Revuforj
revumenib
Sources:FDA multi-discipline review ↗
Species
RatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Toxicology studies with up to 13 weeks of dosing were conducted in rats and dogs.”
Why that species
Supported by in vitro metabolism and nonclinical PK data
“The use of the rat and dog as the rodent and non-rodent species for the pivotal repeat-dose toxicity studies of revumenib is supported by the in vitro metabolism and nonclinical PK data observed.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 13-week toxicology study in dogs, animals received revumenib doses of 12.5, 25, or 40 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“Toxicology studies with up to 13 weeks of dosing were conducted in rats and dogs.”
Pivotal GLP studies
28-day and 13-week oral studies with recovery in rats and dogs
“The pivotal 28-day and 13-week oral toxicity studies with recovery were performed in accordance with OECD Principles of GLP”
Route in tox
Oral gavage, daily
“In GLP-compliant repeat dose toxicology studies, animals were dosed daily via oral gavage.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro micronucleus and in vivo rat micronucleus assays
“Revumenib was tested in GLP in vitro bacterial reverse mutation and mammalian cell micronucleus assays and an in vivo micronucleus assay in Sprague Dawley rats. There were no revumenib-related genotoxic effects in vitro or in vivo.”
Carcinogenicity
Not conducted (not warranted for advanced cancer indication)
“Carcinogenicity studies were not warranted for the proposed indication.”
Reproductive & developmental
Rat EFD: resorptions, post-implantation loss and malformations at all doses (0.6x human AUC)
“There was a dose-dependent increase in the number of resorptions (including total litter resorption at 300 mg/kg/day), post-implantation loss, and malformations at all revumenib doses, suggesting potential fetal toxicity at exposures 0.6 times the human exposure (AUC) at the recommended dose of 270 mg twice daily.”
Safety pharmacology
Revumenib and metabolite M1 inhibit hERG (IC50 4.75 and 3.46 µM); QTc prolongation and premature atrial contractions in dogs
“The IC50 values for hERG inhibition were 4.75 and 3.46 µM for revumenib and M1, respectively, and suggest that M1 contributes to the effects of hERG inhibition. Increased QTc interval duration and premature atrial contractions were seen after repeated dosing with 225 mg/kg/day in dogs.”
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 Revuforj 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: Target organs in rats and dogs: liver, bone marrow, lymphoid tissues, reproductive system; reproductive effects partly irreversible (FDA multi-discipline review, p. 55)
NOAEL / key findings
Target organs in rats and dogs: liver, bone marrow, lymphoid tissues, reproductive system; reproductive effects partly irreversible
“Toxicity target organs common to rats and dogs were the liver, bone marrow, lymphoid tissues, and reproductive system, with the majority of the findings partially or fully recovered following the 4- or 13-week recovery period, except for some effects in the male and female reproductive system.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid atrophy with decreased thymus weights in dogs at all doses
“Decreased thymus weights correlated with lymphoid atrophy in males and females at all doses.”
Biodistribution & persistence
Rat eye uveal tract radioactivity peaked at 168 h and was sustained through 672 h
“The eye uveal tract had a Cmax of 19,500 ng eq/g at 168 hours post-dose at concentrations that were sustained through 672 hours post-dose.”
Modality-specific risk
QTc prolongation via hERG inhibition by revumenib and metabolite M1
“Based on findings from non-GLP and GLP assays, revumenib and its primary metabolite M1 have the potential to block the hERG channel and contribute to QTc prolongation.”