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.”
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”
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)
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: 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.”