Revuforj
revumenib
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.”
Species: general tox
Rat and dog (up to 13 weeks)
“Toxicology studies with up to 13 weeks of dosing were conducted in rats and dogs.”
Species: DART
Rat (EFD only); fertility and pre/postnatal studies not conducted per ICH S9
“Fertility and early embryonic development: As discussed in ICH S9, studies to evaluate the potential effects of revumenib on fertility and early embryonic development were not warranted and therefore not performed.”
Species: carcinogenicity
Not conducted (not warranted for the indication)
“The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
Surrogate used in
No surrogate used; revumenib tested directly
“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.”
Genotox: Ames
Negative with or without S9
“Key findings: No toxicity or precipitate was observed, and no positive mutagenic responses were observed in any tester strains with or without S9 mix.”
Genotox: in vitro mammalian
In vitro mammalian cell micronucleus: negative
“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.”
Genotox: in vivo
Rat micronucleus (up to 400 mg/kg/day): negative
“Administration of revumenib by once daily oral gavage to Sprague Dawley rats at dose levels of 100, 200, and 400 mg/kg/day for 2 consecutive days resulted in a negative response for induction of micronuclei in young erythrocytes (ie, reticulocytes) in peripheral blood in males and females at all dose levels.”
Carcinogenicity model
Not conducted (not warranted for the indication); lymphoma seen in 13-week rat study
“Carcinogenicity studies have not been conducted with revumenib. In a repeat dose toxicity study in rats treated with revumenib for 13 weeks, lymphoma was observed in multiple organs”
Carcinogenicity timing
Not required for the indication
“The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
hERG / QT
hERG IC50 4.75 µM (revumenib) and 3.46 µM (M1); 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)
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: 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.”
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 applicable (small molecule); no immunogenicity studies conducted
“FDA acknowledges that no immunogenicity studies were conducted. As revumenib is a small molecule, there should be little risk of immunogenicity.”
Label warnings
Boxed warning: DIFFERENTIATION SYNDROME, QTc PROLONGATION and TORSADES DE POINTES
- Differentiation Syndrome
- QTc Interval Prolongation and Torsades de Pointes
- Embryo-Fetal Toxicity
CardiovascularEmbryo-fetal toxicity
US prescribing information, Boxed Warning and 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 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)
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: Target organs in rats and dogs: liver, bone marrow, lymphoid tissues, reproductive system; reproductive effects partly irreversible (FDA multi-discipline review, p. 55)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and dog oral studies, each with 13-week recovery
“In the 13-week dog toxicology study, animals were dosed daily at doses of 0, 12.5, 25, or 40 mg/kg/day for 13 weeks followed by a 13-week recovery period.”
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”
DART package
Species: DART
Rat (EFD only); fertility and pre/postnatal studies not conducted per ICH S9
“Fertility and early embryonic development: As discussed in ICH S9, studies to evaluate the potential effects of revumenib on fertility and early embryonic development were not warranted and therefore not performed.”
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.”
PPND / ePPND: when
Not conducted: not warranted for advanced cancer (ICH S9)
“a pre- and post-natal toxicology study is generally not warranted for marketing of pharmaceuticals for the treatment of patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted for the indication)
“The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
Carcinogenicity model
Not conducted (not warranted for the indication); lymphoma seen in 13-week rat study
“Carcinogenicity studies have not been conducted with revumenib. In a repeat dose toxicity study in rats treated with revumenib for 13 weeks, lymphoma was observed in multiple organs”
Carcinogenicity timing
Not required for the indication
“The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
13-week dog HNSTD ~3.1x human AUC
“13-week Dog Repeat-dose study (HNSTD) 64,600d ≈ 3.1”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
MV4;11 and MOLM-13 human AML xenografts in rats and immunocompromised mice
“The anti-tumor activity of revumenib was evaluated using the human AML cell lines MV4;11 and MOLM-13 in rats or immunocompromised mice and with various routes of administration and treatment durations.”
Why that model
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.
Reviewer's view of the efficacy data
FDA: dose-dependent antitumor activity in AML models; activity not evaluated in ALL models
“Overall, revumenib showed dose-dependent antitumor activity in nonclinical models of human AML. The activity of revumenib was not evaluated in nonclinical models of ALL.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
Single preliminary rat embryo-fetal study only; no definitive or second-species embryo-fetal study
Why: Clear embryo-fetal effects already shown · Weight of evidence
“As revumenib caused clear evidence of embryo-fetal effects, further embryo-fetal studies were not conducted.”
“We agree with the Applicant’s assessment of the embryo-fetal toxicity.”
Safety marginVerdict not stated
Embryo-fetal toxicity at all doses, starting at 0.6 times human exposure; no developmental NOAEL
“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.”
Juvenile toxAcceptedBeyond the letter
No definitive juvenile toxicity study; only a sponsor-initiated dose range-finding juvenile rat study
“A juvenile study was not requested by the FDA, and the Applicant conducted this study at their discretion.”
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