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.”
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).”
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)
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: 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.”