COMBINATION OF A CXCR7 ANTAGONIST WITH AN S1P1 RECEPTOR MODULATOR

1 . A pharmaceutical composition comprising, as active principles,

(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide:

or a pharmaceutically acceptable salt thereof,

in combination with an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof,

as well as at least one pharmaceutically acceptable excipient.

2 . The pharmaceutical composition according to claim 1 , wherein said S1P1 receptor modulator is fingolimod, ponesimod, siponimod, ozanimod, cenerimod, or etrasimod; or a pharmaceutically acceptable salt thereof.

3 . The pharmaceutical composition according to claim 1 or 2 , wherein said S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is comprised in a dose of said S1P1 receptor modulator which is a tolerated efficacious dose or lower than a tolerated efficacious dose of said S1P1 receptor modulator when given as a single therapy.

4 . A method for prevention or treatment of an autoimmune or inflammatory disease or disorder, a transplant rejection, or a neurodegenerative disease or disorder, comprising administering (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutically acceptable salt thereof, in combination with an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof.

5 . The method of claim 4 , wherein

the autoimmune and/or inflammatory disease and disorder is

an autoimmune and/or inflammatory demyelinating disease or disorder selected from multiple sclerosis (MS); idiopathic inflammatory demyelinating diseases; neuromyelitis optica spectrum diseases including neuromyelitis optica and acute optic neuritis; auto-immune encephalomyelitis including acute disseminated encephalomyelitis (ADEM) and multiphasic disseminated encephalomyelitis (MDEM); myelitis including transverse myelitis spectrum disorders, acute flaccid myelitis, poliomyelitis, leukomyelitis, and meningococcal myelitis; brain stem encephalitis; anti-myelin oligodendrocyte glycoprotein (anti-MOG) associated diseases including anti-MOG encephalomyelitis; Guillain-Barré syndrome; chronic inflammatory demyelinating polyneuropathy (CIDP); and anti-myelin-associated glycoprotein (anti-MAG) peripheral neuropathy;

rheumatoid arthritis (RA);

an inflammatory bowel disease (IBD) including Crohns disease or ulcerative colitis;

systemic lupus erythematosus (SLE) including lupus nephritis and neuropsychiatric systemic lupus erythematosus;

interstitial cystitis;

celiac disease;

osteoarthritis;

psoriasis;

type I diabetes;

ankylosing spondylitis; or

cytokine release syndrome following a strong viral infection or acute respiratory distress syndrome including COVID-19;

the transplant rejection is rejection of a transplanted organ such as kidney, liver, heart, lung, pancreas, cornea, or skin; graft-versus-host disease brought about by hematopoietic stem cell transplantation; chronic allograft rejection and chronic allograft vasculopathy; or

the neurodegenerative disease or disorder is amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease (AD), Parkinson's disease (PD), or adrenoleukodystrophy.

6 . The method of claim 5 , wherein the method is for prevention or treatment of the autoimmune and/or inflammatory disease or disorder.

7 . The method of claim 5 , wherein said treatment reduces the rate of progression of said autoimmune and/or inflammatory disease or disorder.

8 . The method of claim 7 , wherein said autoimmune and/or inflammatory disease or disorder is

an autoimmune and/or inflammatory demyelinating disease or disorder selected from multiple sclerosis (MS); idiopathic inflammatory demyelinating diseases; auto-immune encephalomyelitis including acute disseminated encephalomyelitis (ADEM) and multiphasic disseminated encephalomyelitis (MDEM); myelitis including transverse myelitis spectrum disorders, acute flaccid myelitis, poliomyelitis, leukomyelitis, and meningococcal myelitis; brain stem encephalitis; Guillain-Barré syndrome; chronic inflammatory demyelinating polyneuropathy (CIDP); anti-myelin-associated glycoprotein (anti-MAG) peripheral neuropathy; and myelin oligodendrocyte glycoprotein (MOG)-antibody associated disease;

an inflammatory bowel disease especially selected from Crohn's disease and ulcerative colitis; or

systemic lupus erythematosus (SLE).

9 . The method of claim 4 , the method is for prevention or treatment of the autoimmune or inflammatory disease or disorder, and the autoimmune or inflammatory disease or disorder is an autoimmune and/or inflammatory demyelinating disease or disorder.

10 . The method of claim 9 , wherein

the method is for the treatment of a patient diagnosed with MS, wherein said treatment

reduces the rate of progression of MS; and/or

improves the symptoms of MS; and/or

reduces the rate of demyelination; and/or

reduces the rate of irreversible neurodegenerative damage such as axonal damage; and/or

has an effect of remyelination; and/or

reduces the rate of brain atrophy/cerebral atrophy; or

the method is for the prevention of MS, wherein said prevention of MS comprises delaying the onset of MS in a subject who is at risk/has been diagnosed as being at risk of developing MS; wherein said subject is especially a subject who has experienced a Clinically Isolated Syndrome (CIS) or has been diagnosed as having experienced a CIS.

11 . The method of claim 4 , wherein said S1P1 receptor modulator is fingolimod, ponesimod, siponimod, ozanimod, cenerimod, or etrasimod; or a pharmaceutically acceptable salt thereof.

12 . The method of claim 11 , wherein said S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical dosage form suitable for the oral administration of said S1P1 receptor modulator, wherein

fingolimod, or a pharmaceutically acceptable salt thereof, if present, is to be administered in said pharmaceutical dosage form in a unit dose suitable for the oral administration of a total of about 0.5 mg or below per day of fingolimod;

siponimod, or a pharmaceutically acceptable salt thereof, if present, is to be administered in said pharmaceutical dosage form in a unit dose suitable for the oral administration of a total of about 2 mg or below per day of siponimod;

ponesimod, or a pharmaceutically acceptable salt thereof, if present, is to be administered in said pharmaceutical dosage form in a unit dose suitable for the oral administration of a total of about 20 mg or below per day of ponesimod; and

ozanimod, or a pharmaceutically acceptable salt thereof, if present, is to be administered in said pharmaceutical dosage form in a unit dose suitable for the oral administration of a total of about 1 mg or below per day of ozanimod;

cenerimod, or a pharmaceutically acceptable salt thereof, if present, is to be administered in said pharmaceutical dosage form in a unit dose suitable for the oral administration of a total of about 4 mg or below per day of cenerimod; and

etrasimod, or a pharmaceutically acceptable salt thereof, if present, is to be administered in said pharmaceutical dosage form in a unit dose suitable for the oral administration of a total of about 2 mg or below per day of etrasimod.

13 . The method of claim 4 , wherein said S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is to be administered in a dose which is a tolerated efficacious dose when given as a single therapy; or in a dose which is lower than such tolerated efficacious dose when given as a single therapy.

14 . (canceled)

15 . A method for the prophylaxis or treatment of an autoimmune or inflammatory disease or disorder, a transplant rejection, or a neurodegenerative disease or disorder; said method comprising the administration of a pharmaceutically effective amount of (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or of a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide is administered in combination with an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof.