Velsipity
etrasimod
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Repeat-dose toxicity studies of up to six months duration in rats and nine months duration in dogs were conducted to support the chronic use of etrasimod in humans.”
Why that species
Rats sufficiently exposed to metabolites M3 and M6
“The overview shows that rats were exposed sufficiently to the metabolites M3 and M6 during toxicity testing.”
Surrogate molecule
No surrogate; the clinical compound was tested
“No adverse effects were observed in rats or dogs at exposures up to 738- and 446-fold, respectively, the exposure at the MRHD (based on AUC comparison).”
Species: general tox
Rat (up to 6 months) and dog (up to 9 months)
“repeat-dose toxicology studies of up to six months duration in rats and nine months duration in dogs”
Species: DART
Rat and rabbit (standard DART battery)
“a standard battery of developmental and reproductive toxicity studies in rats and rabbits”
Species: carcinogenicity
CD-1 mouse and Sprague Dawley rat (lifetime bioassays)
“Bioassays were performed in Crl: CD1 (ICR) mice and Sprague Dawley rats.”
Surrogate used in
No surrogate used; etrasimod is a potent full agonist at mouse, dog and monkey S1P1
“In similar β-arrestin recruitment assays etrasimod was determined to be as well a potent full agonist on mouse, dog, and monkey S1P1 receptors with similar mean EC50 values, ranging from 3.65 to 8.70 nM (mean efficacy > 80% S1P), across species.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“Study TX14008: 9-month toxicology study in dogs”
Pivotal GLP studies
6-month rat and 9-month dog oral studies
“Repeat-dose toxicity studies of up to six months duration in rats and nine months duration in dogs were conducted to support the chronic use of etrasimod in humans.”
Route in tox
Oral gavage
“Route of administration Oral gavage”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, human lymphocyte chromosomal aberration and rat micronucleus assays
“Mutagenesis Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays.”
Carcinogenicity
Hemangioma/hemangiosarcoma at ≥46-fold MRHD exposure; 2-year rat: no carcinogenic potential up to 88–198-fold
“hemangioma/hemangiosarcoma were observed at exposures ≥ 46-fold the exposure at the MRHD (based on AUC comparison). In a two-year carcinogenicity study in rats, no evidence of carcinogenic potential was observed at exposures up to 88- and 198-fold the exposure at the MRHD in males and females, respectively (based on AUC comparison).”
Reproductive & developmental
Rat and rabbit EFD: embryolethality and fetal malformations at 5- and 6-fold MRHD exposure
“In animal reproduction studies, administration of etrasimod during organogenesis produced adverse effects on development, including embryolethality and fetal malformations, in both rats and rabbits at maternal exposures 5 and 6 times, respectively, the exposure at the maximum recommended human dose (MRHD).”
Safety pharmacology
No significant effects on hERG current, dog cardiovascular, rat CNS or rat respiratory function
“In a standard battery of nonclinical safety pharmacology studies, etrasimod had no significant effects on hERG channel current in vitro, cardiovascular function in dogs, CNS parameters in rats, or respiratory function in rats.”
Genotox: Ames
Negative
“Etrasimod was not mutagenic under the tested conditions.”
Genotox: in vitro mammalian
Human lymphocyte chromosome aberration: negative with or without metabolic activation
“Etrasimod did not induce structural aberrations in human peripheral blood lymphocytes under the conditions of the study, with or without metabolic activation.”
Genotox: in vivo
Rat bone marrow micronucleus: negative overall (increase in females at 300 mg/kg/day within historical control range)
“Etrasimod was positive for inducing bone marrow micronuclei in female rats at the highest tested dose of 300 mg/kg/day, a systemically toxic dose; however, this increase was within the historical control range, substantially lower than the positive control, and not observed in males.”
Carcinogenicity model
2-year mouse and 2-year rat
“two-year carcinogenicity studies in mice and rats”
Carcinogenicity timing
2-year mouse and 2-year rat completed; final reports included in the NDA submission
“The NDA submission included the final study reports and corresponding SEND datasets for the 2-year carcinogenicity studies in mice and rats.”
hERG / QT
hERG max 59% inhibition at 3 µM; IC50 likely 4–12x steady-state Cmax at MRHD
“Etrasimod inhibited hERG signaling in vitro, with a maximal inhibitory effect of 59% at the highest tested dose of 3 µM; a specific IC50 value could not be determined based on the study design but is likely between 1000-3000 nM (460-1370 ng/mL; 4-12 times the steady state Cmax at the MRHD).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Velsipity don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Rat: mortality, decreased weight gain, liver and thymus histopathology at >1000-fold MRHD exposure (FDA multi-discipline review, p. 42)
NOAEL / key findings
Rat: mortality, decreased weight gain, liver and thymus histopathology at >1000-fold MRHD exposure
“In repeat-dose toxicity studies, mortalities, decreased body weight gain, and histopathological findings in the liver and thymus were observed in rats at exposures > 1000-fold the exposure at the maximum recommended human dose (MRHD) of 2 mg/day (based on AUC comparison).”
Risksopen answer page →
Immune & cytokine safety
Dose-dependent lymphocyte decreases in rats and dogs; lymphoid depletion in rat lymph nodes and spleen (pharmacological)
“Dose-dependent decreases in circulating lymphocytes were observed in both rats and dogs and correlated with lymphoid depletion in the lymph nodes and spleen of rats only; these findings were attributed to the pharmacological activity of etrasimod and not considered adverse.”
Biodistribution & persistence
Wide distribution incl. GI tract, liver, kidney, myocardium, adrenal, thyroid, brain and spinal cord
“[14C]etrasimod distributed to tissues of GI tract, organs of clearance (kidney and liver), myocardium, secretory glands (adrenal and thyroid), and the non-circumventricular central nervous system tissues (spinal cord and brain) in non-pigmented and pigmented rats.”
Modality-specific risk
Embryo-fetal toxicity: teratogenicity in rats and rabbits below human therapeutic exposure
“As expected, teratogenicity was observed in the embryo-fetal development studies in rats and rabbits already below human therapeutic exposures.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Infections
- Bradyarrhythmia and Atrioventricular Conduction Delays
- Liver Injury
- Macular Edema
- Increased Blood Pressure
- Fetal Risk
- Cutaneous Malignancies
- Posterior Reversible Encephalopathy Syndrome
- Respiratory Effects
- Unintended Additive Immune System Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs
- Immune System Effects After Stopping VELSIPITY
InfectionsCardiovascularHepatotoxicityOcular toxicityEmbryo-fetal toxicitySecondary malignancySkin reactionsNeurotoxicityPulmonary toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Velsipity don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Rat: mortality, decreased weight gain, liver and thymus histopathology at >1000-fold MRHD exposure (FDA multi-discipline review, p. 42)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (273 days of dosing) with 4-week recovery
“2 animals/sex from the vehicle, 10, and 15 mg/kg/day groups were maintained for a 4-week recovery period after 273 consecutive days of dosing.”
Pivotal GLP studies
6-month rat and 9-month dog oral studies
“Repeat-dose toxicity studies of up to six months duration in rats and nine months duration in dogs were conducted to support the chronic use of etrasimod in humans.”
DART package
Species: DART
Rat and rabbit (standard DART battery)
“a standard battery of developmental and reproductive toxicity studies in rats and rabbits”
Reproductive & developmental
Rat and rabbit EFD: embryolethality and fetal malformations at 5- and 6-fold MRHD exposure
“In animal reproduction studies, administration of etrasimod during organogenesis produced adverse effects on development, including embryolethality and fetal malformations, in both rats and rabbits at maternal exposures 5 and 6 times, respectively, the exposure at the maximum recommended human dose (MRHD).”
PPND / ePPND: when
Rat PPND completed and submitted in the NDA package
“As part of the NDA package, the Applicant submitted three in vitro pharmacology studies and a pre- and postnatal development (PPND) study in rats with etrasimod, as well as genetic toxicology studies with two process-related impurities.”
Carcinogenicity
Species: carcinogenicity
CD-1 mouse and Sprague Dawley rat (lifetime bioassays)
“Bioassays were performed in Crl: CD1 (ICR) mice and Sprague Dawley rats.”
Carcinogenicity model
2-year mouse and 2-year rat
“two-year carcinogenicity studies in mice and rats”
Carcinogenicity timing
2-year mouse and 2-year rat completed; final reports included in the NDA submission
“The NDA submission included the final study reports and corresponding SEND datasets for the 2-year carcinogenicity studies in mice and rats.”
Safety marginopen answer page →
Safety margin at NOAEL
No adverse effects in rats and dogs up to 738x and 446x human AUC at MRHD
“No adverse effects were observed in rats or dogs at exposures up to 738- and 446-fold, respectively, the exposure at the MRHD (based on AUC comparison).”
NOAEL / key findings
Rat: mortality, decreased weight gain, liver and thymus histopathology at >1000-fold MRHD exposure
“In repeat-dose toxicity studies, mortalities, decreased body weight gain, and histopathological findings in the liver and thymus were observed in rats at exposures > 1000-fold the exposure at the maximum recommended human dose (MRHD) of 2 mg/day (based on AUC comparison).”
Efficacy evidenceopen answer page →
Efficacy evidence
T-cell transfer colitis in SCID mice: reduced colonic T-cell and monocyte markers
“As primary pharmacology animal model the applicant chose a model employing adoptive transfer of CD4+CD45RBhigh T cells from WT mice to severe combined immunodeficiency (SCID) mice, which showed among other effects that 3 mg/kg bw of etrasimod significantly reduced the expression of the T cell and monocyte markers in isolated colonic tissue.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
EMA: mechanism adequately described and measured as a PD biomarker in humans
“This mechanism is adequately described and additionally measured as a biomarker in primary PD human studies.”
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteQuestioned
Exposure to major human metabolites M3 and M6 not investigated in mice and dogs; coverage shown in rats only
“The overview shows that rats were exposed sufficiently to the metabolites M3 and M6 during toxicity testing. The exposure in mice and dogs was not investigated.”
“The exposure to M3 and M6 remains unclear in dogs and mice.”
Safety pharmacologyAccepted with a conditionBeyond the letter
No hERG assessment of metabolites M3 and M6 before approval; non-GLP patch-clamp test deferred post-authorisation
“Furthermore, an effect on QT prolongation of M3 and M6 will be evaluated post authorisation by an automated patch-clamp test on M3 and M6 for their effects on the hERG potassium channel current in vitro (non-GLP).”
Similar precedents
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