Scemblix
asciminib
Species
MonkeyRatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Rat and cynomolgus monkey (plus 4-week dog)
“The safety of asciminib was assessed in general toxicology (dogs, rats and monkeys up to 4, 26 and 39 weeks, respectively), genotoxicity (in vitro and in rats), and reproductive and developmental toxicology (rats and rabbits) studies.”
Why that species
ABL1/ABL2 kinase domains highly conserved across human and toxicology species
“Because there is a very high overall protein sequence conservation of ABL1 and ABL2 kinase domains across human and toxicology relevant species (mouse, rat, rabbit, dog, minipig, cynomolgus and rhesus monkeys)”
Surrogate molecule
No surrogate; the clinical compound was tested
“Prolonged administration of asciminib (3, 15, and 50 mg/kg/day) for 39 weeks in cynomolgus monkeys induced comparable findings to those observed in the 13-week study”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“The safety of asciminib was assessed in general toxicology (dogs, rats and monkeys up to 4, 26 and 39 weeks, respectively)”
Pivotal GLP studies
26-week rat, 4-week dog and 39-week cynomolgus monkey oral studies
“The safety of asciminib was assessed in general toxicology (dogs, rats and monkeys up to 4, 26 and 39 weeks, respectively)”
Route in tox
Oral (gavage)
“Study title/Study number: 39-week oral gavage toxicity and toxicokinetic study with ABL-001 in cynomolgus monkeys/1470799”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus and in vivo rat reticulocyte micronucleus assays
“Asciminib was not genotoxic in an in vitro bacterial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes (HPBL) or an in vivo rat peripheral blood reticulocyte micronucleus assay.”
Carcinogenicity
2-year rat: benign ovarian Sertoli cell tumors in high-dose females
“In a 2-year carcinogenicity study, rats were administered oral doses of asciminib at 20, 66, and 200 mg/kg/day in males and 10, 30, and 66 mg/kg/day in females. Asciminib induced a statistically significant increase in the incidence of benign Sertoli cell tumors in the ovaries of high-dose females.”
Reproductive & developmental
Rat EFD: cleft palate, anasarca and cardiac malformations at 150 mg/kg/day
“Malformations were evident at 150 mg/kg and included cleft palate, anasarca (edema), and cardiac abnormalities.”
Safety pharmacology
hERG IC50 11.4 µM, >30- to >200-fold above clinical free exposure
“The IC50 for asciminib in the hERG patch clamp was 11.4 µM. This translates into a clinical safety margin > 200- or > 100- or 30- fold when compared to free exposure in subjects at dose of 40 mg BID or 80 mg QD or 200 mg BID, respectively.”
First doseopen answer page →
First-in-human starting dose
10 mg BID, based on 4-week GLP rat and dog toxicology studies
“The starting dose of asciminib for patients with CML-CP/-AP selected for the dose escalation part of this study was set at 10 mg orally administered BID under fasted conditions. The selection of the starting dose of asciminib was based on 4-week GLP toxicology studies conducted in rats and dogs.”
NOAEL / key findings
Target organs: hematopoietic system, liver, kidney, adrenal gland, GI tract, and pancreas (dog only)
“The general toxicology studies identified toxicities in the hematopoietic system, liver, kidney, adrenal gland, gastro-intestinal (GI) tract, and pancreas (dog only).”
Risksopen answer page →
Immune & cytokine safety
Thymic lymphocyte necrosis and splenic lymphoid depletion in one rat at 200 mg/kg/day
“necrosis of thymus lymphocytes, lymphoid depletion in spleen, lesions in the GI (ulceration and inflammation) in one rat at 200 mg/kg/day.”
Biodistribution & persistence
Melanin binding; little blood-brain barrier penetration (brain/blood Cmax ratio 0.0149)
“Melanin binding of asciminib was observed. The brain tissue/blood Cmax ratio of 0.0149 indicated little penetration of the blood-brain barrier.”
Modality-specific risk
No or low safety margins over clinical exposure in repeat-dose toxicity studies
“Because of the relatively high sensitivities of the animal species to the toxic effects of asciminib, a margin of safety either could not be established or was low with respect to the repeat dose toxicity studies relative to the exposure levels obtained in humans at the human oral dose of 40 or 80 mg/day.”