping genes and the arithmetic mean thereof; (iv) calculating the normalized expression of each of the four type 1 interferon-related genes according to formula (I); and (v) calculating the type 1 interferon gene signature score by averaging the normalized expression values ​​of the four type 1 interferon-related genes. Gene i standardized expression = Log2(gene i height)-average(Log2(standardized gene height)) Formula (I)

[0044] An important characteristic of the IFN-1 gene signature is the bimodal distribution in subjects with systemic lupus erythematosus (SLE), allowing for separation into subjects with high type 1 interferon (IFN-1) gene signature scores (high IFN-1 subjects) and subjects with low scores (low IFN-1 subjects) [El-Sherbiny, YM. et al., Scientific Reports 2018, 8, 5793, DOI: 10.1038 / s41598-018-24198-1, PMID: 29643425]. Subjects with high IFN-1 gene signature scores can be defined as subjects with IFN-1 gene signature scores above a threshold (or "cutoff value"); subjects with low IFN-1 gene signature scores can be defined as subjects with IFN-1 gene signature scores equal to or below the threshold. Threshold or critical value can be defined according to any method known in the art (e.g., WO 2011 / 028933 or Northcott M et al. Lupus Science & Medicine 2022; 9: e000625; DOI: 10.1136 / lupus-2021-000625). In particular, the threshold / critical value can be defined relative to the IFN-1 gene feature score of healthy humans: for example, the threshold / critical value can be any IFN-1 gene feature score value that is 1.8 to 4.0 (particularly 2.0 to 3.0) standard deviations higher than the arithmetic mean of at least 20 (particularly at least 200) healthy humans. It is noteworthy that the threshold / critical value of the IFN-1 gene feature score can be defined as 2 standard deviations higher than the arithmetic mean of at least 100 (particularly at least 300) healthy humans. It is noteworthy that the IFN-1 gene signature score of the subject (especially the patient) and the IFN-1 gene signature score of the healthy human (used to determine the cut-off value) are calculated using the same IFN-1 gene signature score determination method.

[0045] Abedi et al. (DxTerity) compared the relative efficacy of four different IFN gene signatures in a group of 687 participants who self-reported having systemic lupus erythematosus (SLE). The commonly used 4-gene IFN signature of IFI27, IFI44, IFI44L, and RSAD2 identified 36.5% of participants as high IFN and 63.5% of participants as low IFN. Three other literature-reported IFN signatures (IFI6, MX1, IFIT1, and HERC5; EIF2AK2, MX1, and IFIT1; and EIF2AK2, IFI44, and IFIT1) provided similar classification results, with participants assigned to the same IFN subgroup (high IFN / low IFN) more than 90% of the time and with almost identical patient distributions; all four IFN gene signatures produced a similar bimodal IFN-1 gene signature score distribution as the 4 genes RSAD2, IFI27, IFIT1, and HERC5, and are shown in Figure 1 A (Abedi M et al. Annals of the Rheumatic Diseases 2018; 77 (Suppl 2: EULAR 2018 Abstracts) 885-886 (#SAT0041), DOI: 10.1136 / annrheumdis-2018-eular.3758, and corresponding poster: Abedi M, Comparison Of Different Type 1 IFN Signatures Demonstrates Concordance In A Real World, Home Monitored Systemic Lupus Erythematosus Cohort, EULAR 2018, Poster #SAT0041).

[0046] 9) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 8), wherein the subject's type 1 interferon gene signature score is equal to or higher than the minimum value of the bimodal distribution curve of the type 1 interferon gene signature score of SLE patients.

[0047] The minimum of the bimodal distribution curve can be obtained by determining the number of SLE patients with a given Type 1 interferon gene signature score that changes with the Type 1 interferon gene signature score. The bimodal distribution curve can be based on the Type 1 interferon gene signature scores of at least 50, at least 100, at least 200 or (preferably) at least 300 SLE patients. The bimodal distribution curve can be obtained from current data (e.g., data collected within 1 year) and / or historical data (e.g., data collected 1 year ago) about the Type 1 interferon gene signature score of SLE patients.

[0048] 10) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in Example 9), wherein the subject's type 1 interferon gene signature score is at least 0.5 unit, at least 1 unit, at least 2 units or at least 3 units (especially at least 1 unit) higher than the minimum value of the bimodal distribution curve of the type 1 interferon gene signature score of SLE patients.

[0049] 11) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 8), wherein the subject has a Type 1 interferon gene signature score that is higher than that of a (representative) healthy subject.

[0050] 12) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 8), wherein the subject's type 1 interferon gene signature score is higher than a threshold value.

[0051] 13) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in embodiment 12), wherein the threshold value is an IFN-1 gene signature score value selected from the following: a value that is 1.8 to 4.0 (i.e., 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0; especially 2.0 to 3.0, and particularly 2.0 to 2.5) standard deviations higher than the arithmetic mean of the IFN-1 gene signature score values ​​of at least 20, at least 50, at least 100, at least 200, at least 300, or (preferably) at least 500 healthy humans.

[0052] 14) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in embodiment 12), wherein the threshold of the IFN-1 gene signature score is 2 standard deviations higher than the arithmetic mean of at least 100, at least 200, at least 300, or (preferably) at least 500 healthy humans.

[0053] 15) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in embodiment 12), wherein the threshold value of the IFN-1 gene signature score is between -1.0 and 0 (especially about -0.5).

[0054] 16) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof as used in embodiment 12), wherein the threshold value of the IFN-1 gene signature score is -0.5.

[0055] 17) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 16), wherein the subject's type 1 interferon gene signature score is calculated (determined) by a method comprising the following steps: (i) measuring the gene (RNA) expression level of type 1 interferon-related genes (especially RSAD2, IFI44, IFI44L and IFI27; or RSAD2, IFI27, IFIT1 and HERC5; and especially RSAD2, IFI27, IFIT1 and HERC5) in a blood sample of a subject (especially measuring the corresponding peak height by capillary electrophoresis); (ii) measuring the gene expression levels of three housekeeping (normalization) genes ACTB, GAPDH and TFRC in the blood sample of the subject; (iii) calculating the binary logarithm (log2) of the expression level of each of the three housekeeping genes and its arithmetic mean; (iv) calculating the normalized expression of each of these type 1 interferon-related genes according to formula (I): Gene i standardized expression = Log2(gene i height)-average(Log2(standardized gene height)) Formula (I) and (v) calculating the Type 1 interferon gene signature score by averaging the normalized expression values ​​of the Type 1 interferon-related genes.

[0056] 18) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 3) to 16), wherein the subject's type 1 interferon gene signature score is calculated (determined) by a method comprising the following steps: (i) measuring the gene (RNA) expression level of type 1 interferon-related genes (especially RSAD2, IFI44, IFI44L and IFI27; or RSAD2, IFI27, IFIT1 and HERC5; and especially RSAD2, IFI27, IFIT1 and HERC5) in a blood sample of a subject (especially measuring the corresponding peak height by capillary electrophoresis); (ii) measuring the gene expression levels of three housekeeping (normalization) genes ACTB, GAPDH and TFRC in the blood sample of the subject; (iii) calculating the binary logarithm (log2) of the expression level of each of the three housekeeping genes and its arithmetic mean; (iv) calculating the normalized expression of each of the four type 1 interferon-related genes according to formula (I): Gene i standardized expression = Log2(gene i height)-average(Log2(standardized gene height)) Formula (I) and (v) calculating the Type 1 interferon gene signature score by averaging the normalized expression values ​​of the four Type 1 interferon-related genes.

[0057] 19) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof, for use in a method for preventing or treating (especially treating) a subject suffering from a type 1 interferon-mediated disease (especially a type 1 interferon-mediated disease responsive to treatment with the S1P1 receptor modulator), the method comprising: a) providing a biological sample (particularly a blood sample or a serum sample, and in particular a blood sample) from the subject; b) analyzing the gene expression of at least three (especially at least four) type 1 interferon-related genes selected from the group consisting of: DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DN in the biological sample. APTP6 (particularly IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6, and in particular EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15); c) determining the normalized expression value of each detected gene; d) calculating the type 1 interferon gene signature score by averaging these normalized expression values; and e) when the Type 1 interferon gene signature score of the subject is above a threshold, treating the subject with the S1P1 receptor modulator.

[0058] 20) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use as described in Example 19), wherein the subject has a Type 1 interferon gene signature score higher than a threshold at the start of treatment and / or has a Type 1 interferon gene signature score higher than the Type 1 interferon gene signature score in a biological sample from a healthy subject at the start of treatment.

[0059] In particular, the subject has a type 1 interferon gene signature score that is higher than a threshold at the start of treatment.

[0060] 21) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) or 20), wherein the biological sample is a blood sample.

[0061] 22) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 21), wherein one of the following group of type 1 interferon-related genes is selected for analysis of gene expression: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) IFI6, RSAD2, IFI44, IFI44L and IFI27; or d) IFI6, RSAD2, IFI44 and IFI44L; or e) IFI6, RSAD2, IFI44L and IFI27; or f) IFI6, RSAD2, IFI44 and IFI27; or g) RSAD2, IFI44, IFI44L and IFI27; or h) IFI6, IFI44, IFI44L and IFI27; or i) IFI6, MX1, IFIT1 and HERC5; or j) EIF2AK2, MX1 and IFIT1; or k) EIF2AK2, IFI44 and IFIT1; or l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0062] 23) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 21), wherein one of the following group of type 1 interferon-related genes is selected for analysis of gene expression: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) RSAD2, IFI44, IFI44L and IFI27; or d) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or e) RSAD2, IFI27, IFIT1 and HERC5.

[0063] 24) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 21), wherein one of the following group of type 1 interferon-related genes is selected for analysis of gene expression: a) RSAD2, IFI44, IFI44L and IFI27; or b) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or c) RSAD2, IFI27, IFIT1 and HERC5.

[0064] 25) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 21), wherein one of the following group of type 1 interferon-related genes is selected for analysis of gene expression: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

[0065] 26) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 21), wherein the type 1 interferon-related genes used for analyzing gene expression are EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15.

[0066] 27) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 21), wherein the type 1 interferon-related genes used for analyzing gene expression are RSAD2, IFI27, IFIT1 and HERC5.

[0067] 28) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 27), wherein gene expression is analyzed by capillary electrophoresis (especially capillary electrophoresis suitable for nucleotide analysis).

[0068] 29) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 27), wherein the gene expression of these type 1 interferon-related genes is analyzed by measuring the peak height in the capillary electrophoresis pattern.

[0069] 30) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 29), wherein the standardized expression values ​​are determined by the following steps: (i) measuring the gene expression levels of three housekeeping (normalization) genes ACTB, GAPDH and TFRC in the subject's blood sample; (ii) calculating the binary logarithm (log2) of the expression level of each of the three housekeeping genes and its arithmetic mean; and (iii) calculating the standardized expression value of each of the type 1 interferon-related genes according to formula (II): Gene i standardized expression = Log2 (gene i expression level) - average (Log2 (normalized gene expression level)) Formula (II).

[0070] In a preferred embodiment, the normalized expression value is calculated based on the peak height of the corresponding gene (especially the peak height in the capillary electropherogram) by using formula (I).

[0071] 31) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 30), wherein the subject's type 1 interferon gene signature score is equal to or higher than the minimum value of the bimodal distribution curve of the type 1 interferon gene signature score of SLE patients.

[0072] The minimum of the bimodal distribution curve can be obtained by determining the number of SLE patients with a given Type 1 interferon gene signature score that changes with the Type 1 interferon gene signature score. The bimodal distribution curve can be based on the Type 1 interferon gene signature scores of at least 50, at least 100, at least 200 or (preferably) at least 300 SLE patients. The bimodal distribution curve can be obtained from current data (e.g., data collected within 1 year) and / or historical data (e.g., data collected 1 year ago) about the Type 1 interferon gene signature score of SLE patients.

[0073] 32) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use as described in Example 31), wherein the subject's type 1 interferon gene signature score is at least 0.5 unit, at least 1 unit, at least 2 units or at least 3 units (especially at least 1 unit) higher than the minimum value of the bimodal distribution curve of the type 1 interferon gene signature score of SLE patients.

[0074] 33) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 30), wherein the threshold value is an IFN-1 gene signature score value selected from the following: a value that is 1.8 to 4.0 (i.e., 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0; especially 2.0 to 3.0, and particularly 2.0 to 2.5) standard deviations higher than the arithmetic mean of the IFN-1 gene signature score values ​​of at least 20, at least 50, at least 100, at least 200, at least 300, or (preferably) at least 500 healthy humans.

[0075] 34) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 30), wherein the threshold of the IFN-1 gene signature score is 2 standard deviations higher than the arithmetic mean of at least 100, at least 200, at least 300, or (preferably) at least 500 healthy humans.

[0076] 35) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 19) to 30), wherein the threshold value of the IFN-1 gene signature score is a value selected from between -1.0 and 0 (especially about -0.5, and in particular -0.5).

[0077] 36) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof as used in embodiment 35), wherein the threshold value of the IFN-1 gene signature score is -0.5.

[0078] 37) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof, for use in a method for preventing or treating (especially treating) a subject suffering from a type 1 interferon-mediated disease (especially a type 1 interferon-mediated disease responsive to treatment with the S1P1 receptor modulator), the method comprising: a) providing a biological sample (particularly a blood sample or a serum sample, and in particular a blood sample) from the subject; b) analyzing the gene expression of type 1 interferon-related genes RSAD2, IFI27, IFIT1 and HERC5 in the biological sample (especially by measuring the peak height in the capillary electrophoresis pattern); c) determining the standardized expression value of each test gene by the following steps: (i) measuring the gene expression level of three housekeeping (normalization) genes ACTB, GAPDH and TFRC in the biological sample of the subject; (ii) calculating the binary logarithm (log2) of the expression level of each of the three housekeeping genes and its arithmetic mean; and (iii) calculating the standardized expression value of each of the type 1 interferon-related genes according to formula (II): Gene i standardized expression = Log2 (gene i expression level) - average (Log2 (normalized gene expression level)) Formula (II); d) calculating the type 1 interferon gene signature score by averaging these normalized expression values; and e) treating the subject with the S1P1 receptor modulator when the Type 1 interferon gene signature score of the subject is above a threshold, wherein the threshold is a value selected from between -1.0 and 0 (especially -0.5).

[0079] In a preferred embodiment, the normalized expression value is calculated based on the peak height of the corresponding gene by using formula (I).

[0080] 38) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for preventing or treating (especially treating) a type 1 interferon-mediated disease in a subject (especially a type 1 interferon-mediated disease responsive to treatment with the S1P1 receptor modulator), wherein at least three (especially at least four) type 1 interferon-related genes in the subject (especially in a biological sample from the subject) are upregulated, wherein the type 1 interferon-related genes are selected from the group consisting of: DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6 (especially IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6, and in particular EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15).

[0081] The up-regulation of type 1 interferon-related genes in the expression profile of the subject may be up-regulated to any extent relative to a control sample (which may be a sample of a non-disease tissue of the subject or a sample of a healthy individual not suffering from the type 1 interferon-mediated disease), or may be up-regulated to any extent relative to genes whose expression in the subject is not changed by the type 1 interferon-mediated disease (so-called housekeeping genes); in particular, genes whose expression in the subject is not changed by the type 1 interferon-mediated disease may be up-regulated to any extent.

[0082] The extent of up-regulation may be at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 300%, or more of the extent of up-regulation in a control or control sample.

[0083] 39) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in embodiment 38), wherein the type 1 interferon-related genes are upregulated in the subject at the start of treatment.

[0084] 40) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 38) or 39), wherein at least three genes in at least one of the following group of type 1 interferon-related genes are upregulated in the subject: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) IFI6, RSAD2, IFI44, IFI44L and IFI27; or d) IFI6, RSAD2, IFI44 and IFI44L; or e) IFI6, RSAD2, IFI44L and IFI27; or f) IFI6, RSAD2, IFI44 and IFI27; or g) RSAD2, IFI44, IFI44L and IFI27; or h) IFI6, IFI44, IFI44L and IFI27; or i) IFI6, MX1, IFIT1 and HERC5; or j) EIF2AK2, MX1 and IFIT1; or k) EIF2AK2, IFI44 and IFIT1; or l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0085] 41) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 38) or 39), wherein at least three genes of at least one of the following group of type 1 interferon-related genes are upregulated in the subject: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) RSAD2, IFI44, IFI44L and IFI27; or d) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or e) RSAD2, IFI27, IFIT1 and HERC5.

[0086] 42) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 38) or 39), wherein at least three genes of at least one of the following group of type 1 interferon-related genes are upregulated in the subject: a) RSAD2, IFI44, IFI44L and IFI27; or b) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or c) RSAD2, IFI27, IFIT1 and HERC5.

[0087] 43) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 38) or 39), wherein at least three genes of at least one of the following group of type 1 interferon-related genes are upregulated in the subject: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

[0088] 44) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 38) or 39), wherein at least three of the following type 1 interferon-related genes are upregulated in the subject: EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15.

[0089] 45) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof as used in any one of embodiments 38) or 39), wherein at least three of the following type 1 interferon-related genes are upregulated in the subject: RSAD2, IFI27, IFIT1 and HERC5.

[0090] 46) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof, for use in preventing or treating (especially treating) a type 1 interferon-mediated disease in a subject, wherein the interferon-γ (IFN-γ) concentration / level in the subject (especially in the plasma of the subject) is elevated compared to that in a healthy subject.

[0091] For the sake of clarity, "a subject, wherein the concentration / level of interferon-gamma (IFN-γ) in the subject (particularly in the plasma of the subject) is elevated compared to a healthy subject" means a subject having and / or identified as having and / or diagnosed as having (particularly in the plasma of the subject) an elevated concentration / level of interferon-gamma (IFN-γ) compared to a healthy subject.

[0092] In particular, "a subject, wherein the interferon-gamma (IFN-γ) concentration / level in the subject (especially in the plasma of the subject) is elevated compared to a healthy subject" means a subject having and / or identified as having and / or diagnosed as having (especially in the plasma of the subject) a higher interferon-gamma (IFN-γ) concentration / level than that in 95% of healthy volunteers in a statistically representative group of healthy volunteers.

[0093] 47) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in preventing or treating (especially treating) a type 1 interferon-mediated disease in a subject, wherein the subject has an interferon-γ (IFN-γ) concentration / level (especially a concentration / level in plasma) higher than 9.5 pg / mL.

[0094] 48) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof, for use in a method for preventing or treating (especially treating) a subject suffering from a type 1 interferon-mediated disease (who is responsive to treatment with the S1P1 receptor modulator), the method comprising: a) providing a biological sample (especially a plasma sample) from the subject; b) measuring the concentration / level of interferon-γ (IFN-γ) in the biological sample; and c) treating the subject with the S1P1 receptor modulator when the interferon-γ (IFN-γ) concentration / level is elevated compared to the interferon-γ (IFN-γ) concentration / level in a biological sample from a healthy subject and / or is above 9.5 pg / mL.

[0095] 49) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 48), wherein the concentration / level of interferon-α (IFN-α) and / or interferon-γ (IFN-γ) in the subject (especially in the plasma of the subject) is increased compared to that in healthy subjects.

[0096] 50) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 48), wherein the subject has an interferon-α (IFN-α) concentration / level (especially a concentration / level in plasma) higher than 0.1 pg / mL and / or an interferon-γ (IFN-γ) concentration / level higher than 9.5 pg / mL.

[0097] 51) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof, which is used in the method of any one of embodiments 19) to 37), wherein the method further comprises: a) providing a biological sample (especially a plasma sample) from the subject; b) measuring the concentration / level of interferon-α (IFN-α) and / or interferon-γ (IFN-γ) in the biological sample; and c) treating the subject with the S1P1 receptor modulator when the interferon-α (IFN-α) and / or interferon-γ (IFN-γ) concentration / level is elevated compared to the concentration / level in a biological sample from a healthy subject.

[0098] For clarity, treatment of the subject with an S1P1 receptor modulator as in dependent Example 51) requires that two conditions are met: (i) the subject's type 1 interferon gene signature score is above the corresponding threshold; and (ii) the interferon-α (IFN-α) and / or interferon-γ (IFN-γ) concentration / level is elevated compared to the concentration / level in a biological sample from a healthy subject.

[0099] 52) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof, which is used in the method of any one of embodiments 19) to 37), wherein the method further comprises: a) providing a biological sample (especially a plasma sample) from the subject; b) measuring the concentration / level of interferon-α (IFN-α) and / or interferon-γ (IFN-γ) in the biological sample; and c) treating the subject with the S1P1 receptor modulator when the interferon-α (IFN-α) concentration / level is above 0.1 pg / mL and / or when the interferon-γ (IFN-γ) concentration / level is above 9.5 pg / mL.

[0100] For clarity, treatment of the subject with an S1P1 receptor modulator as in dependent Example 52) requires that two conditions are met: (i) the subject's type 1 interferon gene signature score is above the corresponding threshold; and (ii) the interferon-α (IFN-α) concentration / level is above 0.1 pg / mL and / or the interferon-γ (IFN-γ) concentration / level is above 9.5 pg / mL.

[0101] 53) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 52), wherein the S1P1 receptor modulator is selected from fingolimod, ozanimod, siponimod, ponesimod, siponimod, etrasimod, mocravimod and amiselimod or a pharmaceutically acceptable salt thereof (especially selected from ozanimod, siponimod, ponesimod, siponimod, etrasimod, mocravimod and amiselimod or a pharmaceutically acceptable salt thereof, and particularly selected from ozanimod, siponimod, ponesimod, siponimod or a pharmaceutically acceptable salt thereof).

[0102] Fingolimod (also known as FTY720, Gilenya, Tascenso ODT, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol) is an S1P receptor modulator that binds to several S1P receptors. Fingolimod is used as a hydrochloride salt, approved by the US Food & Drug administration for the treatment of relapsing forms of multiple sclerosis, and is available in 0.25 mg and 0.5 mg hard capsules. Alternatively, fingolimod is used as a lauryl sulfate salt, approved by the US Food & Drug administration for the treatment of relapsing forms of multiple sclerosis, and is available in 0.25 mg and 0.5 mg orally disintegrating tablets.

[0103] Ozanide (also known as RPC1063, Zeposia, 5-(3-{(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl}-1,2,4-oxadiazol-5-yl)-2-[(propan-2-yl)oxy]benzonitrile) is a S1P receptor modulator that selectively binds to S1P1 and S1P5 receptors. Ozanide, as its hydrochloride salt, is approved by the U.S. Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis and moderately to severely active ulcerative colitis and is available in capsules of 0.23 mg, 0.46 mg, and 0.92 mg (equivalent to 0.25 mg, 0.5 mg, and 1 mg of ozanide hydrochloride as the free base). The recommended maintenance dose is 0.92 mg taken orally once daily.

[0104] Sipofinmod (also known as BAF312, MAYZENT, 1-[[4-[(1E)-1-[[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino]ethyl]-2-ethylphenyl]methyl]-3-azetidinecarboxylic acid) is a dual modulator of the S1P1 and S1P5 receptors. Sipofinmod is used as the (2E)-2-butenedioate ester (2:1 mixture) and is approved by the U.S. Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis and is available in 0.25 mg, 1 mg, and 2 mg tablets. The recommended maintenance dose is 1 mg (in patients with the CYP2C9*1 / *3 or *2 / *3 genotype) or 2 mg orally once daily.

[0105] Ponesimod (also known as ACT-128800, PONVORY, (2Z,5Z)-5-[3-chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene]-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one) is a selective modulator of S1P1, S1P4, and S1P5 receptors. Ponesimod is approved by the U.S. Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis and is available in tablets of 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and 20 mg. The recommended maintenance dose is 20 mg taken orally once daily.

[0106] Siponimod (also known as ACT-334441, (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol) is a selective S1P1 receptor modulator. Siponimod is being developed for the treatment of systemic lupus erythematosus and is being used in a Phase 2b clinical study in the form of 0.5 mg, 1 mg, 2 mg and 4 mg tablets.

[0107] Etrasimod (also known as APD334, 2-[(3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid) is an oral, once-daily selective modulator of S1P1, S1P4, and S1P5. Etrasimod is being studied for a range of immunoinflammatory diseases, including ulcerative colitis, Crohn's disease, atopic dermatitis, eosinophilic esophagitis, and alopecia areata, and is available in 2 mg tablet form.

[0108] 54) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 52), wherein the S1P1 receptor modulator is selected from ozanimod, sipofunmod, bonecimod and siponimod or a pharmaceutically acceptable salt thereof.

[0109] 55) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 52), wherein the S1P1 receptor modulator is siponimod.

[0110] 56) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in embodiment 55), wherein siponimod is contained in a pharmaceutical dosage form for oral administration (especially a tablet formulation, in particular a film-coated tablet).

[0111] 57) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 55) or 56), wherein siponimod is contained in the pharmaceutical dosage form in a unit dose of 4 mg (especially 4.0 mg).

[0112] As used herein, the term "unit dose" refers to the amount of active pharmaceutical ingredient (especially siponimod) administered and / or to be administered to a subject in a single dose. For example, a unit dose is the amount of active pharmaceutical ingredient (especially siponimod) in a tablet or capsule (especially a tablet) for oral administration, where a single tablet or capsule is administered and / or to be administered to a subject per administration.

[0113] 58) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 55) to 57), wherein siponimod is administered to the patient once a day (once daily) and / or siponimod is administered to the patient once a day (once daily).

[0114] 59) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 55) to 58), wherein siponimod is administered to the subject and / or is administered to the subject for a treatment period of at least 6 months (especially at least 12 months, and in particular at least 60 months).

[0115] As used herein (particularly with respect to siponimod), the term "treatment period" refers to the period between the first day of treatment with an active pharmaceutical ingredient (particularly with respect to siponimod), a pharmaceutical composition and / or a medicament and the last day of uninterrupted treatment thereof, wherein treatment is "uninterrupted" if the treatment is according to a regularly repeated dosing regimen (such as once daily). For example, if siponimod is administered and / or is administered once daily for a treatment period of 6 months, this means that siponimod is administered and / or is administered once every day during the 6-month period.

[0116] 60) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 55) to 59), wherein siponimod is administered to the subject chronically and / or is administered to the subject chronically.

[0117] The term "chronic treatment" (or "chronically") refers to a treatment period starting from the first day of treatment with the respective active pharmaceutical ingredient, in particular siponimod, and ending on the day when further continued treatment of the subject with the active pharmaceutical ingredient is no longer possible or indicated. For example, treatment of the subject with the active pharmaceutical ingredient may no longer be possible or indicated due to reasons such as side effects of the treatment, changes in the subject's health status (need for e.g. another drug), changes in other relevant circumstances in the subject's life, death of the subject, and the like. In particular, the term "chronic treatment" (or "chronic") refers to a treatment period of at least 10 years, starting from the first day of treatment with the respective active pharmaceutical ingredient, in particular siponimod, until further continued treatment of the subject with the active pharmaceutical ingredient is no longer possible or indicated.

[0118] The term "start of treatment" refers to the first day of treatment with the corresponding active pharmaceutical ingredient (especially S1P1 receptor modulator; and in particular siponimod).

[0119] The term "type 1 interferon-mediated disease" means a disease that is associated or correlated with and / or has a common cause (particularly associated with and / or has a common cause) with a high type 1 interferon (IFN-1) gene signature score in at least some subjects suffering from the disease.

[0120] 61) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 60), wherein the type 1 interferon-mediated disease is selected from the group consisting of systemic lupus erythematosus, discoid lupus, lupus nephritis, glomerulonephritis, type I diabetes, inflammatory bowel disease (including Crohn's disease, ulcerative colitis and celiac's disease), multiple sclerosis, autoimmune thyroiditis, scleroderma, psoriasis, primary Sjögren's disease ( disease), systemic sclerosis, rheumatoid arthritis, transplant rejection, dermatomyositis, polymyositis, idiopathic inflammatory myositis, sarcoidosis, Aicardi-Goutières syndrome, vasculitis, Sting-associated vasculopathy of infancy (SAVI), or chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE).

[0121] S1P1 receptor modulators, particularly siponimod, can be administered for the treatment of Type 1 interferon-mediated diseases or prophylactically to reduce the risk of developing Type 1 interferon-mediated diseases and / or delay the onset of symptoms.

[0122] The terms "treat" or "treatment" or "treating" used with reference to a disease means that the subject is cured of the disease; or, although the subject is still affected by the disease, some or all symptoms of the disease are alleviated or eliminated.

[0123] The terms "prevent" or "prevention" or "preventing" (or "prophylaxis" or "prophylactical(ly)") as used with reference to a disease mean a reduction in the risk of developing the disease in a subject and / or a delay in the onset of one or more symptoms of the disease in a subject.

[0124] 62) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 60), wherein the type 1 interferon-mediated disease is systemic lupus erythematosus and / or lupus nephritis.

[0125] 63) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 60), wherein the type 1 interferon-mediated disease is systemic lupus erythematosus.

[0126] 64) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 60), wherein the type 1 interferon-mediated disease is lupus nephritis, cutaneous lupus, or lupus with central nervous system (CNS) expression.

[0127] 65) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 64), wherein after treating the subject (especially a subject with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) is reduced relative to baseline.

[0128] The mSLEDAI-2K score is based on the SLEDAI-2K (Gladman DD et al. J Rheumatol 2002; 29(2) 288-291), which has been modified to exclude leukopenia (Hermann V et al. Lupus Science & Medicine 2019; 6: e000354. DOI: 10.1136 / lupus-2019-000354; ClinicalTrials.gov Identifier: NCT03742037).

[0129] As used herein with respect to a value, score, index or the like (such as a type 1 interferon (IFN-1) gene signature score or mSLEDAI-2K, etc.), the term "baseline" refers to a value, score, index or the like measured, calculated or otherwise determined before initiation of treatment with an active pharmaceutical ingredient (such as an S1P1 receptor modulator or siponimod) (particularly shortly before initiation of treatment, and in particular immediately prior to initiation of treatment).

[0130] 66) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 64), wherein after treating the subject (especially a subject with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) is reduced by at least 2 points relative to baseline.

[0131] 67) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 64), wherein after treating subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, at least 30% of these subjects have a modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) reduced by at least 4 points relative to baseline.

[0132] 68) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in embodiment 67), wherein at least 50% of the subjects have a decrease in mSLEDAI-2K relative to baseline.

[0133] 69) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in embodiment 67), wherein at least 70% of the subjects have a decrease in mSLEDAI-2K relative to baseline.

[0134] 70) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 64), wherein after 12 months of treatment of subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) or placebo, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) of the S1P1 receptor modulator-treated subjects is statistically at least 1 point lower than that of the placebo-treated subjects.

[0135] 71) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 64), wherein after 12 months of treatment of subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) or placebo, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) of the S1P1 receptor modulator-treated subjects is statistically at least 1.5 points lower than that of the placebo-treated subjects.

[0136] 72) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 64), wherein after 12 months of treatment of subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) or placebo, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) of the S1P1 receptor modulator-treated subjects is statistically at least 2 points lower than that of the placebo-treated subjects.

[0137] 73) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 72), wherein after treatment of subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, a SRI-4 response is achieved in at least 30% of these subjects.

[0138] 74) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 72), wherein after treatment of subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, a SRI-4 response is achieved in at least 50% of these subjects.

[0139] 75) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 72), wherein after treatment of subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, a SRI-4 response is achieved in at least 70% of these subjects.

[0140] 76) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 72), wherein after 12 months of treatment of the subjects (especially subjects suffering from SLE), the subjects treated with the S1P1 receptor modulator (especially siponimod) have a higher (especially statistically significantly higher) chance of SRI-4 response than the subjects treated with placebo.

[0141] Response to the SLE Responder Index (SRI)-4 was defined as: - A decrease of at least 4 points from baseline in mSLEDAI-2K; and - No new BILAG A organ domain score and no more than one new BILAG B organ domain score compared to baseline; and - The subject has not had a worsening of lupus disease activity relative to baseline, where worsening is defined as an increase of ≥0.30 points on the 3-point Physician's Global Assessment (PGA) visual analog scale (VAS).

[0142] The BILAG (British Isles Lupus Assessment Group) score is defined in Romero-Diaz J et al. Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11(011):S37-46. DOI: 10.1002 / acr.20572.

[0143] Physician's global assessment (PGA) is a visual analog scale (VAS) (Luijten KMAC et al., Autoimmunity Reviews Vol. 11, No. 5, March 2012, pp. 326-329) that uses 3 benchmarks to assess disease activity over the past 2 weeks. Based on a 0 to 3 point analog scale, mild redness will be scored as 1.0, moderate redness will be scored as 2.0 to 2.5, and severe redness will be scored as 3.

[0144] 77) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof as used in any one of embodiments 1) to 76), wherein the time to first confirmed 4-month sustained mSLEDAI-2K response (defined as a decrease of at least 4 points relative to baseline) in subjects (multiple subjects) treated with the S1P1 receptor modulator (especially siponimod) is shorter (especially statistically significantly shorter) than that in subjects (multiple subjects) treated with placebo.

[0145] 78) Another embodiment of the present invention relates to siponimod or a pharmaceutically acceptable salt thereof as used in any one of Examples 1) to 76), wherein the time from the start of treatment with siponimod to the first confirmation of a 4-month sustained mSLEDAI-2K response (defined as a decrease of at least 4 points relative to baseline) in the subject (multiple subjects) treated with siponimod is statistically significantly shorter than that in the subject (multiple subjects) treated with placebo.

[0146] 79) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 76), wherein the time to the first confirmed 4-month sustained response of mucocutaneous manifestations in subjects (multiple subjects) treated with the S1P1 receptor modulator (especially siponimod) is shorter (especially statistically significantly shorter) than that in subjects (multiple subjects) treated with placebo.

[0147] The time to 4-month sustained response from the first confirmed mucocutaneous manifestation was defined as: - No increase in overall mSLEDAI-2K score; and - Remission of mSLEDAI-2K scores relative to baseline (zero points) for mucocutaneous manifestations (i.e., rash, alopecia, mucosal ulcers).

[0148] 80) Another embodiment of the present invention relates to siponimod or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 76), wherein the time from the start of treatment with siponimod to the 4-month sustained response of the first confirmed mucocutaneous manifestation in the subject (multiple subjects) treated with siponimod is statistically significantly shorter than that in the subject (multiple subjects) treated with placebo.

[0149] 81) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 80), wherein the S1P1 receptor modulator is siponimod or a pharmaceutically acceptable salt thereof, and wherein a clinically proven effective amount of siponimod is administered and / or will be administered to the subject.

[0150] 82) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 81), wherein the subject is a human (especially a human patient).

[0151] The term "subject" includes any human or non-human animal. "Non-human animals" include all vertebrates. In particular, the term "subject" refers to a human, and especially a human patient.

[0152] 83) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 81), wherein the subject is a human patient suffering from a type 1 interferon-mediated disease.

[0153] 84) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 81), wherein the subject is a human patient suffering from systemic lupus erythematosus and / or lupus nephritis.

[0154] 85) Another embodiment of the present invention relates to the S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 81), wherein the subject is a human patient suffering from systemic lupus erythematosus.

[0155] 86) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 81), wherein the subject is a human patient suffering from systemic lupus erythematosus, and wherein the subject has an mSLEDAI-2K score ≥6 and a clinical mSLEDAI-2K score ≥4, of which at least 2 points are scores for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers).

[0156] Clinical mSLEDAI-2K is the mSLEDAI-2K assessment score that excludes scores attributed to hematuria, proteinuria, pyuria, low complement, increased DNA binding, and thrombocytopenia.

[0157] 87) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 1) to 81), wherein the subject is a human patient suffering from systemic lupus erythematosus, and wherein the subject: (i) has an mSLEDAI-2K score ≥6 and a clinical mSLEDAI-2K score ≥4, of which at least 2 points are scores for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers); (ii) has British Isles Lupus Assessment Group-2004 (BILAG) grade B in ≥2 organ systems or BILAG grade A in ≥1 organ system; and (iii) has a Physician Global Assessment (PGA) score ≥1.0 based on a 0 to 3 point VAS.

[0158] 88) Another embodiment of the present invention relates to an S1P1 receptor modulator (especially siponimod) or a pharmaceutically acceptable salt thereof as used in any one of embodiments 1) to 87), wherein the subject is a subject receiving standard background therapy (wherein it should be understood that such standard background therapy is suitable for the treatment of type 1 interferon-mediated diseases, especially systemic lupus erythematosus).

[0159] Standard background therapy for the treatment of systemic lupus erythematosus may be an antimalarial such as hydroxychloroquine, chloroquine or quinacrine; mycophenolate mofetil or mycophenolic acid; azathioprine; methotrexate; oral corticosteroids such as prednisone, prednisolone, hydrocortisone, methylprednisolone or dexamethasone; belimumab; anirumab; or any other drug approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) or the corresponding national regulatory authorities and / or used as standard of care on the day of initiation of treatment with an S1P1 receptor modulator.

[0160] Siponimod can be used as a medicament according to the invention, for example, in the form of a pharmaceutical composition especially for enteral administration or for parenteral administration.

[0161] The dosage form suitable for enteral administration may be a tablet or a capsule (especially a tablet) comprising a pharmaceutical composition containing an effective amount of siponimod or a pharmaceutically acceptable salt thereof.

[0162] For the avoidance of any doubt, it should be understood that any pharmaceutical composition comprising a pharmaceutically effective amount of siponimod may additionally comprise other conventional excipients and / or additives, which may be used alone or in combination.

[0163] Reference is made to the extensive literature of the present invention regarding the pharmaceutically acceptable excipients and procedures referred to herein, see, for example, RC Rowe, PJ Seskey, S C Owen, Handbook of Pharmaceutical Excipients, 5th edition, Pharmaceutical Press 2006; Remington, The Science and Practice of Pharmacy, 21st edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams and Wilkins].

[0164] Any reference to S1P1 receptor modulators in this specification should be understood as also referring to pharmaceutically acceptable salts of such S1P1 receptor modulators. In particular, any reference to siponimod refers to siponimod or a pharmaceutically acceptable salt form of siponimod, preferably to siponimod in free base form.

[0165] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compounds of the invention and exhibits minimal undesired toxicological effects. Depending on the basic and / or acidic groups present in the compounds of the invention, such salts include inorganic or organic acid and / or base addition salts. For references, see, for example, "Handbook of Pharmaceutical Salts. Properties, Selection and Use.", P. Heinrich Stahl, Camille G. Wermuth (ed.), Wiley-VCH, 2008 and "Pharmaceutical Salts and Co-crystals," Johan Wouters and Luc Quéré (ed.), RSC Publishing, 2012.

[0166] Unless used with respect to temperature, the term "about" preceding a numerical value "X" herein refers to an interval extending from X minus 10% X to X plus 10% X, and preferably refers to an interval extending from X minus 5% X to X plus 5% X. In the specific case of temperature, the term "about" preceding a temperature "Y" herein refers to an interval extending from temperature Y minus 10°C to Y plus 10°C, and preferably refers to an interval extending from Y minus 5°C to Y plus 5°C.

[0167] Whenever the word "between" is used to describe a numerical range, it should be understood that the endpoints of the indicated range are specifically included in the range.

[0168] It should be understood that any embodiment related to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for preventing or treating (especially treating) a type 1 interferon-mediated disease also relates to: the use of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing or treating (especially treating) a type 1 interferon-mediated disease; and a method for preventing / prophylaxis or treating (especially treating) a type 1 interferon-mediated disease, the method comprising administering an effective amount (especially a pharmaceutically effective amount) of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0169] It should be further understood that any embodiment related to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof in a method for preventing or treating (especially treating) a subject with a type 1 interferon-mediated disease also relates to: the use of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for preparing a medicament for use in a method for preventing or treating (especially treating) a subject with a type 1 interferon-mediated disease; and a method for preventing or treating (especially treating) a subject with a type 1 interferon-mediated disease, the method comprising administering an effective amount (especially a pharmaceutically effective amount) of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0170] 89) Another embodiment of the present invention relates to a method for preventing or treating (especially treating) a type 1 interferon-mediated disease, the method comprising administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has a high type 1 interferon (IFN-1) gene signature score.

[0171] 90) The method of embodiment 89), wherein the subject has a high type 1 interferon (IFN-1) gene signature score at the start of treatment.

[0172] 91) The method of any one of embodiments 89) or 90), wherein the type 1 interferon gene signature score is calculated based on any one of the following groups of type 1 interferon-related genes: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) IFI6, RSAD2, IFI44, IFI44L and IFI27; or d) IFI6, RSAD2, IFI44 and IFI44L; or e) IFI6, RSAD2, IFI44L and IFI27; or f) IFI6, RSAD2, IFI44 and IFI27; or g) RSAD2, IFI44, IFI44L and IFI27; or h) IFI6, IFI44, IFI44L and IFI27; or i) IFI6, MX1, IFIT1 and HERC5; or j) EIF2AK2, MX1 and IFIT1; or k) EIF2AK2, IFI44 and IFIT1; or l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0173] 92) The method of any one of embodiments 89) or 90), wherein the type 1 interferon gene signature score is calculated based on any one of the following groups of type 1 interferon-related genes: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) RSAD2, IFI44, IFI44L and IFI27; or d) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or e) RSAD2, IFI27, IFIT1 and HERC5.

[0174] 93) The method of any one of embodiments 89) or 90), wherein the type 1 interferon gene signature score is calculated based on any one of the following groups of type 1 interferon-related genes: a) RSAD2, IFI44, IFI44L and IFI27; or b) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or c) RSAD2, IFI27, IFIT1 and HERC5.

[0175] 94) The method of any one of embodiments 89) or 90), wherein the type 1 interferon gene signature score is calculated based on any one of the following groups of type 1 interferon-related genes: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

[0176] 95) A method as described in any one of embodiments 89) or 90), wherein the type 1 interferon gene signature score is calculated based on the type 1 interferon-related genes EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15.

[0177] 96) A method as described in any one of embodiments 89) or 90), wherein the type 1 interferon gene signature score is calculated based on the type 1 interferon-related genes RSAD2, IFI27, IFIT1 and HERC5.

[0178] 97) A method as described in any one of embodiments 89) to 96), wherein the subject's Type 1 interferon gene signature score is equal to or higher than the minimum of the bimodal distribution curve of the Type 1 interferon gene signature scores of SLE patients.

[0179] 98) A method as described in Example 97), wherein the subject's Type 1 interferon gene signature score is at least 0.5 unit, at least 1 unit, at least 2 units or at least 3 units (especially at least 1 unit) higher than the minimum value of the bimodal distribution curve of the Type 1 interferon gene signature score of SLE patients.

[0180] 99) The method of any one of embodiments 89) to 96), wherein the subject has a Type 1 interferon gene signature score that is higher than the Type 1 interferon gene signature score of a (representative) healthy subject.

[0181] 100) The method of any one of embodiments 89) to 96), wherein the subject's type 1 interferon gene signature score is above a threshold.

[0182] 101) A method as described in Example 100), wherein the threshold value is an IFN-1 gene signature score value selected from the following: a value that is 1.8 to 4.0 (i.e., 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0; especially 2.0 to 3.0, and particularly 2.0 to 2.5) standard deviations higher than the arithmetic mean of the IFN-1 gene signature score values ​​of at least 20, at least 50, at least 100, at least 200, at least 300, or (preferably) at least 500 healthy humans.

[0183] 102) The method of embodiment 100), wherein the threshold of the IFN-1 gene signature score is 2 standard deviations higher than the arithmetic mean of at least 100, at least 200, at least 300, or (preferably) at least 500 healthy humans.

[0184] 103) The method of embodiment 100), wherein the threshold of the IFN-1 gene signature score is between -1.0 and 0 (especially about -0.5).

[0185] 104) The method of embodiment 100), wherein the threshold value of the IFN-1 gene signature score is -0.5.

[0186] 105) The method of any one of embodiments 89) to 104), wherein the subject's type 1 interferon gene signature score is calculated (determined) by a method comprising the following steps: (i) measuring the gene (RNA) expression level of type 1 interferon-related genes (especially RSAD2, IFI44, IFI44L and IFI27; or RSAD2, IFI27, IFIT1 and HERC5; and especially RSAD2, IFI27, IFIT1 and HERC5) in a blood sample of a subject (especially measuring the corresponding peak height by capillary electrophoresis); (ii) measuring the gene expression levels of three housekeeping (normalization) genes ACTB, GAPDH and TFRC in the blood sample of the subject; (iii) calculating the binary logarithm (log2) of the expression level of each of the three housekeeping genes and its arithmetic mean; (iv) calculating the normalized expression of each of these type 1 interferon-related genes according to formula (I): Gene i standardized expression = Log2(gene i height)-average(Log2(standardized gene height)) Formula (I) and (v) calculating the Type 1 interferon gene signature score by averaging the normalized expression values ​​of the Type 1 interferon-related genes.

[0187] 106) A method as described in any one of embodiments 91) to 104), wherein the subject's type 1 interferon gene signature score is calculated (determined) by a method comprising the following steps: (i) measuring the gene (RNA) expression level of type 1 interferon-related genes (especially RSAD2, IFI44, IFI44L and IFI27; or RSAD2, IFI27, IFIT1 and HERC5; and especially RSAD2, IFI27, IFIT1 and HERC5) in a blood sample of a subject (especially measuring the corresponding peak height by capillary electrophoresis); (ii) measuring the gene expression levels of three housekeeping (normalization) genes ACTB, GAPDH and TFRC in the blood sample of the subject; (iii) calculating the binary logarithm (log2) of the expression level of each of the three housekeeping genes and its arithmetic mean; (iv) calculating the normalized expression of each of the four type 1 interferon-related genes according to formula (I): Gene i standardized expression = Log2(gene i height)-average(Log2(standardized gene height)) Formula (I) and (v) calculating the Type 1 interferon gene signature score by averaging the normalized expression values ​​of the four Type 1 interferon-related genes.

[0188] 107) Another embodiment of the present invention relates to a method for preventing or treating (especially treating) a type 1 interferon-mediated disease (especially a type 1 interferon-mediated disease responsive to treatment with an S1P1 receptor modulator) in a subject, the method comprising: a) providing a biological sample (particularly a blood sample or a serum sample, and in particular a blood sample) from the subject; b) analyzing the gene expression of at least three (especially at least four) type 1 interferon-related genes selected from the group consisting of: DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DN in the biological sample. APTP6 (particularly IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6, and in particular EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15); c) determining the normalized expression value of each detected gene; d) calculating the type 1 interferon gene signature score by averaging these normalized expression values; and e) when the type 1 interferon gene signature score of the subject is higher than a threshold, administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to the subject in need thereof.

[0189] 108) The method of embodiment 107), wherein the subject has a Type 1 interferon gene signature score higher than a threshold value at the start of treatment and / or has a Type 1 interferon gene signature score higher than the Type 1 interferon gene signature score in a biological sample from a healthy subject at the start of treatment.

[0190] 109) A method as described in any of embodiments 107) or 108), wherein the biological sample is a blood sample.

[0191] 110) The method of any one of embodiments 107) to 109), wherein one of the following groups of type 1 interferon-related genes is selected for analysis of gene expression: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) IFI6, RSAD2, IFI44, IFI44L and IFI27; or d) IFI6, RSAD2, IFI44 and IFI44L; or e) IFI6, RSAD2, IFI44L and IFI27; or f) IFI6, RSAD2, IFI44 and IFI27; or g) RSAD2, IFI44, IFI44L and IFI27; or h) IFI6, IFI44, IFI44L and IFI27; or i) IFI6, MX1, IFIT1 and HERC5; or j) EIF2AK2, MX1 and IFIT1; or k) EIF2AK2, IFI44 and IFIT1; or l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0192] 111) The method of any one of embodiments 107) to 109), wherein one of the following groups of type 1 interferon-related genes is selected for analysis of gene expression: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) RSAD2, IFI44, IFI44L and IFI27; or d) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or e) RSAD2, IFI27, IFIT1 and HERC5.

[0193] 112) The method of any one of embodiments 107) to 109), wherein one of the following groups of type 1 interferon-related genes is selected for analysis of gene expression: a) RSAD2, IFI44, IFI44L and IFI27; or b) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or c) RSAD2, IFI27, IFIT1 and HERC5.

[0194] 113) The method of any one of embodiments 107) to 109), wherein one of the following groups of type 1 interferon-related genes is selected for analysis of gene expression: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

[0195] 114) A method as described in any one of embodiments 107) to 109), wherein the type 1 interferon-related genes used for analyzing gene expression are EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15.

[0196] 115) The method of any one of embodiments 107) to 109), wherein the type 1 interferon-related genes used for analyzing gene expression are RSAD2, IFI27, IFIT1 and HERC5.

[0197] 116) The method of any one of embodiments 107) to 115), wherein gene expression is analyzed by capillary electrophoresis.

[0198] 117) The method of any one of embodiments 107) to 115), wherein the gene expression of these type 1 interferon-related genes is analyzed by measuring the peak height in the capillary electrophoresis pattern.

[0199] 118) A method as described in any one of embodiments 107) to 117), wherein the standardized expression values ​​are determined by the following steps: (i) measuring the gene expression levels of three housekeeping (normalization) genes ACTB, GAPDH and TFRC in the subject's blood sample; (ii) calculating the binary logarithm (log2) of the expression level of each of the three housekeeping genes and its arithmetic mean; and (iii) calculating the standardized expression value of each of the type 1 interferon-related genes according to formula (II): Gene i standardized expression = Log2 (gene i expression level) - average (Log2 (normalized gene expression level)) Formula (II).

[0200] 119) A method as described in any one of embodiments 107) to 118), wherein the subject's Type 1 interferon gene signature score is equal to or higher than the minimum of the bimodal distribution curve of the Type 1 interferon gene signature score of SLE patients.

[0201] 120) A method as described in Example 119), wherein the subject's Type 1 interferon gene signature score is at least 0.5 unit, at least 1 unit, at least 2 units or at least 3 units (especially at least 1 unit) higher than the minimum value of the bimodal distribution curve of the Type 1 interferon gene signature score of SLE patients.

[0202] 121) A method as described in any one of embodiments 107) to 118), wherein the threshold value is an IFN-1 gene signature score value selected from the following: a value that is 1.8 to 4.0 (i.e., 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0; especially 2.0 to 3.0, and in particular 2.0 to 2.5) standard deviations higher than the arithmetic mean of the IFN-1 gene signature scores of at least 20, at least 50, at least 100, at least 200, at least 300, or (preferably) at least 500 healthy humans.

[0203] 122) A method as described in any one of embodiments 107) to 118), wherein the threshold value of the IFN-1 gene signature score is 2 standard deviations higher than the arithmetic mean of at least 100, at least 200, at least 300, or (preferably) at least 500 healthy humans.

[0204] 123) A method as described in any one of embodiments 107) to 118), wherein the threshold value of the IFN-1 gene signature score is selected from a value between -1.0 and 0 (especially about -0.5, and in particular -0.5).

[0205] 124) The method of any one of embodiments 107) to 118), wherein the threshold value of the IFN-1 gene signature score is -0.5.

[0206] 125) Another embodiment of the present invention relates to a method for preventing or treating (especially treating) a type 1 interferon-mediated disease (especially a type 1 interferon-mediated disease responsive to treatment with an S1P1 receptor modulator) in a subject, the method comprising: a) providing a biological sample (particularly a blood sample or a serum sample, and in particular a blood sample) from the subject; b) analyzing the gene expression of type 1 interferon-related genes RSAD2, IFI27, IFIT1 and HERC5 in the biological sample (especially by measuring the peak height in the capillary electrophoresis pattern); c) determining the standardized expression value of each test gene by the following steps: (i) measuring the gene expression level of three housekeeping (normalization) genes ACTB, GAPDH and TFRC in the biological sample of the subject; (ii) calculating the binary logarithm (log2) of the expression level of each of the three housekeeping genes and its arithmetic mean; and (iii) calculating the standardized expression value of each of the type 1 interferon-related genes according to formula (II): Gene i standardized expression = Log2 (gene i expression level) - average (Log2 (normalized gene expression level)) Formula (II); d) calculating the type 1 interferon gene signature score by averaging these normalized expression values; and e) administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to the subject in need thereof when the type 1 interferon gene signature score of the subject is higher than a threshold, wherein the threshold is a value selected from between -1.0 and 0 (especially -0.5).

[0207] 126) Another embodiment of the present invention relates to a method for preventing or treating (especially treating) a type 1 interferon-mediated disease in a subject (especially a type 1 interferon-mediated disease responsive to treatment with an S1P1 receptor modulator), the method comprising administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to the subject in need thereof, wherein at least three (especially at least four) type 1 interferon-related genes are upregulated in the subject (especially in a biological sample from the subject), wherein the type 1 interferon-related genes are selected from the group consisting of: DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6 (especially IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6, and in particular EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15).

[0208] 127) The method of embodiment 126), wherein the type 1 interferon-related genes are upregulated in the subject at the start of treatment.

[0209] 128) The method of any one of embodiments 126) or 127), wherein at least three genes of at least one of the following group of type 1 interferon-related genes are upregulated in the subject: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) IFI6, RSAD2, IFI44, IFI44L and IFI27; or d) IFI6, RSAD2, IFI44 and IFI44L; or e) IFI6, RSAD2, IFI44L and IFI27; or f) IFI6, RSAD2, IFI44 and IFI27; or g) RSAD2, IFI44, IFI44L and IFI27; or h) IFI6, IFI44, IFI44L and IFI27; or i) IFI6, MX1, IFIT1 and HERC5; or j) EIF2AK2, MX1 and IFIT1; or k) EIF2AK2, IFI44 and IFIT1; or l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0210] 129) The method of any one of embodiments 126) or 127), wherein at least three genes of at least one of the following group of type 1 interferon-related genes are upregulated in the subject: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5, and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6; or c) RSAD2, IFI44, IFI44L and IFI27; or d) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or e) RSAD2, IFI27, IFIT1 and HERC5.

[0211] 130) The method of any one of embodiments 126) or 127), wherein at least three genes of at least one of the following group of type 1 interferon-related genes are upregulated in the subject: a) RSAD2, IFI44, IFI44L and IFI27; or b) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; or c) RSAD2, IFI27, IFIT1 and HERC5.

[0212] 131) The method of any one of embodiments 126) or 127), wherein at least three genes of at least one of the following group of type 1 interferon-related genes are upregulated in the subject: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

[0213] 132) The method of any one of embodiments 126) or 127), wherein at least three of the following type 1 interferon-related genes are upregulated in the subject: EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15.

[0214] 133) A method as described in any one of embodiments 126) or 127), wherein at least three of the following type 1 interferon-related genes are upregulated in the subject: RSAD2, IFI27, IFIT1 and HERC5.

[0215] 134) Another embodiment of the present invention relates to a method for preventing or treating (especially treating) a type 1 interferon-mediated disease (especially a type 1 interferon-mediated disease responsive to treatment with an S1P1 receptor modulator) in a subject, the method comprising administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to the subject in need thereof, wherein the interferon-γ (IFN-γ) concentration / level in the subject (especially in the plasma of the subject) is increased compared to that in a healthy subject.

[0216] 135) Another embodiment of the present invention relates to a method for preventing or treating (especially treating) a type 1 interferon-mediated disease (especially a type 1 interferon-mediated disease responsive to treatment with an S1P1 receptor modulator) in a subject, the method comprising administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to the subject in need thereof, wherein the subject has an interferon-γ (IFN-γ) concentration / level (especially a concentration / level in plasma) higher than 9.5 pg / mL.

[0217] 136) Another embodiment of the present invention relates to a method for preventing or treating (especially treating) a type 1 interferon-mediated disease (especially a type 1 interferon-mediated disease responsive to treatment with an S1P1 receptor modulator) in a subject, the method comprising: a) providing a biological sample (especially a plasma sample) from the subject; b) measuring the concentration / level of interferon-γ (IFN-γ) in the biological sample; and c) administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to the subject in need thereof when the interferon-γ (IFN-γ) concentration / level is elevated compared to the interferon-γ (IFN-γ) concentration / level in a biological sample from a healthy subject and / or is above 9.5 pg / mL.

[0218] 137) A method as described in any one of embodiments 89) to 136), wherein the concentration / level of interferon-α (IFN-α) and / or interferon-γ (IFN-γ) in the subject (especially in the plasma of the subject) is increased compared to a healthy subject.

[0219] 138) A method as described in any one of embodiments 89) to 136), wherein the subject has an interferon-α (IFN-α) concentration / level (especially concentration / level in plasma) higher than 0.1 pg / mL and / or an interferon-γ (IFN-γ) concentration / level higher than 9.5 pg / mL.

[0220] 139) The method of any one of embodiments 107) to 125), wherein the method further comprises: a) providing a biological sample (especially a plasma sample) from the subject; b) measuring the concentration / level of interferon-α (IFN-α) and / or interferon-γ (IFN-γ) in the biological sample; and c) when, in addition to another condition, the interferon-α (IFN-α) and / or interferon-γ (IFN-γ) concentration / level is elevated compared to the concentration / level in a biological sample from a healthy subject, administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to the subject in need thereof.

[0221] 140) The method of any one of embodiments 107) to 125), wherein the method further comprises: a) providing a biological sample (especially a plasma sample) from the subject; b) measuring the concentration / level of interferon-α (IFN-α) and / or interferon-γ (IFN-γ) in the biological sample; and c) administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to the subject in need thereof when, in addition to another condition, the interferon-α (IFN-α) concentration / level is higher than 0.1 pg / mL and / or the interferon-γ (IFN-γ) concentration / level is higher than 9.5 pg / mL.

[0222] 141) A method as described in any one of embodiments 89) to 140), wherein the S1P1 receptor modulator is selected from fingolimod, ozanid, sipofinmod, bonecimod, siponimod, edrosimod, moclavimod and amicilimod or a pharmaceutically acceptable salt thereof (especially selected from ozanid, sipofinmod, bonecimod, siponimod, edrosimod, moclavimod and amicilimod or a pharmaceutically acceptable salt thereof, and in particular selected from ozanid, sipofinmod, bonecimod, siponimod or a pharmaceutically acceptable salt thereof).

[0223] 142) The method of any one of embodiments 89) to 140), wherein the S1P1 receptor modulator is selected from ozanide, sipofunmod, bonecimod and siponimod or a pharmaceutically acceptable salt thereof.

[0224] 143) The method of any one of embodiments 89) to 140), wherein the S1P1 receptor modulator is siponimod.

[0225] 144) The method of embodiment 143), wherein siponimod is contained in a pharmaceutical dosage form for oral administration (especially a tablet formulation, in particular a film-coated tablet).

[0226] 145) A method according to any one of embodiments 143) or 144), wherein siponimod is contained in the pharmaceutical dosage form in a unit dose of 4 mg (especially 4.0 mg).

[0227] 146) The method of any one of embodiments 143) to 145), wherein siponimod is administered to the patient once a day (once daily) and / or siponimod is administered to the patient once a day (once daily).

[0228] 147) A method as described in any one of embodiments 143) to 146), wherein siponimod is administered to the subject and / or is administered to the subject for a treatment period of at least 6 months (especially at least 12 months, and in particular at least 60 months).

[0229] 148) Another embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in any one of embodiments 143) to 147), wherein siponimod is administered to the subject chronically and / or is administered to the subject chronically.

[0230] 149) A method as described in any one of embodiments 89) to 148), wherein the type 1 interferon-mediated disease is selected from the group consisting of: systemic lupus erythematosus, discoid lupus, lupus nephritis, glomerulonephritis, type I diabetes, inflammatory bowel disease (including Crohn's disease, ulcerative colitis and celiac disease), multiple sclerosis, autoimmune thyroiditis, scleroderma, psoriasis, primary Sjögren's disease, systemic sclerosis, rheumatoid arthritis, transplant rejection, dermatomyositis, polymyositis, idiopathic inflammatory myositis, sarcoidosis, Aicardi-Guterres syndrome, vasculitis, Sting-associated vasculopathy of infancy (SAVI) or chronic atypical neutrophilic dermatosis with lipid dystrophy and elevated body temperature syndrome (CANDLE).

[0231] 150) The method of any one of embodiments 89) to 148), wherein the type 1 interferon-mediated disease is systemic lupus erythematosus and / or lupus nephritis.

[0232] 151) The method of any one of embodiments 89) to 148), wherein the type 1 interferon-mediated disease is systemic lupus erythematosus.

[0233] 152) The method of any one of embodiments 89) to 148), wherein the type 1 interferon-mediated disease is lupus nephritis, cutaneous lupus, or lupus with central nervous system (CNS) expression.

[0234] 153) A method as described in any one of embodiments 89) to 152), wherein after treating the subject (especially a subject with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) is reduced relative to baseline.

[0235] 154) A method as described in any one of embodiments 89) to 152), wherein after treating the subject (especially a subject with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, the modified systemic lupus erythematosus disease activity index 2000 (mSLEDAI-2K) is reduced by at least 2 points (especially at least 4 points) relative to baseline.

[0236] 155) A method as described in any one of embodiments 89) to 152), wherein after treating subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, at least 30% of these subjects have a modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) reduced by at least 4 points relative to baseline.

[0237] 156) The method of any one of embodiments 153) to 155), wherein at least 50% of the subjects have a decrease in mSLEDAI-2K relative to baseline.

[0238] 157) The method of any one of embodiments 153) to 155), wherein at least 70% of the subjects have a decrease in mSLEDAI-2K relative to baseline.

[0239] 158) A method as described in any one of embodiments 89) to 152), wherein after treating subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) or placebo for 12 months, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) of the subjects treated with the S1P1 receptor modulator is statistically at least 1 point lower than that of the subjects treated with the placebo.

[0240] 159) A method as described in any one of embodiments 89) to 152), wherein after treating subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) or placebo for 12 months, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) of the subjects treated with the S1P1 receptor modulator is statistically at least 1.5 points lower than that of the subjects treated with the placebo.

[0241] 160) A method as described in any one of embodiments 89) to 152), wherein after 12 months of treatment of subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) or placebo, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) of the S1P1 receptor modulator-treated subjects is statistically at least 2 points lower than that of the placebo-treated subjects.

[0242] 161) The method of any one of embodiments 89) to 160), wherein after treatment of subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, a SRI-4 response is achieved in at least 30% of these subjects.

[0243] 162) The method of any one of embodiments 89) to 160), wherein after 12 months of treatment of subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod), a SRI-4 response is achieved in at least 50% of these subjects.

[0244] 163) The method of any one of embodiments 89) to 160), wherein after treatment of subjects (especially subjects with SLE) with the S1P1 receptor modulator (especially siponimod) for 12 months, a SRI-4 response is achieved in at least 70% of these subjects.

[0245] 164) A method as described in any one of embodiments 89) to 160), wherein after 12 months of treatment of the subjects (especially subjects with SLE), the probability of SRI-4 response in the subjects treated with the S1P1 receptor modulator (especially siponimod) is higher (especially statistically significantly higher) than that in the subjects treated with placebo.

[0246] 165) A method as described in any one of Examples 89) to 164), wherein the time to first confirmed 4-month sustained mSLEDAI-2K response (defined as a decrease of at least 4 points relative to baseline) in subjects (multiple subjects) treated with the S1P1 receptor modulator (especially siponimod) is shorter (especially statistically significantly shorter) than that in subjects (multiple subjects) treated with placebo.

[0247] 166) A method as described in any one of embodiments 89) to 164), wherein the S1P1 receptor modulator is siponimod, and wherein the time from the start of treatment with siponimod to the first confirmation of a 4-month sustained mSLEDAI-2K response (defined as a decrease of at least 4 points relative to baseline) in the subject (siponimod) treated with siponimod is statistically significantly shorter than that in the subject (siponimod) treated with placebo.

[0248] 167) A method as described in any one of embodiments 89) to 164), wherein the time to first confirmed 4-month sustained response of mucocutaneous manifestations in subjects (multiple subjects) treated with the S1P1 receptor modulator (especially siponimod) is shorter (especially statistically significantly shorter) than that in subjects (multiple subjects) treated with placebo.

[0249] 168) A method as described in any one of embodiments 89) to 164), wherein the S1P1 receptor modulator is siponimod, and wherein the time to 4-month sustained response from the start of treatment with siponimod to the first confirmed mucocutaneous manifestation in the subject (multiple subjects) treated with siponimod is statistically significantly shorter than that in the subject (multiple subjects) treated with placebo.

[0250] 169) The method of any one of embodiments 89) to 168), wherein the S1P1 receptor modulator is siponimod or a pharmaceutically acceptable salt thereof, and wherein a clinically proven effective amount of siponimod is administered and / or will be administered to the subject.

[0251] 170) A method as described in any one of embodiments 89) to 169), wherein the subject is a human (especially a human patient).

[0252] 171) The method of any one of embodiments 89) to 169), wherein the subject is a human patient suffering from a type 1 interferon-mediated disease.

[0253] 172) The method of any one of embodiments 89) to 169), wherein the subject is a human patient suffering from systemic lupus erythematosus and / or lupus nephritis.

[0254] 173) The method of any one of embodiments 89) to 169), wherein the subject is a human patient suffering from systemic lupus erythematosus.

[0255] 174) A method as described in any one of embodiments 89) to 169), wherein the subject is a human patient with systemic lupus erythematosus, and wherein the subject has an mSLEDAI-2K score of ≥6 and a clinical mSLEDAI-2K score of ≥4, of which at least 2 points are scores for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers).

[0256] 175) A method as described in any one of embodiments 89) to 169), wherein the subject is a human patient with systemic lupus erythematosus, and wherein the subject: (i) has an mSLEDAI-2K score of ≥6 and a clinical mSLEDAI-2K score of ≥4, of which at least 2 points are scores for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers); (ii) has British Isles Lupus Assessment Group-2004 (BILAG) grade B in ≥2 organ systems or BILAG grade A in ≥1 organ system; and (iii) has a Physician Global Assessment (PGA) score of ≥1.0 based on a 0 to 3 point VAS.

[0257] 176) A method as described in any one of embodiments 89) to 175), wherein the subject is a subject receiving standard background therapy (wherein it should be understood that such standard background therapy is suitable for treating type 1 interferon-mediated diseases, especially systemic lupus erythematosus).

[0258] 177) Another embodiment of the present invention relates to a method for treating a type 1 interferon-mediated disease (especially systemic lupus erythematosus) in a subject in need thereof, wherein the subject has a high type 1 interferon (IFN-1) gene signature score; the method comprises administering to the subject a pharmaceutical composition comprising a clinically proven effective amount of an S1P1 receptor modulator (especially siponimod) or a pharmaceutically acceptable salt thereof.

[0259] 178) The method of embodiment 177), wherein the S1P1 receptor modulator is siponimod, and wherein the clinically proven effective amount of siponimod is 4.0 mg per day.

[0260] 179) A method as described in any one of embodiments 177) or 178), wherein the method comprises administering to the subject a pharmaceutical composition comprising a clinically proven safe and clinically proven effective amount of the S1P1 receptor modulator (especially siponimod).

[0261] Unless otherwise indicated, as used herein, the term "clinically proven" (used alone or to modify the terms "safe" and / or "effective") shall mean proven by clinical trials, wherein the clinical trials meet the approval standards of the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) or corresponding national regulatory agencies. For example, a clinical study may be a randomized, double-blind study of sufficient size to clinically prove the effect of a drug.

[0262] As used herein in the context of a dose, dosing regimen, treatment or method, the term "clinically proven effective" refers to the effectiveness of a particular dose, dosing or treatment regimen. Efficacy can be measured based on changes in the disease process in response to the agent of the invention. For example, the amount and time of administration of the S1P1 receptor modulator (especially siponimod) to the subject is sufficient to induce improvement in at least one indicator reflecting the severity of the condition being treated, preferably sustained improvement. Various indicators reflecting the extent of the subject's illness, disease or condition can be assessed to determine whether the amount and duration of treatment are sufficient. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms or expression of the condition in question. The degree of improvement is usually determined by a physician, who can make this determination based on signs, symptoms, biopsy or other test results, and can also utilize questionnaires administered to the subject, such as quality of life or patient-reported outcome questionnaires developed for a given disease. For example, the compounds of the invention can be administered to achieve improvement in the condition associated with systemic lupus erythematosus in the subject. Improvement can be indicated by improvement in the disease activity index, relief of clinical symptoms, or any other measure of disease activity.

[0263] In a specific embodiment, such measure of disease activity is the modified SLE Disease Activity Index 2000 compared to baseline and / or compared to placebo.

[0264] In another specific embodiment, such disease measure is the Systemic Lupus Erythematosus Responder Index (SRI-4) compared to baseline and / or compared to placebo.

[0265] In another specific embodiment, such disease measure is the time to first confirmed 4-month sustained mSLEDAI-2K response (defined as a decrease of at least 4 points from baseline) compared to placebo.

[0266] In another specific embodiment, such disease measure is the time to first confirmed mucocutaneous manifestation sustained response at 4 months compared to placebo.

[0267] In certain embodiments, a clinically demonstrated effective amount of siponimod is an amount that causes a decrease in the modified SLE Disease Activity Index 2000 compared to baseline and / or compared to placebo; as demonstrated via a clinical trial having a protocol as described in "Opus Study Overview" herein below.

[0268] When related to the dosage, dosing regimen, treatment or method of using the compound of the invention, siponimod, the term "clinically proven safety" refers to a favorable risk-benefit ratio with an acceptable frequency and / or acceptable severity of adverse events (referred to as AEs or TEAEs) occurring during treatment. As used herein, "adverse events", "adverse events occurring during treatment" and "adverse reactions" mean any harmful, unfavorable, undesirable or undesirable signs or results associated with or caused by the administration of a pharmaceutical composition or therapeutic agent. It is an adverse medical event in a subject to which a drug is administered.

[0269] abbreviation: BICLA British Isles Lupus Assessment Group-based comprehensive lupus assessment BILAG British Isles Lupus Assessment Group CT Computerized tomography DNA deoxyribonucleic acid ECG Electrocardiogram EDTA Ethylenediaminetetraacetic acid FDA U.S. Food and Drug Administration ICF Informed Consent Form IFN Interferon IFNAR interferon alpha receptor IFNGR interferon gamma receptor iv intravenous JAK Janus kinase (m) SLEDAI-2K (modified) Systemic Lupus Erythematosus Disease Activity Index 2000 NSAID Non-steroidal anti-inflammatory drugs (O)CS (Oral) Corticosteroids PCR polymerase chain reaction PD(response) pharmacodynamics(response) PGA (score) Physician's Global Assessment (score) RFU relative fluorescence unit RNA Ribonucleic acid SLE Systemic lupus erythematosus SRI Systemic Lupus Erythematosus Responder Index SRI-4 mSLEDAI-2K SRI improvement of at least 4 points from baseline STAT signal transducer and activator of transcription TYK Tyrosine kinase ULN Upper limit of normal VAS Visual Analogue Scale (VAS).

[0270] Experimental Section In the Phase 2b clinical study (CARE), the distribution of IFN-1 gene expression signature scores in the placebo group and the 4 mg siponimod group ( Figure 1 A). A bimodal distribution was observed and a cutoff value of -0.5 was used to distinguish high from low IFN patients. Surprisingly, IFN scores were significantly reduced after 6 months of treatment with 4 mg siponimod compared with placebo ( Figure 1 B). Subgroup analysis of patients classified as high IFN and low IFN at baseline unexpectedly revealed that a decrease in mSLEDAI-2K from baseline was observed only in the high IFN subgroup ( Figure 1 C). In the high IFN-1 patient subgroup, greater changes from baseline in mSLEDAI-2K were observed in the 4 mg group compared with placebo, with the least squares LS-mean (SE) change from baseline to month 6 being -2.6 for placebo and -5.4 ( Figure 1 C). Although the same degree of reduction in blood lymphocyte counts was observed in low and high IFN-1 patients ( Figure 2 ), but found this improvement in mSLEDAI-2K in patients with high IFN-1, indicating that lymphopenia does not predict mSLEDAI-2K reduction.

[0271] In addition, siponimod reduced both IFN-1 gene signature score and IFN-α protein in the plasma of patients treated with siponimod ( Figure 3 A), both of which were higher in SLE patients compared with healthy volunteers ( Figure 3 B). Patients with high IFN-α protein levels at baseline showed a greater reduction in mSLEDAI-2K scores compared to the low IFNα protein group ( Figure 3 C). In addition, 4 mg siponimod reduced plasma IFNγ protein at 6 months compared with baseline and compared with placebo ( Figure 4 A), and was also higher in SLE patients compared with healthy volunteers ( Figure 4B). Patients with high IFNγ protein levels at baseline showed a greater reduction in mSLEDAI-2K scores compared to the low IFNγ protein group ( Figure 4 C).

[0272] Importantly, the IFN-1 gene signature score correlated with baseline measured IFNα plasma protein values ​​( Figure 5 A), which strengthens the validity of the IFN gene signature score as a readout of IFNα protein. In addition, 4 mg siponimod caused a decrease in IFN-1 scores at 6 months compared with baseline in both high IFN-1 and low IFN-1 patients, which was not observed with placebo ( Figure 5 B). Surprisingly, although 4 mg siponimod reduced IFN scores equally in all patients, the reduction in mSLEDAI-2K was only evident in high IFN-1 patients.

[0273] Gene expression signature Regulation of biological activity is reflected in changes in gene expression. These changes can be described by specific gene expression signatures. Gene signatures are defined by a group of genes that show an increase or decrease in expression based on biological activity. Gene signatures are most often analyzed using quantitative reverse transcription PCR (RT-qPCR), which allows the standardized expression level of each gene of interest to be obtained.

[0274] The IFN-1 signature reflects IFN-regulated genes, meaning those genes that are upregulated due to the biological activity of type 1 IFNs. In 2003, the IFN-1 gene signature was first described in cells isolated from SLE patients [Baechler, EC. et al., PNAS 2003, 100(5), 2610-2615, PMID: 12604793].

[0275] An important feature of the IFN-1 gene signature is the bimodal distribution in SLE patients, allowing for classification into high or low IFN-1 gene signature layers [El-Sherbiny, YM. et al., Scientific Reports 2018, 8, 5793, DOI: 10.1038 / s41598-018-24198-1, PMID: 29643425]. There are two most commonly used IFN-1 gene signatures in clinical studies (AstraZeneca [AZ] and DxTerity signatures). Although both signatures contain 4 genes, the selection of genes is different. Both signatures contain IFI27 and RSAD2, but AZ additionally includes IFI44 and IFI44L, while DxTerity uses IFIT1 and HERC5. Importantly, the two IFN-1 gene signatures are closely correlated, so as long as the cutoff values ​​are obtained in the same way, SLE patients will be classified in the same high and low strata. It has been previously demonstrated that different IFN-1 gene signatures will classify patients into the same IFN-1 status (Abedi M, Comparison Of Different Type 1 IFN Signatures Demonstrates Concordance In A Real World, Home Monitored Systemic Lupus Erythematosus Cohort, EULAR 2018, Poster #SAT0041).

[0276] The DxTerity gene expression assay contains ten interferon genes (EIF2AK2, HERC5, IFI27, IFI44, IFI44L, IFI6, IFIT1, ISG15, MX1, RSAD2). Four of those genes (HERC5, IFIT1, IFI27, and RSAD2) were used for IFN-1 testing to define the IFN-1 gene signature status (high / low). The test uses proprietary chemical ligation-dependent probe amplification (CLPA / DxDirect) technology.

[0277] The DxTerity feature cut-off point of -0.5 (for distinguishing high from low IFN subjects) was based on the 95th percentile of more than 500 healthy humans ( Figure 1 A), whereas the AZ cut-off point would result in more than 10% of healthy subjects being classified as high.

[0278] The expression level of each target gene was normalized to three housekeeping (normalization) genes (ACTB, GAPDH and TFRC). Based on the capillary electrophoresis graph, the gene expression level of each individual subject was calculated using the following formula using the average of the intensity of the fragment peak height corresponding to the four interferon response genes (RFU) and the intensity of the peak height of the three normalization genes (from the same subject): Gene i standardized expression = Log2(gene i height)-average(Log2(standardized gene height))

[0279] The IFN-1 gene signature score of the subject was determined by averaging the standardized expression values ​​of the HERC5, IFI27, IFIT1, and RSAD2 genes.

[0280] The high / low cutoff value (-0.5) was based on the 95th percentile of more than 500 healthy humans, 2 standard deviations above the mean IFN-1 gene signature score in healthy volunteers, and it falls at the trough of the typical bimodal IFN-1 gene signature score distribution found for SLE patients.

[0281] Plasma proteins Interferon alpha (IFNa or IFN-α) in EDTA plasma was measured using an ELISA assay from PBL assay science (41115) following the instructions provided by the supplier. Normal IFNa levels are below the detection limit of the assay (0.1 pg / ml). The high / low cut-off values ​​are based on the 95th percentile of 10 healthy human volunteers ( Figure 3 B).

[0282] Interferon gamma (IFNg or IFN-γ) was measured in EDTA plasma using the V-plex assay from Mesoscale discovery (K151A9H-2) following the instructions provided by the supplier. Normal IFNg levels are reported to be 3.80 pg / ml (median, n=27, 0.46-22.8 pg / ml). For comparison, in-house measurements of 10 EDTA plasma samples from healthy volunteers showed a median level of 1.49 pg / ml (0.49-12.28 pg / ml). High / low cutoffs were based on the 95th percentile of 10 healthy human volunteers ( Figure 4 B).

[0283] CARE Study Overview The study was designed as a double-blind, randomized, placebo-controlled study in SLE patients. A total of 85 patients were included in the 4 mg siponimod group and a total of 86 patients were included in the placebo group.

[0284] When drug treatment was started with 4 mg siponimod and placebo (defined as baseline), the research nurse extracted 12.5 ml of blood via standard venipuncture and collected in PAX-gene tubes for subsequent evaluation of IFN gene characteristics. The test tubes containing blood were frozen and kept frozen until further use. EDTA plasma was prepared from blood by standard protocols.

[0285] At baseline, 36 patients in the 4 mg siponimod group were classified as high IFN-1, and 44 patients were classified as low IFN-1. In the placebo group, 40 patients were classified as high IFN-1, and 40 patients were classified as low IFN-1.

[0286] The study design and key inclusion criteria are as follows: The primary objective of the study is to evaluate the efficacy of 4 mg siponimod for 6 months in subjects with moderate to severe SLE. Secondary and exploratory objectives (6 months) include, but are not limited to: effects on SLE biomarkers and exploratory biomarkers; evaluation of the safety and tolerability of siponimod doses; evaluation of effects on quality of life and fatigue using patient-reported outcome (PRO) tools; and evaluation of effects on SLE biomarkers.

[0287] Inclusion criteria are as follows: SLE diagnosis made at least 6 months before screening (at least 4 ACR criteria); modified SLEDAI-2K (mSLEDAI-2K) score ≥ 6 at screening, of which at least 2 points are musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers). The modified SLEDAI-2K is defined as the SLEDAI-2K with leukopenia deleted, which is one of the scores used in the SLEDAI-2K composite score. SLEDAI-2K is described elsewhere (Gladman et al., J Rheumatol. 2002 February; 29 (2): 288-91). At randomization, a clinical mSLEDAI-2K score of ≥ 4 is required. In addition, at randomization, a positive antinuclear antibody test (ANA) with a titer of ≥ 1:80 (by immunofluorescence assay) and / or a positive anti-dsDNA with a titer of ≥ 30 IU / mL is required. Participants must have been taking stable background SLE medications for at least a 30-day period (corticosteroids for 15 days) prior to randomization. If using corticosteroids, participants must have been taking ≤40 mg / day of prednisone or equivalent. Women of childbearing potential (WOCBP) must agree to use highly effective contraceptive methods.

[0288] Exclusion criteria were as follows: patients with active lupus nephritis (defined as proteinuria >1.5 g / 24 h or equivalent using the spot urine protein to creatinine ratio) or renal biopsy demonstrating immune complex-mediated glomerulonephritis compatible with lupus nephritis. Patients with CNS lupus (e.g., aseptic meningitis, seizures, encephalitis, polyneuropathy, cerebrovascular disease, organic brain syndrome) and severe forms of vasculitis (e.g., retinal vasculitis, coronary vasculitis, pulmonary vasculitis, mesenteric vasculitis) requiring systemic immunosuppressive therapy within 90 days prior to screening. Patients diagnosed with mixed connective tissue disease or with a history of any overlap syndrome of SLE with rheumatoid arthritis, erosive arthritis, scleroderma, or autoimmune hepatitis.

[0289] Study treatment was as follows: one tablet of siponimod or placebo was taken orally daily, irrespective of food intake and preferably in the morning.

[0290] Background therapy criteria: Subjects received at least one of the following SLE background medications, and they must be stable for 30 days before randomization, except for oral corticosteroids (OCS) (which should be stable for at least 15 days before randomization): NSAIDs: Aspirin (acetylsalicylic acid), Ibuprofen, Naproxen, Celecoxib, other NSAIDs; Prednisone or equivalent, ≤40 mg / day; Antimalarials: Hydroxychloroquine, Chloroquine, Quinacrine; Mycophenolate mofetil, Mycophenolic acid; Azathioprine; Methotrexate; Belimumab, these background medications must be started at least 30 days before screening. After randomization, background therapy remained stable throughout the study. However, if clinically relevant, the following changes were allowed: Long-term NSAID therapy was not started or stopped during the study, but temporary use and / or dose changes were allowed to treat non-SLE related conditions (e.g., headache, dysmenorrhea). In addition, immunosuppressive therapy (ie, methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, belimumab) was not started or stopped during the study, and the dose was kept stable. Atropine (intravenous) was used if symptomatic bradycardia occurred.

[0291] The primary efficacy endpoint was the change from baseline to month 6 in the modified SLEDAI-2K score. Other secondary endpoints were: Compared with baseline, the SRI-4 response at month 6 as defined previously (Furie R: et al. Arthritis Rheum. 2009 Sep 15;61(9):1143-51) was defined as follows: - a decrease in mSLEDAI-2K of at least 4 points from baseline; and - No new organ systems affected compared to baseline, as defined by one or more BILAG A or 2 or more BILAG B items as previously defined (Romero-Diaz J et al. Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11(011):S37-46. DOI:10.1002 / acr.20572.); and -Since baseline, the doctor's global assessment (PGA) has increased by no more than 0.3 points. The doctor's global assessment (PGA) is a visual analog scale (VAS) (Luijten KMAC et al., Autoimmunity Reviews Vol. 11, No. 5, March 2012, pp. 326-329) that uses 3 benchmarks to assess disease activity over the past 2 weeks. Based on a 0 to 3 point analog scale, mild redness will be scored as 1.0 points, moderate redness will be scored as 2.0 to 2.5 points, and severe redness will be scored as 3. In addition, the percentage of subjects without new organ systems affected compared to baseline, as defined by one or more BILAG A or 2 or more BILAG B items.

[0292] Opus Research Overview The Opus studies are two Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy, safety, and tolerability of siponimod in adult subjects (18 to 75 years) with moderate to severe systemic lupus erythematosus (SLE) on top of background therapy. Subjects were randomized 1:1 to siponimod or matching placebo. Siponimod was provided as a film-coated tablet once daily at a dose of 4 mg in addition to background SLE therapy.

[0293] Main outcome measures: 1. Change from baseline to month 12 in modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) score (time frame: day 1 (pre-dose baseline) to month 12).

[0294] This endpoint is based on the SLEDAI-2K index, which was modified to exclude leukopenia. All values ​​of mSLEDAI-2K from baseline to the 12-month visit were considered in the assessment of this endpoint.

[0295] Secondary outcome measures: 1. Systemic Lupus Erythematosus Responder Index (SRI-4) response at Month 12 (Time range: Day 1 (pre-dose baseline) to Month 12). The SRI-4 response is defined as: ○ A decrease of at least 4 points from baseline in mSLEDAI-2K, and ○ No new British Isles Lupus Assessment Group-2004 (BILAG) A organ domain score and no more than one new BILAG B organ domain score compared to baseline, and ○ The subject has not had a worsening of lupus disease activity from baseline, where worsening is defined as an increase of ≥ 0.30 points on a 3-point Physician Global Assessment Visual Analog Scale, and ○Do not violate the medication regulations specified in the protocol as detailed in the core protocol. 2. Time to first confirmation of 4-month sustained modified SLE Disease Activity Index-2000 (mSLEDAI-2K) response (time range: Day 1 (pre-dose baseline) to Month 12). A response was defined as a decrease of at least 4 points from baseline. 3. Time to first confirmed 4-month sustained response of mucocutaneous manifestations (time range: Day 1 (pre-dose baseline) to Month 12). The reaction is defined as: ○ No increase in overall mSLEDAI-2K score, and ○ Remission of mSLEDAI-2K score relative to baseline for mucocutaneous manifestations (zero score).

[0296] Inclusion criteria: Inclusion criteria during screening: - Signed the Informed Consent Form (ICF) before any study-specified procedures. - Systemic lupus erythematosus (SLE) diagnosis at least 6 months prior to screening according to the 2019 European League Against Rheumatism / American College of Rheumatology criteria. - Modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) score ≥ 6 and clinical mSLEDAI-2K score ≥ 4, with at least 2 points for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers). The mSLEDAI-2K score does not include "leukopenia." - British Isles Lupus Assessment Group-2004 (BILAG) class B in ≥2 organ systems or BILAG class A in ≥1 organ system. - Physician's global assessment (PGA) score ≥1.0 based on a 0 to 3-point visual analog scale (VAS). - Currently being treated with one or more of the following SLE background medications: ○ Antimalarial drugs (≤ 400 mg / day of hydroxychloroquine, ≤ 500 mg / day of chloroquine, ≤ 100 mg / day of quinacrine). ○Mycophenolate mofetil (≤2 g / day) / Mycophenolic acid (≤1.44 g / day). ○ Azathioprine (≤ 2 mg / kg / day). ○Methotrexate (≤25 mg / week). ○ Oral corticosteroids (OCS): ■When OCS is the only background medication for SLE: ≥ 7.5 mg / day and ≤ 30 mg / day of prednisone or equivalent. ■When OCS is not the sole background medication for SLE: ≤ 30 mg / day of prednisone or equivalent. o Belimumab (≤10 mg / kg intravenously every 4 weeks or 200 mg / week subcutaneously (sc)). Treatment with antimalarials, mycophenolate mofetil, mycophenolic acid, azathioprine, methotrexate, or belimumab must have been started at least 90 days before screening. Treatment with OCS must have been started at least 30 days before screening. -For women of childbearing potential (WoCBP): ○ Negative serum pregnancy test at screening. ○ Agree to monthly urine pregnancy test from randomization until 6 months after cessation of study treatment. ○ Agree to use highly effective contraceptive methods from screening (Visit 1) until 6 months after cessation of study treatment.

[0297] Inclusion criteria for randomization: - Clinical mSLEDAI-2K score ≥ 4, with at least 2 points for musculoskeletal or mucocutaneous manifestations (ie, myositis, arthritis, rash, alopecia, mucosal ulcers). - British Isles Lupus Assessment Group-2004 (BILAG) class B in 2 or more organ systems or BILAG class A in 1 or more organ systems. - Physician's global assessment (PGA) score ≥1.0 based on a 0 to 3-point visual analog scale. - Presence of serological evidence of active SLE or at least one of the following biological variables predictive of a high type 1 interferon (IFN-1) signature (in a screening sample measured in a central laboratory): ○ Anti-dsDNA antibodies are elevated above normal values. ○Complement C3 < lower limit of normal value. o The titer of antinuclear antibodies is at least 1:160. ○ Anti-Smith antibodies are elevated above normal values. ○ Platelets <200 000 / μL. ○ Urine protein / creatinine ratio >12.5 mg / mmol (110.5 mg / g). - Currently being treated with one or more of the following SLE background medications, which must have been stable for at least 30 days prior to randomization (except OCS, which must have been stable for at least 15 days prior to randomization): ○ Antimalarial drugs (≤ 400 mg / day of hydroxychloroquine, ≤ 500 mg / day of chloroquine, ≤ 100 mg / day of quinacrine). ○Mycophenolate mofetil (≤2 g / day) / Mycophenolic acid (≤1.44 g / day). ○ Azathioprine (≤ 2 mg / kg / day). ○Methotrexate (≤25 mg / week). ○OCS: ■When OCS is the only background medication for SLE: ≥ 7.5 mg / day and ≤ 30 mg / day of prednisone or equivalent. ■When OCS is not the sole background medication for SLE: ≤ 30 mg / day of prednisone or equivalent. o Belimumab (≤10 mg / kg intravenously (iv) every 4 weeks or ≤200 mg / week subcutaneously). - WoCBP must have a negative urine pregnancy test at the time of randomization.

[0298] Main exclusion criteria: - Women who are pregnant, planning to become pregnant until final study visit, or breastfeeding. - Severe CNS lupus or active severe or unstable neuropsychiatric SLE characterized by: aseptic meningitis; cerebral vasculitis; myelopathy; demyelinating syndrome (ascending, lateral, acute inflammatory demyelinating polyradiculopathy); acute confusional state; impaired level of consciousness; psychosis; acute stroke or stroke syndrome; cranial neuropathy; status epilepticus; cerebellar ataxia; or mononeuritis multiplex: ○ It will prevent the subject from fully understanding the ICF; or o The principal investigator believes that the protocol-specified standard of care is inadequate and more aggressive treatment is indicated, such as the addition of intravenous cyclophosphamide and / or high-dose intravenous pulse corticosteroid (CS) therapy or other treatment not permitted in the protocol. - A diagnosis of mixed connective tissue disease or a history of any overlap syndrome between SLE and psoriasis, rheumatoid arthritis, erosive arthritis, scleroderma, autoimmune hepatitis, or uncontrolled autoimmune thyroid disease. - History or presence of Mobitz type II or third degree atrioventricular block, atrial dysregulation syndrome, symptomatic bradycardia, or syncope related to cardiac disorders. - Subjects who have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, vascular thrombosis, decompensated heart failure requiring hospitalization, or heart failure defined as Class III / IV by the New York Heart Association within 6 months prior to screening. - Resting heart rate <50 bpm as measured by 12-lead ECG at screening or randomization. - Increased QT interval corrected by the Fridericia formula (QTcF) at screening or randomization, with an interval >470 ms (females) / >450 ms (males). - History or presence of severe respiratory disease or pulmonary fibrosis based on medical history and chest X-ray (or CT scan based on local guidelines) performed at screening or within 6 months prior to screening. - History of clinically relevant bronchial asthma or chronic obstructive pulmonary disease requiring oral or parenteral CS treatment for more than 2 weeks in total within the last 6 months prior to screening. - History or presence of malignancy (except surgically resected basal or squamous cell skin or mucosal lesions, including dysplasia and carcinoma in situ), lymphoproliferative disease, or history of total lymphatic irradiation. - Presence of macular edema or active uveitis as detected by optical coherence tomography (OCT) during the screening period. - Subjects with a history of chronic liver or biliary disease (except Gilbert's Syndrome), or alanine aminotransferase or aspartate aminotransferase >3× upper limit of normal (ULN) or total bilirubin >1.5 ULN (except in the case of known Gilbert's Syndrome). - Significant hematologic abnormalities at the screening evaluation: ○ Lymphocyte count <500 / μL (0.5×10^9 / L); ○Hemoglobin <7 g / dL; ○ White blood cell count <2000 / μL (2.0×10^9 / L); or ○ Platelet count <25,000 / μL (25×10^9 / L) during screening assessment. - Received the following medications within 15 days or 5 half-lives of the drug (whichever is longer) prior to randomization: o Beta-blockers, diltiazem, verapamil, digoxin, digitoxin, or any other antiarrhythmic or heart rate-reducing systemic therapy. ○ QT prolonging drugs with a known risk of torsades de pointes, regardless of indication. - Treatment with the following drugs within 30 days or 5 half-lives of the drug (whichever is longer) prior to randomization: ○Cyclophosphamide, cyclosporine, tacrolimus, sirolimus, mizoribine, etc. o Pulse methylprednisolone. ○ Receive live vaccines (including live vaccines for COVID-19). - Receipt of intra-articular, intramuscular, or intravenous CS within 6 weeks prior to randomization. - Treatment with the following drugs within 90 days or 5 half-lives of the drug (whichever is longer) prior to randomization: ○Leflunomide. ○ Intravenous immunoglobulin. - Has received any investigational agent within 90 days or 5 half-lives of the drug (whichever is longer) prior to randomization. - Treatment with a B-cell depleting biologic agent (e.g., rituximab or ocrelizumab) within 12 months prior to randomization. - Received anirumab treatment within 12 months prior to randomization. - Received any of the following medications at any time prior to screening: ○Alemtuzumab. o Sphingosine-1-phosphate receptor modulators (eg, fingolimod). ○ Subjects previously randomized to receive siponimod or placebo in any trial involving siponimod.

Claims

1. An S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in preventing or treating a type 1 interferon-mediated disease in a subject, wherein the subject has a high type 1 interferon (IFN-1) gene signature score.

2. The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to claim 1, wherein the type 1 interferon gene signature score is calculated based on any one of the following type 1 interferon-related gene groups: a. RSAD2, IFI44, IFI44L and IFI27; or b. RSAD2, IFI27, IFIT1 and HERC5.

3. The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to any one of claims 1 or 2, wherein the Type 1 interferon gene signature score of the subject is equal to or higher than the minimum value of the bimodal distribution curve of the Type 1 interferon gene signature scores of SLE patients.

4. The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to any one of claims 1 or 2, wherein the Type 1 interferon gene signature score of the subject is above a threshold, wherein the threshold for the IFN-1 gene signature score is 2 standard deviations higher than the arithmetic mean of at least 100 healthy humans.

5. An S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in a method for preventing or treating a subject suffering from a type 1 interferon-mediated disease, the method comprising: a) providing a biological sample from the subject; b) analyzing the gene expression of at least three type 1 interferon-related genes selected from the group consisting of: DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPT in the biological sample. P6 (particularly IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6, and in particular EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15); c) determining the normalized expression value of each detected gene; d) calculating the type 1 interferon gene signature score by averaging these normalized expression values; and e) when the Type 1 interferon gene signature score of the subject is above a threshold, treating the subject with the S1P1 receptor modulator.

6. The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to claim 5, wherein one of the following type 1 interferon-related gene groups is selected for analyzing gene expression: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

7. An S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in preventing or treating a type 1 interferon-mediated disease in a subject, wherein the interferon-γ (IFN-γ) concentration / level in the subject is elevated compared to a healthy subject.

8. The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the subject has an interferon-α (IFN-α) concentration / level higher than 0.1 pg / mL and / or an interferon-γ (IFN-γ) concentration / level higher than 9.5 pg / mL.

9. The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the S1P1 receptor modulator is selected from ozanimod, siponimod, ponesimod, cenerimod, etrasimod, mocravimod and amiselimod or a pharmaceutically acceptable salt thereof. 10 . The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 , wherein the S1P1 receptor modulator is siponimod. 11 . The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to claim 10 , wherein siponimod is administered to the subject and / or is administered to the subject for a treatment period of at least 6 months.

12. The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein the type 1 interferon-mediated disease is selected from the group consisting of systemic lupus erythematosus, discoid lupus, lupus nephritis, glomerulonephritis, type I diabetes, inflammatory bowel disease (including Crohn's disease, ulcerative colitis and celiac's disease), multiple sclerosis, autoimmune thyroiditis, scleroderma, psoriasis, primary Sjögren's disease ( disease), systemic sclerosis, rheumatoid arthritis, transplant rejection, dermatomyositis, polymyositis, idiopathic inflammatory myositis, sarcoidosis, Aicardi-Goutièressyndrome, vasculitis, Sting-associated vasculopathy of infancy (SAVI), or chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). 13 . The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 , wherein the type 1 interferon-mediated disease is systemic lupus erythematosus.

14. The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein after the subject is treated with siponimod for 12 months, the modified systemic lupus erythematosus disease activity index 2000 (mSLEDAI-2K) is reduced relative to baseline. 15 . The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 , wherein the subject is a human patient suffering from systemic lupus erythematosus.

16. The S1P1 receptor modulator or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein the subject is a human patient suffering from systemic lupus erythematosus, and wherein the subject has an mSLEDAI-2K score of ≥6 and a clinical mSLEDAI-2K score of ≥4, wherein at least 2 points are scores for musculoskeletal or mucocutaneous manifestations.

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