Koselugo
selumetinib
Species
MonkeyRatMouse
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse, rat and cynomolgus monkey
“The Applicant evaluated the toxicity profile of selumetinib in rats, mice, and monkeys in GLP-compliant studies with durations of up to 3 months (rats) and 26 weeks (mice and monkeys).”
Why that species
Mouse chosen as rodent because it forms the active N-desmethyl metabolite at detectable levels
“The Applicant chose the mouse as the rodent species for the long-term toxicology and developmental studies due to detectable levels of the active N-desmethyl metabolite in this species that allowed for toxicological coverage;”
Surrogate molecule
No surrogate; the clinical compound was tested
“Administration of selumetinib to monkeys for up to 26 weeks was associated with loose/liquid feces, seen at 1.5 mg/kg BID in females and 4 mg/kg BID in males.”
Species: general tox
Mouse, rat and cynomolgus monkey
“The Applicant evaluated the toxicity profile of selumetinib in rats, mice, and monkeys in GLP-compliant studies with durations of up to 3 months (rats) and 26 weeks (mice and monkeys).”
Species: DART
Mouse (fertility, EFD, pre/postnatal); chosen because it forms the active N-desmethyl metabolite
“The Applicant assessed the effects of selumetinib on reproduction and development using mice, as mice, unlike rats, make the active N-desmethyl AZD6244 metabolite at detectable levels.”
Species: carcinogenicity
rasH2 transgenic mouse (6-month) and rat (2-year)
“Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 .”
Surrogate used in
No surrogate used; clinical compound tested in mice, rats and monkeys
“The Applicant evaluated the toxicity profile of selumetinib in rats, mice, and monkeys in GLP-compliant studies with durations of up to 3 months (rats) and 26 weeks (mice and monkeys).”
Study lengthopen answer page →
Longest pivotal study
26 (26-week mouse and monkey)
“The nonclinical safety of selumetinib has been evaluated in repeat dose oral toxicity studies of up to 3 months in rats and up to 26 weeks in mice and monkeys;”
Pivotal GLP studies
26-week mouse and monkey and 3-month rat oral repeat-dose studies
“The nonclinical safety of selumetinib has been evaluated in repeat dose oral toxicity studies of up to 3 months in rats and up to 26 weeks in mice and monkeys;”
Route in tox
Oral gavage
“Route of administration: Oral (gavage)”
Skipped studiesopen answer page →
Genotoxicity
Not mutagenic or clastogenic in vitro; positive (aneugenic) mouse micronucleus at >160 mg/kg (~38x human Cmax)
“Selumetinib was not mutagenic or clastogenic in vitro . Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses > 160 mg/kg (~38-times the human C max at the clinical dose of 25 mg/m 2 ).”
Carcinogenicity
6-month rasH2 mouse and 2-year rat: not carcinogenic at >=15x human AUC
“Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 .”
Reproductive & developmental
Mouse EFD: post-implantation loss, lower fetal weight, open eye and cleft palate at >2.5 mg/kg BID (~5x human AUC)
“In embryo-fetal development studies in mice at doses > 2.5 mg/kg twice daily (~5-times the human exposure based on area under the curve [AUC] at the clinical dose of 25 mg/m 2 twice daily), selumetinib caused increases in post-implantation loss, a reduction in mean fetal and litter weights, and an increased occurrence of open eye and cleft palate”
Safety pharmacology
No CNS or respiratory effects in rats up to 100 mg/kg; no ECG or hemodynamic effects in minipigs
“At doses of up to 100 mg/kg selumetinib had no remarkable effects on open field behavior or respiratory parameters in Sprague-Dawley rats. In a cardiovascular safety study in Gottingen minipigs, oral administration of selumetinib twice daily had no remarkable effects on electrocardiograms or circulatory function”
Genotox: Ames
Negative with and without metabolic activation
“but negative in both the presence and absence of metabolic activation for mutagenicity in the in vitro Ames Assay and for chromosomal aberrations in the in vitro mammalian cell gene mutation assay using the L5178Y/TK+/- mouse lymphoma cells.”
Genotox: in vitro mammalian
L5178Y TK+/- mouse lymphoma assay: negative
“but negative in both the presence and absence of metabolic activation for mutagenicity in the in vitro Ames Assay and for chromosomal aberrations in the in vitro mammalian cell gene mutation assay using the L5178Y/TK+/- mouse lymphoma cells.”
Genotox: in vivo
Mouse micronucleus: positive (predominantly aneugenic) at >160 mg/kg (~38x human Cmax)
“Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses > 160 mg/kg (~38-times the human C max at the clinical dose of 25 mg/m 2 ).”
Carcinogenicity model
6-month rasH2 transgenic mouse and 2-year rat; not carcinogenic at >=15x human AUC
“Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 .”
Carcinogenicity timing
6-month rasH2 mouse and 2-year rat completed and reviewed in the marketing application
“The Applicant’s Position: Selumetinib showed no evidence of carcinogenicity in 6-month CByB6F1/Tg rasH2 transgenic mouse and 2-year Han Wistar rat studies.”
hERG / QT
No hERG inhibition up to 10 µM (390-fold unbound clinical Cmax)
“In the hERG assay, selumetinib was evaluated in stably transfected HEK293 cells at concentrations of 0.1, 0.3, 1 and 3 and 10 µM, which produced no concentration-dependent inhibition of hERG tail current. This maximum test concentration was 390-fold greater than the unbound plasma Cmax of selumetinib”
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 Koselugo 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: Major target organs: GI tract, plus skin and lower urinary tract in rodents (FDA multi-discipline review, p. 43)
NOAEL / key findings
Major target organs: GI tract, plus skin and lower urinary tract in rodents
“In addition to the GI tract, the other major target organs in the rodent toxicology studies were the skin and lower urinary tract.”
Risksopen answer page →
Immune & cytokine safety
Secondary lymphoreticular changes with inflammatory/ulcerative GI findings in mice (~19.5x clinical free AUC)
“Inflammatory and ulcerative GI tract findings associated with secondary changes in the liver and lymphoreticular system at free exposures approximately 19.5 times the clinical free AUC at the MRHD were observed in mice.”
Biodistribution & persistence
Rat QWBA: highest in lung, liver, kidney and adrenal; no high-affinity melanin binding
“Relatively higher concentrations of radioactivity were found in the lung, liver, kidney and adrenal gland at each timepoint. There was no evidence of high affinity melanin-specific binding of radioactivity in the pigmented tissues (pigmented skin and uveal tract).”
Modality-specific risk
Ocular toxicity (MEK-inhibitor class effect), not clear in adult animal studies
“While ocular effects were not clear in the nonclinical toxicology studies in adult animals, ocular toxicity does occur clinically with selumetinb and other MEK inhibitors.”
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 events suggestive of immunogenicity
“In SPRINT Phase II Stratum I data, the Pediatric pool and Adult monotherapy pool, there are no events suggestive immunogenicity or allergy to selumetinib (such as AEs of severe hypersensitivity).”
Label warnings
- Left Ventricular Dysfunction
- Ocular Toxicity
- Gastrointestinal Toxicity
- Skin Toxicity
- Increased Creatine Phosphokinase
- Increased Levels of Vitamin E and Increased Risk of Bleeding (KOSELUGO Capsules)
- Embryo-Fetal Toxicity
CardiovascularOcular toxicityGastrointestinalSkin reactionsMusculoskeletalBleedingMetabolic & endocrineEmbryo-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 Koselugo 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: Major target organs: GI tract, plus skin and lower urinary tract in rodents (FDA multi-discipline review, p. 43)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week mouse (oral) with 13-week recovery; 26-week monkey study had no recovery evaluation
“The reversibility of selumetinib-related findings was evaluated in 1-month studies in mice and monkeys as well as in the 26-week study in mice. All pivotal toxicology studies were appropriately designed in accordance with ICH guidelines and were conducted in compliance with GLP regulations. Study Title/Number: 26-week Oral Toxicity Study in the Mouse with Assessment of Effects on Male Fertility Followed by a 13 Week Recovery Period (VKS/0211)”
Pivotal GLP studies
26-week mouse and monkey and 3-month rat oral repeat-dose studies
“The nonclinical safety of selumetinib has been evaluated in repeat dose oral toxicity studies of up to 3 months in rats and up to 26 weeks in mice and monkeys;”
DART package
Species: DART
Mouse (fertility, EFD, pre/postnatal); chosen because it forms the active N-desmethyl metabolite
“The Applicant assessed the effects of selumetinib on reproduction and development using mice, as mice, unlike rats, make the active N-desmethyl AZD6244 metabolite at detectable levels.”
Reproductive & developmental
Mouse EFD: post-implantation loss, lower fetal weight, open eye and cleft palate at >2.5 mg/kg BID (~5x human AUC)
“In embryo-fetal development studies in mice at doses > 2.5 mg/kg twice daily (~5-times the human exposure based on area under the curve [AUC] at the clinical dose of 25 mg/m 2 twice daily), selumetinib caused increases in post-implantation loss, a reduction in mean fetal and litter weights, and an increased occurrence of open eye and cleft palate”
PPND / ePPND: when
PPND in mouse completed (part of full reproductive package) before the marketing application
“Because of these characteristics, the Applicant conducted a full battery of reproductive toxicology studies as well as carcinogenicity studies to support the development of selumetinib.”
Carcinogenicity
Species: carcinogenicity
rasH2 transgenic mouse (6-month) and rat (2-year)
“Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 .”
Carcinogenicity model
6-month rasH2 transgenic mouse and 2-year rat; not carcinogenic at >=15x human AUC
“Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 .”
Carcinogenicity timing
6-month rasH2 mouse and 2-year rat completed and reviewed in the marketing application
“The Applicant’s Position: Selumetinib showed no evidence of carcinogenicity in 6-month CByB6F1/Tg rasH2 transgenic mouse and 2-year Han Wistar rat studies.”
Safety marginopen answer page →
Safety margin at NOAEL
3-month rat NOAEL (males, 2.5 mg/kg/day) 15x clinical total AUC; no NOAEL in 26-week mouse
“In 3-month study, NOAEL could be established only in males at 2.5 mg/kg/day, the calculated safety margin was 15 times the clinical total AUC.”
NOAEL / key findings
Major target organs: GI tract, plus skin and lower urinary tract in rodents
“In addition to the GI tract, the other major target organs in the rodent toxicology studies were the skin and lower urinary tract.”
Efficacy evidenceopen answer page →
Efficacy evidence
Nf1fl/fl;DhhCre neurofibroma knockout mouse: reduced nerve root size and tumor number/size
“In vivo, selumetinib reduced proximal nerve root sizes as well as the number and size of tumors in a Nf1fl/fl;DhhCre, a mouse model which allows for targeted knockout of NF1 and recapitulates the development of endogenous neurofibromas.”
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
FDA: studies support the mechanism of action and proof-of-concept for the pediatric indication
“These studies support the proposed mechanism of action of selumetinib and the proof-of-concept for the proposed pediatric indication.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
Mouse instead of rat as the rodent for long-term toxicology and developmental studies
Why: Mouse forms detectable levels of the active N-desmethyl metabolite, giving toxicological coverage · Pharmacology or kinetics
“The Applicant chose the mouse as the rodent species for the long-term toxicology and developmental studies due to detectable levels of the active N-desmethyl metabolite in this species that allowed for toxicological coverage; there were no unique human metabolites or other metabolites that needed toxicological coverage in animals.”
DARTAcceptedBeyond the letter
Embryo-fetal development tested in mouse only (no second species)
Why: Embryolethality and teratogenicity already shown in mice · Other reason
“A second species was not used for investigating the potential effects on embryo-foetal development, which is acceptable in view of the toxicological findings reported in mice (embryolethality, teratogenicity).”
Juvenile toxAcceptedBeyond the letter
No dedicated juvenile toxicity studies for a paediatric indication
Why: Studies in sexually immature primates and younger mice cover children from 12 years onwards · Weight of evidence
“No specific juvenile toxicity studies have been conducted but studies performed in sexually immature primates and younger mice cover the age of children from 12 years onwards.”
“Therefore, concerning pharmacokinetics, exposure assessments at dose levels investigated in adults are considered to be sufficient to evaluate exposures expected in the younger population, e.g. from 3 years onwards.”
GenotoxicityAcceptedBeyond the letter
Positive mouse micronucleus test via an aneugenic mode of action accepted for long-term paediatric use
Why: Aneugenicity is a known MEK-inhibitor pharmacological effect; carcinogenicity studies showed no neoplastic changes · Class precedent · Weight of evidence
“Aneugenic effects of selumetinb are known as pharmacological action of MEK inhibitors. However, no neoplastic changes were observed in carcinogenicity studies supporting the long-term treatment of children with selumetinib.”
Safety marginVerdict not stated
No NOAEL or safety margin for irreversible corneal mineralisation in the 1-month mouse study
“In 1-month study in mice, ophthalmology findings (oval opacities across the cornea, rough appearance to the surface of the cornea) were observed at all doses and histopathologic exam revealed a dose-dependent mineralisation of the cornea which is not reversible after cessation of treatment. No NOAEL and no safety margin could be determined.”
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