Ojemda
tovorafenib
Species
MonkeyRat
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“Sprague Dawley rats and cynomolgus monkeys were used as relevant species based on comparison of metabolite profiles generated by isolated hepatocytes from mice, rats, dogs, rabbits, cynomolgus monkeys, and humans.”
Why that species
Metabolite profiles in rat and monkey hepatocytes comparable to human
“Sprague Dawley rats and cynomolgus monkeys were used as relevant species based on comparison of metabolite profiles generated by isolated hepatocytes from mice, rats, dogs, rabbits, cynomolgus monkeys, and humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 3-month study in monkeys, tovorafenib was administered in a Q2D schedule with doses up to 20 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and monkey)
“Repeat-dose toxicity studies of up to 3 months in rats and monkeys with QD, Q2D, every 3 days (Q3D), and/or once weekly (QW) PO dosing were performed.”
Pivotal GLP studies
Up to 3-month oral rat and cynomolgus monkey studies, dosed every other day (Q2D)
“Repeat-dose toxicity studies of up to 3 months in rats and monkeys with QD, Q2D, every 3 days (Q3D), and/or once weekly (QW) PO dosing were performed. Since dose range-finding pilot studies with daily dosing showed intolerability in both species, the Q2D regimen showed improved tolerability.”
Route in tox
Oral
“The oral route was chosen since this is the intended clinical route.”
Skipped studiesopen answer page →
Genotoxicity
Not genotoxic overall: in vitro chromosomal aberrations only at precipitating concentrations; in vivo micronucleus negative
“Despite a transient positive chromosomal aberration result at precipitating concentrations in vitro, the overall evidence strongly indicates that tovorafenib lacks clinically relevant genotoxic potential, a conclusion reinforced by negative in vivo micronucleus testing.”
Carcinogenicity
6-month rasH2 mouse: not carcinogenic up to 100 mg/kg/day
“Tovorafenib was not carcinogenic in the 6-month study in transgenic rasH2 mice that received oral doses up to 100 mg/kg/day.”
Reproductive & developmental
Rat EFD: early resorptions and total litter loss at all doses (37.5–150 mg/kg)
“In an embryo-fetal development study, once daily oral administration of tovorafenib to pregnant rats during the period of organogenesis from gestation days 7 through 17 at doses of 37.5, 75, and 150 mg/kg resulted in early resorptions and total litter loss at all doses.”
Safety pharmacology
Dog and monkey telemetry: dose-dependent heart rate and blood pressure increases with QT shortening
“Both evidenced a dose-dependent increase in HR due to tovorafenib treatment, QT shortening and increase in SAP and MAP.”
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 Ojemda 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: No exposure margin at NOAELs in pivotal studies (rat 0.39-fold, monkey 0.41-fold adult exposure) (EMA assessment report, p. 41)
NOAEL / key findings
No exposure margin at NOAELs in pivotal studies (rat 0.39-fold, monkey 0.41-fold adult exposure)
“However, exposure multiples compared to the NOAEL of the clinical exposure demonstrated no margins of exposure within the pivotal long-term repeat-dose toxicology studies (rats: 0.39 (M) for adults and 0.22 (M) for paediatric patients; monkeys: 0.41 (M) for adults and 0.23 (M) for paediatric patients).”
Risksopen answer page →
Immune & cytokine safety
Rat: minimal to mild thymus and mesenteric lymph node depletion, not reversed after recovery
“Effects on thyroid gland (follicular call atrophy), thymus and mesenteric lymph node (minimal to mild depletion) did not resolve at the end of the recovery period in the 3-month study.”
Biodistribution & persistence
Rat QWBA: crosses blood–brain barrier (brain/plasma AUC ≈0.6); reversible melanin binding
“Notably, brain exposure was measurable (brain/plasma AUC ≈ 0.6), supporting blood–brain barrier penetration adequate for the treatment of paediatric low-grade gliomas. Tovorafenib also demonstrates a reversible affinity for melanin-rich tissues, including pigmented skin, the uveal tract or substantia nigra.”
Modality-specific risk
Limited exposure margins: toxicities at or below clinical exposure
“The data suggest that, although the non-clinical findings are indicative of potential toxicities, the exposure margins relative to the proposed clinical doses are limited.”