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).”
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.”
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.”