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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
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  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4245—Oxadiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders

Definitions

• S1Pi receptor modulators for use in the treatment of type 1 IFN mediated diseases
• the present invention relates to a S1Pi 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 that has a high type 1 interferon (IFN-1) gene signature score or elevated levels of interferon-alpha (IFN-a) and/or interferon-gamma (IFN-y) in blood plasma.
• IFN-1 type 1 interferon
• IFN-a interferon-alpha
• IFN-y interferon-gamma
• Sphingosine 1 -phosphate is a lipid mediator formed by the metabolism of sphingomyelin.
• S1 P is secreted into the extracellular environment and signals via G protein coupled S1 P receptors including the S1 P1 receptor which plays an important role in lymphocyte trafficking [Mendelson, K. et al., Development 2014, 141 , 5-9, PMID:24346695],
• S1 P1 receptor modulators are approved for the treatment of multiple sclerosis and Inflammatory Bowel Disease and are being investigated in further inflammatory diseases involving lymphocyte driven inflammatory processes [Burg, N. et al., Nat Rev Rheumatol. 2022, 18(6), 335-351 , PMID:35508810],
• (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 “COMPOUND” or “cenerimod”) is a potent, selective, and orally active S1 P1 receptor modulator which prevents the egress of lymphocytes from secondary lymphoid organs into the vascular circulation, via internalization of the S1 P1 receptor.
• its immunomodulatory role in autoimmune diseases may be of benefit in treating such diseases in which lymphocytes play an important role in propagating disease.
• SLE systemic lupus erythematosus
• cenerimod reduced both B and T lymphocytes in the circulation confirming the mode of action (Hermann V, et al. Lupus Science & Medicine 2019;6:e000354. doi:10.1136/lupus-2019-000354). Furthermore, cenerimod reduced interferon (IFN)-associated proteins in plasma [Strasser, DS et al., RMD Open 2020, 6, e001261 , PMID: 32917831],
• IFNs are central effector molecules produced in large amounts during an immune response to infection, activating defense mechanisms and resulting in the inhibition of microbial replication.
• Type 1 IFNs are the largest group and comprise several classes and subclasses. Almost all cells can produce IFN-a and I FN-
• IFN-x is the only type 2 IFN and is mainly produced by NK cells and T cells of the immune system [McNab, F. et al., Nat Rev Immunol 2015, 15, 87-103, PMID:25614319; Rbnnblom, L. et al., Lupus Sci Med 2019, 6, e000270, PMID:31497305; Colonna, M. et al., Current Opinion Immunol 2002, 14, 373-379, PMID:11973137],
• Type-1 IFNs signal through a heterodimeric transmembrane receptor composed of the subunits IFNAR1 and IFNAR2, broadly expressed across multiple cell types.
• type 2 IFN engage with the heterodimer IFNGR1 and IFNGR2.
• Both IFNAR and IFNGR complexes recruit JAK kinase family members.
• IFNAR recruits TYK2 and JAK1 while IFNGR recruits JAK1 and JAK2. This leads to subsequent STAT1 and STAT2 phosphorylation and the subsequent translocation of the signaling pathway transcription factors into the nucleus.
• IFNAR recruits TYK2 and JAK1
• IFNGR recruits JAK1 and JAK2.
• STAT1 and STAT2 phosphorylation and the subsequent translocation of the signaling pathway transcription factors into the nucleus.
• Nucleic acids are sensed among other cells by plasmacytoid dendritic cells (pDCs), which are thought to be a key cell type producing type 1 IFNs in SLE.
• pDCs plasmacytoid dendritic cells
• IFN Type 1 Celia, M. et al., Nature Med 1999, 5(8), 919-923, PMID:10426316
• other cell types may be involved in IFN production in SLE including keratinocytes, endothelial cells, fibroblasts and monocytes, NK cells, B cells and T cells.
• genetic risk factors have been identified in SLE that are associated with IFN production or responses to IFNs further supporting the hypothesis that perturbations in IFN regulation may contribute 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],
• IFN-1 signature reflects IFN-regulated genes, meaning that those genes are upregulated due to the biological activity of type 1 IFNs.
• Subsequent studies have demonstrated between 50 and 80% of SLE patients show a consistent presence of an IFN- 1 signature from the blood and this is stable over time [Northcott, M.
• IFN signaling has broad and wide-ranging effects on the body and increased IFN production may be linked to potential disease manifestations in patients with SLE, the principal ones are summarized below.
• IFNs participate in SLE disease, however the association of a blood IFN signature and clinical disease characteristics is not limited to any one manifestation. Further the IFN signature does not distinguish between high and low disease activity [Kennedy, WP. et al., Lupus Sci Med 2015, 2, e000080, PMID:25861459], as defined by various criteria, but can predict the subsequent disease severity over time [Mai, L. et al., Arthritis Research Therapy 2021 , 23, 29, PMID: 33451338],
• IFN-1 gene signature Data on the distribution of type 1 IFN gene signature high vs IFN signature low within the general SLE population is somewhat limited but reports have placed it in the range of 60- 80% [Psarras, A. et al., Rheumatology 2017, 56, 1662-1675, PMID:28122959], An important property of the IFN-1 gene signature is the bimodal distribution in patients with SLE allowing separation into high or low IFN-1 gene signature strata [El-Sherbiny, YM.
• IFN-1 high patients patients with a high type 1 interferon gene signature score (“IFN-1 high patients”) were more likely to be receiving higher immunosuppressants and glucocorticoids than IFN-1 low patients (75% vs 50%), were likely to be younger and of Asian ancestry [Northcott, M.
• phase 3 studies of anifrolumab confirmed the suppression of the interferon signature in patients with IFN-1 high at baseline seen in a phase 2 trial, although the association of this effect with clinical efficacy was not demonstrated.
• TULIP 1 the efficacy of anifrolumab measured with a (SLE) Responder Index (SRI-4) [Furie, R. et al. Arthritis Rheumatism 2009, 61 (9), 1143-1151 , PMID: 19714615] (placebo adjusted) in patients with IFN-1 high at baseline is modest, i.e., 6 percentage points.
• the highest SRI-4 response (the primary end point) had occurred in 44 of 81 patients (54%) receiving the 0.45-mg dose of iberdomide and in 29 of 83 patients (35%) receiving placebo (adjusted difference, 19.4 percentage points).
• Iberdomide and placebo did not have meaningful differences with respect to most secondary end points.
• the responses occurred in 34 of 57 patients (60%) in the 0.45 mg iberdomide group vs 16 of 48 patients (33%) in the placebo group.
• the whiskers indicate the minimum and maximum range.
• a decrease in the mean value of IFN alpha protein in the cenerimod 4mg group is observed after 6 months compared to baseline, whereas a slight elevation in the mean value is observed over 6 months in the placebo group.
• the whiskers indicate the minimum and maximum range.
• a decrease in the mean value of IFN gamma protein in the cenerimod 4mg group is observed between baseline and after 6 months treatment, whereas a slight elevation in the mean value is observed over 6 months in the placebo group.
• a first embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment (especially treatment) of a type 1 interferon mediated disease in a subject, wherein the subject has a high type 1 interferon (IFN-1) gene signature score.
• IFN-1 type 1 interferon
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to embodiment 1), wherein the subject has a high type 1 interferon (IFN-1) gene signature score at treatment onset.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 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-associated 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, PLS
• Group a) is disclosed in WO 2020/084591 ; group b) in WO 2022/074123 and in Yao Y, et al. Human Genomics and Proteomics 2009; article ID 374312, doi:10.4061/2009/374312; groups c) to h) in WO 2011/028933 and in Furie R, et al. Arthritis & Rheumatology 2017; 69(2) 376-386; group i) in Westra H-J, 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.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 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-associated 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,
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 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-associated 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.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 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-associated genes: a) RSAD2, IFI44, IFI44L, and IFI27; or b) RSAD2, IFI27, IFIT1 , and HERC5.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1) or 2), wherein the type 1 interferon gene signature score is calculated based on the type 1 interferon-associated genes EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1 , IFIT1 , HERC5, and ISG15.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1) or 2), wherein the type 1 interferon gene signature score is calculated based on the type 1 interferon-associated genes RSAD2, IFI27, IFIT1 , and HERC5.
• the type 1 interferon gene signature score of a subject can be calculated according to any of the methods given in WO 2011/028933, WO 2020/084591 , Furie R, et al. Arthritis & Rheumatology 2017; 69(2) 376-386 or Northcott M, et al. Lupus Science & Medicine 2022;9:e000625; doi:10.1136/lupus-2021 -000625. Northcott et al.
• the IFN-1 gene signature score of a subject describes especially a method to calculate the IFN-1 gene signature score of a subject based on the 4 genes RSAD2, IFI27, IFIT1 , and HERC5 and further discloses an IFN-1 gene signature score cutoff value of -0.5 between subjects having a low and a high IFN-1 gene signature score.
• Northcott et al. further refers to an IFN-1 test that is commercially available from DxTerity Diagnostics Inc.
• the type 1 interferon gene signature score of a subject can be calculated by the method originally developed by DxTerity Diagnostics Inc.
• RNA gene expression levels of the type 1 interferon-associated genes RSAD2, IFI27, IFIT1 , and HERC5 in a blood sample of a subject (for instance by measuring respective peak height in capillary electrophoresis electropherograms); (ii) measuring the gene expression levels of the three housekeeping (normalizer) genes ACTB, GAPDH, and TFRC in a blood sample of the subject; (iii) calculating the binary logarithm (log 2 ) of the expression levels 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- associated genes according to Formula (I); and (v) calculating the type 1 interferon gene signature score by averaging the normalized expression values of the four type 1 interferon-associated genes.
• RNA gene expression levels of the type 1 interferon-associated genes RSAD2, IFI27, IFIT1 , and HERC5 in a blood sample of a subject
• the minimum of the bimodal distribution curve may be obtained 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, of at least 100, of at least 200, or (preferably) of at least 300 SLE patients.
• the bimodal distribution curve may be obtained from current (e.g., from data collected less than 1 year ago) and/or from historical (e.g., from data collected more than 1 year ago) data on type 1 interferon gene signature scores in SLE patients.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to embodiment 9), wherein the type 1 interferon gene signature score of the subject is at least 0.5 units, at least 1 unit, at least 2 units or at least 3 units (especially at least 1 unit) above the minimum of the bimodal distribution curve of the type 1 interferon gene signature scores of SLE patients.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1) to 8), wherein the subject has a type 1 interferon gene signature score that is higher than the type 1 interferon gene signature score of a (representative) healthy subject.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1) to 8), wherein the type 1 interferon gene signature score of the subject is above a threshold value.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to embodiment 12), wherein the threshold value is an IFN-1 gene signature score value that is selected from values between 1.8 to 4.0 (i.e.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to embodiment 12), wherein the threshold value of the IFN-1 gene signature score is 2 standard deviations above the arithmetic mean value from at least 100, at least 200, at least 300 or (preferably) at least 500 healthy humans.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to embodiment 12), wherein the threshold value of the IFN-1 gene signature score is between -1.0 and 0 (especially about - 0.5).
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to embodiment 12), wherein the threshold value of the IFN-1 gene signature score is -0.5.
• RNA gene expression levels of the type 1 interferon-associated genes (especially of RSAD2, IFI44, IFI44L, and IFI27; or of RSAD2, IFI27, IFIT1 , and HERC5; and notably of RSAD2, IFI27, IFIT1 , and HERC5) in a blood sample of a subject (notably by measuring respective peak height by capillary electrophoresis);
• Formula (I) and (v) calculating the type 1 interferon gene signature score by averaging the normalized expression values of the type 1 interferon-associated genes.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 3) to 16), wherein the type 1 interferon gene signature score of the subject is calculated (determined) by a method comprising the following steps:
• RNA gene expression levels of the type 1 interferon-associated genes (especially of RSAD2, IFI44, IFI44L, and IFI27; or of RSAD2, IFI27, IFIT1 , and HERC5; and notably of RSAD2, IFI27, IFIT1 , and HERC5) in a blood sample of a subject (notably by measuring respective peak height by capillary electrophoresis);
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating (especially treating) a subject having a type 1 interferon mediated disease (especially a type 1 interferon mediated disease that is responsive to treatment with the S1 Pi receptor modulator), the method comprising: a) providing a biological sample (especially a blood sample or a serum sample, and notably a blood sample) from the subject; b) assaying gene expression of at least three (especially at least four) type 1 interferon- associated genes selected from the group consisting of DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1 , IFIT1 , HERC5, ISG15,
• a further embodiment of the invention relates to a S1 Pi 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 that is higher than a threshold value at treatment onset and/or is higher than the type 1 interferon gene signature score in a biological sample from a healthy subject at treatment onset.
• the subject has a type 1 interferon gene signature score that is higher than a threshold value at treatment onset.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 19) or 20), wherein the biological sample is a blood sample.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 19) to 21), wherein one of the following groups of type 1 interferon-associated 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 IFI44,
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 19) to 21), wherein one of the following groups of type 1 interferon-associated 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, IFI44
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 19) to 21), wherein one of the following groups of type 1 interferon-associated 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.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 19) to 21), wherein the type 1 interferon-associated genes for assaying gene expression are EIF2AK2, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1 , IFIT1 , HERC5, and ISG15.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 19) to 21), wherein the type 1 interferon-associated genes for assaying gene expression are RSAD2, IFI27, IFIT1 , and HERC5.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 19) to 27), wherein the gene expression is assayed by capillary electrophoresis (especially capillary electrophoresis suitable for nucleotide analysis).
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 19) to 27), wherein the gene expression of the type 1 interferon-associated genes is assayed by measuring peak height in capillary electrophoresis electropherograms.
• the normalized expression values are calculated based on peak heights (especially peak heights in capillary electrophoresis electropherograms) of the respective genes by using Formula (I).
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 19) to 30), wherein the type 1 interferon gene signature score of the subject is at or above the minimum of the bimodal distribution curve of the type 1 interferon gene signature scores of SLE patients.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to embodiment 31), wherein the type 1 interferon gene signature score of the subject is at least 0.5 units, at least 1 unit, at least 2 units or at least 3 units (especially at least 1 unit) above the minimum of the bimodal distribution curve of the type 1 interferon gene signature scores of SLE patients.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 19) to 30), wherein the threshold value is an IFN-1 gene signature score value that is selected from values between 1.8 to 4.0 (i.e.
• a further embodiment of the invention relates to a S1 Pi 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 2 standard deviations above the arithmetic mean value from at least 100, at least 200, at least 300 or (preferably) at least 500 healthy humans.
• a further embodiment of the invention relates to a S1 Pi 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 (especially about -0.5, and notably -0.5).
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to embodiment 35), wherein the threshold value of the IFN-1 gene signature score is -0.5.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating (especially treating) a subject having a type 1 interferon mediated disease (especially a type 1 interferon mediated disease that is responsive to treatment with the S1 Pi receptor modulator), the method comprising: a) providing a biological sample (especially a blood sample or a serum sample, and notably a blood sample) from the subject; b) assaying gene expression of the type 1 interferon-associated genes RSAD2, IFI27, IFIT1 , and HERC5 in the biological sample (especially by measuring peak height in capillary electrophoresis electropherograms); c) determining a normalised expression value of each assayed gene by (i) measuring the gene expression levels of the three housekeeping (normalizer) genes ACTB, GAPDH, and TFRC in the biological sample of the subject; (ii) calculating the binary logarithm (log 2 ).
• Formula (II) d) calculating a type 1 interferon gene signature score by averaging the normalised expression values; and e) treating the subject with the S1 Pi receptor modulator when the type 1 interferon gene signature score of the subject is higher than a threshold value, wherein the threshold value is selected from values between -1.0 and 0 (especially -0.5).
• the normalized expression values are calculated based on peak heights of the respective genes by using Formula (I).
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment (especially treatment) of a type 1 interferon mediated disease (especially a type 1 interferon mediated disease that is responsive to treatment with the S1 Pi receptor modulator) in a subject, wherein at least three (especially at least four) type 1 interferon-associated genes are upregulated in the subject (especially in a biological sample from the subject), wherein the type 1 interferon-associated genes are selected from the group consisting of DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1 , IFIT1 , HERC5, ISG15, LAMP3, OAS3, OAS1 , EPSTI1 , IFIT3, LY6E, OAS2, PLSCR1 , SIGLEC1 , USP18, RTP4, and DNAPTP6 (especially IFI6,
• the upregulation of type 1 interferon-associated genes in the subject’s expression profile may be by any degree relative to that of a sample from a control (which may be from a sample that is not disease tissue of the subject or from a healthy person not afflicted with the type 1 interferon mediated disease) or may be relative to that of genes from the subject whose expression is not changed by the type 1 interferon mediated disease (so called housekeeping genes); especially relative to that of genes from the subject whose expression is not changed by the type 1 interferon mediated disease.
• a control which may be from a sample that is not disease tissue of the subject or from a healthy person not afflicted with the type 1 interferon mediated disease
• housekeeping genes especially relative to that of genes from the subject whose expression is not changed by the type 1 interferon mediated disease.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 38) or 39), wherein at least three genes of at least one of the following groups of type 1 interferon-associated 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,
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 38) or 39), wherein at least three genes of at least one of the following groups of type 1 interferon-associated 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.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 38) or 39), wherein at least three genes of at least one of the following groups of type 1 interferon-associated genes are upregulated in the subject: a) RSAD2, IFI44, IFI44L, and IFI27; or b) RSAD2, IFI27, IFIT1 , and HERC5.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 38) or 39), wherein at least three of the following type 1 interferon-associated genes are upregulated in the subject: RSAD2, IFI27, IFIT1 , and HERC5.
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment (especially treatment) of a type 1 interferon mediated disease in a subject, wherein the concentration/level of interferon-gamma (IFN-y) in the subject (especially in blood plasma of the subject) is elevated compared to a healthy subject.
• IFN-y interferon-gamma
• a subject wherein the concentration/level of interferon-gamma (IFN-y) in the subject (especially in blood plasma of the subject) is elevated compared to a healthy subject” means a subject having, and/or identified as having, and/or diagnosed as having (especially in blood plasma of the subject) a concentration/level of interferon-gamma (IFN- y) that is higher than the concentration/level of interferon-gamma (IFN-y) in 95% of healthy volunteers in a statistically representative group of the healthy volunteers.
• IFN-y concentration/level of interferon-gamma
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to embodiment 67), wherein the reduction from baseline in mSLEDAI-2K is reached in at least 50% of the subjects.
• Standard background therapy for the treatment of systemic lupus erythematosus may be an antimalarial, such as hydroxychloroquine, chloroquine, or quinacrine; mycophenolate mofetil or mycophenolic acid; azathioprine; methotrexate; an oral corticosteroid, such as prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; belimumab; anifrolumab; or any other drug approved by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) or a corresponding national regulatory agency and/or used as standard of care at the date of treatment onset with the S1 Pi receptor modulator.
• FDA U.S. Food and Drug Administration
• EMA European Medicines Agency
• Cenerimod can be used as medicament according to this invention, e.g. in the form of pharmaceutical compositions especially for enteral, or for parenteral administration.
• the term “about” placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
• the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C.
• a further embodiment of the invention relates to a method for the prophylaxis or treatment (especially treatment) of a type 1 interferon mediated disease, the method comprising administering a pharmaceutically effective amount of a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject has a high type 1 interferon (IFN-1) gene signature score.
• a S1 Pi receptor modulator or a pharmaceutically acceptable salt thereof
• type 1 interferon gene signature score is calculated based on any one of the following groups of type 1 interferon-associated 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 ,
• RNA gene expression levels of the type 1 interferon-associated genes (especially of RSAD2, IFI44, IFI44L, and IFI27; or of RSAD2, IFI27, IFIT1 , and HERC5; and notably of RSAD2, IFI27, IFIT1 , and HERC5) in a blood sample of a subject (notably by measuring respective peak height by capillary electrophoresis);
• RNA gene expression levels of the type 1 interferon-associated genes (especially of RSAD2, IFI44, IFI44L, and IFI27; or of RSAD2, IFI27, IFIT1 , and HERC5; and notably of RSAD2, IFI27, IFIT1 , and HERC5) in a blood sample of a subject (notably by measuring respective peak height by capillary electrophoresis);
• a further embodiment of the invention relates to a method for the prophylaxis or treatment (especially treatment) of a type 1 interferon mediated disease (especially a type 1 interferon mediated disease that is responsive to treatment with a S1 Pi receptor modulator) in a subject, the method comprising: a) providing a biological sample (especially a blood sample or a serum sample, and notably a blood sample) from the subject; b) assaying gene expression of the type 1 interferon-associated genes RSAD2, IFI27, IFIT1 , and HERC5 in the biological sample (especially by measuring peak height in capillary electrophoresis electropherograms); c) determining a normalised expression value of each assayed gene by (i) measuring the gene expression levels of the three housekeeping (normalizer) genes ACTB, GAPDH, and TFRC in the biological sample of the subject; (ii) calculating the binary logarithm (log 2 ) of the expression levels of each of the three housekeeping genes
• a further embodiment of the invention relates to a method for the prophylaxis or treatment (especially treatment) of a type 1 interferon mediated disease (especially a type 1 interferon mediated disease that is responsive to treatment with a S1 Pi receptor modulator) in a subject, the method comprising administering a pharmaceutically effective amount of a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, to the subject in need thereof, wherein at least three (especially at least four) type 1 interferon- associated genes are upregulated in the subject (especially in a biological sample from the subject), wherein the type 1 interferon-associated genes are selected from the group consisting of DHX58, EIF2AK2, IRF7, PARP9, SAMD9L, IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1 , IFIT1 , HERC5, ISG15, LAMP3, OAS3, OAS1 , EPSTI1 , IFIT3, LY6E, OAS2, PLSCR1
• a further embodiment of the invention relates to a method for the prophylaxis or treatment (especially treatment) of a type 1 interferon mediated disease (especially a type 1 interferon mediated disease that is responsive to treatment with a S1 Pi receptor modulator) in a subject, the method comprising administering a pharmaceutically effective amount of a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, to the subject in need thereof, wherein the concentration/level of interferon-gamma (IFN-y) in the subject (especially in blood plasma of the subject) is elevated compared to a healthy subject.
• IFN-y interferon-gamma
• a further embodiment of the invention relates to a method for the prophylaxis or treatment (especially treatment) of a type 1 interferon mediated disease (especially a type 1 interferon mediated disease that is responsive to treatment with a S1 Pi receptor modulator) in a subject, the method comprising administering a pharmaceutically effective amount of a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, to the subject in need thereof, wherein the subject has a concentration/level (especially a concentration/level in blood plasma) of interferon-gamma (IFN-y) above 9.5 pg/mL.
• a concentration/level especially a concentration/level in blood plasma
• a further embodiment of the invention relates to a method for the prophylaxis or treatment (especially treatment) of a type 1 interferon mediated disease (especially a type 1 interferon mediated disease that is responsive to treatment with a S1 Pi receptor modulator) in a subject, the method comprising: a) providing a biological sample (especially a plasma sample) from the subject; b) measuring the concentration/level of interferon-gamma (IFN-y) in the biological sample; and c) administering a pharmaceutically effective amount of a S1Pi receptor modulator, or a pharmaceutically acceptable salt thereof, to the subject in need thereof when the concentration/level of interferon-gamma (IFN-y) is elevated compared to the concentration/level of interferon-gamma (IFN-y) in a biological sample from a healthy subject and/or is above 9.5 pg/mL.
• a biological sample especially a plasma sample
• IFN-y concentration/level of interferon-gamma
• the method further comprises: a) providing a biological sample (especially a plasma sample) from the subject; b) measuring the concentration/level of interferon-alpha (IFN-a) and/or interferon-gamma (IFN-y) in the biological sample; and c) administering a pharmaceutically effective amount of a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, to the subject in need thereof when in addition to the other condition the concentration/level of interferon-alpha (IFN-a ) and/or of interferon- gamma (IFN-y) is elevated compared to the concentration/level in a biological sample from a healthy subject.
• a biological sample especially a plasma sample
• IFN-y interferon-gamma
• the method further comprises: a) providing a biological sample (especially a plasma sample) from the subject; b) measuring the concentration/level of interferon-alpha (IFN-a) and/or interferon-gamma (IFN-y) in the biological sample; and c) administering a pharmaceutically effective amount of a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, to the subject in need thereof when in addition to the other condition the concentration/level of interferon-alpha (IFN-a ) is above 0.1 pg/mL and/or when the concentration/level of interferon-gamma (IFN-y) is above 9.5 pg/mL.
• a biological sample especially a plasma sample
• IFN-y interferon-gamma
• the S1 Pi receptor modulator is selected from fingolimod, ozanimod, siponimod, ponesimod, cenerimod, etrasimod, mocravimod and amiselimod, or a pharmaceutically acceptable salt thereof (especially from ozanimod, siponimod, ponesimod, cenerimod, etrasimod, mocravimod and amiselimod, or a pharmaceutically acceptable salt thereof, and notably from ozanimod, siponimod, ponesimod, cenerimod, or a pharmaceutically acceptable salt thereof).
• S1 Pi receptor modulator is selected from ozanimod, siponimod, ponesimod, and cenerimod, or a pharmaceutically acceptable salt thereof.
• cenerimod is comprised in a pharmaceutical dosage form for oral administration (especially in a tablet formulation, notably in a film coated tablet).
• cenerimod is comprised in the pharmaceutical dosage form in a unit dose of 4 mg (especially 4.0 mg).
• cenerimod is to be administered and/or is administered to a patient once per day (once daily).
• cenerimod is to be administered and/or is administered to a subject for a treatment period of at least 6 months (especially at least 12 months, and notably at least 60 months).
• a further embodiment of the invention relates to a S1 Pi receptor modulator, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 143) to 147), wherein cenerimod is to be administered and/or is administered to a subject chronically.
• the type 1 interferon mediated disease is selected from the group consisting of systemic lupus erythematosus, discoid lupus, lupus nephritis, glomerulonephritis, type I diabetes, inflammatory bowel disease (including Crohn’s disease, ulcerative colitis, and Celiac’s disease), multiple sclerosis, autoimmune thyroiditis, scleroderma, psoriasis, primary Sjogren’s disease, systemic sclerosis, rheumatoid arthritis, transplant rejection, dermatomyositis, polymyositis, idiopathic inflammatory myositis, sarcoidosis, Aicardi- Goutieres syndrome, vasculitis, Sting associated vasculopathy with onset in infancy (SAVI) or chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature
• SAVI Sting associated vasculopathy with onset in infancy
• such measure of disease activity is the modified systemic lupus erythematosus disease activity index 2000 as compared to baseline and/or as compared to placebo.
• AEs treatment- emergent adverse events
• TEAEs treatment- emergent adverse events
• “adverse event”, “treatment-emergent adverse event”, and “adverse reaction” mean any harm, unfavorable, unintended, or undesired sign or outcome associated with or caused by administration of a pharmaceutical composition or therapeutic. It is an untoward medical occurrence in a subject administered a medicinal product.
• VAS Visual analogue scale
• cenerimod reduces both the IFN-1 gene signature score and IFN-oc protein in the plasma of patients treated with cenerimod (Figure 3A) both of which are more abundant in patients with SLE compared to healthy volunteers (figure 3B). Patients with high IFN-oc protein levels at baseline display a larger reduction in the mSLEDAI-2K score as compared to the IFN alpha protein low cohort (figure 3C).
• cenerimod 4 mg reduces IFN gamma protein in plasma at 6 months compared to baseline and compared to placebo (Figure 4A), which also is more abundant in patients with SLE compared to healthy volunteers (figure 4B). Patients with high IFN gamma protein levels at baseline display a larger reduction in the mSLEDAI-2K score as compared to the IFN gamma protein low cohort (figure 4C).
• the primary efficacy endpoint is the change from baseline to Month 6 in the modified SLEDAI-2K score. Further secondary endpoints were:
• the Physician Global Assessment is a visual analog scale (VAS) using 3 benchmarks for assessing disease activity over the last 2 weeks (Luijten KMAC et al, Autoimmunity Reviews Volume 11 , Issue 5, March 2012, Pages 326-329). Mild flare will score 1.0 point, moderate flares will score a 2.0-2.5 point and severe flares will score a 3 on the 0-3 analog scale.
• Opus studies are two phase 3, multicenter, randomized, double-blind, placebo- controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of cenerimod in adult subjects (18 years to 75 years) with moderate-to-severe systemic lupus erythematosus (SLE) on top of background therapy.
• Subjects are randomized 1 :1 to either cenerimod or matching placebo.
• Cenerimod is supplied once daily in addition to background SLE therapy as film-coated tablets at the dose of 4 mg.
• This endpoint is based on the SLEDAI-2K index, modified to exclude leukopenia. All values of mSLEDAI-2K from baseline through Month 12 visits are accounted for in the assessment of this endpoint.
• SRI-4 Systemic Lupus Erythematosus Responder Index
• a response is defined as a reduction of at least 4 points from baseline.
• Time to first confirmation of a 4-month sustained response in mucocutaneous manifestations (Time Frame: Day 1 (pre-dose baseline) to Month 12).
• mSLEDAI-2K Response is defined as: o No increase in the overall mSLEDAI-2K score, and o Remission (score of zero) from baseline in the mSLEDAI-2K score of mucocutaneous manifestations.
• ICF Signed Informed Consent Form
• BILAG British Isles Lupus Assessment Group-2004
• OCS OCS is not the only SLE background medication: ⁇ 30 mg/day prednisone or equivalent.
• o Belimumab ⁇ 10 mg/kg every 4 weeks intravenously, or 200 mg/week subcutaneously (s.c.).
• Treatment with antimalarials, mycophenolate mofetil, mycophenolic acid, azathioprine, methotrexate or belimumab must have been started at least 90 days prior to Screening. Treatment with OCS must have been started at least 30 days prior to Screening.
• OCS OCS is the only SLE background medication: > 7.5 mg/day and ⁇ 30 mg/day prednisone or equivalent.
• OCS OCS is not the only SLE background medication: ⁇ 30 mg/day prednisone or equivalent).
• o Belimumab ⁇ 10 mg/kg every 4 weeks intravenous (i.v.) or ⁇ 200 mg/week s.c.).
• o lymphocyte count ⁇ 500 /pL (0.5 x 10 A 9/L) ; o hemoglobin ⁇ 7 g/dL; o white blood cell count ⁇ 2000/pL (2.0 x 10 A 9/L); or o platelets ⁇ 25000/pL (25 x 10 A 9/L) at screening assessment.

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