General
Preferred name
Siponimod
Synonyms
BAF-312 ()
BAF312 (Siponimod) ()
Siponimod (BAF312) ()
BAF312 ()
NVP-BAF312-NX ()
Mayzent ()
SIPONIMOD FUMARATE ()
NVP-BAF312-AEA ()
Siponimod hemifumaric acid ()
Siponimod hemifumarate ()
SIPONIMOD FUMARIC ACID ()
P&D ID
PD012981
CAS
1230487-00-9
Tags
available
drug
Approved by
FDA
PMDA
EMA
First approval
2019
Drug indication
Multiple sclerosis
Rheumatoid arthritis
Hepatocellular carcinoma
Drug Status
approved
investigational
Max Phase
4.0
Structure
Probe scores
P&D probe-likeness score
[[ v.score ]]%
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
INDICATION This drug is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults [FDA label].
ROE Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine [FDA label].
METABOLISM Siponimod is extensively metabolized, mainly by CYP2C9 enzyme (79.3%), and subsequently by CYP3A4 enzyme (18.5%). The pharmacological activity of the main metabolites M3 and M17 is not expected to be responsible for the clinical effect and the safety of siponimod in humans [FDA label].
HALF-LIFE The apparent elimination half-life is approximately 30 hours [FDA label].
ABSORPTION The time (Tmax) to attain maximum plasma concentrations (Cmax) after oral administration of immediate-release oral doses of siponimod was found to be approximately 4 hours ( with a range 3 - 8 hours). Siponimod is heavily absorbed (at a rate greater than or equal to 70%). The absolute oral bioavailability of siponimod is about 84%. Steady-state concentrations were attained after approximately 6 days of daily administration of a single dose of siponimod [FDA label]. **Effects of food on absorption** Food ingestion leads to delayed siponimod absorption (the median Tmax increased by approximately 2-3 hours). Food intake has no effect on the systemic exposure of siponimod (Cmax and AUC). Therefore, siponimod may be taken without regard to food [FDA label].
ROE Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine [FDA label].;
TOXICITY **Carcinogenesis**; ; Oral carcinogenicity studies of siponimod were performed in mice and rats. There was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dose tested is approximately 5 times the recommended human dose (RHD) of 2 mg/day [FDA label].; ; **Mutagenesis**; ; Siponimod was negative in several in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays [FDA label].; ; **Impairment of fertility**; ; When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) before and throughout the mating period, there was a dose-related increase in the precoital interval at any dose. A decrease in implantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were noted at the highest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg) is approximately 100 times the recommended human dose [FDA label].; ; When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to and during mating, and continuing to Day 6 of gestation, no effects on fertility were noted up to the highest dose studied (1 mg/kg). Plasma siponimod exposure (AUC) at the highest dose studied is about 16 times that in humans at the recommended human dose [FDA label]. ; ; **Use in pregnancy and lactation**; ; Siponimod may cause fetal harm, based on the results of animal studies. Because it takes about 10 days to eliminate this drug from the body, women of childbearing potential should use adequate contraception to avoid pregnancy during and for 10 days after the cessation of treatment [FDA label]. ; No data currently exist regarding the presence of siponimod in human milk [FDA label]. A study in lactating rats demonstrated excretion of the drug and/or its metabolites in milk. The benefits nursing should be considered as well as the mother’s clinical requirement for this drug and any possible adverse effects on the breastfed infant from siponimod [FDA label].
ABSORPTION The time (Tmax) to attain maximum plasma concentrations (Cmax) after oral administration of immediate-release oral doses of siponimod was found to be approximately 4 hours ( with a range 3 - 8 hours). Siponimod is heavily absorbed (at a rate greater than or equal to 70%). The absolute oral bioavailability of siponimod is about 84%. Steady-state concentrations were attained after approximately 6 days of daily administration of a single dose of siponimod [FDA label]. ; ; **Effects of food on absorption**; ; Food ingestion leads to delayed siponimod absorption (the median Tmax increased by approximately 2-3 hours). Food intake has no effect on the systemic exposure of siponimod (Cmax and AUC). Therefore, siponimod may be taken without regard to food [FDA label].;
DESCRIPTION Pharmacologically, siponimod (BAF312) is a selective sphingosine-1-phosphate (S1P) receptor agonist, with some selectivity for the S1P1 and S1P5 receptor isoforms . It is an orally active drug. Siponimod was developed by Novartis for secondary progressive multiple sclerosis (SPMS), originally as a back-up compound for . Compared to fingolimod it has more favourable pharmacokinetics.
Novartis announced positive results from their Phase 3 EXPAND study (BAF312 versus placebo) in SPMS (August 2016- link to announcement here).
The SIPR signalling pathway is important in autoimmune biology. (GtoPdb)
DESCRIPTION Siponimod (BAF312) is a Phase 3 clinical candidate being developed by Novartis for secondary progressive multiple sclerosis (SPMS), originally as a back-up compound for . Pharmacologically, siponimod is a selective sphingosine-1-phosphate (S1P) receptor agonist with improved pharmacokinetics compared to fingolimod.
Novartis announced positive results from their Phase 3 EXPAND study (BAF312 versus placebo) in SPMS (August 2016- link to announcement here).
The SIPR signalling pathway is important in autoimmune biology.
PHARMACODYNAMICS **Immune system effects** Siponimod causes a dose-dependent decrease of the peripheral blood lymphocyte count within 6 hours of the first dose, caused by the reversible accumulation of lymphocytes in lymphoid tissues, due to lack of lymphocyte release [FDA label]. This results in a decrease in the inflammation that is involved in multiple sclerosis. Lymphocyte counts return to normal in 90% of patients within 10 days after the cessation of therapy [FDA label]. **Effects on heart rate and rhythm** Siponimod causes a temporary decrease in heart rate and atrioventricular conduction upon beginning treatment. The maximum fall in heart rate is observed in the first 6 hours post ingestion. Autonomic heart responses, including diurnal variation of heart rate and response to exercise activities, are not altered by siponimod treatment [FDA label]. **Effects on pulmonary function** Dose-dependent decreases in absolute forced expiratory volume over a time frame of 1 second were noted in siponimod-treated patients and were higher than in patients taking placebo [FDA label].
MOA Inflammation of the white and gray matter tissues in the central nervous system caused by localized immune cell infiltration and their cytokines are the initial cause of damage in MS. B lymphocytes and their cytokines are other factors in the pathogenesis of MS. Lymphotoxin [or transforming growth factor beta (TGF-β)] and TNF-α produced by these cells encourage inflammation [A176474]. The S1P receptor is an important receptor related to the function of lymphocytes and can be found in the central nervous system [A176492]. S1P receptor (S1PR) signaling is associated with a wide variety of physiological processes for lymphocytes, including their egress and recirculation [A176486, A176489]. Siponimod is classified as a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to both S1P receptors 1 and 5. This drug blocks the ability of lymphocytes to release from the lymph nodes, decreasing the number of lymphocytes found in the peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is not known at this time, but may involve the abovementioned decrease of lymphocytes into the central nervous system, decreasing the inflammatory effects of MS [FDA label].
TOXICITY **Carcinogenesis** Oral carcinogenicity studies of siponimod were performed in mice and rats. There was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dose tested is approximately 5 times the recommended human dose (RHD) of 2 mg/day [FDA label]. **Mutagenesis** Siponimod was negative in several in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays [FDA label]. **Impairment of fertility** When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) before and throughout the mating period, there was a dose-related increase in the precoital interval at any dose. A decrease in implantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were noted at the highest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg) is approximately 100 times the recommended human dose [FDA label]. When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to and during mating, and continuing to Day 6 of gestation, no effects on fertility were noted up to the highest dose studied (1 mg/kg). Plasma siponimod exposure (AUC) at the highest dose studied is about 16 times that in humans at the recommended human dose [FDA label]. **Use in pregnancy and lactation** Siponimod may cause fetal harm, based on the results of animal studies. Because it takes about 10 days to eliminate this drug from the body, women of childbearing potential should use adequate contraception to avoid pregnancy during and for 10 days after the cessation of treatment [FDA label]. No data currently exist regarding the presence of siponimod in human milk [FDA label]. A study in lactating rats demonstrated excretion of the drug and/or its metabolites in milk. The benefits nursing should be considered as well as the mother’s clinical requirement for this drug and any possible adverse effects on the breastfed infant from siponimod [FDA label].
PHARMACODYNAMICS **Immune system effects**; ; Siponimod causes a dose-dependent decrease of the peripheral blood lymphocyte count within 6 hours of the first dose, caused by the reversible accumulation of lymphocytes in lymphoid tissues, due to lack of lymphocyte release [FDA label]. This results in a decrease in the inflammation that is involved in multiple sclerosis. Lymphocyte counts return to normal in 90% of patients within 10 days after the cessation of therapy [FDA label].; ; **Effects on heart rate and rhythm**; ; Siponimod causes a temporary decrease in heart rate and atrioventricular conduction upon beginning treatment. The maximum fall in heart rate is observed in the first 6 hours post ingestion. Autonomic heart responses, including diurnal variation of heart rate and response to exercise activities, are not altered by siponimod treatment [FDA label].; ; **Effects on pulmonary function**; ; Dose-dependent decreases in absolute forced expiratory volume over a time frame of 1 second were noted in siponimod-treated patients and were higher than in patients taking placebo [FDA label].
MOA Inflammation of the white and gray matter tissues in the central nervous system caused by localized immune cell infiltration and their cytokines are the initial cause of damage in MS. B lymphocytes and their cytokines are other factors in the pathogenesis of MS. Lymphotoxin [or transforming growth factor beta (TGF-β)] and TNF-α produced by these cells encourage inflammation [A176474]. The S1P receptor is an important receptor related to the function of lymphocytes and can be found in the central nervous system [A176492]. S1P receptor (S1PR) signaling is associated with a wide variety of physiological processes for lymphocytes, including their egress and recirculation [A176486, A176489]. ; ; Siponimod is classified as a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to both S1P receptors 1 and 5. This drug blocks the ability of lymphocytes to release from the lymph nodes, decreasing the number of lymphocytes found in the peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is not known at this time, but may involve the abovementioned decrease of lymphocytes into the central nervous system, decreasing the inflammatory effects of MS [FDA label].
Compound Sets
24
Cayman Chemical Bioactives
22057
ChEMBL Approved Drugs
CHEMBL2336071
CHEMBL4298150
ChEMBL Drugs
CHEMBL2336071
CHEMBL4298150
Concise Guide to Pharmacology 2017/18
9289
Concise Guide to Pharmacology 2019/20
9289
Concise Guide to Pharmacology 2021/22
9289
Concise Guide to Pharmacology 2023/24
9289
CZ-OPENSCREEN Bioactive Library
Drug Repurposing Hub
DrugBank
DB12371
DrugBank Approved Drugs
DB12371
DrugCentral
5326
DrugCentral Approved Drugs
5326
DrugMAP
DM2R86O
DrugMAP Approved Drugs
DM2R86O
EU-OPENSCREEN Bioactive Compound Library
EOS101184
Guide to Pharmacology
9289
LSP-MoA library (Laboratory of Systems Pharmacology)
CHEMBL2336071
MedChem Express Bioactive Compound Library
HY-12355
NCATS Inxight Approved Drugs
RR6P8L282I
Novartis Chemogenetic Library (NIBR MoA Box)
ReFrame library
Selleckchem Bioactive Compound Library
baf312-siponimod
TargetMol Bioactive Compound Library
T6403
External IDs
34
Properties
(calculated by RDKit )
Molecular Weight
516.26
Hydrogen Bond Acceptors
4
Hydrogen Bond Donors
1
Rotatable Bonds
9
Ring Count
4
Aromatic Ring Count
2
cLogP
6.77
TPSA
62.13
Fraction CSP3
0.52
Chiral centers
0.0
Largest ring
6.0
QED
0.3
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Pathway
GPCR/G protein
Target
S1P1
S1P2
S1P3
S1P4
S1P5
S1PR1
LPL Receptor
S1P Receptor
Member status
virtual
MOA
Angiogenesis Inhibitors
Lysophospholipid edg1 (S1P1) Receptor Agonists
Lysophospholipid edg1 (S1P1) Receptor Ligands
Lysophospholipid edg8 (S1P5) Receptor Ligands
sphingosine 1-phosphate receptor modulator
Indication
multiple sclerosis
Source data