Veppanu
vepdegestrant
Sources:FDA multi-discipline review ↗
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
“daily oral administration of vepdegestrant was assessed in repeat-dose toxicity studies for up to 6 months in rats and up to 9 months in dogs, using the clinical route of administration and intended dosing schedule.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“daily oral administration of vepdegestrant was assessed in repeat-dose toxicity studies for up to 6 months in rats and up to 9 months in dogs, using the clinical route of administration and intended dosing schedule.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“daily oral administration of vepdegestrant was assessed in repeat-dose toxicity studies for up to 6 months in rats and up to 9 months in dogs, using the clinical route of administration and intended dosing schedule.”
Pivotal GLP studies
6-month rat and 9-month dog oral studies
“daily oral administration of vepdegestrant was assessed in repeat-dose toxicity studies for up to 6 months in rats and up to 9 months in dogs, using the clinical route of administration and intended dosing schedule.”
Route in tox
Oral (clinical route)
“daily oral administration of vepdegestrant was assessed in repeat-dose toxicity studies for up to 6 months in rats and up to 9 months in dogs, using the clinical route of administration and intended dosing schedule.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames (parent and ARV-473), in vitro human lymphocyte micronucleus and in vivo rat micronucleus assays
“Vepdegestrant and its major metabolite ARV-473 did not induce mutations in the bacterial reverse mutation (Ames) assay. Vepdegestrant was not clastogenic in the in vitro human lymphocyte micronucleus assay or in the in vivo micronucleus study in rats.”
Carcinogenicity
6-month rasH2 mouse: no statistically significant ovarian tumors up to 800 mg/kg/day
“Administration of ARV-471 did not result in statistically significant ovarian tumors in transgenic rasH2 mice at daily doses up to 800 mg/kg/day for 6 months.”
Reproductive & developmental
Pilot rat EFD: embryo-fetal mortality at ≥30 mg/kg/day (0.3x human AUC)
“Oral administration of vepdegestrant resulted in embryo-fetal mortality (increased resorptions, post-implantation loss and reduced number of live fetuses) at ≥30 mg/kg/day (0.3 times the human AUC at the recommended dose).”
Safety pharmacology
No adverse cardiovascular, respiratory or FOB effects in rats and dogs
“Vepdegestrant did not demonstrate adverse cardiovascular, respiratory, or functional observational battery (FOB) effects in standalone safety pharmacology studies or repeated-dose toxicology studies in rats and dogs at the tested doses.”
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 Veppanu 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 oncology small molecules (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Dose-dependent reproductive organ changes in both sexes in rats and dogs, from 1-month studies onward (FDA multi-discipline review, p. 48)
NOAEL / key findings
Dose-dependent reproductive organ changes in both sexes in rats and dogs, from 1-month studies onward
“Administration of vepdegestrant to rats and dogs resulted in dose-dependent changes in the reproductive systems of both sexes, observed as early as 1-month studies and persisting in longer-duration studies.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Highest in liver, ovaries, kidneys, thyroid, spleen; melanin binding (uveal tract, eye, pigmented skin)
“Following oral administration of [14C]- vepdegestrant and whole-body autoradiography, the highest distribution of vepdegestrant in rats was in the liver, ovaries, kidneys, thyroid, spleen, and melanin-containing tissues (uveal tract, whole eye, and pigmented skin).”
Modality-specific risk
Embryofetal toxicity (fetal harm based on animal findings and mechanism of action)
“Based on findings in animals and mechanism of action, vepdegestrant can cause fetal harm when administered to a pregnant woman.”