NAV

Etrasimod

Identification

Summary

Etrasimod is an S1P receptors modulator used to treat moderate to severely active ulcerative colitis in adults

Brand Names
Velsipity
Generic Name
Etrasimod
DrugBank Accession Number
DB14766
Background

Etrasimod is a synthetic next-generation selective Sphingosine 1-phosphate (S1P) receptor modulator that targets the S1P1,4,5 with no detectable activity on S1P2 and S1P3 receptors. S1P receptors are membrane-derived lysophospholipid signaling molecules that are involved in the sequestration of circulating peripheral lymphocytes in lymph nodes.1 Therefore, S1P receptor modulators like etrasimod were investigated in treating immune-mediated diseases like ulcerative colitis where a high level of inflammatory T cells is present in the gastrointestinal tract, thus causing diffuse mucosal inflammation.1 In fact, it has been observed that antigen-activated T cells within peripheral lymphoid organs can transiently downregulate S1P receptor levels to facilitate immune cells trafficking into the intestinal mucosa.2

Etrasimod was approved on October 13, 2023, by the FDA under the brand name VELSIPITY for the treatment of adults with moderately to severely active ulcerative colitis. This approval was based on favorable results obtained from Pfizer’s Elevate UC Phase III registrational program, consisting of the Elevate UC 52 and Elevate UC 12 clinical trials, that investigates the efficacy of a 2-mg daily dose regimen of etrasimod, with a 32% and 26% remission rate observed in UC 52 and UC 12 trials respectively.4

Type
Small Molecule
Groups
Approved
Structure
3D
Similar Structures
Weight
Average: 457.493
Monoisotopic: 457.18647819
Chemical Formula
C26H26F3NO3
Synonyms
  • Etrasimod
External IDs
  • APD334
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Pharmacology

Indication

Etrasimod is indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adults.3

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofModerately to severely active ulcerative colitis•••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Etrasimod causes a reduction in peripheral blood lymphocyte count. In UC-1 and UC-2, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 x 109/L) and the lower lymphocyte counts were maintained during treatment with etrasimod.3

Dose-response relationship analysis indicates there is a dose-dependent reduction in blood lymphocyte counts. After discontinuing etrasimod 2 mg once daily, the median time for peripheral blood lymphocytes to return to the normal range was 2.6 weeks, with approximately 90% of subjects in the normal range within 4.7 weeks.3

Etrasimod may result in a transient decrease in heart rate and AV conduction upon treatment initiation. In UC-1 and UC-2, the mean (SD) decrease in heart rate was 7.2 (8.98) bpm at 2 to 3 hours after the first dose of etrasimod on Day 1. At 2 times the maximum recommended dose, etrasimod does not cause clinically significant QTc interval prolongation. Reductions in absolute FEV1 were also observed in subjects treated with etrasimod.3

Mechanism of action

Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5 (S1P1,4,5). Etrasimod has minimal activity on S1P3 (25-fold lower than Cmax at the recommended dose) and no activity on S1P2. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood. The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines.3

TargetActionsOrganism
ASphingosine 1-phosphate receptor 1
modulator
Humans
ASphingosine 1-phosphate receptor 4
modulator
Humans
ASphingosine 1-phosphate receptor 5
modulator
Humans
Absorption

Etrasimod mean (SD) steady-state maximum plasma concentration (Cmax) was 113 (27.5) ng/mL and the area under the time concentration curve at the dosing interval (AUCtau) was 2162 (488) ng*h/mL at the recommended dosage. Etrasimod Cmax and AUC are approximately dose-proportional from 0.7 mg to 2 mg (0.35 times up to the recommended dosage). Etrasimod steady state is reached within 7 days with an accumulation of approximately 2- to 3-fold compared to the first dose. The median (range) time to reach etrasimod Cmax (Tmax) is approximately 4 hours (range 2 to 8 hours) after oral administration.3

No clinically significant differences in the pharmacokinetics of etrasimod were observed following administration of etrasimod with a high-fat meal (800 to 1000 calories).3

Volume of distribution

The mean apparent volume of distribution of etrasimod is 66 (24) L.3

Protein binding

Etrasimod plasma protein binding is 97.9%.3

Metabolism

Etrasimod is metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8, CYP2C9, and CYP3A4, with a minor contribution by CYP2C19 and CYP2J2. Etrasimod also undergoes conjugation primarily mediated by UGTs, with a minor contribution by sulfotransferases. Unchanged etrasimod is the main circulating component in plasma.3

Route of elimination

Approximately 82% of the total radioactive etrasimod dose was recovered in the feces and 5% in the urine within 336 hours. Approximately 11% of the administered radioactive dose was excreted as unchanged etrasimod in feces and none was excreted unchanged in urine.3

Half-life

The mean plasma elimination half-life (t1/2) of etrasimod is approximately 30 hours.3

Clearance

The apparent steady-state oral clearance of etrasimod is approximately 1 L/h after oral administration.3

Adverse Effects
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Toxicity

Based on findings from animal studies, etrasimod may cause fetal harm when administered to a pregnant woman. Available data from reports of pregnancies from the clinical development program with etrasimod are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with increased disease activity in women with inflammatory bowel disease during pregnancy, including preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.3

In an embryo-fetal development study in pregnant rats, etrasimod was orally administered at 1, 2, or 4 mg/kg/day (5, 11, and 21 times the exposure at the maximum recommended human dose (MRHD) of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 6 to 17. No maternal toxicity was observed up to 21 times the exposure at the MRHD. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 4 mg/kg/day (21 times the exposure at the MRHD). Etrasimod-related fetal external and/or visceral malformations were noted at all dose levels (≥5 times the exposure at the MRHD).3

In an embryo-fetal development study in pregnant rabbits, etrasimod was orally administered at 2, 10, or 20 mg/kg/day (0.8, 6, and 11 times the exposure at the MRHD of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 7 to 20. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 10 and 20 mg/kg/day (7 and 11 times the exposure at the MRHD). Etrasimod-related fetal malformations including aortic arch defects and fused sternebrae were noted at 10 and/or 20 mg/kg/day (7 and 11 times the exposure at the MRHD). There were no adverse effects on embryofetal development at 2 mg/kg/day (less than the exposure at the MRHD).3

In a pre-and post-natal development study in rats, etrasimod was orally administered at 0.4, 2, or 4 mg/kg/day (2, 10, and 24 times the exposure at the MRHD of 2 mg, based on AUC comparison) throughout pregnancy and lactation, from gestation day 6 through lactation day 20. Mortality during delivery and impaired maternal performance including increased post-implantation loss, increased number of females with stillborn pups, increased number of stillborn pups per litter, decreased viability index, and/or decreased lactation index was observed at 2 and 4 mg/kg/day (10 and 24 times the exposure at the MRHD). Etrasimod was detected in the plasma of F1 offspring, indicating exposure from the milk of the lactating dam. Decreased pup body weights were observed during the preweaning period at all dose levels (maternal exposures ≥2 times the exposure at the MRHD), and decreased pup viability was observed at 2 and 4 mg/kg/day (maternal exposures 10 and 24 times the exposure at the MRHD). Reduced fertility and reproductive performance including reduction in implantations and increased preimplantation loss in F1 offspring occurred at the highest dose tested (maternal exposures 24 times the exposure at the MRHD).3

Oral carcinogenicity studies with etrasimod were conducted in mice and rats. In mice administered etrasimod (2, 6, or 20 mg/kg/day) for up to 104 weeks, there was an increase in hemangiosarcoma and hemangioma in males and females at 6 and 20 mg/kg/day (exposures approximately 42 and 121 times, respectively, the exposure at the MRHD of 2 mg, based on AUC comparison). In rats, oral administration of etrasimod (2, 6, or 20 mg/kg/day) for up to 91 weeks did not result in an increase in tumors (male and female exposures 80 and 179 times, respectively, the exposure at MRHD).3

Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays.3

Etrasimod administered orally to male rats at 25, 100, or 200 mg/kg/day from pre-mating through mating had no adverse effects on male fertility at exposures up to 467 times the exposure at the MRHD of 2 mg, based on AUC comparison. Etrasimod administered orally to female rats at 1, 2, or 4 mg/kg/day from pre-mating to implantation had no adverse effects on female fertility at exposures up to 21 times the exposure at the MRHD.3

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbametapirThe serum concentration of Etrasimod can be increased when it is combined with Abametapir.
AbataceptThe risk or severity of immunosuppression can be increased when Abatacept is combined with Etrasimod.
AbemaciclibThe risk or severity of immunosuppression can be increased when Abemaciclib is combined with Etrasimod.
AbirateroneThe risk or severity of immunosuppression can be increased when Abiraterone is combined with Etrasimod.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Etrasimod.
Food Interactions
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Etrasimod arginineMXE5EMA09L1206123-97-8GVPVVOSNDUAUKM-BPGOJFKZSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VelsipityTablet, film coated2 mg/1OralU.S. Pharmaceuticals2023-11-09Not applicableUS flag
VelsipityTablet, film coated2 mg/1OralPfizer Laboratories Div Pfizer Inc2023-10-19Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
6WH8495MMH
CAS number
1206123-37-6
InChI Key
MVGWUTBTXDYMND-QGZVFWFLSA-N
InChI
InChI=1S/C26H26F3NO3/c27-26(28,29)22-11-15(5-8-19(22)16-3-1-2-4-16)14-33-18-7-10-23-21(13-18)20-9-6-17(12-24(31)32)25(20)30-23/h5,7-8,10-11,13,16-17,30H,1-4,6,9,12,14H2,(H,31,32)/t17-/m1/s1
IUPAC Name
2-[(3R)-7-{[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy}-1H,2H,3H,4H-cyclopenta[b]indol-3-yl]acetic acid
SMILES
OC(=O)C[C@H]1CCC2=C1NC1=C2C=C(OCC2=CC(=C(C=C2)C2CCCC2)C(F)(F)F)C=C1

References

General References
  1. Sandborn WJ, Vermeire S, Peyrin-Biroulet L, Dubinsky MC, Panes J, Yarur A, Ritter T, Baert F, Schreiber S, Sloan S, Cataldi F, Shan K, Rabbat CJ, Chiorean M, Wolf DC, Sands BE, D'Haens G, Danese S, Goetsch M, Feagan BG: Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet. 2023 Apr 8;401(10383):1159-1171. doi: 10.1016/S0140-6736(23)00061-2. Epub 2023 Mar 2. [Article]
  2. Al-Shamma H, Lehmann-Bruinsma K, Carroll C, Solomon M, Komori HK, Peyrin-Biroulet L, Adams J: The Selective Sphingosine 1-Phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis. J Pharmacol Exp Ther. 2019 Jun;369(3):311-317. doi: 10.1124/jpet.118.254268. Epub 2019 Mar 14. [Article]
  3. FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
  4. FDA Approves Pfizer’s Ulcerative Colitis Drug, $6.7B Arena Buy Pays Off [Link]
ChemSpider
52084233
BindingDB
50041691
RxNav
2668045
ChEMBL
CHEMBL3358920
ZINC
ZINC000117522788
Wikipedia
Etrasimod

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentModerately to Severely Active Ulcerative Colitis1
3CompletedTreatmentUlcerative Colitis3
3RecruitingTreatmentCrohn's Disease (CD)1
3RecruitingTreatmentUlcerative Colitis1
2Active Not RecruitingTreatmentUlcerative Colitis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral2 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11007175No2016-01-062036-01-06US flag
US10676435No2016-06-212036-06-21US flag
US9126932No2009-07-222029-07-22US flag
US11091435No2016-06-212036-06-21US flag
US10301262No2016-06-212036-06-21US flag
US8580841No2010-03-052030-03-05US flag

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000477 mg/mLALOGPS
logP5.73ALOGPS
logP6.45Chemaxon
logS-6ALOGPS
pKa (Strongest Acidic)4.26Chemaxon
pKa (Strongest Basic)-4.9Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area62.32 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity119.44 m3·mol-1Chemaxon
Polarizability47.7 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0000900000-bc5d4334d338cda70baa
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-06ri-0702900000-9df028da12be275d8bb7
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0010900000-c13450118d596464eae8
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0btc-2325900000-80615e97034967a986dc
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-060r-3209700000-ce63e8d4ffb7c1e3596e
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-053r-2923300000-bb2fae459fa864d78b0f
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details1. Sphingosine 1-phosphate receptor 1
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Modulator
General Function
Sphingosine-1-phosphate receptor activity
Specific Function
G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activatio...
Gene Name
S1PR1
Uniprot ID
P21453
Uniprot Name
Sphingosine 1-phosphate receptor 1
Molecular Weight
42810.195 Da
References
  1. FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
Details2. Sphingosine 1-phosphate receptor 4
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Modulator
General Function
Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. May be involved in cell migration processes that are specific for lymphocytes.
Specific Function
G protein-coupled receptor activity
Gene Name
S1PR4
Uniprot ID
O95977
Uniprot Name
Sphingosine 1-phosphate receptor 4
Molecular Weight
41622.525 Da
References
  1. FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
Details3. Sphingosine 1-phosphate receptor 5
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Modulator
General Function
Sphingosine-1-phosphate receptor activity
Specific Function
Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. Is coupled to both...
Gene Name
S1PR5
Uniprot ID
Q9H228
Uniprot Name
Sphingosine 1-phosphate receptor 5
Molecular Weight
41774.515 Da
References
  1. FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]

Enzymes

Details1. Cytochrome P450 2C8
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
Details2. Cytochrome P450 2C9
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
Details3. Cytochrome P450 2C19
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
Details4. Cytochrome P450 2J2
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
This enzyme metabolizes arachidonic acid predominantly via a NADPH-dependent olefin epoxidation to all four regioisomeric cis-epoxyeicosatrienoic acids. One of the predominant enzymes responsible f...
Gene Name
CYP2J2
Uniprot ID
P51589
Uniprot Name
Cytochrome P450 2J2
Molecular Weight
57610.165 Da
References
  1. FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
Details5. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]

Drug created at May 20, 2019 14:25 / Updated at October 16, 2023 22:06