Tepmetko
tepotinib
Species
RatDog
Longest study
39 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
“To assess the safety of tepotinib, the Applicant conducted GLP-compliant toxicology studies of up to 26-weeks in Sprague Dawley rats and 39 weeks Marshall Beagle dogs.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Dogs received 3, 10, or 30 mg/kg of tepotinib via oral administration of a hard gelatin capsule every day for 39 weeks, followed by a 12-week recovery period.”
Species: general tox
Sprague Dawley rat (26-week) and Beagle dog (39-week)
“To assess the safety of tepotinib, the Applicant conducted GLP-compliant toxicology studies of up to 26-weeks in Sprague Dawley rats and 39 weeks Marshall Beagle dogs.”
Species: DART
Rabbit only (two EFD studies)
“To assess the potential developmental and reproductive toxicity, the Applicant conducted two embryo-fetal development studies of oral tepotinib dosed daily during organogenesis on Gestation Days (GD) 6-18 in New Zealand White (NZW) rabbits”
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Dedicated carcinogenicity studies were not conducted with tepotinib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Surrogate used in
No surrogate used; tepotinib tested directly
“Dogs received 3, 10, or 30 mg/kg of tepotinib via oral administration of a hard gelatin capsule every day for 39 weeks, followed by a 12-week recovery period.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“To assess the safety of tepotinib, the Applicant conducted GLP-compliant toxicology studies of up to 26-weeks in Sprague Dawley rats and 39 weeks Marshall Beagle dogs.”
Pivotal GLP studies
26-week rat and 39-week dog GLP oral studies
“To assess the safety of tepotinib, the Applicant conducted GLP-compliant toxicology studies of up to 26-weeks in Sprague Dawley rats and 39 weeks Marshall Beagle dogs.”
Route in tox
Oral (clinical route); capsules in dogs
“A comprehensive set of non-clinical toxicity studies with tepotinib administered by the oral route (clinical route) in rats, dogs and rabbits have been performed.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro and in vivo micronucleus assays (parent and M506)
“In a standard genotoxicity battery, neither tepotinib nor the major metabolite M506 were positive in either the Ames or the in vitro micronucleus assay regardless of metabolic activation. Tepotinib was also negative in the in vivo micronucleus assay.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Dedicated carcinogenicity studies were not conducted with tepotinib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Reproductive & developmental
Rabbit EFD: skeletal malformations at doses of 5 mg/kg and above
“At dose levels ≥ 5 mg/kg there was an increased frequency of skeletal abnormalities, including misshapen scapula and clavicle, malpositioned calcaneus and talus, malrotated hind paw, and incomplete ossification of sternebra.”
Safety pharmacology
hERG IC50 1.2 µM (24-fold unbound Cmax); no rat telemetry, dog hemodynamic or ECG effects
“Tepotinib (hydrochloride hydrate) inhibited the Kv11.1 (hERG) channel current with an IC50 of 1.2 µM, at a concentration 24-fold higher than the equivalent unbound maximum plasma concentration of the proposed clinical dose of 500 mg.”
Genotox: Ames
Negative (tepotinib and major metabolite)
“Tepotinib and its major circulating metabolite were not mutagenic in vitro in the bacterial reverse mutation (Ames) assay , or a mouse lymphoma assay.”
Genotox: in vitro mammalian
Mouse lymphoma assay: negative (tepotinib and major metabolite)
“Tepotinib and its major circulating metabolite were not mutagenic in vitro in the bacterial reverse mutation (Ames) assay , or a mouse lymphoma assay.”
Genotox: in vivo
Rat micronucleus: negative, but rat exposure ~3-fold below clinical exposure
“The micronucleus test was negative, although it should be noted that the exposure levels in the rat is estimated to be 3-fold lower than clinical exposure, resulting in an uncertainty.”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“In line with the ICH S9 guideline, no studies have been performed to evaluate the carcinogenic potential of tepotinib”
Carcinogenicity timing
Not conducted: not needed for an advanced cancer indication
“Dedicated carcinogenicity studies were not conducted with tepotinib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
hERG / QT
hERG IC50 1.2 µM, 24-fold above unbound Cmax at 500 mg
“Tepotinib (hydrochloride hydrate) inhibited the Kv11.1 (hERG) channel current with an IC50 of 1.2 µM, at a concentration 24-fold higher than the equivalent unbound maximum plasma concentration of the proposed clinical dose of 500 mg.”
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 Tepmetko 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: Liver toxicity in rats and dogs: elevated enzymes, histopathology, liver enlargement (FDA multi-discipline review, p. 40)
NOAEL / key findings
Liver toxicity in rats and dogs: elevated enzymes, histopathology, liver enlargement
“Both species experienced liver toxicity following tepotinib exposure, with dose-dependent elevated liver enzymes (AST, ALT, and/or ALP), histopathologic changes, liver enlargement”
Risksopen answer page →
Immune & cytokine safety
No immunotoxic potential in rat and dog repeat-dose studies
“Data collected from repeat-dose toxicity studies in rats and dogs, including haematology and clinical chemistry investigations, absolute and relative weights and histopathology of lymphoid organs were not indicative for an immunotoxic potential of tepotinib.”
Biodistribution & persistence
Rat QWBA: liver, lungs, kidneys, lymph nodes; eye and skin retention suggesting melanin binding
“In the remaining body, highest concentrations of radioactivity were detected in the liver, lungs, and kidneys and, 24 hours after administration, in the lymph nodes. In pigmented animals, medium levels of radioactivity were found in the eyes and skin throughout the investigational period of 96 hours”
Modality-specific risk
Animal exposures well below clinical exposure, limiting safety margins
“The systemic exposure in the toxicology studies were, overall, considerably lower than observed in humans at clinical dose.”
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)
“Immunogenicity Data and the Applicant’s Position: Not applicable. The FDA’s Assessment: FDA agrees.”
Label warnings
- Interstitial Lung Disease (ILD)/Pneumonitis
- Hepatotoxicity
- Pancreatic Toxicity
- Embryo-Fetal Toxicity
Immune-mediated reactionsPulmonary toxicityHepatotoxicityGastrointestinalEmbryo-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
28-day GLP rat and dog repeat-dose studies submitted under the original IND
“Dr. Whitney Helms reviewed the 28-day repeat-dose toxicology studies in rats and dogs under the original IND submission (IND 106103).”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Tepmetko 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: Liver toxicity in rats and dogs: elevated enzymes, histopathology, liver enlargement (FDA multi-discipline review, p. 40)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral capsule) with 12-week recovery
“Dogs received 3, 10, or 30 mg/kg of tepotinib via oral administration of a hard gelatin capsule every day for 39 weeks, followed by a 12-week recovery period.”
Pivotal GLP studies
26-week rat and 39-week dog GLP oral studies
“To assess the safety of tepotinib, the Applicant conducted GLP-compliant toxicology studies of up to 26-weeks in Sprague Dawley rats and 39 weeks Marshall Beagle dogs.”
DART package
Species: DART
Rabbit only (two EFD studies)
“To assess the potential developmental and reproductive toxicity, the Applicant conducted two embryo-fetal development studies of oral tepotinib dosed daily during organogenesis on Gestation Days (GD) 6-18 in New Zealand White (NZW) rabbits”
Reproductive & developmental
Rabbit EFD: skeletal malformations at doses of 5 mg/kg and above
“At dose levels ≥ 5 mg/kg there was an increased frequency of skeletal abnormalities, including misshapen scapula and clavicle, malpositioned calcaneus and talus, malrotated hind paw, and incomplete ossification of sternebra.”
PPND / ePPND: when
PPND not conducted: not warranted for the advanced cancer indication
“FDA also agrees that fertility and pre- and postnatal development studies are not warranted to support approval in the proposed indication in patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Dedicated carcinogenicity studies were not conducted with tepotinib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“In line with the ICH S9 guideline, no studies have been performed to evaluate the carcinogenic potential of tepotinib”
Carcinogenicity timing
Not conducted: not needed for an advanced cancer indication
“Dedicated carcinogenicity studies were not conducted with tepotinib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: NOAEL AUC ~4% of human exposure at 500 mg in rats and dogs
“The total AUC in the chronic repeat-dose toxicity studies at the no observed adverse effect level (NOAEL) is approximately 4% of the exposure achieved in patients at the proposed clinical dose of 500 mg in both rats and dogs.”
NOAEL / key findings
Liver toxicity in rats and dogs: elevated enzymes, histopathology, liver enlargement
“Both species experienced liver toxicity following tepotinib exposure, with dose-dependent elevated liver enzymes (AST, ALT, and/or ALP), histopathologic changes, liver enlargement”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenografts of human METex14-skipping tumor cell lines; complete regression at 6 mg/kg with MET amplification
“In mice implanted with human tumor cell lines harboring METex14 skipping alterations with and without gene amplification, maximal anti-tumor activity occurred at doses as low as 6 mg/kg once daily, leading to complete tumor regression in 100% of mice bearing tumors with both the METex14 skipping alteration and gene amplification.”
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: pharmacology studies support efficacy in humans
“Overall, the pharmacological studies provide evidence that support efficacy in humans.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin: NOAEL AUC in chronic rat and dog studies about 4% of human exposure at 500 mg
“The total AUC in the chronic repeat-dose toxicity studies at the no observed adverse effect level (NOAEL) is approximately 4% of the exposure achieved in patients at the proposed clinical dose of 500 mg in both rats and dogs.”
Impurity or metaboliteAccepted
Disproportionate major human metabolite MSC2571109A not further qualified nonclinically (low exposure in rats and dogs)
Why: Indication falls under ICH S9 · Within the guideline
“The exposure in both rats and dogs to MSC2571109A was comparatively low indicating that it represents a disproportionate metabolite. Given that the current indication falls under ICH S9, no further non-clinical qualification of metabolites is required.”
GenotoxicityVerdict not stated
In vivo rat micronucleus test at the maximum feasible dose gave exposure about 3-fold below clinical exposure
“However, the maximally feasible dose used in the in vivo micronucleus test in rats provided an estimated systemic exposure close to 3 fold lower than the clinical plasma exposure.”
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