Siponimod

Summary

Siponimod (CHEMBL2336071) is an approved small molecule (ATC L04AE03) targeting S1PR1, S1PR3, and S1PR4; indicated across 7 conditions including multiple sclerosis and secondary progressive multiple sclerosis.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: L04AE03
• Targets: 4 (S1PR1, S1PR3, S1PR4…)
• Indications: 7 conditions
• Clinical trials: 22
• Chemistry: 516.6 Da · C29H35F3N2O3

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL2336071
Name	Siponimod
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	44599207
ATC	L04AE03
Molecular formula	C29H35F3N2O3
Molecular weight	516.6
InChIKey	KIHYPELVXPAIDH-HNSNBQBZSA-N

SMILES: CCC1=C(C=CC(=C1)/C(=N/OCC2=CC(=C(C=C2)C3CCCCC3)C(F)(F)F)/C)CN4CC(C4)C(=O)O

IUPAC name: 1-[[4-[(E)-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid

Also known as: BAF-312, Baf312, BAF312, Mayzent, Siponimod, SIPONIMOD, BAF312 (SIPONIMOD), BAF312 (Siponimod)

Parent form; salt/anhydrous children: CHEMBL4298150

Patent coverage: 540 distinct patent families (1,508 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 1,052 (70%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
S1PR1	S1P1 receptor	Agonist	10.11	0.2%	P21453
S1PR3	S1P3 receptor	Agonist	5.3	0.2%	Q99500
S1PR4	S1P4 receptor	Agonist	6.12	0.2%	O95977
S1PR5	S1P5 receptor	Agonist	9.01	0%	Q9H228

Broader ChEMBL bioactivity targets: 4 (assay-derived). Sample: Sphingosine 1-phosphate receptor 5, Sphingosine 1-phosphate receptor 4, Sphingosine 1-phosphate receptor 3, Sphingosine 1-phosphate receptor 1.

Bioactivity

ChEMBL activities: 5 potent at pChembl ≥ 5 of 5 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
S1PR1	9.4	EC50	0.4	nM	CHEMBL_ACT_12688309
S1PR1	9.4	EC50	0.4	nM	CHEMBL_ACT_25708618
S1PR5	9.01	EC50	0.98	nM	CHEMBL_ACT_13828990
S1PR4	6.12	EC50	750	nM	CHEMBL_ACT_13828991
S1PR3	5.3	EC50	5000	nM	CHEMBL_ACT_12688293

Target pathways

Aggregated over 4 target gene(s): S1PR1, S1PR3, S1PR4, S1PR5.

Top Reactome pathways

19 total, by targets touching each:

Pathway	Targets	Genes
Signal Transduction	4	S1PR1, S1PR3, S1PR4, S1PR5
Signaling by GPCR	4	S1PR1, S1PR3, S1PR4, S1PR5
Class A/1 (Rhodopsin-like receptors)	4	S1PR1, S1PR3, S1PR4, S1PR5
Lysosphingolipid and LPA receptors	4	S1PR1, S1PR3, S1PR4, S1PR5
GPCR ligand binding	4	S1PR1, S1PR3, S1PR4, S1PR5
GPCR downstream signalling	3	S1PR3, S1PR4, S1PR5
G alpha (i) signalling events	3	S1PR3, S1PR4, S1PR5
Cytokine Signaling in Immune system	1	S1PR1
Disease	1	S1PR1
Immune System	1	S1PR1
Signaling by Interleukins	1	S1PR1
Infectious disease	1	S1PR1
Interleukin-4 and Interleukin-13 signaling	1	S1PR1
ESR-mediated signaling	1	S1PR3
Signaling by Nuclear Receptors	1	S1PR3
Extra-nuclear estrogen signaling	1	S1PR3
Potential therapeutics for SARS	1	S1PR1
SARS-CoV Infections	1	S1PR1
Viral Infection Pathways	1	S1PR1

Dominant GO biological processes

GO term	Targets
sphingosine-1-phosphate receptor signaling pathway	4
G protein-coupled receptor signaling pathway	4
adenylate cyclase-activating G protein-coupled receptor signaling pathway	4
signal transduction	4
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	2
positive regulation of cell population proliferation	2
angiogenesis	1
blood vessel maturation	1
cardiac muscle tissue growth involved in heart morphogenesis	1
chemotaxis	1
cell adhesion	1
phospholipase C-activating G protein-coupled receptor signaling pathway	1
brain development	1
cell population proliferation	1
cell migration	1

Indications & clinical

Indications

7 indications (1 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
multiple sclerosis	4	MONDO:0005301	MONDO:0005301
secondary progressive multiple sclerosis	3	MONDO:0000450	EFO:0008522
polymyositis	2	MONDO:0019127	EFO:0003063
relapsing-remitting multiple sclerosis	2	MONDO:0005314	EFO:0003929
dermatomyositis	2	MONDO:0016367	EFO:0000398
liver disorder	1	MONDO:0005154	EFO:0001421
kidney disorder	1	MONDO:0005240	EFO:0003086

Clinical trials

Total trials: 22.

Phase distribution

Phase	Trials
Not specified	8
PHASE2	7
PHASE3	3
PHASE1	2
PHASE4	1
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04792567	PHASE4	COMPLETED	Exploring the Immune Response to SARS-CoV-2 modRNA Vaccines in Patients With Secondary Progressive Multiple Sclerosis (AMA-VACC)
NCT04926818	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Ofatumumab and Siponimod Compared to Fingolimod in Pediatric Patients With Multiple Sclerosis
NCT01665144	PHASE3	COMPLETED	Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND)
NCT03623243	PHASE3	COMPLETED	Safety and Tolerability of Conversion From Oral, Injectable, or Infusion Disease Modifying Therapies to Dose-titrated Oral Siponimod (Mayzent) in Advancing RMS Patients
NCT04925557	PHASE2/PHASE3	TERMINATED	Study to Assess the Efficacy of Mayzent on Microglia in Secondary Progressive Multiple Sclerosis
NCT06639282	PHASE2	RECRUITING	Repurposing Siponimod for Alzheimer’s Disease
NCT00879658	PHASE2	COMPLETED	Safety, Tolerability, Efficacy and Optimal Dose Finding Study of BAF312 in Patients With Relapsing-remitting Multiple Sclerosis
NCT01148810	PHASE2	TERMINATED	Efficacy and Tolerability of BAF312 in Patients With Polymyositis and Dermatomyositis
NCT01185821	PHASE2	COMPLETED	Long-term Safety, Tolerability and Efficacy of BAF312 Given Orally in Patients With Relapsing-remitting Multiple Sclerosis
NCT01801917	PHASE2	TERMINATED	Efficacy and Tolerability of BAF312 in Patients With Polymyositis
NCT02029274	PHASE2	TERMINATED	Safety and Efficacy of BAF312 in Dermatomyositis
NCT03338998	PHASE2	COMPLETED	Efficacy, Safety and Tolerability of BAF312 Compared to Placebo in Patients With Intracerebral Hemorrhage (ICH).
NCT01565902	PHASE1	COMPLETED	Pharmacokinetics of BAF312 in Patients With Hepatic Impairment
NCT01904214	PHASE1	COMPLETED	A Single-dose, Open-label, Parallel-group Study to Assess the Pharmacokinetics of BAF312 in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function
NCT00162474	Not specified	RECRUITING	Determinants of Warfarin Metabolism
NCT03500328	Not specified	ACTIVE_NOT_RECRUITING	Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial
NCT04933552	Not specified	RECRUITING	Post-Authorization Safety Study for Assessment of Pregnancy Outcomes in Patients Treated With Mayzent
NCT05688436	Not specified	RECRUITING	A Study to Learn More About The Safety of Diroximel Fumarate (VUMERITY®) in Participants Who Took it During Pregnancy And About the Health of Their Babies
NCT04540861	Not specified	NO_LONGER_AVAILABLE	Managed Access Program (MAP) for Patients Diagnosed With Secondary Progressive Multiple Sclerosis With Active Disease
NCT04593927	Not specified	COMPLETED	Long Term Special Drug Use-results Surveillance for Mayzent in SPMS Patients
NCT04895202	Not specified	TERMINATED	Swiss Study of the Impact of Mayzent on SPMS Patients in a Long-term Non-interventional Study
NCT05376579	Not specified	COMPLETED	Impact of Mayzent on aSPMS Patients in a Long-term NIS in Italy

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

PharmGKB dosing guidelines (1) — CPIC / DPWG genotype-guided dosing for this drug (drug × pharmacogene):

Guideline	Source	Gene(s)	Dosing	Recommendation
Annotation of DPWG Guideline for siponimod and CYP2C9	DPWG	CYP2C9	yes	yes

PharmGKB also curates 1 clinical and 3 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

10 molecules share ≥1 primary target. Top 10 by shared-target count:

Molecule	Source	Status	Shared targets
FINGOLIMOD	ChEMBL + PubChem	Phase 4 (approved)	S1PR1, S1PR3, S1PR4, S1PR5
OZANIMOD	ChEMBL + PubChem	Phase 4 (approved)	S1PR1, S1PR3, S1PR4, S1PR5
ETRASIMOD	ChEMBL + PubChem	Phase 4 (approved)	S1PR1, S1PR4, S1PR5
PONESIMOD	ChEMBL	Phase 4 (approved)	S1PR1, S1PR3
CENERIMOD	ChEMBL	Phase 3	S1PR1
AMISELIMOD	ChEMBL	Phase 2	S1PR1
ICANBELIMOD	ChEMBL	Phase 2	S1PR1
NIGULDIPINE	ChEMBL	Phase 2	S1PR1
PINAFIDE	ChEMBL	Phase 2	S1PR1
Belzutifan	PubChem	Approved	S1PR3