Table 2.

Novel S1P modulators in clinical studies.

S1P modulator	Target	Mode of delivery	Indication	Developmental phase	Reference
Ozanimod (RPC-1063)	S1PR1, S1PR5	Oral	RRMS	FDA and EMA approved in 2020	[186]
			IBD	Phase II completed and phase III recruiting for CD	[187]
				Phase III completed for UC	[188, 189]
			COVID-19 pneumonia	Phase II recruiting
			Liver diseases-Digestive system diseases	Phase I
Etrasimod (APD-334)	S1PR1, S1PR4, S1PR5	Oral	IBD	Phase II/III recruiting for CD
				Phase II completed and phase III recruiting for UC	[190]
			Eosinophilic esophagitis	Phase II
			Primary biliary cholangitis	Phase II
			Alopecia areata	Phase II
			Atopic dermatitis	Phase II
			Pyoderma gangrenosum	Phase II
			Autoimmune diseases	Phase I
			Rheumatoid arthritis
Amiselimod (MT-1303)	S1PR1, S1PR5	Oral	IBD	Phase II completed for CD	[191]
				Phase II for UC
			RRMS	Phase II completed	[192]
			Plaque psoriasis	Phase II completed
			SLE	Phase II completed
Mocravimod (KRP-203)	S1PR1, S1PR3	Oral	UC	Phase II terminated	[193]
			Subacute cutaneous lupus erythematosus	Phase II completed
			Transplant rejection (for hematological malignancies)	Phase I completed	[194]
Fingolimod (FTY720)	S1PR1, S1PR3, S1PR4, S1PR5	Oral	RRMS and PPMS	FDA and EMA approved for RRMS in 2010	[186]
				Phase III for PPMS	[195]
			Cognition, Brain volume loss	Phase IV
			Chronic inflammatory demyelinating polyradiculoneuropathy	Phase III completed	[196]
			De novo renal transplantation	Phase III completed	[197]
			Rett’s Syndrome	Phase II completed	[198]
			Amyotrophic lateral sclerosis	Phase II completed	[199]
			Acute demyelinating optic neuritis	Phase II
			Ischaemic stroke	Phase II completed	[200]
			Intracerebral haemorrhage	Phase II completed	[201]
			Schizophrenia	Phase II completed
			Uveitis	Phase II
			Asthma	Phase II completed	[202]
			COVID-19 pneumonia	Phase II
			High grade glioma	Phase I completed
			Breast carcinoma	Phase I
			Anaplastic astrocytoma	Phase I
			Cerebral edema	Phase I
			Chemotherapy-induced peripheral neuropathy	Phase I recruiting
			Renal insufficiency	Phase I
Siponimod (BAF-312)	S1PR1, S1PR5	Oral	RRMS and active SPMS	FDA approved for RRMS in 2019	[186]
				EMA approved for active SPMS in 2019
			Intracerebral haemorrhage	Phase II recruiting
			Hemorrhagic stroke	Phase II
			Active dermatomyositis	Phase II
			Polymyositis	Phase II
			Renal impairment	Phase I
			Hepatic impairment	Phase I
Ponesimod (ACT-128800)	S1PR1	Oral	RRMS and active RMS	FDA and EMA approved for RRMS in 2021	[186]
				Phase III for active RMS
			Plaque psoriasis	Phase II completed	[203]
			Graft rejection	Phase II
Ceralifimod (ONO-4641)	S1PR1, S1PR5	Oral	RRMS	Phase II completed	[204]
Cenerimod (ACT-334441)	S1PR1	Oral	SLE	Phase II completed	[205]
AKP11	S1PR1	Oral	Psoriasis	Phase II recruiting
GSK2018682	S1PR1	Oral	RRMS	Phase I completed
CS-0777	S1PR1	Oral	MS	Phase I completed
LX-3305 (LX-2931)	S1P lyase inhibitor	Oral	Rheumatoid arthritis	Phase II completed
Sonepcizumab (LT-1009)	S1P	Intravenous injection	Macular degeneration	Phase II
			Renal cell carcinoma	Phase II completed	[206]

MS multiple sclerosis, RRMS relapsing remitting MS, EMA European Medicine Agency, FDA food and drug administration, IBD inflammatory bowel disease, CD Crohn’s disease, UC ulcerative colitis, SLE systemic lupus erythematosus, PPMS primary progressive multiple sclerosis, RMS relapsing MS.