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.”
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.”
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.”