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.”
Species: general tox
Rat (up to 6 months) and dog (up to 9 months)
“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.”
Species: DART
Rat (pilot embryo-fetal development study only)
“The Applicant conducted a pilot embryo-fetal development study in rats.”
Species: carcinogenicity
Tg rasH2 mouse (6-month)
“However, a pivotal 6-month carcinogenicity study in rasH2 mice was conducted”
Surrogate used in
No surrogate used; vepdegestrant tested directly in rats and dogs
“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.”
Genotox: Ames
Negative (vepdegestrant and metabolite ARV-473)
“Vepdegestrant and its major metabolite ARV-473 did not induce mutations in the bacterial reverse mutation (Ames) assay.”
Genotox: in vitro mammalian
Human lymphocyte micronucleus: negative
“Vepdegestrant was not clastogenic in the in vitro human lymphocyte micronucleus assay or in the in vivo micronucleus study in rats.”
Genotox: in vivo
Rat micronucleus: negative
“Vepdegestrant was not clastogenic in the in vitro human lymphocyte micronucleus assay or in the in vivo micronucleus study in rats.”
Carcinogenicity model
6-month Tg rasH2 mouse (not required under ICH S9 for advanced cancer)
“Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer per ICH S9. However, a pivotal 6-month carcinogenicity study in rasH2 mice was conducted”
Carcinogenicity timing
26-week rasH2 mouse study completed and included in the NDA submission
“In this submission the sponsor included Study 8500921 “A 26-Week Once or Twice Daily Oral Gavage Carcinogenicity Study with ARV-471 (PF-07850327) in Transgenic RasH2 Mice” with the electronic SEND datasets and Tumor.xpt files.”
hERG / QT
No hERG effect up to 30 µM (>1000-fold free Cmax at clinical dose)
“Vepdegestrant had no effect on hERG tail current at concentrations up to 30 µM (the limit of solubility) when compared with vehicle-treated cells. This represents greater than 1000-fold the Cmax of free vepdegestrant at the recommended clinical dose, given that the free fraction is less than 1%.”
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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.”
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 assessed in the pivotal trial
“No immunogenicity assessments were included in Study C4891001.”
Label warnings
- QTc Interval Prolongation
- Embryo-Fetal Toxicity
CardiovascularEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US: first-in-human open-label dose escalation and cohort expansion study at 16 US sites (patients)
“ARV-471-mBC-101 (NCT04072952); 16 sites in US (Parts A & B [completed]) Phase 1/2, FIH, open-label, sequential group, dose escalation 3+3 and cohort expansion”
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 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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Up to 9 months in dogs (39 weeks) and 6 months in rats; no recovery phase in these longer studies
“While studies beyond 3 months duration are not needed to support the proposed indication per ICH S9 recommendations, 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.”
DART package
Species: DART
Rat (pilot embryo-fetal development study only)
“The Applicant conducted a pilot embryo-fetal development study in rats.”
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).”
PPND / ePPND: when
No PPND study; only a preliminary rat EFD study, further reproductive studies judged unwarranted
“Based on the primary pharmacology of ER degradation, findings in pivotal repeat-dose toxicity studies in sexually mature rats and dogs, and a preliminary embryofetal development study in rats, reproductive organs are key target organs of vepdegestrant. With this risk identified and reported in the label, no additional studies are warranted.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (6-month)
“However, a pivotal 6-month carcinogenicity study in rasH2 mice was conducted”
Carcinogenicity model
6-month Tg rasH2 mouse (not required under ICH S9 for advanced cancer)
“Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer per ICH S9. However, a pivotal 6-month carcinogenicity study in rasH2 mice was conducted”
Carcinogenicity timing
26-week rasH2 mouse study completed and included in the NDA submission
“In this submission the sponsor included Study 8500921 “A 26-Week Once or Twice Daily Oral Gavage Carcinogenicity Study with ARV-471 (PF-07850327) in Transgenic RasH2 Mice” with the electronic SEND datasets and Tumor.xpt files.”
Safety marginopen answer page →
Safety margin at NOAEL
Repeat-dose: female reproductive organ toxicity at ≥30 mg/kg/day, 0.3x human AUC (below clinical exposure)
“In repeat-dose toxicity studies, oral administration of vepdegestrant resulted in decreased corpora lutea, follicle hemorrhage and granulosa cell hyperplasia in the ovary and atrophy of the uterus, oviduct, cervix and vagina at doses ≥30 mg/kg/day (0.3 times the human AUC at the recommended dose).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
MCF7 xenograft mice: tumor shrinkage (124% TGI) and >94% ER reduction at 30 mg/kg/day
“In the ER+ ESR1 WT MCF7 xenograft model, 30 mg/kg/day of vepdegestrant led to tumor shrinkage (124% TGI on Day 28) and reduced ER levels by >94% in tumor tissue, and both ER degradation and TGI were significantly better following vepdegestrant treatment compared to fulvestrant in this model.”
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
FDA: tumor growth inhibition and ER reduction in wild-type and mutant ER xenograft and PDX models
“In vivo, vepdegestrant inhibited tumor growth and reduced ER levels in tumor tissue in mouse xenograft models expressing either wild-type or mutant ER, as well as in patient-derived xenograft (PDX) models.”
Flexibilityopen answer page →
Flexibility accepted
DARTVerdict not stated
Only a preliminary rat embryo-fetal study; no definitive or second-species embryo-fetal study
Why: Reproductive risk already identified and reported in the label
“Based on the primary pharmacology of ER degradation, findings in pivotal repeat-dose toxicity studies in sexually mature rats and dogs, and a preliminary embryofetal development study in rats, reproductive organs are key target organs of vepdegestrant. With this risk identified and reported in the label, no additional studies are warranted.”
Safety marginVerdict not stated
Embryo-fetal mortality and female reproductive toxicity at 0.3 times human AUC; no margin
“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).”
RecoveryVerdict not stated
No recovery assessment in the longer-duration (chronic) rat and dog studies
“Recovery assessment was not included in longer-duration studies.”
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