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.”
Species: general tox
Mouse (up to 3 months), rat (up to 6 months) and dog (up to 9 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)”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“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.”
Species: carcinogenicity
Mouse and rat
“genetic toxicology studies (Ames test, in vitro chromosomal aberration assay, and in vivo rat micronucleus assay), and carcinogenicity studies in mice and rats.”
Surrogate used in
No surrogate used; clinical compound tested in all species
“The most frequently observed effects were decreases in T4 (total and free), T3 (total and free), and TSH. These effects were observed in all general toxicology studies in rats, mice, and dogs and were likely related to the pharmacological activity of resmetirom.”
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.”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
Chromosomal aberration (human lymphocytes) and micronucleus (L5178Y mouse lymphoma cells): negative
“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.”
Genotox: in vivo
Rat micronucleus: negative
“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 model
2-year CD-1 mouse: uterine leiomyoma/leiomyosarcoma at 100 mg/kg/day (51x AUC)
“In a 2-year study in CD-1 mice, resmetirom produced leiomyoma or leiomyosarcoma in the uterus at a dose of 100 mg/kg/day (51 times the maximum recommended dose based on AUC).”
Carcinogenicity timing
2-year CD-1 mouse and SD rat studies completed before the marketing application
“2-year carcinogenicity studies were conducted with resmetirom in CD-1 mice and in SD rats.”
hERG / QT
18.2% hERG current inhibition at 30 µM
“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”
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
- Hepatotoxicity
- Gallbladder-Related Adverse Reactions
- Drug Interaction with Certain Statins
Hepatotoxicity
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) dog with 4-week recovery
“A 9-Month Oral Toxicity Study With MGL-3196 in Dogs With a 4-Week Recovery Period, Study 0472DM72.001”
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)”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“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.”
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”
PPND / ePPND: when
PPND in rat completed before the marketing application
“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.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat
“genetic toxicology studies (Ames test, in vitro chromosomal aberration assay, and in vivo rat micronucleus assay), and carcinogenicity studies in mice and rats.”
Carcinogenicity model
2-year CD-1 mouse: uterine leiomyoma/leiomyosarcoma at 100 mg/kg/day (51x AUC)
“In a 2-year study in CD-1 mice, resmetirom produced leiomyoma or leiomyosarcoma in the uterus at a dose of 100 mg/kg/day (51 times the maximum recommended dose based on AUC).”
Carcinogenicity timing
2-year CD-1 mouse and SD rat studies completed before the marketing application
“2-year carcinogenicity studies were conducted with resmetirom in CD-1 mice and in SD rats.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog NOAEL (45 mg/kg/day) ~7-fold human AUC at MRHD
“At the NOAEL of 45 mg/kg/day the AUC-based safety margin to human exposure at the MRHD is approximately 7-fold (mean male and female dog day 272 exposure levels of 54.450 ng*h/ml and human exposure level at 100 mg of 7.740 ng*h/ml).”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
High-fat diet-induced obese (DIO) mice for 25 weeks: reduced liver weight and vacuolation
“Decreases in liver weight and severity of liver vacuolation were observed in mice fed an admixture of resmetirom (RO4923659) and high-fat diet (HFD) for 25 weeks compared to placebo+HFD admixture-fed control animals.”
Why that model
No available in vivo model reproduced all histological features of NASH
“The dataset did not include any in vivo models that produced all the histological features of NASH (i.e., steatosis, inflammation, hepatocyte ballooning, and fibrosis).”
Reviewer's view of the efficacy data
FDA: nonclinical pharmacology data adequate to support approval
“However, from a nonclinical perspective, the data are considered as adequate for supporting approval from pharmacology/toxicology perspective.”
Flexibilityopen answer page →
Flexibility accepted
DARTQuestioned
Rat pre/postnatal study lacked behavior, motor activity, sensory function and reflex development testing
“The PPND study in rats is deficient based on current ICH standards. Background The PPND study in rats is incomplete due to the absence of testing for behavior, motor activity, sensory or sensorimotor functions, and reflex development”
Impurity or metaboliteAcceptedBeyond the letter
Major human plasma metabolite oxalic acid not detected in rat or dog toxicity studies
Why: Resmetirom-associated oxalic acid exposure expected within the physiological range · Pharmacology or kinetics
“Oxalic acid was not detected in toxicity studies in rats and dogs and was not investigated further in clinical studies. However, resmetirom associated oxalic acid intake and exposure is expected to be in the physiological range, hence it was agreed that further studies were not necessary.”
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