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”
Species: general tox
Rat (26-week), dog (4-week) and monkey (39-week)
“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.”
Species: DART
Rat (fertility, EFD) and rabbit (EFD); no pre/postnatal study
“The potential for reproductive and/or developmental toxicity of asciminib was investigated in a study on fertility and early embryonic development in the rat and studies on embryo-foetal development in rats and rabbits.”
Species: carcinogenicity
Rat (2-year)
“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.”
Surrogate used in
No surrogate used; asciminib tested directly in rats, dogs, monkeys and rabbits
“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.”
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.”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
Negative in vitro micronucleus assay in human peripheral blood lymphocytes
“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.”
Genotox: in vivo
Negative in vivo rat peripheral blood reticulocyte micronucleus assay
“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 model
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.”
Carcinogenicity timing
Not conducted before approval; not required under ICH S9
“Carcinogenicity studies have not been conducted in accordance with ICH S9.”
hERG / QT
hERG IC50 11.4 µM; >200-fold margin vs free exposure at 40 mg BID
“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.”
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; immunogenicity not assessed (FDA agreed)
“Immunogenicity The Applicant’s Position: Not applicable as this was assessed nor expected. The FDA’s Assessment: FDA agrees with the Applicant’s position.”
Label warnings
- Myelosuppression
- Pancreatic Toxicity
- Hypertension
- Hypersensitivity
- Cardiovascular Toxicity
- Embryo-Fetal Toxicity
CytopeniasGastrointestinalCardiovascularHypersensitivity & infusion reactionsEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Australia, France, Germany, Italy, Japan, Singapore, South Korea, Spain, Netherlands, United States: first-in-human dose escalation in CML patients
“CABL001X2101 Countries: Australia, France, Germany, Italy, Japan, Singapore, South Korea, Spain, The Netherlands, United States”
Repeat-dose tox before first-in-human
4-week GLP rat and dog studies supported the first-in-human starting dose
“The selection of the starting dose of asciminib was based on 4-week GLP toxicology studies conducted in rats and dogs.”
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.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (oral); recovery not stated
“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”
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)”
DART package
Species: DART
Rat (fertility, EFD) and rabbit (EFD); no pre/postnatal study
“The potential for reproductive and/or developmental toxicity of asciminib was investigated in a study on fertility and early embryonic development in the rat and studies on embryo-foetal development in rats and rabbits.”
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.”
PPND / ePPND: when
No PPND study; not considered necessary for the advanced-cancer indication
“Pre- and postnatal development: A pre- and postnatal development study has not been performed and is not considered necessary to support the proposed indication.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year)
“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.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not conducted before approval; not required under ICH S9
“Carcinogenicity studies have not been conducted in accordance with ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
No rat NOAEL: hepatocellular necrosis at lowest dose (15 mg/kg/day), exposure equivalent to or below 80 mg QD
“A NOAEL could not be established in the rat studies since hepatocellular necrosis occurred already at the lowest dose tested (≥15 mg/kg/day). This exposure was equivalent or even below the intended clinical dose of 80 mg QD.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
KCL-22 CML xenograft mice, including a T315I-mutant model
“The same treatment schedule of asciminib (3-30 mg/kg) resulted in dose-dependent inhibition of tumor growth in mice with a KCL-22 xenograft harboring a T315I mutant.”
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: nonclinical pharmacology and toxicology data adequate to support approval
“The nonclinical pharmacology and toxicology data submitted to this NDA are adequate to support the approval of asciminib for the proposed indications.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted
No carcinogenicity studies submitted for chronic-phase CML in patients pretreated with two or more TKIs
Why: Pretreated Ph+ CML-CP population; in accordance with ICH S9 · Within the guideline · Serious disease
“As this application is for the use of asciminib for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase (Ph+ CML-CP) previously treated with two or more tyrosine kinase inhibitors no carcinogenicity studies were submitted, which was considered acceptable.”
“Carcinogenicity studies have not been conducted in accordance with ICH S9.”
DARTAcceptedBeyond the letter
No pre/postnatal development study
Why: Teratogenic in rats and rabbits at human therapeutic exposures; agreed in EMA scientific advice · Weight of evidence
“Since asciminib showed teratogenicity in rats and rabbits at human therapeutic exposures, a pre- /postnatal development study was not performed”
“A study on pre-postnatal development was not performed which was agreed beforehand in a Scientific Advice by EMA.”
Safety marginVerdict not stated
No rat NOAEL: hepatocellular necrosis at the lowest dose, at or below clinical exposure
“A NOAEL could not be established in the rat studies since hepatocellular necrosis occurred already at the lowest dose tested (≥15 mg/kg/day). This exposure was equivalent or even below the intended clinical dose of 80 mg QD.”
Safety marginAccepted with a conditionBeyond the letter
No dog NOAEL: pancreatic toxicity at exposures below the clinical dose; cause not established
Why: Pancreatic enzymes to be monitored clinically per SmPC section 4.4
“Although asciminib was tolerated up to the highest dose tested (60 mg/kg), a NOAEL could not be established due to the pancreatic toxicity which was observed at ≥3 mg/kg/day (corresponding to exposure multiples below the intended human dose of 40 mg BID or 80 mg QD).”
“Pancreatic enzyme increase should be carefully monitored in the clinical setting (see section 4.4 of the SmPC).”
GLPAcceptedBeyond the letter
Follow-up Ames tests of in silico positive impurities not GLP-compliant
Why: Studies followed OECD and UK MHRA general rules · Other reason
“In silico positive impurities were tested with follow up Ames tests. Theses assays were not performed under GLP conditions however according to the study protocols, general rules of OECD and UK MHRA were followed and lack of full GLP compliance is acceptable.”
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