S1P1 receptor modulators for use in the 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 type 1 interferon (IFN-1) gene signature score or elevated plasma levels of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ).

Description

[Technical Field]

[0001] 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 (IFN-1) mediated disease in a subject having a high type 1 interferon (IFN-1) gene signature score or elevated plasma levels of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ). [Background technology]

[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 signals through 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 have been approved for the treatment of multiple sclerosis and inflammatory bowel disease, and are being investigated for additional inflammatory diseases involving lymphocyte-mediated 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 blocks lymphocyte egress from secondary lymphoid organs into the vascular circulation via internalization of the S1P1 receptor. As such, its immunomodulatory role in autoimmune diseases may be beneficial for the treatment of such diseases in which lymphocytes play a key role in disease propagation. 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 applications WO2011 / 007324, WO2013 / 175397 and WO2016 / 184939.

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

[0006] In a phase 2 clinical trial, cenerimod reduced both circulating B and T lymphocytes, confirming its mechanism of action (Hermann V et al., Lupus Science & Medicine 2019;6:e000354.doi:10.1136 / lupus-2019-000354). Furthermore, cenerimod reduced plasma interferon (IFN)-related proteins [Strasser, DS et al., RMD Ope n 2020, 6, e001261, PMID:32917831].

[0007] IFNs are central effector molecules produced in large amounts during the immune response to infection, activating defense mechanisms and inhibiting microbial replication. Type 1 IFNs are the largest group and consist of several classes and subclasses. Almost all cells in the immune system, including dendritic cells, monocytic T and B cells, can produce type 1 IFN members IFN-α and IFN-β. 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; Roennblom, 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 IFNs signal through heterodimeric transmembrane receptors composed of the subunits IFNAR1 and IFNAR2, which are widely expressed in many cell types. Similarly, type 2 IFNs engage the heterodimers IFNGR1 and IFNGR2. Both the IFNAR and IFNGR complexes recruit members of the JAK kinase family. IFNAR recruits TYK2 and JAK1, and IFNGR recruits JAK1 and JAK2. This leads to the subsequent phosphorylation of STAT1 and STAT2 and the subsequent translocation of signaling pathway transcription factors into the nucleus. These then bind to IFN response elements on DNA and initiate the transcription of numerous genes [Platanias, L.C., Nat Rev Immunol 2005, 5, 375–386, PMID: 15864272].

[0009] Importantly, activation of these pathways overlaps to some extent. IFN-induced activation of gene transcription can be described by IFN gene signatures, which can consist of hundreds of genes and can have numerous and differential outcomes depending on the dynamics and cell types involved [Roennblom, L. et al., Curr Opin Rheumatol 2013, 25(2), 248-253, PMID:23249830].

[0010] The observation that IFN levels are elevated in SLE was made as early as the late 1970s, and the suggestion that IFN actually causes SLE-like symptoms came from studies of interferonopathies. In interferonopathies, constitutive overproduction of type 1 IFN has been found, caused by genetic mutations in genes involved in both type 1 and type 2 IFN induction pathways. These individuals have a prominent IFN signature, and some patients exhibit an SLE-like phenotype [Lee-Kirsch, MA., Annu Rev Med 2017, 68, 297–315, PMID: 27813875]. The reasons for elevated IFN levels in SLE are not clearly understood, and not all patients diagnosed with SLE exhibit elevated type 1 IFN levels [Northcott, M. et al., Lupus Sci Med 2022, 9, e000625, PMID: 35197305]. Mounting evidence suggests that genetic predisposition and environmental risk factors lead to elevated IFN levels. This largely reflects the involvement of multiple pattern recognition receptors in IFN activation and the means by which they are activated, as described above. Prominent mechanisms are thought to be autoantibodies, such as anti-dsDNA antibodies and antinuclear antibodies, and immune complexes composed of nucleic acids and nucleic acid-binding proteins. This suggests that nucleic acids may be a potential trigger and that having autoantibodies against nucleic acids is a risk factor for the development of SLE.

[0011] Nucleic acids are sensed by, among other cells, plasmacytoid dendritic cells (pDCs), which are thought to be the key cell type producing type 1 IFN in SLE.

[0012] Enhanced IFN signaling has been shown not only in SLE but also in other autoimmune diseases. However, the frequency and distribution within the population varies depending on the autoimmune disease [Roennblom, L. et al., Curr Opin Rheumatol 2013, 25(2), 248-253, PMID:23249830].

[0013] pDCs produce large amounts of IFN1 [Cella, M. et al., Nature Med 1999, 5(8), 919-923, PMID:10426316]. IFN production in SLE may also involve other cell types, 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 disrupted IFN regulation contributes 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 transcriptional analysis of IFN-induced genes was first performed in 2003 using peripheral blood from SLE patients, demonstrating the induction of hundreds of genes associated with IFN activation [Baechler, E.C. et al., PNAS 2003, 100(5), 2610-2615, PMID: 12604793], providing evidence for an IFN gene signature in SLE patients. Thus, the IFN-1 signature reflects genes regulated by IFNs, implying that these genes are upregulated by the biological activity of type 1 IFNs. Subsequent studies have shown that blood samples from 50-80% of SLE patients consistently display an IFN-1 signature, and that this signature is stable over time [Northcott, M. et al., Lupus Sci Med 2022, 9, e000625, PMID: 35197305; Kirou, K. A. 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; Roennblom, L. et al., Lupus Sci Med 2019, 6, e000270, PMID: 31497305). A commonality among all IFN-I gene signatures is the presence of IFN response elements in genes induced by IFN signaling.

[0015] Enhanced IFN signaling has widespread and widespread effects throughout the body, and increased IFN production is thought to be associated with potential disease manifestations in SLE patients, the main of which are summarized below.

[0016] A significant correlation has been found between elevated IFN levels and SLE-associated nephritis [Feng, X. et al., Arthritis Rheumatism 2006, 54(9), 2951-2962, PMID:16947629; Kirou, K.A. et al., Arthritis Rheumatism 2005, 52(5), 1491-1503, PMID:15880830]. Furthermore, IFN levels have been shown to be elevated in kidney tissue, suggesting a strong correlation between IFN and renal injury [Castellano, G. et al., Arthritis Research Therapy 2015, 17, 72, PMID:25889472].

[0017] Although this evidence clearly implicates IFNs in SLE disease, the association between circulating IFN signatures and clinical disease characteristics is not limited to any one condition. Furthermore, the IFN signature does not distinguish between high and low disease activity as defined by various criteria. Kennedy, W.P. et al., Lupus Sci Med 2015, 2, e000080, PMID:25861459] 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 vs. low type 1 IFN gene signatures within the general SLE population are somewhat limited, but reports suggest a range of 60–80% [Psarras, A. et al., Rheumatology 2017, 56, 1662–1675, PMID: 28122959]. An important characteristic of the IFN-I gene signature is its bimodal distribution in SLE patients, which can be divided into high and low IFN-I gene signature strata [El-Sherbiny, Y.M. et al., Scientific Reports 2018, 8, 5793, DOI: 10.1038 / s41598-018-24198-1, PMID: 29643425], as observed in a double-blind, randomized, placebo-controlled phase 2b clinical trial in SLE patients (CARE trial; Figure 1A). In populations with elevated IFN-1 levels, reports have shown an association with renal aspects of the disease, low complement C3 levels, and autoantibodies, consistent with a 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, K.A. et al., Arthritis Rheumatism, 2005, 52(5), 1491-1503, PMID:15880830]. In a longitudinal study, patients with a high type 1 interferon (IFN-1) gene signature score ("IFN-1 high patients") were more likely to receive more immunosuppressants and glucocorticoids than IFN-1 low patients (75% vs. 50%), be younger, and be of Asian ancestry [Northcott, M. et al., Lupus Sci Med 2022, 9, e000625, PMID:35197305]. The effect of glucocorticoids on IFN gene expression was evaluated in a small cohort of SLE patients. The authors found no effect of glucocorticoid dose on type 1 interferon-regulated gene expression. Patients with a high type 1 interferon gene signature had reduced glucocorticoid gene signature expression compared with patients with a low type 1 interferon gene signature matched for glucocorticoid dose, suggesting that type 1 interferon regulates glucocorticoid-stimulated genes. 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 IFNs in SLE has stimulated efforts to target this pathway as a therapeutic avenue for SLE, and these efforts are being investigated in clinical trials. A prime example is the antibody anifrolumab, which targets the IFN-1 receptor. Additionally, additional therapeutic possibilities that modulate the IFN-1 gene signature score are being investigated.

[0020] A phase 3 trial of anifrolumab confirmed the suppression of the interferon signature in patients with elevated baseline IFN-1 levels observed in the phase 2 trial, but this effect was not associated with clinical efficacy. In TULIP1, the placebo-adjusted efficacy of anifrolumab, as measured by the (SLE) Responder Index (SRI-4) [Furie, R. et al., Arthritis Rheumatism 2009, 61(9), 1143-1151, PMID:19714615], in patients with elevated baseline IFN-1 levels was modest, i.e., 6 percentage points. In TULIP2, the placebo-adjusted efficacy of anifrolumab, as measured by the SRI-4, was significantly lower in patients with elevated baseline IFN-1 levels. The TULIP2 manuscript authors noted that the number of patients with low IFN-1 levels was small (30 low vs. 150 high, 17%), and the effect of anifrolumab in these patients requires further analysis. The pooled phase 3 TULIP1&2 trial allows for a larger sample size comparison of the low IFN-1 group (i.e., 122 patients with low IFN-1 levels were treated with 300 mg or placebo (60 and 62, respectively)) [Vital, EM, et al., Ann Rheum Dis 2022, 81, 951-961, PMID: 35338035]. No treatment effect was observed in the low IFN-1 group on SRI-4 (45.2% and 45.3% for anifrolumab 300 mg and placebo, respectively), but a small benefit of 9 percentage points was observed on BICLA (British Isles Lupus Assessment Group-based Composite Lupus Assessment) (46.8% and 37.5% for anifrolumab 300 mg and placebo, respectively).

[0021] The FDA's analysis of the NDA for anifrolumab 150 mg, 300 mg, and 1000 mg concluded that "neutralization of the IFN-1 gene signature reflects a direct pharmacologic effect of anifrolumab, with clear dose-dependent PD responses, although its clinical relevance remains unclear due to higher PD responses in non-responders in the 300 mg arm compared with responders in the 150 mg arm" [FDA SAPHNELO Comprehensive Evaluation, p. 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's analysis of PD responses (neutralization of the type 1 gene signature and responder / non-responder analyses for SRI-4 and BICLA).

[0022] In summary, although AZ noted that further studies are needed to examine differences in efficacy between IFN-1 high and low populations, the FDA broadly indicated the indication for SLE on the label. This suggests that specifically targeting the type 1 IFN pathway may not be beneficial only in patients with high IFN levels, but it is unclear whether it may also benefit patients with low IFN levels. Conversely, it is unclear whether targeting a mechanism unrelated to regulation of the type 1 interferon pathway would be beneficial only in SLE patients with high IFN levels, but not in patients with low IFN levels, as observed with cenerimod (Figure 1c).

[0023] Iberdomide is a high-affinity cereblon ligand that promotes the proteasomal degradation of the 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, P.E., et al., Ann Rheum Dis 2022, 81, 1136-1142, PMID: 35477518].

[0024] In a phase 2 study testing iverdimide at doses of 0.15, 0.30, and 0.45 mg versus placebo, 179 of 288 patients (62%) had elevated IFN-1 levels at baseline. This study did not stratify patients by baseline gene signature, and the highest proportion of patients with elevated IFN-1 levels was in the 0.45 mg group (70%) and the lowest in the placebo group (58%) [Merrill, JT., et al., N Engl J Med 2022, 386, 1034–1045, PMID: 35294813].

[0025] At week 24, the highest SRI-4 response (primary endpoint) was observed in 44 of 81 patients (54%) receiving iverdomide 0.45 mg compared with 29 of 83 patients (35%) receiving placebo (adjusted difference, 19.4 percentage points). No significant differences were observed between iverdomide and placebo for most secondary endpoints. Among patients with elevated IFN-1 levels, 34 of 57 patients (60%) in the iverdomide 0.45 mg group responded compared with 16 of 48 patients (33%) in the placebo group. Even though exploratory analyses showed that the highest cutpoint for the IFN-1 subgroup (representing 31% of the total study population) was associated with the strongest relationship to response, resulting in a treatment difference of 54 percentage points versus placebo (5 of 27 (20.0%) vs. 17 of 23 (74%)) [Lipsky, PE. et al., Ann Rheum Dis 2022, 81, 1136-1142, PMID:35477518], 10 of 24 patients (42%) with low IFN-1 levels still responded to iverdin 0.45 mg. Analysis of biomarker changes showed that phase 2 SLE patients with high baseline IFN-1 levels experienced a significant decline in the IFN signature following active treatment, whereas patients with low baseline IFN signatures did not [[Lipsky, P.E. et al., Ann Rheum Dis 2022, 81, 1136-1142, PMID:35477518]]. Treatment with iverdomide was associated with a significant and dose-dependent decrease in pDCs and mDCs, which are thought to be the primary source of type 1 IFN.

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

[0027] Sifalimumab is a fully human immunoglobulin G1κ monoclonal antibody that binds to and neutralizes most IFN-α subtypes. Sifalimumab was developed by AstraZeneca, but its development was discontinued in favor of anifrolumab. Prior clinical trials of sifalimumab demonstrated suppression of IFN-α-induced genes and suggested favorable effects on clinical outcome measures [Petri, M. et al., Arthritis Rheumatism 2013, 65(4), 1011–1021, PMID: 23400715].

[0028] Despite extensive research on the IFN pathway and its relationship to SLE, the relationship between S1P1 receptor regulation and IFN signaling has remained largely unexplored to date. Initial evidence linking IFN-alpha to S1P1 was published in 2006 (Shiow, L. et al., Nature 2006, 440, 540-544, PMID: 16525420). Recently, it was reported that treatment of mice with poly(I:C), a double-stranded RNA mimetic that induces IFN signaling, downregulated CD69 and subsequently inhibited lymphocyte egress from lymph nodes via downregulation of the S1P1 signaling pathway. This suggests that IFN signaling may regulate lymphocyte migration via S1P1. Teijaro (Teijaro, JR. et al., PNAS 2016, 113(5), 1351-1356, PMID: 26787880) further reported that sphingosine-1-phosphate (S1P)-S1PR1 signaling in plasmacytoid dendritic cells (pDCs) directly inhibits IFN-α self-amplification by inducing degradation of the interferon alpha receptor 1 (IFNAR1) receptor, again suggesting that S1P1 receptor modulators can lead to a decrease in IFN-mediated signaling. However, in a mouse model of influenza, In this study, it was reported that S1P1 receptor signaling on pulmonary endothelial cells blunted but did not abolish IFN-α production in vivo [Teijaro, JR. et al., Cell 2011, 146(6), 980-991, PMID:21925319].

[0029] The potential role of S1P modulators in regulating IFN-related proteins in relation to SLE was recently investigated by Strasser et al. In the MRL / lpr mouse model of SLE, efficacy was demonstrated by peripheral lymphocyte reduction and improved survival. Furthermore, a small exploratory study treated 13 patients diagnosed with SLE with cenerimod for 12 weeks. This study observed significant heterogeneity in IFN-related biomarkers among patients, and cenerimod treatment led to a trend toward a decrease in IFN-related biomarkers [Strasser, DS et al., RMD Open 2020, 6, e001261, PMID: 32917831].

[0030] Taken together, these data suggest a complex and contradictory interplay between the IFN-1 and S1P1 signaling pathways in the context of disease. For SLE patients who specifically display a high IFN-1 gene signature and elevated IFN-related proteins, there has been no evidence to date that S1P1 modulation translates into improved health as measured by mSLEDAI-2K in these patients. [Brief explanation of the drawings]

[0031] [Figure 1]A) Histogram showing the distribution of type 1 IFN gene signature scores for the combined placebo and cenerimod 4 mg cohorts at baseline in the CARE study. A clear bimodal distribution is evident. The gray line represents the cutoff value between low and high IFN-1 levels at -0.5. B) Box plots showing individual (high IFN-1) patients represented by dots in the placebo and 4 mg cenerimod treatment groups in the CARE study at baseline and 6 months of treatment, with the type 1 IFN gene signature score (IFN-1 score) measured from blood for each individual. In the box plot, whiskers indicate the minimum and maximum range. A decrease in mean IFN-1 scores was observed after 6 months compared to baseline in the cenerimod 4 mg group, whereas only a small mean difference was observed at 6 months in the placebo group. C) Graphs showing least squares mean (LS) change from baseline to 6 months in the modified SLEDAI-2K (mSLEDAI-2K). The upper graph shows patients classified as having high IFN-1 levels at baseline and compares placebo with cenerimod 4 mg up to 6 months. The lower graph shows patients classified as having low IFN-1 levels at baseline and compares placebo with cenerimod 4 mg. In the low IFN-1 group, no difference in mSLEDAI-2K is observed between placebo and cenerimod 4 mg at 6 months. In the high IFN-1 group, a clear difference is observed in the reduction observed between cenerimod 4 mg and placebo at 6 months compared to baseline. [Figure 2] Figure 2 shows the effect of placebo and cenerimod 4 mg on blood lymphocyte counts over a 6-month treatment period. The mean change from baseline in lymphocyte counts is shown. While placebo does not reduce blood lymphocyte counts, rapid and sustained reductions are observed in both the IFN-1 high and IFN-1 low patient subgroups treated with cenerimod 4 mg. [Figure 3]A) Box plots show individual patients (represented by dots) in the placebo and 4 mg cenelimod treatment groups of the CARE study at baseline and 6 months of treatment, with the amount of IFN-alpha protein (pg / ml) measured in plasma for each individual. The whiskers indicate the minimum and maximum ranges in the box plots. Compared to baseline, a decrease in mean IFN-alpha protein is observed after 6 months in the 4 mg cenelimod group, while only a slight increase in mean value is observed in the placebo group at 6 months. B) Box plots show baseline plasma IFN-alpha protein (pg / ml) in the healthy volunteer cohort (control) and the placebo and 4 mg cenelimod cohorts of the CARE study. Individual patients are represented by dots. 95% of healthy volunteers had values ​​below 0.1 pg / ml, represented by a line. This is the cutoff point for high and low values. The patient cohort had higher levels of IFN-alpha protein than the healthy volunteer cohort. C) Box plots show the delta of mSLEDAI-2K values ​​at 6 months compared to baseline for the placebo and cenerimod 4 mg cohorts in the CARE study. The placebo and cenerimod 4 mg cohorts were divided into low-IFN alpha and high-IFN alpha groups based on baseline IFN alpha measurements. The reduction in mSLEDAI-2K scores (i.e., improvement in clinical information) was similar in both the placebo and cenerimod 4 mg low-IFN alpha protein groups. The reduction in mSLEDAI-2K in the placebo high-IFN group was small. However, the cenerimod 4 mg high-IFN alpha protein group showed a significant reduction in mSLEDAI-2K compared to the other three groups. [Figure 4]A) Box plots show individual patients represented by dots in the placebo and 4 mg cenelimod treatment groups of the CARE study at baseline and 6 months after treatment, with the amount of IFN gamma protein (pg / ml) measured in plasma for each individual. The whiskers in the box plots indicate the minimum and maximum ranges. A decrease in mean IFN gamma protein is observed between baseline and 6 months after treatment in the 4 mg cenelimod group, while only a slight increase in mean value is observed in the placebo group at 6 months. B) Box plots show baseline plasma IFN gamma protein (pg / ml) in the healthy volunteer cohort (control) and the placebo and 4 mg cenelimod cohorts of the CARE study. Individual patients are represented by dots. 95% of healthy volunteers had values ​​below 9.5 pg / ml, represented by a line. This is the cutoff point for high and low values. The patient cohort had higher levels of IFN gamma protein than the healthy volunteer cohort. C) Box plots show the delta of mSLEDAI-2K values ​​at 6 months compared to baseline for the placebo and cenerimod 4 mg cohorts in the CARE study. The placebo and cenerimod 4 mg cohorts were divided into low IFN gamma and high IFN gamma groups based on baseline IFN gamma measurements. The reduction in mSLEDAI-2K scores (i.e., improvement in clinical information) was similar in both the placebo and cenerimod 4 mg low IFN gamma protein groups. The reduction in mSLEDAI-2K in the placebo high IFN gamma group was small. However, the cenerimod 4 mg high IFN gamma group showed a significant reduction in mSLEDAI-2K compared to the other three groups. [Figure 5] A significant correlation was observed between plasma IFN-α levels and blood IFN-1 gene expression scores (A). Six months of treatment with 4 mg of cenerimod reduced IFN-1 gene expression scores in both high- and low-IFN-1 patients. In contrast, six months of placebo treatment increased IFN-1 gene expression scores in both high- and low-IFN-1 patients (B). Summary of the Invention

[0032] Detailed Description of the Invention Various aspects of the invention are described below: 1) A first aspect of the present invention relates to an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment (in particular the treatment) of a type 1 interferon-mediated disease in a subject, wherein said subject has a high type 1 interferon (IFN-1) gene signature score.

[0033] "The subject has a high type 1 interferon (IFN-1) gene signature score. In the context of "having," the term "having" means a subject who has and / or is identified as having and / or is diagnosed as having a high type 1 interferon (IFN-1) gene signature score.

[0034] 2) A further aspect of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to aspect 1), wherein said subject has a high type 1 interferon (IFN-1) gene signature score at the start of treatment.

[0035] 3) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 1) or 2), wherein said 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.

[0036] l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0037] Group a) in WO2020 / 084591; group b) in WO2022 / 074123 and Yao Y et al., Human Genomics and Proteomics 2009; article ID 374312, doi:10.4061 / 2009 / 374312; groups c)-h) in WO2011 / 028933 and Furie R et al., Arthritis&Rheumatology 2017;69(2) 376-386; group i) in Westra HJ et al., Nature Genetics 2013;45(10) 1238-1243, doi:10.1038 / ng.2756; group j) in Niewold, T et al., Genes and Immunity 2007;8 492-502, doi:10.1038 / sj.gene.6364408; group k) in Kirou, K. et al., Arthritis&Rheum. 2005;52(5) 1491-1503; and groups l) and m) in Northcott M et al., Lupus Science&Medicine 2022;9:e000625; doi:10.1136 / lupus-2021-000625.

[0038] 4) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to aspect 1) or 2), wherein the type 1 interferon gene signature score is calculated based on any one of the following groups of type 1 interferon-related genes: Regarding salt: 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) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 1) or 2), wherein said 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.

[0040] 6) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 1) or 2), wherein said 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.

[0041] 7) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to aspect 1) or 2), wherein said type 1 interferon gene signature score is calculated based on type 1 interferon-related genes EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15.

[0042] 8) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to aspect 1) or 2), wherein said type 1 interferon gene signature score is calculated based on type 1 interferon-related genes RSAD2, IFI27, IFIT1 and HERC5.

[0043] A subject's type 1 interferon gene signature score can be calculated according to any of the methods described in WO2011 / 028933, WO2020 / 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. specifically 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 an IFN-1 gene signature score cutoff value of -0.5 between subjects with low and high IFN-1 gene signature scores. Northcott et al. further disclose ... The article refers to a commercially available IFN-1 test from Inc., specifically targeting type 1 interferon-1 receptor agonists. The type 1 interferon gene signature score can be calculated using a method proprietary to DxTerity Diagnostics Inc. by (i) measuring the gene (RNA) expression levels of type 1 interferon-related genes, RSAD2, IFI27, IFIT1, and HERC5, in a subject's blood sample (e.g., by measuring the height of each peak in capillary electrophoresis electropherograms); (ii) measuring the gene expression levels of three housekeeping (normalizer) genes, ACTB, GAPDH, and TFRC, in the subject's blood sample; (iii) calculating the binary logarithm (log2) of the expression levels of each of the three housekeeping genes and their arithmetic mean; (iv) calculating normalized expression for each of the four type 1 interferon-related genes using 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.

[0044] Normalized expression of gene i = Log2(height of gene i) - mean(Log2(height of normalizer gene)) (Normalized Expression Gene i=Log2(Height Gene i)-Mean(Log2(Normalizer Genes Height))) Formula (I) An important characteristic of the IFN-1 gene signature is its bimodal distribution in subjects with systemic lupus erythematosus (SLE), allowing for separation into subjects with high type 1 interferon (IFN-1) gene signature scores (IFN-1-high subjects) and subjects with low scores (IFN-1-low subjects) [El-Sherbiny, YM. et al., Scientific Reports 2018, 8, 5793, DOI: 10.1038 / s41598-018-24198-1, PMID: 29643425]. Subjects with a high IFN-1 gene signature score can be defined as those with an IFN-1 gene signature score above a threshold (or "cutoff value"); subjects with a low IFN-1 gene signature score can be defined as those with an IFN-1 gene signature score below the threshold. The threshold or cutoff value can be defined according to any method known in the art (e.g., WO2011 / 028933 or Northcott M et al., Lupus Science & Medicine 2022;9:e000625;doi:10.1136 / lupus-2021-000625). In particular, the threshold / cutoff value can be defined for the IFN-1 gene signature score of a healthy individual: for example, the threshold / cutoff value can be any IFN-1 gene signature score value that is 1.8 to 4.0 (particularly 2.0 to 3.0) standard deviations above the arithmetic mean value of at least 20 (particularly at least 200) healthy individuals. In particular, the threshold / cutoff value for the IFN-1 gene signature score can be defined as 2 standard deviations above the arithmetic mean value of at least 100 (particularly at least 300) healthy individuals. In particular, the IFN-1 gene signature scores of subjects (especially patients) and healthy individuals (for determining the cutoff value) are calculated using the same method as for determining the IFN-1 gene signature score.

[0045] In a study, Abedi et al. (DxTerity) compared the relative performance of four different IFN gene signatures in a cohort of 687 participants with self-reported systemic lupus erythematosus (SLE). The frequently used four-gene IFN signature of IFI27, IFI44, IFI44L, and RSAD2 identified 36.5% of participants as IFN-high and 63.5% as IFN-low. Three other literature-reported IFN signatures (IFI6, MX1, IFIT1, and HERC5; EIF2AK2, MX1, and IFIT1; and EIF2AK2, IFI44, and IFIT1) also performed poorly. Similar classification results were obtained, with participants assigned to the same IFN subgroup (IFN-high / IFN-low) with a probability of over 90% and a similar patient distribution; all four IFN gene signatures were found in four genes: RSAD2, IFI27, IFIT1, and HERC5, resulting in a bimodal IFN-1 gene signature score distribution similar to that shown in Figure 1A (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) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1) to 8), wherein the type 1 interferon gene signature score of the subject is equal to or greater than the minimum of a bimodal distribution curve of type 1 interferon gene signature scores of SLE patients.

[0047] The minimum of the bimodal distribution curve may be determined by determining the number of SLE patients with a given type 1 interferon gene signature score as a function of the type 1 interferon gene signature score. The bimodal distribution curve may 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 may be obtained from current data (e.g., from data collected less than one year ago) and / or from historical data (e.g., from data collected more than one year ago) regarding the type 1 interferon gene signature scores of SLE patients.

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

[0049] 11) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1) to 8), wherein the subject has a type 1 interferon gene signature score that is higher than a type 1 interferon gene signature score of a (representative) healthy subject.

[0050] 12) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1) to 8), wherein the subject has a type 1 interferon gene signature score higher than a threshold value.

[0051] 13) In a further embodiment of the present invention, the threshold value is an IFN-1 gene signature score value selected from values ​​that are 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; particularly 2.0 to 3.0, and more 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 individuals. The present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 12).

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

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

[0054] 16) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 12), wherein said threshold value of the IFN-1 gene signature score is −0.5.

[0055] 17) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1) to 16), wherein the type 1 interferon gene signature score of the subject is calculated (determined) by a method comprising the steps of: (i) measuring the gene (RNA) expression level of type 1 interferon-related genes (particularly RSAD2, IFI44, IFI44L and IFI27; or RSAD2, IFI27, IFIT1 and HERC5; especially RSAD2, IFI27, IFIT1 and HERC5) in a blood sample from the subject (particularly by measuring the height of each peak by capillary electrophoresis); (ii) measuring the gene expression levels of three housekeeping (normalizer) genes, ACTB, GAPDH, and TFRC, in a blood sample from the subject; (iii) calculating the logarithm of the expression level of each of the three housekeeping genes and the arithmetic mean thereof; (iv) calculating the normalized expression for each of the type 1 interferon-related genes according to formula (I): Normalized expression of gene i = Log2(height of gene i) - mean(Log2(height of normalizer gene)) Formula (I) and (v) calculating a type 1 interferon gene signature score by averaging the normalized expression values ​​of said type 1 interferon-related genes.

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

[0057] 19) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in a method for the prevention or treatment (particularly the treatment) of a subject having a type 1 interferon mediated disease (particularly a type 1 interferon mediated disease that responds to treatment with an S1P1 receptor modulator), said method comprising the steps of: a) providing a biological sample (particularly a blood sample or serum sample, especially a blood sample) from said subject; b) the presence 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 (in particular, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, H assaying gene expression of at least three (particularly at least four) type 1 interferon-related genes selected from the group consisting of ERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6, especially EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; c) determining a normalized expression value for each gene assayed; d) calculating a type 1 interferon gene signature score by averaging the normalized expression values; and e) if the subject's type 1 interferon gene signature score is greater than a threshold, treating the subject with an S1P1 receptor modulator.

[0058] 20) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 19), wherein the subject has a type 1 interferon gene signature score at the start of treatment that is higher than a threshold value and / or higher than a 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 above a threshold at the start of treatment.

[0060] 21) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 19) or 20), wherein said biological sample is a blood sample.

[0061] 22) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 19) to 21), in which one of the following groups of type 1 interferon-related genes is selected for assaying gene expression: a) DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, IFI44, IFI44L, HERC5 and PLSCR1; or b) IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFI T1, 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.

[0062] l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0063] 23) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 19) to 21), in which one of the following groups of type 1 interferon-related genes is selected for assaying 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.

[0064] 24) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 19) to 21), in which one of the following groups of type 1 interferon-related genes is selected for assaying 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.

[0065] 25) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 19) to 21), in which one of the following groups of type 1 interferon-related genes is selected for assaying gene expression: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

[0066] 26) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 19) to 21), wherein the type 1 interferon-related genes for assaying gene expression are EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15.

[0067] 27) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 19) to 21), wherein the type 1 interferon-related genes for assaying gene expression are RSAD2, IFI27, IFIT1, and HERC5.

[0068] 28) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 19) to 27), wherein said gene expression is assayed by capillary electrophoresis (particularly capillary electrophoresis suitable for nucleotide analysis).

[0069] 29) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 19) to 27), wherein said gene expression of type 1 interferon-related genes is assayed by measuring peak heights in a capillary electrophoresis electropherogram.

[0070] 30) A further aspect of the present invention is a method for determining the normalized expression value by the steps of: (i) measuring the gene expression levels of the three housekeeping (normalizer) genes, ACTB, GAPDH, and TFRC, in a blood sample from the subject; (ii) calculating the logarithm of the binary logarithm (log2) of the expression level of each of the three housekeeping genes and the arithmetic mean thereof; and (iii) calculating the normalized expression value for each of the type 1 interferon-related genes using formula (II): Normalized expression of gene i = Log2(expression level of gene i) - mean(Log2(expression level of normalizer gene)) (Normalized Expression Gene i=Log2(Expression Level of Gene i)-Mean(Log2(Expression Level of Normalizer Genes))) Formula (II); The present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 19) to 29).

[0071] In a preferred embodiment, the normalized expression value is calculated based on the peak height of each gene (particularly the peak height in a capillary electrophoresis electropherogram) using formula (I).

[0072] 31) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 19) to 30), wherein the type 1 interferon gene signature score of the subject is equal to or greater than the minimum of the bimodal distribution curve of type 1 interferon gene signature scores of SLE patients.

[0073] The minimum of the bimodal distribution curve may be determined by determining the number of SLE patients with a given type 1 interferon gene signature score as a function of the type 1 interferon gene signature score. The bimodal distribution curve may 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 may be obtained from current data (e.g., from data collected less than one year ago) and / or from historical data (e.g., from data collected more than one year ago) regarding the type 1 interferon gene signature scores of SLE patients.

[0074] 32) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 31), wherein the type 1 interferon gene signature score of said subject is at least 0.5 units, at least 1 unit, at least 2 units, or at least 3 units (in particular at least 1 unit) higher than the minimum of the bimodal distribution curve of type 1 interferon gene signature scores of SLE patients.

[0075] 33) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 19) to 30), wherein the threshold value is an IFN-1 gene signature score value selected from values ​​that are 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; particularly 2.0 to 3.0, and more 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 individuals.

[0076] 34) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 19) to 30), wherein the threshold value of the IFN-1 gene signature score is two standard deviations higher than the arithmetic mean value from at least 100, at least 200, at least 300, or (preferably) at least 500 healthy individuals.

[0077] 35) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 19) to 30), wherein the threshold value of the IFN-1 gene signature score is selected from values ​​between −1.0 and 0 (particularly about −0.5, especially −0.5).

[0078] 36) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 35), wherein said threshold value of the IFN-1 gene signature score is −0.5.

[0079] 37) A further aspect of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in a method for the prevention or treatment (particularly the treatment) of a subject having a type 1 interferon mediated disease (particularly a type 1 interferon mediated disease that responds to treatment with an S1P1 receptor modulator), said method comprising the steps of: a) providing a biological sample (particularly a blood sample or serum sample, especially a blood sample) from said subject; b) assaying gene expression of type 1 interferon-related genes, RSAD2, IFI27, IFIT1 and HERC5 in said biological sample (particularly by measuring peak heights in capillary electrophoresis electropherograms); c) determining a normalized expression value for each assayed gene by (i) measuring the gene expression levels of the three housekeeping (normalizer) genes, ACTB, GAPDH, and TFRC, in the subject's biological sample; (ii) calculating the logarithm of the expression level of each of the three housekeeping genes and the arithmetic mean thereof; and (iii) calculating a normalized expression value for each of the type 1 interferon-related genes according to formula (II): Normalized expression of gene i = Log2(expression level of gene i) - mean(Log2(expression level of normalizer gene)) Formula (II); determining the d) calculating a type 1 interferon gene signature score by averaging the normalized expression values; and e) treating said subject with an S1P1 receptor modulator if said subject's type 1 interferon gene signature score is higher than a threshold value, said threshold value being selected from the values ​​between -1.0 and 0 (particularly -0.5).

[0080] In a preferred embodiment, the normalized expression value is calculated based on the peak height of each gene by using formula (I).

[0081] 38) A further aspect of the present invention relates to an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment (particularly the treatment) of a type 1 interferon mediated disease in a subject (particularly a type 1 interferon mediated disease that is responsive to treatment with an S1P1 receptor modulator), wherein at least three (particularly at least four) type 1 interferon related genes are upregulated in said subject (particularly in a biological sample from said subject), said type 1 interferon related genes being selected from the group consisting of DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HER2, HER3, HER4, HER5, HER6, HER7, HER8, HER9, HER1, HER2, HER3, HER5, HER6, HER7, HER8, HER9, HER10, HER11, HER2, HER3, HER4, HER5, HER6, HER2, HER3, HER4, HER5, HER6, HER7, HER8, HER9, HER11, HER12, HER13, HER14, HER15, HER2, HER3, HER2, HER3, HER4, HER5, HER6, HER2 ...2, HER3, HER3, HER4, HER2, HER2, HER2, HER3, HER4, HER C5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6 (in particular IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6, especially EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15).

[0082] The upregulation of type 1 interferon-related genes in the expression profile of the subject may be relative to a control sample (which may be derived from a sample not from diseased tissue of the subject or from a healthy individual not suffering from a type 1 interferon-mediated disease), or may be relative to genes of the subject whose expression is not altered by the type 1 interferon-mediated disease (so-called housekeeping genes); in particular, relative to genes of the subject whose expression is not altered by the type 1 interferon-mediated disease.

[0083] The degree of upregulation 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 that of a control or control sample.

[0084] 39) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 38), in which the type 1 interferon-related gene is upregulated in the subject at the start of treatment.

[0085] 40) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 38) or 39), in which at least three genes from at least one of the following groups 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, IF IT3, 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.

[0086] l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0087] 41) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 38) or 39), in which at least three genes from at least one of the following groups 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.

[0088] 42) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 38) or 39), in which at least three genes from at least one of the following groups 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.

[0089] 43) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 38) or 39), in which at least three genes from at least one of the following groups of type 1 interferon-related genes are upregulated in the subject: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

[0090] 44) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 38) or 39), in which 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.

[0091] 45) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 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.

[0092] 46) A further aspect of the invention relates to an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment (in particular the treatment) of a type 1 interferon mediated disease in a subject, wherein said subject (in particular in the plasma of said subject) has an elevated concentration / level of interferon-gamma (IFN-γ) compared to a healthy subject.

[0093] For clarity, "a subject in which the concentration / level of interferon-gamma (IFN-γ) in the subject (particularly in the subject's plasma) is elevated compared to a healthy subject" means a subject who has, and / or has been identified as having, and / or has been diagnosed as having, a concentration / level of interferon-gamma (IFN-γ) in the subject (particularly in the subject's plasma) that is elevated compared to a healthy subject.

[0094] In particular, "a subject in which the concentration / level of interferon-gamma (IFN-γ) in the subject (especially in the subject's plasma) is elevated compared to a healthy subject" means a subject who has, and / or has been identified as having, and / or has been diagnosed as having, a concentration / level of interferon-gamma (IFN-γ) (especially in the subject's plasma) that is higher than the concentration / level of interferon-gamma (IFN-γ) in 95% of healthy volunteers from a statistically representative group of healthy volunteers.

[0095] 47) A further aspect of the invention relates to an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment (particularly the treatment) of a type 1 interferon mediated disease in a subject, wherein said subject has a concentration / level (particularly plasma concentration / level) of interferon-gamma (IFN-γ) greater than 9.5 pg / mL.

[0096] 48) A further aspect of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in a method for the prevention or treatment (in particular treatment) of a subject having a type 1 interferon mediated disease (which responds to treatment with an S1P1 receptor modulator), said method comprising the steps of: a) providing a biological sample (particularly a plasma sample) from said subject; b) measuring the concentration / level of interferon-gamma (IFN-γ) in said biological sample; and c) treating the subject with an S1P1 receptor modulator if the concentration / level of interferon-gamma (IFN-γ) is elevated compared to the concentration / level of interferon-gamma (IFN-γ) in a biological sample from a healthy subject and / or is greater than 9.5 pg / mL.

[0097] 49) A further aspect of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1) to 48), wherein the concentration / level of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ) in the subject (particularly in the plasma of the subject) is elevated compared to a healthy subject.

[0098] 50) A further aspect of the invention is characterized in that the subject has a concentration / level (particularly a plasma concentration / level) of interferon-alpha (IFN-α) higher than 0.1 pg / mL, and / or relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1) to 48), having a concentration / level (particularly a plasma concentration / level) of interferon-gamma (IFN-γ) greater than 9.5 pg / mL.

[0099] 51) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in a method according to any one of embodiments 19) to 37), the method further comprising the step of: a) providing a biological sample (particularly a plasma sample) from said subject; b) measuring the concentration / level of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ) in said biological sample; and c) treating the subject with an S1P1 receptor modulator if the concentration / level of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ) is elevated compared to the concentration / level in a biological sample from a healthy subject.

[0100] For clarity, treatment of the subject with an S1P1 receptor modulator according to subembodiment 51) requires that both of the following conditions are met: (i) the subject's type 1 interferon gene signature score is higher than the respective threshold, and (ii) the concentration / level of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ) is elevated compared to the concentration / level in a biological sample from a healthy subject.

[0101] 52) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in a method according to any one of embodiments 19) to 37), the method further comprising the step of: a) providing a biological sample (particularly a plasma sample) from said subject; b) measuring the concentration / level of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ) in said biological sample; and c) treating the subject with an S1P1 receptor modulator if the concentration / level of interferon-alpha (IFN-α) is greater than 0.1 pg / mL and / or if the concentration / level of interferon-gamma (IFN-γ) is greater than 9.5 pg / mL.

[0102] For clarity, treatment of the subject with an S1P1 receptor modulator according to subembodiment 52) ​​requires that both of the following conditions are met: (i) the subject's type 1 interferon gene signature score is higher than the respective threshold, and (ii) the interferon-alpha (IFN-α) concentration / level is higher than 0.1 pg / mL and / or the interferon-gamma (IFN-γ) concentration / level is higher than 9.5 pg / mL.

[0103] 53) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 52), wherein the S1P1 receptor modulator is selected from fingolimod, ozanimod, siponimod, ponesimod, cenerimod, etrasimod, mocravimod and amiselimod or a pharmaceutically acceptable salt thereof (in particular from ozanimod, siponimod, ponesimod, cenerimod, etrasimod, mocravimod and amiselimod or a pharmaceutically acceptable salt thereof, especially from ozanimod, siponimod, ponesimod, cenerimod or a pharmaceutically acceptable salt thereof).

[0104] Fingolimod (also known as FTY720, Gilenya, Tascenso ODT, and 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol) is an S1P receptor modulator that binds to several S1P receptors. Fingolimod is available as the hydrochloride salt and is approved by the U.S. Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis. Fingolimod is approved by the U.S. Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis and is available as hard capsules in 0.25 mg and 0.5 mg strengths. Alternatively, fingolimod, used as the lauryl sulfate salt, is approved by the U.S. Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis and is available as orally disintegrating tablets in 0.25 mg and 0.5 mg strengths.

[0105] Ozanimod (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 an S1P receptor modulator that selectively binds to the S1P1 and S1P5 receptors. Ozanimod is used as the hydrochloride salt and 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. It is available as capsules in strengths of 0.23 mg, 0.46 mg, and 0.92 mg (equivalent to 0.25 mg, 0.5 mg, and 1 mg of ozanimod hydrochloride, based on the free base). The recommended maintenance dose is 0.92 mg orally once daily.

[0106] Siponimod (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 receptor modulator of S1P1 and S1P5. Siponimod, used as (2E)-2-butenedioate (2:1 mixture), is approved by the U.S. Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis and is available as tablets in strengths of 0.25 mg, 1 mg, and 2 mg. The recommended maintenance dose is 1 mg orally once daily (CYP2C9 * 1 / * 3 or * 2 / * 3 genotype) or 2 mg.

[0107] 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 the 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 as tablets in strengths 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 orally once daily.

[0108] Cenelimod (ACT-334441, also known as (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. Cenelimod was developed for the treatment of systemic lupus erythematosus and was available in tablet strengths of 0.5 mg, 1 mg, 2 mg, and 4 mg in a phase 2b clinical trial.

[0109] 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 a once-daily oral selective modulator of S1P1, S1P4, and S1P5. Etrasimod is being studied for various immune-inflammatory disorders, including ulcerative colitis, Crohn's disease, atopic dermatitis, eosinophilic esophagitis, and alopecia areata, and is available as a 2 mg tablet.

[0110] 54) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 52), wherein the S1P1 receptor modulator is selected from ozanimod, siponimod, ponesimod and cenerimod or a pharmaceutically acceptable salt thereof.

[0111] 55) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 52), wherein the S1P1 receptor modulator is cenerimod.

[0112] 56) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 55), wherein cenerimod is comprised in a pharmaceutical dosage form for oral administration (in particular a tablet formulation, especially a film-coated tablet).

[0113] 57) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 55) or 56), wherein cenerimod is contained in a pharmaceutical dosage form with a unit dose of 4 mg (particularly 4.0 mg).

[0114] The term "unit dose" as used herein means the amount of an active pharmaceutical ingredient (particularly cenerimod) administered and / or intended to be administered to a subject in a single dose. For example, if a single tablet or capsule is administered and / or intended to be administered to said subject per administration, the unit dose is the amount of an active pharmaceutical ingredient (particularly cenerimod) in a tablet or capsule (particularly a tablet) for oral administration.

[0115] 58) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 55) to 57), wherein cenerimod is intended to be and / or is administered to a patient once per day (once daily).

[0116] 59) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 55) to 58), wherein cenerimod is intended to be and / or is administered to a subject for a treatment period of at least 6 months (particularly at least 12 months, more particularly at least 60 months).

[0117] The term "treatment period" as used herein (particularly in relation to cenelimod) means the period between the first day of treatment with an active pharmaceutical ingredient, pharmaceutical composition and / or medicament (particularly in relation to cenelimod) and the last day of uninterrupted treatment, and treatment is "continuous" if it follows a regular repeated administration scheme, e.g., once daily. For example, if cenelimod is administered and / or is intended to be administered once daily for a treatment period of 6 months, this means that cenelimod is administered and / or is intended to be administered once every day for a period of 6 months.

[0118] 60) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 55) to 59), wherein cenerimod is intended to be and / or is administered chronically to a subject.

[0119] The term "chronic treatment" (or "chronically") means a treatment period which starts from the first day of treatment with the respective active pharmaceutical ingredient (especially cenelimod) and ends on the day on which further continuation of the treatment of the subject with the active pharmaceutical ingredient is no longer possible or indicated. Treatment of the subject with the active pharmaceutical ingredient may, for example, no longer be possible or indicated due to reasons such as side effects of the treatment, changes in the subject's health status (e.g., the need for a different drug treatment), changes in other relevant circumstances in the subject's life, death of the subject, etc. In particular, the term "chronic treatment" (or "chronically") means a treatment period which starts from the first day of treatment with the respective active pharmaceutical ingredient (especially cenelimod) and ends on the day on which further continuation of the treatment of the subject with the active pharmaceutical ingredient is no longer possible or indicated. This means a treatment period of at least 10 years before further treatment is no longer possible or indicated.

[0120] The term "start of treatment" refers to the first day of treatment with each of the above active pharmaceutical ingredients (particularly S1P1 receptor modulators; especially cenerimod).

[0121] The term "type 1 interferon-mediated disease" means a disease that is linked or associated with and / or shares a common cause (particularly linked and / or shares a common cause) with a high type 1 interferon (IFN-1) gene signature score in at least some of the subjects suffering from the disease.

[0122] 61) A further aspect of the present invention is directed to a method for treating type 1 interferon-mediated diseases, wherein the type 1 interferon-mediated disease is selected from the group consisting of systemic lupus erythematosus, discoid lupus, lupus nephritis, glomerulonephritis, type 1 diabetes, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, and celiac disease), multiple sclerosis, autoimmune thyroiditis, scleroderma, psoriasis, primary Sjogren's disease, systemic sclerosis, rheumatoid arthritis, transplant rejection, dermatomyositis, polymyositis, idiopathic inflammatory myositis, sarcoidosis, Aicardi-Goutières syndrome, vasculitis, sting-associated vasculopathy with onset in infancy, and inflammatory bowel disease (including Crohn's disease, ulcerative colitis, and celiac disease). The present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of Aspects 1) to 60), wherein the S1P1 receptor modulator is selected from the group consisting of chronic atypical neutrophilic dermatosis with infancy (SAVI) or chronic atypical neutrophilic dermatosis with lipodystrophy and hyperthermia syndrome (CANDLE).

[0123] S1P1 receptor modulators (particularly cenerimod) may be administered to treat type 1 interferon-mediated diseases or prophylactically to reduce the risk of developing and / or delay the onset of symptoms of type 1 interferon-mediated diseases.

[0124] The terms "treat" or "treatment" or "treating" when used in reference to a disease means that either the disease is cured in the subject; or that the subject continues to be adversely affected by the disease, but some or all of the symptoms of the disease are reduced or eliminated.

[0125] The terms "prevent" or "prevention" or "preventing" (or "prophylaxis" or "prophylactically"), when used in reference to a disease, mean that the risk of developing the disease in the subject is reduced and / or the onset of one or more symptoms of the disease is delayed in the subject.

[0126] 62) A further aspect of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1) to 60), wherein the type 1 interferon-mediated disease is systemic lupus erythematosus and / or lupus nephritis.

[0127] 63) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 60), wherein the type 1 interferon-mediated disease is systemic lupus erythematosus.

[0128] 64) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to 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) symptoms.

[0129] 65) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 64), which leads to a decrease from baseline in the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) after 12 months of treatment of said subject (particularly a subject with SLE) with said S1P1 receptor modulator (particularly cenerimod).

[0130] The mSLEDAI-2K score is based on the SLEDAI-2K (Gladman DD et al., J Rheumatol 2002;29(2) 288-291), modified to exclude leukopenia (Hermann V et al., Lupus Science&Medicine 2019;6:e000354.doi:10.1136 / lupus-2019-000354; ClinicalTrials.gov Identifier: NCT03742037).

[0131] The term "baseline" as used herein in relation to a value, score, index, etc. (e.g., a type 1 interferon (IFN-1) gene signature score or mSLEDAI-2K, etc.) means a value, score, index, etc. that is measured, calculated, or otherwise determined before (particularly shortly before, especially immediately before) the start of treatment with an active pharmaceutical ingredient (e.g., an S1P1 receptor modulator or cenerimod).

[0132] 66) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 64), which results in a reduction from baseline in the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) of at least 2 points after 12 months of treatment of said subject (particularly a subject with SLE) with said S1P1 receptor modulator (particularly cenerimod).

[0133] 67) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 64), wherein after 12 months of treatment of said subjects (particularly subjects with SLE) with said S1P1 receptor modulator (particularly cenerimod), results in a reduction from baseline of at least 4 points in the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) in at least 30% of said subjects.

[0134] 68) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 67), which leads to said decrease from baseline in mSLEDAI-2K in at least 50% of said subjects.

[0135] 69) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to embodiment 67), which leads to said decrease from baseline in mSLEDAI-2K in at least 70% of said subjects.

[0136] 70) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 64), in which after 12 months of treatment of said subject (particularly a subject with SLE) with either said S1P1 receptor modulator (particularly cenerimod) or a placebo, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) is statistically at least 1 point lower in the S1P1 receptor modulator-treated subject than in the placebo-treated subject.

[0137] 71) A further aspect of the invention relates to a method for treating a subject (particularly a subject with SLE) after 12 months of treatment with either an S1P1 receptor modulator (particularly cenerimod) or a placebo, The present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1) to 64), wherein the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) in subjects treated with the S1P1 receptor modulator is statistically at least 1.5 points lower than in placebo-treated subjects.

[0138] 72) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 64), wherein after 12 months of treatment of said subject (particularly a subject with SLE) with either said S1P1 receptor modulator (particularly cenerimod) or a placebo, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) is statistically at least 2 points lower in the S1P1 receptor modulator-treated subject than in the placebo-treated subject.

[0139] 73) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 72), wherein after 12 months of treatment of said subjects (particularly subjects with SLE) with said S1P1 receptor modulator (particularly with cenerimod), a response to SRI-4 is achieved in at least 30% of said subjects.

[0140] 74) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 72), wherein after 12 months of treatment of said subjects (especially subjects with SLE) with said S1P1 receptor modulator (especially with cenerimod), a response to SRI-4 is achieved in at least 50% of said subjects.

[0141] 75) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 72), wherein after 12 months of treatment of said subject (particularly a subject with SLE) with said S1P1 receptor modulator (particularly with cenerimod), a response to SRI-4 is achieved in at least 70% of said subjects.

[0142] 76) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 72), wherein the probability of a subject (especially a subject with SLE) responding to SRI-4 after 12 months of treatment is higher (especially statistically significantly higher) in subjects treated with said S1P1 receptor modulator (especially with cenerimod) than in subjects treated with placebo.

[0143] Response to the SLE responder index (SRI)-4 is defined as: - a decrease of at least 4 points on the mSLEDAI-2K compared to baseline; and - no new BILAG A organ domain score and no new BILAG B organ domain score of >1 compared to baseline; and - Subject's lupus disease activity has not worsened from baseline (worsening defined as an increase of ≥ 0.30 points on a 3-point Physician's Global Assessment (PGA) visual analog scale (VAS)).

[0144] 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(0 11):S37-46. doi:10.1002 / acr.20572.

[0145] The Physician's Global Assessment (PGA) is a visual analogue scale (VAS) with three benchmarks to assess disease activity over the past two weeks (Luijten KMAC et al., Autoimmunit (Eyelash Examination Reviews Volume 11, Issue 5, March 2012, pp. 326-329). On an analog scale of 0 to 3, mild flare is scored as 1.0 point, moderate flare as 2.0 to 2.5 points, and severe flare as 3 points.

[0146] 77) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 76), in which the time to first observation of a sustained mSLEDAI-2K response (defined as a reduction from baseline of at least 4 points) over 4 months is shorter (in particular statistically significantly shorter) in subjects treated with said S1P1 receptor modulator (in particular with cenerimod) than in subjects treated with placebo.

[0147] 78) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 76), wherein the time from initiation of treatment with cenerimod to first observation of a sustained mSLEDAI-2K response (defined as at least a 4-point reduction from baseline) over 4 months is statistically significantly shorter in subjects treated with cenerimod than in subjects treated with placebo.

[0148] 79) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 76), in which the time to first observation of a sustained response over 4 months in a mucocutaneous symptom is shorter (in particular statistically significantly shorter) in subjects treated with said S1P1 receptor modulator (in particular with cenerimod) than in subjects treated with placebo.

[0149] Time to first confirmation of a 4-month sustained mucocutaneous response was defined as: - There is no increase in the mSLEDAI-2K overall score, and - mSLEDAI-2K score for mucocutaneous symptoms (i.e., rash, alopecia, mucosal ulcers) has resolved (a score of zero) from baseline. 80) A further embodiment of the invention relates to cenelimod or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 76), in which the time from initiation of treatment with cenelimod to first observation of a 4-month sustained response in mucocutaneous symptoms is statistically significantly shorter in subjects treated with cenelimod than in subjects treated with placebo.

[0150] 81) A further embodiment of the present invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 80), wherein the S1P1 receptor modulator is cenerimod or a pharmaceutically acceptable salt thereof, and a clinically effective amount of cenerimod is administered and / or is intended to be administered to the subject.

[0151] 82) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 81), wherein the subject is a human (particularly a human patient).

[0152] The term "subject" includes a human or non-human animal. "Non-human animal" includes all vertebrates. In particular, the term "subject" refers to a human, especially a human patient.

[0153] 83) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 81), wherein the subject is a human patient suffering from a type 1 interferon-mediated disease.

[0154] 84) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 81), wherein the subject is a human patient suffering from systemic lupus erythematosus and / or lupus nephritis.

[0155] 85) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 81), wherein the subject is a human patient suffering from systemic lupus erythematosus.

[0156] 86) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 81), wherein the subject is a human patient suffering from systemic lupus erythematosus, and the subject has an mSLEDAI-2K score of ≧6 and a clinical mSLEDAI-2K score of ≧4, with at least 2 points for musculoskeletal or mucocutaneous symptoms (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers).

[0157] The clinical mSLEDAI-2K is an mSLEDAI-2K assessment score that does not include points due to hematuria, proteinuria, pyuria, low complement, increased DNA binding, and thrombocytopenia.

[0158] 87) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 81), wherein the subject is a human patient suffering from systemic lupus erythematosus, and the subject has: (i) an mSLEDAI-2K score of ≧6 and a clinical mSLEDAI-2K score of ≧4, with at least 2 points for musculoskeletal or mucocutaneous symptoms (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers); (ii) British Isles Lupus Assessment Group-2004 (BILAG) Grade B in two or more organ systems or BILAG Grade A in one or more organ systems; and (iii) a Physician's Global Assessment (PGA) score of ≧1.0 on a VAS of 0 to 3.

[0159] 88) A further embodiment of the invention relates to an S1P1 receptor modulator (in particular cenerimod) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1) to 87), wherein the subject is receiving standard background treatment (such standard background treatment shall be suitable for the treatment of type 1 interferon-mediated diseases, in particular systemic lupus erythematosus).

[0160] Standard background therapy for the treatment of systemic lupus erythematosus may be an antimalarial drug such as hydroxychloroquine, chloroquine, or quinacrine; mycophenolate mofetil or mycophenolic acid; azathioprine; methotrexate; oral corticosteroids such as prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; belimumab; anifrolumab; or any other agent approved by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or a corresponding national regulatory authority, and / or used as standard therapy at the date of initiation of treatment with an S1P1 receptor modulator.

[0161] Cenerimod can be used according to the invention as a medicament, for example in the form of a pharmaceutical composition, especially for enteral or parenteral administration.

[0162] Suitable dosage forms for enteral administration may be tablets or capsules (especially tablets) containing a pharmaceutical composition having an effective amount of cenerimod or a pharmaceutically acceptable salt thereof.

[0163] For the avoidance of any doubt, any pharmaceutical composition having a pharmaceutically effective amount of cenerimod may further comprise additional conventional excipients and / or additives, and may be formulated in accordance with the above. The excipients and / or additives may be used alone or in combination.

[0164] Reference is made to the extensive literature on the subject of pharmaceutically acceptable excipients and techniques referred to herein, see, e.g., R.C. Rowe, P.J. Seskey, S.C. Owen, Handbook of Pharmaceutical Excipients, 5th ed., Pharmaceutical Press 2006; Remington, The Science and Practice of Pharmacy, 21st ed. (2005), Part 5, "Pharmaceutical Manufacturing," published by Lippincott Williams & Wilkins.

[0165] Any reference herein to an S1P1 receptor modulator is also intended to refer to a pharmaceutically acceptable salt of such an S1P1 receptor modulator. In particular, any reference to cenelimod refers to cenelimod or a pharmaceutically acceptable salt form of cenelimod, preferably cenelimod in its free base form.

[0166] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxic effects. Such salts include inorganic or organic acid and / or base addition salts, depending on the presence of basic and / or acidic groups in the subject compound. References include, for example, "Handbook of Pharmaceutical Salts. Properties, Selection and Use.", P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co-crystals," Johan Wouters and Luc See Quere (Eds.), RSC Publishing, 2012.

[0167] When not used in reference to temperature, the term "about" placed before a numerical value "X" means in this application between 10% of XX and 10% of X+X, preferably between 5% of XX and 5% of X+X. In the specific case of temperatures, the term "about" placed before a temperature "Y" means in this application between Y-10°C and Y+10°C, preferably between Y-5°C and Y+5°C.

[0168] Whenever the term "between" is used to describe a range of numerical values, it is understood that the endpoints of the stated range are expressly included in the range.

[0169] Any of the aspects relating to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in the prevention or treatment (particularly the treatment) of a type 1 interferon-mediated disease also relates to the use of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment (particularly the treatment) of a type 1 interferon-mediated disease; and a method for the prevention or treatment (particularly the treatment) of a type 1 interferon-mediated disease, which comprises administering to a subject in need thereof an effective amount (particularly a pharmaceutically effective amount) of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof.

[0170] Furthermore, any of the aspects relating to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use in a method of prevention or treatment (particularly treatment) of a subject having a type 1 interferon-mediated disease also include use of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in a method of prevention or treatment (particularly treatment) of a subject having a type 1 interferon-mediated disease; and a method of prevention or treatment (particularly treatment) of a subject having a type 1 interferon-mediated disease, comprising administering to a subject in need thereof an effective amount (particularly a pharmaceutically effective amount) of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof. This also relates to:

[0171] 89) A further aspect of the present invention relates to a method for the prevention or treatment (in particular the treatment) of a type 1 interferon mediated disease, said 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 said subject has a high type 1 interferon (IFN-1) gene signature score.

[0172] 90) The method according to embodiment 89), wherein the subject has a high type 1 interferon (IFN-1) gene signature score at the start of treatment.

[0173] 91) The method according to embodiment 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.

[0174] l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0175] 92) The method according to embodiment 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.

[0176] 93) The method according to embodiment 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.

[0177] 94) The method according to embodiment 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.

[0178] 95) The method according to embodiment 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.

[0179] 96) The method according to embodiment 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.

[0180] 97) The method according to any one of embodiments 89) to 96), wherein the subject's type 1 interferon gene signature score is equal to or greater than the minimum of the bimodal distribution curve of type 1 interferon gene signature scores of SLE patients.

[0181] 98) The method according to embodiment 97), wherein the subject's type 1 interferon gene signature score is at least 0.5 units, at least 1 unit, at least 2 units, or at least 3 units (in particular at least 1 unit) higher than the minimum of the bimodal distribution curve of type 1 interferon gene signature scores of SLE patients.

[0182] 99) The method according to any one of embodiments 89) to 96), wherein the subject has a type 1 interferon gene signature score that is higher than a type 1 interferon gene signature score of a (representative) healthy subject.

[0183] 100) The method according to any one of embodiments 89) to 96), wherein the subject has a type 1 interferon gene signature score higher than a threshold.

[0184] 101) The method according to embodiment 100), wherein the threshold is an IFN-1 gene signature score selected from values ​​that are 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; particularly 2.0 to 3.0, and more 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 individuals.

[0185] 102) The method according to embodiment 100), wherein said threshold value of the IFN-1 gene signature score is 2 standard deviations higher than the arithmetic mean value from at least 100, at least 200, at least 300, or (preferably) at least 500 healthy individuals.

[0186] 103) The above threshold of the IFN-1 gene signature score is between -1.0 and 0 (especially The method according to embodiment 100), wherein the ρ is about −0.5).

[0187] 104) The method according to embodiment 100), wherein the threshold value of the IFN-1 gene signature score is −0.5.

[0188] 105) The method according to any one of embodiments 89) to 104), wherein the type 1 interferon gene signature score of the subject is calculated (determined) by a method comprising the steps of: (i) measuring the gene (RNA) expression level of type 1 interferon-related genes (particularly RSAD2, IFI44, IFI44L and IFI27; or RSAD2, IFI27, IFIT1 and HERC5; especially RSAD2, IFI27, IFIT1 and HERC5) in a blood sample from the subject (particularly by measuring the height of each peak by capillary electrophoresis); (ii) measuring the gene expression levels of three housekeeping (normalizer) genes, ACTB, GAPDH, and TFRC, in a blood sample from the subject; (iii) calculating the logarithm of the expression level of each of the three housekeeping genes and the arithmetic mean thereof; (iv) calculating the normalized expression for each of the type 1 interferon-related genes according to formula (I): Normalized expression of gene i = Log2(height of gene i) - mean(Log2(height of normalizer gene)) Formula (I) and (v) calculating a type 1 interferon gene signature score by averaging the normalized expression values ​​of said type 1 interferon-related genes.

[0189] 106) The type 1 interferon gene signature score of the subject is calculated (determined) by a method according to any one of embodiments 91) to 104), comprising the steps of: (i) measuring the gene (RNA) expression level of type 1 interferon-related genes (particularly RSAD2, IFI44, IFI44L and IFI27; or RSAD2, IFI27, IFIT1 and HERC5; especially RSAD2, IFI27, IFIT1 and HERC5) in a blood sample from the subject (particularly by measuring the height of each peak by capillary electrophoresis); (ii) measuring the gene expression levels of three housekeeping (normalizer) genes, ACTB, GAPDH, and TFRC, in a blood sample from the subject; (iii) calculating the logarithm of the expression level of each of the three housekeeping genes and the arithmetic mean thereof; (iv) calculating the normalized expression for each of the four type 1 interferon-related genes according to formula (I): Normalized expression of gene i = Log2(height of gene i) - mean(Log2(height of normalizer gene)) Formula (I) and (v) calculating a type 1 interferon gene signature score by averaging the normalized expression values ​​of the four type 1 interferon-related genes.

[0190] 107) A further aspect of the invention relates to a method for the prevention or treatment (particularly the treatment) of a type 1 interferon mediated disease in a subject (particularly a type 1 interferon mediated disease that responds to treatment with an S1P1 receptor modulator), said method comprising the steps of: a) providing a biological sample (particularly a blood sample or serum sample, especially a blood sample) from said subject; b) the presence 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 (in particular, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, H assaying gene expression of at least three (particularly at least four) type 1 interferon-related genes selected from the group consisting of ERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6, especially EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; c) determining a normalized expression value for each gene assayed; d) calculating a type 1 interferon gene signature score by averaging the 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 if the subject's type 1 interferon gene signature score is higher than a threshold value.

[0191] 108) The method according to embodiment 107), wherein the subject has a type 1 interferon gene signature score at the start of treatment that is higher than a threshold value and / or higher than a type 1 interferon gene signature score in a biological sample of a healthy subject at the start of treatment.

[0192] 109) The method according to embodiment 107) or 108), wherein the biological sample is a blood sample.

[0193] 110) The method according to any one of embodiments 107) to 109), wherein one of the following groups of type 1 interferon-related genes is selected for assaying 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.

[0194] l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0195] 111) The method according to any one of embodiments 107) to 109), wherein one of the following groups of type 1 interferon-related genes is selected for assaying 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.

[0196] 112) The method according to any one of embodiments 107) to 109), wherein one of the following groups of type 1 interferon-related genes is selected for assaying 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.

[0197] 113) The method according to any one of embodiments 107) to 109), wherein one of the following groups of type 1 interferon-related genes is selected for assaying gene expression: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

[0198] 114) The method according to any one of embodiments 107) to 109), wherein the type 1 interferon-related genes for assaying gene expression are EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15.

[0199] 115) The method according to any one of embodiments 107) to 109), wherein the type 1 interferon-related genes for assaying gene expression are RSAD2, IFI27, IFIT1, and HERC5.

[0200] 116) The method according to any one of embodiments 107) to 115), wherein said gene expression is assayed by capillary electrophoresis.

[0201] 117) The method according to any one of embodiments 107) to 115), wherein said gene expression of type 1 interferon-related genes is assayed by measuring peak heights in a capillary electrophoresis electropherogram.

[0202] 118) The method according to any one of aspects 107) to 117), wherein the normalized expression value comprises: (i) measuring gene expression levels of the three housekeeping (normalizer) genes, ACTB, GAPDH, and TFRC, in a blood sample from the subject; (ii) calculating the binary logarithm (log2) of the expression level of each of the three housekeeping genes and the arithmetic mean thereof; and (iii) calculating a normalized expression value for each of the type 1 interferon-related genes using formula (II): Normalized expression of gene i = Log2(expression level of gene i) - mean(Log2(expression level of normalizer gene)) Formula (II); The method is determined by:

[0203] 119) The type 1 interferon gene signature score of the above subjects is The method according to any one of embodiments 107) to 118), wherein the type 1 interferon gene signature score is greater than or equal to the minimum of a bimodal distribution curve.

[0204] 120) The method according to embodiment 119), wherein the subject's type 1 interferon gene signature score is at least 0.5 units, at least 1 unit, at least 2 units, or at least 3 units (particularly at least 1 unit) higher than the minimum of the bimodal distribution curve of type 1 interferon gene signature scores of SLE patients.

[0205] 121) The method according to any one of aspects 107) to 118), wherein the threshold is an IFN-1 gene signature score selected from the group consisting of values ​​that are 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; particularly 2.0 to 3.0, and more 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 individuals.

[0206] 122) The method according to any one of embodiments 107) to 118), wherein the threshold value for the IFN-I gene signature score is two standard deviations higher than the arithmetic mean value from at least 100, at least 200, at least 300, or (preferably) at least 500 healthy individuals.

[0207] 123) The method according to any one of embodiments 107) to 118), wherein the threshold value of the IFN-1 gene signature score is selected from values ​​between −1.0 and 0 (particularly about −0.5, especially −0.5).

[0208] 124) The method according to any one of embodiments 107) to 118), wherein the threshold value for the IFN-1 gene signature score is −0.5.

[0209] 125) A further aspect of the invention relates to a method for the prevention or treatment (particularly the treatment) of a type 1 interferon mediated disease in a subject (particularly a type 1 interferon mediated disease that responds to treatment with an S1P1 receptor modulator), said method comprising the steps of: a) providing a biological sample (particularly a blood sample or serum sample, especially a blood sample) from said subject; b) assaying gene expression of type 1 interferon-related genes, RSAD2, IFI27, IFIT1 and HERC5 in said biological sample (particularly by measuring peak heights in capillary electrophoresis electropherograms); c) determining a normalized expression value for each assayed gene by (i) measuring the gene expression levels of the three housekeeping (normalizer) genes, ACTB, GAPDH, and TFRC, in the subject's biological sample; (ii) calculating the logarithm of the expression level of each of the three housekeeping genes and the arithmetic mean thereof; and (iii) calculating a normalized expression value for each of the type 1 interferon-related genes according to formula (II): Normalized expression of gene i = Log2(expression level of gene i) - mean(Log2(expression level of normalizer gene)) Formula (II); determining the d) calculating a type 1 interferon gene signature score by averaging the normalized expression values; and e) If the subject's type 1 interferon gene signature score is higher than the threshold The method comprises administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the threshold value is selected from values ​​between -1.0 and 0 (particularly -0.5).

[0210] 126) A further aspect of the present invention relates to a method for the prevention or treatment (particularly treatment) of a type 1 interferon mediated disease in a subject (particularly a type 1 interferon mediated disease that responds to treatment with an S1P1 receptor modulator), said method comprising administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to said subject in need thereof, wherein at least three (particularly at least four) type 1 interferon related genes are upregulated in said subject (particularly in a biological sample from said subject), said type 1 interferon related genes being DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, RSAD2, IFI44, IFI44L, IF I27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6 (in particular IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6, especially EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15).

[0211] 127) The method according to embodiment 126), wherein the type 1 interferon-related gene in the subject is upregulated at the start of treatment.

[0212] 128) The method according to embodiment 126) or 127), wherein at least three genes from at least one of the following groups 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.

[0213] l) EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, and ISG15; or m) RSAD2, IFI27, IFIT1 and HERC5.

[0214] 129) The method according to embodiment 126) or 127), wherein at least three genes from at least one of the following groups 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.

[0215] 130) The method according to embodiment 126) or 127), wherein at least three genes from at least one of the following groups 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.

[0216] 131) The method according to embodiment 126) or 127), wherein at least three genes from at least one of the following groups of type 1 interferon-related genes are upregulated in the subject: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

[0217] 132) The method according to embodiment 126) or 127), in which 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.

[0218] 133) The method according to embodiment 126) or 127), in which at least three of the following type 1 interferon-related genes are upregulated in the subject: RSAD2, IFI27, IFIT1, and HERC5.

[0219] 134) A further aspect of the present invention relates to a method for the prevention or treatment (particularly the treatment) of a type 1 interferon mediated disease in a subject (particularly a type 1 interferon mediated disease that responds to treatment with an S1P1 receptor modulator), said method comprising administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to said subject in need thereof, wherein said subject has an elevated concentration / level of interferon-gamma (IFN-γ) (particularly in the plasma of said subject) compared to a healthy subject.

[0220] 135) A further aspect of the invention relates to a method for the prevention or treatment (particularly the treatment) of a type 1 interferon mediated disease (particularly a type 1 interferon mediated disease that responds to treatment with an S1P1 receptor modulator) in a subject, said method comprising administering a pharmaceutically effective amount of an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof to said subject in need thereof, wherein said subject has a concentration / level (particularly a plasma concentration / level) of interferon-gamma (IFN-γ) greater than 9.5 pg / mL.

[0221] 136) A further aspect of the invention is the prevention of a type 1 interferon mediated disease in a subject, particularly a type 1 interferon mediated disease that responds to treatment with an S1P1 receptor modulator. Or a method for treatment (particularly treatment), said method comprising the steps of: a) providing a biological sample (particularly a plasma sample) from said subject; b) measuring the concentration / level of interferon-gamma (IFN-γ) in said 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 if the concentration / level of interferon-gamma (IFN-γ) is elevated compared to the concentration / level of interferon-gamma (IFN-γ) in a biological sample from a healthy subject and / or is higher than 9.5 pg / mL.

[0222] 137) The method according to any one of embodiments 89) to 136), wherein the concentration / level of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ) in the subject (particularly in the plasma of the subject) is elevated compared to a healthy subject.

[0223] 138) The method according to any one of embodiments 89) to 136), wherein the subject has a concentration / level (particularly a plasma concentration / level) of interferon-alpha (IFN-α) greater than 0.1 pg / mL and / or a concentration / level (particularly a plasma concentration / level) of interferon-gamma (IFN-γ) greater than 9.5 pg / mL.

[0224] 139) The method according to any one of embodiments 107) to 125), further comprising the step of: a) providing a biological sample (particularly a plasma sample) from said subject; b) measuring the concentration / level of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ) in said 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 the other conditions, the concentration / level of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ) is elevated compared to the concentration / level in a biological sample from a healthy subject.

[0225] 140) The method according to any one of embodiments 107) to 125), further comprising the step of: a) providing a biological sample (particularly a plasma sample) from said subject; b) measuring the concentration / level of interferon-alpha (IFN-α) and / or interferon-gamma (IFN-γ) in said 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 the other conditions, the concentration / level of interferon-alpha (IFN-α) is greater than 0.1 pg / mL and / or the concentration / level of interferon-gamma (IFN-γ) is greater than 9.5 pg / mL.

[0226] 141) The method according to any one of aspects 89) to 140), wherein the S1P1 receptor modulator is selected from fingolimod, ozanimod, siponimod, ponesimod, cenerimod, etrasimod, moclavimod, and amiselimod, or a pharmaceutically acceptable salt thereof (particularly from ozanimod, siponimod, ponesimod, cenerimod, etrasimod, moclavimod, and amiselimod, or a pharmaceutically acceptable salt thereof, especially from ozanimod, siponimod, ponesimod, cenerimod, or a pharmaceutically acceptable salt thereof).

[0227] 142) The method according to any one of embodiments 89) to 140), wherein the S1P1 receptor modulator is selected from ozanimod, siponimod, ponesimod, and cenerimod, or a pharmaceutically acceptable salt thereof.

[0228] 143) The method according to any one of embodiments 89) to 140), wherein the S1P1 receptor modulator is cenerimod.

[0229] 144) The method according to embodiment 143), wherein cenerimod is contained in a pharmaceutical dosage form for oral administration (particularly a tablet formulation, especially a film-coated tablet).

[0230] 145) The method according to embodiment 143) or 144), wherein cenerimod is contained in a pharmaceutical dosage form with a unit dose of 4 mg (particularly 4.0 mg).

[0231] 146) The method according to any one of embodiments 143) to 145), wherein cenerimod is intended to be and / or is administered to the patient once per day (QD).

[0232] 147) The method according to any one of embodiments 143) to 146), wherein cenerimod is intended to be and / or is administered to the subject for a treatment period of at least 6 months (particularly at least 12 months, more particularly at least 60 months).

[0233] 148) A further embodiment of the invention relates to an S1P1 receptor modulator or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 143) to 147), wherein cenerimod is intended to be and / or is administered chronically to a subject.

[0234] 149) The method according to any one of aspects 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 Sjogren's 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 hyperthermia syndrome (CANDLE).

[0235] 150) The method according to any one of embodiments 89) to 148), wherein the type 1 interferon-mediated disease is systemic lupus erythematosus and / or lupus nephritis.

[0236] 151) The method according to any one of embodiments 89) to 148), wherein the type 1 interferon-mediated disease is systemic lupus erythematosus.

[0237] 152) The method according to 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) symptoms.

[0238] 153) A method according to any one of embodiments 89) to 152), which leads to a decrease from baseline in modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) after 12 months of treatment of said subject (particularly a subject with SLE) with an S1P1 receptor modulator (particularly cenerimod).

[0239] 154) A method according to any one of embodiments 89) to 152), which results in a reduction of at least 2 points (particularly at least 4 points) from baseline in the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) after 12 months of treatment of said subject (particularly a subject with SLE) with an S1P1 receptor modulator (particularly cenerimod).

[0240] 155) A method according to any one of embodiments 89) to 152), wherein after 12 months of treatment of said subjects (particularly subjects with SLE) with an S1P1 receptor modulator (particularly cenerimod), at least 30% of said subjects experience a reduction from baseline in the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) of at least 4 points.

[0241] 156) The method according to any one of embodiments 153) to 155), wherein said decrease from baseline in mSLEDAI-2K is achieved in at least 50% of said subjects.

[0242] 157) A method according to any one of embodiments 153) to 155), which results in the reduction from baseline in mSLEDAI-2K in at least 70% of the subjects.

[0243] 158) The method according to any one of embodiments 89) to 152), wherein after 12 months of treatment of the subject (particularly a subject with SLE) with either the S1P1 receptor modulator (particularly cenerimod) or a placebo, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) is statistically at least 1 point lower in the S1P1 receptor modulator-treated subjects than in the placebo-treated subjects.

[0244] 159) The method according to any one of embodiments 89) to 152), wherein after 12 months of treatment of said subject (particularly a subject with SLE) with either said S1P1 receptor modulator (particularly cenerimod) or a placebo, the modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) is statistically at least 1.5 points lower in S1P1 receptor modulator-treated subjects than in placebo-treated subjects.

[0245] 160) The method according to any one of embodiments 89) to 152), wherein after 12 months of treatment of the subject (particularly a subject with SLE) with either the S1P1 receptor modulator (particularly cenerimod) or a placebo, the modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) is statistically at least 2 points lower in the S1P1 receptor modulator-treated subjects than in the placebo-treated subjects.

[0246] 161) A method according to any one of embodiments 89) to 160), wherein after 12 months of treatment of said subject (particularly a subject with SLE) with said S1P1 receptor modulator (particularly with cenerimod), a response to SRI-4 is achieved in at least 30% of said subjects.

[0247] 162) The method according to any one of embodiments 89) to 160), wherein after 12 months of treatment of said subject (particularly a subject with SLE) with said S1P1 receptor modulator (particularly with cenerimod), a response to SRI-4 is achieved in at least 50% of said subjects.

[0248] 163) The method according to any one of embodiments 89) to 160), wherein after 12 months of treatment of said subject (particularly a subject with SLE) with said S1P1 receptor modulator (particularly with cenerimod), a response to SRI-4 is achieved in at least 70% of said subjects.

[0249] 164) The method according to any one of embodiments 89) to 160), wherein the probability of a subject (especially a subject with SLE) responding to SRI-4 after 12 months of treatment is higher (especially statistically significantly higher) in subjects treated with said S1P1 receptor modulator (especially with cenerimod) than in subjects treated with placebo.

[0250] 165) According to any one of aspects 89) to 164), the time to first confirmation of a 4-month sustained mSLEDAI-2K response (defined as a reduction of at least 4 points from baseline) is shorter (particularly statistically significantly shorter) in subjects treated with the S1P1 receptor modulator (particularly with cenerimod) than in subjects treated with placebo. method.

[0251] 166) The method according to any one of aspects 89) to 164), wherein the S1P1 receptor modulator is cenerimod, and the time from initiation of treatment with cenerimod to first confirmation of a 4-month sustained mSLEDAI-2K response (defined as at least a 4-point reduction from baseline) is statistically significantly shorter in subjects treated with cenerimod than in subjects treated with placebo.

[0252] 167) A method according to any one of embodiments 89) to 164), in which the time to first observation of a sustained response over 4 months in mucocutaneous symptoms is shorter (particularly statistically significantly shorter) in subjects treated with the S1P1 receptor modulator (particularly with cenerimod) than in subjects treated with placebo.

[0253] 168) The method according to any one of aspects 89) to 164), wherein the S1P1 receptor modulator is cenelimod, and the time from initiation of treatment with cenelimod to first confirmation of a 4-month sustained response in mucocutaneous symptoms is statistically significantly shorter in subjects treated with cenelimod than in subjects treated with placebo.

[0254] 169) The method according to any one of embodiments 89) to 168), wherein the S1P1 receptor modulator is cenerimod or a pharmaceutically acceptable salt thereof, and a clinically effective amount of cenerimod is administered and / or is intended to be administered to the subject.

[0255] 170) The method according to any one of embodiments 89) to 169), wherein the subject is a human (particularly a human patient).

[0256] 171) The method according to any one of embodiments 89) to 169), wherein the subject is a human patient suffering from a type 1 interferon-mediated disease.

[0257] 172) The method according to any one of embodiments 89) to 169), wherein the subject is a human patient suffering from systemic lupus erythematosus and / or lupus nephritis.

[0258] 173) The method according to any one of embodiments 89)-169), wherein the subject is a human patient suffering from systemic lupus erythematosus.

[0259] 174) The method according to any one of embodiments 89)-169), wherein the subject is a human patient suffering from systemic lupus erythematosus, and the subject has an mSLEDAI-2K score of ≧6 and a clinical mSLEDAI-2K score of ≧4, with at least 2 points for musculoskeletal or mucocutaneous symptoms (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers).

[0260] 175) The subject is a human patient with systemic lupus erythematosus, and the subject has (i) an mSLEDAI-2K score of ≥ 6 and a clinical mSLEDAI-2K score of ≥ 4, with at least 2 points for musculoskeletal or mucocutaneous symptoms (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers); (ii) British Isles Lupus Assessment Group-2004 (BILAG) Grade B in two or more organ systems or BILAG Grade A in one or more organ systems; and (iii) The method according to any one of embodiments 89) to 169), wherein the patient has a Physician's Global Assessment (PGA) score of ≧1.0 on a VAS of 0 to 3.

[0261] 176) The method according to any one of embodiments 89) to 175), wherein the subject is receiving standard background treatment (such standard background treatment being suitable for the treatment of type 1 interferon-mediated diseases, in particular systemic lupus erythematosus).

[0262] 177) A further aspect of the present invention relates to a method of treating a type 1 interferon mediated disease (particularly systemic lupus erythematosus) in a subject in need thereof, wherein the subject has an elevated type 1 interferon (IFN-1) gene signature score; the method comprising administering to the subject a pharmaceutical composition comprising a clinically effective amount of an S1P1 receptor modulator (particularly cenerimod) or a pharmaceutically acceptable salt thereof.

[0263] 178) The method according to embodiment 177), wherein the S1P1 receptor modulator is cenerimod and the clinically effective amount of cenerimod is 4.0 mg per day.

[0264] 179) A method according to embodiment 177) or 178), wherein the method comprises administering to the subject a pharmaceutical composition comprising an amount of the S1P1 receptor modulator (particularly cenerimod) that has been clinically proven to be safe and clinically proven to be effective.

[0265] Unless otherwise indicated, the term "clinically proven" as used herein (either independently or to modify the terms "safety" and / or "efficacy") means proven through a clinical trial that meets the approval standards of the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or an equivalent national regulatory authority. For example, the clinical trial may be a randomized, double-blind study of any suitable size used to clinically prove the efficacy of a drug.

[0266] The term "clinically proven effective" as used herein in connection with a dose, dosing regimen, treatment, or method refers to the effectiveness of a particular dose, dosing, or treatment regimen. Efficacy can be measured based on changes in the course of a disease in response to the agent of the invention. For example, an S1P1 receptor modulator (particularly cenerimod) is administered to a subject in an amount and for a duration sufficient to elicit an improvement, preferably a sustained improvement, in at least one indicator reflecting the severity of the disorder being treated. Various indicators reflecting the degree of a subject's condition, disease, or symptoms can be assessed to determine whether the amount and duration of treatment are sufficient. Such indicators include clinically recognized indicators of, for example, disease severity, symptoms, or manifestations of the disorder in question. The degree of improvement is generally determined by a physician, who can base their determination on signs, symptoms, biopsies, or other test results, and can also use questionnaires administered to the subject, such as quality of life or patient-reported outcome questionnaires developed for a particular disease. For example, a compound of the invention can be administered to achieve improvement in a subject's symptoms associated with systemic lupus erythematosus. Improvement can be demonstrated by an improvement in an index of disease activity, by an improvement in clinical symptoms, or by any other indicator of disease activity.

[0267] In certain embodiments, such an index of disease activity is the Modified Systemic Lupus Erythematosus Disease Activity Index 2000 compared to baseline and / or compared to placebo.

[0268] In another particular embodiment, such indicator of disease is the Systemic Lupus Erythematosus Responder Index (SRI-4) compared to baseline and / or compared to placebo.

[0269] In another particular embodiment, such indicators of disease are measured by a 4-month sustained improvement in the response rate compared to placebo. Time to first confirmed mSLEDAI-2K response (defined as at least a 4-point decrease from baseline).

[0270] In another particular embodiment, such indicator of disease is time to first confirmation of a sustained response in a mucocutaneous symptom over 4 months compared to placebo.

[0271] In certain embodiments, a clinically effective amount of cenerimod is an amount that results in a reduction in the Modified Systemic Lupus Erythematosus Disease Activity Index 2000 compared to baseline and / or compared to placebo, as demonstrated by a clinical trial having the protocol described in the "Opus Trial Summary" below.

[0272] The term "clinically proven safe," when associated with a dose, dosing regimen, treatment, or method using the compound of the present invention, cenerimod, means a favorable risk:benefit ratio, with treatment-emergent adverse events (AEs or TEAEs) occurring at an acceptable frequency and / or severity. As used herein, the terms "adverse event," "treatment-emergent adverse event," and "adverse reaction" mean any adverse, undesired, unintended, or undesirable symptom or outcome associated with or resulting from the administration of a pharmaceutical composition or treatment. It is an untoward medical occurrence in a subject administered a pharmaceutical product.

[0273] Abbreviation: BICLA British Isles Lupus Assessment Group-based Composite Lupus Assessment BILAG British Isles Lupus Assessment Group CT Computed Tomography DNA deoxyribonucleic acid ECG electrocardiogram EDTA Ethylenediaminetetraacetic acid FDA US 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 NSAIDs (nonsteroidal anti-inflammatory drugs) (O)CS (oral) corticosteroid PCR polymerase chain reaction PD (response) Pharmacodynamic (response) PGA (score) Physician's Global Assessment (score) RFU Relative Fluorescence Unit(s) RNA ribonucleic acid SLE Systemic lupus erythematosus SRI Systemic Lupus Erythematosus Response Index Erythematosus Responder Index) SRI-4 SRI with at least a 4-point improvement from baseline on the mSLEDAI-2K STAT signal transduction and activator of transcription TYK tyrosine kinase ULN Upper limit of normal VAS Visual Analogue Scale (VAS)

[0274] Experimental section In a phase 2b clinical trial (CARE study), the distribution of IFN-1 gene expression signature scores was measured between the placebo and cenerimod 4 mg cohorts (Figure 1A). A bimodal distribution was observed, and a cutoff value of -0.5 was used to separate IFN-high and IFN-low patients. Surprisingly, after 6 months of treatment with cenerimod 4 mg, the IFN score significantly decreased compared to placebo (Figure 1B). Contrary to expectations, a subgroup analysis of patients classified as IFN-high and IFN-low at baseline revealed that only a decrease in mSLEDAI-2K from baseline was observed in the IFN-high subgroup (Figure 1C). In the IFN-1-high subgroup, a larger change from baseline in mSLEDAI-2K was observed in the 4 mg group compared with placebo, with least-squares LS-Means (SE) changes from baseline to month 6 of -2.6 for placebo and -5.4 for cenerimod 4 mg (Figure 1C). This improvement in mSLEDAI-2K in IFN-1-high patients was observed despite a similar decrease in blood lymphocyte counts observed in both IFN-1-low and -IFN-high patients (Figure 2), suggesting that lymphopenia is not predictive of a decrease in mSLEDAI-2K.

[0275] Furthermore, cenelimod reduced both the IFN-1 gene signature score and IFN-α protein in the plasma of cenelimod-treated patients (Figure 3A), both of which are more abundant in SLE patients compared with healthy volunteers (Figure 3B). Patients with higher baseline IFN-α protein levels exhibited a greater reduction in mSLEDAI-2K scores compared with the low IFN-α protein cohort (Figure 3C). In addition, cenelimod 4 mg reduced plasma IFN-gamma protein at baseline and at 6 months compared with placebo (Figure 4A), which is also more abundant in SLE patients compared with healthy volunteers (Figure 4B). Patients with higher baseline IFN-gamma protein levels exhibited a greater reduction in mSLEDAI-2K scores compared with the low IFN-gamma protein cohort (Figure 4C).

[0276] Importantly, the IFN-1 gene signature score correlated with baseline IFN-alpha plasma protein measurements (Figure 5A), strengthening the validity of the IFN-alpha gene signature score as a proxy for IFN-alpha protein. Additionally, cenerimod 4 mg reduced IFN-1 scores at 6 months compared to baseline in both IFN-1-high and IFN-1-low patients, a reduction not observed with placebo (Figure 5B). Surprisingly, despite cenerimod 4 mg reducing IFN scores equally in all patients, the reduction in mSLEDAI-2K was evident only in patients with high IFN-1 levels.

[0277] Gene expression signatures Regulation of biological activity is reflected by changes in gene expression. These changes can be described by specific gene expression signatures. A gene signature is defined by a set of genes that show increased or decreased expression in association with a biological activity. Gene signatures can be calculated using quantitative reverse transcription PCR. These are often analyzed using RT-qPCR (RT-qPCR), which allows for the derivation of normalized expression levels for each gene of interest.

[0278] The IFN-1 signature reflects IFN-regulated genes, meaning that these genes are upregulated by the biological activity of type 1 IFN. The IFN-1 gene signature was first described in 2003 in cells isolated from SLE patients [Baechler, E. C. et al., PNAS 2003, 100(5), 2610-2615, PMID: 12604793].

[0279] A key feature of the IFN-I gene signature is its bimodal distribution in SLE patients, which can be divided into high and low IFN-I gene signatures [El-Sherbiny, YM. et al., Scientific Reports 2018, 8, 5793, DOI: 10.1038 / s41598-018-24198-1, PMID: 29643425]. There are two IFN-I gene signatures most commonly used in clinical studies: the AstraZeneca [AZ] and DxTerity signatures. Both signatures consist of four genes, but the difference lies in the gene selection. Both signatures include IFI27 and RSAD2, but AZ also includes IFI44 and IFI44L, whereas DxTerity uses IFIT1 and HERC5. Importantly, the two IFN-I gene signatures correlate highly and therefore classify SLE patients into the same high and low IFN-I status strata, as long as the cutoff values ​​are derived in the same way. It has previously been shown that different IFN-I gene signatures classify patients into the same IFN-I 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).

[0280] The DxTerity Gene Expression Assay includes 10 interferon genes (EIF2AK2, HERC5, IFI27, IFI44, IFI44L, IFI6, IFIT1, ISG15, MX1, and RSAD2). Four of these genes (HERC5, IFIT1, IFI27, and RSAD2) are used in the IFN-1 test to define the IFN-1 gene signature status (high / low). The assay uses proprietary Chemical Ligation-dependent Probe Amplification (CLPA / DxDirect) technology.

[0281] The DxTerity signature cutoff point of -0.5 (to distinguish between high and low IFN subjects) is based on the 95th percentile of over 500 healthy subjects (Figure 1A), whereas the AZ cutoff point would classify over 10% of healthy subjects as high.

[0282] Each target gene expression level is normalized to three housekeeping (normalizer) genes (ACTB, GAPDH, and TFRC). The gene expression level for an individual subject is calculated from the capillary electrophoresis electropherogram using the intensity of the fragment peak heights (RFU) corresponding to the four interferon-responsive genes relative to the average peak height intensity of the three normalizer genes (from the same subject) using the following formula: Normalized expression of gene i = Log2(height of gene i) - mean(Log2(height of normalizer gene)) A subject's IFN-I gene signature score is determined by averaging the normalized expression values ​​of the HERC5, IFI27, IFIT1 and RSAD2 genes.

[0283] The high / low cutoff (-0.5) was based on the 95th percentile of over 500 healthy individuals and is located two standard deviations above the mean IFN-I gene signature score of healthy volunteers, which lies in the trough of the classic bimodal IFN-I gene signature score distribution seen in SLE patients.

[0284] Plasma proteins Interferon alpha (IFNa or IFN-α) was measured in EDTA plasma using an ELISA assay (41115) from PBL Assay Science according to the manufacturer's instructions. Normal IFNa levels are below the detection limit of the assay (0.1 pg / ml). The high / low cutoffs were based on the 95th percentile of 10 healthy human volunteers (Figure 3B).

[0285] Interferon gamma (IFNg or IFN-γ) was measured in EDTA plasma using Mesoscale discovery's V-plex assay (K151A9H-2) according to the manufacturer's instructions. Normal IFNg levels have been reported to be 3.80 pg / ml (median, n = 27, 0.46-22.8 pg / ml). For comparison, our in-house analysis of 10 EDTA plasma samples from healthy volunteers revealed a median of 1.49 pg / ml (0.49-12.28 pg / ml). The high / low cutoffs were based on the 95th percentile of 10 healthy volunteers (Figure 4B).

[0286] Overview of the CARE Study The study design was a double-blind, non-randomized, placebo-controlled trial in patients with SLE. A total of 85 patients were enrolled in the 4 mg cenerimod arm and 86 in the placebo arm.

[0287] At the start of 4 mg cenelimod and placebo administration (defined as baseline), 12.5 ml of blood was drawn by a study nurse via standard venipuncture and collected in PAX-gene tubes for subsequent assessment of IFN gene signatures. Tubes containing blood were frozen and remained frozen until further use. EDTA plasma was prepared from the blood using standard protocols.

[0288] At baseline, 36 patients in the 4 mg cenelimod arm were classified as IFN-1 high and 44 as IFN-1 low, while 40 patients in the placebo arm were classified as IFN-1 high and 40 as IFN-1 low.

[0289] The study design and main inclusion criteria were as follows: The primary objective of this study was to evaluate the 6-month efficacy of cenerimod at 4 mg in subjects with moderate to severe SLE. Secondary and exploratory objectives (6 months) included, but were not limited to, effects on SLE biomarkers and exploratory biomarkers, evaluation of the safety and tolerability of cenerimod doses, evaluation of the effects on quality of life and fatigue using patient-reported outcome (PRO) measures, and evaluation of the effects on SLE biomarkers.

[0290] Inclusion criteria were as follows: diagnosed with SLE at least 6 months prior to screening (at least four ACR criteria), modified SLEDAI-2K (mSLEDAI-2K) score ≥ 6 at screening, and no musculoskeletal or mucocutaneous symptoms (i.e., Participants were required to have at least 2 points for each of the following symptoms: myositis, arthritis, rash, alopecia, and mucosal ulcers. The modified SLEDAI-2K is defined as the SLEDAI-2K excluding leukopenia, one of the scores used in the SLEDAI-2K composite score (Gladman et al., J Rheumatol. 2002 Feb;29(2):288-91). A clinical mSLEDAI-2K score of ≥4 was required at the time of randomization. Additionally, participants were required to have a positive antinuclear antibody test (ANA) with a titer of ≥1:80 (by immunofluorescence) and / or a positive anti-dsDNA titer of ≥30 IU / mL at the time of randomization. Participants were required to have received stable background SLE medication for at least 30 days (15 days for corticosteroids) prior to randomization. If using corticosteroids, participants were required to be on ≤40 mg / day of prednisone or equivalent. Women of childbearing potential (WOCBP) agree to use highly effective contraception.

[0291] Exclusion criteria were as follows: patients with active lupus nephritis (defined by proteinuria >1.5 g / 24 h or equivalent using a spot urine protein-to-creatinine ratio) or patients with a renal biopsy showing 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 vasculitis requiring systemic immunosuppressive treatment (e.g., retinal vasculitis, coronary vasculitis, pulmonary vasculitis, mesenteric vasculitis) within 90 days prior to screening; patients with a diagnosis of mixed connective tissue disease or a history of overlap syndromes between SLE and rheumatoid arthritis, erosive arthritis, scleroderma, or autoimmune hepatitis.

[0292] Study treatment was as follows: one daily tablet of cenerimod or placebo taken orally, preferably in the morning, regardless of food intake.

[0293] Criteria for Background Treatment: Subjects were receiving at least one of the following background SLE medications, which had to be stable for 30 days prior to randomization, except for oral corticosteroids (OCS), which should have been stable for at least 15 days prior to randomization: NSAIDs: aspirin (acetylsalicylic acid), ibuprofen, naproxen, celecoxib, other NSAIDs, prednisone or equivalent ≤ 40 mg / day; antimalarials: hydroxychloroquine, chloroquine, quinacrine, mycophenolate mofetil, mycophenolate, azathioprine, methotrexate, and belimumab. Background treatments were to be maintained stable throughout the study after randomization. However, changes were permitted if clinically relevant, as follows: Chronic NSAID treatment should not be initiated or discontinued during the study, but temporary use and / or dose changes for the treatment of symptoms unrelated to SLE (e.g., headache, menstrual pain) were permitted. Furthermore, immunosuppressive treatment (i.e., methotrexate, azathioprine, mycophenolate mofetil, mycophenolate, belimumab) was not initiated or discontinued during the study period, and the dose was maintained stable. Atropine was administered in the event of symptomatic bradycardia (iv).

[0294] The primary efficacy endpoint was the change in modified SLEDAI-2K score from baseline to month 6. Additional secondary endpoints were: Response to the previously defined SRI-4 (Furie R: et al., Arthritis Rheum. 2009) at 6 months compared to baseline, defined as follows: Sep 15;61(9):1143~51): - 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 items of BILAG A or two or more items of BILAG B as previously defined (Romero-Diaz J et al., Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11(0 11):S37-46. doi:10.1002 / acr.20572.); and - No increase of more than 0.3 points from baseline in the Physician's Global Assessment (PGA). The PGA is a visual analog scale (VAS) that uses three criteria to assess disease activity over the past two weeks (Luijten KMAC et al., Autoimmunity Reviews Volume 11, Issue 5, March 2012, pp. 326-329). On a 0-3 analog scale, a mild flare is scored as 1.0 point, a moderate flare as 2.0-2.5 points, and a severe flare as 3 points.

[0295] Additionally, the percentage of subjects with no new organ systems affected as defined by one or more items in BILAG A or two or more items in BILAG B compared to baseline.

[0296] Overview of the Opus Test The Opus studies are two Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy, safety, and tolerability of cenerimod in addition to background treatment in adult subjects (18-75 years of age) with moderate to severe systemic lupus erythematosus (SLE). Subjects are randomized 1:1 to receive cenerimod or matching placebo. Cenerimod is supplied as a 4 mg film-coated tablet once daily in addition to background SLE treatment.

[0297] Primary 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).

[0298] This endpoint is based on the SLEDAI-2K index modified to exclude leukopenia. All mSLEDAI-2K values ​​from baseline to 12 months are considered in the evaluation of this endpoint.

[0299] Secondary Outcome Measures : 1. Systemic Lupus Erythematosus at 12 months Response to the Responder Index (SRI-4) (time frame: Day 1 (pre-dose baseline) to Month 12).

[0300] Response to SRI-4 is defined as follows: - A decrease in mSLEDAI-2K of at least 4 points from baseline, and - No new British Isles Lupus Assessment Group-2004 (BILAG) A organ domain score and no new BILAG B organ domain score greater than 1 compared to baseline, and - Subject's lupus disease activity has not worsened from baseline (worsening is defined as a 3-point Physician's Global Assessment visual analogue scale) defined as an increase of ≥ 0.30 points on the Scale), and - Not violating protocol-specific medication treatment rules detailed in the Core Protocol.

[0301] 2. Time to first confirmed sustained modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) response for 4 months (time frame: Day 1 (pre-dose baseline) to Month 12).

[0302] Response is defined as at least a 4-point reduction from baseline.

[0303] 3. Time to first documented sustained mucocutaneous response for 4 months (time frame: Day 1 (pre-dose baseline) to Month 12).

[0304] The response was: - There is no increase in the mSLEDAI-2K overall score, and - Mucocutaneous symptoms mSLEDAI-2K score has improved from baseline (score of zero), It is defined as follows.

[0305] Selection Criteria : Screening inclusion criteria: - Signed an Informed Consent Form (ICF) prior to any study-mandated procedures.

[0306] - A diagnosis of systemic lupus erythematosus (SLE) according to the 2019 European League Against Rheumatism / American College of Rheumatology Criteria made at least 6 months prior to screening.

[0307] - Corrected Systemic Lupus Erythematosus Disease A mSLEDAI-2K Activity Index-2000 (mSLEDAI-2K) score of ≥ 6 and a clinical mSLEDAI-2K score of ≥ 4 with at least 2 points for musculoskeletal or mucocutaneous symptoms (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers). The mSLEDAI-2K score does not include "leukopenia."

[0308] - British Isles Lupus Assessment in 2 or more organ systems Group-2004 (BILAG) Grade B or BILAG Grade A in at least one organ system.

[0309] - Physician's Global Assessment (PGA) score ≥ 1.0 on a 0-3 Visual Analogue Scale (VAS).

[0310] - Currently receiving one or more of the following background medications for SLE: --Antimalarials (≤400 mg / day hydroxychloroquine, ≤500 mg / day chloroquine, ≤100 mg / day quinacrine).

[0311] --Mycophenolate mofetil (≤2 g / day) / mycophenolic acid (≤1.44 g / day).

[0312] --Azathioprine (≤2 mg / kg / day).

[0313] --Methotrexate (≤25 mg / week).

[0314] -- Oral corticosteroids (OCS): --- If OCS is the only background drug treatment for SLE: ≥ 7.5 mg / day and ≤ 30 mg / day of prednisone or equivalent.

[0315] ---If OCS is not the only background SLE medication: ≤30 mg / day prednisone or equivalent.

[0316] Belimumab (≤10 mg / kg intravenously every 4 weeks or 200 mg / week subcutaneously (sc)).

[0317] Treatment with antimalarials, mycophenolate mofetil, mycophenolate, azathioprine, methotrexate, or belimumab had to have started at least 90 days before screening. Treatment with OCS had to have started at least 30 days before screening.

[0318] - For women of childbearing potential (WoCBP): --A negative serum pregnancy test at screening.

[0319] --Agree to undergo monthly urine pregnancy tests from randomization until 6 months after discontinuation of study treatment.

[0320] --Agree to use highly effective contraception from screening (Visit 1) until 6 months after discontinuing study treatment.

[0321] Randomization criteria: - Clinical mSLEDAI-2K score ≥ 4 with at least 2 points for musculoskeletal or mucocutaneous symptoms (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers).

[0322] - British Isles Lupus Assessment Group-2004 (BILAG) Grade B in two or more organ systems or BILAG Grade A in one or more organ systems.

[0323] - Physician's Global Assessment (PGA) score ≥ 1.0 on a visual analogue scale of 0 to 3.

[0324] - Presence of at least one of the following biological variables predictive of serologic evidence of active SLE or a high type 1 interferon (IFN-1) signature (in a screening specimen measured at a central laboratory): --Anti-dsDNA antibodies elevated above normal levels.

[0325] -- Complement C3<lower limit of normal.

[0326] --Antinuclear antibodies with a titer of at least 1:160.

[0327] --Anti-Smith antibodies elevated above normal levels.

[0328] -- Platelets <200000 / μL.

[0329] --Urine protein / creatinine ratio >12.5 mg / mmol (110.5 mg / g).

[0330] - Currently receiving one or more of the following background SLE medications, which must be stable for at least 30 days prior to randomization (except for OCS, which must be stable for at least 15 days prior to randomization): --Antimalarials (≤400 mg / day hydroxychloroquine, ≤500 mg / day chloroquine, ≤100 mg / day quinacrine).

[0331] --Mycophenolate mofetil (≤2 g / day) / mycophenolic acid (≤1.44 g / day).

[0332] --Azathioprine (≤2 mg / kg / day).

[0333] --Methotrexate (≤25 mg / week).

[0334] -- OCS: --- If OCS is the only background drug treatment for SLE: ≥ 7.5 mg / day and ≤ 30 mg / day of prednisone or equivalent.

[0335] ---If OCS is not the only background SLE medication: ≤30 mg / day prednisone or equivalent.

[0336] Belimumab (≤10 mg / kg intravenously (iv) every 4 weeks or ≤200 mg / week sc).

[0337] - WoCBP must have a negative urine pregnancy test at the time of randomization.

[0338] Main exclusion criteria : - Women who are pregnant, planning to become pregnant by the Final Study Visit, or breastfeeding.

[0339] - Severe central nervous system lupus or active severe or unstable neuropsychiatric SLE characterized by: aseptic meningitis; cerebral vasculitis; myelopathy; demyelinating syndromes (ascending, transverse, acute inflammatory demyelinating polyradiculopathy); acute confusional state; impaired consciousness; psychosis; acute stroke or stroke syndrome; cranial nerve disorder; status epilepticus; cerebellar ataxia; or mononeuritis multiplex. -- prevents the subject from fully understanding the ICF; or -- The investigator determines that the protocol-specified standard of care is insufficient and requires the use of more aggressive treatment, such as intravenous cyclophosphamide and / or high-dose intravenous corticosteroid (CS) pulse therapy, or the addition of other treatments not permitted by the protocol.

[0340] - Diagnosis of mixed connective tissue disease or a history of overlap syndrome of SLE and psoriasis, rheumatoid arthritis, erosive arthritis, scleroderma, autoimmune hepatitis, or uncontrolled autoimmune thyroid disease.

[0341] - History or presence of Mobitz type II or third-degree atrioventricular block, sick sinus syndrome, symptomatic bradycardia, or syncope associated with cardiac disease.

[0342] - Subjects who have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, vascular thrombosis, decompensated heart failure requiring hospitalization, or New York Heart Association Class III / IV heart failure within 6 months prior to screening.

[0343] - Resting heart rate <50 bpm measured by 12-lead electrocardiogram at screening or randomization.

[0344] - An elevation of the QT interval corrected according to the Fridericia formula (QTcF) >470 ms (women) / >450 ms (men) at screening or randomization.

[0345] - History or presence of severe respiratory disease or pulmonary fibrosis based on medical history and chest x-ray (or CT scan according to local guidelines) performed at screening or within 6 months prior to screening.

[0346] - A history of clinically relevant bronchial asthma or chronic obstructive pulmonary disease that required treatment with oral or parenteral CS for a total of more than 2 weeks within the last 6 months before screening.

[0347] - Malignant tumors (excluding surgically resected basal or squamous cell skin or mucosal lesions (including dysplasia and carcinoma in situ)), history or presence of lymphoproliferative disorders, or history of total body lymph node irradiation.

[0348] - Presence of macular edema or active uveitis detected by optical coherence tomography (OCT) during screening.

[0349] - Subjects with a history of chronic liver or biliary disease (other than Gilbert syndrome) or an alanine aminotransferase or aspartate aminotransferase >3 x upper limit of normal (ULN) or total bilirubin >1.5 ULN (unless associated with known Gilbert syndrome).

[0350] - Significant hematological abnormalities on 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 -- Platelets <25,000 / μL (25×10^9 / L) at screening evaluation.

[0351] - Treatment with any of the following medications within 15 days or 5 half-lives of the medication (whichever is longer) prior to randomization: --Beta-blockers, diltiazem, verapamil, digoxin, digitoxin, or other antiarrhythmic drugs or systemic treatments that slow heart rate.

[0352] --QT prolonging drugs with a known risk of torsade de pointes, regardless of indication.

[0353] - Treatment with any of the following medications within 30 days or within 5 half-lives of the medication (whichever is longer) prior to randomization: -- Cyclophosphamide, cyclosporine, tacrolimus, sirolimus, mizoribine, etc.

[0354] --Pulse administration of methylprednisolone.

[0355] -- Administering live vaccines (including live COVID-19 vaccines).

[0356] - Intra-articular, intramuscular, or ivCS within 6 weeks prior to randomization.

[0357] - Treatment with any of the following medications within 90 days or within 5 half-lives of the medication (whichever is longer) prior to randomization: --Leflunomide.

[0358] --Immunoglobulin iv.

[0359] - Treatment with any investigational drug within 90 days or within 5 half-lives of that drug (whichever is longer) prior to randomization.

[0360] - Treatment with a B-cell depleting biologic agent, e.g., rituximab or ocrelizumab, within 12 months prior to randomization.

[0361] - Treatment with anifrolumab within 12 months prior to randomization.

[0362] - If at any time before screening you have been treated with any of the following medications:-- alemtuzumab.

[0363] --Sphingosine-1-phosphate receptor modulators (e.g., fingolimod).

[0364] --Subjects previously randomized to cenerimod or placebo in a study involving cenerimod.

Claims

1. S1P FOR USE IN THE PREVENTION OR TREATMENT OF TYPE 1 INTERFERON-MEDIATED DISEASES IN A SUBJECT - Patent application １ A receptor modulator or a pharmaceutically acceptable salt thereof, wherein the subject has a high type 1 interferon (IFN-1) gene signature score, １ A receptor modulator or a pharmaceutically acceptable salt thereof.

2. 2. The S1P for use according to claim 1, wherein the type 1 interferon gene signature score is calculated based on any one of the following groups of type 1 interferon-related genes: １ Receptor modulator or a pharmaceutically acceptable salt thereof: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

3. 3. The method of claim 1, wherein the type 1 interferon gene signature score of the subject is equal to or greater than the minimum of the bimodal distribution curve of type 1 interferon gene signature scores of SLE patients. １ A receptor modulator or a pharmaceutically acceptable salt thereof.

4. 3. The method of claim 1, wherein the subject has a type 1 interferon gene signature score higher than a threshold value, the threshold value of the IFN-1 gene signature score being 2 standard deviations higher than the arithmetic mean value from at least 100 healthy individuals. １ A receptor modulator or a pharmaceutically acceptable salt thereof.

5. S1P FOR USE IN A METHOD OF PROPHYLAXIS OR TREATMENT OF A SUBJECT HAVING A TYPE 1 INTERFERON-MEDIATED DISEASE - Patent application １ An S1P receptor modulator or a pharmaceutically acceptable salt thereof, wherein the method comprises the steps of: １ Receptor modulator or a pharmaceutically acceptable salt thereof: a) providing a biological sample of said subject; b) detecting in said biological sample the expression 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 (in particular IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, I assaying gene expression of at least three type 1 interferon-related genes selected from the group consisting of FIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPSTI1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4 and DNAPTP6, especially EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5 and ISG15; c) determining a normalized expression value for each gene assayed; d) calculating a type 1 interferon gene signature score by averaging the normalized expression values; and e) if the subject's type 1 interferon gene signature score is higher than a threshold, then administering S1P １ Treating with a receptor modulator.

6. S1P for use according to claim 5, wherein one of the following groups of type 1 interferon-related genes is selected for assaying gene expression: １ Receptor modulator or a pharmaceutically acceptable salt thereof: a) RSAD2, IFI44, IFI44L and IFI27; or b) RSAD2, IFI27, IFIT1 and HERC5.

7. S1 for use in the prevention or treatment of type 1 interferon mediated diseases in a subject P １ A receptor modulator or a pharmaceutically acceptable salt thereof, wherein the subject has an elevated concentration / level of interferon-gamma (IFN-γ) compared to a healthy subject. １ A receptor modulator or a pharmaceutically acceptable salt thereof.

8. S1P for use according to any one of claims 1 to 7, wherein the subject has a concentration / level of interferon-alpha (IFN-α) higher than 0.1 pg / mL and / or interferon-gamma (IFN-γ) higher than 9.5 pg / mL. １ A receptor modulator or a pharmaceutically acceptable salt thereof.

9. The S1P １ S1P for use according to any one of claims 1 to 8, wherein the receptor modulator is selected from ozanimod, siponimod, ponesimod, cenerimod, etrasimod, moclavimod and amiselimod or a pharmaceutically acceptable salt thereof. １ A receptor modulator or a pharmaceutically acceptable salt thereof.

10. The S1P １ S1P for use according to any one of claims 1 to 8, wherein the receptor modulator is cenerimod. １ A receptor modulator or a pharmaceutically acceptable salt thereof.

11. 11. The S1P for use according to claim 10, wherein cenerimod is intended to be and / or is administered to the subject for a treatment period of at least 6 months. １ A receptor modulator or a pharmaceutically acceptable salt thereof.

12. 12. S1P for use 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 disease), multiple sclerosis, autoimmune thyroiditis, scleroderma, psoriasis, primary Sjogren's disease, systemic sclerosis, rheumatoid arthritis, transplant rejection, dermatomyositis, polymyositis, idiopathic inflammatory myositis, sarcoidosis, Aicardi-Goutières syndrome, vasculitis, stab wound-associated vasculopathy of infancy (SAVI) or chronic atypical neutrophilic dermatosis with lipodystrophy and hyperthermia syndrome (CANDLE). １ A receptor modulator or a pharmaceutically acceptable salt thereof.

13. S1P for use according to any one of claims 1 to 11, wherein the type 1 interferon mediated disease is systemic lupus erythematosus １ A receptor modulator or a pharmaceutically acceptable salt thereof.

14. S1P for use according to any one of claims 1 to 13, which leads to a reduction from baseline in modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) after 12 months of treatment of said subject with cenerimod. １ A receptor modulator or a pharmaceutically acceptable salt thereof.

15. S1P for use according to any one of claims 1 to 14, wherein the subject is a human patient suffering from systemic lupus erythematosus. １ A receptor modulator or a pharmaceutically acceptable salt thereof.

16. S1P for use according to any one of claims 1 to 14, wherein the subject is a human patient suffering from systemic lupus erythematosus, and the subject has a mSLEDAI-2K score of ≥ 6 and a clinical mSLEDAI-2K score of ≥ 4, with at least 2 points for musculoskeletal or mucocutaneous symptoms. １ A receptor modulator or a pharmaceutically acceptable salt thereof.

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