Ayvakit
avapritinib
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The Applicant evaluated the toxicity of avapritinib in GLP-compliant repeated-dose toxicity studies in rats and dogs.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Rats received up to 30 mg/kg/day of oral avapritinib, once per day, for 3 months, resulting in mean exposure levels (AUC) up to 6 times the AUC of 15400 ng.h/mL in humans at the 300 mg daily dose.”
Species: general tox
Rat and dog
“The Applicant evaluated the toxicity of avapritinib in GLP-compliant repeated-dose toxicity studies in rats and dogs.”
Species: DART
Rat (dedicated fertility and early embryonic development study)
“There were no direct effects on fertility in rats of either sex in a dedicated fertility and early embryonic development study.”
Species: carcinogenicity
Transgenic mouse (6-month)
“Avapritinib was not mutagenic in a 6-month transgenic mouse study up to the highest dose evaluated at 20 mg/kg/day.”
Surrogate used in
No surrogate used; avapritinib itself tested in rats and dogs
“The Applicant evaluated the toxicity of avapritinib in GLP-compliant repeated-dose toxicity studies in rats and dogs.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“choroid plexus edema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1 or 0.4 times the human exposure based on AUC at the 25 mg, 200 mg or 300 mg dose, respectively), but were not observed in a 9-month study at 5 mg/kg/day.”
Pivotal GLP studies
28-day and 3-month oral studies in rats and dogs
“Local tolerance was assessed by reviewing the digestive track changes in the GLP-compliant 28-day and 3-month toxicology studies in rats and dogs.”
Route in tox
Oral (gavage)
“3-month oral (gavage) toxicity and toxicokinetic study in Sprague Dawley rats”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; positive in vitro chromosome aberration; negative rat bone marrow micronucleus; overall non-genotoxic
“Avapritinib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Avapritinib was positive in the in vitro chromosome aberration test in human peripheral blood lymphocytes but negative in the in vivo rat bone marrow micronucleus test, and overall non-genotoxic.”
Carcinogenicity
6-month transgenic mouse study: negative up to 20 mg/kg/day
“Avapritinib was not mutagenic in a 6-month transgenic mouse study up to the highest dose evaluated at 20 mg/kg/day.”
Reproductive & developmental
Rat EFD: reduced fetal weight, post-implantation loss, visceral and skeletal malformations at >=10 mg/kg/day (~2.7x human AUC)
“Daily oral administration of avapritinib to pregnant rats resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses ≥ 10 mg/kg/day (a dose resulting in exposures approximately 2.7 times the exposure based on AUC at the 300 mg human dose).”
Safety pharmacology
No pulmonary or cardiovascular effects up to 45 mg/kg; hERG IC50 2.4 μM (1.5x human free Cmax)
“There were no avapritinib-related adverse effects on pulmonary function or the cardiovascular system at single doses up to 45 mg/kg. Avapritinib blocked hERG channel potential with an IC50 of 2.4 μM; however, this IC50 is 1.5 times the free Cmax in humans at the 300 mg dose.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Avapritinib was not mutagenic in a bacterial reverse mutation (Ames) assay.”
Genotox: in vitro mammalian
Chromosome aberration in human lymphocytes: positive (clastogenic at >=5 μg/mL, 22-hour)
“Avapritinib was clastogenic in the in vitro chromosome aberration test in human peripheral blood lymphocytes at concentrations ≥ 5 μg/mL (22-hour incubation); these aberrations appeared structural rather than numerical.”
Genotox: in vivo
Rat bone marrow micronucleus: negative up to 150 mg/kg
“Avapritinib was, however, not clastogenic in the in vivo rat bone marrow micronucleus test at doses up to 150 mg/kg.”
Carcinogenicity model
6-month transgenic mouse study, negative up to 20 mg/kg/day
“Avapritinib was not mutagenic in a 6-month transgenic mouse study up to the highest dose evaluated at 20 mg/kg/day.”
Carcinogenicity timing
Not needed for an advanced cancer marketing application; none conducted before approval
“The Applicant did not conduct studies investigating the carcinogenic potential of avapritinib as such studies are not needed to support a marketing application for patients with advanced cancer.”
hERG / QT
hERG IC50 2.4 μM, 1.5x human free Cmax at 300 mg; no QT prolongation clinically or in vivo
“Avapritinib blocked hERG channel potential with an IC50 of 2.4 μM; however, this IC50 is 1.5 times the free Cmax in humans at the 300 mg dose. Consistent with these findings, avapritinib did not have effects on QT prolongation clinically or in in vivo nonclinical studies.”
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 Ayvakit 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: Dogs: brain hemorrhage and choroid plexus edema at >=0.4x human exposure; rat convulsions at >=8x (EMA assessment report, p. 50)
NOAEL / key findings
Dogs: brain hemorrhage and choroid plexus edema at >=0.4x human exposure; rat convulsions at >=8x
“Repeat dose studies in dogs indicated haemorrhage and choroid plexus oedema in the brain at ≥ 0.4 times the human exposure at the clinical dose of 300 mg once daily. Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemic exposures ≥8-fold higher than the exposure in patients at the clinical dose of 300 mg once daily.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid system effects (spleen, thymus) did not reverse
“All effects were reversible or reversing with three notable exceptions: effects in the lymphoid system (spleen and thymus), brain and the gonads.”
Biodistribution & persistence
Pigmented rats: uveal tract and skin levels 2-330-fold higher than in albino rats, with slower elimination
“The concentration of [14C]-avapritinib-derived radioactivity in the uveal tract and skin of pigmented Long Evans rats was eliminated more slowly and was approximately 2 to 330-fold higher than in these tissues in nonpigmented rats.”
Modality-specific risk
CNS toxicity: convulsions in rats, possibly via Nav1.2 inhibition, at >=8x clinical exposure
“Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemic exposures ≥8-fold higher than the exposure in patients at the clinical dose of 300 mg once daily.”
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 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.
Label warnings
- Intracranial Hemorrhage
- Cognitive Effects
- 3 Photosensitivity
- Embryo-Fetal Toxicity
BleedingNeurotoxicitySkin reactionsEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Europe, US and Asia: first-in-human dose escalation in patients with GIST and solid tumours (NAVIGATOR)
“Overall, 22 (58%) patients were treated at study sites in Europe, 11 (29%) patients were treated at study sites in the US, and 5 (13%) patients were treated at study sites in Asia.”
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 Ayvakit 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: Dogs: brain hemorrhage and choroid plexus edema at >=0.4x human exposure; rat convulsions at >=8x (EMA assessment report, p. 50)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month dog (oral); recovery phase not stated
“and choroid plexus edema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1 or 0.4 times the human exposure based on AUC at the 25 mg, 200 mg or 300 mg dose, respectively), but were not observed in a 9-month study at 5 mg/kg/day.”
Pivotal GLP studies
28-day and 3-month oral studies in rats and dogs
“Local tolerance was assessed by reviewing the digestive track changes in the GLP-compliant 28-day and 3-month toxicology studies in rats and dogs.”
DART package
Species: DART
Rat (dedicated fertility and early embryonic development study)
“There were no direct effects on fertility in rats of either sex in a dedicated fertility and early embryonic development study.”
Reproductive & developmental
Rat EFD: reduced fetal weight, post-implantation loss, visceral and skeletal malformations at >=10 mg/kg/day (~2.7x human AUC)
“Daily oral administration of avapritinib to pregnant rats resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses ≥ 10 mg/kg/day (a dose resulting in exposures approximately 2.7 times the exposure based on AUC at the 300 mg human dose).”
PPND / ePPND: when
PPND not conducted: not necessary for advanced cancer
“Dedicated fertility and pre- and post-natal development studies were neither conducted nor necessary to support the development of avapritinib in patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Transgenic mouse (6-month)
“Avapritinib was not mutagenic in a 6-month transgenic mouse study up to the highest dose evaluated at 20 mg/kg/day.”
Carcinogenicity model
6-month transgenic mouse study, negative up to 20 mg/kg/day
“Avapritinib was not mutagenic in a 6-month transgenic mouse study up to the highest dose evaluated at 20 mg/kg/day.”
Carcinogenicity timing
Not needed for an advanced cancer marketing application; none conducted before approval
“The Applicant did not conduct studies investigating the carcinogenic potential of avapritinib as such studies are not needed to support a marketing application for patients with advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: dog choroid plexus edema at >=7.5 mg/kg/day, ~0.4x human AUC at 300 mg; absent at 5 mg/kg/day (9-month)
“choroid plexus edema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1 or 0.4 times the human exposure based on AUC at the 25 mg, 200 mg or 300 mg dose, respectively), but were not observed in a 9-month study at 5 mg/kg/day.”
NOAEL / key findings
Dogs: brain hemorrhage and choroid plexus edema at >=0.4x human exposure; rat convulsions at >=8x
“Repeat dose studies in dogs indicated haemorrhage and choroid plexus oedema in the brain at ≥ 0.4 times the human exposure at the clinical dose of 300 mg once daily. Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemic exposures ≥8-fold higher than the exposure in patients at the clinical dose of 300 mg once daily.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse P815 mastocytoma (KIT exon 17) model and imatinib-resistant GIST patient-derived xenograft (KIT exon 11/17)
“Avapritinib also exhibited anti-tumor activity in a mouse mastocytoma tumor model with an activating KIT exon 17 mutation and in an imatinib-resistant patient-derived xenograft model of human GIST with activating KIT exon 11/exon17 mutations.”
Why that model
No PDGFRA-driven in vivo tumour model was examined; in vivo efficacy shown only in KIT-mutant models
“Although inhibition of PDGFRα exon 18 mutants by avapritinib at low nM concentrations has been demonstrated, the effect of avapritinib in PDGFRα driven in vivo animal tumour models have not been examined.”
Reviewer's view of the efficacy data
EMA: lack of PDGFRA in vivo data acceptable under ICH S9, as in vitro pharmacology systems generated relevant data
“According to the ICH S9 Q&A document, the lack of in vivo characterization can be accepted if in vitro systems used for pharmacology studies of anti-tumour activity are demonstrated to generate relevant data. This is considered fulfilled in the non-clinical dossier for avapritinib.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No dedicated fertility or pre- and postnatal development studies
Why: Not necessary for development in patients with advanced cancer · Within the guideline · Serious disease
“Dedicated fertility and pre- and post-natal development studies were neither conducted nor necessary to support the development of avapritinib in patients with advanced cancer.”
Efficacy modelAccepted
No in vivo PDGFRA-driven tumour model; PDGFRA exon 18 activity shown in vitro only
Why: ICH S9 Q&A allows lack of in vivo data when in vitro pharmacology systems generate relevant data · Within the guideline · Pharmacology or kinetics
“Although inhibition of PDGFRα exon 18 mutants by avapritinib at low nM concentrations has been demonstrated, the effect of avapritinib in PDGFRα driven in vivo animal tumour models have not been examined.”
“According to the ICH S9 Q&A document, the lack of in vivo characterization can be accepted if in vitro systems used for pharmacology studies of anti-tumour activity are demonstrated to generate relevant data. This is considered fulfilled in the non-clinical dossier for avapritinib.”
Impurity or metaboliteAcceptedBeyond the letter
Impurity BLU112316 at 0.55%, above the ICH Q3A qualification threshold of 0.15%
Why: Qualified up to 0.78% by the 3-month rat toxicity study · Other reason
“Despite impurity BLU112316 level (0.55%) is above the qualification thresholds defined in ICH Q3A (0.15%), it is qualified up to 0.78% based on the 3-month rat toxicity study.”
Safety marginVerdict not stated
Dog choroid plexus edema at exposure about 0.4 times human AUC at 300 mg
“choroid plexus edema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1 or 0.4 times the human exposure based on AUC at the 25 mg, 200 mg or 300 mg dose, respectively), but were not observed in a 9-month study at 5 mg/kg/day.”
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