Rezdiffra
resmetirom
Species
RatMouseDog
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 (plus mouse up to 3 months)
“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and dog studies of up to 9 months)”
Why that species
Monkey not selected because of ~3% oral bioavailability
“since the bioavailability in monkey was determined to be approximately 3%, it was not selected as a suitable”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 9-month oral toxicity study in beagle dogs, resmetirom at ≥45 mg/kg/day (7 times the maximum recommended dose based on AUC) produced a significant increase in ALT, AST, total ALP, liver ALP, and bone ALP.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and dog studies of up to 9 months)”
Pivotal GLP studies
26-week rat and 39-week dog oral studies (mouse up to 13 weeks)
“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and dog studies of up to 9 months)”
Route in tox
Oral (gavage)
“In the GLP-compliant studies, the animals were treated orally once daily (by gavage) for 28 days (0, 5, 20, or 50 mg/kg/day), 3 months (0, 2.5, 5, 15, or 45 mg/kg/day) or 9 months (0, 5, 15, 45, or 100 mg/kg/day).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration, in vitro micronucleus and in vivo rat micronucleus assays
“Resmetirom was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using cultured human peripheral blood lymphocytes, the in vitro micronucleus test using L5178Y tk+/- mouse lymphoma cells, or the in vivo rat micronucleus assay.”
Carcinogenicity
2-year mouse: uterine leiomyoma/leiomyosarcoma in females at 100 mg/kg/day (51x MRHD AUC)
“In a 2-year carcinogenicity study in mice, resmetirom at 100 mg/kg/day (51 times the maximum recommended dose based on AUC) produced a statistically significant increase in combined incidence of leiomyoma (benign) and leiomyosarcoma (malignant) in uterus”
Reproductive & developmental
Rat fertility, rat and rabbit EFD, rat PPND; no fertility or early embryonic effects at 30 mg/kg/day
“Reproductive and developmental toxicology studies of resmetirom included a fertility study in male and female rats, EFD studies in rats and rabbits, and a pre- and postnatal development study in rats. No effects on fertility and early embryonic development were observed at 30 mg/kg/day”
Safety pharmacology
No neurobehavioral or respiratory effects in rats up to 300 mg/kg; 18.2% hERG inhibition at 30 µM
“A single oral administration of resmetirom at doses up to 300 mg/kg in rats had no significant effect on neurobehavioral or respiratory functions. Resmetirom at concentrations up to 30 µmol/L produced 18.2% inhibition of human Ether-à-go-go-related gene current.”
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 Rezdiffra 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: Liver mononuclear infiltrates and hepatocellular alteration at ≥30 mg/kg/day; fibrosis at 200 mg/kg/day (57x MRHD AUC) (FDA integrated review, p. 110)
NOAEL / key findings
Liver mononuclear infiltrates and hepatocellular alteration at ≥30 mg/kg/day; fibrosis at 200 mg/kg/day (57x MRHD AUC)
“Resmetirom at ≥ 30 mg/kg/day produced an increased incidence of mononuclear cell infiltrates in liver, nonspecific hepatocellular cytoplasmic alteration, and subcapsular/interlobular fibrosis (200 mg/kg/day only; 57 times the maximum recommended dose based on AUC).”
Risksopen answer page →
Immune & cytokine safety
Increased spleen weight in female mice without other immune findings; immunotoxicity risk low
“Resmetirom induced an increase in spleen weight of female mice at 3 and 100 mg/kg/day dose, however since correlation with other immune-related finding was not observed, the risk of immunotoxicity was considered low.”
Biodistribution & persistence
Liver ~10x and renal cortex ~3x plasma AUC; no melanin association in pigmented rats
“Liver AUC and renal cortex AUC for total radioactivity after dosing with [14C]MGL-3196 were approximately 10 times and 3 times the plasma AUC value, respectively. [14C]MGL-3196-related radioactivity was not specifically associated with the melanin-containing tissues in the pigmented LE rats.”
Modality-specific risk
Disproportionate major human metabolite MGL-3623 (MIST) required separate toxicity testing
“MGL-3623, a major (disproportionate) human metabolite of resmetirom, was tested in a 3-month oral toxicity study in CD-1 mice at doses up to 100 mg/kg/day”