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.”
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.”
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)
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: 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.”