Foundayo
orforglipron
Species
MonkeyRat
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 cynomolgus monkey
“Toxicology studies of orforglipron were conducted in Wistar rats and cynomolgus monkeys.”
Why that species
Monkey: pharmacologically relevant species; rat: most suitable rodent but an off-target model
“Wistar rats were selected as the most suitable rodent species; however, rats represent an off-target model of toxicology. Cynomolgus monkeys were selected as the nonrodent species because they are a pharmacologically relevant species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Toxicology studies of orforglipron were conducted in Wistar rats and cynomolgus monkeys.”
Species: general tox
Wistar rat and cynomolgus monkey
“Toxicology studies of orforglipron were conducted in Wistar rats and cynomolgus monkeys.”
Species: DART
Rat and rabbit (reproductive safety; pharmacologically inactive species)
“Off-target safety was further characterized in several nonpharmacologically relevant species, including rats (general toxicology and reproductive safety assessment), rasH2 transgenic mice (carcinogenicity assessment), and rabbits (reproductive safety assessment).”
Species: carcinogenicity
Rat (lifetime) and rasH2 transgenic mouse (6-month)
“FDA concurs with the Applicant that orforglipron was not carcinogenic in a lifetime study in rats and a 6-month study in rasH2 transgenic mice.”
Surrogate used in
Transgenic model: humanized GLP-1 receptor Glp1rS33W rats for in vivo pharmacology
“The pharmacological characteristics of orforglipron were assessed in vitro (receptor-binding, potency, and specificity) and in vivo (wild-type monkeys and “humanized GLP-1 receptor” Glp1rS33W rats).”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“The Good Laboratory Practice repeat-dose studies in rats were 1 month, 3 months and 6 months in duration, and the repeat-dose studies in monkeys were 1 month, 3 months, and 9 months in duration.”
Pivotal GLP studies
1-, 3- and 6-month rat and 1-, 3- and 9-month monkey GLP studies
“The Good Laboratory Practice repeat-dose studies in rats were 1 month, 3 months and 6 months in duration, and the repeat-dose studies in monkeys were 1 month, 3 months, and 9 months in duration.”
Route in tox
Oral
“In rats, which are not a pharmacologically relevant species, no adverse off-target effects were observed up to the maximum feasible dose, at systemic exposures up to 35-fold the MRHD, based on AUC, when administered orally up to 6 months.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro micronucleus (human lymphoblastoid cells) and in vivo rat bone marrow micronucleus assays
“Orforglipron was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro micronucleus test in human lymphoblastoid cells, or in an in vivo bone marrow micronucleus study in rats.”
Carcinogenicity
Lifetime rat and 6-month rasH2 mouse: not carcinogenic
“FDA concurs with the Applicant that orforglipron was not carcinogenic in a lifetime study in rats and a 6-month study in rasH2 transgenic mice.”
Reproductive & developmental
Rabbit EFD: off-target decreased fetal and placental weights and malformations at 14x MRHD
“In a rabbit embryofetal development study, orforglipron caused off-target embryofetal effects which included decreased fetal and placental weights and malformations at exposures 14x the MRHD.”
Safety pharmacology
No respiratory or CNS effects in monkeys; GLP-1 class increases in heart rate and PR interval prolongation
“Orforglipron did not affect respiratory or CNS functions in monkeys. In cardiovascular studies in monkeys, orforglipron produces effects consistent with GLP-1 pharmacology including increases in heart rate and PR interval prolongation.”
Genotox: Ames
Negative
“Orforglipron was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro micronucleus test in human lymphoblastoid cells, or in an in vivo bone marrow micronucleus study in rats.”
Genotox: in vitro mammalian
Negative: in vitro micronucleus in human lymphoblastoid cells
“Orforglipron was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro micronucleus test in human lymphoblastoid cells, or in an in vivo bone marrow micronucleus study in rats.”
Genotox: in vivo
Negative: in vivo rat bone marrow micronucleus
“Orforglipron was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro micronucleus test in human lymphoblastoid cells, or in an in vivo bone marrow micronucleus study in rats.”
Carcinogenicity model
Lifetime rat and 6-month rasH2 mouse: not carcinogenic
“FDA concurs with the Applicant that orforglipron was not carcinogenic in a lifetime study in rats and a 6-month study in rasH2 transgenic mice.”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 2-year rat studies completed before the marketing application; not carcinogenic
“Carcinogenicity assessments were conducted in a 26-week study in Tg.RasH2 transgenic mice and a 2-year study in rats.”
hERG / QT
IC50 not reached (<50% inhibition) in 2 hERG assays; >1700-fold free Cmax at 36 mg
“At the highest concentration tested in 2 different hERG assays, an IC50 for orforglipron was not determined (<50% inhibition). The free Cmax exposure multiple in these hERG assays to the estimated exposure at the 36 mg capsule human dose is >1700-fold.”
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 Foundayo 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: No target organ toxicity or adverse histopathology in rats or monkeys up to the highest doses tested (FDA multi-discipline review, p. 58)
NOAEL / key findings
No target organ toxicity or adverse histopathology in rats or monkeys up to the highest doses tested
“No target organ toxicity or adverse histopathologic effects were noted in monkeys or rats up to the highest doses tested for each species.”
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
No placental transfer in rats: radioactivity absent from fetal blood, tissues and amniotic fluid
“While radioactivity was detected in the amniotic sac and placenta of pregnant rats, it was not detected in fetal blood, fetal tissues, or amniotic fluid, indicating that orforglipron did not cross the placental barrier in rats.”
Modality-specific risk
On-target developmental and carcinogenicity risk cannot be differentiated from peptide GLP-1 receptor agonists
“Therefore, the on-target developmental and carcinogenicity risk for orforglipron cannot be differentiated from peptide-based GLP-1 receptor agonists.”
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 applicable (FDA agreed)
“Immunogenicity The Applicant’s Position: Not applicable The FDA’s Assessment: The Agency agrees with the Applicant’s position.”
Label warnings
Boxed warning: Risk of thyroid c-cell tumors
- Risk of Thyroid C-Cell Tumors
- Acute Pancreatitis
- Severe Gastrointestinal Reactions
- Acute Kidney Injury Due to Volume Depletion
- Hypoglycemia
- Hypersensitivity Reactions
- Diabetic Retinopathy Complications in Patients with Type 2 Diabetes
- Acute Gallbladder Disease
- Pulmonary Aspiration During General Anesthesia or Deep Sedation
Secondary malignancyMetabolic & endocrineGastrointestinalNephrotoxicityHypersensitivity & infusion reactionsPulmonary toxicity
US prescribing information, Boxed Warning and 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 Foundayo 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: No target organ toxicity or adverse histopathology in rats or monkeys up to the highest doses tested (FDA multi-discipline review, p. 58)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month oral cynomolgus monkey study with off-dose recovery (length not stated); body weight loss reversible
“Thereafter, decreases in body weight gain were observed throughout the duration of the study leading to a ~ 37% decrease in body weight at Month 9. Body weight loss and decreased weight gain were reversible upon dosing cessation.”
Pivotal GLP studies
1-, 3- and 6-month rat and 1-, 3- and 9-month monkey GLP studies
“The Good Laboratory Practice repeat-dose studies in rats were 1 month, 3 months and 6 months in duration, and the repeat-dose studies in monkeys were 1 month, 3 months, and 9 months in duration.”
DART package
Species: DART
Rat and rabbit (reproductive safety; pharmacologically inactive species)
“Off-target safety was further characterized in several nonpharmacologically relevant species, including rats (general toxicology and reproductive safety assessment), rasH2 transgenic mice (carcinogenicity assessment), and rabbits (reproductive safety assessment).”
Reproductive & developmental
Rabbit EFD: off-target decreased fetal and placental weights and malformations at 14x MRHD
“In a rabbit embryofetal development study, orforglipron caused off-target embryofetal effects which included decreased fetal and placental weights and malformations at exposures 14x the MRHD.”
PPND / ePPND: when
PPND in rat completed and reviewed with the marketing application; no effects up to 200 mg/kg
“No effects were noted at any dose tested in the pre- and post-natal development study in rats up to the maximum feasible dose of 200 mg/kg.”
Carcinogenicity
Species: carcinogenicity
Rat (lifetime) and rasH2 transgenic mouse (6-month)
“FDA concurs with the Applicant that orforglipron was not carcinogenic in a lifetime study in rats and a 6-month study in rasH2 transgenic mice.”
Carcinogenicity model
Lifetime rat and 6-month rasH2 mouse: not carcinogenic
“FDA concurs with the Applicant that orforglipron was not carcinogenic in a lifetime study in rats and a 6-month study in rasH2 transgenic mice.”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 2-year rat studies completed before the marketing application; not carcinogenic
“Carcinogenicity assessments were conducted in a 26-week study in Tg.RasH2 transgenic mice and a 2-year study in rats.”
Safety marginopen answer page →
Safety margin at NOAEL
6-month rat (pharmacologically inactive species): no adverse effects up to 35-fold MRHD AUC
“In rats, which are not a pharmacologically relevant species, no adverse off-target effects were observed up to the maximum feasible dose, at systemic exposures up to 35-fold the MRHD, based on AUC, when administered orally up to 6 months.”
NOAEL / key findings
No target organ toxicity or adverse histopathology in rats or monkeys up to the highest doses tested
“No target organ toxicity or adverse histopathologic effects were noted in monkeys or rats up to the highest doses tested for each species.”
Efficacy evidenceopen answer page →
Efficacy evidence
Cynomolgus monkeys and humanized GLP-1R knock-in (Glp1rS33W) rats, including diet-induced obese
“Efficacy was demonstrated in cynomolgus monkeys and in Glp1rS33W rats (a model of humanized GLP-1 receptor), the latter of which are genetically modified to be sensitive to orforglipron.”
Why that model
Wild-type rodents unresponsive: GLP-1R has serine instead of tryptophan at position 33, required for binding
“Wild-type rodents lack pharmacological responsiveness to orforglipron because their GLP-1 receptor contains serine (S) at position 33 instead of tryptophan (W), which is present in humans and monkeys and is required for orforglipron binding.”
Reviewer's view of the efficacy data
FDA: efficacy in Glp1rS33W rats comparable to semaglutide
“Notably, the observed efficacy in Glp1rS33W rats was comparable to that of semaglutide (FDA Figure 5).”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Lifetime rat and rasH2 mouse studies in pharmacologically inactive species; on-target thyroid C-cell tumor risk not assessable
Why: On-target risk cannot be differentiated from peptide GLP-1 receptor agonists; class boxed warning for thyroid C-cell tumors · Class precedent
“Since orforglipron is not pharmacologically active in wild-type rodents or rasH2 transgenic mice, the absence of thyroid C-cell neoplasia, an on-target effect, was expected.”
“The Applicant’s label should therefore carry the boxed warning for thyroid C-cell adenomas/carcinomas and include a statement in Section 5 (WARNINGS AND PRECAUTIONS), consistent with the class.”
DARTAccepted with a conditionBeyond the letter
Reproductive toxicity tested only in pharmacologically non-relevant rats and rabbits (off-target assessment)
Why: On-target developmental risk cannot be differentiated from peptide GLP-1 receptor agonists; residual uncertainty addressed in labeling · Class precedent
“Off-target safety was further characterized in several nonpharmacologically relevant species, including rats (general toxicology and reproductive safety assessment), rasH2 transgenic mice (carcinogenicity assessment), and rabbits (reproductive safety assessment).”
“While the clinical relevance of reproductive findings and thyroid C-cell tumors for humans is uncertain, we recommend residual uncertainty be addressed in product labeling.”
SpeciesVerdict not stated
Rodent general toxicology in rat, an off-target model; monkey the only pharmacologically relevant species
Why: Rat is an off-target model; monkey is pharmacologically relevant
“Wistar rats were selected as the most suitable rodent species; however, rats represent an off-target model of toxicology. Cynomolgus monkeys were selected as the nonrodent species because they are a pharmacologically relevant species.”
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