Orgovyx
relugolix
Species
MonkeyRatMouse
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 (mouse up to 13 weeks)
“The repeat-dose toxicity studies for relugolix were conducted in mice (up to 13 weeks), rats (up to 26-weeks) and monkeys (up to 39 weeks) using the intended oral route of administration.”
Why that species
Monkey: high GnRH receptor homology (97.5%) and similar affinity and potency at the GnRH receptor
“The cynomolgus monkey was selected as the non-rodent species because of the high sequence homology with the human GnRH receptor (97.5% compared to 92.1% in dog) and the similar affinity and potency at the GnRH receptor relative to dogs.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 39-week study, relugolix (1.5, 5, 15, or 50 mg/kg/day) was administered by oral gavage to cynomolgus monkeys followed by a 13-week recovery period.”
Species: general tox
Rat (26-week) and cynomolgus monkey (39-week); mouse up to 13 weeks
“The repeat-dose toxicity studies for relugolix were conducted in mice (up to 13 weeks), rats (up to 26-weeks) and monkeys (up to 39 weeks) using the intended oral route of administration.”
Species: DART
Rat and rabbit
“Reproductive and developmental toxicology studies were conducted in rats and rabbits.”
Species: carcinogenicity
Mouse and rat (2-year)
“Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day.”
Surrogate used in
Yes: human GnRH receptor knock-in mice for in vivo pharmacology (low affinity for mouse receptor)
“As relugolix has only low affinity for the mouse GnRH receptor, a human GnRHR knock-in mice was generated, in which mouse GnRHR was replaced by human GnRHR, to evaluate the effect of relugolix on a hypothalamic-pituitary-gonadal axis.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“The repeat-dose toxicity studies for relugolix were conducted in mice (up to 13 weeks), rats (up to 26-weeks) and monkeys (up to 39 weeks) using the intended oral route of administration.”
Pivotal GLP studies
26-week rat and 39-week monkey oral studies; mouse up to 13 weeks
“The repeat-dose toxicity studies for relugolix were conducted in mice (up to 13 weeks), rats (up to 26-weeks) and monkeys (up to 39 weeks) using the intended oral route of administration.”
Route in tox
Oral (gavage)
“The repeat-dose toxicity studies for relugolix were conducted in mice (up to 13 weeks), rats (up to 26-weeks) and monkeys (up to 39 weeks) using the intended oral route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and rat bone marrow micronucleus assays
“Relugolix was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay nor clastogenic in the in vitro chromosomal aberration assay and in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
2-year mouse and rat: not carcinogenic
“Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day. Relugolix was not carcinogenic in mice or rats at exposures up to approximately 75 or 224 times, respectively, the human exposure at the recommended dose of 120 mg daily based on AUC.”
Reproductive & developmental
Rabbit EFD: embryo-fetal lethality at 9 mg/kg/day (~0.3x human exposure)
“In an embryo-fetal development study in rabbits, oral administration of relugolix during the period of organogenesis resulted in embryo-fetal lethality at the highest dose tested, 9 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC).”
Safety pharmacology
No CNS/respiratory effects in rats up to 2000 mg/kg; hERG IC50 9.7 µg/mL; QTc prolongation up to 47 msec in monkeys at ≥100 mg/kg
“In safety pharmacology studies, there were no relugolix-related adverse effects on the central nervous and respiratory systems in rats at doses up to 2000 mg/kg. While relugolix was a low-potency hERG blocker in vitro (IC50 = 9.7 µg/mL), a single dose of relugolix in monkeys resulted in QT/QTc prolongation of up to 47 msec at ≥ 100 mg/kg (90 times the human Cmax based on toxicokinetics from a 4-week repeat-dose monkey study).”
Genotox: Ames
Negative
“Relugolix was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells or the in vivo rat bone marrow micronucleus assay.”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster lung cells: negative
“Relugolix was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells or the in vivo rat bone marrow micronucleus assay.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Relugolix was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells or the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
2-year mouse (up to 100 mg/kg/day) and rat (up to 600 mg/kg/day): not carcinogenic at up to 75x and 224x human AUC
“Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day. Relugolix was not carcinogenic in mice or rats at exposures up to approximately 75 or 224 times, respectively, the human exposure at the recommended dose of 120 mg daily based on AUC.”
Carcinogenicity timing
2-year mouse and rat carcinogenicity studies completed and reviewed with the NDA
“TAK-385 was evaluated at doses up to 100 mg/kg/day in mice and up to 600 mg/kg/day in rats in the 2-year carcinogenicity studies.”
hERG / QT
hERG IC50 9.7 µg/mL (15.5 µM), ~123x steady-state Cmax
“Relugolix inhibited hERG potassium channel current by 3.4%, 20.5% and 78.5% at 0.3, 3 and 30 µg/mL respectively and with an IC50 of 9.7 µg/mL (15.5 μM). This IC50 is approximately 123-fold higher than the mean total steady state Cmax of 79.1 ng/mL”
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 Orgovyx 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: Liver toxicity in monkeys at ≥50 mg/kg/day (~53x clinical AUC), with some reversibility (FDA multi-discipline review, p. 33)
NOAEL / key findings
Liver toxicity in monkeys at ≥50 mg/kg/day (~53x clinical AUC), with some reversibility
“Relugolix caused liver toxicity (increased liver enzymes with or without histopathology correlates of up to severe yellow/brown pigment deposition and up to moderate bile plug) in monkeys at ≥ 50 mg/kg/day (approximately 53x the clinical exposure based on AUC). This effect exhibited some reversibility.”
Risksopen answer page →
Immune & cytokine safety
No immunotoxicity studies; no immune-system findings in general toxicity studies
“Furthermore, there were no findings suggestive of effects on the immune system in general toxicity studies conducted in mice for up to 13 weeks, rats for up to 26 weeks, or monkeys for up to 39 weeks.”
Biodistribution & persistence
Rat: highest in liver, intestine, thyroid, stomach, pituitary; radioactivity in melanin-rich eye tissues sustained up to 12 weeks
“Following a single oral dose of radiolabeled relugolix to rats, the highest radioactivity was observed in liver, intestine, thyroid, stomach and pituitary gland. Radioactivity in the eyes, mainly localized to the melanin rich tissues - anterior and posterior parts, was detected at 4 h and sustained for up to 12 weeks post-dose.”
Modality-specific risk
Phospholipidosis in multiple organs (rat ≥100 mg/kg; monkey ≥1.5 mg/kg, 0.6x clinical exposure)
“In repeat-dose studies, phospholipidosis in multiple organs was observed in both rats (≥ 100 mg/kg) and monkeys (≥ 1.5 mg/kg) at exposures 18 times and 0.6 times, respectively, the clinical exposure at the human recommended dose based on AUC.”
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 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.
Label warnings
- QT/QTc Interval Prolongation
- Hypersensitivity Reactions
- Embryo-Fetal Toxicity
- Laboratory Testing
CardiovascularHypersensitivity & infusion reactionsEmbryo-fetal toxicity
US prescribing information, 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 Orgovyx 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: Liver toxicity in monkeys at ≥50 mg/kg/day (~53x clinical AUC), with some reversibility (FDA multi-discipline review, p. 33)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey oral gavage study with 13-week recovery
“Study title/ number: Thirty-nine week oral gavage toxicity study of TAK-385 in monkeys with a 13 week recovery period / TAK-385-000144”
Pivotal GLP studies
26-week rat and 39-week monkey oral studies; mouse up to 13 weeks
“The repeat-dose toxicity studies for relugolix were conducted in mice (up to 13 weeks), rats (up to 26-weeks) and monkeys (up to 39 weeks) using the intended oral route of administration.”
DART package
Species: DART
Rat and rabbit
“Reproductive and developmental toxicology studies were conducted in rats and rabbits.”
Reproductive & developmental
Rabbit EFD: embryo-fetal lethality at 9 mg/kg/day (~0.3x human exposure)
“In an embryo-fetal development study in rabbits, oral administration of relugolix during the period of organogenesis resulted in embryo-fetal lethality at the highest dose tested, 9 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC).”
PPND / ePPND: when
PPND in rat conducted and submitted with the NDA; not reviewed by FDA for the prostate cancer indication
“The pre- and post-natal study conducted in rats (Study# TAK-385-300136) was not reviewed at this time based on a prostate cancer indication and may not be relevant due to the low binding affinity.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (2-year)
“Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day.”
Carcinogenicity model
2-year mouse (up to 100 mg/kg/day) and rat (up to 600 mg/kg/day): not carcinogenic at up to 75x and 224x human AUC
“Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day. Relugolix was not carcinogenic in mice or rats at exposures up to approximately 75 or 224 times, respectively, the human exposure at the recommended dose of 120 mg daily based on AUC.”
Carcinogenicity timing
2-year mouse and rat carcinogenicity studies completed and reviewed with the NDA
“TAK-385 was evaluated at doses up to 100 mg/kg/day in mice and up to 600 mg/kg/day in rats in the 2-year carcinogenicity studies.”
Safety marginopen answer page →
Safety margin at NOAEL
39-week monkey NOAEL (liver toxicity) 15 mg/kg ~9.3x human exposure
“The NOAEL for organ toxicity was 15 mg/kg in both sexes based on liver toxicity, which is 9.3-fold higher than the human intended dose.”
NOAEL / key findings
Liver toxicity in monkeys at ≥50 mg/kg/day (~53x clinical AUC), with some reversibility
“Relugolix caused liver toxicity (increased liver enzymes with or without histopathology correlates of up to severe yellow/brown pigment deposition and up to moderate bile plug) in monkeys at ≥ 50 mg/kg/day (approximately 53x the clinical exposure based on AUC). This effect exhibited some reversibility.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human GnRH receptor knock-in mice (testosterone reduction) and castrated monkeys (LH decrease)
“In vivo, administration of relugolix suppressed the pituitary-gonadal axis, causing a decrease in plasma luteinizing hormone in castrated monkeys after a single dose and reduction of serum testosterone levels in human GnRH receptor knock-in male mice after repeat dosing.”
Why that model
~19,000-24,000x lower binding affinity for rat GnRH receptor than monkey/human
“In contrast, a 19,000x and 24,000x reduction in binding affinity was noted to rat GnRH receptor (IC50 = 2900 nM) compared to monkey and human receptors, respectively.”
Reviewer's view of the efficacy data
EMA: knock-in mouse studies did not address LH and FSH decreases
“Unexpectedly, two of the primary effects of antagonism of the GnRH receptor, i.e. decreases in LH and FSH, were not addressed in these studies.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
Rat reproductive and developmental data discounted because of low relugolix affinity for rat GnRH receptors; rabbit EFD used for labeling
Why: Low binding affinity of relugolix to rat receptors
“The limited results noted in rats in reproductive and developmental parameters may be misleading given the low binding affinity of relugolix to rat receptors and thus, these results were not included in the label.”
Efficacy modelVerdict not stated
Knock-in mouse pharmacology studies did not measure LH and FSH decreases, the primary effects of GnRH antagonism
“Unexpectedly, two of the primary effects of antagonism of the GnRH receptor, i.e. decreases in LH and FSH, were not addressed in these studies.”
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