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
Structure for Etrasimod (DB14766)
- Weight
- Average: 457.493
Monoisotopic: 457.18647819 - Chemical Formula
- C26H26F3NO3
- Synonyms
- Etrasimod
- External IDs
- APD334
Pharmacology
- Indication
Etrasimod is indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adults.3
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Moderately to severely active ulcerative colitis •••••••••••• ••••• •••••• - Contraindications & Blackbox Warnings
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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
Target Actions Organism ASphingosine 1-phosphate receptor 1 modulatorHumans ASphingosine 1-phosphate receptor 4 modulatorHumans ASphingosine 1-phosphate receptor 5 modulatorHumans - 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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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
- Not Available
Interactions
- Drug Interactions
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Etrasimod can be increased when it is combined with Abametapir. Abatacept The risk or severity of immunosuppression can be increased when Abatacept is combined with Etrasimod. Abemaciclib The risk or severity of immunosuppression can be increased when Abemaciclib is combined with Etrasimod. Abiraterone The risk or severity of immunosuppression can be increased when Abiraterone is combined with Etrasimod. Abrocitinib The metabolism of Abrocitinib can be decreased when combined with Etrasimod. - Food Interactions
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Etrasimod arginine MXE5EMA09L 1206123-97-8 GVPVVOSNDUAUKM-BPGOJFKZSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Velsipity Tablet, film coated 2 mg/1 Oral U.S. Pharmaceuticals 2023-11-09 Not applicable US 
Velsipity Tablet, film coated 2 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 2023-10-19 Not applicable US
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
- 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]
- 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]
- FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
- FDA Approves Pfizer’s Ulcerative Colitis Drug, $6.7B Arena Buy Pays Off [Link]
- External Links
- ChemSpider
- 52084233
- BindingDB
- 50041691
- 2668045
- ChEMBL
- CHEMBL3358920
- ZINC
- ZINC000117522788
- Wikipedia
- Etrasimod
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Atopic Dermatitis / Atopic Dermatitis, Unspecified 1 3 Active Not Recruiting Treatment Moderately to Severely Active Ulcerative Colitis 1 3 Completed Treatment Ulcerative Colitis 3 3 Recruiting Treatment Crohn's Disease (CD) 1 3 Recruiting Treatment Ulcerative Colitis 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 2 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11007175 No 2016-01-06 2036-01-06 US US10676435 No 2016-06-21 2036-06-21 US US9126932 No 2009-07-22 2029-07-22 US US11091435 No 2016-06-21 2036-06-21 US US10301262 No 2016-06-21 2036-06-21 US US8580841 No 2010-03-05 2030-03-05 US US11884626 No 2016-06-21 2036-06-21 US
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.000477 mg/mL ALOGPS logP 5.73 ALOGPS logP 6.45 Chemaxon logS -6 ALOGPS pKa (Strongest Acidic) 4.26 Chemaxon pKa (Strongest Basic) -4.9 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 62.32 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 119.44 m3·mol-1 Chemaxon Polarizability 47.7 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0000900000-bc5d4334d338cda70baa Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-06ri-0702900000-9df028da12be275d8bb7 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0010900000-c13450118d596464eae8 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0btc-2325900000-80615e97034967a986dc Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-060r-3209700000-ce63e8d4ffb7c1e3596e Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-053r-2923300000-bb2fae459fa864d78b0f Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- 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
- FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
- 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
- FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
- 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
- FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
Enzymes
- 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
- FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
- 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
- FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
- 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
- FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
- 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
- FDA Approved Drug Products: VELSIPITY™ (etrasimod) tablets, for oral use [Link]
- 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
- 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