Gomekli
mirdametinib
Species
RatDog
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 dog
“Exploratory studies were conducted in mice, rats, dogs, and monkeys, while definitive toxicity studies were conducted in rats and dogs.”
Why that species
PK and metabolism properties compared across species
“The rat and dog were selected as the general toxicology species based on mirdametinib’s PK and metabolism properties compared across species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Mirdametinib was administrated for 13 weeks at dose of 0.1, 0.3 and 1 mg/kg/day (same doses used in the 4-weeks study).”
Species: general tox
Rat and dog (pivotal studies up to 3 months)
“Pivotal studies were performed in rats and dogs up to 3 months.”
Species: DART
Rat and rabbit (preliminary EFD only); rat (fertility); no definitive EFD studies
“Preliminary embryo-foetal development (pEFD) toxicity studies were conducted in rats and rabbits. No definitive EFD studies were conducted. A fertility study was conducted in male and female rats.”
Species: carcinogenicity
Tg rasH2 mouse (26-week); 2-year rat study ongoing
“A 26-week carcinogenicity study in mice was performed after a dose range study and a 2-year carcinogenicity study in rats is currently ongoing (started in August 2024).”
Surrogate used in
No surrogate used; mirdametinib tested directly
“Mirdametinib was administrated for 13 weeks at dose of 0.1, 0.3 and 1 mg/kg/day (same doses used in the 4-weeks study).”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and dog)
“Pivotal studies were performed in rats and dogs up to 3 months.”
Pivotal GLP studies
Pivotal oral studies in rats and dogs up to 3 months; no chronic studies
“Pivotal studies were performed in rats and dogs up to 3 months. No chronic studies were performed.”
Route in tox
Oral (gavage)
“Studies were based on daily oral (gavage) dosing with a limited number of studies involving IV administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative Ames; not clastogenic in vitro or in rat chromosome aberration assay; positive rat micronucleus
“Mirdametinib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow chromosomal aberration assay. Mirdametinib was positive in the in vivo micronucleus assay in rats.”
Carcinogenicity
6-month rasH2 mouse: not carcinogenic up to 5 mg/kg/day
“Mirdametinib was not carcinogenic in a 6-month study in transgenic rasH2 mice that received oral doses up to 5 mg/kg/day”
Reproductive & developmental
Rat and rabbit dose-range EFD: embryofetal lethality at non-maternotoxic 0.64 and 0.3 mg/kg/day
“In the dose-range finding embryo-foetal development studies, embryofoetal lethality was observed from the non-maternotoxic dose levels of 0.64 and 0.3 mg/kg/day in rats and rabbits, respectively.”
Safety pharmacology
hERG IC50 >100 µM (39.5% inhibition at 100 µM)
“Mirdametinib at 100 µM reduced significantly the mean hERG current amplitude by 39.5% (IC50 >100 µM).”
Genotox: Ames
Negative (bacterial reverse mutation)
“Mirdametinib was negative in an in vitro bacterial reverse mutation test (Ames assay) and an in vitro human lymphocyte chromosomal aberration assay.”
Genotox: in vitro mammalian
Chromosomal aberration in human lymphocytes: negative
“Mirdametinib was negative in an in vitro bacterial reverse mutation test (Ames assay) and an in vitro human lymphocyte chromosomal aberration assay.”
Genotox: in vivo
FDA: positive for aneugenicity based on both in vivo studies (rat micronucleus, rat chromosomal aberration)
“Considering the totality of the data from both in vivo genotoxicity studies, the FDA has determined mirdametinib to be positive for aneugenicity.”
Carcinogenicity model
6-month Tg rasH2 mouse: not carcinogenic up to 5 mg/kg/day; 2-year rat ongoing
“In a 6- month carcinogenicity study in CByB6F1/Tg rasH2 hemizygous mice, the FDA concluded that no carcinogenic effect related to mirdametinib administration was observed at any dose level tested (up to 5 mg/kg/day).”
Carcinogenicity timing
26-week rasH2 mouse completed; 2-year rat ongoing at approval, final report a postmarketing requirement
“The Applicant is currently conducting a 2-year carcinogenicity study in rats and a post-marketing requirement (PMR) will be issued for the submission of the final study report.”
hERG / QT
39.5% hERG inhibition at 100 µM (IC50 >100 µM); no effect at 10 µM (12000-fold unbound Cmax)
“Mirdametinib at 100 µM reduced significantly the mean hERG current amplitude by 39.5% (IC50 >100 µM). No significant effect was observed at 10 µM (12000-fold greater than the unbound plasma Cmax at the intended dose).”
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 Gomekli 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Rat NOAEL 0.1 mg/kg/day (males) and 0.3 mg/kg/day (females), at exposures below clinical exposure (EMA assessment report, p. 32)
NOAEL / key findings
Rat NOAEL 0.1 mg/kg/day (males) and 0.3 mg/kg/day (females), at exposures below clinical exposure
“The determined NOAEL was 0.1 mg/kg/day in male rats and 0.3 mg/kg/day in female rats. Exposures at these doses are below the clinical predicted exposure at the intended posology.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid hyperplasia, lymphoid depletion and increased plasma cells in lymph nodes of rats and dogs
“findings correlated with histologic signs in the lymph nodes in the 3-month studies in rats and dogs, including minimal to moderate lymphoid hyperplasia, lymphoid depletion, and increases in plasma cells, as well as hypocellularity in rats.”
Biodistribution & persistence
Rat QWBA: peak tissue levels within 4 h after oral dosing; no retention in melanin-containing tissues
“For all tissues, the highest measured concentrations were observed within 4 hours and 0.5 hours post dose for the oral and IV routes, no specific retention was observed in melanin-containing tissues.”
Modality-specific risk
Embryofetal lethality (selective developmental toxicant)
“Overall, mirdametinib is considered as a selective developmental toxicant, and the clinical relevance of drug-induced embryofoetal lethality identified in rats and rabbits cannot be excluded.”
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, no immune response expected)
“Mirdametinib is a small molecule and not expected to elicit an immune response.”
Label warnings
- Ocular Toxicity
- Left Ventricular Dysfunction
- Dermatologic Adverse Reactions
- Embryo-Fetal Toxicity
Ocular toxicityCardiovascularSkin reactionsEmbryo-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 Gomekli 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Rat NOAEL 0.1 mg/kg/day (males) and 0.3 mg/kg/day (females), at exposures below clinical exposure (EMA assessment report, p. 32)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and dog GLP studies; no recovery phase
“Mirdametinib was administrated for 13 weeks at dose of 0.1, 0.3 and 1 mg/kg/day (same doses used in the 4-weeks study). Only rat exposures at the highest dose were demonstrated to be in the range of the clinical exposure at the intended recommended dose (as per the indication). The exposures at low and mid dose are below the clinical range exposure. No recovery period was added.”
Pivotal GLP studies
Pivotal oral studies in rats and dogs up to 3 months; no chronic studies
“Pivotal studies were performed in rats and dogs up to 3 months. No chronic studies were performed.”
DART package
Species: DART
Rat and rabbit (preliminary EFD only); rat (fertility); no definitive EFD studies
“Preliminary embryo-foetal development (pEFD) toxicity studies were conducted in rats and rabbits. No definitive EFD studies were conducted. A fertility study was conducted in male and female rats.”
Reproductive & developmental
Rat and rabbit dose-range EFD: embryofetal lethality at non-maternotoxic 0.64 and 0.3 mg/kg/day
“In the dose-range finding embryo-foetal development studies, embryofoetal lethality was observed from the non-maternotoxic dose levels of 0.64 and 0.3 mg/kg/day in rats and rabbits, respectively.”
PPND / ePPND: when
No PPND study; embryo-fetal lethality in rat and rabbit dose-range EFD studies and MEK-inhibitor class effect justified it
“This justifies the absence of further DART studies and that the SmPC section 5.3 mentions that the EFD studies were exploratory studies and that definitive EFD studies and PPND studies were not conducted with mirdametinib.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (26-week); 2-year rat study ongoing
“A 26-week carcinogenicity study in mice was performed after a dose range study and a 2-year carcinogenicity study in rats is currently ongoing (started in August 2024).”
Carcinogenicity model
6-month Tg rasH2 mouse: not carcinogenic up to 5 mg/kg/day; 2-year rat ongoing
“In a 6- month carcinogenicity study in CByB6F1/Tg rasH2 hemizygous mice, the FDA concluded that no carcinogenic effect related to mirdametinib administration was observed at any dose level tested (up to 5 mg/kg/day).”
Carcinogenicity timing
26-week rasH2 mouse completed; 2-year rat ongoing at approval, final report a postmarketing requirement
“The Applicant is currently conducting a 2-year carcinogenicity study in rats and a post-marketing requirement (PMR) will be issued for the submission of the final study report.”
Safety marginopen answer page →
Safety margin at NOAEL
4-week dog NOAEL 0.1 mg/kg/day at 0.35x clinical exposure
“The NOAEL was identified at 0.1 mg/kg/day (0.35-fold the clinical exposure).”
NOAEL / key findings
Rat NOAEL 0.1 mg/kg/day (males) and 0.3 mg/kg/day (females), at exposures below clinical exposure
“The determined NOAEL was 0.1 mg/kg/day in male rats and 0.3 mg/kg/day in female rats. Exposures at these doses are below the clinical predicted exposure at the intended posology.”
Efficacy evidenceopen answer page →
Efficacy evidence
Genetically engineered Nf1fl/fl;Dhh-Cre neurofibroma mouse model
“Mirdametinib was administrated to a genetically engineered mouse model of the NF1 neurofibroma disease (Nf1fl/fl;Dhh-Cre mouse model).”
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 in the GEM model sufficient; optimal efficacious dose not determinable
“Tumour volume and cell proliferation biomarkers were reduced; however, the most efficacious levels could not be determined as the three dose levels resulted in similar response amplitudes. The proof-of-concept in this genetically modified mouse model could be considered sufficient to support the intended indication.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
2-year rat carcinogenicity study ongoing at approval; final report required postmarketing (rasH2 mouse study completed)
“The Applicant is currently conducting a 2-year carcinogenicity study in rats and a post-marketing requirement (PMR) will be issued for the submission of the final study report.”
DARTAcceptedBeyond the letter
Only dose-range-finding EFD studies in rat and rabbit; no definitive EFD or PPND studies
Why: Embryofoetal lethality already shown in dose-range-finding studies; pharmacology-related MEK-inhibitor class effect · Pharmacology or kinetics · Class precedent
“In addition, it is agreed with the applicant that definitive embryofoetal development and pre/postnatal development studies are not needed in view of this pharmacology-related developmental toxicity as mentioned in section 4.6 of the SmPC containing warnings related to the use of mirdametinib during pregnancy and breastfeeding.”
“From both dose-range finding EFD studies conducted with mirdametinib and considering the data with other MEK inhibitors supporting a class effect, mirdametinib has toxic/lethal effects on embryo-foetal development. This justifies the absence of further DART studies”
Study lengthAcceptedBeyond the letter
No chronic toxicity studies beyond three months for a long-term paediatric and adult therapy
Why: Clinical experience with mirdametinib and its metabolite sufficient to waive long-term animal studies · Human data
“The non-clinical programme conducted according to ICH M3 recommendations could be considered sufficient as clinical experience with mirdametinib and its metabolite PD 0315209 is demonstrated to be sufficient to waive the need for long-term animal studies.”
Juvenile toxAcceptedBeyond the letter
No juvenile animal study despite use from age two years
Why: In line with the agreed paediatric investigation plan · Other reason
“A marketing authorisation is currently sought for patients aged 2 years and older. No juvenile animal study (JAS) was conducted with mirdametinib. This is in line with the agreed PIP.”
Safety marginVerdict not stated
4-week dog NOAEL at 0.35-fold clinical exposure
“The NOAEL was identified at 0.1 mg/kg/day (0.35-fold the clinical exposure).”
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