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.”
Species: general tox
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.”
Species: DART
Rat only (fertility and preliminary EFD)
“In consistency with reproductive toxicity findings in the FEED study, in the preliminary EFD study, administration of tovorafenib caused 100% early resorptions and total litter loss in all treated pregnant rats at doses of 37.5, 75, or 150 mg/kg/day.”
Species: carcinogenicity
Tg rasH2 mouse (26-week)
“The study report of 26-week Tg Ras mouse carcinogenicity study was submitted. In this study Tg Ras mice were dosed at 10, 30, and 100 mg/kg/day by oral gavage for 26 weeks.”
Surrogate used in
No surrogate used
“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.”
Genotox: Ames
Negative
“Tovorafenib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay.”
Genotox: in vitro mammalian
Human lymphocyte chromosomal aberration: positive with S9 at a single concentration (precipitating)
“Tovorafenib induced chromosomal aberrations in cultured human lymphocytes with metabolic activation at a single concentration in vitro.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Tovorafenib was not genotoxic in an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
26-week Tg rasH2 mouse up to 100 mg/kg/day: no effect on carcinogenicity
“In this study Tg Ras mice were dosed at 10, 30, and 100 mg/kg/day by oral gavage for 26 weeks. It was concluded that tovorafenib was well tolerated at all doses with no effects on carcinogenicity, survival rate, or adverse findings.”
Carcinogenicity timing
26-week Tg rasH2 mouse completed before the marketing application; 2-year rat ongoing at approval
“The 2-year rat carcinogenicity study is ongoing. The carcinogenicity evaluation is considered adequate considering the ongoing 2-year study.”
hERG / QT
hERG IC50 8.9 µM, 32-fold unbound adult clinical Cmax
“In vitro testing revealed potential for hERG inhibition by tovorafenib with an IC50 of 8.9 µM, resulting in an exposure margin of 32-fold compared to unbound clinical Cmax in adult of 0.280 µM.”
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)
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: 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.”
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 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.
Label warnings
- Hemorrhage
- Skin Toxicity Including Photosensitivity
- Hepatotoxicity
- Effect on Growth
- Embryo-Fetal Toxicity
- NF1 Associated Tumors
BleedingSkin reactionsHepatotoxicityEmbryo-fetal toxicitySecondary malignancy
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 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)
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: No exposure margin at NOAELs in pivotal studies (rat 0.39-fold, monkey 0.41-fold adult exposure) (EMA assessment report, p. 41)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month rat and 3-month monkey (oral); rat 3-month study with 2-week recovery
“In males, the 3-month study highlighted decreased testes and epididymal weights with associated microscopic findings of seminiferous tubules degeneration/atrophy and reduced epididymal luminal sperm at all doses (≥ 50 mg/kg Q2D, 0.3-fold human exposure); lower testes weight persisted after 2 weeks of recovery.”
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.”
DART package
Species: DART
Rat only (fertility and preliminary EFD)
“In consistency with reproductive toxicity findings in the FEED study, in the preliminary EFD study, administration of tovorafenib caused 100% early resorptions and total litter loss in all treated pregnant rats at doses of 37.5, 75, or 150 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.”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (26-week)
“The study report of 26-week Tg Ras mouse carcinogenicity study was submitted. In this study Tg Ras mice were dosed at 10, 30, and 100 mg/kg/day by oral gavage for 26 weeks.”
Carcinogenicity model
26-week Tg rasH2 mouse up to 100 mg/kg/day: no effect on carcinogenicity
“In this study Tg Ras mice were dosed at 10, 30, and 100 mg/kg/day by oral gavage for 26 weeks. It was concluded that tovorafenib was well tolerated at all doses with no effects on carcinogenicity, survival rate, or adverse findings.”
Carcinogenicity timing
26-week Tg rasH2 mouse completed before the marketing application; 2-year rat ongoing at approval
“The 2-year rat carcinogenicity study is ongoing. The carcinogenicity evaluation is considered adequate considering the ongoing 2-year study.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: NOAEL exposure 0.39x (rat) and 0.41x (monkey) adult clinical 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”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse tumour xenografts (BRAF-mutant WM-266-4 melanoma; Calu-6, BxPC-3): tumour growth inhibition or regression
“Overall, in vivo, tovorafenib distributed to different tumour types xenografts (WM-266-4 B-Raf mutant melanoma model, Calu-6 B-Raf wild-type lung cancer model, and BxPC-3 B-Raf wild-type pancreatic cancer model) and resulted in TGI or even regression”
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: BRAF fusion models supportive but of limited translational relevance to pLGG; biomarker relies on clinical data
“However, the translational relevance of these models is limited, as they do not adequately reflect the genetic and biological characteristics of paediatric low-grade gliomas, particularly with regard to TP53 status.”
Flexibilityopen answer page →
Flexibility accepted
Juvenile toxCriticised but accepted
No juvenile toxicity studies for a paediatric indication; youngest animals corresponded to 12 to 16 years of human age
Why: In line with ICH S9 for oncology indications, though a deviation from ICH M3(R2) · Within the guideline
“Furthermore, no juvenile toxicity studies were conducted. Rats were about 8 to 10 weeks of age and monkeys 2.3 to 3.9 years of age corresponding to 12 to 16 years of human age. While this is in line with ICH S9 guidance for oncology indications, it represents a deviation from ICH M3(R2) and should be considered in the context of the intended paediatric use.”
“The available data were considered sufficient to characterise the non-clinical safety prodile of tovorafneib for the proposed use.”
Safety marginCriticised but acceptedBeyond the letter
No exposure margins at the NOAEL in pivotal repeat-dose studies: rat 0.39 and monkey 0.41 (adults), 0.22 and 0.23 (paediatric)
“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).”
“The available data were considered sufficient to characterise the non-clinical safety prodile of tovorafneib for the proposed use.”
Study lengthCriticised but acceptedBeyond the letter
Several high-dose monkey groups terminated early and planned dosing duration shortened because of toxicity below clinical exposure
“In monkeys, the studies indicated that gastrointestinal and haematological adverse effects occurred at exposures below those expected clinically. These effects led to early termination of several high-dose groups and shortening of the planned dosing duration, which limits the interpretation of long-term toxicity at clinically relevant exposures.”
“The available data were considered sufficient to characterise the non-clinical safety prodile of tovorafneib for the proposed use.”
CarcinogenicityAcceptedBeyond the letter
2-year rat carcinogenicity study still ongoing at approval
“The 2-year rat carcinogenicity study is ongoing. The carcinogenicity evaluation is considered adequate considering the ongoing 2-year study.”
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