Voranigo
vorasidenib
Species
MonkeyRat
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 cynomolgus monkey
“The Applicant evaluated the safety of vorasidenib administered orally once daily in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and cynomolgus monkeys.”
Why that species
Standard rodent and non-rodent species, also chosen for their metabolite profiles
“Rat and cynomolgus monkey were selected as standard species and due to their metabolite profiles to assess the safety profile of vorasidenib.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The Applicant evaluated the safety of vorasidenib administered orally once daily in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and cynomolgus monkeys.”
Species: general tox
Sprague Dawley rat and cynomolgus monkey (28-day and 13-week)
“The Applicant evaluated the safety of vorasidenib administered orally once daily in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and cynomolgus monkeys.”
Species: DART
Rat and rabbit (EFD); fertility and pre/postnatal studies not conducted (not required for indication)
“Dedicated studies to assess vorasidenib-related effects on fertility and pre- and postnatal development were not conducted, as these evaluations are not required for the current indication. Effects were observed on reproductive organs in male and female rats during 28-day and 13-week repeat-dose toxicity studies. Embryo-fetal development (EFD) studies were conducted in gravid rats and rabbits.”
Species: carcinogenicity
Not conducted; mouse and rat carcinogenicity studies required as postmarketing requirements
“Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”
Surrogate used in
No surrogate used; vorasidenib tested directly in rats and monkeys
“The Applicant evaluated the safety of vorasidenib administered orally once daily in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and monkey)
“The Applicant evaluated the safety of vorasidenib administered orally once daily in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and cynomolgus monkeys.”
Pivotal GLP studies
28-day and 13-week oral studies in rats and cynomolgus monkeys
“The safety evaluation included 28-day and 13-week repeat-dose toxicity studies in Sprague-Dawley rats and cynomolgus monkeys”
Route in tox
Oral gavage
“The non-clinical toxicity studies were conducted via oral gavage in rats and monkeys as the intended route of administration in patients.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro micronucleus, chromosomal aberration and rat bone marrow micronucleus assays (parent and AGI-69460)
“Vorasidenib and its major circulating metabolite, AGI-69460, were negative for genotoxicity in a full battery of tests including an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in human lymphocytes, a chromosomal aberration assay, and an in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted; mouse and rat carcinogenicity studies are postmarketing requirements
“Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”
Reproductive & developmental
Rat EFD: early resorptions and kidney/testis visceral malformations at maternally toxic 75 mg/kg/day (~170x human AUC)
“Embryo-fetal toxicity (higher incidence of early resorptions, and visceral malformations of kidney and testes) occurred in rats at the maternally toxic dose of 75 mg/kg/day (approximately 170 times the human exposure based on the AUC at the highest recommended dose).”
Safety pharmacology
Assessed within repeat-dose studies; marginal 32 msec QTc prolongation in a single monkey at non-tolerable 40 mg/kg/day
“Safety pharmacology assessments conducted in the repeat-dose general toxicity studies resulted in marginal prolongation of the corrected QT interval (QTc) of 32 msec in a single male monkey administered the non-tolerable dose of 40 mg/kg/day.”
Genotox: Ames
Negative (vorasidenib and metabolite AGI-69460)
“Vorasidenib and its major circulating metabolite, AGI-69460, were negative for genotoxicity in a full battery of tests including an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in human lymphocytes, a chromosomal aberration assay, and an in vivo bone marrow micronucleus assay in rats.”
Genotox: in vitro mammalian
Negative: in vitro micronucleus in human lymphocytes and chromosomal aberration assay
“Vorasidenib and its major circulating metabolite, AGI-69460, were negative for genotoxicity in a full battery of tests including an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in human lymphocytes, a chromosomal aberration assay, and an in vivo bone marrow micronucleus assay in rats.”
Genotox: in vivo
Negative: rat bone marrow micronucleus
“Vorasidenib and its major circulating metabolite, AGI-69460, were negative for genotoxicity in a full battery of tests including an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in human lymphocytes, a chromosomal aberration assay, and an in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity model
Not conducted pre-approval; rodent (mouse and rat) carcinogenicity studies required postmarketing
“Carcinogenicity studies in mice and rats are warranted to determine the risk of carcinogenicity from vorasidenib for chronic use given the life expectancy of the proposed patient population.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies not conducted before approval; postmarketing requirements
“Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”
hERG / QT
hERG IC50 >30 µM, >3500-fold unbound human Cmax at 40 mg daily
“Based on the results from clinical study AG881-C-004, an IC50 value of > 30 µM for vorasidenib for hERG current inhibition is > 3500-fold greater than the unbound human steady-state Cmax at the proposed therapeutic dose of 40 mg daily of vorasidenib (Cmax = 133 ng/ml).”
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 Voranigo 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: NOAEL 2 mg/kg/day in the 13-week study, safety margin about 2 (EMA assessment report, p. 29)
NOAEL / key findings
NOAEL 2 mg/kg/day in the 13-week study, safety margin about 2
“A NOAEL was set at 2 mg/kg/day in the 13-week study. The safety margins obtained were around 2.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid organs (lymph nodes, Peyer's patches, spleen, thymus) among rat target organs
“Additional organs of toxicity in the rat included middle ear, eye, gastrointestinal tract, kidney, lymph nodes, pancreas, Peyer’s patches, pituitary, skin, spleen, and thymus.”
Biodistribution & persistence
No significant melanin binding; rat brain-to-plasma ratios 0.604 to 1.24
“There was no significant distribution to melanin-containing tissues. Brain to plasma ratios ranged from 0.604 to 1.24 in rats from the 28-day and 13-week repeat-dose general toxicology studies with ratios decreasing with an increase in dose.”
Modality-specific risk
Hepatotoxicity in rats and monkeys (liver enzymes, hepatocellular hypertrophy), mirroring clinical findings
“In addition, hepatotoxicity observed clinically in patients also occurred in rats and monkeys with increased liver enzymes, increased liver weights, and microscopic findings of hepatocellular hypertrophy which partially recovered.”
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; no immunogenicity safety issues identified
“Immunogenicity The Applicant’s Description: Not applicable. The FDA’s Assessment: No safety issues related to immunogenicity were identified for vorasidenib.”
Label warnings
- Hepatotoxicity
- Embryo-Fetal Toxicity
HepatotoxicityEmbryo-fetal toxicity
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 Voranigo 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: NOAEL 2 mg/kg/day in the 13-week study, safety margin about 2 (EMA assessment report, p. 29)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP oral studies in rat and cynomolgus monkey (no chronic study); rat study with 4-week recovery
“5, 15, 50 mg/kg/day for 13 weeks, once daily followed by a 4-week recovery period”
Pivotal GLP studies
28-day and 13-week oral studies in rats and cynomolgus monkeys
“The safety evaluation included 28-day and 13-week repeat-dose toxicity studies in Sprague-Dawley rats and cynomolgus monkeys”
DART package
Species: DART
Rat and rabbit (EFD); fertility and pre/postnatal studies not conducted (not required for indication)
“Dedicated studies to assess vorasidenib-related effects on fertility and pre- and postnatal development were not conducted, as these evaluations are not required for the current indication. Effects were observed on reproductive organs in male and female rats during 28-day and 13-week repeat-dose toxicity studies. Embryo-fetal development (EFD) studies were conducted in gravid rats and rabbits.”
Reproductive & developmental
Rat EFD: early resorptions and kidney/testis visceral malformations at maternally toxic 75 mg/kg/day (~170x human AUC)
“Embryo-fetal toxicity (higher incidence of early resorptions, and visceral malformations of kidney and testes) occurred in rats at the maternally toxic dose of 75 mg/kg/day (approximately 170 times the human exposure based on the AUC at the highest recommended dose).”
PPND / ePPND: when
Rat PPND not done before approval; post-approval commitment, final report due Q2 2026
“the applicant has committed to perform and submit a PPND study in rats post-approval with submission of the final study report by Q2 2026.”
Carcinogenicity
Species: carcinogenicity
Not conducted; mouse and rat carcinogenicity studies required as postmarketing requirements
“Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”
Carcinogenicity model
Not conducted pre-approval; rodent (mouse and rat) carcinogenicity studies required postmarketing
“Carcinogenicity studies in mice and rats are warranted to determine the risk of carcinogenicity from vorasidenib for chronic use given the life expectancy of the proposed patient population.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies not conducted before approval; postmarketing requirements
“Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 13-week NOAEL 2 mg/kg/day; safety margin around 2
“A NOAEL was set at 2 mg/kg/day in the 13-week study. The safety margins obtained were around 2.”
NOAEL / key findings
NOAEL 2 mg/kg/day in the 13-week study, safety margin about 2
“A NOAEL was set at 2 mg/kg/day in the 13-week study. The safety margins obtained were around 2.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenografts: subcutaneous U87 IDH2-R140Q and orthotopic TS603 IDH1-R132H glioma (tumor 2-HG reduction)
“In mouse xenograft studies using a subcutaneous U87 IDH2R140Q glioma model and an orthotopic TS603 IDH1R132H glioma model, vorasidenib had a liner dose-PK relationship, tumor to plasma ratios greater than 1, and dose-dependent decrease in 2-HG levels in the tumor tissue.”
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
EMA: proof-of-concept limited (only 2-HG inhibition, no tumour growth endpoints), not pursued given clinical data
“These studies evaluated the inhibition of 2-HG; however, the biological consequences of this suppression were not investigated (e.g. decrease of tumour size). Therefore, it could be considered that the non-clinical proof-of-concept is limited but in view of the clinical information is not further pursued.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthCriticised but acceptedBeyond the letter
No chronic toxicity study, although the long-life-expectancy indication falls outside ICH S9
Why: Clinical experience (136 patients over 12 months, 79 over 24 months) considered sufficient; 3Rs principles · Human data
“The applicant has submitted a non-clinical package according to the recommendations mentioned in the ICH guideline S9; however, given the long-life expectancy of the patients the claimed indication does not fall under the scope of the ICH S9 guideline.”
“Since the current clinical experience (more than 136 patients are treated for more than 12 months of which 79 are treated for more than 24 months) could be considered sufficient and in accordance with the 3R’s principles, no chronic toxicity studies will be requested.”
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; mouse and rat studies required post-marketing given long survival
Why: Chronic use given the life expectancy of the patient population
“Carcinogenicity studies in mice and rats are warranted to determine the risk of carcinogenicity from vorasidenib for chronic use given the life expectancy of the proposed patient population. Two nonclinical Post Marketing Requirements (PMRs) for rodent carcinogenicity studies were communicated to the Applicant.”
DARTAccepted with a conditionBeyond the letter
No fertility or pre- and postnatal development studies; ICH S9 waiver not accepted by CHMP for this indication
Why: Women of childbearing potential with long life expectancy; rat PPND study committed post-approval
“The claimed indication being out of the scope of the ICH S9 guideline, therefore waiving the conduct of other developmental and reproduction toxicity studies is not considered justified on this sole basis.”
“Since the patient population also includes women of childbearing potential who might have a wish to become pregnant due to the relatively long life-expectancy, the applicant has committed to perform and submit a PPND study in rats post-approval with submission of the final study report by Q2 2026.”
Impurity or metaboliteCriticised but acceptedBeyond the letter
No longer-term toxicity data for the major human metabolite AGI-69460
Why: Slow formation in humans limits long-term exposure; no safety concern in substantial clinical experience · Human data · Pharmacology or kinetics
“The lack of longer term toxicity data for metabolite AGI-69460 is not considered acceptable considering that the claimed indication does not fall under the ICH S9 guideline. Formation and accumulation of AGI-69460 is slow in humans, and therefore significant long-term exposure is limited.”
“Since no safety concern was detected in significant clinical experience (more than 136 patients were treated for more than 12 months of which 79 were treated for more than 24 months), dedicated chronic toxicity studies of AGI-69460 are not considered required.”
Similar precedents
RezlidhiaSmall molecules · olutasidenib · IDH1 (mutant)Monkey + rodent · 13 wkAvmapki Fakzynja Co-packSmall molecules · avutometinib and defactinib · RAF/MEK clamp; FAKMonkey + rodent · 13 wkInluriyoSmall molecules · imlunestrant · Estrogen receptor (SERD)Monkey + rodent · 26 wkInqoviSmall molecules · decitabine and cedazuridine · DNMT (decitabine); cytidine deaminase (cedazuridine)Monkey + rodent · 13 wkKoselugoSmall molecules · selumetinib · MEK1/2Monkey + rodent · 26 wkLifyorliSmall molecules · relacorilant · Glucocorticoid receptor (antagonist)Monkey + rodent · 39 wk