Field of the invention

The present invention relates to a combination medicament comprising a corticosteroid drug and an inhibitor of mTOR that is useful in the treatment of multiple sclerosis Background of the invention

Multiple sclerosis (MS) is an inflammatory autoimmune disease characterized by the destruction of myelin sheaths of neurons and formation of plaques in the central nervous system. Disease courses are categorized as relapsing-remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS) and progressive relapsing (PRMS). Glucocorticoids are a mainstay in the treatment of MS-relapses. However, patients may acquire a GC-resistance that results in accumulation of disability. Several lines of evidence indicate that rapid termination of the autoimmune inflammatory reaction by methylprednisolone leads to attenuation of tissue damage. Thus, supportive strategies to enhance GC signalling are warranted to improve MS relapse therapy. As the glucocorticoid receptor (GCR) is involved in most of the GC mediated immunological mechanisms, alterations of the GCR complex may improve GC signalling and possibly help to overcome GC-resistance.

MS relapses lead to sustained residual disability in more than 40% of the patients, independent from clinical characteristics such as age and gender. Thus, up to 49% of the patients were reported to have a residual increase of disability post relapse of at least 0.5 EDSS point (Expanded disability status scale), 33% exhibited a deterioration of at least one EDSS point. Relapses affecting pyramidal, cerebellar and bowel/bladder function have the greatest association with accrual of disability. Incomplete remission from relapse also has high socioeconomic implications since costs of severe relapses are about 1 .5-fold (US$) to 6.5-fold higher (€) than for low/moderate intensity relapses. If new relapse symptoms persist over 2-3 months, probability of resolution decreases strongly, which argues for early and consequent treatment of relapses.

Glucocorticoids (GC) are a class of hormones that are secreted by the adrenal gland. The regulation of glucose metabolism and the reduction of inflammation are main effects among diverse glucocorticoid functions. Glucocorticoids bind to glucocorticoid receptors that reside in the cytoplasm of cells. Upon binding, the receptor-glucocorticoid complex translocates into the nucleus and up-regulates the expression of anti-inflammatory proteins. In addition, the expression of pro-inflammatory proteins is inhibited by preventing the translocation of other transcription factors from the cytosol into the nucleus. Here, the mammalian (or "mechanistic") target of rapamycin (rmTOR), a highly conserved serine/threonine kinase, might play an important role, as it has been demonstrated in a blood cancer cell line to phosphorylate the GCR leading to activation of the receptor (Miller AL. et al. Cancer Cell International 2007;7:3). Evidence, however, is conflicting, because in other cells (L6 myotubes) inhibition of rmTOR leads to an inhibition of GCR signalling by altering the intranuclear behaviour of the GCR by rmTOR (Shimizi, N. et al., Cell Metabolism, 201 1 , 13(2):170-182).

Based on the above-mentioned state of the art, the objective of the present invention is to provide means and methods for the treatment of multiple sclerosis.

This objective is attained by the combination medicament of the present specification.

Description

Terms and definitions

The term corticosteroid drug in the context of the present specification relates to any compound of the class of steroid hormones having a proven efficacy in treating MS and/or MS relapse, as well as to any derivative or any analogue thereof.

The term mTOR inhibitor in the context of the present specification relates to compounds that selectively bind to the protein referred to as "mammalian target of rapamycin" (mTOR), or to molecular interaction partners of the mTOR complex, thereby decreasing or abolishing its molecular function. The term is not meant to encompass vitamin D or any of its metabolites. The term selective inhibitor of mTOR is an inhibitor that down-regulates mTOR biological function, by direct interaction with mTOR or members of a protein complex of which mTOR is a functional part, particularly the rmTORd protein complex. Particularly, upstream transcription factors or ligands for transcription factors that modulate expression of interaction partners of mTOR are not encompassed by the term, which can be used synonymously with direct inhibitor of mTOR in the definition of any aspect or embodiment of the invention as disclosed herein. A selective mTOR inhibitor may additionally inhibit structurally closely related proteins that comprise a similar site of interaction with the inhibitor, compared to the mTOR protein, or interact with the same partners, with which mTOR may form a complex as a consequence of the inhibitor's interaction. Different degrees of cross-inhibitory activity are reflected in the sub-classification of mTOR inhibitors as highly exclusive or highly exclusive.

The inventors evaluated inhibition of mTOR in the context of multiple sclerosis to assess its ability to overcome GC-resistance in multiple sclerosis. They surprisingly found that a combination medicament comprising a corticosteroid drug and an inhibitor of mTOR in the same or two different formulations significantly improves GC responsiveness. A first aspect of the invention relates to a combination medicament that comprises a corticosteroid drug and a selective inhibitor of mTOR. The combination medicament is for the use in the treatment or therapy of multiple sclerosis (encephalomyelitis disseminata).

The combination therapy is novel in the field of MS treatment. Previous attempts at combination therapies have often led to unwanted or even opposing effects, in addition to potential adverse drug events [Cohen et al. Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Neurology 2009; 72: 535-41 ; Havrdova et al. Randomized study of interferon beta-1 a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis. Mult Scler 2009; 15: 965-76; Sorensen et al. NORdic trial of oral Methylprednisolone as add- on therapy to Interferon beta-1 a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial. Lancet Neurol 2009;8: 519-29.; Ravnborg et al. Monthly cycles of methylprednisolone in combination with interferon beta-1 a IM are effi cacious in the treatment of early relapsing-remitting multiple sclerosis. The MECOMBIN study. Mult Scler 2009; 15: S5-29.]. As for the specific clinical situation, improvement of therapeutic efficacy during acute exacerbation several approaches have failed [O'Connor et al., Natalizumab Multiple Sclerosis Trial Group. Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. Neurology. 2004 Jun 8;62(1 1 ):2038-43]. The inventors herein provide the first experimental evidence that mTOR inhibition leads to increased efficacy of glucocorticoid suppression of MS-typical immune malfunction in experimental models.

In certain embodiments, the selective inhibitor of mTOR specifically binds to mTOR Complex 1 (mTORCI ).

mTORd is composed of mTOR (UniProt No. P42345) itself, regulatory-associated protein of mTOR (Raptor; Uniprot No. Q8N122), mammalian lethal with SEC13 protein 8 (MLST8, Uniprot No.Q9BVC4) and the recently identified PRAS40 and DEPTOR (Uniprot No. Q8TB45). mTORd (also referred to in the literature as TORC1 ) is a major component of the PI3K/AKT pathway.

In certain embodiments, the inhibitor of mTOR is selected from rapamycin (sirolimus, CAS No. 53123-88-9), and the group of rapamycin analogues (rapalogues) characterized by a modification of the oxygen in position 40 of the rapamycin scaffold; particularly from everolimus (RAD001 , CAS No. 159351 -69-6), temsirolimus (CCI-779, NSC 683864, CAS No. 162635-04-3), 32 deoxy-rapamycin (SAR943, CAS No. 186752-78-3), ridaforolimus (Deforolimus, MK-8669, CAS No. 572924-54-0), Zotarolimus (ABT-578, CAS No. 221877-54- 9), and NAB Rapamycin (nanoparticle albumin-bound rapamycin). Rapamycin and rapalogue mTOR inhibitors act by binding to FKBP12, which in turn forms a ternary complex with mTOR in presence of rapamycin or rapalogues, which has a sub- nanomolar dissociation constant.

In certain embodiments, the inhibitor of mTOR is a heteroaromatic kinase inhibitor mTOR inhibitor that shares specificity for mTOR and other PI3K molecules, which shall be referred to as PI3 kinase inhibitors herein. In certain embodiments, this inhibitor is selected from the group consisting of

- PI-103 (3-(4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl)p henol; CAS No.

71935-74-9),

- apitolisib ((2S)-1 -[4-[[2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholin-4-ylthi eno[3,2- d]pyrimidin-6-yl]methyl]piperazin-1 -yl]-2-hydroxypropan-1 -one;

- GDC-0980, RG7422, CAS No. 1032754-93-0),

- Dactolisib (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro -1 H- imidazo[4,5-c]quinolin-1 -yl)phenyl)propanenitrile;

- NVP-BEZ235 (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro -1 H- imidazo[4,5-c]quinolin-1 -yl)phenyl)propanenitrile; BEZ235, CAS No. 915019-65-7),

- BGT226 ((Z)-but-2-enedioic acid; 8-(6-methoxypyridin-3-yl)-3-methyl-1 -[4-piperazin-1 - yl-3-(trifluoromethyl)phenyl]imidazo[4,5-c]quinolin-2-one; NVP-BGT226, CAS No. 1245537-68-1 ),

- Omipalisib (2,4-difluoro-N-[2-methoxy-5-(4-pyridazin-4-ylquinolin-6-yl) pyridin-3- yl]benzenesulfonamide; GSK2126458, GSK458, CAS No. 1086062-66-9), voxtasilib (XL765, 2-amino-8-ethyl-4-methyl-6-(IH-pyrazol-5-yl)pyrido[2,3-d]pyr imidin- 7(8H)-one; SAR245409; CAS No. 934493-76-2) and

"Voxtasilib analogue" (N-[4-[[3-(3,5-dimethoxyanilino)quinoxalin-2- yl]sulfamoyl]phenyl]-3-methoxy-4-methylbenzamide, CAS No. 1349796-36-6).

In certain embodiments, the inhibitor of mTOR is a heteroaromatic kinase inhibitor mTOR inhibitor that has a≥10 fold specificity for mTOR over other PI3K molecules, which shall be referred to as mTOR exclusive kinase inhibitor herein. In certain embodiments, this mTOR exclusive kinase inhibitor is selected from

- Torkinib ((2Z)-2-(4-amino-1 -propan-2-yl-2H-pyrazolo[3,4-d]pyrimidin-3-ylidene)indol-

5-ol; PP242, CAS No. 1092351 -67-1 ),

- PP30 (Feldman et al., PLoS Biol., 2009, 7(2):e 1000038 (Figure 1 )),

- WAY-600 (4-[6-(1 H-indol-5-yl)-1 -[1 -(pyridin-3-ylmethyl)piperidin-4-yl]pyrazolo[3,4- d]pyrimidin-4-yl]morpholine; CAS No. 1062159-35-6),

- WYE-687 (methyl N-[4-[4-morpholin-4-yl-1 -[1 -(pyridin-3-ylmethyl)piperidin-4- yl]pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]carbamate; CAS No. 1062161 -90-3), - PP121 (1 -cyclopentyl-3-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4- amine; CAS No. 1092788-83-4),

WYE-354 (methyl 4-[6-[4-(methoxycarbonylamino)phenyl]-4-morpholin-4- ylpyrazolo[3,4-d]pyrimidin-1 -yl]piperidine-1 -carboxylate; CAS No. 1062169-56-5), - KU-0063794 ([5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-morpholin-4-yl pyrido[2,3- d]pyrimidin-7-yl]-2-methoxyphenyl]methanol; CAS No. 938440-64-3) and

- AZD8055 ([5-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimi din-7-yl]-2- methoxyphenyl]methanol; 1009298-09-2).

In certain embodiments, the inhibitor of mTOR is a heteroaromatic kinase inhibitor mTOR inhibitor that has a≥100 fold specificity for mTOR over other PI3K molecules, which shall be referred to as mTOR highly exclusive kinase inhibitor herein. In certain embodiments, this mTOR highly exclusive kinase inhibitor is selected from

- OSI-027 (4-[(5Z)-4-amino-5-(7-methoxyindol-2-ylidene)-1 H-imidazo[5,1 - f][1 ,2,4]triazin-7-yl]cyclohexane-1 -carboxylic acid; CAS No. 936890-98-1 ),

- AZD2014 (3-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimid in-7-yl]-N- methylbenzamide; CAS No. 1009298-59-2),

sapanisertib (5-(4-amino-1 -propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1 ,3-benzoxazol- 2-amine MLN0128, INK 128, CAS No. 1224844-38-5),

Torin 1 (1 -[4-[4-(1 -oxopropyl)-1 -piperazinyl]-3-(trifluoromethyl)phenyl]-9-(3-quinolinyl)- benzo[h]-1 ,6-naphthyridin-2(1 H)-one; CAS No. 1222998-36-8),

Torin 2 (9-(6-Amino-3-pyridinyl)-1 -[3-(trifluoromethyl)phenyl]-benzo[h]-1 ,6- naphthyridin-2(1 H)-one, CAS No. 1223001 -51 -1 ),

- GDC-0349 (1 -ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-7-(oxetan-3-yl) -6,8-dihydro- 5H-pyrido[3,4-d]pyrimidin-2-yl]phenyl]urea, CAS No. 1207360-89-1 ),

- XL388 ([7-(6-Aminopyridin-3-yl)-2,3-dihydro-1 ,4-benzoxazepin-4(5H)-yl][3-fluoro-2- methyl-4-(methylsulfonyl)phenyl]methanone, CAS No. 1251 156-08-7),

- WYE-125132 (1 -[4-[1 -(1 ,4-Dioxaspiro[4.5]decan-8-yl)-4-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)pyrazolo[3,4-d]pyrimidin-6-yl]ph enyl]-3-methylurea;

- WYE-132, CAS No. 1 144068-46-1 ),

- Palomid 529 (3-(4-methoxybenzyloxy)-8-(1 -hydroxyethyl)-2-methoxy-6H- benzo[c]chromen-6-one, P529, CAS No. 914913-88-5),

- PF-04691502 (CAS No. 1013101 -36-4); GSK1059615 ((Z)-5-((4-(pyridin-4-yl)quinolin- 6-yl)methylene)thiazolidine-2,4-dione, CAS No. 958852-01 -2), Gedatolisib (1 -(4-((4-(Dimethylamino)piperidin-1 -yl)carbonyl)phenyl)-3-(4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl)urea,

- MHY1485 (4 _! 6-di-4-morpholinyl-N-(4-nitrophenyl)-1 _! 3,5-triazin-2-amine; CAS No.

326914-06-1 ),

- PF-05212384,

- PKI-587, CAS No. 1 196160-78-3) and

- ETP-46464 (2-methyl-2-[4-(2-oxo-9-quinolin-3-yl-4H-[1 ,3]oxazino[5,4-c]quinolin-1 - yl)phenyl]propanenitrile, CAS No. 1345675-02-6).

In certain embodiments, inhibitor of mTOR is Tacrolimus (FK506, CAS No. 104987-1 1 -3). In certain embodiments, the corticosteroid drug is selected from prednisone (CAS No. 53-03- 2), prednisolone (CAS No. 50-24-8), methylprednisolone (CAS No. 83-43-2), dexamethasone (CAS No. 50-02-2), hydrocortisone (CAS No. 50-23-7), hydrocortisone acetate (CAS No. 50- 03-3), cortisone acetate (CAS No. 50-04-4), triamcinolone (CAS No. 124-94-7), triamcinolone acetonide (76-25-5), triamcinolone acetonide acetate (CAS No. 76-25-25) and tixocortol pivalate (CAS No. 55560-96-8).

In certain embodiments, the corticosteroid drug and the inhibitor of mTOR are present in the same administration form.

In certain embodiments, the corticosteroid drug and the inhibitor of mTOR are present in the same administration form and administered parenterally.

In certain embodiments, the corticosteroid drug and the inhibitor of mTOR are present in the same administration form and administered by intravenous injection.

In certain embodiments, the corticosteroid drug and the inhibitor of mTOR are present in separate administration forms.

In certain embodiments, the corticosteroid drug is present in an administration form prepared for intravenous administration, and the inhibitor of mTOR is present in an administration form for enteral administration, more particularly in an administration form prepared for oral administration.

In certain embodiments, the corticosteroid drug is present in an administration form prepared for oral administration, and the inhibitor of mTOR is present in an administration form for parenteral administration, more particularly in an administration form prepared for intravenous injection.

In certain embodiments, both the corticosteroid drug and the inhibitor of mTOR are present in an administration form prepared for oral administration. In certain embodiments, both active ingredients are present in the same administration form. In certain other embodiments, the active ingredients are each present in a separate administration form.

In certain embodiments, both the corticosteroid drug and the inhibitor of rmTOR are present in separate administration forms, each prepared for parenteral administration, particularly for intravenous administration.

In certain embodiments, the corticosteroid drug is administered at a dosage of 0.25 mg to 2000 mg, in particular 500 mg to 1000 mg. This is equivalent to a dosage of 0.003 mg/kg to 30 mg/kg, in particular 7 mg/kg to 14 mg/kg assuming a standard body weight of 70 kg.

In certain embodiments, the inhibitor of rmTOR is administered at a dosage of 0.1 mg to 1200 mg, in particular 2.5 mg to 30 mg. This is equivalent to a dosage of 0.001 mg/kg to 16 mg/kg, in particular 0.04 mg/kg to 0.4 mg/kg assuming a standard body weight of 70 kg.

In certain embodiments, the combination medicament is used in the treatment or therapy of multiple sclerosis that does not respond to corticosteroid monotherapy.

The skilled person is aware that any specifically mentioned drug mentioned herein may be present as a pharmaceutically acceptable salt of said drug. Pharmaceutically acceptable salts comprise the ionized drug and an oppositely charged counterion. Non-limiting examples of pharmaceutically acceptable anionic salt forms include acetate, benzoate, besylate, bitatrate, bromide, carbonate, chloride, citrate, edetate, edisylate, embonate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate, phosphate, diphosphate, salicylate, disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide and valerate. Non-limiting examples of pharmaceutically acceptable cationic salt forms include aluminium, benzathine, calcium, ethylene diamine, lysine, magnesium, meglumine, potassium, procaine, sodium, tromethamine and zinc.

Similarly, a dosage form for the prevention or treatment of multiple sclerosis is provided, comprising a corticosteroid drug and an inhibitor of rmTOR according to one of the above aspects of the invention. Dosage forms may be for enteral administration, such as nasal, buccal, rectal, transdermal or oral administration, or as an inhalation form or suppository. Alternatively, parenteral administration may be used, such as subcutaneous, intravenous, intrahepatic, intrathecal or intramuscular injection forms. Optionally, a pharmaceutically acceptable carrier and/or excipient may be present.

Further aspects and embodiments of the invention are contained in the following items:

Item 1 : A combination medicament comprising

a. a corticosteroid drug and b. a selective inhibitor of mTOR

for use in treatment or therapy of multiple sclerosis (encephalomyelitis disseminata).

Item 2: The combination medicament according to item 1 for use in treatment or therapy of multiple sclerosis, wherein the selective inhibitor of mTOR selectively binds to mTOR or a member of the rmTORd complex, particularly with a kD <10 ^"7 mol/l, <10 ^"8 mol/l,

or even with a kD <10 ^"9 mol/l,

Item 3: The combination medicament according to item 1 or 2 for use in treatment or therapy of multiple sclerosis, wherein the selective inhibitor of mTOR is selected from

a. rapamycin and rapalogues, particularly the group consisting of rapamycin (sirolimus), everolimus (RAD001 ), temsirolimus (CCI-779, NSC 683864), 32 deoxy-rapamycin (SAR943), ridaforolimus (deforolimus, MK-8669), zotarolimus (ABT-578), NAB rapamycin;

b. the group of mTOR exclusive kinase inhibitors, particularly the group consisting of torkinib (PP242), PP30, WAY-600, WYE-687, WYE-354, AZD8055, KU-0063794 and PP121 ;

c. the group of mTOR highly exclusive kinase inhibitors, particularly the group consisting of OSI-027, AZD2014, INK 128 (MLN0128), torin 1 , torin 2, GDC- 0349, XL388, WYE-125132 (WYE-132), palomid 529 (P529), MHY1485, PF- 04691502, GSK1059615, gedatolisib (PF-05212384, PKI-587), CH5132799 and ETP-46464;

d. the group of PI3K kinase inhibitors, particularly the group consisting of PI-103, apitolisib (GDC-0980, RG7422), BEZ235 (NVP-BEZ235, Dactolisib), BGT226 (NVP-BGT226), omipalisib (GSK2126458, GSK458), voxtasilib, voxtasilib analogue.

Item 4: The combination medicament according to item 3 for use in treatment or therapy of multiple sclerosis, wherein the selective inhibitor of mTOR is selected from rapamycin, everolimus, temsirolimus and tacrolimus.

Item 5: The combination medicament according to any one of the preceding items for use in treatment or therapy of multiple sclerosis, wherein the corticosteroid drug is selected from the group consisting of prednisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone, triamcinolone acetonide, triamcinolone acetonide acetate, hydrocortisone, hydrocortisone acetate, cortisone acetate and tixocortol pivalate. Item 6: The combination medicament according to any one of the preceding items for use in treatment or therapy of multiple sclerosis, wherein the corticosteroid drug and the inhibitor of mTOR are present in the same administration form, particularly in an administration form prepared for parenteral administration, more particularly in an administration form prepared for intravenous injection.

Item 7: The combination medicament according to any one of the preceding items for use in treatment or therapy of multiple sclerosis, wherein the corticosteroid drug and the inhibitor of mTOR are present in separate administration forms.

Item 8A: The combination medicament according to item 7 for use in treatment or therapy of multiple sclerosis, wherein the corticosteroid drug is present in an administration form prepared for intravenous administration, and the inhibitor of mTOR is present in an administration form for enteral administration, more particularly in an administration form prepared for oral administration.

Item 8B: The combination medicament according to item 7 for use in treatment or therapy of multiple sclerosis, wherein the corticosteroid drug is present in an administration form prepared for oral administration, and the inhibitor of mTOR is present in an administration form for enteral administration, more particularly in an administration form prepared for oral administration.

Item 9: The combination medicament according to any one of the preceding items 1 to 6 for use in treatment or therapy of multiple sclerosis, wherein the corticosteroid drug and the inhibitor of mTOR are present in the same administration form, for use in treatment or therapy of multiple sclerosis.

Item 10: The combination medicament according to item 9 for use in treatment or therapy of multiple sclerosis, wherein the administration form is prepared for enteral administration, particularly for oral administration.

Item 1 1 : The combination medicament according to item 9 for use in treatment or therapy of multiple sclerosis, wherein the administration form is prepared for parenteral administration, particularly for intravenous injection.

Item 12: The combination medicament according to any one of the preceding items for use in treatment or therapy of multiple sclerosis, wherein the corticosteroid drug is present at a dosage of 0.25 mg to 2000 mg, in particular 500 mg to 1000 mg; and the inhibitor of mTOR is present at a dosage of 0.1 mg to 1200 mg, in particular 2.5 mg to 30 mg.

Item 13: The combination medicament according to any one of the preceding items for use in treatment or therapy of multiple sclerosis, wherein the multiple sclerosis does not respond to corticosteroid monotherapy. Item 14: A selective inhibitor of mTOR for use in treatment or therapy of multiple sclerosis, particularly an inhibitor selected from

a. rapamycin and rapalogues, particularly the group consisting of rapamycin (sirolimus), everolimus (RAD001 ), temsirolimus (CCI-779, NSC 683864), 32 deoxy-rapamycin (SAR943), ridaforolimus (deforolimus, MK-8669), zotarolimus (ABT-578), NAB rapamycin;

b. the group of mTOR exclusive kinase inhibitors, particularly the group consisting of torkinib (PP242), PP30, WAY-600, WYE-687, WYE-354, AZD8055, KU-0063794 and PP121 ;

c. the group of mTOR highly exclusive kinase inhibitors, particularly the group consisting of OSI-027, AZD2014, INK 128 (MLN0128), torin 1 , torin 2, GDC- 0349, XL388, WYE-125132 (WYE-132), palomid 529 (P529), MHY1485, PF- 04691502, GSK1059615, gedatolisib (PF-05212384, PKI-587), CH5132799 and ETP-46464;

d. the group of PI3K kinase inhibitors, particularly the group consisting of PI-103, apitolisib (GDC-0980, RG7422), BEZ235 (NVP-BEZ235, Dactolisib), BGT226 (NVP-BGT226), omipalisib (GSK2126458, GSK458), voxtasilib, voxtasilib analogue,

wherein the selective inhibitor of mTOR is administered together with a corticosteroid drug. Item 15: The selective inhibitor of mTOR for use in treatment or therapy of multiple sclerosis according to item 14, wherein the corticosteroid drug is selected from the group consisting of prednisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone, triamcinolone acetonide, triamcinolone acetonide acetate, hydrocortisone, hydrocortisone acetate, cortisone acetate and tixocortol pivalate.

Item 16: The selective inhibitor of mTOR for use in treatment or therapy of multiple sclerosis according to item 14 or 15, wherein the selective inhibitor of mTOR is administered by enteral administration, particularly per os.

Item 17: The selective inhibitor of mTOR for use in treatment or therapy of multiple sclerosis according to item 14 to 16, wherein the corticosteroid drug is administered by parenteral administration, particularly by intravenous injection.

Item 18: The selective inhibitor of mTOR for use in treatment or therapy of multiple sclerosis according to item 14 to 17, wherein the multiple sclerosis does not respond to corticosteroid monotherapy. Item 19: The combination medicament according to any one of items 1 to 13, or the selective inhibitor of mTOR according to any one of items 14 to 18, for use in the treatment of MS exacerbation or MS relapse.

Item 20: Use of a selective inhibitor of mTOR, particularly as specified in item 3 or 4, in combination with a corticosteroid drug, particularly as specified in item 2, for use in the manufacture of a medicament for the treatment or therapy of multiple sclerosis.

Item 21 : A method for treating multiple sclerosis, comprising:

administering to a subject in need thereof a selective inhibitor of mTOR; and administering to the subject a corticosteroid drug,

thereby treating the multiple sclerosis and in particular MS exacerbations.

The invention is further illustrated by the following examples and figures, from which further embodiments and advantages can be drawn. These examples are meant to illustrate the invention but not to limit its scope.

Brief description of the figures

Fig. 1 shows the relative protein expression of phP70S6K (reflecting rmTORd pathway) after in vitro incubation of splenic derived murine T cells with 1 ,25(OH)D ₃ (Vitamin D: 10nM, 100nM) or rapamycin (547pM, 547nM) over 24 hours . N=2 independent experiments.

Fig. 2 shows the MOG EAE disease course after control treatment or treatment with methylprednisolone (MPS) and/or everolimus over 3 consecutive days.

Concentrations: MPS: 0.8 mg/kg/day (i.p.); everolimus: 5 mg/kg/day (p.o.). Mean +/- standard error (SE), Kruskal-Wallis test: ## <0.01 , ### <0.001.

Fig. 3 shows the synergistic effect of rapamycin (Rapa) and methylprednisolone

(MP) on apoptosis of human CD3+ T cells after 24 hours of incubation.

Fig. 4 as Fig. 3; temsirolimus (Tern); 24 hours of incubation.

Fig. 5 as Fig. 3; everolimus (Eve); 24 hours of incubation.

Fig. 6 as Fig. 3; AZD 2014 (AZD); 24 hours of incubation.

Fig. 7 as Fig. 3; Palomid 529 (Palomid); 48 hours of incubation.

Fig. 8 as Fig. 3; Omipalisib; 48 hours of incubation.

Fig. 9 as Fig. 3; Voxtalisib Analogue (VOXANA, XL765); 24 hours of incubation.

Fig. 10 as Fig. 3; Voxtalisib (VOX); 24 hours of incubation.

Fig. 1 1 as Fig. 3; Dactolisib (DACT, BEZ235); 48 hours of incubation. Fig. 12 as Fig. 3; XL388; 48 hours of incubation.

Fig. 13 as Fig. 3; Torin I (T); 24 hours of incubation.

Examples

Inhibition of rmTOR by vitamin D has previously been described in osteoblasts via up regulation of damage inducible transcript 4 (Lisse, T.S. et al., FASEB J, 201 1 , 25:937-947). VD reduced rmTORcl signalling in a dose dependent manner in murine T-cells (Fig. 1 ), which was less severe compared to rapamycin (547pM / 547nM). The inventors set out to investigate the impact of a specific rmTORcl inhibition on the therapeutic efficacy of MP in EAE by using everolimus, a rapalog allosterically inhibiting rmTOR (Dienstmann, R. et al., Molecular Cancer Therapeutics, 2014, 13:1021 -1031 ). Everolimus was administered in a dose (5mg/kg, p.o.), which had demonstrated in murine cancer studies to exert a potent rmTOR inhibition without relevant side effects when given on 14 consecutive days (Dubois, M. et al., Plos One, 2014, 9:e1 1353). Everolimus monotherapy as well as MP (0.8mg/kg, i.p.) did not ameliorate EAE clinical course (modulation of EAE disease severity compared to control: everolimus +8.1 %; MP -1.4 %, p>0.05) However, combining everolimus with MP led to a marked decrease of EAE disease severity by 23.4% compared to control (p=0.002; figure 2). Also maximal EAE disease severity was reduced by the combination therapy (everolimus + MP) by 20 % (p>0.05) whereas it was not affected in MP and everolimus monotherapy, respectively (each peak of disease score: 5.5). Material and Methods:

EAE Experiment

Animals were immunized with 100μg MOG35-55 peptide (Institute of Medical Immunology, Charite, Berlin, Germany) in PBS emulsified in complete Freund ^' s adjuvant containing 100μg Mycobacterium tuberculosis H37RA (Difco, Detroit Ml, USA). On days 0 and 2 post immunization, 200ng pertussis toxin (Quadratech, Epsom, United Kingdom) were applied by intraperitoneal injection (i.p.). Treatment was initiated when≥50% of the animals had an EAE score≥2. MP (0.8 mg/kg/day i.p.); everolimus (5mg/kg/day, oral gavage) and controls (solvents for MP (PBS) or everolimus (peanut oil)) were given for three consecutive days. Animals were assessed daily on a 10 point clinical EAE scale (Cotte S et al. Brain 2009; 2517-2530).

Protein Experiments

T cells were treated in vitro with 10nM and 100nM 1 ,25(OH)2D3 or 547pM and 547nM rapamycin (Millipore, Darmstadt, Germany) for 24 hours. After lysis (Lysis buffer: HEPES

50mM, NaCI 150mM, Glycerol 10%, EDTA 1 mM, Nonidet P-40 1 %) and western blot, following antibodies were used: beta-Actin (Sigma-Aldrich, St. Louis, USA, 1 :15000), phAktT308 (Cell Signalling, Danvers, Massachusetts, USA, 1 :500), phP70S6K (Cell Signalling, Danvers, Massachusetts, USA), and phAktS473 (Cell Signalling, Danvers, Massachusetts, USA, 1 :500). Protein expression is expressed as ratio of target/housekeeping protein (beta-Actin; Image Studio 4.0, LI-COR, Lincoln USA).

Apoptosis

Method: CD3+ T cells were isolated using gradient centrifugation and negative magnetic cell sorting (Pan T cell isolation kit®, Miltenyi Biotec, Cologne, Germany). 1 x10 ⁶ /ml T cells (RPMI, Invitrogen, Karlsruhe, Germany; 10% FCS, Sigma-Aldrich, St. Louis, USA; 1 % penicillin/atreptomycin (PenStrep), Invitrogen; L-Glutamine, Invitrogen, 0.05% phytohemagglutinin, Sigma-Aldrich) were treated with different mTOR inhibitors (Seleckchem, Houston, USA) in different concentrations alone or in combination with methylprednisolone (MP) (MIBE GmbH, Brehna, Germany) for 24 - 72 hours (37°C, 5% CO2). T cell apoptosis was analyzed by fluorescence-activated cell sorting (annexin V/propidium iodide, Becton Dickinson Bioscience, Franklin Lakes, New Jersey, USA). To demonstrate the increase in glucocorticosteroid induced apoptosis by mTOR inhibition, the following calculation was performed:

(A) (MP) - (vehicle control) = Apoptosis caused by MP without mTOR inhibiton

(B) (MP + mTOR inhibitor) - (mTOR inhibitor) = Apoptosis caused by MP if mTOR is inhibited by a specific drug

Afterwards the apoptosis caused by MP with and without additional mTOR inhibition was compared using Wilcoxon signed rank test. For all 1 1 mTOR inhibitors tested, mTOR inhibitors lead to a significant increase in MP induced apoptosis of human CD3 positive T cells (see Fig. 3-13).